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

项目摘要 催产素是一种在下丘脑室旁核和视上核产生的神经肽类激素。 下丘脑与生理过程有关，如出生和哺乳，以及 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一直没有得到充分的研究。我的初步数据显示 与感觉处理和社会行为有关的许多大脑区域将单突触输入发送到 室旁核，包括丘脑的后板层(PIL)复合体。我进一步表明，许多PIL-PVN 投射是谷氨酸能的，PIL直接输入到催产素细胞，而PIL是 在社交互动期间被激活。先前的研究表明，谷氨酸调节催产素的神经活动 在哺乳期雌性啮齿动物体内和从成年雄性和新生儿获得的切片中进行体外实验。然而， 谷氨酸-催产素回路在社会行为中的功能相关性仍不清楚。 新的研究表明，谷氨酸能信号转导功能障碍导致突触受损 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危险基因都是谷氨酸能的关键成分。 突触，包括SHANK3。因此，我推测下丘脑室旁核的谷氨酸能传入，尤其是那些 起源于与社会刺激的处理有关的大脑区域，对调节 催产素神经元在社会行为中的活动，而Shank3突变干扰了这种活动。在这 提议，我将通过描述下丘脑室旁核内催产素神经元的输入的特性来说明我的假设 并使用病毒和化学遗传工具操纵它们，以评估它们在社会行为中的作用。我还将使用 Miniscope技术对催产素神经元进行体内钙成像以捕捉神经活动 自由活动野生型和Shank3基因缺陷小鼠的社会行为。此外，使用这项技术在 结合化学发生学工具，我将剖析特定的谷氨酸能-室旁核回路在脑内的作用。 调节催产素神经元的活动。这项研究将提供有关功能角色的知识 谷氨酸能传入下丘脑室旁核，调节社会行为和催产素神经活动。此外，这项研究 将研究Shank3突变对催产素系统的特定影响，这可能会为潜在的靶点提供信息 接受治疗。

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.