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

项目摘要 海马体对空间导航、学习和记忆至关重要，并与 许多皮质和皮质下区域。除了明确的长期谷氨酸能投射外， 新的证据表明，一组不同的GABA能抑制神经元也可以发送长距离 投射到遥远地区。这种长程抑制非常适合于同步节律活动和 协调多个脑区的细胞集合活动，以参与各种行为任务。这样的一个 Theta振荡就是一个例子，这是一种4-12赫兹的节律活动，对记忆编码和提取很重要。 然而，尽管远程抑制在协调两种动物之间的活动方面具有潜在的重要性 海马区和其他脑区，其细胞特性，电生理特性，连通性，以及 人们对行为角色仍知之甚少。在我们的初步实验中，我们进行了顺行追踪 证明生长抑素表达，而不是小白蛋白表达，抑制神经元 海马CA3区投射到两个皮质下区域，称为theta振荡的起搏器-内侧 下丘脑的Broca隔-斜角带(MS-DB)和乳突上核(Sum)。体外实验 ChannelRhotopin2(ChR2)辅助的膜片钳记录进一步揭示了这些长程抑制作用 MS-DB和GABA能神经元优先抑制GABA能和谷氨酸能神经元 总之，神经元和光遗传刺激的生长抑素表达轴突强烈地携带着放电 突触后的MS-DB神经元的频率为theta。因此，我们假设生长抑素的表达 CA3区抑制性神经元发出长程投射以协调CA3、MS-DB和 在theta振荡期间求和。在这项提议中，我们将进行基于病毒的交叉神经追踪和 活体脑片膜片钳记录确定解剖连接及细胞和突触特性 远距离投射生长抑素表达神经元，并确定它们与 包括本地和远程目标区域。此外，我们将采用体内电生理学，闭环系统 光遗传刺激和行为分析，以确定这些远程生长抑素是否表达 抑制性神经元在协调记忆中MS-DB或SUM的活动中起作用 队形。作为海马体和其他大脑之间的协调和同步的异常 这些区域与许多大脑疾病有关，如阿尔茨海默氏症、精神分裂症和 对于重度抑郁症，建议的研究不仅将加深我们对生理功能的了解 对海马区的远程抑制作用，也为今后的研究提供了知识基础，以考察其作用 对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.