CN104846015B - The composition of GABA serotonergic neurons in special heat nucleus accumbens septi and its application in schizophrenia difference behavior is improved - Google Patents
The composition of GABA serotonergic neurons in special heat nucleus accumbens septi and its application in schizophrenia difference behavior is improved Download PDFInfo
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- CN104846015B CN104846015B CN201510279845.3A CN201510279845A CN104846015B CN 104846015 B CN104846015 B CN 104846015B CN 201510279845 A CN201510279845 A CN 201510279845A CN 104846015 B CN104846015 B CN 104846015B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
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- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
- C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
- C12N15/86—Viral vectors
- C12N15/867—Retroviral vectors
Abstract
Application the invention provides the composition of the GABA serotonergic neurons in a species specificity excitement nucleus accumbens septi and its in schizophrenia difference behavior is improved, the composition include：For the viral vector for the carrying light sensation gene for infecting the GABA serotonergic neurons in nucleus accumbens septi；The carrier includes promoter, light sensation gene, green fluorescent label gene, wherein, the promoter is Syn promoters；The illumination apparatus of blue light can be produced, for carrying out illumination regulation and control so that it is excited to metainfective nucleus accumbens septi.The present composition can accurately in special heat nucleus accumbens septi GABA serotonergic neurons, schizophrenia difference behavior can be effectively improved.
Description
Technical field
The present invention is on the composition of the GABA serotonergic neurons in a species specificity excitement nucleus accumbens septi and its smart improving
Application in refreshing Split disease difference behavior.
Background technology
12 Local spirit ailments epidemiological investigation displays of China, the current whole nation, which there are about 100,000,000 people, mental disease, sternly
The people of weight psychiatric patient about 16,000,000,250,000 people are there are about every year and die from suicide.3.4 hundred million youngsters of China less than 17 years old
In virgin, teenager, it there are about three million peoples and perplexed by emotional handicap and psychological behavior problems.Current neural mental illness is at me
State's disease ranks the first in always bearing, and accounts for disabled and disability 1/5th caused by whole diseases and wound.According to expert
Prediction, 21 century will be mental disease popular century, as economic construction of China and the paces of social development are accelerated, life section
Playing and competing increasingly strengthens, and mental illness may proceed to increase, it is contemplated that to the year two thousand twenty, mental illness will in China's disease always burden
Account for 25%.The First Year of new century is set to mental hygiene year by the World Health Organization, whether so we are ready, we
Just unfeelingly enter " mental illness epoch ".
Schizophrenia (schizophrenia) is one of psychotic disorder of mankind's most serious, with basic personality change,
The uncoordinated of thinking, consciousness, emotion, the division of behavior, cerebration and environment is principal character.Epidemiology survey data shows
Show, patient of the whole world with schizophrenia and neural two-stage entanglement accounts for the 2% of total population at present.Schizophrenia has
Disability rate height, high recurrence rate, the features such as prognosis is bad, burden on society is heavy, China human mortality health and economic hair are had a strong impact on
Exhibition.
Main flow thinks that the symptom that schizophreniac occurs has certain with the hyperfunction of Dopamine inside brain at present
Contact.Clinically D2 types dopamine receptor (Dopamine Receptor D2, DRD2) antagonist as treatment chlorpromazine
Thing shows obvious therapeutic effect.On the contrary, this kind of increase dopamine D_2 receptors of Reusability amphetamine in healthy individuals
Neuroactive substance can induce mental disease, can also aggravate the psychotic symptoms of schizophreniac.Equally, to pa
The gloomy patient of gold uses the precursor L-dopa of dopamine, and it is (typically unreal psychotic symptoms can be induced in many patients
Feel and vainly hope).
More than 30 years has been continue for now for schizophrenia dopaminergic agent, the foundation of the pros and cons has, but
All without breakthrough progress.Moreover, schizophreniac also lacks direct evidence extremely with the presence or absence of dopamine level：
With healthy individuals ratio, whether the neuron of schizophreniac to cynapse discharges more dopamines under stimulation, so far
Do not come to a conclusion；Also there are some researches show schizophreniac there may be to be adjusted to dopamine transport and the abnormal of function.Cause
This, controls the morbidity of mental disease to rely primarily on the support of drug therapy and family social at present, can not be in abnormal neuron loop
Dopamine system carries out specific regulation and control and can not realize the purpose really treated, and simply " takes stopgap measures ".
γ-aminobutyric acid (GABA) energy network is in diseases such as schizophrenia, depression, self-closing disease and anxiety disorders in recent years
In effect just progressively recognized by people.Newest international research evidence shows that the abnormal of GABA neurons divides in spirit
Split and very important effect is played in disease.Nucleus accumbens septi is located at basal nuclei and limbic system intersection, the outer lower side of septal area, tail shell
The interior lower section of core, front are connected with anterior olfactory nucleus, follow-up bed nucleus of stria terminalis, and veutro is ventral pallidum and olfactory tubercle, is basal forebrain
A larger core group.The elementary cell type of core group is medium spiny neurons.Nerve caused by this kind of neuron is passed
Matter is γ-aminobutyric acid (GABA).But whether nucleus accumbens septi can not carried out also as the target spot of regulation and control schizophrenia abnormal behaviour
Research, prior art also not yet provide a species specificity and intervene nucleus accumbens septi and then improve the method for schizophrenia abnormal behaviour.
The content of the invention
It is a primary object of the present invention to provide a kind of specific regulatory control target and then be effectively improved schizophrenia exception
The technology of behavior.
The present invention utilizes light genetic regulation technology, specifically regulates and controls schizophrenia animal nucleus accumbens septi and carries photosensitive passage
The cell of albumen, while monitor ethological change, it is found that after nucleus accumbens septi brain area is specifically excited, it is congenital that its can be significantly improved
Fear reduction and/or the abnormal behaviour of anxiety, it is thus regarded that nucleus accumbens septi is likely to intervene the new of schizophrenia difference behavior
Target spot.
So as to, on the one hand, the present invention provides the composition of the GABA serotonergic neurons in a species specificity excitement nucleus accumbens septi, should
Composition includes：
For the viral vector for the carrying light sensation gene for infecting the GABA serotonergic neurons in nucleus accumbens septi；The carrier includes opening
Mover, light sensation gene, green fluorescent label gene, wherein, the promoter is Syn promoters；
The illumination apparatus of blue light can be produced, for carrying out illumination regulation and control so that it is excited to metainfective nucleus accumbens septi.
The slow virus carrier for carrying photosensitizing effect is injected into nucleus accumbens septi area in the present invention, it will be infected in nucleus accumbens septi area
GABA serotonergic neurons, corresponding photosensitive acceptor is expressed in GABA serotonergic neurons, by illumination system to express it is photosensitive by
The GABA serotonergic neurons of body carry out light stimulus, make it excited, and after GABA serotonergic neuron light excitements, playing improves schizophrenia
The function of peculiar behavior.After the present invention proves that the composition for passing through the present invention stimulates nucleus accumbens septi excitement by elevated plus-maze test experiment,
Schizophrenia difference behavior, such as congenital reduction fear and/or anxiety can significantly be improved, spirit point can be effectively improved
False judgment of the disease animal model to hazards is split, it is improved and avoids the ability of related adverse environment.Therefore, the present invention provides
Lack the characteristic abnormal behaviour of awareness of safety for schizophreniac, improving it, to avoid dangerous cognitive ability new
Therapy target；Simultaneously new strategy is provided to develop newtype drug.
According to specific embodiments of the present invention, the GABA in heretofore described special heat nucleus accumbens septi can nerve
The composition of member is referred to as a kind of " set group " or " external member ", and which includes in special heat nucleus accumbens septi in the present invention
The component such as each reagent, material and instrument and equipment used by GABA serotonergic neurons, as a kind of form of product such as kit,
Each component can be placed respectively in big packaging according to predetermined position or independent packaging after complete sale and use.
According to specific embodiments of the present invention, the GABA in heretofore described special heat nucleus accumbens septi can nerve
The composition of member also includes：Make the reagent of the GABA serotonergic neurons in the viral vector infection nucleus accumbens septi of the carrying light sensation gene
Material.Specifically for example it may include：Stereotaxic instrument and related sampling system, accurately the virus for carrying photosensitizing effect can be carried
Body is injected into nucleus accumbens septi area, so that it infects the GABA serotonergic neuron cells in nucleus accumbens septi area.
In the specific embodiment of the present invention, construct for infect in nucleus accumbens septi GABA serotonergic neurons cell or its
The viral vector of the carrying light sensation gene of precursor；Promoter in the carrier is Syn promoters；Light sensation gene is ChR2；
Green fluorescent label gene is eYFP；The virus is slow virus；Specific building process is referred to showing in art
There is technology progress.
According to the embodiment of the present invention, wherein the viral vector of described carrying photosensitizing effect is containing with Syn
The slow virus carrier of plasmid.After GABA serotonergic neurons cell infection contains the slow virus carrier with Syn plasmids in nucleus accumbens septi, start
Sub- Syn, which starts, to be carried photosensitizing effect and starts to transcribe, in nucleus accumbens septi area GABA serotonergic neurons cell inner expression it is corresponding it is photosensitive by
Body, so that nucleus accumbens septi brain area is excited after by light stimulus, play a part of improving schizophrenia difference behavior.According to this
The embodiment of invention, the composition of heretofore described improvement schizophrenia difference behavior, wherein, described takes
Slow virus carrier with photosensitizing effect is that its structure is as shown in Figure 1A containing the slow virus carrier with Syn-ChR2-eYFP plasmids.
In the specific embodiment of the present invention, described Syn-ChR2-eYFP can be built with the following method, will contain photosensitive base
Because of, green fluorescent label gene and for specificity labeled neurons promoter Synapsin (Syn) plasmid and with slow disease
Poison packaging related mixing plasmid pCMV Δs R8.74, pMD2.G. together, are transfected to 293FT cells, training together using liposome
Rupture of membranes is obtained containing the slow virus carrier with Syn-ChR2-eYFP plasmids after supporting.
According to the embodiment of the present invention, GABA serotonergic neurons are thin in special heat nucleus accumbens septi of the present invention
In the composition of born of the same parents, wherein, the blue light is the blue light of 460~480nm of wavelength blue light, preferably wavelength 470nm.
On the other hand, the composition of the GABA serotonergic neurons in the special heat nucleus accumbens septi of present invention offer is used in preparation
Improve the application in schizophrenia difference system of behavior.Such as the combination of the GABA serotonergic neurons in special heat nucleus accumbens septi
Thing is composition of the present invention, and the composition of the described invention that bases on practicality causes in preparation for improving schizophrenia
Congenital frightened reduction and/or anxiety system in application.
According to the present invention embodiment, in application of the present invention, wherein, described improvement schizophrenia
Disease difference system of behavior is utilized in the viral vector infection brain nucleus accumbens septi area that light sensation gene is carried in the composition
GABA serotonergic neurons, and blue light light stimulation is carried out to metainfective nucleus accumbens septi by illumination apparatus, to improve schizophrenia
Peculiar behavior.
According to the present invention embodiment, in application of the present invention, wherein, the system also include be used for
Blue light is conducted to the optical fiber of metainfective nucleus accumbens septi.In the specific embodiment of the present invention, using 200 μm of optical fiber by light
Brain nucleus accumbens septi is introduced according to light caused by device, for carrying out light regulation and control to metainfective nucleus accumbens septi.
According to the present invention embodiment, in application of the present invention, wherein, the blue light illumination condition
For：470~480nm of blue light wavelength, 12~20mW of outlet power of optical fiber or so, 40~80Hz of illumination frequency light；1：1 accounts for
Empty ratio, continue more than 5min.
On the other hand, the present invention also provides a kind of improvement schizophrenia difference system of behavior, and the system includes the present invention
Described composition.For example, described schizophrenia difference behavior is congenital frightened reduction and/or anxiety.
The advantageous effects of the present invention：The technology of the present invention can accurately in special heat nucleus accumbens septi GABA energy
Neuron, schizophrenia difference behavior can be effectively improved, more traditional Dopamine D2 receptor drug therapy, is truly realized
Specificity, it is significant.
Brief description of the drawings
Figure 1A is Syn-ChR2-eYFP plasmid schematic diagrames；
Figure 1B~1C is the schematic diagram of GABA serotonergic neuron cell successful expressions Syn-ChR2-eYFP in mouse nucleus accumbens septi,
Acbc is nucleus accumbens septi in figure, and Acbsh is nucleus accumbens septi housing；
Fig. 2 is the schematic diagram for carrying out illumination to mouse nucleus accumbens septi area by illumination, and Acbc is nucleus accumbens septi in figure, and Acbsh is
Nucleus accumbens septi housing；
Fig. 3 is to improve the excitatoty experimental result picture of nucleus accumbens septi brain area under illumination condition in embodiment 1；
Fig. 4 is wild type, DISC1 in embodiment 1::ChR2 and DISC1::The Elevated plus-maze of eYFP type mouse is real
Test result schematic diagram；
Fig. 5 is wild type, DISC1 in embodiment 1::ChR2 and DISC1::The Elevated plus-maze of eYFP type mouse is real
Test the statistical results chart of result.
Embodiment
In order to which technical characteristic, purpose and the beneficial effect of the present invention is more clearly understood, in conjunction with instantiation
Technical scheme is carried out described further below, it should be understood that these examples are merely to illustrate the present invention rather than limitation
The scope of the present invention.The experimental method of unreceipted actual conditions in the following example, generally according to the normal condition of art
Or according to the condition proposed by manufacturer.
In following examples, Starting reagents and material used are commercially available, or can be according to the record system of prior art
It is standby to obtain.
Embodiment 1
(1) preparation of the slow virus carrier of Syn-ChR2-eYFP plasmids, is carried.
Prepare for the slow virus carrier in living animal infection nucleus accumbens septi, it carries Syn-ChR2-eYFP plasmids：Will
Containing photosensitizing effect, green fluorescent label gene and for specificity mark nerve cell promoter Syn plasmid (0.5 μ g)
(the fusion plasmid structure is as shown in Figure 1A), and mixing plasmid pCMV Δ R8.74, the pMD2.G. related to slow virus packaging
(1.5 μ g) together, is transfected to 293FT cells and (ATCC Products, is somebody's turn to do together using liposome (Invitrogen Products)
The a collection of cell line that more renews is needed after passage to 25 generations) in (6 μ L liposomes of every 200,000 cells).24 is small
Shi Hou, culture 293FT cells nutrient solution change the DMEM that serum-free contains 5mM Sodium Pyruvates into after continue to be incubated.After 16 hours,
Using ultracentrifuge under 50,000g speed rupture of membranes, by suspension by 20% sucrose filter column, collect supernatant.The virus is dripped
Degree can be up to 3 × 108More than TU/mL, the virion of output is with the phosphate buffer that sterilizes with 1：1000 volume ratio is carried out
It is resuspended.The viral re-suspension liquid of acquisition is pressed 1：400 volume ratio is mixed into serum-free DMEM, the target for infected animal model
Brain area：Nucleus accumbens septi.
(2) the slow virus carrier injection control region for carrying Syn-ChR2-eYFP plasmids, is made into its infection cell.
Using the conventional stereotaxic technique of neuroscience field and micro-sampling system by it is above-mentioned be prepared take
Slow virus with photosensitizing effect is injected into the nucleus accumbens septi of mouse, and injection rate is generally 0.4 μ L, after injection, waits 3 weeks, takes 1~3
Mice brain tissues, carry out immunohistofluorescence stain identification, and qualification result shows green fluorescence, shows Syn-ChR2-
EYFP is expressed successfully (reference can be made to Figure 1B and Fig. 1 C) in the original location, you can carries out the schizoid mouse behavior of trouble under light regulation and control
Detection is learned, wherein it is to induce the expression of DISC1 mutains using TAM (tamoxifen) to suffer from schizoid mouse
Transgenic mice.
(3) the schizoid mice behavior detection of trouble, under light regulation and control.
As shown in Fig. 2 it is inserted perpendicularly into city in the above-mentioned Syn-ChR2-eYFP nucleus accumbens septi brain areas in situ for expressing successful mouse
A diameter of 200 μm of optical fiber is sold, carrying out 470nm blue light stimulates, and light intensity 1.1mW, illumination frequency is 60Hz, is irradiated every 50ms
50ms, dutycycle 1:1, after continuing 5min, using the method for integrally stimulating and recording in body optical-electronic to nucleus accumbens septi brain area nerve
First discharge characteristic carries out extraction and analysis, after its result is as shown in figure 3, Fig. 3 results show light stimulus, improves brain nucleus accumbens septi brain
The excitability in area, then to mouse (numbering DISC1::ChR2 elevated plus-maze test) is carried out, while to wild-type mice
And DISC1 types and schizophrenia mouse (the numbering DISC1 for only transfecting eYFP genes::EYFP contrast experiment) is carried out, its
As a result as shown in figure 4, Fig. 5 is its statistical result.DISC1 in Fig. 4 and Fig. 5::ChR2 represents to suffer from schizoid nucleus accumbens septi
GABA serotonergic neuron cell transfectings ChR2 and express the DISC1 transgenic mices of photaesthesia channel protein, DISC1::
The GABA serotonergic neurons cell that eYFP represents to suffer from schizoid nucleus accumbens septi has only infected eYFP and has expressed the gene
DISC1 transgenic mices, ON represents to open light stimulus in figure, and the mode of shown light stimulus is as described above, OFF represents to close light
Stimulate.
Described Elevated plus-maze (High plus maze) is to probe into characteristic and right to strange environment using animal
Uphang the frightened of unlimited arm and form contradiction behavior to investigate the anxiety state of animal.Elevated plus-maze has a pair of open arms
With close arm for a pair, rodent due to thermophilic dark property can tend to it is movable in arm is closed, but out of curiosity with inquiry meeting again
Movable in open arms, when in face of novel stimulus, animal produces the impulsion probed into frightened simultaneously, and this has resulted in probing into returning
The conflict behavior kept away, so as to produce anxious psychology.And anxiolytic drugs can substantially increase number and the time into open arms, cross
Labyrinth is higher apart from ground, equivalent to people station on cliff, experimental subjects is produced frightened and uneasiness psychology.The fan of the present embodiment
Palace is liftoff high 60cm, open arms are 25 × 5cm (long × wide), 25 × 5 × 14.3cm of closure arm (length × width × height).
Elevated plus-maze test is can be seen that from Fig. 4 and Fig. 5 to show, under the OFF state before regulation and control, DISC1 spirit
Split disease type mouse (DISC1::ChR2 and DISC1::EYFP wild-type mice) is less than to the congenital fear of open arms, into opening
The probability for putting arm is more than wild type.But under ON states, the NAc brain areas of light genetic technique specific regulatory control DISC1 mouse
(DISC1：：ChR2) afterwards (injection containing photogene ChR2 in NAc brain areas, and use up directly stimulate the brain area), its contrast is wild
Type control group, it enters the probability of open arms and is just not significantly different, and prompt, adjusting and control works；In addition, gutless has been beaten in contrast
(DISC1：：EYFP DISC1 mouse), it considerably lowers the probability for entering open arms.
Claims (7)
1. the composition of the GABA serotonergic neurons in special heat nucleus accumbens septi is being prepared for improving schizophrenia difference row
For system in application；
The composition includes：
For the viral vector for the carrying light sensation gene for infecting the GABA serotonergic neurons in nucleus accumbens septi；The carrier includes starting
Son, light sensation gene, green fluorescent label gene, wherein, the promoter is Syn promoters；
The light sensation gene is ChR2, and the green fluorescent label gene is eGFP；
The illumination apparatus of blue light can be produced, for carrying out illumination regulation and control so that it is excited to metainfective nucleus accumbens septi.
2. application according to claim 1, wherein, said composition also includes：Make the virus load of the carrying light sensation gene
The reagent material of GABA serotonergic neurons in body-sensing dye nucleus accumbens septi.
3. application according to claim 1, wherein, the blue light is 460 ~ 480nm of wavelength blue light.
4. application according to claim 3, wherein, the blue light is wavelength 470nm blue light.
5. application according to claim 1, wherein, the system of described improvement schizophrenia difference behavior is to utilize institute
The GABA serotonergic neurons in the viral vector infection nucleus accumbens septi that light sensation gene is carried in composition are stated, and by illumination apparatus to sense
Nucleus accumbens septi after dye carries out blue light light stimulation, to improve schizophrenia difference behavior.
6. application according to claim 5, wherein, the system for improving schizophrenia difference behavior also includes being used for
Blue light is conducted to the optical fiber of metainfective nucleus accumbens septi.
7. application according to claim 6, wherein, the blue light illumination condition is：470 ~ 480nm of blue light wavelength, optical fiber
The mW of outlet power 12 ~ 20,40 ~ 80Hz of illumination frequency light；1：1 dutycycle, continue more than 5min.
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| PCT/CN2015/099667 WO2016188112A1 (en) | 2015-05-27 | 2015-12-30 | Composition for specifically exciting gabaergic neurons in nucleus accumbens and use thereof in improving abnormal schizophrenic behaviours |
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