Application of BLAWFS1-NAc neural circuit as drug target in preparation of drug for treating risk assessment abnormality
By activating the BLAWFS1-NAc neural circuit, optogenetic or pharmacogenetic methods were used to correct the abnormal risk assessment in patients with mental illnesses, solving the problem of the lack of effective treatment methods in existing technologies and achieving a significant improvement in risk assessment behavior.
Patent Information
- Application Number
- CN202511163016.9
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-19
- Publication Date
- 2026-01-06
AI Technical Summary
Current technology lacks effective methods to treat abnormal risk assessments in patients with mental illnesses, which leads to worsening of negative symptoms and places a burden on families and society.
By using the BLAWFS1-NAc neural circuit as a drug target, NMDA receptors on WFS1 neurons are activated through optogenetics or pharmacogenetics. Glutamate or serine drugs are then used to activate the BLAWFS1-NAc neural circuit, thereby correcting abnormal risk assessment behaviors.
Significantly increases risk assessment behavior, improves abnormal risk assessment behavior with lack of risk avoidance, and corrects abnormal risk assessment behavior in patients with mental illnesses.
Smart Images
Figure CN121265778A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of bioscience and technology, and more particularly to BLA. WFS1 Application of -NAc neural circuits as drug targets in the preparation of drugs for treating abnormal risk assessment. Background Technology
[0002] Risk assessment is crucial for an individual's survival and development, and many patients with mental illnesses exhibit abnormal risk assessment abilities. On the one hand, mental illnesses manifest as abnormal risk assessment; on the other hand, risk assessment is critical to behavioral choices, and abnormal risk assessment can maintain or even exacerbate the negative symptoms of mental illnesses, placing a greater burden on families and society. Given the complex pathogenesis and diverse phenotypes of mental illnesses, and the lack of effective assessment and treatment methods, abnormal risk assessment, as a symptom often associated with multiple mental illnesses, represents a valuable potential cross-diagnostic factor and intervention target for mental illnesses. Summary of the Invention
[0003] In view of the shortcomings of the prior art, the object of the present invention is to provide a BLA. WFS1 The application of -NAc neural circuits as drug targets in the preparation of drugs for treating abnormal risk assessment is first demonstrated by BLA. WFS1 -NAc neural circuits can serve as drug targets, providing new treatment options for those with abnormal risk assessment.
[0004] The technical solution of the present invention is as follows:
[0005] In a first aspect, the present invention provides a BLA. WFS1 Application of -NAc neural circuits as drug targets in the preparation of drugs for treating abnormal risk assessment.
[0006] A second aspect of the invention is the activation of BLA. WFS1 Application of substances in the NAc neural circuit in the preparation of drugs for treating abnormal risk assessment.
[0007] Preferably, the activation method is optogenetics or pharmacogenetics.
[0008] Preferably, the drug activates BLA WFS1 -NAc neural circuits are used to correct abnormal risk assessment behaviors.
[0009] Preferably, it is activated by 470nm light at 20Hz.
[0010] Preferably, the BLA WFS1 - The NAc neural circuit is a neural circuit in which WFS1 neurons in the basolateral amygdala (BLA) project to the nucleus accumbens (NAc).
[0011] Preferably, BLA is activated by activating NMDA receptors on WFS1 neurons. WFS1 -NAc neural circuit.
[0012] Preferably, glutamate or serine drugs are used to activate NMDA receptors on WFS1 neurons.
[0013] Preferably, the drug comprises:
[0014] (1) The first active ingredient, which can activate BLA WFS1 -NAc neural circuit;
[0015] (2) The second active ingredient, wherein the second active ingredient is an active ingredient with abnormal treatment risk assessment;
[0016] (3) Pharmaceutically acceptable carrier.
[0017] The present invention has the following beneficial effects:
[0018] The circuit in the BLA that projects WFS1 neurons to the nucleus accumbens (NAc) brain region (BLA) WFS1 The -NAc neural circuit can participate in risk assessment behavior and serves as a key target for regulating abnormal risk assessment behavior. Activation of the BLA through optogenetics and pharmacogenetics... WFS1 -NAc neural circuits can significantly enhance risk assessment behavior and improve abnormal risk assessment behavior such as lack of risk avoidance. Attached Figure Description
[0019] Figure 1 To activate BLA WFS1 -NAc neurons can enhance risk assessment behavior mapping in mice.
[0020] Figure 2 Photoactivated BLA WFS1 A graph showing the results of c-Fos expression in downstream brain regions after neuronal post-synaptic analysis.
[0021] Figure 3 To activate BLA WFS1 -NAc neural circuits can correct abnormal risk assessment behavior patterns in mice. Detailed Implementation
[0022] This invention provides a BLA WFS1 The application of NAc neural circuits as drug targets in the preparation of drugs for treating abnormal risk assessment is further explained below to make the objectives, technical solutions, and effects of this invention clearer and more explicit. It should be understood that the specific embodiments described herein are only for explaining the invention and are not intended to limit the invention.
[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used herein in the description of this invention is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.
[0024] This invention provides a BLA WFS1 Application of -NAc neural circuits as drug targets in the preparation of drugs for treating abnormal risk assessment.
[0025] In previous studies, the inventors discovered that a type of WFS1 (Wolfram Syndrome 1) neuron in the basolateral amygdala (BLA) can participate in the regulation of risk assessment behavior by increasing the frequency and duration of risk assessment in mice (see [link to previous research]). Figure 1 ).
[0026] This invention provides a circuit in which WFS1 neurons in the brain's brain project to the nucleus accumbens (NAc) region, which can participate in risk assessment behavior and serve as a key target for regulating abnormal risk assessment behavior. The BLA is activated through optogenetics and pharmacogenetics. WFS1 -NAc neural circuits can significantly increase risk assessment behavior in mice and improve abnormal risk assessment behavior such as risk avoidance deficiency. BLA WFS1 - The NAc neural circuit, as a target for regulating abnormal risk assessment behavior, is more specific than the WFS1 neurons in previously published articles.
[0027] The following detailed description uses specific examples.
[0028] Example 1: Risk Assessment Behavioral Detection in Mice
[0029] In this embodiment of the invention, the elevated plus maze (EPM) and rat exposure test (RET) were used to detect the risk assessment behavior of mice.
[0030] Elevated Cross Maze Experiment: The elevated cross maze is made of white acrylic sheet and consists of a central platform (5×5cm), two white open arms (25×5cm), and two white closed arms (25×5cm, wall height 17cm). The open and closed arms extend from the central platform at a vertical angle, forming a cross shape. The open arms are 58cm above the ground. At the start of the experiment, mice are placed at the edge of the central platform of the elevated cross maze, with their heads facing the open arms. They can freely choose to enter the open arm or one of the two closed arms. The mice explore freely for 3 minutes, and a camera is installed directly above the instrument to record the test process.
[0031] This embodiment statistically analyzed the frequency and percentage of time of the stretch-attendposture (SAP) in mice in an open arm.
[0032] Rat Exposure Experiment: The rat exposure experiment apparatus consists of stainless steel side walls and white acrylic bottom. The entire enclosure is 60cm long, 30cm wide, and 20cm high. The interior is divided into three rectangular / square areas: a protection area (30cm long, 10cm wide), an exploration area (30cm long, 30cm wide), and a rat area (30cm long, 20cm wide). The exploration area and rat area are separated by a metal grid, preventing mice from passing directly or squeezing through the grid gaps. A 10cm smooth surface is left above the metal grid to prevent mice from climbing over it. A 4×4cm door is placed in the center between the protection area and the exploration area, allowing mice to pass freely.
[0033] The RET experiment consisted of a three-day acclimatization period and a fourth-day testing phase. During the first three days of acclimatization, mice were placed in the center of the exploration area and allowed to freely explore the device for 10 minutes. On the day of testing, an anesthetized Sprague-Dawley rat (weighing 400-450 grams) was placed in the rat area, and then the mice were placed in the exploration area and allowed to freely explore for 10 minutes. A camera was mounted directly above the device to record the testing process. In this embodiment, the total time the mice spent in contact with (including climbing) the grid wall, the frequency of their stretching postures, and the percentage of time spent in these postures were recorded. The higher the total time the mice spent in contact with the grid wall, and the lower the frequency and percentage of time spent in stretching postures (SAP), the lower the risk avoidance of the mice (excessively high or low risk avoidance behaviors are considered abnormal risk assessment behaviors).
[0034] Example 2 uses optogenetics combined with transgenic mice to regulate the function of target neurons.
[0035] Using stereotactic techniques, a virus carrying DIO was injected into the target brain region (BLA) of mice. Combined with Wfs1-iCre transgenic mice, WFS1 neurons in the BLA brain region expressed ChR2 (or hM3Dq). By applying light stimulation to the target brain region (or administering CNO drugs to the mice), WFS1 neurons were activated.
[0036] Example 3 uses DISC1 transgenic mice as a model of abnormal risk assessment behavior.
[0037] DISC1 (disrupted-in-schizophrenia-1) transgenic mice are a commonly used genetic manipulation model for mental illnesses. The DISC1 gene, resulting from a balanced translocation (1;11)(q42.1;q14.3) between chromosomes 1 and 11, was discovered in a large family in Scotland and identified as being associated with mental illnesses through co-segregation. The protein encoded by the DISC1 gene is a crucial pivotal protein in the central nervous system, participating in various signaling pathways, including neuronal development and synaptic plasticity. Increasing research indicates a close association between the DISC1 gene and many mental illnesses, such as schizophrenia, depression, and bipolar disorder. However, systematic research on abnormal risk assessment behavior and its neural mechanisms in mental illness phenotypes caused by DISC1 protein mutations remains lacking. In previous research, the inventors discovered that these mice exhibit abnormal risk assessment behavior: a reduced level of risk avoidance.
[0038] Specifically, Figure 1 To activate BLA WFS1 -NAc neurons can increase risk assessment behavior in mice. A. Flowchart of a behavioral experiment using pharmacogenetic regulation of WFS1 neurons in the BLA brain region: Wfs1-iCre transgenic mice were injected with the virus for 4 weeks, then given saline for half an hour before the behavioral experiment was conducted. After a one-week rest, they were given CNO and the behavioral experiment was conducted again. BC. Statistical analysis of the results of the elevated test (B) and rat exposure test (C) (statistical data are the percentage and frequency of time mice exhibited the SAP posture in the risk area). D. Mouse risk assessment scores calculated based on the elevated test and rat exposure test. From Figure 1 It can be seen that BLA WFS1 Neurons can enhance risk assessment behavior in mice.
[0039] In the resting state, the expression level of the c-Fos gene is very low in cells. However, once the cells are stimulated by external factors, the expression of the c-Fos gene will be rapidly and transiently induced to be upregulated. In neurobiology, the expression of the c-Fos gene is often used to screen downstream brain regions with functional relevance. Figure 2Photoactivated BLA WFS1 A diagram showing the results of statistical analysis of c-Fos expression in downstream brain regions after neuronal stimulation. A. Flowchart showing statistical analysis of c-Fos expression in downstream brain regions after light stimulation. B. Photoactivated BLA. WFS1 Schematic diagram of c-Fos expression in the postneuronal NAc brain region. C. Photoactivation of BLA WFS1 Statistical analysis of c-Fos expression in neurons and downstream brain regions. Figure 2 As can be seen, photo-activated BLA WFS1 c-Fos expression was highest in the NAc region of the brain, which is downstream of neurons, and BLA expression was highest. WFS1 Neurons can project functionally into the NAc brain region.
[0040] By implanting optical fibers in the NAc brain region and applying light stimulation to the NAc brain region during the experiment, the BLA projected into the NAc brain region can be activated. WFS1 The function of neurons. Figure 3 To activate BLA WFS1 - Following the NAc neural circuit, abnormal risk assessment behavior in mice can be corrected. A. DISC1 mice exhibit abnormal risk avoidance behavior. B. Photoactivation of BLA WFS1 Following the -NAc neural circuit, the abnormal risk-avoidance behavior of DISC1 mice can be corrected. From Figure 3 This can explain BLA WFS1 -NAc neural circuits can serve as targets for regulating abnormal risk assessment behaviors.
[0041] It should be understood that the application of the present invention is not limited to the examples above. Those skilled in the art can make improvements or modifications based on the above description, and all such improvements and modifications should fall within the protection scope of the appended claims.
Claims
1. BLA WFS1 - Use of the NAc neural circuit as a drug target in the preparation of a medicament for treating abnormal risk assessment.
2. Activation of BLA WFS1 Use of substances of the NAc neural circuit in the preparation of a medicament for treating abnormal risk assessment.
3. Use according to claim 2, characterized in that, The activation is optogenetic or pharmacogenetic.
4. Use according to claim 1 or 2, characterized in that, The drug corrects the abnormal risk assessment behavior by activating the BLA WFS1 the NAc neural circuit.
5. Use according to claim 4, characterized in that, Activation is by light at 470 nm at 20 Hz.
6. Use according to claim 1 or 2, characterized in that, The BLA WFS1 - NAc circuit is a neural circuit in which WFS1 neurons in the basolateral amygdala (BLA) project to the nucleus accumbens (NAc).
7. Use according to claim 6, characterized in that, activating BLA by activating NMDA receptors on WFS1 neurons WFS1 -NAc neural circuit.
8. Use according to claim 7, characterized in that, NMDA receptors on WFS1 neurons are activated with glutamate or serine drugs.
9. Use according to claim 1 or 2, characterized in that, The drugs include: (1) a first active ingredient that can activate the BLA WFS1 - NAc neural circuit; (2) a pharmaceutically acceptable carrier.