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AREA: Investigating the effects of stress-induced noradrenergic neurotransmission of inflammatory transcription in the hippocampus

Award Number: R15MH143199
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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AREA: Investigating the effects of stress-induced noradrenergic neurotransmission of inflammatory transcription in the hippocampus - Project Summary/Abstract It is well established that inflammatory markers are increased in individuals with stress-related psychiatric disorders and can contribute to their pathology. However, we lack a thorough understanding of the circuits, receptors, and transcriptional mechanisms driving these inflammatory processes in the brain and how they might differ in males and females. Stress activates the canonical “fight or flight” sympathetic nervous system, which uses noradrenaline as a neurotransmitter. Noradrenaline activates nuclear factor kappa B (NFkB), a master transcriptional regulator of inflammatory genes, to increase inflammation in peripheral immune cells. Stress also activates the locus coeruleus (LC), the primary source of noradrenaline in the brain. However, it is unknown whether the LC increases pro-inflammatory NFkB-mediated transcription in the hippocampus, a brain region that controls stress-related behaviors and is prone to stress-induced inflammatory processes. We found 1) 10 days of chronic social defeat stress (CSDS) increases nuclear NFkB in the hippocampus of males and females, 2) overall levels of NFkB are higher in females compared to males, suggesting it might be primed to transcribe inflammatory transcripts more readily, 3) compared to female in metestrus, females in proestrus transcribe more genes known to regulated by NFkB, which might be because the female LC is particularly sensitive to the neuroendocrine stress response, which is active during proestrus, and 4) daily administration of the α1 adrenergic receptor (α1-AR) antagonist prazosin prior to daily CSDS prevents reductions in sociability normally caused by CSDS, a stress paradigm that increases pro-inflammatory effects in the hippocampus. We hypothesize that inhibiting α1-ARs promotes sociability by mitigating inflammatory processes normally caused by CSDS. Our central hypothesis is that stress-induced noradrenergic neurotransmission increases NFkB- mediated inflammatory transcription in the hippocampus to reduce sociability. In Aim 1, we will determine whether chemogenetically inhibiting the LC throughout stress mitigates NFkB-mediated transcription in the hippocampus of males and females. We predict that the inhibitory Designer Receptor Exclusively Activated by Designer Drug (DREADD), hM4D, in noradrenergic LC neurons will increase subsequent sociability in a social interaction paradigm and reduce the transcription of a pre-defined set of transcripts regulated by NFkB, which we will identify using RNA-sequencing in hippocampal tissue. In Aim 2, we will determine whether five days of systemic administration of the α1 adrenergic receptor agonist, cirazoline, is sufficient to drive NFkB-mediated transcription in hippocampal microglia in males and estrus cycle-tracked females in metestrus or proestrus. We predict that cirazoline will increase nuclear NFKB in hippocampal microglia and neurons and increase NFkB- mediated transcripts in hippocampal microglia, with the strongest effects in females in proestrus. This project is highly conducive to undergraduates, who have already demonstrated they can successfully complete most assays described in this proposal.


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 = $558,051 )
2026	2026	RUTGERS THE STATE UNIVERSITY	303 COOPER ST	CAMDEN	NJ	08102	CAMDEN	USA	Mental Health Research Grants	000	1	4/23/2026	NEW	$558,051
														Subtotal = $558,051

Grand Total All Awards = $558,051

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AREA: Investigating the effects of stress-induced noradrenergic neurotransmission of inflammatory transcription in the hippocampus

Award Number: R15MH143199

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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