Long-range GABAergic inhibition coordinates hippocampal-subcortical circuit activity in memory formation

项目摘要 海马体对于空间导航、学习和记忆至关重要，并且与 许多皮层和皮层下区域。除了明确的长距离电磁投射外， 新出现的证据表明，一组不同的GABA能抑制性神经元也可以发送长距离 向遥远的地方投射。这种长距离抑制是同步节律活动的理想位置， 协调多个大脑区域的细胞整体活动，以参与各种行为任务。一个这样 例如，θ振荡--一种4-12 Hz的节律活动，对记忆编码和提取很重要。 然而，尽管长程抑制在协调细胞间活性方面具有潜在的重要性， 海马和其他大脑区域，其细胞身份，电生理特性，连接性， 行为角色仍然知之甚少。在我们的初步实验中，我们进行了顺行追踪， 为了证明生长抑素表达，而不是小清蛋白表达，抑制神经元中， 海马CA 3区投射到两个皮质下区域，称为θ振荡的起搏器-内侧 下丘脑的Broca隔对角束（MS-DB）和乳头体上核（SUM）。离体 Rhodopsin 2（ChR 2）辅助的膜片钳记录进一步揭示了这些长距离抑制性细胞凋亡的机制。 神经元优先抑制MS-DB和GABA能神经元中假定的GABA能和谷氨酸能神经元， SUM中的神经元，以及表达生长抑素的轴突的光遗传学刺激强烈地夹带了 突触后MS-DB神经元在θ频率。因此，我们假设生长抑素表达 CA 3中的抑制性神经元发送长距离投射以协调CA 3、MS-DB和 θ振荡期间的SUM。在这个建议中，我们将执行交叉病毒为基础的神经跟踪和执行 活体脑切片膜片钳记录，以确定解剖学连接和细胞及突触特性 长距离投射生长抑素表达神经元，并确定其功能连接， 本地和远程目标区域。此外，我们将采用体内电生理学，闭环 光遗传学刺激和行为分析，以确定这些长距离生长抑素表达 抑制性神经元在记忆中起着协调海马和MS-DB或SUM之间活动的作用 阵海马体和其他大脑之间的协调和同步异常 这些区域与许多大脑疾病有关，如阿尔茨海默病，精神分裂症， 抑郁症，建议的研究不仅会加深我们对生理功能的认识， 海马长程抑制，也为今后的研究提供了知识基础，探讨其作用 这些疾病的长期抑制作用。

PROJECT ABSTRACT The hippocampus is vital for spatial navigation, learning and memory, and is extensively interconnected with many cortical and subcortical regions. In addition to the well-defined long-range glutamatergic projections, emerging evidence suggests that a diverse group of GABAergic inhibitory neurons can also send long-range projections to distant areas. This long-range inhibition is ideally positioned to synchronize rhythmic activity and coordinate cell ensemble activity of multiple brain areas to participate in various behavioral tasks. One such example is theta oscillations – a 4-12 Hz rhythmic activity important for memory encoding and retrieval. However, despite the potential importance of the long-range inhibition in coordinating activity between the hippocampus and other brain regions, its cell identity, electrophysiological properties, connectivity, and behavioral roles remain poorly understood. In our preliminary experiments, we performed anterograde tracing to demonstrate that somatostatin-expressing, but not parvalbumin-expressing, inhibitory neurons in the hippocampal CA3 region project to two subcortical areas known as pacemakers for theta oscillations – medial septum-diagonal band of Broca (MS-DB) and supramammillary nucleus (SUM) in the hypothalamus. Ex vivo ChannelRhodopsin2 (ChR2)-assisted patch-clamp recordings further revealed that these long-range inhibitory neurons preferentially inhibit presumptive GABAergic and glutamatergic neurons in MS-DB and GABAergic neurons in SUM, and optogenetic stimulation of somatostatin-expressing axons robustly entrained firing of postsynaptic MS-DB neurons at theta frequencies. We, therefore, hypothesize that somatostatin-expressing inhibitory neurons in CA3 send long-range projection to coordinate cell ensemble activity of CA3, MS-DB and SUM during theta oscillations. In this proposal, we will perform intersectional viral-based neural tracing and ex vivo brain-slice patch-clamp recordings to define anatomical connectivity and cellular and synaptic properties of long-range projecting somatostatin-expressing neurons, and determine their functional connections with both local and remote target regions. Furthermore, we will employ in vivo electrophysiology, closed-loop optogenetic stimulation, and behavior analysis to determine whether these long-range somatostatin-expressing inhibitory neurons play a role in coordinating activity between the hippocampus and MS-DB or SUM in memory formation. As abnormalities in coordination and synchronization between the hippocampus and other brain areas have been implicated in numerous brain disorders, such as Alzheimer’s disease, schizophrenia, and major depression, the proposed studies will not only deepen our understanding of physiological functions of hippocampal long-range inhibition, but also provide a knowledge base for future studies to examine the role of long-range inhibition in these diseases.