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

Award Number: R01MH130367
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/06/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $485,020 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Mental Health Research Grants	000	4	1/20/2026	NON-COMPETING CONTINUATION	$485,020
														Subtotal = $485,020

Issue Date FY: 2025 ( Subtotal = $485,020 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Mental Health Research Grants	000	3	2/19/2025	NON-COMPETING CONTINUATION	$412,267
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Mental Health Research Grants	001	3	9/19/2025	NON-COMPETING CONTINUATION	$72,753
														Subtotal = $485,020

Issue Date FY: 2024 ( Subtotal = $485,020 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Mental Health Research Grants	001	2	8/14/2024	NON-COMPETING CONTINUATION	$48,502
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Mental Health Research Grants	000	2	1/19/2024	NON-COMPETING CONTINUATION	$436,518
														Subtotal = $485,020

Issue Date FY: 2023 ( Subtotal = $500,270 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Mental Health Research Grants	000	1	3/6/2023	NEW	$500,270
														Subtotal = $500,270

Grand Total All Awards = $1,955,330

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

Award Number: R01MH130367

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/06/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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