Experience-dependent maturation of prefrontal circuitry in control of social behavior

控制社会行为的前额叶回路的经验依赖性成熟

• 批准号: 9980495
• 负责人: Hirofumi Morishita
• 金额: $ 52.35万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-18 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980495
• 关键词: Action Potentials; Acute; Adolescent; Adult; Affect; Animals; Behavior; Calcium; Cells; Childhood; Coupled; Dimensions; Disease; Electrophysiology (science); Exhibits; Female; Fiber; Frequencies; Goals; Image; Interneurons; Measures; Medial; Mediating; Mental disorders; Monitor; Motor Activity; Mus; Neurodevelopmental Disorder; Neurons; Photometry; Play; Population; Positioning Attribute; Prefrontal Cortex; Process; Pyramidal Cells; Shapes; Signal Transduction; Slice; Social Behavior; Social Controls; Social Interaction; Social isolation; Somatostatin; Source; Structure of paraventricular nucleus of thalamus; Synapses; Techniques; Technology; Testing; Thalamic structure; Wireless Technology; anxiety-related behavior; base; cell type; experience; hippocampal pyramidal neuron; improved; in vivo; inhibitory neuron; insight; male; novel; optogenetics; p65; patch clamp; preference; recruit; relating to nervous system; reward circuitry; sensory cortex; social; social deficits; therapeutic target

Social experience during childhood is essential to establish proper function in the adult prefrontal cortex (PFC) and related behaviors including social behavior, a fundamental process across species. However, the specific circuits that undergo social experience-dependent maturation to regulate social behavior are poorly understood. Given that social process deficit is a common dimension of many neurodevelopmental and psychiatric disorders, identifying the specific circuits sensitive to experience-dependent modulation will point toward therapeutic targets that allow amelioration of social processing deficits shared across of range of disorders. The objective of this study is to elucidate the PFC circuit mechanisms underlying social experience- dependent maturation crucial to mediate proper social behavior. In mice, juvenile social isolation leads to adult social behavior deficits and accompanies deficits in sub-cortically projecting deep layer medial PFC (mPFC) pyramidal neurons. Among various sub-cortical targets, our preliminary study identified the limbic thalamus which receives and relays signals to various components of the classical reward circuitry, as the most prominent projection target from mPFC that is preferentially recruited by social interaction. Importantly, juvenile social isolation reduced excitability of this projection neuron and increased their inhibitory drive. Among various types of inhibitory neurons, a selective subclass of deep layer inhibitory neuron, known to be essential to oscillate subcortically projecting deep layer cortical neurons, were the only population that exhibited elevated excitability after juvenile social isolation. This project will test the hypothesis that juvenile social experience- dependent maturation of deep layer mPFC projection neurons to limbic thalamus and its modulation by deep layer mPFC inhibitory neurons drives coordinated activity in mPFC and limbic thalamus to effectively modulate social behavior. We will test this hypothesis by integrating techniques to measure (fiber photometry imaging, patch-clamp/ in vivo electrophysiology) and manipulate (optogenetics/chemogenetics) the activities of selective circuits during social behavior in mice.

童年时期的社交经验对于在成人前额叶皮层（PFC）中建立适当的功能至关重要 以及相关行为，包括社会行为，一个跨物种的基本过程。但是，具体 经历社会经验的成熟以调节社会行为的电路很差 理解。鉴于社会过程赤字是许多神经发育和 精神疾病，确定对经验依赖性调制敏感的特定电路将指向 实现治疗靶标，可以改善社会处理缺陷的范围 疾病。这项研究的目的是阐明社会经验的PFC电路机制 - 依赖的成熟对于调解适当的社会行为至关重要。在小鼠中，少年社会隔离导致成人 社会行为不足，并伴随着下层投射深层内侧PFC（MPFC）的缺陷 金字塔神经元。在各种亚皮质靶标中，我们的初步研究确定了边缘丘脑 它接收和继电器信号与经典奖励电路的各个组成部分，是最多的 MPFC的著名投影目标优先通过社会互动招募。重要的是，少年 社会隔离降低了这种投射神经元的兴奋性，并增加了其抑制作用。在各种 抑制性神经元的类型，一种深层抑制神经元的选择性子类，已知对 振荡振荡的从下皮层投射深层皮质神经元，是唯一表现出升高的人群 少年社会隔离后的兴奋性。该项目将检验少年社交经验的假设 - 深层MPFC投影神经元对边缘丘脑的依赖性成熟及其调节 层MPFC抑制性神经元驱动MPFC和边缘丘脑中的协调活性，以有效调节 社会行为。我们将通过集成技术来测量（纤维光度成像， 斑块夹/体内电生理学）和操纵（光遗传学/化学遗传学）选择性的活性 小鼠社会行为期间的电路。