CN104846014A - Specificity excitory astrocyte composition and application of composition thereof for improving schizophrenia abnormal behavior - Google Patents
Specificity excitory astrocyte composition and application of composition thereof for improving schizophrenia abnormal behavior Download PDFInfo
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- CN104846014A CN104846014A CN201510092222.5A CN201510092222A CN104846014A CN 104846014 A CN104846014 A CN 104846014A CN 201510092222 A CN201510092222 A CN 201510092222A CN 104846014 A CN104846014 A CN 104846014A
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Abstract
The invention provides a specificity excitory astrocyte composition and an application of the composition thereof for improving schizophrenia abnormal behavior. The composition comprises viral vector carrying with light-sensing gene used for infecting cerebral basolateral amygdala astrocyte; the vector comprises promoters, light-sensing genes and green fluorescence-labeled gene, wherein, the promoters are GFAP promoters; and an illumination apparatus capable of generating blue light is provided for regulation and control of illumination for the infected astrocyte so as to make the astrocyte to be excited. The composition can accurately and specifically excite the cerebral basolateral amygdala astrocyte, and can effectively improve the schizophrenia abnormal behavior.
Description
Technical field
The invention relates to the composition of the excited star spongiocyte of a species specificity and improving the application in the behavior of schizophrenia difference.
Background technology
Numerous psychosis such as schizophrenia is the principal disease threatening human health, puzzlement human normal life always, according to the sick epidemiology survey display of China's 12 Local spirits, about there is major mood Disease 1,600 ten thousand in the current whole nation, if the moderate of adding and patients with mild, sum can up to 6,700 ten thousand.Mental disorder ranks the first in China's disease is always born, and has accounted for 20%, and has expected the year two thousand twenty, and this numeral also rises to 25% by continuing.Therefore, for many years, the numerous neuroscientist in the whole world is attempting many new therapy target and method always, but still thoroughly cures it and is stymied by.Therefore to the cause of disease of such disease and new therapy target research and related drugs exploitation extremely urgent.
Star spongiocyte (astrocytes) is the major cell types of central nervous system.Increasing research confirms, star spongiocyte is different to the regulating and controlling effect of neural network under tranquillization and active state.Up-to-date research confirms that star spongiocyte participates in cognitive activities and the related emotional activity of regulation and control brain gradually.
Traditional sense controls the support that psychotic morbidity mainly relies on pharmacological agent and family social.The deep brain core group of rising in recent years stimulates (Deep Brain Stimulation, DBS) namely electricity irritation is carried out for some brain districts of brain, also certain curative effect is obtained clinically at present, but DBS treatment up to now or improve the cell mechanism of schizophrenia abnormal behaviour and indefinite.No matter be traditional pharmacological agent or DBS therapeutic intervention, all for want of cell-specific, target intervention truly cannot be realized, just " taking stopgap measures ".At present, treatment of schizophrenia effect is not remarkable, poor prognosis, cannot improve the behavior of schizophrenia difference targetedly.
Summary of the invention
Main purpose of the present invention is the technology providing a kind of specific regulatory control target cell and then effectively improve schizophrenia abnormal behaviour.
The present invention utilizes light genetic regulation technology, regulate and control the star spongiocyte that schizophrenia animal basolateral amygdaloid nuclei carries photosensitive channel protein specifically, monitor ethological change simultaneously, find that star spongiocyte is by after excitement specifically, significantly can improve the abnormal behaviour that its congenital fear weakens, thus think that the star spongiocyte of basolateral amygdaloid nuclei is likely the novel targets of intervening the behavior of schizophrenia difference.
Thus on the one hand, the invention provides the composition of the excited star spongiocyte of a species specificity, said composition comprises:
For infecting the virus vector carrying light sensation gene of brain basolateral amygdaloid nuclei star spongiocyte, this carrier comprises promotor, light sensation gene, green fluorescent label gene, and wherein, described promotor is GFAP promotor;
The illumination apparatus of blue light can be produced, for carrying out illumination regulation and control to metainfective star spongiocyte to make it excited.
In the present invention, the lentiviral vectors carrying photosensitizing effect is injected into brain basolateral amygdaloid nuclei district, it will infect star spongiocyte, corresponding photosensitive acceptor is expressed in star spongiocyte, by illumination system, light stimulus is carried out to the star spongiocyte that have expressed photosensitive acceptor, thus make it excited, after the excitement of star spongiocyte light, the neural factor of its release as regulation and control medium, will play the function improving the behavior of schizophrenia difference.The present invention is tested by spacious field and elevated plus-maze test experiment proves that significantly can improve the behavior of schizophrenia difference, such as congenital fear weakens and/or anxiety by after composition stimulation star spongiocyte of the present invention excitement.
According to specific embodiment of the invention scheme, the composition of the excited star spongiocyte of the specificity described in the present invention also can be called one " cover group " or " external member ", which includes the assemblies such as each reagent, material and the plant and instrument that in the present invention, specificity excitement star spongiocyte adopts, as the form of a kind of product such as test kit, each assembly can be placed or complete sale and use after independent packaging in large packaging respectively according to preposition.
According to specific embodiment of the invention scheme, the composition of the excited star spongiocyte of the specificity described in the present invention also comprises: the reagent material carrying the viral vector infection brain basolateral amygdaloid nuclei star spongiocyte of light sensation gene described in making.Concrete example is as comprised: stereotaxic instrument and relevant sampling system, accurately the virus vector carrying photosensitizing effect can be injected into brain basolateral amygdaloid nuclei district, thus make it infect the star spongiocyte of brain basolateral amygdaloid nuclei.
In a specific embodiments of the present invention, construct the virus vector carrying light sensation gene for infecting brain basolateral amygdaloid nuclei star spongiocyte; Promotor in this carrier is GFAP promotor; Light sensation gene is ChR2; Green fluorescent label gene is eYFP; Described virus is slow virus; Concrete building process can carry out with reference to the prior art in affiliated field.
According to the specific embodiment of the present invention, the wherein said virus vector carrying photosensitizing effect is containing the lentiviral vectors with GFAP plasmid.The star spongiocyte of brain basolateral amygdaloid nuclei infects containing after the lentiviral vectors with GFAP plasmid, photosensitizing effect transcriptional start is carried in promotor GFAP startup, GFAP promotor only can start in star spongiocyte carries photosensitizing effect transcriptional start, corresponding photosensitive acceptor is expressed in star spongiocyte, after being subject to light stimulus thus specificity only makes star spongiocyte excited, play the effect improving the behavior of schizophrenia difference.According to the specific embodiment of the present invention, in the composition of the improvement schizophrenia difference behavior described in the present invention, wherein, the described lentiviral vectors carrying photosensitizing effect is that its structure as shown in Figure 1A containing the lentiviral vectors with GFAP-ChR2-eYFP plasmid.In a specific embodiment of the present invention, described GFAP-ChR2-eYFP can adopt and build with the following method, by containing photosensitizing effect, green fluorescent label gene and be used for specificity mark spongiocyte promotor GFAP plasmid and pack relevant mixing plasmid pCMV Δ R8.74, pMD2.G. together to slow virus, transfection is to 293FT cell together to utilize liposome, and after cultivating, rupture of membranes obtains containing the lentiviral vectors with GFAP-ChR2-eYFP plasmid.
According to the specific embodiment of the present invention, in the composition of the excited star spongiocyte of specificity of the present invention, wherein, described blue light is the blue light of wavelength 460 ~ 480nm, is preferably the blue light of wavelength 470nm.
On the other hand, the composition that the invention provides the excited star spongiocyte of specificity is for the preparation of the application improved in schizophrenia difference system of behavior.The composition of the excited star spongiocyte of such as specificity is composition of the present invention, and the described inventive composition that bases on practicality is weakening and/or application in anxiety system for the preparation of improving congenital fear that schizophrenia causes.
According to the specific embodiment of the present invention, in application of the present invention, wherein, described improvement schizophrenia difference system of behavior utilizes the viral vector infection brain basolateral amygdaloid nuclei star spongiocyte carrying light sensation gene in described composition, and by illumination apparatus, blue light light stimulation is carried out to metainfective star spongiocyte, to improve the behavior of schizophrenia difference.
According to the specific embodiment of the present invention, in application of the present invention, wherein, described blue light illumination condition is: blue light wavelength 470nm ~ 480nm, light intensity 1.1 ~ 2mW, and illumination frequency 10 ~ 20Hz, dutycycle are the light of 1:1, continues more than 5min.
According to the specific embodiment of the present invention, in application of the present invention, wherein, described system also comprises the optical fiber for blue light being conducted to metainfective brain basolateral amygdaloid nuclei star spongiocyte, in a specific embodiment of the present invention, the light adopting the optical fiber of 200 μm to be produced by illumination apparatus introduces brain basolateral amygdaloid nuclei, carries out light regulation and control to metainfective star spongiocyte.
On the other hand, the present invention also provides one to improve schizophrenia difference system of behavior, and this system comprises composition of the present invention.Such as, described schizophrenia difference behavior is that congenital fear weakens and/or anxiety.
Advantageous Effects of the present invention: technology of the present invention can the star spongiocyte of the accurately excited brain basolateral amygdaloid nuclei of specificity, effectively can improve the behavior of schizophrenia difference, more traditional DBS or pharmacological agent, really achieve specificity, significant.
Accompanying drawing explanation
Fig. 1 is that in the embodiment of the present invention 1, GFAP-ChR2-eYFP plasmid schematic diagram and infection contain the brain sheet electro physiology experimental result picture with the mouse of the slow virus of this plasmid.
Fig. 2 is the schematic diagram of the spongiocyte successful expression GFAP-ChR2-eYFP of the embodiment of the present invention 1 small mouse brain basolateral amygdaloid nuclei.
Fig. 3 is the result figure tested with the spacious field of control mice after inducing DISC1 transgenic mice phenotype by tamoxifen.
Fig. 4 is the result figure that the elevated plus-maze test of light stimulus DISC1::Astro type mouse and wild-type mice is tested.
Embodiment
In order to there be understanding clearly to technical characteristic of the present invention, object and beneficial effect, now in conjunction with specific examples, following detailed description is carried out to technical scheme of the present invention, these examples should be understood and be only not used in for illustration of the present invention and limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually according to the normal condition in affiliated field or the condition of advising according to manufacturer.
In following examples, all commercially available acquisition of Starting reagents used and material, or can record conventionally prepare.
Embodiment 1
(1) preparation of the lentiviral vectors of GFAP-ChR2-eYFP plasmid, is carried.
For the preparation of the lentiviral vectors infecting star spongiocyte at living animal, it carries GFAP-ChR2-eYFP plasmid: will containing photosensitizing effect, plasmid (0.5 μ g) (this fusion plasmid structure is as shown in the A in Fig. 1) of green fluorescent label gene and the promotor GFAP for specificity mark spongiocyte, and pack relevant mixing plasmid pCMV Δ R8.74 to slow virus, pMD2.G. (1.5 μ g) together, utilize liposome (Invitrogen Products) together transfection to 293FT cell (ATCC Products, namely need a collection of cell strain more renewed after this passage to 25 generation) in (every 200, 000 cell 6 μ L liposome), concrete transfection procedure utilizes calcium phosphate mammalian transfection reagent box (Promega, E1200) carry out according to the description of its specification sheets.After 24 hours, the nutrient solution cultivating 293FT cell changes into after serum-free contains the DMEM of 5mM Sodium.alpha.-ketopropionate and continues to hatch.After 16 hours, utilize ultracentrifuge rupture of membranes under 50,000g speed, by suspension by the sucrose filter post of 20%, collect supernatant.This virus titer can reach 3 × 10
8more than TU/mL, the virion of output carries out resuspended with the phosphate buffered saline buffer of sterilizing with the volume ratio of 1:1000.The viral re-suspension liquid obtained is mixed in serum-free DMEM by the volume ratio of 1:400, for infecting target cell star spongiocyte.
(2), the lentiviral vectors carrying GFAP-ChR2-eYFP plasmid being injected control region makes it infect star spongiocyte.
Adopt the stereotaxic technique of neuroscience field routine and micro-sampling system that the above-mentioned slow virus of carrying photosensitizing effect prepared is injected into the basolateral amygdaloid nuclei of mouse, injection rate is generally 0.4 μ L, after injection, wait for 3 weeks, get 1 ~ 3 Mice brain tissues, brain sheet Potential Examination is carried out to it, its result is as shown in B ~ G in Fig. 1, confirm that (blue light of 470nm stimulates in light stimulus, light intensity 1.1mW, illumination frequency 10Hz, dutycycle is 1:1, continue 5min) under, corresponding photoelectric current is had to produce, prove the functional expression success on spongiocyte of photaesthesia channel protein, light stimulus specificity improves star spongiocyte excitability, and immunohistofluorescence stain qualification is carried out to Mice brain tissues, qualification result shows green fluorescence, show that GFAP-ChR2-eYFP expresses successfully (Fig. 2) in position, the schizoid mice behavior of trouble can carried out under light regulation and control detects, and wherein suffering from schizoid mouse is the transgenic mice (DISC1+tamo) adopting tamoxifen (tamoxifen) to induce DISC1 mutain to express.
(3) the schizoid mice behavior of trouble, under light regulation and control detects.
It is 200 μm of optical fiber that the brain basolateral amygdaloid nuclei of successfully suffering from schizoid mouse in above-mentioned GFAP-ChR2-eYFP expressed in situ vertically inserts commercially available diameter, the blue light carrying out 470nm stimulates, light intensity is 1.1mW, illumination frequency is 10Hz, dutycycle is 1:1, after continuing 5min, the experiment of spacious field is carried out to the schizoid mouse of trouble (DISC1+tamo), and with wild-type mice, give the DISC1 transgenic mice (DISC1+veh) of the solvent (vehicle) of amount identical with tamoxifen and wild-type mice (wild-type+veh) in contrast, its result as shown in Figure 3, elevated plus-maze test is carried out to the schizoid mouse of trouble, and with wild-type mice in contrast, its result as shown in Figure 4, in Fig. 4, namely DISC1::Astro represents the spongiocyte transfection of suffering from schizoid amygdala ChR2 and have expressed the DISC1 transgenic mice of photaesthesia channel protein, in figure, ON represents and opens light stimulus, the mode of shown light stimulus is described above, and OFF represents closedown light stimulus.
Wherein, described spacious field experiment (Open field test) is also known as Open field test.Carry out in the synthetic glass box of a 50 × 50cm, bottom this box, be divided into region intermediate (25 × 25cm) and outer region artificially.It is a kind of method of evaluation experimental animal independent behaviour, exploratory behavior and tensity in strange environment.With the occurrence frequency of laboratory animal some behavior among novel environment and time length etc., the independent behaviour of reaction experiment animal in foreign environment and exploratory behavior.Such as animal is mainly movable in neighboring area to the fear of new free environments, less in middle section activity, but the characteristic of probing into of animal impels again it to produce in the motivation of middle section activity, spacious field experiment video analytic system is the anxious psychology that produces therefrom of observable also.
Described Elevated plus-maze (High plus maze) utilizes animal probing into characteristic and forming contradiction behavior to investigate the anxiety state of animal to the fear of uphanging unlimited arm strange environment.Elevated plus-maze has a pair open arms and closes arm a pair, rodent is owing to can tend to addicted to dark property closing activity in arm, but out of curiosity again can be movable in open arms with inquiry, when in the face of novel stimulus, animal produces the impulsion and fear probed into simultaneously, this just causes the conflict behavior of probing into avoiding, thus produces anxious psychology.And anxiolytic medicament obviously can increase the number of times and time that enter open arms, plus maze distance ground is higher, is equivalent to people and stands on cliff, makes experimental subjects produce frightened and uneasiness psychology.The liftoff high 60cm in labyrinth of the present embodiment, open arms is 25 × 5cm (long × wide), closure arm 25 × 5 × 14.3cm (long × wide × high).
As can be seen from Figure 3, the experiment of spacious field shows DISC1 its congenital frightened behavior generation mutation after drug-induced phenotype, and show as and reduce the avlidance behavior of middle depletion region, the time stayed in wherein increases.
Elevated plus-maze test shows as can be seen from Figure 4, before regulation and control under OFF state, suffer from schizophrenia DISC1 mouse (DISC1::Astro) to the congenital fear of open arms lower than wild-type mice, so be greater than wild-type in the time of open arms.But, under ON state, light genetic technique specific regulatory control is suffered from schizophrenia DISC1 mouse (DISC1::Astro) and is contrasted wild type control group, its time entering open arms does not just have significant difference, prompt, adjusting and control onset, the star spongiocyte of light specificity intervention basolateral amygdaloid nuclei effectively can improve the congenital fear reduction abnormal behaviour of schizophrenia animal.
Claims (10)
1. the composition of the excited star spongiocyte of a species specificity, said composition comprises:
For infecting the virus vector carrying light sensation gene of brain basolateral amygdaloid nuclei star spongiocyte, this carrier comprises promotor, light sensation gene, green fluorescent label gene, and wherein, described promotor is GFAP promotor;
The illumination apparatus of blue light can be produced, for carrying out illumination regulation and control to metainfective star spongiocyte to make it excited.
2. the composition of the excited star spongiocyte of specificity according to claim 1, said composition also comprises:
The reagent material of the viral vector infection brain basolateral amygdaloid nuclei star spongiocyte of light sensation gene is carried described in making.
3. the composition of the excited star spongiocyte of specificity according to claim 1, wherein, described blue light is the blue light of wavelength 460 ~ 480nm, is preferably the blue light of wavelength 470nm.
4. the composition of the excited star spongiocyte of specificity is for the preparation of the application improved in the system of schizophrenia difference behavior, and wherein, the composition of the excited star spongiocyte of described specificity is preferably the composition described in any one of claims 1 to 3.
5. application according to claim 4, wherein, the system of described improvement schizophrenia difference behavior utilizes the viral vector infection brain basolateral amygdaloid nuclei star spongiocyte carrying light sensation gene in described composition, and by illumination apparatus, blue light light stimulation is carried out to metainfective star spongiocyte, to improve the behavior of schizophrenia difference.
6. application according to claim 4, wherein, described schizophrenia difference behavior is that congenital fear weakens and/or anxiety.
7. application according to claim 5, wherein, described blue light illumination condition is: blue light wavelength 470 ~ 480nm, light intensity 1.1 ~ 2mW, and illumination frequency 10 ~ 20Hz, dutycycle are the light of 1:1, continues more than 5min.
8. application according to claim 7, wherein, the described system improving the behavior of schizophrenia difference also comprises the optical fiber for blue light being conducted to metainfective brain basolateral amygdaloid nuclei star spongiocyte.
9. improve a system for schizophrenia difference behavior, this system comprises the composition described in any one of claims 1 to 3.
10. the system improving the behavior of schizophrenia difference according to claim 9, wherein, described schizophrenia difference behavior is that congenital fear weakens and/or anxiety.
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| WO2021098613A1 (en) * | 2019-11-22 | 2021-05-27 | 中国科学院深圳先进技术研究院 | Novel microglial cell activation method |
| CN113456646A (en) * | 2021-07-05 | 2021-10-01 | 中国科学院深圳先进技术研究院 | Pharmaceutical composition for specifically regulating and controlling activity of hypothalamus ventral-medial-nucleus astrocytes and application of pharmaceutical composition |
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| WO2021098613A1 (en) * | 2019-11-22 | 2021-05-27 | 中国科学院深圳先进技术研究院 | Novel microglial cell activation method |
| CN113456646A (en) * | 2021-07-05 | 2021-10-01 | 中国科学院深圳先进技术研究院 | Pharmaceutical composition for specifically regulating and controlling activity of hypothalamus ventral-medial-nucleus astrocytes and application of pharmaceutical composition |
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