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Thalamo-hippocampal interplay in early life trauma-induced aggression

Award Number: R01MH137465
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2025
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Thalamo-hippocampal interplay in early life trauma-induced aggression - PROJECT SUMMARY/ABSTRACT Understanding the top-down control of the neurobiological basis for aggression could help us identify ways to reduce uncontrolled rage eliciting numerous social issues and economic burdens. Cognitive control that includes abilities to pay attention is a fundamental ability essential for recognizing social cue and establishing social relationships. Individuals with cognitive impairment like inattention, however, often externalize socially disruptive behaviors, such as impulsive aggression. Notably, early life trauma (ELT), in the form of child abuse/neglect, is a critical risk factor for cognitive decline and pathological aggression in later life, yet the neural circuit mechanisms that transduce ELT into maladaptive neuronal changes resulting in impulsive aggression are not well understood. The thalamic nucleus reuniens (RE), the largest midline thalamic nucleus, is thought to be a key component connecting an extensive network between the ventral hippocampus (vHip) and medial prefrontal cortex (mPFC). The RE highly expresses L-type calcium channels (LTCCs), potential therapeutic targets for psychiatric diseases. Our preliminary data showed that mice received a systemic treatment of Bay K8644 (Bay K; LTCCs agonist) display decline in cognitive performance with poor attention and impulsive responses during the five-choice serial reaction time task (5-CSRTT), while they exhibit escalated aggression in the social context. Likewise, a same set of behavioral phenotypes was observed in mice exposed to ELT (e.g., pup-dam/littermate separation) who exhibit increased LTCC expression in the RE. We also found that optogenetic/chemogenetic activation of the vGlut2 RE projecting to the vHip (vGlut2 RE vHip), but not vGlut2 RE mPFC, is sufficient to induce the aggression in control mice, whereas optogenetic inhibition of vGlut2 RE vHip circuit normalizes aggression of ELT mice. Our long-term goal is to test the hypothesis that vGlut2 RE vHip is the primary circuit that mediates the maladaptive effects of LTCCs on early adversity-induced aggression. To achieve our objective, we will first characterize the in vivo activity of vGlut2 REvHip neurons during aggressive behaviors of ELT mice. We will examine whether ELT disinhibits in vivo vGlut2 RE vHip activity leading to increased neural responses during aggression (Aim 1). Using CRISPR-Cas9 approach, we will then test whether LTCCs in the RE circuitry are necessary for eliciting impulsive aggression associated with cognitive decline. Using molecular profiling methods, we will further examine how ELT induces circuit-specific molecular adaptation in the vHip- projecting RE neurons (Aim 2). Lastly, we will focus on circuit-specific role of the vHip in controlling ELT-induced aggression. Using intersectional optogenetic manipulation, we will determine whether REvHip hypothalamus circuit plays a key role in promoting impulsive aggression following ELT (Aim 3). Completion of these experiments will transform our understanding of the social aggression associated with dysregulated cognitive control and provide new insight into the circuit-specific roles of RE in driving the risk of maladaptive aggression that often follows early adversities.


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 = $575,171 )
2026	2026	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Mental Health Research Grants	000	2	5/5/2026	NON-COMPETING CONTINUATION	$575,171
														Subtotal = $575,171

Issue Date FY: 2025 ( Subtotal = $592,831 )
2025	2025	VIRGINIA POLYTECHNIC INSTITUTE & STATE UNIVERSITY	300 TURNER ST NW	BLACKSBURG	VA	24060	MONTGOMERY	USA	Mental Health Research Grants	000	1	6/24/2025	NEW	$592,831
														Subtotal = $592,831

Grand Total All Awards = $1,168,002

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Thalamo-hippocampal interplay in early life trauma-induced aggression

Award Number: R01MH137465

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2025

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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