BCCMA: Cognitive phenotypes of emotion regulation and suicide risk in Veterans with TBI: Mechanistic Neurobehavioral Model of Emotional Reactivity

About This Grant

This VA Merit proposal is part of a BLR&D/CSR&D Collaborative Merit Award for traumatic brain injury (TBI; BCCMA) proposal (RFP #BX-24-007) involving four separate but integrated proposals that together investigate the overarching model that TBI impacts cognitive phenotypes and emotion dysregulation via multiple pathways, which in turn increase risk of suicide. The rationale for the collaborative project is to translationally evaluate, across animals and humans, several pathways in the CNS, PNS, and brain-gut axis related to emotion regulation. Specific to this project is the utilization a rat model of TBI to discern the causal relationships between TBI, emergent changes in brainstem noradrenergic neurons functioning, and emotional reactivity to fear-eliciting stimuli. The TBI model involves a lateral fluid percussion injury to male and female Sprague Dawley (SD) rat brain dura. This injury causes long-lasting changes in sensory reactivity (acoustic startle response) and sex specific changes to brainstem functioning, including in the locus coeruleus (LC). The LC provides norepinephrine signaling to forebrain areas and the autonomic nervous system, supporting both CNS and PNS components of arousal and emotional reactions. Emotional reactivity in this model will be assessed by measuring fear reactions to learned threats (fear potentiated startle) and unlearned threats (predator odor enhanced startle). Using these two primary assessments of elicited emotional reactivity, LC and central and peripheral norepinephrine signaling contributions to TBI-induced emotional reactivity will be functionally assessed up to 6 months post-injury. This will involve pharmacologically manipulating central and peripheral noradrenergic signal reception and activating versus inactivating the LC during the emotional reactivity tests post-injury. Identified sex specific effects of TBI on the LC morphology and functioning will be further investigated involving signals of chronic neuroinflammation (females) and reductions in orexin signaling (males). Secondary measures will include autonomic nervous system responses (ECG) determine if the TBI changes the balance of the sympathetic and parasympathetic nervous system during pretest baseline assessments and during emotional reactivity testing. Tertiary measures include repeated collection of fecal samples over the 6 months post-injury to determine if the animal model exhibits a shift in gut bacteria diversity, as previously reported in patients with a prior history of TBI. Although not necessary, these additional secondary and tertiary measures will promote increased face and construct validity between the animal model of TBI and measures taken from Veterans at collaborating sites. In all, this proposed research project will provide critical information regarding potential sex differences in how TBI causes emotional dysregulation and the contribution of the brainstem LC and associated noradrenergic circuits to that dysregulation. These are all highly translational experimental goals that will provide causal/mechanistic connections between TBI and the emotional processes. Combined with the greater collaborative project, the parallel analogous assessments will provide a unique, potentially synergistic, opportunity to address how TBI increases suicide risk in Veterans.