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（5HT）系统已广泛与压力诱导的情绪的病理生理有关 疾病，例如焦虑和严重抑郁症。选择性5-羟色胺再摄取抑制剂（SSRI）最多 广泛使用的抗抑郁药治疗这些疾病。与情绪障碍和 SSRI治疗的功效是对成年海马神经发生的调节 成人齿状回（DG）中神经前体细胞（NPC）的神经元。重要的是，压力，情绪 疾病和SSRI治疗均已证明可以改变5HT系统并影响成年海马 神经发生，表明5HT信号对于调节此过程至关重要。目前，我们有限 了解成年海马神经发生的血清素能调节，这在很大程度上是由于广泛的作用 在神经源性的小众市场上的5HT和成人出生中5HT受体表达模式的信息缺乏信息 细胞。 5HT受体的细胞类型特异性表达的鉴定是具有挑战性的，因为5HT能够 与14个不同的5HT受体亚型结合。为了填补这些空白，我们进行了初步 研究并证明功能性5HT1A受体（5HT1AR）在成年NPC的早期表达， 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5HT1AR NPC仅在雌性（但没有雄性）小鼠中发现。支持5HT1AR的性别依赖性表达 NPC，我们发现成人NPC中5HT1AR的选择性删除导致新生儿的显着降低 仅在女性（不是男性）中衍生自NPC的细胞。这些结果表明5HT1AR在 NPC以性别依赖性方式适当地进行NPC的谱系进展。这些很有趣 调查结果引发了我们提出的几个直接方向：在AIM 1中，我们将检查5HT1AR对外部神经发生反应的细胞自主和性依赖性贡献 和血清素能电路刺激；在AIM 2中，我们将研究膜潜力在调节中的因果作用 正常和5HT1AR缺乏的成年NPC的发展；在AIM 3中，我们将研究5HT1AR骨缺失的新生神经元在海马网络活性和海马依赖性行为中的作用。