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

血清素（5HT）系统广泛涉及压力诱发情绪的病理生理学 疾病，例如焦虑症和重度抑郁症。选择性血清素再摄取抑制剂（SSRIs）是最有效的 广泛使用抗抑郁药来治疗这些疾病。与情绪障碍和 SSRI 治疗的功效在于调节成人海马神经发生，这是产生新神经元的过程。 来自成人齿状回 (DG) 神经前体细胞 (NPC) 的神经元。重要的是压力、心情 疾病和 SSRI 治疗均已被证明可以改变 5HT 系统并影响成人海马 神经发生，表明 5HT 信号传导对于调节这一过程至关重要。目前，我们有限 对成人海马神经发生的血清素调节的了解，很大程度上是由于 5HT 对神经源性生态位的影响以及成人出生的 5HT 受体表达模式信息的缺乏 细胞。鉴定 5HT 受体的细胞类型特异性表达具有挑战性，因为 5HT 能够 与 14 种不同的 5HT 受体亚型结合。为了填补我们理解上的这些空白，我们进行了初步的研究 研究并证明功能性 5HT1A 受体 (5HT1AR) 在成年 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。引人注目的是，功能性 5HT1AR NPC 仅存在于雌性（而非雄性）小鼠中。支持 5HT1AR 的性别依赖性表达 NPCs，我们发现成人NPCs中选择性删除5HT1AR会导致新生儿的显着减少 源自 NPC 的细胞仅存在于女性（而非男性）中。这些结果表明 5HT1AR 的表达 NPC 是 NPC 以性别依赖性方式正确谱系进展所必需的。这些有趣的 研究结果激发了我们建议追求的几个直接方向：在目标 1 中，我们将检查 5HT1AR 对外部诱导的早期神经源性反应的细胞自主和性别依赖性贡献 和血清素能回路刺激；在目标 2 中，我们将研究膜电位在调节中的因果作用 正常和 5HT1AR 缺陷的成年 NPC 的发育；在目标 3 中，我们将研究 5HT1AR 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。

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.