WO2023151701A1 - Système d'évaluation de l'effet de traitement de maladies mentales et/ou de maladies neurodégénératives - Google Patents

Système d'évaluation de l'effet de traitement de maladies mentales et/ou de maladies neurodégénératives Download PDF

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WO2023151701A1
WO2023151701A1 PCT/CN2023/083089 CN2023083089W WO2023151701A1 WO 2023151701 A1 WO2023151701 A1 WO 2023151701A1 CN 2023083089 W CN2023083089 W CN 2023083089W WO 2023151701 A1 WO2023151701 A1 WO 2023151701A1
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auditory cortex
activation
primary auditory
treatment
neurons
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朱心红
朱旻桢
李环宇
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人工智能与数字经济广东省实验室(广州)
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    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B25/00—ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
    • G16B25/10—Gene or protein expression profiling; Expression-ratio estimation or normalisation
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
    • G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H10/00—ICT specially adapted for the handling or processing of patient-related medical or healthcare data
    • G16H10/40—ICT specially adapted for the handling or processing of patient-related medical or healthcare data for data related to laboratory analysis, e.g. patient specimen analysis
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H70/00—ICT specially adapted for the handling or processing of medical references
    • G16H70/40—ICT specially adapted for the handling or processing of medical references relating to drugs, e.g. their side effects or intended usage

Definitions

  • the invention relates to the technical field of psychiatric diseases, in particular to a system for evaluating therapeutic effects of psychiatric diseases and/or neurodegenerative diseases.
  • Depression Major depressive disorder
  • depression has become a public health problem due to its high incidence, high disability rate and serious suicidal tendency.
  • stress factors such as fast-paced life and high competitive pressure have led to an increase in the incidence of depression year by year.
  • depression ranks first in both developed and developing countries.
  • Depression has a high disability rate and will become the first cause of disability.
  • Anhedonia is the main symptom of depression, usually accompanied by difficulty concentrating, abnormal appetite, sleep disturbance, sense of worthlessness and even recurrent suicidal tendencies (the vast majority of suicides originate from depression and are minor deaths primary reason), which has brought endless misery to patients and their families, and seriously endangered human life and health.
  • Stress is the main cause of depression, and stress can seriously disrupt the balance of an individual's physiology and psychology.
  • Stress-related psychopathology such as major depressive disorder, anxiety, conduct disorder, and post-traumatic stress disorder, disrupts behavior, cognition, and social interaction, and exacerbates people's responses to stressful events.
  • traumatic stress does not affect everyone similarly. While susceptible individuals are less adaptive to stress and express inappropriate responses that can become a persistent stressful state, individuals with depressive insensitivity can perceive adversity as the smallest threat and develop adaptive physical and psychological responses .
  • depressive non-vulnerability most people maintain normal mental and physical functioning and avoid serious mental illness even in times of great stress and trauma.
  • Resilience in this context, refers to an individual's ability to avoid the negative social, psychological, and physical consequences of extreme stress that would otherwise compromise their mental or physical health. Recent reports suggest that resilience in humans represents an active, adaptive process rather than merely the absence of pathological responses in more susceptible individuals.
  • Neurons in the brain are the most basic structural and functional units of the nervous system. According to the type of neurotransmitter it releases, it is mainly divided into: glutamatergic excitatory neurons that release excitatory neurotransmitters such as glutamate and neurons that release inhibitory neurotransmitters 4-aminobutyric acid (GABA ) of GABAergic inhibitory interneurons (GABAergic interneurons).
  • GABA 4-aminobutyric acid
  • CaMKII calcium/calmodulin-dependent protein kinase II, calcium/calmodulin-dependent protein kinase II
  • CaMKII positive neurons are excitatory neurons.
  • GABAergic inhibitory interneurons can be further subdivided into microalbumin positive neurons (PV-positive neurons), somatostatin-expressing neurons (SST-positive neurons) according to the characteristic proteins expressed by them. neurons) and others.
  • PV-positive neurons microalbumin positive neurons
  • SST-positive neurons somatostatin-expressing neurons
  • PV-positive neurons and SST-positive neurons accounted for about 65% of inhibitory neurons.
  • the above neurons in the auditory cortex are involved in neurological diseases such as depression and anxiety. And it is generally believed that the important symptoms of diseases such as depression are significant and persistent depression, loss of interest, etc. Therefore, the commonly used drugs are tricyclic imipramine and norepinephrine that increase the excitability of neurons and increase the activity of excitatory neurons. stetin reuptake inhibitors, such as sitines.
  • the Cre/loxP recombinase system is a widely used in vivo gene targeting technology, which can achieve conditional, inducible and spatiotemporal specific gene targeting.
  • Inducible Cre recombinase cyclization recombinase estrogen receptor; Tamoxifen, Cre-ERT
  • ERT ligand-binding region mutant
  • ER estrogen receptor
  • the FLP/FRT recombinase system is similar to the Cre/loxP recombinase system, in which FLP is a recombinase (flippase, Flp), and its recognition site is FRT (short flippase recognition target, FRT).
  • the purpose of the present invention is to overcome the above-mentioned deficiencies in the prior art, and to provide the application of the activator of the PV-positive neuron cells of the primary auditory cortex in the preparation of antidepressant drugs.
  • the first object of the present invention is to provide a product for detecting the activation of PV-positive neuron cells in the primary auditory cortex in the preparation and diagnosis of mental diseases and/or neurodegenerative diseases, assessment of the risk of mental diseases and/or neurodegenerative diseases and and/or applications in products that assess the efficacy of treatments for psychiatric and/or neurodegenerative diseases.
  • a second object of the present invention is to provide a system for evaluating the effects of treatments for psychiatric and/or neurodegenerative diseases.
  • the third object of the present invention is to provide the application of the product for activating or enhancing the activation of PV-positive neuron cells in the primary auditory cortex in the preparation of antipsychotic and/or neurodegenerative disease products.
  • the fourth object of the present invention is to provide a product that activates or enhances the activation of neurons projecting to the medial geniculate nucleus of the primary auditory cortex in the preparation of products for antipsychotic and/or neurodegenerative diseases.
  • the fifth object of the present invention is to provide a product that activates or enhances the projection of the medial geniculate nucleus to the primary auditory cortex in the preparation of products for antipsychotic and/or neurodegenerative diseases.
  • a sixth object of the present invention is to provide a tangible computer-readable medium encoded with a program.
  • the seventh object of the present invention is to provide a method for antipsychotic and/or neurodegenerative diseases.
  • Products that detect the activation of PV-positive neurons in the primary auditory cortex are used in the preparation of diagnosis of psychiatric diseases and/or neurodegenerative diseases, assessment of the risk of psychiatric diseases and/or neurodegenerative diseases and/or evaluation of mental diseases and/or neurodegenerative diseases Application of products for the treatment of degenerative diseases.
  • the PV-positive neuron cells in the primary auditory cortex specifically activate only the PV-positive neuron cells in the primary auditory cortex that receive MG projections.
  • the psychiatric diseases and/or neurodegenerative diseases include but are not limited to depression, major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder, anorexia, anxiety disorder, dementia (including Alzheimer's disease) Alzheimer's disease), drug addiction, deficit and hyperactivity disorder Or one or more of autism, etc.
  • the mental disease and/or neurodegenerative disease is depression.
  • a system for evaluating the therapeutic effect of mental illness and/or neurodegenerative disease including an information collection module, a data processing module and a result output module;
  • the information collection module is used to obtain the activation of PV positive neuron cells in the primary auditory cortex of the patient before and after treatment, or to obtain the activation of PV positive neuron cells in the primary auditory cortex of the treatment group and the control group;
  • the data processing module is used to compare the activation degree of PV positive neuron cells in the primary auditory cortex before and after the treatment, or to compare the activation degree of PV positive neuron cells in the primary auditory cortex of the treatment group and the control group;
  • the activation degree of PV-positive neurons in the primary auditory cortex after treatment is higher than that of PV-positive neurons in the primary auditory cortex before treatment, and the treatment is effective; otherwise, the treatment is ineffective;
  • the activation degree of PV-positive neuron cells in the primary auditory cortex of the treatment group is higher than that of the primary auditory cortex in the control group, and the treatment is effective; otherwise, the treatment is ineffective.
  • the PV-positive neuron cells in the primary auditory cortex specifically activate only the PV-positive neuron cells in the primary auditory cortex that receive MG projections.
  • the activator specifically activates PV-positive neuronal cells of the primary auditory cortex.
  • MG medial geniculate nucleus
  • said activation or enhanced activation is a sustained, or intermittent but long-term activation of the product of medial geniculate nucleus (MG) neurons projecting to primary auditory cortex, or intermittent but long-term activation of MG neurons projecting to primary auditory cortex.
  • MG medial geniculate nucleus
  • the medial geniculate nucleus neurons projecting to the primary auditory cortex specifically activate only PV-positive neurons in the primary auditory cortex.
  • the psychiatric diseases and/or neurodegenerative diseases include but are not limited to depression, major depressive disorder, schizophrenia, bipolar disorder, post-traumatic stress disorder, anorexia, anxiety disorder, dementia (including Alzheimer's disease) Alzheimer's disease), drug addiction, deficit and hyperactivity disorder, or autism.
  • the mental disease and/or neurodegenerative disease is depression.
  • the projection of the medial geniculate nucleus to the primary auditory cortex is the projection of the medial geniculate nucleus to the PV-positive neurons of the primary auditory cortex.
  • the antipsychotic and/or neurodegenerative disease is treatment and/or prevention of mental disease and/or neurodegenerative disease.
  • the device is one or more of transcranial magnetic stimulators, brainwave recorders, vibrators, sound frequency generators, and current stimulators.
  • the treatment of suppressing the activity of medial geniculate nucleus neurons for less than 14 days is a course of treatment
  • the treatment comprises one or more courses of treatment.
  • the inhibition of the neuron activity of the medial geniculate nucleus for less than 14 days is: 8 times of light for 10 seconds per day for three days inhibits the activity of the neurons of the medial geniculate nucleus.
  • the device is an instrument that stimulates neurons through nuclear magnetic resonance, sound waves, vibration or electric current.
  • a method for evaluating the effect of antidepressant treatment Experimental animals are modeled with a social failure model. After successful modeling, they are randomly divided into two groups, the control group and the treatment group, and the experimental animals in the treatment group are treated with antidepressants. After treatment, the control group is compared.
  • the PV positive neuron cell activation degree of the primary auditory cortex of experimental animals in the treatment group and the treatment group, the PV positive neuron cell activation degree of the primary auditory cortex of the treatment group is higher than the PV positive neuron cell activation degree of the primary auditory cortex of the control group, and the treatment is effective. , otherwise the treatment is ineffective.
  • the present invention also claims a method for treating and/or preventing depression, using one or more of the following methods for treatment:
  • one course of treatment is less than 14 days, but not limited to one course of treatment.
  • the activation or enhanced activation is performed using one or more of transcranial magnetic stimulators, brain wave recorders, vibrators, sound frequency generators, and current stimulators.
  • the present invention has the following beneficial effects:
  • the present invention finds that early activation of PV-positive neurons in the primary auditory cortex can prevent depression in advance; when resisting external continuous or intermittent but long-term adverse stimuli, the organism can increase the activity of PV-positive neurons in the primary auditory cortex. Depression-like behaviors that may result from resistance to long-term stimuli. Therefore, drugs that specifically activate PV-positive neurons in the primary auditory cortex can effectively treat depression, and provide new ideas and directions for the development of depression drugs.
  • Figure 1 shows that PV positive neurons in the primary auditory cortex of depression non-susceptible mice are activated in the social failure model: a is the co-staining result of CamkII positive neurons in the primary auditory cortex and c-fos protein in the social failure model; b is the co-staining result of SST-positive neurons in the primary auditory cortex and c-fos protein in the social failure model; c is the co-staining result of PV-positive neurons in the primary auditory cortex and c-fos protein in the social failure model; d is the three states of the mice in the social failure model; e is the calcium signal result of the PV positive neurons in the primary auditory cortex of the RES mice (depression non-susceptible mice); f is the calcium signal result of the SS mice (depression-susceptible mice) Calcium signal results of PV-positive neurons in the primary auditory cortex of ).
  • Figure 2 shows that compound-targeted activation of PV-positive neurons in the primary auditory cortex can produce antidepressant-like effects: a is the compound-targeted activation of PV-positive neurons in the primary auditory cortex, and its antidepressant effect is verified by FST experiments; Cortical PV-positive nerves The neuron does not affect the motor ability of the mice; c is the targeted activation of the compound's PV-positive neurons in the primary auditory cortex can reverse the depression-like behavior.
  • Figure 3 shows that the chemical genetic method specifically activates the PV positive neurons of the primary auditory cortex to produce an antidepressant-like effect: a shows that the chemical genetic method specifically activates the PV positive neurons of the primary auditory cortex to verify its antidepressant effect through FST experiments; b The specific activation of PV-positive neurons in the primary auditory cortex by chemical genetic method does not affect the exercise ability of mice; c is the specific activation of PV-positive neurons in the primary auditory cortex by chemical genetic method can significantly reduce the possibility of stress-induced depression-like behavior Sex; d is chemical genetic method to specifically activate PV-positive neurons in the primary auditory cortex can reverse depression-like behavior.
  • FIG. 4 shows that PV-positive neurons in the primary auditory cortex are mainly regulated by neurons in the MG brain area: a is the main brain area of PV-positive neurons projecting to the primary auditory cortex; b is the PV-positive neurons projecting to the primary auditory cortex MG neuron types.
  • Figure 5 shows that the specific activation of neurons in the MG brain area projecting to the primary auditory cortex can produce antidepressant-like effects: a is the specific activation of neurons in the MG brain area projecting to the primary auditory cortex to verify its antidepressant effect through FST experiments; b The specific activation of neurons in the MG brain area projecting to the primary auditory cortex does not affect the motor ability of mice; c is the specific activation of neurons in the MG brain area projecting to the primary auditory cortex can significantly reduce the possibility of stress-induced depression-like behavior Sex; d, specific activation of neurons in the MG brain area projecting to the primary auditory cortex can reverse depression-like behavior.
  • Figure 6 shows that the specific activation of PV-positive neurons in the primary auditory cortex that accepts MG brain area projections can produce antidepressant-like effects: a is the specific activation of PV-positive neurons in the primary auditory cortex that accepts MG brain area projections through FST Experiments verify its antidepressant effect; b is the specific activation of PV positive neurons in the primary auditory cortex that accepts the projection of the MG brain area does not affect the motor ability of the mice; c is the specific activation of the primary auditory cortex that accepts the projection of the MG brain area of PV-positive neurons can reverse depression-like behavior.
  • Figure 7 shows that antidepressant individuals show the characteristics of decreased neuron activity in the MG brain area projected to the primary auditory cortex in the early stage of stress stimulation: a is SS mice (depression susceptible mice) in the early stage of stress stimulation, Calcium activity of neurons in the MG brain area projecting to the primary auditory cortex; b is the calcium activity of neurons in the MG brain area projecting to the primary auditory cortex in RES mice (depression non-susceptible mice) in the early stage of stress stimulation; c is The calcium signal activity when the mice were challenged (Attack) in the early stage (2nd day) was negatively correlated with the Interaciotn Ratio value after 10 days of modeling.
  • a SS mice (depression susceptible mice) in the early stage of stress stimulation, Calcium activity of neurons in the MG brain area projecting to the primary auditory cortex
  • b is the calcium activity of neurons in the MG brain area projecting to the primary auditory cortex in RES mice (depression non-susceptible mice) in the early stage of stress stimulation
  • Figure 8 shows that short-term inhibition of neurons in the MG brain area projecting to the primary auditory cortex can activate PV-positive neurons in the primary auditory cortex, thereby having an antidepressant effect: a shows that short-term inhibition of neurons in the MG brain area projecting to the primary auditory cortex can activate PV-positive neurons in the primary auditory cortex; b, short-term inhibition of MG neurons projecting to the primary auditory cortex can significantly reverse the depression-like phenotype.
  • test methods used in the following examples are conventional methods unless otherwise specified; the materials and reagents used are commercially available reagents and materials unless otherwise specified.
  • mouse-derived anti-PV mouse-derived anti-PV
  • mouse-derived anti-CamkII ⁇ Invitrogen Company, product number: MA1-048
  • rabbit-derived anti-c-fos CST Company, product number: 2250s
  • mice Male C57BL/6J mice (8-12 weeks old) used in the experiment were from the Experimental Animal Center of Southern Medical University (permit number: SCXK-2011-0015, Guangzhou, China).
  • the sources of transgenic mouse strains used are as follows:
  • PV-Cre No. 008069
  • SST-Cre No. 013044
  • Camk2-Cre ERT No. 012362
  • ROSA26-tdTomato Reporter mice No. 007909
  • PV; tdTomato mice are obtained by mating PV-Cre and ROSA26-tdTomato, SST; tdTomato mice are obtained by mating SST-Cre and ROSA26-tdTomato, CamkII-Cre ERT ; tdTomato mice are obtained by mating CamkII-Cre ERT and ROSA26 -tdTomato mating obtained.
  • viruses and article numbers used The following viruses are from Wuhan Privy Technology Co., Ltd.: rAAV-Ef1a-DIO-mCherry-WPRE-pA (article number PT-0013), rAAV-Ef1a-DIO-hM3D(Gq)-mCherry-WPRE- pA (Cat. No. PT-0042),
  • AAV2/1-CAG-FLEX-Flpo-WPRE-pA (Cat. No. S0273-9),
  • AAV2/2Retro-CAG-FLEX-Flpo-WPRE-pA (Cat. No. S0273-2/R).
  • mice were all raised in exhaust-ventilated closed cages (EVC), 4 to 5 per cage, and the feeding environment followed the standard laboratory environment, with the temperature controlled at 24°C and a 12-hour day and night cycle (7:00A.M to 7:00AM). 00P.M), with free access to food and water. Before the animal behavior test was carried out, all the mice were touched for 3-4 days (2 times/day, 5min/time). Animal behavior testing was carried out between 1:00P.M and 5:00P.M, and all animal experiments strictly followed the relevant regulations of the China Animal Ethics Committee.
  • mice were perfused with 0.1M PBS and 4% formaldehyde solution. After the perfusion, the brains were dissected out, fixed in 4% formaldehyde solution for 4-6 hours, washed with tap water for 1 hour, and finally soaked in 30% saturated sucrose solution. After the sugar precipitation of the mouse brain was completed, the Leica cryostat (CM1850, Lecia, Nussloch, Germany) was used to slice the brain, and the coronal brain slices (thickness: 40 ⁇ m) containing A1 were cut.
  • Leica cryostat CM1850, Lecia, Nussloch, Germany
  • the brain slices were first blocked with goat serum blocking solution containing 0.3% triton X-100 for 2 hours, then incubated with the primary antibody overnight (4°C), then rinsed with 0.1M PBS (5min ⁇ 3) and then incubated with the secondary antibody at room temperature in the dark 2 hours. Finally, brain slices were mounted with DAPI-containing mounting medium (Vectro Laboratories Inc.). Eight slices containing A1 from a single mouse brain were selected for colocalization analysis of c-fos with CamkII, PV and SST, respectively.
  • Immunofluorescence imaging was performed using a Nikon A1R confocal microscope (Nikon Instruments Inc, Japan), and positive cell counts were performed using Image J analysis software (US National Institutes of Health).
  • mice were anesthetized, they were fixed on a brain stereotaxic instrument, the hair on the top of the head was removed, the skin was disinfected, the median incision was made, and the bregma was exposed, and the positioning was performed according to the mouse brain atlas.
  • mice were injected with 0.1 ⁇ l of virus bilaterally in MG and 0.15 ⁇ l bilaterally in A1, using a 33GA microsyringe needle (Hamilton) and a microsyringe pump (Stoelting, Wood Dale, IL) to inject 0.03 ⁇ l The virus was injected at a rate of min -1 .
  • the social failure model is carried out with reference to the existing literature.
  • the social defeat model was performed using CD1 retired breed mice with aggressive behavior.
  • the experimental mice were challenged by different CD1 retired breed mice for 10 minutes every day for 10 consecutive days.
  • mice and the CD1 retired breed mice were separated by a transparent plexiglass partition with air holes, and they were rotated before being challenged the next day.
  • the control mice were also raised in two cages, separated by a transparent plexiglass partition with air holes, and rotated once a day.
  • Depression susceptible group (SS) and depression non-susceptible group (RES) were distinguished by Interaction Ratio. Interaction Ratio less than 100 was the depression-susceptible group, and Interaction Ratio greater than or equal to 100 was the depression-non-susceptible group. In the experiments after modeling, the mice were housed in single cages.
  • the forced swimming experiment was carried out according to the existing reports.
  • the mice whose behavior was to be tested were put into the testing room 1 hour in advance to adapt.
  • a cylindrical transparent glass cylinder (45cm high, 19cm inner diameter) is used for detection, and water is added (water depth 23cm, water temperature 22-25°C).
  • the mice were gently put into the cylinder, allowed to swim freely in the cylinder for 6 minutes, and the immobility time (Immobility) of the mice after 4 minutes was recorded.
  • Immobility immobility time
  • a higher mouse immobility time indicates a higher degree of depression in the mouse, and conversely, a lower immobility time indicates that the mouse is more resistant to depression.
  • mice whose behavior was to be tested were put into the testing room 1 hour in advance to adapt.
  • the detection device is an open detection box (Accuscan Instruments, Columbus, OH), surrounded by transparent plexiglass. Put the mouse into the detection box and allow it to freely explore for 5min. The total amount of mouse movement The distance (Total distance) was analyzed using Versmax analysis software.
  • Example 1 The number of PVs in the primary auditory cortex brain area in the brain of depressive non-sensitive mice increased and the activity was significantly enhanced
  • mice in the depression non-susceptible group in the social failure model have the ability to resist depression
  • fluorescent reporter mice labeled with different types of neurons that is, the corresponding neurons will express red fluorescence
  • social failure model After modeling, observe whether various neurons in the primary auditory cortex of the mouse brain are activated or inhibited, that is, analyze whether a certain type of neuron in the primary auditory cortex of the brain is involved in antidepressant.
  • PV;tdTomato mice PV positive neuronal reporter mice
  • SST;tdTomato mice SST positive neuronal reporter mice
  • CamkII-Cre ERT ;tdTomato mice red fluorescent reporter mice for excitatory neurons
  • CSDS depression model - social failure model
  • CRL Normal control group
  • SS Depression-susceptible group
  • RES Depression-non-susceptible group
  • c-fos genes that are rapidly and transiently activated after a series of external stimuli.
  • the earliest immediate genes found in cells include c-fos, c-myc and c-jun.
  • the expression of c-fos is usually observed by immunofluorescence staining to judge whether the neuron is activated or in a silent state: neurons expressing c-fos protein indicate that the neuron is activated rapidly after being stimulated by the outside world, otherwise, there is no c-fos Protein neurons are silent.
  • Immunofluorescent staining of c-fos was performed on the primary auditory cortex of the three neuron fluorescent reporter mice grouped according to the results of the interactive behavior detection after the above modeling, and the three types of neurons labeled by the above three fluorescent reporter mice were analyzed
  • the social failure model models whether neurons are activated or silenced following this external stimulus.
  • CamkII positive neurons were also detected by c- The number of fos-labeled cells and the proportion of total CamkII-positive neurons were significantly reduced, indicating that the excitatory neurons in the primary auditory cortex of the depression non-susceptible group (RES) were significantly inhibited.
  • RES depression non-susceptible group
  • mice in the depression non-susceptible group had an antidepressant-like phenotype without any treatment, and the activation of PV-positive neurons was characteristic of depression non-susceptible mice. That is, the activation of PV-positive neurons is an instinctive response to anti-depression in antidepressant individuals. From this, it can be judged that early activation of PV-positive neurons in the primary auditory cortex can prevent depression in advance.
  • Calcium ion imaging technology is the use of calcium ion indicators to detect the concentration of calcium ions in tissues. Calcium ion imaging is primarily used in the study of the nervous system, where changes in calcium ions indicate neuronal activity. Calcium ion optical fiber recording (Fiber Photometry) is a commonly used method for recording calcium signals in vivo (in vivo), which can be used to examine and record changes in cell activity in real time.
  • the activity of PV-positive neurons in the primary auditory cortex of mice was detected in real time by calcium ion imaging.
  • mice After 10 days of modeling, the depression-susceptible group (SS) and depression-non-susceptible group (RES) of the mice were also separated by social interaction detection.
  • the model mice are mainly divided into three states (see Figure 1d for the schematic diagram): CD1 retired breed mice attack C57BL/6J mice (Attack); The CD1 retired breeder approached (attempted to approach) the C57BL/6J mouse (Approach); the CD1 retired breeder left the C57BL/6J mouse (Non-approach).
  • Example 3 Activation of PV-positive neurons in the primary auditory cortex can produce antidepressant-like effects
  • Example 2 Based on the experimental results of Example 1 and Example 2, in individuals with the ability to resist stress stimuli and exhibit antidepression (RES), Activation of PV-positive neurons in the primary auditory cortex plays a key role. Based on this conclusion, pharmacological methods were further used to activate PV-positive neurons in the primary auditory cortex for behavioral testing.
  • RES antidepression
  • Muscimol is an activator of inhibitory receptors (GABA), which can broadly activate inhibitory neurons, but some studies have found that muscimol is selective for PV-positive neurons in inhibitory neurons, so muscimol Can cause increased activity of PV-positive neurons.
  • GABA inhibitory receptors
  • FST forced swimming test
  • OFT open field test
  • the cannula was implanted in the bilateral primary auditory cortex of C57BL/6J mice. Three days later, 1 microliter of 10mM muscimol (medication Muscimol group) was directly administered to the primary auditory cortex through the buried cannula, and the control group was given the same treatment. Dosage of normal saline (control Saline group), 10min after the forced swimming test (FST). Three days later, the drug was administered again (the Muscimol group was given 1 microliter of 10mM muscimol, and the control Saline group was given 1 microliter of normal saline), and the open field test (OFT) was performed 10 minutes later.
  • 10mM muscimol medication Muscimol group
  • C57BL/6J mice were used to establish a 10-day social failure model to study the antidepressant effect of pharmacologically activating PV-positive neurons in the primary auditory cortex.
  • mice in the depression-susceptible group were obtained.
  • the bilateral primary auditory cortex of the depression-susceptible group mice was implanted, and randomized three days later. They were divided into two groups and given 1 microliter of 10mM muscimol (model-making drug Muscimol group) and the same dose of normal saline (model-making control group saline group), and social interaction behavior was tested again 10 minutes later.
  • GABA receptor agonists can cause rapid antidepressant effects in mice; in addition, GABA receptor agonists Targeted activation of GABA receptors in the primary auditory cortex (including PV-positive neurons) also reversed the behavioral phenotype of depression-susceptible mice. It is suggested that activation of GABA neurons (including PV-positive neurons) in the primary auditory cortex by using drugs such as GABA agonists can rapidly treat depression.
  • Chemical genetics technology is a receptor activated by specific drugs (Designer receptors exclusively activatedby designer drugs, DREADDs) technology, using it to change the structure of the G protein-coupled receptor-acetylcholine receptor, so that it can only be treated by a specific compound, clozapine-N-oxide (Clozapine-N-oxide, CNO) activate or inhibit.
  • the modified hM3Dq was induced by CNO to depolarize neurons, promote the firing activity of neurons, and enhance the excitability of neurons.
  • the transgenic mice using PV-cre were randomly divided into two groups, and the chemical genetic virus rAAV-Ef1a-DIO-hM3D(Gq )-mCherry-WPRE-pA (Product No. PT-0042) (hM3Dq group) and the control virus rAAV-Ef1a-DIO-mCherry-WPRE-pA (Product No. PT-0013) (mCherry group) that only expresses red fluorescent protein after infection of cells .
  • FST forced swimming test
  • OFT open field test
  • the social failure model was established for 10 days. During the 10-day modeling process, 2 mg/kg CNO was injected intraperitoneally twice a day in the morning and evening, so that the PV-positive neurons in the primary auditory cortex were always activated. After 10 days of modeling, the social interaction behavior test was carried out. Compare the proportion of depression non-susceptible mice in the hM3Dq group injected with chemical genetic virus and the mcherry group injected with control virus after the same modeling.
  • the continuous activation of PV-positive neurons in the primary auditory cortex can significantly increase the proportion of mice in the non-depression-susceptible group, that is, reduce the occurrence of stress-induced depression and prevent depression. Depression after stress. Activating the PV-positive neurons in the primary auditory cortex can resist the occurrence of depression caused by long-term and continuous stress stimulation.
  • rAAV-Ef1a-DIO-hM3D(Gq)-mCherry-WPRE-pA (Cat. No. PT-0042) (hM3Dq group) and the control virus were injected into the primary auditory cortex of two groups of randomly assigned PV-cre mice.
  • rAAV-Ef1a-DIO-mCherry-WPRE-pA (Product No. PT-0013) (mcherry group).
  • the social failure model was established, and the depression-susceptible mice with Interaction Ratio less than 100 were obtained. According to the virus injected 21 days ago, they were divided into the depression-susceptible hM3Dq group and the depression-susceptible mcherry group. All were given intraperitoneal injection of CNO to activate PV-positive neurons in the primary auditory cortex of depressed mice in the hM3Dq group. The social interaction behavior detected 35 minutes after the intraperitoneal injection, the depression-like behavior of the mice was observed.
  • the depressive phenotype of the mice in the mcherry group injected with the control virus did not improve after administration of CNO, indicating that the mice would maintain depression-like behavior after the model was established, while the injection of the virus itself had no effect, and CNO itself had no antidepressant effect.
  • the Interaction Ratio of SS mice in Pre-SI was increased after CNO was given to activate PV-positive neurons in the primary auditory cortex (Post-SI after CNO injection), and the depression-like phenotype was significantly improved, indicating that specific sexual activation of PV-positive neurons in the primary auditory cortex significantly reversed the depressive phenotype, leading to an antidepressant phenotype.
  • Example 5 PV-positive neurons in the primary auditory cortex are mainly regulated by neurons in the MG brain region
  • a neural circuit tracing method for retrograde transmonosynaptic rabies virus (Rhabdoviridae, RV). After RV infects the central system, it mainly labels neurons and barely labels glial cells.
  • the replication-deficient recombinant RV constructed based on the infectious clone of the RV vaccine strain Sad-B19 has low toxicity and high safety, can clearly mark the fine morphology of neurons, and realizes the neural network through the reverse complementation strategy Retrograde tracing of connections across single-level synapses.
  • Cre transgenic mice combined with Cre-LoxP to control the expression of TVA and G protein AAV helper virus can realize the expression of TVA and G protein only in specific types of neurons in specific regions, so that RV-EnvA- ⁇ G can be used to achieve specific types of neurons. Reverse labeling across single-level synapses.
  • Determining how PV-positive neurons in the primary auditory cortex are regulated can increase the pathways and means of activating PV-positive neurons in A1.
  • PV-positive neurons in the primary auditory cortex are mainly regulated by neurons in the MG brain area
  • RV transmonosynaptic rabies virus
  • PV-cre mice were stereotaxically microinjected into the primary auditory cortex the cre expression-dependent AAV virus rAAV-Ef1a-DIO-His-EGFP-2a- TVA-WPRE-pA (Cat. No. 9-21-K180918), and AAV virus rAAV-CMV-DIO-RVG-WPRE-pA (Cat. No. 9-991-K180726) expressing RVG for assisting rabies virus retrograde across monosynapses .
  • RV-ENVA- ⁇ G-dsRed Product No. R01002
  • RV-ENVA- ⁇ G-dsRed Product No. R01002
  • the brain areas of PV-positive neurons projecting (input) to the primary auditory cortex mainly include the primary auditory cortex (A1) (41.17%), and the surrounding secondary auditory cortex, including: ventral Secondary auditory cortex (AuV) (16.69%), dorsal secondary auditory cortex (AuD) (15.86%).
  • the medial geniculate nucleus (MG) was the main projection brain region, accounting for 16.58%, and the rest totaled 9.7%.
  • the excitability and activity of PV-positive neurons can also be enhanced to achieve the purpose of antidepressant or treatment of depression .
  • the neurons in the MG brain area that regulate the primary auditory cortex are excitatory neurons
  • the characteristic protein of excitatory glutamatergic neurons - glutamate transporter 2 gene (Vglut2, also known as Slc17a6) is expressed in multiple brain regions.
  • Slc17a6-cre mice were used to label excitatory neurons
  • Gad2-cre mice were used to label GABAergic inhibitory interneurons
  • retrograde-projecting AAV2/2Retro-CAG-FLEX-Flpo was injected into the primary auditory cortex of two kinds of cre mice -WPRE-pA (Cat. No. S0273-2/R), and inject AAV2/9-hEF1a-fDIO-mCherry-WPRE-pA (Cat. No. S0553-9) in MG at the same time, perfuse the slices 21 days later, and observe the red fluorescent labeling of MG.
  • the MG is the main outer projection (non-auditory cortex) brain area of PV-positive neurons in the primary auditory cortex, and those projecting to the primary auditory cortex are excitatory neurons.
  • Example 6 Specific activation of neurons in the MG brain region projecting to the primary auditory cortex can produce antidepressant-like effects
  • the neurons projecting to the MG of the primary auditory cortex were specifically activated by chemical genetic techniques, and their antidepressant effects were detected.
  • C57BL/6J mice were randomly divided into two groups, and the retrovirus rAAV2/R-hSyn-Cre-WPRE-hGH-pA was stereotaxically injected into the primary auditory cortex. Strong, and at the same time retrograde transport along the axon to the synaptic terminal receiving the projection.
  • the retrovirus can infect primary auditory cortex neurons and transport retrogradely along the dendrites to the synaptic terminal, and the Cre enzyme can be transported across the synapse to the upper-level neurons that receive the terminal.
  • the external projection brain area received by the PV-positive neurons of the primary auditory cortex is mainly MG.
  • the two groups of mice were stereotaxically microinjected into the MG brain area with the chemical genetic virus rAAV-Ef1a-DIO-hM3D(Gq)-mCherry-WPRE-pA (product number PT-0042) (hM3Dq group ) and the control virus rAAV-Ef1a-DIO-mCherry-WPRE-pA (product number PT-0013) expressing only red fluorescence (mcherry group).
  • mice 21 days after the virus injection, all mice were intraperitoneally injected with CNO 2mg/kg, and the forced swimming test (FST) was performed 35 minutes after the intraperitoneal injection. After 3 days, the intraperitoneal injection of CNO was performed again. Carry out modeling of social failure model (refer to embodiment 4 for specific experimental process).
  • Figure 5c shows that during the modeling process of the social failure model, the mcherry group of the control virus and the hM3Dq group of the chemical genetic virus were intraperitoneally injected with CNO once a day in the morning and evening.
  • the social interaction test after modeling showed that the proportion of the non-susceptible group (Interaction Ratio greater than 100) in the normal control mcherry group was 50%, and the proportion of the non-susceptible group in the hM3Dq group was 68.4%, showing a significant upward trend, and the hM3Dq group The overall Interaction Ratio was significantly increased compared with the control group.
  • Pre-SI is the Interaction Ratio measured for the first time after the model was established to separate the depressed mice (Interaction Ratio is less than 100), and Post-SI is the Interaction Ratio measured after 35 minutes of administration of CNO.
  • the results in Figure 5d show that the depressive phenotype of the mice in the mcherry group injected with the control virus was not improved after administration of CNO, indicating that the control injection of the virus had no effect and CNO itself had no antidepressant effect.
  • the Interaction Ratio of SS mice in Pre-SI was significantly improved (Post-SI after CNO injection), and the depression-like phenotype was significantly improved, indicating that the activation projected to the primary auditory cortex.
  • MG neurons in the primary auditory cortex can significantly reverse the depressive phenotype, making them exhibit an antidepressant phenotype.
  • Example 7 Specific activation of PV-positive neurons in the primary auditory cortex receiving MG brain region projections can produce antidepressant-like effects
  • mice were stereotaxically microinjected into the MG brain area with Cre enzyme-dependent expression of Flp enzyme virus AAV2/1-CAG-FLEX-Flpo-WPRE-pA (Cat. No. S0273-9) , the expression of Cre enzyme in PV-positive neurons of PV-cre mice can lead to the expression of Flp enzyme projected from MG, thereby causing the expression of hM3D (Gq) protein in the primary auditory cortex, and the intraperitoneal injection of CNO activates the projection of MG in the primary auditory cortex PV-positive neuronal cells.
  • Cre enzyme virus AAV2/1-CAG-FLEX-Flpo-WPRE-pA
  • mice 21 days after the virus injection, all mice were intraperitoneally injected with CNO 2mg/kg, and the forced swimming test (FST) was performed 35 minutes after the intraperitoneal injection. After 3 days, the intraperitoneal injection of CNO was performed again. After 35 minutes, the behavior of the open field test (OFT) was tested. Carry out modeling of social failure model (refer to implementation case 4 for specific experimental process).
  • mice were detected for the first time after modeling (Interaction Ratio was less than 100), and in the Post-SI group, the Interaction Ratio was measured after 35 minutes of administration of CNO.
  • Figure 6c all mice were subjected to the social defeat model after virus injection, and intraperitoneal injection of CNO in the detected SS mice activated PV-positive neurons in the part of the primary auditory cortex that received MG projections.
  • the depressive phenotype of mice in the control mcherry group was not improved after administration of CNO, indicating that injection of the control virus had no effect and that CNO itself had no antidepressant effect.
  • the Interaction Ratio of SS mice in Pre-SI was significantly improved after CNO was given to activate PV-positive neurons in the primary auditory cortex that received MG projections (Post-SI after CNO injection), and the depression-like phenotype was significantly improved, indicating that Activation of PV-positive neurons in the MG-projecting portion of the primary auditory cortex significantly reversed the depressive phenotype, rendering it antidepressant.
  • Example 8 Early antidepressant individuals receive stress stimulation and reduce the activity of neurons in the MG brain area projected to the primary auditory cortex
  • mice were used to stereotaxically microinject retrovirus rAAV2/R-hSyn-Cre-WPRE into the primary auditory cortex - hGH pA (Cat. No. PT-0136).
  • rAAV-Ef1a-DIO-GCaMp6f-WPRE-hGH pA (Cat. No. PT-0106-9) expressing calcium ion indicator dependent on Cre enzyme and the optical fiber plug for optical fiber recording.
  • the GCaMP6f calcium indicator protein with green fluorescence is expressed by cleavage with Cre enzyme, excited by excitation light with a wavelength of 470nm, and its fluorescence signal is collected and recorded by the corresponding program in the computer.
  • the depression-susceptible group (the Interaciotn Ratio of the mice who had experienced social failure was less than 100) and the depression-non-susceptible group (RES) (the Interaciotn Ratio greater than 100).
  • the neurons in the MG brain area projecting to the primary auditory cortex in SS mice did not have large ups and downs during the modeling process, indicating that the neurons in the MG brain area did not participate in the process of depression.
  • Example 9 Short-term inhibition of neurons in the MG brain region projecting to A1 can activate PV-positive neurons in A1
  • Example 8 shows that in the early stage when individuals with antidepressant ability face external stimuli, MG neurons will be temporarily inhibited when the organism is stimulated (Attack). Subsequent anti-stress stimulation (Approach) can increase the activity of MG neurons, thereby increasing the activity of PV-positive neurons in the primary auditory cortex to achieve antidepressant effects.
  • Optogenetics refers to the combination of optical and genetic means to precisely control the activity of specific neurons.
  • the activity of cells regulated by optogenetics depends on the type of light-sensitive channel protein, that is, excitatory light-sensitive channel and inhibitory light-sensitive channel. If the channel transferred into the cell is NpHR, when the cell is irradiated by yellow light, the channel will open, and a large number of anions will flow inward, resulting in hyperpolarization, which will make it difficult to emit action potentials and inhibit cell activity.
  • the virus AAV2/2Retro-CAG-FLEX-Flpo-WPRE-pA (Cat. No. S0273-2/R) reversely expressing the FLP protein was simultaneously stereotaxically microinjected into the primary auditory cortex of PV-Cre mice.
  • virus rAAV-Ef1a-DIO-GCaMp6f-WPRE-hGH pA (catalogue number PT-0106-9) expressing calcium ion indicator, and at the same time injected into MG stereotaxically dependent on Flp enzyme expression inhibitory light-sensitive channel protein Virus rAAV-nEF1a-fDIO-eNpHR3.0-mCherry-WPRE-hGH polyA (Cat. No. PT-1261), the virus expresses NpHR3.0 protein after being cleaved by Flp enzyme after injection, and can be activated by excitation light with a wavelength of 589nm Inhibits neuronal activity.
  • mice MG brain area was given 8 times of 10-second photoinhibition every day, with an interval of 25 seconds between each stimulation, within 5 minutes of the total daily duration, for three consecutive days, and the total duration of the daily suppression 80 s of inhibitory projections to MG neurons in the primary auditory cortex.
  • mice were placed in the cage of the social failure model, and the CD1 challenge was carried out for one day: first, the mice were placed in a glass baffle with small ventilation holes and a CD1 decommissioned mouse cage, and the PV of the primary auditory cortex of the mice was detected The normal calcium activity of the positive neurons when facing the CD1 retired breed mouse approach (Pre-approach) without stimulation, then remove the baffle CD1 retired breed mouse to attack the mouse (Attack), and finally put the baffle The two mice were separated by a board, and the PV of A1 was recorded under the isolation of the baffle (Approach) and when there was no interaction (Non-approach) calcium activity.
  • mice when mice were attacked by CD1 retired breed mice, when CD1 retired breed mice approached the mice again, the mice would be stimulated by the threat of being attacked, and the mice that had experienced short-term inhibition of MG neurons in advance Under this Approach stress, mice learned to enhance the PV-positive neuron activity of the primary auditory cortex in advance, so after only being attacked once, the PV-positive neuron activity of the primary auditory cortex of the mouse was rapidly enhanced, which is consistent with Example 2
  • Example 10 Short-term inhibition of neurons in the MG brain region projecting to the primary auditory cortex can treat depression
  • Example 9 before exposure to external stimuli, short-term inhibition of MG neurons projected to the primary auditory cortex can activate PV-positive neurons of the primary auditory cortex, thereby having an antidepressant effect. Whether short-term suppression has therapeutic effects in reversing depressive-like behaviors in depressed individuals.
  • C57BL/6J mice were randomly divided into two groups, and both groups were stereotaxically injected into the primary auditory cortex with the virus rAAV2/R-hSyn-NLS-FLP-bGH pA (product number PT-0133) reversely expressing Flp protein: photoinhibition group
  • virus rAAV2/R-hSyn-NLS-FLP-bGH pA product number PT-0133
  • stereotaxic microinjection of virus rAAV-nEF1a-fDIO-eNpHR3.0-mCherry-WPRE-hGH polyA product number PT-1261
  • eNpHR3.0 group dependent on Flp enzyme expression inhibitory channelrhodose protein
  • NpHR3.0 protein was expressed by cleavage by Flp enzyme, and neuronal activity could be inhibited after being activated by excitation light with a wavelength of 589nm; the control group was microinjected with a control virus AAV2/9-hEF1a that only expressed red fluorescence in MG stereotaxic - fDIO-mCherry-WPRE-pA (Cat. No. S0553-9) (mcherry group).
  • the social failure model was established for 10 days, and the depression-susceptible (SS) mice were detected by the social interaction experiment.
  • SS mice an optical fiber was embedded in the MG brain area, and 8 times a day was given after 3 days 10 seconds of photoinhibition, 25 seconds between each stimulation, within 5 minutes per day, for three consecutive days, after the photoinhibition was given every day, the mice were put back into the cage with CD1, and CD1 was separated by a glass baffle of the air hole On, so that the mice still face the stimulation of CD1 proximity every day.
  • mice in the mcherry group did not undergo the process of inhibiting MG neurons, and still maintained a depression-susceptible phenotype (Interaction Ratio was less than 100), indicating that the depressed mice after modeling could still maintain depression-like behaviors.
  • the social avoidance depression-like behavior of mice was significantly reversed. It shows that for individuals who have developed into depression, even if they are still exposed to the stressful stimulus environment, a short-term (3 days in this embodiment) method of inhibiting the projection of MG neurons to the primary auditory cortex for less than 14 days can produce Significant effect of treating/improving depression-like behavior.
  • Examples 8 to 10 currently commonly used antidepressants take at least 4 weeks to take effect, short-term rapid application lasts for 6-8 consecutive weeks, and then long-term use for at least 6 months to maintain the effect.
  • the present invention suppresses the activity of MG neurons by simulating the short-term stress stimulation less than 14 days (3 days in this embodiment), which can quickly make the organism have the ability to resist depression, and quickly reverse the depression-like behavior .
  • This short-term suppression intervention has a better acceptance in clinical application, and patients do not need to insist on taking medicine for a long time; and for potential high-risk groups who have not yet developed the disease, giving short-term suppression intervention in advance can be effective Reduce the occurrence of mental and neurological diseases such as depression in the future.

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Abstract

Est divulgué dans la présente invention un système d'évaluation de l'effet de traitement de maladies mentales et/ou de maladies neurodégénératives. Selon la présente invention, il a été découvert que l'activation précoce de neurones positifs PV dans le cortex auditif primaire pouvait générer un effet de prévention précoce de la dépression ; en cas de résistance à la stimulation indésirable persistante ou intermittente mais durable, le corps vivant résiste à un comportement de type dépression qui peut être provoqué par une stimulation durable au moyen de l'augmentation de l'activité de cellules neuronales positives PV du cortex auditif primaire. Par conséquent, le médicament permettant d'activer spécifiquement les neurones positifs PV dans le cortex auditif primaire peut traiter efficacement la dépression, et une nouvelle école et un nouveau courant de pensée sont fournis pour le développement de médicaments contre la dépression.
PCT/CN2023/083089 2022-07-12 2023-03-22 Système d'évaluation de l'effet de traitement de maladies mentales et/ou de maladies neurodégénératives WO2023151701A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103251951A (zh) * 2013-01-16 2013-08-21 南方医科大学 P2x2受体的激动剂或开通剂在制备抗抑郁和/或抗焦虑药物中的应用
US20140058189A1 (en) * 2012-02-20 2014-02-27 William F. Stubbeman Systems and methods using brain stimulation for treating disorders
US20140129495A1 (en) * 2012-11-06 2014-05-08 Qualcomm Incorporated Methods and apparatus for transducing a signal into a neuronal spiking representation
CN110721176A (zh) * 2019-11-18 2020-01-24 华东师范大学 氟西汀在制备诱导听觉皮层可塑性的药物中的应用
CN110734924A (zh) * 2019-10-25 2020-01-31 山东大学第二医院 一种抑郁症检测、治疗和预后靶点及应用
CN111477299A (zh) * 2020-04-08 2020-07-31 广州艾博润医疗科技有限公司 结合脑电检测分析控制的声电刺激神经调控方法及装置
CN113349158A (zh) * 2021-07-06 2021-09-07 上海市东方医院（同济大学附属东方医院） 一种小鼠抑郁症模型的构建方法

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140058189A1 (en) * 2012-02-20 2014-02-27 William F. Stubbeman Systems and methods using brain stimulation for treating disorders
US20140129495A1 (en) * 2012-11-06 2014-05-08 Qualcomm Incorporated Methods and apparatus for transducing a signal into a neuronal spiking representation
CN103251951A (zh) * 2013-01-16 2013-08-21 南方医科大学 P2x2受体的激动剂或开通剂在制备抗抑郁和/或抗焦虑药物中的应用
CN110734924A (zh) * 2019-10-25 2020-01-31 山东大学第二医院 一种抑郁症检测、治疗和预后靶点及应用
CN110721176A (zh) * 2019-11-18 2020-01-24 华东师范大学 氟西汀在制备诱导听觉皮层可塑性的药物中的应用
CN111477299A (zh) * 2020-04-08 2020-07-31 广州艾博润医疗科技有限公司 结合脑电检测分析控制的声电刺激神经调控方法及装置
CN113349158A (zh) * 2021-07-06 2021-09-07 上海市东方医院（同济大学附属东方医院） 一种小鼠抑郁症模型的构建方法

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