Corticothalamic control of social motivation

皮质丘脑控制社会动机

基本信息

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
项目类别：
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

项目摘要

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.

皮质丘脑控制社会动机抽象的社交障碍是抑郁症、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的机制社会行为仍不清楚。在人类和啮齿类动物中，内侧前额叶皮层 (mPFC) 被认为发挥着对社会行为的自上而下的抑制控制，但所涉及的独特神经回路尚未阐明。虽然 mPFC 神经元的非特异性整体激活会降低社交能力，但最近的报告表明了这些影响由后室旁丘脑 (pPVT)（丘脑中线核）的活动变化介导已知在动机和情感行为中发挥作用。该提案旨在确定小清蛋白是否 pPVT 投射 mPFC 神经元中 mPFC 门控活动的 (PV) 中间神经元，以调节社会动机。我们的试验数据表明，mPFC-pPVT 通路的化学遗传学激活抑制了男性的社交动机但不是雌性老鼠。基于这一观察，我们假设 pPVT 投射的 mPFC 神经元发挥顶部- 以特定性别的方式降低对社会动机的抑制控制。在雄性小鼠中，我们预测有效社交参与需要通过激活附近的 PV 来抑制 mPFC-pPVT 回路的活动中间神经元。该假设将使用转基因小鼠、病毒光遗传学结构、行为测试、体内钙成像和膜片钳记录。目标 1 将利用光遗传学精确地激活或抑制 pPVT 中 mPFC 神经元的轴突末端，以揭示如何操纵该电路进行调节社会动机。目标 2 将通过纤维光度测定、化学遗传学、和转基因小鼠以确定 mPFC-pPVT 神经元在社交互动过程中是否沉默方式依赖于 PV 中间神经元活动。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 电路。这项研究将提供第一个针对性别的证据 mPFC-pPVT 通路代表了社交大脑中以前被忽视的一个组成部分，尤其是在女性中小鼠，并对 mPFC 中的 PV 中间神经元在社会动机的调节。