Sex-dependent role of 5HT1A receptors in adult neurogenesis and hippocampal function

5HT1A受体在成人神经发生和海马功能中的性别依赖性作用

• 批准号: 10326829
• 负责人: Juan Song
• 金额: $ 57.1万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10326829
• 关键词: Adult; Alzheimer' s Disease; Antidepressive Agents; Anxiety; Behavior; Behavioral; Binding; Cells; Cognitive; Data; Development; Disease; Electrophysiology (science); Female; Fiber; Functional disorder; Hippocampus (Brain); Impairment; Link; Major Depressive Disorder; Mediating; Membrane; Membrane Potentials; Mood Disorders; Mus; Neurons; Newborn Infant; Nuclear Pore Complex; Pattern; Photometry; Play; Process; Production; Proliferating; Regulation; Role; Selective Serotonin Reuptake Inhibitor; Serotonin; Sex Differences; Signal Transduction; Slice; Stimulus; Stress; System; Testing; Treatment Efficacy; Woman; adult neurogenesis; cell type; density; dentate gyrus; improved; in vivo; men; nerve stem cell; neurogenesis; newborn neuron; personalized strategies; receptor; receptor expression; response; selective expression; serotonergic regulation; sex

The serotonin (5HT) system has been widely implicated in the pathophysiology of stress-induced mood disorders, such as anxiety and major depression. Selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants for treating these disorders. Strongly linked to both mood disorders and the efficacy of SSRI treatment is the regulation of adult hippocampal neurogenesis, a process of generating new neurons from neural precursor cells (NPCs) in the adult dentate gyrus (DG). Importantly, stress, mood disorders, and SSRI treatment have all been shown to alter the 5HT system and influence adult hippocampal neurogenesis, suggesting that 5HT signaling is critical for regulating this process. Currently, we have limited understanding of serotonergic regulation of adult hippocampal neurogenesis, largely due to the broad action of 5HT on the neurogenic niche and lack of information on the expression patterns of 5HT receptors in adult-born cells. Identification of cell-type specific expression of 5HT receptors is challenging because 5HT is capable of binding to 14 distinct 5HT receptor subtypes. To fill these gaps in our understanding, we performed preliminary studies and demonstrated that functional 5HT1A receptors (5HT1ARs) are expressed early in adult NPCs, including type 1 neural stem cells and type 2a early neural progenitors. Strikingly, the functional 5HT1ARs in NPCs are only found in female (but not male) mice. Supporting sex-dependent expression of 5HT1ARs in NPCs, we found that selective deletion of 5HT1ARs in adult NPCs leads to a significant reduction of newborn cells derived from NPCs only in females (not males). These results suggest that expression of 5HT1ARs in NPCs are required for proper lineage progression of NPCs in a sex-dependent manner. These interesting findings sparked several immediate directions we propose to pursue: In Aim 1, we will examine cell-autonomous and sex-dependent contributions of 5HT1ARs to early neurogenic responses induced by external and serotonergic circuit stimuli; In Aim 2, we will investigate the causal role of membrane potential in regulating development of normal and 5HT1AR-deficient adult NPCs; In Aim 3, we will examine the role of 5HT1AR-deleted newborn neurons in hippocampal network activity and hippocampus-dependent behavior.

5-羟色胺（5-HT）系统广泛参与应激诱导的情绪的病理生理学 焦虑症和重度抑郁症等疾病。选择性5-羟色胺再摄取抑制剂（SSRIs）是最 广泛使用的抗抑郁药来治疗这些疾病。与情绪障碍和 SSRI治疗的疗效是调节成年海马神经发生，这是一个产生新的海马神经元的过程。 成年齿状回（DG）的神经前体细胞（NPC）的神经元。重要的是，压力，情绪 这些疾病和SSRI治疗都显示出改变5 HT系统并影响成年海马 神经发生，表明5 HT信号传导对于调节这一过程至关重要。目前，我们拥有的 了解成年海马神经发生的多巴胺能调节，主要是由于 5-HT在神经原性生态位上的作用以及缺乏关于成人出生时5-HT受体表达模式的信息 细胞5 HT受体的细胞类型特异性表达的鉴定是具有挑战性的，因为5 HT能够 与14种不同的5 HT受体亚型结合。为了填补我们理解中的这些空白，我们进行了初步的 研究并证明功能性5 HT 1A受体（5 HT 1AR）在成人NPC中早期表达， 包括1型神经干细胞和2A型早期神经祖细胞。令人惊讶的是，功能性的5 HT 1AR在 NPC只存在于雌性（而非雄性）小鼠中。支持5 HT 1AR的性别依赖性表达， 我们发现，在成年NPC中选择性缺失5 HT 1ARs导致新生儿 仅在雌性（而非雄性）中源自NPC的细胞。这些结果表明，5 HT 1ARs的表达在人乳腺癌组织中是显著的。 NPC是以性别依赖的方式进行NPC的适当谱系进展所必需的。这些有趣 这些发现引发了我们提出的几个直接方向：在目标1中，我们将研究5 HT 1AR对外部刺激诱导的早期神经原性反应的细胞自主性和性别依赖性贡献。 在目标2中，我们将研究膜电位在调节神经元兴奋性和兴奋性回路刺激中的因果作用。 在目标3中，我们将研究5 HT 1AR缺失的新生神经元在海马网络活动和海马依赖性行为中的作用。