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

长程 GABA 能抑制协调记忆形成中的海马-皮层下回路活动

• 批准号: 10658072
• 负责人: Qian Sun
• 金额: $ 50.03万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-06 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658072
• 关键词: Address; Affect; Alzheimer' s Disease; Anatomy; Area; Ataxia; Axon; Behavior; Behavioral; Brain; Brain Diseases; Brain region; Cell Nucleus; Cells; Dependovirus; Diagonal Band of Broca; Disease; Distant; Electrophysiology (science); FLP recombinase; Frequencies; Future; Glutamates; Hippocampus; Hypothalamic structure; Immunohistochemistry; Injections; Interneurons; Knowledge; Label; Learning; Literature; Major Depressive Disorder; Medial; Memory; Mental Depression; Mental disorders; Mus; Neurons; Pacemakers; Pathway interactions; Periodicity; Physiological; Population; Population Dynamics; Positioning Attribute; Property; Research; Role; Schizophrenia; Slice; Somatostatin; Subgroup; Synapses; Testing; Viral; Whole-Cell Recordings; cell type; cholinergic neuron; electrical property; experimental study; hippocampal pyramidal neuron; in vivo; inhibitory neuron; insight; knowledge base; memory encoding; memory retrieval; nervous system disorder; neural; neurochemistry; optogenetics; patch clamp; postsynaptic; spatial memory; way finding

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.

项目摘要 海马体对于空间导航、学习和记忆至关重要，并且主要与 许多皮质和皮质下区域除了明确的长程谷氨酸投射外， 新出现的证据表明，多种 GABA 能抑制神经元也可以发送长距离信号 这种远程抑制非常适合同步节律活动和 协调多个大脑区域的细胞群活动以参与各种行为任务。 例如，theta 振荡——一种 4-12 Hz 的节奏活动，对于记忆编码和检索非常重要。 然而，尽管远程抑制在协调细胞之间的活动方面具有潜在的重要性， 海马体和其他大脑区域，其细胞身份、电生理特性、连接性和 在我们的初步实验中，我们对行为角色仍然知之甚少，我们进行了顺行追踪。 证明生长抑素表达而非小白蛋白表达的抑制性神经元 海马 CA3 区域投射到两个皮层下区域，称为 θ 振荡起搏器 – 内侧 下丘脑中布罗卡（MS-DB）和乳头上核（SUM）的隔对角带。 ChannelRhodopsin2 (ChR2) 辅助的膜片钳记录进一步揭示了这些长程抑制 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 中的神经元和表达生长抑素的轴突的光遗传学刺激强烈地带动了 因此，我们捕获了表达生长抑素的突触后 MS-DB 神经元。 CA3 中的抑制性神经元发送远程投射来协调 CA3、MS-DB 和 θ 振荡期间的 SUM 在本提案中，我们将执行基于交叉病毒的神经追踪和 ex。 体内脑切片膜片钳记录，用于定义解剖连接以及细胞和突触特性 长程投射生长抑素表达神经元，并确定它们与 此外，我们将采用体内电生理学、闭环技术。 光遗传学刺激和行为分析以确定这些长程生长抑素表达是否 抑制性神经元在协调记忆中海马体和 MS-DB 或 SUM 之间的活动中发挥作用 由于海马体和其他大脑之间的协调和同步异常。 这些区域与许多脑部疾病有关，例如阿尔茨海默病、精神分裂症和 重度抑郁症，所提出的研究不仅将加深我们对抑郁症生理功能的理解 海马长程抑制，也为未来研究检验其作用提供知识基础 长程抑制这些疾病。