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

5-羟色胺(5-HT)系统广泛参与应激情绪的病理生理学过程。 精神障碍，如焦虑和严重抑郁。选择性5-羟色胺再摄取抑制剂(SSRI)是最多的 广泛使用的抗抑郁药物来治疗这些疾病。与情绪障碍和 SSRI治疗的疗效在于对成年海马神经发生的调节，这是一个新的产生过程 成体齿状回(DG)神经前体细胞(NPC)神经元。重要的是，压力，情绪 疾病和SSRI治疗都被证明改变了5-羟色胺系统并影响成年海马区 神经发生，提示5-羟色胺信号在调节这一过程中起着关键作用。目前，我们有有限的 了解5-羟色胺能对成年海马神经发生的调节，主要是由于5-羟色胺能调节神经发生的广泛作用。 5-羟色胺对神经源性壁龛的影响及成人出生时5-羟色胺受体表达模式的缺乏信息 细胞。鉴定5-羟色胺受体的细胞类型特异性表达是具有挑战性的，因为5-羟色胺能够 与14种不同的5-羟色胺受体亚型结合。为了填补我们理解上的这些空白，我们进行了初步的 研究表明，功能性5HT1a受体(5HT1ARs)早期在成人鼻咽癌中表达， 包括1型神经干细胞和2a型早期神经前体细胞。令人惊讶的是，功能强大的5HT1AR Npc只在雌性(而不是雄性)小鼠中发现。支持5HT1ARs的性别依赖性表达 我们发现，成人鼻咽癌中5HT1ARs的选择性缺失会导致新生儿显著减少 仅在女性(不包括男性)中从鼻咽癌细胞中获得细胞。这些结果表明，5HT1ARs在脑内的表达 鼻咽癌是以性别相关的方式进行正常的谱系进化所必需的。这些有趣的东西 这些发现引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在外部刺激诱导的早期神经源性反应中的细胞自主和性别依赖的贡献 和5-羟色胺能回路刺激；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缺陷的成年神经前体细胞的发育；在目标3中，我们将研究5HT1AR缺失的新生神经元在海马区网络活动和海马依赖行为中的作用。

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.