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Decoding the Mechanisms of Oxytocinergic Regulation in the Hippocamposeptal Circuit: Implications for Social Dysfunction in Alzheimer's Disease

Award Number: K01AG086573
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Decoding the Mechanisms of Oxytocinergic Regulation in the Hippocamposeptal Circuit: Implications for Social Dysfunction in Alzheimer's Disease - Project Summary/Abstract This K01 mentored training grant is designed to support Dr. Jinjing Liu in becoming an independent investigator in the Alzheimer’s disease (AD) field. The proposal’s scientific and training goals center on the study of the neurobiological basis of pathological social aggression in AD. Pathological social aggression appears in 30-50% of AD patients, impacting their quality of life, causing distress for caregivers, and imposing immense socioeconomic burden. Yet the neural mechanisms that contribute to social aggressive behavior, particularly within the context of AD, remain largely unknown and options to treat aggression in AD patients are limited. Under non-disease conditions, socially aggressive behavior is the result of complex signal integration involving information about internal state (social motivation, anxiety) and social stimuli (familiarity/novelty/threat perception). Classical lesion studies as well as more recent neurophysiological studies implicate the lateral septum (LS) in the control of this behavior. However, we do not understand the circuit-level mechanisms, nor do we know how AD-related pathology disrupts its function. This proposal’s overarching goal is to identify these circuits so that we may identify therapeutic targets for social dysfunction associated with AD. Existing literature and preliminary data support a hypothesis that AD-related pathology disrupts a specific extrahippocampal projection (CA2 to LSi pathway) by impairing neuropeptide oxytocin (OXT) function within this circuit. The proposed work will test this hypothesis by (1) establishing the role of the intermediate lateral septum (LSi) as a key integrator of cognitive information coming from the hippocampus (CA2) and OXT- sensitive inputs about internal motivation and anxiety state; (2) determining how AD-related pathology impacts CA2LSi circuitry to disrupt the normal regulation of social aggressive behavior; and (3) exploring the translational potential of enhanced OXT signaling in the LSi to restore circuit function and improve behavioral outcomes. The approach is innovative and achieves technical training goals by leveraging an array of modern neuronal recording and manipulation techniques, including Patch-seq, in combination with neural tracing and the use of a novel optically-sensitive caged OXT reagent developed in our lab that can achieve closed-loop spatiotemporal control over OXT release when combined with large-scale in vivo recording. The mentor team includes experts Dr. Richard Tsien (biophysics and synaptic physiology); Dr. Arjun Masurkar (clinical manifestations and mechanisms of AD); and Dr. György Buzsáki (systems and computational neuroscience). Building off extensive expertise in synaptic and ion channel physiology and animal behavior Dr. Liu will pursue this work under the guidance of her mentors to advance her long-term career goal of establishing an independent research program studying how neuromodulation at the molecular, cellular, and systems levels contributes to symptoms of AD.


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: 2025 ( Subtotal = $129,168 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	2	7/23/2025	NON-COMPETING CONTINUATION	$129,168
														Subtotal = $129,168

Issue Date FY: 2024 ( Subtotal = $129,168 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Aging Research	000	1	6/20/2024	NEW	$129,168
														Subtotal = $129,168

Grand Total All Awards = $258,336

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Decoding the Mechanisms of Oxytocinergic Regulation in the Hippocamposeptal Circuit: Implications for Social Dysfunction in Alzheimer's Disease

Award Number: K01AG086573

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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