Function of thalamic excitatory synapses in social reward processing

丘脑兴奋性突触在社会奖励处理中的功能

• 批准号: 9110025
• 负责人: Daniel Joseph Christoffel
• 金额: $ 2.81万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110025
• 关键词: Antidepressive Agents; Autistic Disorder; Behavior; Behavioral Assay; Brain; Brain region; Cell Nucleus; Cells; Cellular Morphology; Characteristics; Chronic; Chronic stress; Clinical; Cocaine; Communication; Deep Brain Stimulation; Development; Disease; Dose; Electrophysiology (science); Emotional; Excitatory Amino Acid Antagonists; Excitatory Synapse; Figs - dietary; Functional disorder; Glutamates; Gold; Impairment; Investigation; Ion Channel; Ketamine; Knowledge; Light; Major Depressive Disorder; Measures; Membrane; Mental Depression; Mental disorders; Modeling; Modification; Nature; Neurobiology; Neuronal Dysfunction; Neurons; Neurotransmitters; Nucleus Accumbens; Pathway interactions; Patients; Pharmacotherapy; Physical Restraint; Physiologic pulse; Physiological; Physiology; Population; Prefrontal Cortex; Process; Property; Proteins; Proxy; Psyche structure; Regulation; Research; Rewards; Schizophrenia; Social Behavior; Social Conditions; Social Interaction; Stress; Structure of paraventricular nucleus of thalamus; Symptoms; Synapses; System; Techniques; Thalamic structure; Therapeutic; Training; Transgenic Mice; Transgenic Organisms; Viral; anxiety-related disorders; base; cell type; common symptom; dopamine system; electrical property; experience; information gathering; neural circuit; novel; optogenetics; postsynaptic; preference; psychiatric symptom; public health relevance; research study; response; restraint; restraint stress; reward processing; social; social stress; stressor; success; synaptic function

 DESCRIPTION (provided by applicant): It is fast becoming clear that symptoms of psychiatric disorders, such as social avoidance, which are present in multiple conditions, may have singular neural dysfunctions underlying their presentation. Social abnormalities are present in autism, schizophrenia, depression and anxiety-related disorders, representing a significant portion of the population afflicted with mental disease. While many pharmacotherapies exist, the success rate of treating a majority of patients is surprisingly low. This highlights the urgency in studyin common symptoms across multiple models, while examining new brain circuits to parse out specific adaptations responsible for maladaptive behaviors. While the brain's dopamine system is clearly involved in psychiatric disorders, the brain's major neurotransmitter glutamate has also recently been implicated in underlying certain psychiatric symptoms, yet due to its ubiquity throughout the brain, its function has been difficult to determine. Many studies of the effects of stress on the brain have seen that it alters cell morphology and electrical properties, however many of these studies have occurred in discrete brain regions without knowledge of the input to the cell. With the advent of novel viral techniques and transgenic mouse lines it is now possible to isolate specific synapses, the point of communication between cells, to discover which glutamatergic pathways are involved in a specific behavior. In this proposal I will utilize two stress paradigms (a social and non-social) to isolate the effects of social stress on social reward processing. I will utilize manipulation of specific cells with light-activated ion channels and transgenic lines in combination with electrophysiology to study glutamatergic synapses of the thalamus impinging upon regions important in reward processing and social behavior, specifically the prefrontal cortex and nucleus accumbens. This proposal hypothesizes that social stress will have unique synaptic adaptations when compared to non-social stress and these adaptions are specifically involved in regulating social reward processing. Preliminary results demonstrate the involvement of thalamic cells synapsing on nucleus accumbens neurons in social interaction and the impaired acquisition of a social conditioned-place preference selectively by social stress. This study will seek to further understand how altering activity at these synapses can alleviate stress induced impairments in social behavior, as well as examining other thalamic based circuits that may regulate social behavior. The information gathered from these studies will provide novel starting points for developing unique therapies to alter circuit function and alleviate specific symptoms of psychiatric disorders.

 描述（由申请人提供）：人们很快就清楚地认识到，精神疾病的症状，如社交回避，存在于多种情况下，可能具有单一的神经功能障碍，这些神经功能障碍是其表现的基础。自闭症、精神分裂症、抑郁症和与焦虑有关的疾病都存在社会异常，这些疾病在精神疾病患者中占很大比例。虽然存在许多药物疗法，但治疗大多数患者的成功率低得令人惊讶。这突出了在多个模型中研究共同症状的紧迫性，同时检查新的大脑回路以解析出导致适应不良行为的特定适应。虽然大脑的多巴胺系统显然与精神疾病有关，但大脑的主要神经递质谷氨酸也与精神疾病有关。 最近被认为与某些潜在的精神症状有关，但由于它在整个大脑中无处不在，其功能一直难以确定。许多关于压力对大脑影响的研究已经发现，它会改变细胞形态和电特性，然而这些研究中的许多都发生在离散的大脑区域，而不知道细胞的输入。随着新型病毒技术和转基因小鼠品系的出现，现在有可能分离出特定的突触，细胞之间的通信点，以发现哪些突触能通路参与特定的行为。在这个建议中，我将利用两种压力范式（社会和非社会）来隔离社会压力对社会奖励的影响 处理.我将利用光激活离子通道和转基因细胞系结合电生理学的特定细胞的操作来研究丘脑的突触对奖励处理和社会行为的重要区域的影响，特别是前额叶皮层和丘脑核。这个建议假设，社会压力将有独特的突触适应相比，非社会压力和这些适应具体参与调节社会奖励处理。初步结果表明，参与丘脑神经元突触上的丘脑神经元在社会互动和受损的收购社会条件的地方偏好选择性的社会压力。这项研究将寻求进一步了解如何改变这些突触的活动可以减轻压力引起的社会行为障碍，以及检查其他可能调节社会行为的丘脑回路。从这些研究中收集的信息将为开发独特的治疗方法提供新的起点，以改变回路功能并减轻精神疾病的特定症状。