Corticothalamic control of social motivation

皮质丘脑控制社会动机

基本信息

批准号：
10529968
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/10529968
关键词：
Affect Anxiety Behavior Behavioral Mechanisms Brain Brain region Calcium Cells Data Dose Exposure to Female Fiber 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 Techniques Testing Thalamic structure Time Transgenic Mice Viral Work autism spectrum disorder base behavior test clinically relevant common symptom designer receptors exclusively activated by designer drugs emotional behavior 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.

皮质丘脑对社会动机的控制抽象的社会障碍是抑郁症，精神分裂症等精神疾病中的常见症状和自闭症。但是，大脑处理社会信息并使用它来指导的机制社会行为尚不清楚。在人类和啮齿动物中，内侧前额叶皮层（MPFC）被认为施加自上而下的抑制性控制对社会行为，但涉及的独特神经回路尚未阐明。虽然非特异性的MPFC神经元的全球激活降低了社交性，但最近的报告表明这些影响由后脊髓丘脑（PPVT）的活性变化（一种中线丘脑核）介导知道在动机和情感行为中发挥作用。该建议旨在确定白细胞素是否（PV）MPFC栅极活性中的中间神经元在PPVT投射MPFC神经元中以调节社会动机。我们的试验数据表明，MPFC-PPVT途径的化学发生激活抑制了男性的社会动机但不是雌鼠。基于这一观察结果，我们假设PPVT投射MPFC神经元在以性别特定方式对社会动机的抑制作用。在雄性小鼠中，我们预测有效社交参与需要抑制通过附近PV介导的MPFC-PPVT电路的活动中间神经元。该假设将使用转基因小鼠，病毒遗传构建体的组合进行检验行为测试，体内钙成像和斑块钳记录。 AIM 1将使用光遗传学精确激活或抑制PPVT中MPFC神经元的轴突末端，以揭示如何操纵该电路调节社会动机。 AIM 2将通过纤维光度法，化学遗传学，结合途径特异性钙成像，和转基因小鼠，以确定在社交互动过程中是否沉默的MPFC-PPVT神经元取决于PV中间神经元活性的方式。 AIM 3将确定生理差异是否存在男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的证据 MPFC-PPVT途径代表了社交大脑的先前被忽视的组成部分，尤其是在女性中小鼠，以及对MPFC中PV中间神经元在该电路机制中发挥作用的新颖见解调节社会动机。