The role of glutamatergic inputs to the paraventricular nucleus of the hypothalamus in social behavior and oxytocin neural activity

下丘脑室旁核谷氨酸能输入在社会行为和催产素神经活动中的作用

• 批准号: 10383996
• 负责人: Amanda Leithead
• 金额: $ 4.52万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-20 至 2025-01-19
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10383996
• 关键词: Address; Adult; Affect; Anatomy; Back; Behavioral; Birth; Brain; Brain Diseases; Brain region; Calcium; Cells; Complex; Data; Disease; Female; Functional disorder; Gene Mutation; Glutamates; Goals; Hormones; Hypothalamic structure; Imaging Device; Immunohistochemistry; Impairment; In Vitro; Knowledge; Lactation; Light; Link; Milk Ejection; Mus; Mutation; Neural Pathways; Neuroendocrinology; Neurons; Neuropeptides; Outcome; Oxytocin; Pattern; Peripheral; Physiological; Physiological Processes; Play; Rattus; Research; Rodent; Role; Sensory; Slice; Social Behavior; Social Interaction; Stimulus; Symptoms; Synapses; Synaptic Transmission; System; Techniques; Technology; Testing; Thalamic structure; Training; Viral; Virus; autism spectrum disorder; calcium indicator; career; designer receptors exclusively activated by designer drugs; glutamatergic signaling; high risk; in vivo; in vivo calcium imaging; innovation; insight; interest; male; neonate; neural circuit; neuromechanism; paraventricular nucleus; promoter; relating to nervous system; risk variant; social; social deficits; supraoptic nucleus; tool; treatment strategy

Project Summary Oxytocin is a neuropeptide hormone produced in the paraventricular (PVN) and supraoptic nuclei of the hypothalamus that is implicated in physiological processes such as birth and lactation, as well as in the expression of social behaviors. To date, many studies have linked brain oxytocin with particular social behaviors, yet the neural pathways by which external social information is primarily conveyed to oxytocin neurons to modulate their neural activity and regulate social behavior have been understudied. My preliminary data indicates that many brain regions implicated in sensory processing and social behavior send monosynaptic inputs to the PVN, including the posterior intralaminar (PIL) complex of the thalamus. I further show that many PIL-PVN projections are glutamatergic, that the PIL inputs directly onto oxytocin cells specifically, and that the PIL is activated during social interaction. Previous studies have shown that glutamate regulates oxytocin neural activity in vivo in lactating female rodents and in vitro in slices obtained from adult males and neonates. However, the functional relevance of glutamate-oxytocin circuits in social behavior remains unknown. Emerging research indicates that dysfunction in glutamatergic signaling leads to impairments in synaptic transmission causing deficits in social behavior, which is a core symptom of autism spectrum disorder. Additionally, many of the identified risk genes for autism spectrum disorder are key components of glutamatergic synapses, including SHANK3. Therefore, I hypothesize that glutamatergic inputs to the PVN, especially those originating from brain regions that are implicated in the processing of social stimuli, are essential for regulating the activity of oxytocin neurons during social behavior and that Shank3 mutations disturb this activity. In this proposal, I will address my hypothesis by characterizing the identity of inputs to oxytocin neurons in the PVN and manipulating them, using viral and chemogenetic tools, to assess their role in social behavior. I will also use Miniscope technology to perform in vivo calcium imaging of oxytocin neurons to capture neural activity during social behavior in freely moving wild-type and Shank3-deficient mice. Furthermore, using this technology in combination with chemogenetic tools, I will dissect the contribution of specific glutamatergic-PVN circuits in modulating the activity of oxytocin neurons. This study will provide knowledge about the functional role of glutamatergic inputs to the PVN in regulating social behavior and oxytocin neural activity. Additionally, this study will examine the specific effect of Shank3 mutations on the oxytocin system, which could inform potential targets for treatment.

项目摘要 催产素是一种神经肽激素，产生于室旁核（PVN）和视上核， 下丘脑，涉及生理过程，如出生和哺乳，以及在 社会行为的表达。到目前为止，许多研究已经将大脑催产素与特定的社会行为联系起来， 然而，外部社会信息主要传递给催产素神经元的神经通路， 调节他们的神经活动和调节社会行为的研究还不够深入。我的初步数据显示 许多与感觉处理和社会行为有关的大脑区域将单突触输入发送到 PVN，包括丘脑的后板内（PIL）复合体。我进一步表明，许多PIL-PVN PIL直接输入到催产素细胞上，并且PIL是 在社会交往中被激活。先前的研究表明谷氨酸调节催产素神经活动 在哺乳期雌性啮齿动物体内以及在成年雄性和新生儿切片中进行体外研究。但 谷氨酸-催产素回路在社会行为中的功能相关性仍然未知。 新兴的研究表明，突触能信号传导功能障碍导致突触神经元的损伤。 传播导致社会行为缺陷，这是自闭症谱系障碍的核心症状。 此外，许多已确定的自闭症谱系障碍的风险基因是自闭症的关键组成部分。 突触，包括SHANK 3。因此，我假设PVN的神经元输入，特别是那些 来自涉及处理社会刺激的大脑区域，对于调节 催产素神经元在社会行为中的活动以及Shank 3突变干扰了这种活动。在这 在一个建议中，我将通过描述PVN中催产素神经元的输入的身份来解决我的假设 操纵它们，使用病毒和化学遗传学工具，来评估它们在社会行为中的作用。我也会用 微型显微镜技术进行催产素神经元的体内钙成像，以捕获 自由活动的野生型和Shank 3缺陷小鼠的社会行为。此外，利用这项技术， 结合化学发生学工具，我将剖析特定的介电-PVN电路在 调节催产素神经元的活性。这项研究将提供有关功能作用的知识， 在调节社会行为和催产素神经活动中对PVN的兴奋性输入。此外，这项研究 将研究Shank 3突变对催产素系统的具体影响，这可能会告知潜在的目标 接受治疗