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

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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.