JP6328424B6 - 記憶機能の制御および特性化 - Google Patents
記憶機能の制御および特性化 Download PDFInfo
- Publication number
- JP6328424B6 JP6328424B6 JP2013537853A JP2013537853A JP6328424B6 JP 6328424 B6 JP6328424 B6 JP 6328424B6 JP 2013537853 A JP2013537853 A JP 2013537853A JP 2013537853 A JP2013537853 A JP 2013537853A JP 6328424 B6 JP6328424 B6 JP 6328424B6
- Authority
- JP
- Japan
- Prior art keywords
- memory
- light
- protein
- neurons
- recall
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 230000006386 memory function Effects 0.000 title description 33
- 238000012512 characterization method Methods 0.000 title description 2
- 230000015654 memory Effects 0.000 claims description 193
- 210000002569 neuron Anatomy 0.000 claims description 188
- 108090000623 proteins and genes Proteins 0.000 claims description 146
- 102000004169 proteins and genes Human genes 0.000 claims description 137
- 238000000034 method Methods 0.000 claims description 96
- 230000007595 memory recall Effects 0.000 claims description 83
- 230000015572 biosynthetic process Effects 0.000 claims description 76
- 230000028161 membrane depolarization Effects 0.000 claims description 55
- 210000001320 hippocampus Anatomy 0.000 claims description 54
- 241000282414 Homo sapiens Species 0.000 claims description 42
- 230000002964 excitative effect Effects 0.000 claims description 40
- 210000004326 gyrus cinguli Anatomy 0.000 claims description 35
- 210000004727 amygdala Anatomy 0.000 claims description 33
- 239000003795 chemical substances by application Substances 0.000 claims description 29
- 125000003275 alpha amino acid group Chemical group 0.000 claims description 27
- 210000000170 cell membrane Anatomy 0.000 claims description 26
- 239000013598 vector Substances 0.000 claims description 26
- 239000003814 drug Substances 0.000 claims description 20
- 210000002472 endoplasmic reticulum Anatomy 0.000 claims description 20
- 208000028173 post-traumatic stress disease Diseases 0.000 claims description 20
- 101000903581 Natronomonas pharaonis Halorhodopsin Proteins 0.000 claims description 19
- 229940079593 drug Drugs 0.000 claims description 19
- 230000002401 inhibitory effect Effects 0.000 claims description 15
- 108091033319 polynucleotide Proteins 0.000 claims description 15
- 102000040430 polynucleotide Human genes 0.000 claims description 15
- 239000002157 polynucleotide Substances 0.000 claims description 15
- 230000008172 membrane trafficking Effects 0.000 claims description 10
- 239000013607 AAV vector Substances 0.000 claims description 6
- 238000012216 screening Methods 0.000 claims description 6
- 239000013603 viral vector Substances 0.000 claims description 5
- 108090000301 Membrane transport proteins Proteins 0.000 claims description 3
- 102000003939 Membrane transport proteins Human genes 0.000 claims description 3
- 230000009061 membrane transport Effects 0.000 claims description 3
- 230000001177 retroviral effect Effects 0.000 claims description 2
- 241000699670 Mus sp. Species 0.000 description 112
- 230000001629 suppression Effects 0.000 description 80
- 210000004027 cell Anatomy 0.000 description 71
- 230000001537 neural effect Effects 0.000 description 66
- 238000012360 testing method Methods 0.000 description 66
- 230000000694 effects Effects 0.000 description 60
- 230000006390 fear memory Effects 0.000 description 41
- 238000012549 training Methods 0.000 description 38
- 230000000971 hippocampal effect Effects 0.000 description 34
- 230000003750 conditioning effect Effects 0.000 description 32
- 230000007774 longterm Effects 0.000 description 28
- 238000002474 experimental method Methods 0.000 description 27
- 230000014509 gene expression Effects 0.000 description 27
- 210000004556 brain Anatomy 0.000 description 24
- 108010035848 Channelrhodopsins Proteins 0.000 description 23
- 239000012528 membrane Substances 0.000 description 20
- 230000004913 activation Effects 0.000 description 19
- 230000003287 optical effect Effects 0.000 description 17
- 102100033093 Calcium/calmodulin-dependent protein kinase type II subunit alpha Human genes 0.000 description 16
- 101000944249 Homo sapiens Calcium/calmodulin-dependent protein kinase type II subunit alpha Proteins 0.000 description 16
- 241000699666 Mus <mouse, genus> Species 0.000 description 16
- 108050001704 Opsin Proteins 0.000 description 16
- 241001465754 Metazoa Species 0.000 description 15
- 108090000862 Ion Channels Proteins 0.000 description 14
- 102000004310 Ion Channels Human genes 0.000 description 14
- 230000035772 mutation Effects 0.000 description 14
- 230000004044 response Effects 0.000 description 14
- 102000010175 Opsin Human genes 0.000 description 13
- 230000009849 deactivation Effects 0.000 description 12
- 230000006870 function Effects 0.000 description 12
- 239000013307 optical fiber Substances 0.000 description 11
- 230000002441 reversible effect Effects 0.000 description 11
- 230000000638 stimulation Effects 0.000 description 11
- 230000002123 temporal effect Effects 0.000 description 11
- 238000012986 modification Methods 0.000 description 10
- 230000000144 pharmacologic effect Effects 0.000 description 10
- CFMYXEVWODSLAX-QOZOJKKESA-N tetrodotoxin Chemical compound O([C@@]([C@H]1O)(O)O[C@H]2[C@@]3(O)CO)[C@H]3[C@@H](O)[C@]11[C@H]2[C@@H](O)N=C(N)N1 CFMYXEVWODSLAX-QOZOJKKESA-N 0.000 description 10
- 229950010357 tetrodotoxin Drugs 0.000 description 10
- CFMYXEVWODSLAX-UHFFFAOYSA-N tetrodotoxin Natural products C12C(O)NC(=N)NC2(C2O)C(O)C3C(CO)(O)C1OC2(O)O3 CFMYXEVWODSLAX-UHFFFAOYSA-N 0.000 description 10
- 230000001054 cortical effect Effects 0.000 description 9
- 238000005286 illumination Methods 0.000 description 9
- 230000004048 modification Effects 0.000 description 9
- 239000002953 phosphate buffered saline Substances 0.000 description 9
- 230000008569 process Effects 0.000 description 9
- 238000003860 storage Methods 0.000 description 9
- RPXVIAFEQBNEAX-UHFFFAOYSA-N 6-Cyano-7-nitroquinoxaline-2,3-dione Chemical compound N1C(=O)C(=O)NC2=C1C=C([N+](=O)[O-])C(C#N)=C2 RPXVIAFEQBNEAX-UHFFFAOYSA-N 0.000 description 8
- 102000007568 Proto-Oncogene Proteins c-fos Human genes 0.000 description 8
- 108010071563 Proto-Oncogene Proteins c-fos Proteins 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 210000004295 hippocampal neuron Anatomy 0.000 description 8
- 238000001727 in vivo Methods 0.000 description 8
- 238000005259 measurement Methods 0.000 description 8
- 230000002829 reductive effect Effects 0.000 description 8
- 108091005957 yellow fluorescent proteins Proteins 0.000 description 8
- 108091006146 Channels Proteins 0.000 description 7
- 230000003213 activating effect Effects 0.000 description 7
- 230000002146 bilateral effect Effects 0.000 description 7
- 239000000835 fiber Substances 0.000 description 7
- 230000005764 inhibitory process Effects 0.000 description 7
- 238000002347 injection Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 7
- 230000002452 interceptive effect Effects 0.000 description 7
- 230000036982 action potential Effects 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000001143 conditioned effect Effects 0.000 description 6
- 230000007246 mechanism Effects 0.000 description 6
- 210000000956 olfactory bulb Anatomy 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- FWBHETKCLVMNFS-UHFFFAOYSA-N 4',6-Diamino-2-phenylindol Chemical compound C1=CC(C(=N)N)=CC=C1C1=CC2=CC=C(C(N)=N)C=C2N1 FWBHETKCLVMNFS-UHFFFAOYSA-N 0.000 description 5
- 241001634120 Adeno-associated virus - 5 Species 0.000 description 5
- 241000713666 Lentivirus Species 0.000 description 5
- 208000012902 Nervous system disease Diseases 0.000 description 5
- 241000700605 Viruses Species 0.000 description 5
- 230000006397 emotional response Effects 0.000 description 5
- 230000014061 fear response Effects 0.000 description 5
- 230000002068 genetic effect Effects 0.000 description 5
- 230000001771 impaired effect Effects 0.000 description 5
- 230000003902 lesion Effects 0.000 description 5
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- 108020004414 DNA Proteins 0.000 description 4
- 241000669298 Pseudaulacaspis pentagona Species 0.000 description 4
- 229930006000 Sucrose Natural products 0.000 description 4
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 150000001413 amino acids Chemical class 0.000 description 4
- 230000006399 behavior Effects 0.000 description 4
- 239000003479 dental cement Substances 0.000 description 4
- 230000005284 excitation Effects 0.000 description 4
- 230000002102 hyperpolarization Effects 0.000 description 4
- 230000001976 improved effect Effects 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 150000007523 nucleic acids Chemical group 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 230000002186 photoactivation Effects 0.000 description 4
- 238000011084 recovery Methods 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 239000005720 sucrose Substances 0.000 description 4
- 210000001519 tissue Anatomy 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- NCYCYZXNIZJOKI-IOUUIBBYSA-N 11-cis-retinal Chemical group O=C/C=C(\C)/C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-IOUUIBBYSA-N 0.000 description 3
- 208000019901 Anxiety disease Diseases 0.000 description 3
- 241000702421 Dependoparvovirus Species 0.000 description 3
- 241000283074 Equus asinus Species 0.000 description 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 3
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 108010083687 Ion Pumps Proteins 0.000 description 3
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 3
- 241000124008 Mammalia Species 0.000 description 3
- 108091028043 Nucleic acid sequence Proteins 0.000 description 3
- 229930040373 Paraformaldehyde Natural products 0.000 description 3
- 108010076504 Protein Sorting Signals Proteins 0.000 description 3
- 108010083204 Proton Pumps Proteins 0.000 description 3
- 241000125945 Protoparvovirus Species 0.000 description 3
- 102000004330 Rhodopsin Human genes 0.000 description 3
- 108090000820 Rhodopsin Proteins 0.000 description 3
- 239000012190 activator Substances 0.000 description 3
- 230000036506 anxiety Effects 0.000 description 3
- 230000003542 behavioural effect Effects 0.000 description 3
- 230000000903 blocking effect Effects 0.000 description 3
- 210000005013 brain tissue Anatomy 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 239000008103 glucose Substances 0.000 description 3
- 210000001362 glutamatergic neuron Anatomy 0.000 description 3
- 238000003364 immunohistochemistry Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 150000002500 ions Chemical class 0.000 description 3
- 229960003299 ketamine Drugs 0.000 description 3
- 238000013507 mapping Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 206010027175 memory impairment Diseases 0.000 description 3
- 210000000478 neocortex Anatomy 0.000 description 3
- 229920002866 paraformaldehyde Polymers 0.000 description 3
- 239000013612 plasmid Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 230000001737 promoting effect Effects 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 210000003625 skull Anatomy 0.000 description 3
- 210000001082 somatic cell Anatomy 0.000 description 3
- 238000010561 standard procedure Methods 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 230000032258 transport Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 3
- 229960001600 xylazine Drugs 0.000 description 3
- 108030005456 Calcium/calmodulin-dependent protein kinases Proteins 0.000 description 2
- 241000195585 Chlamydomonas Species 0.000 description 2
- 206010013654 Drug abuse Diseases 0.000 description 2
- 206010016275 Fear Diseases 0.000 description 2
- 101000944277 Homo sapiens Inward rectifier potassium channel 2 Proteins 0.000 description 2
- 108700002232 Immediate-Early Genes Proteins 0.000 description 2
- 102000006391 Ion Pumps Human genes 0.000 description 2
- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
- 208000025966 Neurological disease Diseases 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 102000006270 Proton Pumps Human genes 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 241000195615 Volvox Species 0.000 description 2
- 210000003484 anatomy Anatomy 0.000 description 2
- 210000004102 animal cell Anatomy 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 230000007177 brain activity Effects 0.000 description 2
- 230000003925 brain function Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 230000019771 cognition Effects 0.000 description 2
- 230000002596 correlated effect Effects 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 238000012217 deletion Methods 0.000 description 2
- 230000037430 deletion Effects 0.000 description 2
- 210000001787 dendrite Anatomy 0.000 description 2
- 230000002999 depolarising effect Effects 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 206010013663 drug dependence Diseases 0.000 description 2
- 238000012252 genetic analysis Methods 0.000 description 2
- 229940050410 gluconate Drugs 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 230000004694 hippocampus damage Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000002779 inactivation Effects 0.000 description 2
- 230000007787 long-term memory Effects 0.000 description 2
- 230000025350 membrane depolarization involved in regulation of action potential Effects 0.000 description 2
- 230000012241 membrane hyperpolarization Effects 0.000 description 2
- 230000006996 mental state Effects 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 238000012758 nuclear staining Methods 0.000 description 2
- 238000012346 open field test Methods 0.000 description 2
- 230000001936 parietal effect Effects 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 230000008521 reorganization Effects 0.000 description 2
- 230000010076 replication Effects 0.000 description 2
- 235000020945 retinal Nutrition 0.000 description 2
- 239000011604 retinal Substances 0.000 description 2
- 201000009570 retrograde amnesia Diseases 0.000 description 2
- 239000000523 sample Substances 0.000 description 2
- 230000006403 short-term memory Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000012732 spatial analysis Methods 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 208000011117 substance-related disease Diseases 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 230000000946 synaptic effect Effects 0.000 description 2
- 238000012731 temporal analysis Methods 0.000 description 2
- 238000004448 titration Methods 0.000 description 2
- 238000001890 transfection Methods 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 230000001960 triggered effect Effects 0.000 description 2
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 description 2
- 229910052721 tungsten Inorganic materials 0.000 description 2
- 239000010937 tungsten Substances 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- NCYCYZXNIZJOKI-UHFFFAOYSA-N vitamin A aldehyde Natural products O=CC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-UHFFFAOYSA-N 0.000 description 2
- 241001655883 Adeno-associated virus - 1 Species 0.000 description 1
- 241000702423 Adeno-associated virus - 2 Species 0.000 description 1
- 241000202702 Adeno-associated virus - 3 Species 0.000 description 1
- 241000580270 Adeno-associated virus - 4 Species 0.000 description 1
- 241000972680 Adeno-associated virus - 6 Species 0.000 description 1
- 241001164823 Adeno-associated virus - 7 Species 0.000 description 1
- 241001164825 Adeno-associated virus - 8 Species 0.000 description 1
- 241000649045 Adeno-associated virus 10 Species 0.000 description 1
- 241000649046 Adeno-associated virus 11 Species 0.000 description 1
- 241000649047 Adeno-associated virus 12 Species 0.000 description 1
- 241000300529 Adeno-associated virus 13 Species 0.000 description 1
- 206010001497 Agitation Diseases 0.000 description 1
- HJCMDXDYPOUFDY-WHFBIAKZSA-N Ala-Gln Chemical compound C[C@H](N)C(=O)N[C@H](C(O)=O)CCC(N)=O HJCMDXDYPOUFDY-WHFBIAKZSA-N 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 239000012583 B-27 Supplement Substances 0.000 description 1
- 238000011740 C57BL/6 mouse Methods 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 101150044789 Cap gene Proteins 0.000 description 1
- 108090000565 Capsid Proteins Proteins 0.000 description 1
- 101710132601 Capsid protein Proteins 0.000 description 1
- 102100023321 Ceruloplasmin Human genes 0.000 description 1
- 102000034573 Channels Human genes 0.000 description 1
- 108010077544 Chromatin Proteins 0.000 description 1
- 101710094648 Coat protein Proteins 0.000 description 1
- 229920001651 Cyanoacrylate Polymers 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 208000003556 Dry Eye Syndromes Diseases 0.000 description 1
- 206010013774 Dry eye Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 102100021181 Golgi phosphoprotein 3 Human genes 0.000 description 1
- 108010043121 Green Fluorescent Proteins Proteins 0.000 description 1
- 102000004144 Green Fluorescent Proteins Human genes 0.000 description 1
- 108010050754 Halorhodopsins Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 102100033114 Inward rectifier potassium channel 2 Human genes 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- 101710125418 Major capsid protein Proteins 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 108010008445 Microbial Rhodopsins Proteins 0.000 description 1
- 101710141454 Nucleoprotein Proteins 0.000 description 1
- QMGVPVSNSZLJIA-UHFFFAOYSA-N Nux Vomica Natural products C1C2C3C4N(C=5C6=CC=CC=5)C(=O)CC3OCC=C2CN2C1C46CC2 QMGVPVSNSZLJIA-UHFFFAOYSA-N 0.000 description 1
- 101710131038 Opsin-2 Proteins 0.000 description 1
- 102000002512 Orexin Human genes 0.000 description 1
- 108090000526 Papain Proteins 0.000 description 1
- LHNKBXRFNPMIBR-UHFFFAOYSA-N Picrotoxin Natural products CC(C)(O)C1(O)C2OC(=O)C1C3(O)C4OC4C5C(=O)OC2C35C LHNKBXRFNPMIBR-UHFFFAOYSA-N 0.000 description 1
- 102100032709 Potassium-transporting ATPase alpha chain 2 Human genes 0.000 description 1
- 241000288906 Primates Species 0.000 description 1
- 101710083689 Probable capsid protein Proteins 0.000 description 1
- 239000004365 Protease Substances 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- NCYCYZXNIZJOKI-OVSJKPMPSA-N Retinaldehyde Chemical compound O=C\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C NCYCYZXNIZJOKI-OVSJKPMPSA-N 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 238000000692 Student's t-test Methods 0.000 description 1
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 1
- 239000004473 Threonine Substances 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 241000287433 Turdus Species 0.000 description 1
- 241000195614 Volvox carteri Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000001720 action spectrum Methods 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 230000000949 anxiolytic effect Effects 0.000 description 1
- 238000003491 array Methods 0.000 description 1
- 238000013528 artificial neural network Methods 0.000 description 1
- 230000002238 attenuated effect Effects 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 239000007975 buffered saline Substances 0.000 description 1
- RMRJXGBAOAMLHD-IHFGGWKQSA-N buprenorphine Chemical compound C([C@]12[C@H]3OC=4C(O)=CC=C(C2=4)C[C@@H]2[C@]11CC[C@]3([C@H](C1)[C@](C)(O)C(C)(C)C)OC)CN2CC1CC1 RMRJXGBAOAMLHD-IHFGGWKQSA-N 0.000 description 1
- 229960001736 buprenorphine Drugs 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 210000000234 capsid Anatomy 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 230000001364 causal effect Effects 0.000 description 1
- 210000003483 chromatin Anatomy 0.000 description 1
- 238000010367 cloning Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000013267 controlled drug release Methods 0.000 description 1
- 238000007428 craniotomy Methods 0.000 description 1
- 239000002577 cryoprotective agent Substances 0.000 description 1
- 210000004748 cultured cell Anatomy 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 108010082025 cyan fluorescent protein Proteins 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002900 effect on cell Effects 0.000 description 1
- 230000001614 effect on membrane Effects 0.000 description 1
- 230000007831 electrophysiology Effects 0.000 description 1
- 238000002001 electrophysiology Methods 0.000 description 1
- JJJFUHOGVZWXNQ-UHFFFAOYSA-N enbucrilate Chemical compound CCCCOC(=O)C(=C)C#N JJJFUHOGVZWXNQ-UHFFFAOYSA-N 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- 238000010304 firing Methods 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 238000002073 fluorescence micrograph Methods 0.000 description 1
- 108091006047 fluorescent proteins Proteins 0.000 description 1
- 102000034287 fluorescent proteins Human genes 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- 238000001476 gene delivery Methods 0.000 description 1
- 231100000722 genetic damage Toxicity 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000005090 green fluorescent protein Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000002427 irreversible effect Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000020796 long term synaptic depression Effects 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 210000005171 mammalian brain Anatomy 0.000 description 1
- 238000007726 management method Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 108010082117 matrigel Proteins 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000005056 memory consolidation Effects 0.000 description 1
- 230000010407 memory-related activity Effects 0.000 description 1
- CVRPVRHBAOPDIG-UHFFFAOYSA-N methyl 2-methylprop-2-enoate;2-(2-methylprop-2-enoyloxy)ethyl 1,3-dioxo-2-benzofuran-5-carboxylate Chemical compound COC(=O)C(C)=C.CC(=C)C(=O)OCCOC(=O)C1=CC=C2C(=O)OC(=O)C2=C1 CVRPVRHBAOPDIG-UHFFFAOYSA-N 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 230000001423 neocortical effect Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000003061 neural cell Anatomy 0.000 description 1
- 210000000118 neural pathway Anatomy 0.000 description 1
- 230000010004 neural pathway Effects 0.000 description 1
- 230000008555 neuronal activation Effects 0.000 description 1
- 230000003961 neuronal insult Effects 0.000 description 1
- 230000008906 neuronal response Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 108060005714 orexin Proteins 0.000 description 1
- 229940055729 papain Drugs 0.000 description 1
- 235000019834 papain Nutrition 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 230000026731 phosphorylation Effects 0.000 description 1
- 238000006366 phosphorylation reaction Methods 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- VJKUPQSHOVKBCO-AHMKVGDJSA-N picrotoxin Chemical compound O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(=C)C)[C@@H]1C(=O)O2.O=C([C@@]12O[C@@H]1C[C@]1(O)[C@@]32C)O[C@@H]3[C@H]2[C@@H](C(C)(O)C)[C@@H]1C(=O)O2 VJKUPQSHOVKBCO-AHMKVGDJSA-N 0.000 description 1
- 230000010287 polarization Effects 0.000 description 1
- 230000001242 postsynaptic effect Effects 0.000 description 1
- 210000002442 prefrontal cortex Anatomy 0.000 description 1
- 230000002360 prefrontal effect Effects 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 210000001176 projection neuron Anatomy 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 108010054624 red fluorescent protein Proteins 0.000 description 1
- 101150066583 rep gene Proteins 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000014624 response to red light Effects 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 230000002207 retinal effect Effects 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- 230000006886 spatial memory Effects 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000012453 sprague-dawley rat model Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 210000001103 thalamus Anatomy 0.000 description 1
- 239000003106 tissue adhesive Substances 0.000 description 1
- 238000010361 transduction Methods 0.000 description 1
- 230000026683 transduction Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 238000007492 two-way ANOVA Methods 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 230000006648 viral gene expression Effects 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 210000002845 virion Anatomy 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2217/00—Genetically modified animals
- A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
- A01K2217/052—Animals comprising random inserted nucleic acids (transgenic) inducing gain of function
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/04—Fusion polypeptide containing a localisation/targetting motif containing an ER retention signal such as a C-terminal HDEL motif
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2319/00—Fusion polypeptide
- C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
- C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Environmental Sciences (AREA)
- Zoology (AREA)
- Epidemiology (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Animal Husbandry (AREA)
- Marine Sciences & Fisheries (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biotechnology (AREA)
- Immunology (AREA)
- Gastroenterology & Hepatology (AREA)
- Biodiversity & Conservation Biology (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Investigating Or Analysing Biological Materials (AREA)
Description
本出願は、2010年11月5日に出願された米国仮特許出願第61/410,732号、および2011年9月29日に出願された第61/540,926号の優先権利益を主張し、それらそれぞれの内容は、参照することによりそれら全体が本明細書に組み込まれる。
遠隔記憶の固定は、数分から数時間の時間スケールでのシナプス固定プロセス、および数週間から数年にわたる回路固定プロセスの両方に依存する(Frankland and Bontempi,2005、Squire and Bayley,2007)。長期文脈的恐怖記憶固定のプロセスは、海馬に続いて新皮質の早期関与を必要とし、このプロセスの過程で、新皮質に対する海馬の影響により、海馬は、記憶自体を安定に蓄積するよりもむしろ、記憶の長期皮質保持を促進できるようにし得る。研究は、海馬損傷が、訓練の翌日に近時記憶を障害するが、訓練から数週間後の遠隔記憶には影響がないことを示した(Anagnostaras et al.,1999、Bontempi et al.,1999、Debiec et al.,2002、Frankland et al.,2004、Kim and Fanselow,1992、Kitamura et al.,2009、Maren et al.,1997、Maviel et al.,2004、Shimizu et al.,2000、Wang et al.,2003、Winocur et al.,2009)。さらなる研究は、海馬記憶および皮質記憶の両方が連続的に相互作用することを示唆する。
本開示は、時間ベースで記憶機能を修正するのに有用であると考えられる。本発明の特定の適用は、記憶想起および/または記憶想起に結合される感情応答の妨害を促進する。本明細書に開示される例示の実施形態の多くの態様は、この分野のこれまでの開発に関し、それらを基礎とするため、以下の論考は、そのようなこれまでの開発をまとめて、実装の詳細および修正が描かれ得る基礎および根底をなす教示に関する強固な理解を提供する。この文脈において、以下の論考は、参照することにより本明細書に組み込まれるこれらの参考文献における教示とともに提供される。本発明は、必ずしもそのような適用に限定されないが、発明の様々な態様は、この文脈を使用して様々な実施例の考察を通して理解されてよい。
ニューロン(例えば、記憶機能に関与するニューロン)の活動は、多様な機序を使用して影響されてよい。ニューロン活動に影響する決定論的な方法を使用して、様々な脳機能の基礎となる神経回路を制御および/または特性化してよい。例えば、ニューロン応答は、薬剤(例えば、テトロドトキシン(TTX)、6−シアノ−7−ニトロキノキサリン−2,3−ジオン(CNQX)、ピクロトキシン、ストリキニーネなど)を適用することにより、および/または電気刺激(例えば、電極)により影響され得る。いくつかの変型例では、ニューロン活動は、ニューロンの膜上である種類のタンパク質を活性化することにより影響される場合があり、細胞膜を過分極化または脱分極化し得る。例えば、ある波長を有する光の存在下で、あるイオン(例えば、カチオン、アニオン)に透過性となる光活性化タンパク質は、ニューロン内で発現され得る。光活性化タンパク質の例には、以下でさらに説明される、光活性化イオンチャネルおよび/またはポンプが挙げられ得る。
本明細書に記載される光活性化タンパク質またはオプシンは、当該技術分野において既知の方法により、例えば、タンパク質をコードする配列を含むポリヌクレオチドによりニューロンに送達されてよい。いくつかの実施形態では、ポリヌクレオチドは、発現カセットを含む。いくつかの実施形態では、ポリヌクレオチドは、ベクターであり、例えば、AAVベクター、レトロウイルスベクター、アデノウイルスベクター、HSVベクター、およびレンチウイルスベクターからなる群から選択されるウイルスベクターである。
ニューロン内で発現した光活性化タンパク質を活性化する波長を有する光を適用することができる任意のデバイスを使用して、ニューロンを脱分極化および/または過分極化してよい。例えば、図1に表される1つ以上のニューロンの膜電圧に影響を及ぼすイオンチャネルおよび/またはイオンポンプを活性化するための光送達デバイス(100)が使用されてもよい。そこに示されるように、光送達デバイス(100)は、光刺激を脳の標的領域に提供するように構成される。光送達デバイス(100)は、基部(102)、基部に取り付けられるカニューレガイド(104)、およびカニューレガイドを介して基部に取り付けられた1つ以上の光学導管(106)を含んでよい。基部(102)は、光学導管(106)から標的組織領域(101)、例えば、CA1領域(103)に光を送達するように位置付けられた1つ以上の光送達ポート(108)を含む。光学導管(106)は、ファイバーの近位端が、光学光源(図示せず)に取り付けられ、遠位端が、光送達ポート(108)と連通している光ファイバーであってよい。光学光源は、連続光および/またはパルス光を提供することができ、既定のパルス配列で光を提供するようにプログラム可能であってよい。光送達デバイス(100)は、任意の数の光学導管(106)を有してよく、望ましくは、例えば、1、2、3、4、5、10、15、20などであってよい。光学導管(106)は、それぞれ同一または異なる波長の光を運んでよい。送達された光は、450nm〜600nmの間の波長、例えば、黄色光または緑色光を有してよい。光送達デバイス(100)は、任意の数の光送達ポート(108)を有してよく、望ましくは、例えば、1、2、3、4、5、10、15、20などであってよい。いくつかの変型例では、光学導管と同数の光送達ポートであってよいが、他の変型例では、異なる数の光学導管および光送達ポートであり得る。例えば、2つ以上の光送達ポートに光を運ぶ単一の光学導管であってもよい。代替または付加的に、単一の光学導管は、単一の光送達ポートに接続してよい。カニューレガイド(104)は、光学導管(106)を光送達ポート(108)に固定および整列するのを助けるように構成されてよい。いくつかの実施形態では、光送達デバイス(100)は、記憶の形成および想起に影響を及ぼすように、両側光をCA1領域(103)に送達するように構成される。光送達デバイスは、ニューロン活性を測定するために構成され得る、1つ以上の測定電極を含んでもよい。例えば、測定電極は、ニューロンが刺激に応答するとき、1つ以上のニューロンの膜全体の膜電位(例えば、活動電位)および/または電流の変化を記録し得る。いくつかの変型例では、測定電極は、光学刺激に対する1つ以上のニューロンの電気応答を測定し得る。測定電極は、細胞外または細胞内電極であり得る。
本明細書に記載されるように、標的組織領域(101)は、光に応答して細胞の膜電圧を修正するように設計された光活性化タンパク質を有する細胞を持つ神経組織を含んでよい。いくつかの変型例では、光活性化タンパク質を使用して、脳のCA1、BLA、およびACC領域におけるニューロンの脱分極化を抑制することにより記憶の形成および/または想起を妨害してよい。本開示の実施形態は、記憶の取得、呼び出し、および/または記憶と感情的な反応、例えば恐怖との関連付けを妨害することを対象とする。特定の実施形態では、記憶に関与する神経回路の機能は、光活性化イオンチャネル(例えば、NpHR、BR、ARなど)および/またはポンプ(例えば、プロトンポンプGtR3)の活性化により妨害される。ある実装では、この妨害は、記憶形成の間に実装され得る。他の実装では、この妨害は、記憶想起前またはその間に実装され得る。これは、記憶の呼び出しを伴う精神疾患または神経疾患、例えばPTSDに特に有用であり得る。ある実施形態と一致して、妨害は、その妨害に対して提示される、および/または制御される記憶トリガー事象または他の外部刺激に応答してトリガーされ得る。例えば、妨害は、トリガーに応答するように条件付けられた個体に対して、記憶のトリガーに応答して提供され得る。別の例では、個体は、妨害を活発にトリガーし得る。例えば、個体は、PTSDと関連付けられた記憶を経験するとき、妨害をトリガーし得る。本開示の他の実施形態は、記憶の取得、呼び出し、および/または記憶と感情的な反応との関連付けを促進することを対象とする。本明細書に記載される方法は、記憶機能におけるニューロン(複数可)および/または神経回路の役割を確認するように、および/または記憶障害と関連付けられる疾患を治療するように使用され得る。
記憶想起を妨害するための方法の一変型例は、CA1領域の興奮性ニューロンを抑制することを含んでよい(例えば、膜脱分極化を遮断または低減することにより、および/または膜過分極を促進することにより)。光活性化イオンチャネル、例えば、eNpHR3.1またはNpHR3.0は、チャネルタンパク質をコードするポリヌクレオチドを領域に投与することにより個体のCA1領域内に位置するニューロン上に発現されてよい。eNpHR3.1またはNpHR3.0イオンチャネルは、黄色光の存在下で活性化される(例えば、約591nmの波長を有する)。個体には、上述される光送達デバイス(100)などの光送達デバイスが提供されてよい。光送達デバイスは、黄色光がCA1ニューロンに送達され得るように個体上に位置付けられてよい。記憶(例えば、恐怖記憶またはストレス記憶などの任意の望ましくない記憶)の想起後または想起中に、光送達デバイスは、黄色光をCA1ニューロンに送達するように活性化されてよく、それによりそれらの脱分極化を抑制し、記憶の呼び出しを妨害する。記憶の呼び出しが十分に妨害されると、光送達デバイスは非活性化され得る。光送達デバイスの非活性化時に、個体は、妨害なしに記憶を想起する能力を再取得し得る。この方法を使用して、近時記憶(例えば、過去1日未満に起こった事象の記憶)の呼び出しおよび遠隔記憶(例えば、過去1日、過去1週間、過去2週間、過去4週間を超えて、過去8週間以前に起こった事象の記憶)の呼び出しを妨害してよい。いくつかの変型例では、ACCの興奮性ニューロンは、同様の光活性化タンパク質を発現してよく、遠隔記憶の想起を妨害するように同様に抑制されてよい。
CA1領域における興奮性ニューロンの脱分極化を抑制すること(および場合によってはこれらのニューロンを過分極化すること)は、記憶想起を抑制し得るが、そのような抑制は、記憶形成も妨害し得る。記憶形成を妨害するための方法の一変型例は、文脈的記憶などの記憶の形成中にCA1領域のニューロンを抑制することを含んでよい。光活性化イオンチャネル、例えば、eNpHR3.1は、前述される個体のCA1領域内に位置するニューロン上に発現されてよい。個体には、本明細書に記載される光送達デバイス(100)などの光送達デバイスが提供されてよい。記憶(例えば、恐怖記憶またはストレス記憶)の形成の間に、光送達デバイスは活性化されて、緑色光をCA1ニューロンに送達し、それによりそれらの脱分極化を抑制し、記憶の形成を妨害し得る。記憶形成が十分に妨害されると、光送達デバイスは、非活性化され得る。光送達デバイスの非活性化時に、個体は、妨害なしに記憶を形成する能力を再取得する場合がある。
記憶形成を妨害するための方法のいくつかの変型例は、記憶形成の間にBLA内でeNpHR3.1を発現するニューロンに光を送達することを含んでよい。eNpHR3.1などの光活性化イオンチャネルは、個体のBLA内に位置するニューロン上に発現されてよい。個体には、上述される光送達デバイス(100)などの光送達デバイスが提供されてよい。光送達デバイスは、緑色光がBLAニューロンに送達され得るように、個体上に位置付けられてよい。記憶(例えば、恐怖記憶またはストレス記憶)の形成後またはその間に、光送達デバイスは活性化されて、緑色光をBLAニューロンに送達し、それによりそれらの脱分極化を抑制し、記憶の形成を妨害し得る。記憶形成が十分に妨害されると、光送達デバイスは非活性化され得る。光送達デバイスの非活性化時に、個体は、妨害なしに記憶を取得する能力を再取得する場合がある。
BLA領域のニューロンを抑制することを含む、記憶取得を妨害するための方法は、マウスなどの非ヒト動物において使用されてよい。例えば、緑色光は、上述される恐怖条件付け訓練セッションの間に、BLAのニューロン内でeNpHR3.1を発現するマウスに送達され得る。次いでマウスは、訓練セッションの恐怖記憶を取得したか否かを決定するように試験され得る。訓練セッションの間にBLAに送達される緑色光は、マウスが恐怖またはストレス記憶を取得する能力を妨害し得る。
記憶機能の基礎となる神経回路を制御することは、記憶想起に対する薬剤の効果を評価するためのツールを提供し得る。例えば、CA1領域および/またはACCおよび/またはBLAのeNpHR3.1を発現するニューロンの抑制を使用して、記憶の呼び出しを回復させるための様々な薬剤の効果を評価してよい。A1領域および/またはACCおよび/またはBLA内で非ヒト動物興奮性ニューロンの脱分極化または励起を活性化する薬剤を識別するための方法の一例は、図3Aに表される。方法(300)は、光活性化タンパク質を脳(302)のCA1領域および/またはACCおよび/またはBLAに送達すること、ならびにCA1および/またはACC領域(303)の興奮性ニューロンの脱分極化を抑制することを含んでよい。上述されるように、脱分極化を抑制することは、活動電位の生成を防止するために、選択された波長(例えば、黄色または緑色)を有する光をCA1および/またはACC領域のニューロン上に発現されたeNpHR3.1イオンチャネルに適用することを含んでよい。他の型の光活性化チャネルは、NpHR、BR、ARの変異型などのこれらの興奮性細胞およびGtR3などのプロトンポンプの脱分極化を抑制するように発現されてもよい。eNpHR3.1イオンチャネルの活性化を抑制する効果は、遊離細胞または全細胞パッチクランプ法(304)を使用することにより電気的に測定され得る。いくつかの変異型では、CA1および/またはACC領域の興奮性細胞の電気活動は、単一電極および/または多電極配列を使用して測定されてよい。CA1および/またはACC領域の抑制されたニューロンは、次に試験薬剤(306)と接触されてよい。ニューロンの電気活動は、同様に測定されてよい(308)。試験薬剤と接触させる前および後のCA1領域および/またはACCおよび/またはBLAの興奮性ニューロンの電気測定値を比較して、試験薬剤が、ニューロンの脱分極化を活性化および/または回復したか否かを決定してよい(310)。この方法(300)は、必要に応じて繰り返し使用し、任意の数または様々な薬剤をスクリーニングしてよい。
上述される方法のいくつかの変型例では、光活性化タンパク質(例えば、eNpHR3.1またはeNpHR3.0)を発現するニューロンの抑制は、正確な時点で適用され得る。例えば、CA1領域内でeNpHR3.1を発現するニューロンは、試験セッションの間だけ光を照射されてよい。eNpHR3.1を発現するニューロンの時間精度抑制は、記憶の呼び出しを妨害し得る。試験セッションの間にマウスのCA1領域内でeNpHR3.1を発現するニューロンに光を正確に適用することは、動物において遠隔および/または近時恐怖記憶想起を抑制し得る。上述される方法の他の変型例では、eNpHR3.1を発現するニューロンの抑制は、長期間にわたって適用されてよい。例えば、CA1領域内でeNpHR3.1を発現するニューロンは、試験セッション前(例えば、試験セッションの30分以上前)に光が照射されてよい。海馬のCA1領域内でeNpHR3.1を発現するニューロンの長期抑制は、CA1ニューロンの正確な抑制とは異なって記憶の想起に影響し得る。例えば、CA1ニューロンに対する長期の光適用(すなわち、長期抑制)は、近時の文脈的恐怖呼び出しに影響し得るが、遠隔の文脈的記憶の呼び出しには影響しなかった。
上述される方法の1つ以上を使用してPTSDのある個体を治療してよい。本開示の態様を使用して、PTSD患者を治療することができ、再強化前後の実時間、または記憶が既に想起された後の実時間に、遠隔恐怖記憶を可逆的にシャットダウンすることにより、再発する妨害記憶が現れると、それが停止され得る。いくつかの変型例では、PTSDを治療するための方法は、光活性化タンパク質をコードするウイルスベクターを個体に投与することを含んでよい。光活性化タンパク質は、特定波長を有する光の存在下で、ニューロンの脱分極を抑制するように構成され得る。そのような光活性化タンパク質の例には、NpHR、BR、AR、およびGrR3が挙げられ得る。前述のように、ウイルスベクターは、任意のニューロン集団または型に送達され得る(例えば、CA1、ACC、およびBLA脳領域の興奮性ニューロン)。望ましくない記憶(例えば、恐怖またはストレス記憶)を呼び出す間に、光活性化タンパク質を発現するニューロン(複数可)は、脱分極化から抑制され、それにより望ましくない記憶の想起を妨害し得る。いくつかの変型例では、ニューロン(複数可)の脱分極化を抑制することは、特定波長の光を光活性化タンパク質を発現するニューロンに適用することを含んでよい。続いて(例えば、望ましくない記憶の呼び出しが妨害された後)、光は除去されてよい。これは、記憶が妨害なしに呼び出され得るように、記憶機能を回復させ得る。これらのステップは、PTSD治療の経過において所望され得るだけ反復されてよい。
対象。 6〜8週齢のC57BL6マウスは、Charles Riverから入手した。マウスは、逆12時間明/暗サイクルで維持され、食餌および水が自由に与えられるコロニー内にケージ当たり4〜5匹収容した。実験プロトコルは、スタンフォード大学IACUCにより承認され、国立衛生研究所実験動物の管理と使用に関する指針のガイドラインに適合する。
背側CA1における興奮性ニューロンの特異的光遺伝的抑制はニューロン活性を低減する。 CaMKIIα::eNpHR3.1ベクターの定位送達は、CA1特異的発現をもたらすことがわかった(図4A)。eNpHR3.1は、膜電位に対して同等の効果を有する内因性N末端シグナルペプチドの欠失を伴うeNpHR3.0の切断バージョンである。eNpHR3.1は、ニューロン膜を標的とし、体細胞の周囲、ならびにCA1ニューロンの先端および基底樹状突起内で発現される(図4B)。トランスフェクションした領域内で、CaMKIIα細胞の94%(458/486細胞、3匹のマウスから)がeNpHR3.1を発現し、プロモータは完全な特異性を提供した。すべてのeNpHR3.1−EYFP細胞は、CaMKIIα陽性でもあった(図4C)。eNpHR3.1タンパク質は、CA1内で発現されたが、これらの発現条件下で、単海馬部分体内、注入部位の上の頭頂葉皮質内、視床内、または手綱内では発現しなかった。カニューレ追跡は(ブレグマ−1.94)、発現部位の上で見ることができた。感染の容積は、背側CA1のかなりの割合を占めた(0.875±0.05mm3、N=12マウス)。
Adamantidis, A.R., Zhang, F., Aravanis, A.M., Deisseroth, K., and de Lecea, L. (2007). Neural substrates of awakening probed with optogenetic control of hypocretin neurons. Nature 450, 420-424.
Anagnostaras, S.G., Maren, S., and Fanselow, M.S. (1999). Temporally graded retrograde amnesia of contextual fear after hippocampal damage in rats: within-subjects examination. J N eurosci 19, 1106-1114.
Aravanis, A.M., Wang, L.P., Zhang, F., Meltzer, L.A., Mogri, M.Z., Schneider, M.B., and Deisseroth, K. (2007). An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology. J Neural Eng 4, S143-156.
Bolhuis, J.J., Stewart, C.A., and Forrest, E.M. (1994). Retrograde amnesia and memory reactivation in rats with ibotenate lesions to the hippocampus or subiculum. Q J Exp Psychol B 47, 129-150.
Bontempi, B., Laurent-Demir, C., Destrade, C., and Jaffard, R. (1999). Timedependent reorganization of brain circuitry underlying long-term memory storage. Nature 400, 671-675.
Boyden, E.S., Zhang, F., Bamberg, E., Nagel, G., and Deisseroth, K. (2005). Millisecond-timescale, genetically targeted optical control of neural activity. Nat Neurosci 8, 1263-1268.
Broadbent, N.J., Squire, L.R., and Clark, R.E. (2006). Reversible hippocampal lesions disrupt water maze performance during both recent and remote memory tests. Learn Mem 13, 187-191.
Cipolotti, L., and Bird, C.M. (2006). Amnesia and the hippocampus. Curr Opin Neurol 19, 593-598.
Debiec, J., LeDoux, J.E., and Nader, K. (2002). Cellular and systems reconsolidation in the hippocampus. Neuron 36, 527-538.
Deisseroth, K., Feng, G., Majewska, A.K., Miesenbock, G., Ting, A., and Schnitzer, M.J. (2006). Next-generation optical technologies for illuminating genetically targeted brain circuits. J Neurosci 26, 10380-10386.
Dudai, Y. (2006). Reconsolidation: the advantage of being refocused. Curr Opin Neurobiol 16, 174-178.
Everitt, B.J., Dickinson, A., and Robbins, T.W. (2001). The neuropsychological basis of addictive behaviour. Brain Res Brain Res Rev 36, 129-138.
Fanselow, M.S. (2000). Contextual fear, gestalt memories, and the hippocampus. Behav Brain Res 110, 73-81.
Fischer, A., Sananbenesi, F., Wang, X., Dobbin, M., and Tsai, L.H. (2007). Recovery of learning and memory is associated with chromatin remodelling. Nature 447, 178-182.
Frankland, P.W., and Bontempi, B. (2005). The organization of recent and remote memories. Nat Rev Neurosci 6,119-130.
Frankland, P.W., Bontempi, B., Talton, L.E., Kaczmarek, L., and Silva, A.J. (2004). The involvement of the anterior cingulate cortex in remote contextual fear memory. Science 304, 881-883.
Gradinaru, V., Thompson, K.R., Zhang, F., Mogri, M., Kay, K., Schneider, M.B., and Deisseroth, K. (2007). Targeting and readout strategies for fast optical neural control in vitro and in vivo. J Neurosci 27, 14231-14238.
Gradinaru, V., Zhang, F., Ramakrishnan, C., Mattis, J., Prakash, R., Diester, 1., Goshen, 1., Thompson, K.R., and Deisseroth, K. (2010). Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154-165.
Hall, J., Thomas, K.L., and Everitt, B.J. (2001). Cellular imaging of zif268 expression in the hippocampus and amygdala during contextual and cued fear memory retrieval: selective activation of hippocampal CA1 neurons during the recall of contextual memories. J Neurosci 21, 2186-2193.
Han, J.H., Kushner, S.A., Yiu, A.P., Hsiang, H.L., Buch, T., Waisman, A., Bontempi, B., Neve, R.L., Frankland, P.W., and Josselyn, S.A. (2009). Selective erasure of a fear memory. Science 323, 1492-1496.
Johansen, J.P., Hamanaka, H., Monfils, M.H., Behnia, R., Deisseroth, K., Blair, H.T., and LeDoux, J.E. (2010). Optical activation of lateral amygdala pyramidal cells instructs associative fear learning. Proc Natl Acad Sci U S A 107,12692-12697.
Killcross, S., Robbins, T.W., and Everitt, B.J. (1997). Different types of fearconditioned behaviour mediated by separate nuclei within amygdala. Nature 388, 377-380.
Kim, J.J., and Fanselow, M.S. (1992). Modality-specific retrograde amnesia of fear. Science 256, 675-677.
Kitamura, T., Saitoh, Y., Takashima, N., Murayama, A., Niibori, Y., Ageta, H., Sekiguchi, M., Sugiyama, H., and Inokuchi, K. (2009). Adult neurogenesis modulates the hippocampus-dependent period of associative fear memory. Cell 139, 814-827.
LeDoux, J.E. (2000). Emotion circuits in the brain. Annu Rev Neurosci 23, 155-184.
Lee, J.L., Di Ciano, P., Thomas, K.L., and Everitt, B.J. (2005). Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior. Neuron 47, 795-801.
Lee, J.L., Milton, A.L., and Everitt, B.J. (2006). Reconsolidation and extinction of conditioned fear: inhibition and potentiation. J Neurosci 26, 10051-10056.
Maren, S. (2001). Neurobiology of Pavlovian fear conditioning. Annu Rev Neurosci 24, 897-931.
Maren, S., Aharonov, G., and Fanselow, M.S. (1997). Neurotoxic lesions of the dorsal hippocampus and Pavlovian fear conditioning in rats. Behav Brain Res 88, 261-274.
Maren, S., and Quirk, G.J. (2004). Neuronal signalling of fear memory. Nat Rev Neurosci 5, 844-852.
Martin, S.J., de Hoz, L., and Morris, R.G. (2005). Retrograde amnesia: neither partial nor complete hippocampal lesions in rats result in preferential sparing of remote spatial memory, even after reminding. Neuropsychologia 43, 609-624.
Maviel, T., Durkin, T.P., Menzaghi, F., and Bontempi, B. (2004). Sites of neocortical reorganization critical for remote spatial memory. Science 305, 96-99.
McHugh, T.J., Jones, M.W., Quinn, J.J., Balthasar, N., Coppari, R., Elmquist, J.K., Lowell, B.B., Fanselow, M.S., Wilson, M.A., and Tonegawa, S. (2007). Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network. Science 317, 94-99.
McHugh, T.J., and Tonegawa, S. (2007). Spatial exploration is required for the formation of contextual fear memory. Behav Neurosci 121, 335-339.
Moita, M.A., Rosis, S., Zhou, Y., LeDoux, J.E., and Blair, H.T. (2004). Putting fear in its place: remapping of hippocampal place cells during fear conditioning. J Neurosci 24, 7015-7023.
Morris, R.G., Inglis, J., Ainge, J.A., Olverman, H.J., Tulloch, J., Dudai, Y., and Kelly, P .A. (2006). Memory reconsolidation: sensitivity of spatial memory to inhibition of protein synthesis in dorsal hippocampus during encoding and retrieval. Neuron 50, 479-489.
Moscovitch, M., Nadel, L., Winocur, G., Gilboa, A., and Rosenbaum, R.S. (2006). The cognitive neuroscience of remote episodic, semantic and spatial memory. Curr Opin Neurobiol 16, 179-190.
Moser, E.l., Kropff, E., and Moser, M.B. (2008). Place cells, grid cells, and the brain's spatial representation system. Annu Rev Neurosci 31, 69-89.
Nadel, L., and Moscovitch, M. (1997). Memory consolidation, retrograde amnesia and the hippocampal complex. Curr Opin Neurobiol 7, 217-227.
Nader, K., and Hardt, O. (2009). A single standard for memory: the case for reconsolidation. Nat Rev Neurosci 10, 224-234.
Nakashiba, T., Young, J.Z., McHugh, T.J., Buhl, D.L., and Tonegawa, S. (2008). Transgenic inhibition of synaptic transmission reveals role of CA3 output in hippocampal learning. Science 319, 1260-1264.
Phelps, E.A., and LeDoux, J.E. (2005). Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48, 175-187.
Riedel, G., Micheau, J., Lam, A.G., Roloff, E.L., Martin, S.J., Bridge, H., de Hoz, L., Poeschel, B., McCulloch, J., and Morris, R.G. (1999). Reversible neural inactivation reveals hippocampal participation in several memory processes. Nat Neurosci 2, 898-905.
Robbins, T.W., Ersche, K.D., and Everitt, B.J. (2008). Drug addiction and the memory systems of the brain. Ann NY Acad Sci 1141, 1-21.
Shimizu, E., Tang, Y.P., Rampon, C., and Tsien, J.Z. (2000). NMDA receptordependent synaptic reinforcement as a crucial process for memory consolidation. Science 290, 1170-1174.
Squire, L.R., and Alvarez, P. (1995). Retrograde amnesia and memory consolidation: a neurobiological perspective. Curr Opin Neurobiol 5, 169-177.
Squire, L.R., and Bayley, P.J. (2007). The neuroscience of remote memory. Curr Opin Neurobiol 17, 185-196.
Sutherland, R.J., O'Brien, J., and Lehmann, H. (2008). Absence of systems consolidation of fear memories after dorsal, ventral, or complete hippocampal damage. Hippocampus 18, 710-718.
Sutherland, R.J., Sparks, F.T., and Lehmann, H. (2010). Hippocampus and retrograde amnesia in the rat model: a modest proposal for the situation of systems consolidation. Neuropsychologia 48, 2357-2369.
Tronson, N.C., and Taylor, J.R. (2007). Molecular mechanisms of memory reconsolidation. Nat Rev Neurosci 8, 262-275.
Wang, H., Shimizu, E., Tang, Y.P., Cho, M., Kyin, M., Zuo, W., Robinson, D.A., Alaimo, P.J., Zhang, C., Morimoto, H., et al. (2003). Inducible protein knockout reveals temporal requirement of CaMKII reactivation for memory consolidation in the brain. Proc Natl Acad Sci USA 100, 4287-4292.
Wang, S.H., and Morris, R.G. (2010). Hippocampal-neocortical interactions in memory formation, consolidation, and reconsolidation. Annu Rev Psychol 61, 49-79, C41-44.
Wang, S.H., Teixeira, C.M., Wheeler, A.L., and Frankland, P.W. (2009). The precision of remote context memories does not require the hippocampus. Nat Neurosci 12, 253-255.
Wiltgen, B.J., Zhou, M., Cai, Y., Balaji, J., Karlsson, M.G., Parivash, S.N., Li, W., and Silva, A.J. (2010). The Hippocampus Plays a Selective Role in the Retrieval of Detailed Contextual Memories. Curr Biol 20, 1336-1344.
Winocur, G., Frankland, P.W., Sekeres, M., Fogel, S., and Moscovitch, M. (2009). Changes in context-specificity during memory reconsolidation: selective effects of hippocampal lesions. Learn Mem 16, 722-729.
Winocur, G., Moscovitch, M., and Bontempi, B. (2010). Memory formation and long-term retention in humans and animals: convergence towards a transformation account of hippocampal-neocortical interactions. Neuropsychologia 48, 2339-2356.
Winocur, G., Moscovitch, M., and Sekeres, M. (2007). Memory consolidation or transformation: context manipulation and hippocampal representations of memory. Nat Neurosci 10, 555-557.
Zhang, F., Wang, L.P., Brauner, M., Liewald, J.F., Kay, K., Watzke, N., Wood, P.G., Bamberg, E., Nagel, G., Gottschalk, A., et al. (2007). Multimodal fast optical interrogation of neural circuitry. Nature 446, 633-639.
Claims (18)
- 個体において記憶想起または記憶形成を可逆的に抑制するための薬剤であって、光活性化タンパク質をコードするポリヌクレオチドからなり、
前記タンパク質がNpHR(配列番号3)と90%を超えて同一であるアミノ酸配列を含み、
このとき前記薬剤が、
個体の海馬の背側CA1野、前帯状皮質または扁桃体基底外側部に投与されるものであって、このとき前記光活性化タンパク質が、個体の海馬の背側CA1野、前帯状皮質または扁桃体基底外側部の興奮性ニューロンの細胞膜上に発現され、前記タンパク質が光に応答性であり、前記ニューロンが光で照射されると、前記ニューロンの脱分極を抑制することができるものである、薬剤。 - 前記タンパク質が、NpHR(配列番号3)と95%を超えて同一であるアミノ酸配列を含む、請求項1に記載の薬剤。
- 前記タンパク質が、配列番号3に示される配列と少なくとも98%同一であるアミノ酸配列を含む、請求項2に記載の薬剤。
- 前記タンパク質が、小胞体(ER)輸出シグナルおよび/または膜輸送シグナルをさらに含む、請求項1から3のいずれか一項に記載の薬剤。
- 前記アミノ酸配列が、リンカーを通して前記ER輸出シグナルに連結される、請求項4に記載の薬剤。
- 前記ER輸出シグナルがアミノ酸配列FCYENEVを含むか、前記膜輸送シグナルがアミノ酸配列KSRITSEGEYIPLDQIDINVを含む、請求項4に記載の薬剤。
- 前記タンパク質が、配列番号5または配列番号6に示されるアミノ酸配列を含む、請求項6に記載の薬剤。
- 前記ポリヌクレオチドが、ベクターである、請求項1から7のいずれか一項に記載の薬剤。
- 前記ベクターが、AAVベクター、レトロウイルスベクター、アデノウイルスベクター、HSVベクター、およびレンチウイルスベクターからなる群から選択されるウイルスベクターである、請求項8に記載の薬剤。
- 前記事象が恐怖事象である、請求項1から9のいずれか一項に記載の薬剤。
- 前記個体が心的外傷後ストレス障害を有している、請求項1から10のいずれか一項に記載の薬剤。
- 前記個体がヒトまたは非ヒト動物である、請求項1から11のいずれか一項に記載の薬剤。
- 記憶想起または記憶形成に影響を及ぼす薬剤をスクリーニングする方法であって、
a)事象の記憶想起または記憶形成の間に、マウスの海馬の背側CA1野、前帯状皮質または扁桃体基底外側部内の興奮性ニューロンを薬剤と接触させることであって、このとき前記マウスが、その海馬の背側CA1野、前帯状皮質または扁桃体基底外側部内の興奮性ニューロンの細胞膜上に発現された光活性化タンパク質を含み、前記タンパク質が、NpHR(配列番号3)と90%を超えて同一であるアミノ酸配列を含み、光に応答性であり、前記ニューロンが光で照射されると前記ニューロンの脱分極を抑制することができ、そのタンパク質の照射が記憶想起または記憶形成を可逆的に抑制することと、
b)事象の記憶想起または記憶形成の間に、前記海馬の背側CA1野、前帯状皮質または扁桃体基底外側部内で、前記興奮性ニューロンの脱分極を抑制することと、
c)光の存在下または非存在下で、前記薬剤が記憶想起または記憶形成に影響を及ぼすか否かを決定する、方法。 - 前記タンパク質が、NpHR(配列番号3)と95%を超えて同一であるアミノ酸配列を含む、請求項13に記載の方法。
- 前記タンパク質が、配列番号3に示される配列と少なくとも98%同一であるアミノ酸配列を含む、請求項14に記載の方法。
- 前記タンパク質が、小胞体(ER)輸出シグナルおよび/または膜輸送シグナルをさらに含む、請求項13から15のいずれか一項に記載の方法。
- 前記アミノ酸配列が、リンカーを通して前記ER輸出シグナルに連結される、請求項16に記載の方法。
- 前記ER輸出シグナルがアミノ酸配列FCYENEVを含むか、前記膜輸送シグナルがアミノ酸配列KSRITSEGEYIPLDQIDINVを含む、請求項16または17に記載の方法。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US41073210P | 2010-11-05 | 2010-11-05 | |
US61/410,732 | 2010-11-05 | ||
US201161540926P | 2011-09-29 | 2011-09-29 | |
US61/540,926 | 2011-09-29 | ||
PCT/US2011/059283 WO2012061681A1 (en) | 2010-11-05 | 2011-11-04 | Control and characterization of memory function |
Publications (4)
Publication Number | Publication Date |
---|---|
JP2014500717A JP2014500717A (ja) | 2014-01-16 |
JP2014500717A5 JP2014500717A5 (ja) | 2014-12-25 |
JP6328424B2 JP6328424B2 (ja) | 2018-05-23 |
JP6328424B6 true JP6328424B6 (ja) | 2018-07-11 |
Family
ID=46024836
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2013537853A Expired - Fee Related JP6328424B6 (ja) | 2010-11-05 | 2011-11-04 | 記憶機能の制御および特性化 |
Country Status (8)
Country | Link |
---|---|
US (2) | US10086012B2 (ja) |
EP (1) | EP2635295B1 (ja) |
JP (1) | JP6328424B6 (ja) |
CN (2) | CN103298480B (ja) |
AU (2) | AU2011323228B2 (ja) |
CA (1) | CA2816972C (ja) |
ES (1) | ES2661093T3 (ja) |
WO (1) | WO2012061681A1 (ja) |
Families Citing this family (41)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8926959B2 (en) | 2005-07-22 | 2015-01-06 | The Board Of Trustees Of The Leland Stanford Junior University | System for optical stimulation of target cells |
US10052497B2 (en) | 2005-07-22 | 2018-08-21 | The Board Of Trustees Of The Leland Stanford Junior University | System for optical stimulation of target cells |
US9238150B2 (en) | 2005-07-22 | 2016-01-19 | The Board Of Trustees Of The Leland Stanford Junior University | Optical tissue interface method and apparatus for stimulating cells |
US9274099B2 (en) | 2005-07-22 | 2016-03-01 | The Board Of Trustees Of The Leland Stanford Junior University | Screening test drugs to identify their effects on cell membrane voltage-gated ion channel |
WO2007024391A2 (en) | 2005-07-22 | 2007-03-01 | The Board Of Trustees Of The Leland Stanford Junior University | Light-activated cation channel and uses thereof |
US8398692B2 (en) | 2007-01-10 | 2013-03-19 | The Board Of Trustees Of The Leland Stanford Junior University | System for optical stimulation of target cells |
WO2008101128A1 (en) | 2007-02-14 | 2008-08-21 | The Board Of Trustees Of The Leland Stanford Junior University | System, method and applications involving identification of biological circuits such as neurological characteristics |
WO2008106694A2 (en) | 2007-03-01 | 2008-09-04 | The Board Of Trustees Of The Leland Stanford Junior University | Systems, methods and compositions for optical stimulation of target cells |
US10434327B2 (en) | 2007-10-31 | 2019-10-08 | The Board Of Trustees Of The Leland Stanford Junior University | Implantable optical stimulators |
US10035027B2 (en) | 2007-10-31 | 2018-07-31 | The Board Of Trustees Of The Leland Stanford Junior University | Device and method for ultrasonic neuromodulation via stereotactic frame based technique |
EP2281039B1 (en) | 2008-04-23 | 2016-09-28 | The Board of Trustees of the Leland Stanford Junior University | Systems, methods and compositions for optical stimulation of target cells |
JP5890176B2 (ja) | 2008-05-29 | 2016-03-22 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | セカンドメッセンジャーを光制御するためのセルライン、システム、および方法 |
MX2010014100A (es) | 2008-06-17 | 2011-03-04 | Univ Leland Stanford Junior | Metodos, sistemas y dispositivos para estimulacion optica de celulas objetivo usando un elemento de transmision optica. |
BRPI0915583A2 (pt) | 2008-06-17 | 2016-01-26 | Univ Leland Stanford Junior | aparelho e métodos para controle do desenvolvimento celular |
US9101759B2 (en) | 2008-07-08 | 2015-08-11 | The Board Of Trustees Of The Leland Stanford Junior University | Materials and approaches for optical stimulation of the peripheral nervous system |
NZ602416A (en) | 2008-11-14 | 2014-08-29 | Univ Leland Stanford Junior | Optically-based stimulation of target cells and modifications thereto |
CN106011073A (zh) | 2010-03-17 | 2016-10-12 | 小利兰·斯坦福大学托管委员会 | 光敏离子透过性分子 |
WO2012061681A1 (en) * | 2010-11-05 | 2012-05-10 | The Board Of Trustees Of The Leland Stanford Junior University. | Control and characterization of memory function |
CN105941328B (zh) | 2010-11-05 | 2019-04-09 | 斯坦福大学托管董事会 | 一种鉴定抑制前额叶皮质中的兴奋性或抑制性神经元的去极化的化合物的系统 |
WO2012061676A1 (en) | 2010-11-05 | 2012-05-10 | The Board Of Trustees Of The Leland Stanford Junior University | Light-activated chimeric opsins and methods of using the same |
US9992981B2 (en) | 2010-11-05 | 2018-06-12 | The Board Of Trustees Of The Leland Stanford Junior University | Optogenetic control of reward-related behaviors |
US8932562B2 (en) | 2010-11-05 | 2015-01-13 | The Board Of Trustees Of The Leland Stanford Junior University | Optically controlled CNS dysfunction |
JP6145043B2 (ja) | 2010-11-05 | 2017-06-07 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | 光遺伝的方法で使用するための光の上方変換 |
US8696722B2 (en) | 2010-11-22 | 2014-04-15 | The Board Of Trustees Of The Leland Stanford Junior University | Optogenetic magnetic resonance imaging |
WO2013090356A2 (en) | 2011-12-16 | 2013-06-20 | The Board Of Trustees Of The Leland Stanford Junior University | Opsin polypeptides and methods of use thereof |
ES2728077T3 (es) | 2012-02-21 | 2019-10-22 | Univ Leland Stanford Junior | Composiciones para el tratamiento de trastornos neurogénicos del suelo pélvico |
CA2906756A1 (en) | 2013-03-15 | 2014-09-18 | The Board Of Trustees Of The Leland Stanford Junior University | Optogenetic control of behavioral state |
US9636380B2 (en) | 2013-03-15 | 2017-05-02 | The Board Of Trustees Of The Leland Stanford Junior University | Optogenetic control of inputs to the ventral tegmental area |
CA2908864A1 (en) | 2013-04-29 | 2014-11-06 | The Board Of Trustees Of The Leland Stanford Junior University | Devices, systems and methods for optogenetic modulation of action potentials in target cells |
JP6621747B2 (ja) | 2013-08-14 | 2019-12-18 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | 疼痛を制御するための組成物及び方法 |
EP3581580A1 (en) | 2014-03-28 | 2019-12-18 | The Board of Trustees of the Leland Stanford Junior University | Engineered light-activated anion channel proteins and methods of use thereof |
US20180154170A1 (en) * | 2015-06-16 | 2018-06-07 | Massachusetts Institute Of Technology | Methods and compositions for treating mental disorders and conditions |
AU2016279532B2 (en) * | 2015-06-18 | 2020-01-23 | Inter-University Research Institute Corporation National Institutes Of Natural Sciences | Evaluation of inhibitory circuit and use thereof |
US10568516B2 (en) | 2015-06-22 | 2020-02-25 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and devices for imaging and/or optogenetic control of light-responsive neurons |
JP7204192B2 (ja) * | 2015-11-24 | 2023-01-16 | マサチューセッツ インスティテュート オブ テクノロジー | 認知症の予防、軽減、及び/または治療のためのシステムならびに方法 |
CN106226509B (zh) * | 2016-08-12 | 2019-09-06 | 中国人民解放军第四军医大学 | 一种在小鼠前扣带回皮层诱发dse现象的方法 |
US11294165B2 (en) | 2017-03-30 | 2022-04-05 | The Board Of Trustees Of The Leland Stanford Junior University | Modular, electro-optical device for increasing the imaging field of view using time-sequential capture |
EP3694464A4 (en) | 2017-10-10 | 2021-07-07 | Massachusetts Institute of Technology | SYSTEMS AND PROCEDURES FOR PREVENTION, RELIEF AND / OR TREATMENT OF DEMENTIA |
WO2019094596A1 (en) | 2017-11-09 | 2019-05-16 | The Trustees Of Columbia University In The City Of New York | Biomarkers for efficacy of prophylactic treatments against stress-induced affective disorders |
CN116323196A (zh) | 2020-08-12 | 2023-06-23 | 博里利斯股份公司 | 具有低密封起始温度的多层膜 |
CN114588263A (zh) * | 2022-03-28 | 2022-06-07 | 中国人民解放军军事科学院军事医学研究院 | 光敏通道蛋白在空间学习记忆障碍的哺乳动物中的用途 |
Family Cites Families (290)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2968302A (en) | 1956-07-20 | 1961-01-17 | Univ Illinois | Multibeam focusing irradiator |
US3131690A (en) | 1962-10-22 | 1964-05-05 | American Optical Corp | Fiber optics devices |
US3499437A (en) | 1967-03-10 | 1970-03-10 | Ultrasonic Systems | Method and apparatus for treatment of organic structures and systems thereof with ultrasonic energy |
US3567847A (en) | 1969-01-06 | 1971-03-02 | Edgar E Price | Electro-optical display system |
US4343301A (en) | 1979-10-04 | 1982-08-10 | Robert Indech | Subcutaneous neural stimulation or local tissue destruction |
US4559951A (en) | 1982-11-29 | 1985-12-24 | Cardiac Pacemakers, Inc. | Catheter assembly |
US4616231A (en) | 1984-03-26 | 1986-10-07 | Hughes Aircraft Company | Narrow-band beam steering system |
FR2580277B1 (fr) | 1985-04-15 | 1988-06-10 | Oreal | Nouveaux derives naphtaleniques a action retinoique, le ur procede de preparation et compositions medicamenteuse et cosmetique les contenant |
US4865042A (en) | 1985-08-16 | 1989-09-12 | Hitachi, Ltd. | Ultrasonic irradiation system |
CA1322439C (en) | 1988-03-28 | 1993-09-28 | Junji Ohyama | Ion permeable membrane and ion transport method by utilizing said membrane |
US5082670A (en) | 1988-12-15 | 1992-01-21 | The Regents Of The University Of California | Method of grafting genetically modified cells to treat defects, disease or damage or the central nervous system |
JP2882818B2 (ja) | 1989-09-08 | 1999-04-12 | 株式会社エス・エル・ティ・ジャパン | レーザ光の照射装置 |
CA2028261C (en) | 1989-10-28 | 1995-01-17 | Won Suck Yang | Non-invasive method and apparatus for measuring blood glucose concentration |
US5032123A (en) | 1989-12-28 | 1991-07-16 | Cordis Corporation | Laser catheter with radially divergent treatment beam |
CA2096418C (en) | 1990-11-26 | 2001-11-20 | Philip J. Barr | Expression of pace in host cells and methods of use thereof |
US5550316A (en) | 1991-01-02 | 1996-08-27 | Fox Chase Cancer Center | Transgenic animal model system for human cutaneous melanoma |
US6497872B1 (en) | 1991-07-08 | 2002-12-24 | Neurospheres Holdings Ltd. | Neural transplantation using proliferated multipotent neural stem cells and their progeny |
US5249575A (en) | 1991-10-21 | 1993-10-05 | Adm Tronics Unlimited, Inc. | Corona discharge beam thermotherapy system |
SE9103752D0 (sv) | 1991-12-18 | 1991-12-18 | Astra Ab | New compounds |
US5670113A (en) | 1991-12-20 | 1997-09-23 | Sibia Neurosciences, Inc. | Automated analysis equipment and assay method for detecting cell surface protein and/or cytoplasmic receptor function using same |
US5739273A (en) | 1992-02-12 | 1998-04-14 | Yale University | Transmembrane polypeptide and methods of use |
US5460954A (en) | 1992-04-01 | 1995-10-24 | Cheil Foods & Chemicals, Inc. | Production of human proinsulin using a novel vector system |
US5330515A (en) | 1992-06-17 | 1994-07-19 | Cyberonics, Inc. | Treatment of pain by vagal afferent stimulation |
US5382516A (en) | 1992-09-15 | 1995-01-17 | Schleicher & Schuell, Inc. | Method and devices for delivery of substrate for the detection of enzyme-linked, membrane-based binding assays |
US6315772B1 (en) | 1993-09-24 | 2001-11-13 | Transmedica International, Inc. | Laser assisted pharmaceutical delivery and fluid removal |
US5527695A (en) | 1993-01-29 | 1996-06-18 | Purdue Research Foundation | Controlled modification of eukaryotic genomes |
EP0690913A1 (en) | 1993-03-25 | 1996-01-10 | The Regents Of The University Of California | Expression of heterologous polypeptides in halobacteria |
US5411540A (en) | 1993-06-03 | 1995-05-02 | Massachusetts Institute Of Technology | Method and apparatus for preferential neuron stimulation |
GB2278783A (en) | 1993-06-11 | 1994-12-14 | Daniel Shellon Gluck | Method of magnetically stimulating neural cells |
US6346101B1 (en) | 1993-07-19 | 2002-02-12 | Research Foundation Of City College Of New York | Photon-mediated introduction of biological materials into cells and/or cellular components |
US5445608A (en) | 1993-08-16 | 1995-08-29 | James C. Chen | Method and apparatus for providing light-activated therapy |
JPH07171162A (ja) | 1993-09-07 | 1995-07-11 | Olympus Optical Co Ltd | レーザプローブ |
US5470307A (en) | 1994-03-16 | 1995-11-28 | Lindall; Arnold W. | Catheter system for controllably releasing a therapeutic agent at a remote tissue site |
DE69535703T2 (de) | 1994-04-13 | 2009-02-19 | The Rockefeller University | AAV-vermittelte Zufuhr von DNA an Zellen des Nervensystems |
US6436908B1 (en) | 1995-05-30 | 2002-08-20 | Duke University | Use of exogenous β-adrenergic receptor and β-adrenergic receptor kinase gene constructs to enhance myocardial function |
US5495541A (en) | 1994-04-19 | 1996-02-27 | Murray; Steven C. | Optical delivery device with high numerical aperture curved waveguide |
US5503737A (en) | 1994-07-25 | 1996-04-02 | Ingersoll-Rand Company | Air inflow restrictor for disc filters |
US5807285A (en) | 1994-08-18 | 1998-09-15 | Ethicon-Endo Surgery, Inc. | Medical applications of ultrasonic energy |
US5520188A (en) | 1994-11-02 | 1996-05-28 | Focus Surgery Inc. | Annular array transducer |
US6334846B1 (en) | 1995-03-31 | 2002-01-01 | Kabushiki Kaisha Toshiba | Ultrasound therapeutic apparatus |
US5795581A (en) | 1995-03-31 | 1998-08-18 | Sandia Corporation | Controlled release of molecular components of dendrimer/bioactive complexes |
WO1996032076A1 (en) | 1995-04-11 | 1996-10-17 | Baxter Internatonal Inc. | Tissue implant systems |
US6342379B1 (en) | 1995-06-07 | 2002-01-29 | The Regents Of The University Of California | Detection of transmembrane potentials by optical methods |
US6480743B1 (en) | 2000-04-05 | 2002-11-12 | Neuropace, Inc. | System and method for adaptive brain stimulation |
US5755750A (en) | 1995-11-13 | 1998-05-26 | University Of Florida | Method and apparatus for selectively inhibiting activity in nerve fibers |
US5722426A (en) | 1996-02-26 | 1998-03-03 | Kolff; Jack | Coronary light probe and method of use |
US5703985A (en) | 1996-04-29 | 1997-12-30 | Eclipse Surgical Technologies, Inc. | Optical fiber device and method for laser surgery procedures |
US5898058A (en) | 1996-05-20 | 1999-04-27 | Wellman, Inc. | Method of post-polymerization stabilization of high activity catalysts in continuous polyethylene terephthalate production |
US5939320A (en) | 1996-05-20 | 1999-08-17 | New York University | G-coupled receptors associated with macrophage-trophic HIV, and diagnostic and therapeutic uses thereof |
US20040076613A1 (en) | 2000-11-03 | 2004-04-22 | Nicholas Mazarakis | Vector system |
US7732129B1 (en) | 1998-12-01 | 2010-06-08 | Crucell Holland B.V. | Method for the production and purification of adenoviral vectors |
US5741316A (en) | 1996-12-02 | 1998-04-21 | Light Sciences Limited Partnership | Electromagnetic coil configurations for power transmission through tissue |
US5756351A (en) | 1997-01-13 | 1998-05-26 | The Regents Of The University Of California | Biomolecular optical sensors |
US5782896A (en) | 1997-01-29 | 1998-07-21 | Light Sciences Limited Partnership | Use of a shape memory alloy to modify the disposition of a device within an implantable medical probe |
US5904659A (en) | 1997-02-14 | 1999-05-18 | Exogen, Inc. | Ultrasonic treatment for wounds |
JP2000514094A (ja) | 1997-04-17 | 2000-10-24 | レオネ,パオラ | 脳への遺伝子治療のための送達システム |
US5816256A (en) | 1997-04-17 | 1998-10-06 | Bioanalytical Systems, Inc. | Movement--responsive system for conducting tests on freely-moving animals |
US7276488B2 (en) | 1997-06-04 | 2007-10-02 | Oxford Biomedica (Uk) Limited | Vector system |
US5984861A (en) | 1997-09-29 | 1999-11-16 | Boston Scientific Corporation | Endofluorescence imaging module for an endoscope |
US6647296B2 (en) | 1997-10-27 | 2003-11-11 | Neuropace, Inc. | Implantable apparatus for treating neurological disorders |
US6597954B1 (en) | 1997-10-27 | 2003-07-22 | Neuropace, Inc. | System and method for controlling epileptic seizures with spatially separated detection and stimulation electrodes |
US6016449A (en) | 1997-10-27 | 2000-01-18 | Neuropace, Inc. | System for treatment of neurological disorders |
US6790652B1 (en) | 1998-01-08 | 2004-09-14 | Bioimage A/S | Method and apparatus for high density format screening for bioactive molecules |
ATE397887T1 (de) | 1998-04-07 | 2008-07-15 | Cytyc Corp | Vorrichtungen zur lokalisierung von läsionen in festem gewebe |
US6319241B1 (en) | 1998-04-30 | 2001-11-20 | Medtronic, Inc. | Techniques for positioning therapy delivery elements within a spinal cord or a brain |
US6108081A (en) | 1998-07-20 | 2000-08-22 | Battelle Memorial Institute | Nonlinear vibrational microscopy |
WO2000011155A1 (en) | 1998-08-19 | 2000-03-02 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and compositions for genomic modification |
US6377842B1 (en) | 1998-09-22 | 2002-04-23 | Aurora Optics, Inc. | Method for quantitative measurement of fluorescent and phosphorescent drugs within tissue utilizing a fiber optic probe |
US6253109B1 (en) | 1998-11-05 | 2001-06-26 | Medtronic Inc. | System for optimized brain stimulation |
US7211054B1 (en) | 1998-11-06 | 2007-05-01 | University Of Rochester | Method of treating a patient with a neurodegenerative disease using ultrasound |
US6303362B1 (en) | 1998-11-19 | 2001-10-16 | The Board Of Trustees Of The Leland Stanford Junior University | Adenoviral vector and methods for making and using the same |
US6790657B1 (en) | 1999-01-07 | 2004-09-14 | The United States Of America As Represented By The Department Of Health And Human Services | Lentivirus vector system |
US7507545B2 (en) | 1999-03-31 | 2009-03-24 | Cardiome Pharma Corp. | Ion channel modulating activity method |
US6224566B1 (en) | 1999-05-04 | 2001-05-01 | Cardiodyne, Inc. | Method and devices for creating a trap for confining therapeutic drugs and/or genes in the myocardium |
US6161045A (en) | 1999-06-01 | 2000-12-12 | Neuropace, Inc. | Method for determining stimulation parameters for the treatment of epileptic seizures |
US7655423B2 (en) | 1999-06-14 | 2010-02-02 | Henry Ford Health System | Nitric oxide donors for inducing neurogenesis |
US6662039B2 (en) | 1999-06-18 | 2003-12-09 | The Trustees Of Columbia University In The City Of New York | Optical probing of neuronal connections with fluorescent indicators |
US7674463B1 (en) | 1999-07-15 | 2010-03-09 | Research Development Foundation | Method of inhibiting angiogenesis by administration of a corticotropin releasing factor receptor 2 agonist |
US20040034882A1 (en) | 1999-07-15 | 2004-02-19 | Vale Wylie W. | Corticotropin releasing factor receptor 2 deficient mice and uses thereof |
EP1207788A4 (en) | 1999-07-19 | 2009-12-09 | St Jude Medical Atrial Fibrill | FABRIC ABLATION TECHNIQUES AND CORRESPONDING DEVICE |
ES2152900B1 (es) | 1999-07-23 | 2001-08-16 | Palleja Xavier Estivill | Ratones transgenicos y modelo de sobreexpresion del gen ntrk3 (trkc) basado en los mismos para el estudio y monitorizacion de tratamientos de la ansiedad, depresion y enfermedades psiquiatricas relacionadas. |
KR100630292B1 (ko) | 1999-08-06 | 2006-09-29 | 알프스 덴키 가부시키가이샤 | 자기 디스크용 자기헤드를 반송하기 위한 트레이 |
ES2478635T3 (es) | 1999-08-09 | 2014-07-22 | Targeted Genetics Corporation | Incremento de la expresión de una secuencia de nucleótidos heteróloga monocatenaria de vectores virales recombinantes diseñando la secuencia de modo que forma pares de bases intracatenarios |
GB9923558D0 (en) | 1999-10-05 | 1999-12-08 | Oxford Biomedica Ltd | Producer cell |
GB9928248D0 (en) | 1999-12-01 | 2000-01-26 | Gill Steven S | An implantable guide tube for neurosurgery |
AU2001241420A1 (en) | 2000-01-14 | 2001-07-24 | Mitokor | Screening assays using intramitochondrial calcium |
US7706882B2 (en) | 2000-01-19 | 2010-04-27 | Medtronic, Inc. | Methods of using high intensity focused ultrasound to form an ablated tissue area |
US6595934B1 (en) | 2000-01-19 | 2003-07-22 | Medtronic Xomed, Inc. | Methods of skin rejuvenation using high intensity focused ultrasound to form an ablated tissue area containing a plurality of lesions |
ES2355493T3 (es) | 2000-02-18 | 2011-03-28 | The Board Of Trustees Of The Leland Stanford Junior University | Recombinasas alteradas para la modificación del genoma. |
US6473639B1 (en) | 2000-03-02 | 2002-10-29 | Neuropace, Inc. | Neurological event detection procedure using processed display channel based algorithms and devices incorporating these procedures |
IL152549A0 (en) | 2000-05-01 | 2003-05-29 | Novartis Ag | Vectors for ocular transduction and use thereof for genetic therapy |
US6599281B1 (en) | 2000-05-03 | 2003-07-29 | Aspect Medical Systems, Inc. | System and method for adaptive drug delivery |
US7250294B2 (en) | 2000-05-17 | 2007-07-31 | Geron Corporation | Screening small molecule drugs using neural cells differentiated from human embryonic stem cells |
US6551346B2 (en) | 2000-05-17 | 2003-04-22 | Kent Crossley | Method and apparatus to prevent infections |
AU2001268149B2 (en) | 2000-06-01 | 2005-08-18 | University Of North Carolina At Chapel Hill | Methods and compounds for controlled release of recombinant parvovirus vectors |
WO2002002639A2 (en) | 2000-07-05 | 2002-01-10 | Pharmacia & Upjohn Company | Human ion channels |
US6969449B2 (en) | 2000-07-10 | 2005-11-29 | Vertex Pharmaceuticals (San Diego) Llc | Multi-well plate and electrode assemblies for ion channel assays |
US6921413B2 (en) | 2000-08-16 | 2005-07-26 | Vanderbilt University | Methods and devices for optical stimulation of neural tissues |
US6567690B2 (en) | 2000-10-16 | 2003-05-20 | Cole Giller | Method and apparatus for probe localization in brain matter |
US6584357B1 (en) | 2000-10-17 | 2003-06-24 | Sony Corporation | Method and system for forming an acoustic signal from neural timing difference data |
US6536440B1 (en) | 2000-10-17 | 2003-03-25 | Sony Corporation | Method and system for generating sensory data onto the human neural cortex |
US7350522B2 (en) | 2000-10-17 | 2008-04-01 | Sony Corporation | Scanning method for applying ultrasonic acoustic data to the human neural cortex |
US6631283B2 (en) | 2000-11-15 | 2003-10-07 | Virginia Tech Intellectual Properties, Inc. | B/B-like fragment targeting for the purposes of photodynamic therapy and medical imaging |
US6506154B1 (en) | 2000-11-28 | 2003-01-14 | Insightec-Txsonics, Ltd. | Systems and methods for controlling a phased array focused ultrasound system |
SE525540C2 (sv) | 2000-11-30 | 2005-03-08 | Datainnovation I Lund Ab | System och förfarande för automatisk provtagning från ett provobjekt |
US20070196838A1 (en) | 2000-12-08 | 2007-08-23 | Invitrogen Corporation | Methods and compositions for synthesis of nucleic acid molecules using multiple recognition sites |
US6489115B2 (en) | 2000-12-21 | 2002-12-03 | The Board Of Regents Of The University Of Nebraska | Genetic assays for trinucleotide repeat mutations in eukaryotic cells |
US6615080B1 (en) | 2001-03-29 | 2003-09-02 | John Duncan Unsworth | Neuromuscular electrical stimulation of the foot muscles for prevention of deep vein thrombosis and pulmonary embolism |
US7047078B2 (en) | 2001-03-30 | 2006-05-16 | Case Western Reserve University | Methods for stimulating components in, on, or near the pudendal nerve or its branches to achieve selective physiologic responses |
AU2002303283A1 (en) | 2001-04-04 | 2002-10-21 | Irm Llc | Methods for treating drug addiction |
US7107996B2 (en) | 2001-04-10 | 2006-09-19 | Ganz Robert A | Apparatus and method for treating atherosclerotic vascular disease through light sterilization |
US6961045B2 (en) | 2001-06-16 | 2005-11-01 | Che-Chih Tsao | Pattern projection techniques for volumetric 3D displays and 2D displays |
US6810285B2 (en) | 2001-06-28 | 2004-10-26 | Neuropace, Inc. | Seizure sensing and detection using an implantable device |
US7144733B2 (en) | 2001-08-16 | 2006-12-05 | Sloan-Kettering Institute For Cancer Research | Bio-synthetic photostimulators and methods of use |
US6858429B2 (en) | 2001-08-23 | 2005-02-22 | The Regents Of The University Of California | Universal light-switchable gene promoter system |
US6974448B2 (en) | 2001-08-30 | 2005-12-13 | Medtronic, Inc. | Method for convection enhanced delivery catheter to treat brain and other tumors |
US7904176B2 (en) | 2006-09-07 | 2011-03-08 | Bio Control Medical (B.C.M.) Ltd. | Techniques for reducing pain associated with nerve stimulation |
WO2003020103A2 (en) | 2001-09-04 | 2003-03-13 | Amit Technology Science & Medicine Ltd. | Method of and device for therapeutic illumination of internal organs and tissues |
WO2003026618A1 (en) | 2001-09-28 | 2003-04-03 | Saoirse Corporation | Localized non-invasive biological modulation system |
US20040054952A1 (en) | 2002-09-13 | 2004-03-18 | Morrow James W. | Device verification system and method |
US7175596B2 (en) | 2001-10-29 | 2007-02-13 | Insightec-Txsonics Ltd | System and method for sensing and locating disturbances in an energy path of a focused ultrasound system |
US7303578B2 (en) | 2001-11-01 | 2007-12-04 | Photothera, Inc. | Device and method for providing phototherapy to the brain |
US8308784B2 (en) | 2006-08-24 | 2012-11-13 | Jackson Streeter | Low level light therapy for enhancement of neurologic function of a patient affected by Parkinson's disease |
US7790845B2 (en) | 2001-11-08 | 2010-09-07 | Children's Medical Center Corporation | Bacterial ion channel |
WO2003041496A1 (fr) | 2001-11-14 | 2003-05-22 | Yamanouchi Pharmaceutical Co., Ltd. | Animal transgenique |
JP2005510232A (ja) | 2001-11-26 | 2005-04-21 | アドバンスド セル テクノロジー、インク. | 再プログラムされたヒト体細胞核ならびに自系および同系なヒト幹細胞の製造および使用方法 |
US20030104512A1 (en) | 2001-11-30 | 2003-06-05 | Freeman Alex R. | Biosensors for single cell and multi cell analysis |
US6873868B2 (en) | 2001-12-31 | 2005-03-29 | Infraredx, Inc. | Multi-fiber catheter probe arrangement for tissue analysis or treatment |
US6721603B2 (en) | 2002-01-25 | 2004-04-13 | Cyberonics, Inc. | Nerve stimulation as a treatment for pain |
US6666857B2 (en) | 2002-01-29 | 2003-12-23 | Robert F. Smith | Integrated wavefront-directed topography-controlled photoablation |
US20050107753A1 (en) | 2002-02-01 | 2005-05-19 | Ali Rezai | Microinfusion device |
JP4551090B2 (ja) | 2002-02-20 | 2010-09-22 | メディシス テクノロジーズ コーポレイション | 脂肪組織の超音波処理および画像化 |
JP4363843B2 (ja) | 2002-03-08 | 2009-11-11 | オリンパス株式会社 | カプセル型内視鏡 |
US20030186249A1 (en) | 2002-04-01 | 2003-10-02 | Zairen Sun | Human TARPP genes and polypeptides |
US20070135875A1 (en) | 2002-04-08 | 2007-06-14 | Ardian, Inc. | Methods and apparatus for thermally-induced renal neuromodulation |
DE10216005A1 (de) | 2002-04-11 | 2003-10-30 | Max Planck Gesellschaft | Verwendung von biologischen Photorezeptoren als direkt lichtgesteuerte Ionenkanäle |
US9592409B2 (en) | 2002-04-30 | 2017-03-14 | The Regents Of The University Of California | Methods for modifying electrical currents in neuronal circuits |
US7283861B2 (en) | 2002-04-30 | 2007-10-16 | Alexander Bystritsky | Methods for modifying electrical currents in neuronal circuits |
AU2003224374A1 (en) | 2002-05-13 | 2003-11-11 | Koninklijke Philips Electronics N.V. | Reduction of susceptibility artifacts in subencoded single-shot magnetic resonance imaging |
EP1532452A4 (en) | 2002-05-31 | 2006-11-29 | Sloan Kettering Inst Cancer | HETEROLOGY STIMULUS-CONTROLLED ION CHANNELS AND METHOD FOR USE THEREOF |
AU2003239957A1 (en) | 2002-06-04 | 2003-12-19 | Cyberkinetics, Inc. | Optically-connected implants and related systems and methods of use |
EP1519947A1 (de) | 2002-06-12 | 2005-04-06 | Fraunhofer-Gesellschaft Zur Förderung Der Angewandten Forschung E.V. | Pflanzliche proteinpräparate und deren verwendung |
US7292890B2 (en) | 2002-06-20 | 2007-11-06 | Advanced Bionics Corporation | Vagus nerve stimulation via unidirectional propagation of action potentials |
US20050020945A1 (en) | 2002-07-02 | 2005-01-27 | Tosaya Carol A. | Acoustically-aided cerebrospinal-fluid manipulation for neurodegenerative disease therapy |
US20040049134A1 (en) | 2002-07-02 | 2004-03-11 | Tosaya Carol A. | System and methods for treatment of alzheimer's and other deposition-related disorders of the brain |
US20060106543A1 (en) | 2002-08-09 | 2006-05-18 | Gustavo Deco | Method for analyzing effectiveness of pharmaceutical preparation |
WO2004016315A1 (en) | 2002-08-19 | 2004-02-26 | Arizona Board Regents | Neurostimulator |
US20060014206A1 (en) | 2002-10-10 | 2006-01-19 | Menghang Xia | Assay methods for state-dependent calcium channel agonists/antagonists |
US7355033B2 (en) | 2002-11-18 | 2008-04-08 | Health Research, Inc. | Screening for West Nile Virus antiviral therapy |
US7402728B2 (en) | 2002-12-16 | 2008-07-22 | Genentech, Inc. | Transgenic mice expressing human CD20 and/or CD16 |
US20040122475A1 (en) | 2002-12-18 | 2004-06-24 | Myrick Andrew J. | Electrochemical neuron systems |
US20050102708A1 (en) * | 2003-03-12 | 2005-05-12 | Laurent Lecanu | Animal model simulating neurologic disease |
US20040216177A1 (en) | 2003-04-25 | 2004-10-28 | Otsuka Pharmaceutical Co., Ltd. | Congenic rats containing a mutant GPR10 gene |
US7377900B2 (en) | 2003-06-02 | 2008-05-27 | Insightec - Image Guided Treatment Ltd. | Endo-cavity focused ultrasound transducer |
CA2432810A1 (en) | 2003-06-19 | 2004-12-19 | Andres M. Lozano | Method of treating depression, mood disorders and anxiety disorders by brian infusion |
US8367410B2 (en) | 2003-06-20 | 2013-02-05 | Massachusetts Institute Of Technology | Application of electrical stimulation for functional tissue engineering in vitro and in vivo |
US7091500B2 (en) | 2003-06-20 | 2006-08-15 | Lucent Technologies Inc. | Multi-photon endoscopic imaging system |
JP2005034073A (ja) | 2003-07-16 | 2005-02-10 | Masamitsu Iino | ミオシン軽鎖リン酸化の測定用蛍光性プローブ |
US20050153885A1 (en) | 2003-10-08 | 2005-07-14 | Yun Anthony J. | Treatment of conditions through modulation of the autonomic nervous system |
US7548775B2 (en) | 2003-10-21 | 2009-06-16 | The Regents Of The University Of Michigan | Intracranial neural interface system |
US6952097B2 (en) | 2003-10-22 | 2005-10-04 | Siemens Aktiengesellschaft | Method for slice position planning of tomographic measurements, using statistical images |
US20060034943A1 (en) | 2003-10-31 | 2006-02-16 | Technology Innovations Llc | Process for treating a biological organism |
US20080119421A1 (en) | 2003-10-31 | 2008-05-22 | Jack Tuszynski | Process for treating a biological organism |
AU2004294933B2 (en) | 2003-11-21 | 2011-11-17 | Johns Hopkins University | Biomolecule partition motifs and uses thereof |
US20050124897A1 (en) | 2003-12-03 | 2005-06-09 | Scimed Life Systems, Inc. | Apparatus and methods for delivering acoustic energy to body tissue |
US7783349B2 (en) | 2006-04-10 | 2010-08-24 | Cardiac Pacemakers, Inc. | System and method for closed-loop neural stimulation |
CN1236305C (zh) | 2004-02-03 | 2006-01-11 | 复旦大学 | 生物光敏蛋白-纳米半导体复合光电极的制备方法 |
US7662114B2 (en) | 2004-03-02 | 2010-02-16 | Focus Surgery, Inc. | Ultrasound phased arrays |
US20050215764A1 (en) | 2004-03-24 | 2005-09-29 | Tuszynski Jack A | Biological polymer with differently charged portions |
ITMI20040598A1 (it) | 2004-03-26 | 2004-06-26 | Carlotta Giorgi | Metodo per la rilevazione di parametri intracellulari con sonde proteiche luminescenti per lo screening di molecole in grado di alterare detti parametri |
US9801527B2 (en) | 2004-04-19 | 2017-10-31 | Gearbox, Llc | Lumen-traveling biological interface device |
US7313442B2 (en) | 2004-04-30 | 2007-12-25 | Advanced Neuromodulation Systems, Inc. | Method of treating mood disorders and/or anxiety disorders by brain stimulation |
US7670838B2 (en) | 2004-05-24 | 2010-03-02 | The Board Of Trustees Of The Leland Stanford Junior University | Coupling of excitation and neurogenesis in neural stem/progenitor cells |
US20050279354A1 (en) | 2004-06-21 | 2005-12-22 | Harvey Deutsch | Structures and Methods for the Joint Delivery of Fluids and Light |
US20060057614A1 (en) | 2004-08-04 | 2006-03-16 | Nathaniel Heintz | Tethering neuropeptides and toxins for modulation of ion channels and receptors |
US7699780B2 (en) | 2004-08-11 | 2010-04-20 | Insightec—Image-Guided Treatment Ltd. | Focused ultrasound system with adaptive anatomical aperture shaping |
US8409099B2 (en) | 2004-08-26 | 2013-04-02 | Insightec Ltd. | Focused ultrasound system for surrounding a body tissue mass and treatment method |
US8821559B2 (en) | 2004-08-27 | 2014-09-02 | Codman & Shurtleff, Inc. | Light-based implants for treating Alzheimer's disease |
WO2006047265A1 (en) | 2004-10-21 | 2006-05-04 | Advanced Neuromodulation Systems, Inc. | Stimulation of the amygdalophippocampal complex to treat neurological conditions |
US7544171B2 (en) | 2004-10-22 | 2009-06-09 | General Patent Llc | Methods for promoting nerve regeneration and neuronal growth and elongation |
US7833257B2 (en) | 2004-11-12 | 2010-11-16 | Northwestern University | Apparatus and methods for optical stimulation of the auditory nerve |
JP2008520280A (ja) | 2004-11-15 | 2008-06-19 | デチャームス,クリストファー | 光を使用した神経組織の刺激の適用 |
US8109981B2 (en) | 2005-01-25 | 2012-02-07 | Valam Corporation | Optical therapies and devices |
US7686839B2 (en) | 2005-01-26 | 2010-03-30 | Lumitex, Inc. | Phototherapy treatment devices for applying area lighting to a wound |
US9034650B2 (en) | 2005-02-02 | 2015-05-19 | Intrexon Corporation | Site-specific serine recombinases and methods of their use |
US7553284B2 (en) | 2005-02-02 | 2009-06-30 | Vaitekunas Jeffrey J | Focused ultrasound for pain reduction |
JP2006217866A (ja) | 2005-02-10 | 2006-08-24 | Tohoku Univ | 光感受性を新たに賦与した神経細胞 |
US7548780B2 (en) | 2005-02-22 | 2009-06-16 | Cardiac Pacemakers, Inc. | Cell therapy and neural stimulation for cardiac repair |
US7288108B2 (en) | 2005-03-14 | 2007-10-30 | Codman & Shurtleff, Inc. | Red light implant for treating Parkinson's disease |
US20070059775A1 (en) | 2005-03-29 | 2007-03-15 | The Trustees Of Columbia University In The City Of New York | Synthesis and conjugation of iron oxide nanoparticles to antibodies for targeting specific cells using fluorescence and MR imaging techniques |
EP1871476B1 (en) | 2005-03-31 | 2018-01-03 | Esther Mayer | Probe device for photobiomodulation of tissue lining a body cavity |
JP2006295350A (ja) | 2005-04-07 | 2006-10-26 | Sony Corp | 撮像装置及び撮像結果の処理方法 |
US9445211B2 (en) | 2005-04-11 | 2016-09-13 | St. Jude Medical, Atrial Fibrillation Division, Inc. | Methods for manufacturing high intensity ultrasound transducers |
GB0508254D0 (en) | 2005-04-23 | 2005-06-01 | Smith & Nephew | Ultrasound device |
US7640057B2 (en) | 2005-04-25 | 2009-12-29 | Cardiac Pacemakers, Inc. | Methods of providing neural markers for sensed autonomic nervous system activity |
US8066908B2 (en) | 2005-04-26 | 2011-11-29 | Uvic Industry Partnerships Inc. | Production of light from sol-gel derived thin films made with lanthanide doped nanoparticles, and preparation thereof |
DK1879623T3 (da) | 2005-05-02 | 2012-12-17 | Genzyme Corp | Genterapi til rygmarvssygdomme |
CN1879906A (zh) | 2005-06-15 | 2006-12-20 | 郑云峰 | 中枢神经系统磁刺激装置及其使用方法 |
US20070027443A1 (en) | 2005-06-29 | 2007-02-01 | Ondine International, Ltd. | Hand piece for the delivery of light and system employing the hand piece |
US9238150B2 (en) | 2005-07-22 | 2016-01-19 | The Board Of Trustees Of The Leland Stanford Junior University | Optical tissue interface method and apparatus for stimulating cells |
US9274099B2 (en) | 2005-07-22 | 2016-03-01 | The Board Of Trustees Of The Leland Stanford Junior University | Screening test drugs to identify their effects on cell membrane voltage-gated ion channel |
WO2007024391A2 (en) | 2005-07-22 | 2007-03-01 | The Board Of Trustees Of The Leland Stanford Junior University | Light-activated cation channel and uses thereof |
US8926959B2 (en) | 2005-07-22 | 2015-01-06 | The Board Of Trustees Of The Leland Stanford Junior University | System for optical stimulation of target cells |
US10052497B2 (en) | 2005-07-22 | 2018-08-21 | The Board Of Trustees Of The Leland Stanford Junior University | System for optical stimulation of target cells |
US7736382B2 (en) | 2005-09-09 | 2010-06-15 | Lockheed Martin Corporation | Apparatus for optical stimulation of nerves and other animal tissue |
US8852184B2 (en) | 2005-09-15 | 2014-10-07 | Cannuflow, Inc. | Arthroscopic surgical temperature control system |
US7988688B2 (en) | 2006-09-21 | 2011-08-02 | Lockheed Martin Corporation | Miniature apparatus and method for optical stimulation of nerves and other animal tissue |
US8058509B2 (en) | 2005-12-21 | 2011-11-15 | Pioneer Hi-Bred International, Inc. | Methods and compositions for in planta production of inverted repeats |
US7610100B2 (en) | 2005-12-30 | 2009-10-27 | Boston Scientific Neuromodulation Corporation | Methods and systems for treating osteoarthritis |
US20070191906A1 (en) | 2006-02-13 | 2007-08-16 | Anand Iyer | Method and apparatus for selective nerve stimulation |
US20070219600A1 (en) | 2006-03-17 | 2007-09-20 | Michael Gertner | Devices and methods for targeted nasal phototherapy |
US20070282404A1 (en) | 2006-04-10 | 2007-12-06 | University Of Rochester | Side-firing linear optic array for interstitial optical therapy and monitoring using compact helical geometry |
US20070253995A1 (en) | 2006-04-28 | 2007-11-01 | Medtronic, Inc. | Drug Delivery Methods and Devices for Treating Stress Urinary Incontinence |
US8057464B2 (en) | 2006-05-03 | 2011-11-15 | Light Sciences Oncology, Inc. | Light transmission system for photoreactive therapy |
CA2685900A1 (en) | 2006-05-04 | 2007-11-15 | Wayne State University | Restoration of visual responses by in vivo delivery of rhodopsin nucleic acids |
US20080176076A1 (en) | 2006-05-11 | 2008-07-24 | University Of Victoria Innovation And Development Corporation | Functionalized lanthanide rich nanoparticles and use thereof |
US20080262411A1 (en) | 2006-06-02 | 2008-10-23 | Dobak John D | Dynamic nerve stimulation in combination with other eating disorder treatment modalities |
JP5250549B2 (ja) | 2006-06-19 | 2013-07-31 | ハイランド インストゥルメンツ, インコーポレイテッド | 生体組織の刺激のための器具および方法 |
US7795632B2 (en) | 2006-06-26 | 2010-09-14 | Osram Sylvania Inc. | Light emitting diode with direct view optic |
US9284363B2 (en) | 2006-07-26 | 2016-03-15 | Case Western Reserve University | System and method for controlling G-protein coupled receptor pathways |
US20080027505A1 (en) | 2006-07-26 | 2008-01-31 | G&L Consulting, Llc | System and method for treatment of headaches |
SG139588A1 (en) | 2006-07-28 | 2008-02-29 | St Microelectronics Asia | Addressable led architecure |
US7848797B2 (en) | 2006-08-17 | 2010-12-07 | Neurometrix, Inc. | Motor unit number estimation (MUNE) for the assessment of neuromuscular function |
US7521590B2 (en) | 2006-09-01 | 2009-04-21 | Korea Institute Of Science And Technology | Phospholipase C β1 (PLCβ1) knockout mice as a model system for testing schizophrenia drugs |
US10420948B2 (en) | 2006-10-30 | 2019-09-24 | Medtronic, Inc. | Implantable medical device with variable data retransmission characteristics based upon data type |
WO2008070765A2 (en) | 2006-12-06 | 2008-06-12 | Case Western Reserve University | Light-sensitive constructs for inducing cell death and cell signaling |
EE200600039A (et) | 2006-12-12 | 2008-10-15 | Tartu Ülikool | Transgeenne loommudel patoloogilise ärevuse modelleerimiseks, meetod patoloogilisest ärevusest p?hjustatud haiguste v?i seisundite ravimiseks sobilike ühendite tuvastamiseks ja meetod Wfs1 valgu kasutamiseks sihtmärgina patoloogilise ärevuse vastase |
US8398692B2 (en) | 2007-01-10 | 2013-03-19 | The Board Of Trustees Of The Leland Stanford Junior University | System for optical stimulation of target cells |
US7883536B1 (en) | 2007-01-19 | 2011-02-08 | Lockheed Martin Corporation | Hybrid optical-electrical probes |
WO2008101128A1 (en) | 2007-02-14 | 2008-08-21 | The Board Of Trustees Of The Leland Stanford Junior University | System, method and applications involving identification of biological circuits such as neurological characteristics |
WO2008106694A2 (en) | 2007-03-01 | 2008-09-04 | The Board Of Trustees Of The Leland Stanford Junior University | Systems, methods and compositions for optical stimulation of target cells |
US8282559B2 (en) | 2007-03-09 | 2012-10-09 | Philip Chidi Njemanze | Method for inducing and monitoring long-term potentiation and long-term depression using transcranial doppler ultrasound device in head-down bed rest |
US8139339B2 (en) | 2007-03-16 | 2012-03-20 | Old Dominion University Research Foundation | Modulation of neuromuscular functions with ultrashort electrical pulses |
US20080287821A1 (en) | 2007-03-30 | 2008-11-20 | Searete Llc, A Limited Liability Corporation Of The State Of Delaware | Computational user-health testing |
CN101288768A (zh) * | 2007-04-20 | 2008-10-22 | 中央研究院 | 用于治疗渐进神经退化症的医药组合物 |
WO2008137579A1 (en) | 2007-05-01 | 2008-11-13 | Neurofocus, Inc. | Neuro-informatics repository system |
US20110165681A1 (en) | 2009-02-26 | 2011-07-07 | Massachusetts Institute Of Technology | Light-Activated Proton Pumps and Applications Thereof |
US8097422B2 (en) | 2007-06-20 | 2012-01-17 | Salk Institute For Biological Studies | Kir channel modulators |
US9138596B2 (en) | 2007-08-22 | 2015-09-22 | Cardiac Pacemakers, Inc. | Optical depolarization of cardiac tissue |
US10434327B2 (en) | 2007-10-31 | 2019-10-08 | The Board Of Trustees Of The Leland Stanford Junior University | Implantable optical stimulators |
US10035027B2 (en) | 2007-10-31 | 2018-07-31 | The Board Of Trustees Of The Leland Stanford Junior University | Device and method for ultrasonic neuromodulation via stereotactic frame based technique |
DE112008003192T5 (de) | 2007-11-26 | 2010-10-07 | Micro-Transponder, Inc., Dallas | Übertragungsspulenarchitektur |
US8562658B2 (en) | 2007-12-06 | 2013-10-22 | Technion Research & Development Foundation Limited | Method and system for optical stimulation of neurons |
US8883719B2 (en) | 2008-01-16 | 2014-11-11 | University Of Connecticut | Bacteriorhodopsin protein variants and methods of use for long term data storage |
US20090254134A1 (en) | 2008-02-04 | 2009-10-08 | Medtrode Inc. | Hybrid ultrasound/electrode device for neural stimulation and recording |
JP5544659B2 (ja) | 2008-03-24 | 2014-07-09 | 国立大学法人東北大学 | 改変された光受容体チャネル型ロドプシンタンパク質 |
CA3095369C (en) | 2008-04-04 | 2023-09-26 | Immunolight, Llc | Non-invasive systems and methods for in-situ photobiomodulation |
EP2281039B1 (en) | 2008-04-23 | 2016-09-28 | The Board of Trustees of the Leland Stanford Junior University | Systems, methods and compositions for optical stimulation of target cells |
MX2010012592A (es) | 2008-05-20 | 2011-05-05 | Eos Neuroscience Inc | Vectores para la administracion de proteinas sensibles a la luz y metodos de uso de las mismas. |
JP5890176B2 (ja) | 2008-05-29 | 2016-03-22 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | セカンドメッセンジャーを光制御するためのセルライン、システム、および方法 |
US8636653B2 (en) | 2008-06-09 | 2014-01-28 | Capso Vision, Inc. | In vivo camera with multiple sources to illuminate tissue at different distances |
MX2010014100A (es) | 2008-06-17 | 2011-03-04 | Univ Leland Stanford Junior | Metodos, sistemas y dispositivos para estimulacion optica de celulas objetivo usando un elemento de transmision optica. |
BRPI0915583A2 (pt) | 2008-06-17 | 2016-01-26 | Univ Leland Stanford Junior | aparelho e métodos para controle do desenvolvimento celular |
US9101759B2 (en) | 2008-07-08 | 2015-08-11 | The Board Of Trustees Of The Leland Stanford Junior University | Materials and approaches for optical stimulation of the peripheral nervous system |
JP2012503798A (ja) | 2008-09-25 | 2012-02-09 | ザ トラスティーズ オブ コロンビア ユニヴァーシティ イン ザ シティ オブ ニューヨーク | 構造物の光刺激およびイメージングを提供するためのデバイス、装置、および方法 |
NZ602416A (en) | 2008-11-14 | 2014-08-29 | Univ Leland Stanford Junior | Optically-based stimulation of target cells and modifications thereto |
JP2012521801A (ja) | 2009-03-24 | 2012-09-20 | スパイナル・モデュレーション・インコーポレイテッド | 錯感覚に対する閾値以下の刺激を伴う疼痛の管理 |
KR101081360B1 (ko) | 2009-03-25 | 2011-11-08 | 한국과학기술연구원 | 어레이형 광 자극 장치 |
EP2421376A4 (en) | 2009-04-21 | 2016-04-27 | Immunolight Llc | NON-INVASIVE ENERGY UPGRADING METHODS AND SYSTEMS FOR IN-SITU PHOTO BODY MODULATION |
WO2011005978A2 (en) | 2009-07-08 | 2011-01-13 | Duke University | Methods of manipulating cell signaling |
US20110112463A1 (en) | 2009-11-12 | 2011-05-12 | Jerry Silver | Compositions and methods for treating a neuronal injury or neuronal disorders |
US8936630B2 (en) | 2009-11-25 | 2015-01-20 | Medtronic, Inc. | Optical stimulation therapy |
EP3088044B1 (en) | 2010-02-26 | 2020-04-08 | Cornell University | Retina prosthesis |
CN106011073A (zh) | 2010-03-17 | 2016-10-12 | 小利兰·斯坦福大学托管委员会 | 光敏离子透过性分子 |
WO2011127088A2 (en) | 2010-04-05 | 2011-10-13 | Eos Neuroscience, Inc. | Methods and compositions for decreasing chronic pain |
US10051240B2 (en) | 2010-06-14 | 2018-08-14 | Howard Hughes Medical Institute | Structured plane illumination microscopy |
CA2838330C (en) | 2010-08-23 | 2021-01-26 | President And Fellows Of Harvard College | Optogenetic probes for measuring membrane potential |
AU2011298745B2 (en) | 2010-09-08 | 2015-05-07 | Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. | Mutant channelrhodopsin 2 |
US9992981B2 (en) | 2010-11-05 | 2018-06-12 | The Board Of Trustees Of The Leland Stanford Junior University | Optogenetic control of reward-related behaviors |
JP6145043B2 (ja) | 2010-11-05 | 2017-06-07 | ザ ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティー | 光遺伝的方法で使用するための光の上方変換 |
CN103339505B (zh) | 2010-11-05 | 2016-08-24 | 斯坦福大学托管董事会 | 精神病状态的控制和表征 |
WO2012061681A1 (en) | 2010-11-05 | 2012-05-10 | The Board Of Trustees Of The Leland Stanford Junior University. | Control and characterization of memory function |
US8932562B2 (en) | 2010-11-05 | 2015-01-13 | The Board Of Trustees Of The Leland Stanford Junior University | Optically controlled CNS dysfunction |
WO2012061676A1 (en) | 2010-11-05 | 2012-05-10 | The Board Of Trustees Of The Leland Stanford Junior University | Light-activated chimeric opsins and methods of using the same |
CN105941328B (zh) | 2010-11-05 | 2019-04-09 | 斯坦福大学托管董事会 | 一种鉴定抑制前额叶皮质中的兴奋性或抑制性神经元的去极化的化合物的系统 |
US8957028B2 (en) | 2010-11-13 | 2015-02-17 | Massachusetts Institute Of Technology | Red-shifted opsin molecules and uses thereof |
US8696722B2 (en) | 2010-11-22 | 2014-04-15 | The Board Of Trustees Of The Leland Stanford Junior University | Optogenetic magnetic resonance imaging |
US9939449B2 (en) | 2011-02-01 | 2018-04-10 | The University Of Vermont And State Agricultural College | Diagnostic and therapeutic methods and products related to anxiety disorders |
US20120253261A1 (en) | 2011-03-29 | 2012-10-04 | Medtronic, Inc. | Systems and methods for optogenetic modulation of cells within a patient |
WO2013003557A1 (en) | 2011-06-28 | 2013-01-03 | University Of Rochester | Photoactivatable receptors and their uses |
EP2736402B1 (en) | 2011-07-25 | 2018-01-10 | NeuroNexus Technologies, Inc. | Opto-electrical device and method for artifact reduction |
JP2014521956A (ja) | 2011-07-27 | 2014-08-28 | ザ ボード オブ トラスティーズ オブ ザ ユニヴァーシティー オブ イリノイ | 生体分子を特徴付けるためのナノ細孔センサー |
WO2013090356A2 (en) | 2011-12-16 | 2013-06-20 | The Board Of Trustees Of The Leland Stanford Junior University | Opsin polypeptides and methods of use thereof |
ES2728077T3 (es) | 2012-02-21 | 2019-10-22 | Univ Leland Stanford Junior | Composiciones para el tratamiento de trastornos neurogénicos del suelo pélvico |
CN104471462B (zh) | 2012-02-23 | 2017-09-19 | 美国卫生与公共服务秘书部 | 多焦结构化照明显微系统和方法 |
CA2867567A1 (en) | 2012-03-20 | 2013-09-26 | The Board Of Trustees Of The Leland Stanford Junior Unversity | Non-human animal models of depression and methods of use thereof |
JP6580487B2 (ja) | 2012-11-21 | 2019-09-25 | サーキット セラピューティクス, インコーポレイテッド | 光遺伝学的治療のためのシステムおよび方法 |
JP2016507078A (ja) | 2013-01-25 | 2016-03-07 | ザ トラスティーズ オブ コロンビア ユニバーシティ イン ザ シティオブ ニューヨーク | 被写界深度3dイメージングslm顕微鏡 |
US20150112411A1 (en) | 2013-10-18 | 2015-04-23 | Varaya Photoceuticals, Llc | High powered light emitting diode photobiology compositions, methods and systems |
EP3174600A4 (en) | 2014-07-29 | 2018-03-14 | Circuit Therapeutics, Inc. | System and method for optogenetic therapy |
-
2011
- 2011-11-04 WO PCT/US2011/059283 patent/WO2012061681A1/en active Application Filing
- 2011-11-04 ES ES11838856.0T patent/ES2661093T3/es active Active
- 2011-11-04 JP JP2013537853A patent/JP6328424B6/ja not_active Expired - Fee Related
- 2011-11-04 CN CN201180061696.3A patent/CN103298480B/zh not_active Expired - Fee Related
- 2011-11-04 CA CA2816972A patent/CA2816972C/en not_active Expired - Fee Related
- 2011-11-04 CN CN201610831188.3A patent/CN106376525A/zh active Pending
- 2011-11-04 AU AU2011323228A patent/AU2011323228B2/en not_active Ceased
- 2011-11-04 US US13/882,705 patent/US10086012B2/en active Active
- 2011-11-04 EP EP11838856.0A patent/EP2635295B1/en not_active Not-in-force
-
2017
- 2017-02-09 AU AU2017200881A patent/AU2017200881B2/en not_active Ceased
-
2018
- 2018-08-24 US US16/112,202 patent/US20190046554A1/en not_active Abandoned
Also Published As
Publication number | Publication date |
---|---|
ES2661093T3 (es) | 2018-03-27 |
EP2635295A1 (en) | 2013-09-11 |
EP2635295A4 (en) | 2014-04-30 |
CN103298480A (zh) | 2013-09-11 |
AU2011323228B2 (en) | 2016-11-10 |
AU2017200881B2 (en) | 2019-03-07 |
JP6328424B2 (ja) | 2018-05-23 |
CA2816972C (en) | 2019-12-03 |
CA2816972A1 (en) | 2012-05-10 |
AU2011323228A1 (en) | 2013-05-09 |
CN106376525A (zh) | 2017-02-08 |
JP2014500717A (ja) | 2014-01-16 |
US20190046554A1 (en) | 2019-02-14 |
EP2635295B1 (en) | 2017-12-20 |
AU2017200881A1 (en) | 2017-03-02 |
WO2012061681A1 (en) | 2012-05-10 |
US20130343998A1 (en) | 2013-12-26 |
US10086012B2 (en) | 2018-10-02 |
CN103298480B (zh) | 2016-10-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6328424B6 (ja) | 記憶機能の制御および特性化 | |
JP6445602B2 (ja) | 報酬関連行動の光遺伝学的制御 | |
US20200121942A1 (en) | Compositions and methods for controlling pain | |
JP6594854B2 (ja) | 行動状態の光遺伝学的制御方法 | |
JP6002140B2 (ja) | 安定化階段関数オプシンタンパク質及びその使用方法 | |
AU2018208657A1 (en) | Control and characterization of psychotic states |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20141031 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20141031 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20141107 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20151204 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20160301 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20160401 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20160502 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20161021 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20170117 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20170315 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170421 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170901 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20171130 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180131 |
|
A521 | Written amendment |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180228 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20180323 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20180418 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6328424 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |