Corticothalamic control of social motivation

皮质丘脑控制社会动机

• 批准号: 10661763
• 负责人: Wen-Jun Gao
• 金额: $ 37.64万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-07 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10661763
• 关键词: Affect; Anxiety; Behavior; Brain; Brain region; Calcium; Cells; Data; Dose; Equilibrium; Exposure to; Female; Fiber; Genetic; Genetic Techniques; Home; Human; Image; Impairment; Interneurons; Investigation; Link; Medial; Mediating; Mental Depression; Mental disorders; Midline Thalamic Nuclei; Monitor; Motivation; Mus; Neurons; Optics; Parvalbumins; Pathway interactions; Photometry; Physiological; Physiology; Pilot Projects; Play; Population; Prefrontal Cortex; Presynaptic Terminals; Process; Property; Publishing; Regulation; Reporting; Rewards; Rodent; Role; Same-sex; Schizophrenia; Sex Differences; Shapes; Slice; Social Behavior; Social Conditions; Social Controls; Social Interaction; Stimulus; Testing; Thalamic structure; Time; Transgenic Mice; Viral; Work; autism spectrum disorder; behavior test; clinically relevant; common symptom; designer receptors exclusively activated by designer drugs; emotional behavior; genetic approach; in vivo calcium imaging; insight; male; motivated behavior; neural circuit; neurotransmission; novel; optogenetics; patch clamp; pre-clinical; preference; sex; social; social contact; social engagement

Corticothalamic control of social motivation Abstract Social impairments are a common symptom among psychiatric disorders such as depression, schizophrenia, and autism. However, the mechanisms by which the brain processes social information and uses it to guide social behaviors remain unclear. In humans and rodents, the medial prefrontal cortex (mPFC) is thought to exert top-down inhibitory control over social behaviors, but the distinct neural circuitry involved has yet to be elucidated. While non-specific global activation of mPFC neurons decreases sociability, recent reports indicate these effects are mediated by activity changes in the posterior paraventricular thalamus (pPVT), a midline thalamic nucleus known to play a role in motivated and emotional behaviors. This proposal aims to determine whether parvalbumin (PV) interneurons in the mPFC gate activity in pPVT-projecting mPFC neurons to regulate social motivation. Our pilot data indicate that chemogenetic activation of mPFC-pPVT pathway suppressed social motivation in male but not female mice. Based on this observation, we hypothesize that pPVT-projecting mPFC neurons exert top- down inhibitory control over social motivation in a sex-specific manner. In male mice, we predict that effective social engagement requires suppressed activity of the mPFC-pPVT circuit mediated by activation of nearby PV interneurons. This hypothesis will be tested using a combination of transgenic mice, viral optogenetic constructs, behavioral testing, in vivo calcium imaging, and patch-clamp recording. Aim 1 will use optogenetics to precisely activate or inhibit axonal terminals of mPFC neurons in the pPVT to reveal how manipulating this circuit regulates social motivation. Aim 2 will combine pathway-specific calcium imaging via fiber photometry, chemogenetics, and transgenic mice to determine whether mPFC-pPVT neurons are silenced during social interaction in a manner that is dependent on PV interneuron activity. Aim 3 will determine if physiological differences exist in the mPFC-pPVT circuit between male and female mice. This study will provide the first sex-specific evidence that the mPFC-pPVT pathway represents a previously overlooked component of the social brain, especially in female mice, and novel insights into the circuit mechanisms by which the PV interneurons in the mPFC play in the regulation of social motivation.

皮质丘脑对社会动机的控制 摘要 社交障碍是抑郁症、精神分裂症等精神疾病的常见症状， 和自闭症。然而，大脑处理社会信息并利用它来指导 社会行为仍然不清楚。在人类和啮齿类动物中，内侧前额叶皮层（mPFC）被认为发挥了 自上而下的抑制控制社会行为，但涉及的独特的神经回路尚未阐明。 虽然mPFC神经元的非特异性全局激活会降低社交性，但最近的报告表明这些影响 是由丘脑中线核室旁后核（pPVT）的活动变化介导的 在动机和情感行为中扮演着重要角色。该建议旨在确定小清蛋白是否 (PV)在pPVT投射的mPFC神经元中，mPFC门控活动中的中间神经元调节社会动机。我们 初步数据表明，mPFC-pPVT通路的化学发生激活抑制了男性的社会动机， 而不是雌性小鼠。基于这一观察结果，我们假设pPVT投射mPFC神经元发挥顶- 以性别特异的方式抑制对社会动机的控制。在雄性小鼠中，我们预测， 社会参与需要通过激活附近PV介导的mPFC-pPVT回路的抑制活动 中间神经元将使用转基因小鼠、病毒光遗传学构建体 行为测试、体内钙成像和膜片钳记录。Aim 1将使用光遗传学精确地 激活或抑制pPVT中mPFC神经元的轴突终末，以揭示如何操纵该回路调节 社会动机Aim 2将联合收割机通过纤维光度法，化学遗传学， 和转基因小鼠，以确定mPFC-pPVT神经元是否在社交互动中沉默， 这取决于PV中间神经元的活动。目标3将确定是否存在生理差异 雄性和雌性小鼠之间的mPFC-pPVT回路。这项研究将提供第一个性别特异性证据， mPFC-pPVT通路代表了以前被忽视的社会脑成分，特别是在女性中。 小鼠，以及对mPFC中PV中间神经元在mPFC中发挥作用的电路机制的新见解。 社会动机的调节。