Blast-Induced Mild Traumatic Brain Injury Alterations of Corticotropin-Releasing Factor Neuronal Activity in the Mouse Hypothalamic Paraventricular Nucleus

Abstract

Blast-induced mild traumatic brain injury (mbTBI) is the most common cause of TBI in US service members and veterans. Those exposed to TBI are at greater risk of developing neuropsychiatric disorders such as posttraumatic stress disorder, anxiety and depressive disorders, and substance use disorders following TBI. Previously, we have demonstrated that mbTBI increases anxiety-like behaviors in mice and dysregulates stress at the level of corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus (PVN). To expand on how mTBI may dysregulate the stress axis centrally, here PVN CRF neuronal activity was evaluated using whole cell-patch clamp recordings in hypothalamic slices from sham and mbTBI adult male CRF:tdTomato mice 7 days post-injury. We found that mbTBI generally did not affect the neuronal excitability and intrinsic membrane properties of PVN CRF neurons; this injury selectively increased the frequency of spontaneous neuronal firing of PVN CRF neurons localized to the dorsal PVN (dPVN) but not ventral PVN (vPVN). Consistently, mbTBI-induced dPVN CRF hyperactivity was associated with pre- and post-synaptic depression of spontaneous GABAergic transmission onto dPVN CRF neurons suggesting that mbTBI-induced GABAergic synaptic dysfunction may underlie dPVN CRF neuronal hyperactivity and increases in dPVN CRF signaling. The present results provide the first evidence for mbTBI-induced alterations in PVN CRF neuronal activity and GABAergic synaptic function that could mediate hypothalamic CRF dysregulation following mbTBI contributing to stress psychopathology associated with blast injury.

Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior

“…Up to 30% of TBI patients experience neuroendocrine dysfunction [41][42][43][44] with a high incidence of HPA axis dysregulation 42,44 . Hypothalamic and extra-hypothalamic CRF systems are also responsive to mTBI injuries and have significant impact on stress-related neuronal responses and affective states following mTBI [45][46][47][48][49] . The mouse LHb shows immunoreactivity and mRNA expression for both CRF and CRFR1 69,70 , and receives inputs from the structures that contain CRF neurons including the paraventricular nucleus of hypothalamus (PVN) and the extrahypothalamic CRF system such as the bed nucleus of stria terminalis (BNST) 71 .…”

“…TBI patients also experience neuroendocrine dysfunction 41–44 with dysregulation of the hypothalamic pituitary axis (HPA) stress neuromodulator, corticotropin releasing factor (CRF), that has significant impact on stress neuronal responses and affective states following mTBI 45–49 . Our previous studies have demonstrated that the rodent LHb is highly responsive to CRF 50, 51 .…”

“…We demonstrated that limiting LHb hyperactivity by chemogenetic inhibition of LHb neurons was sufficient to reverse mTBI-induced delays in self-care grooming behavior in male mice supporting a causal link between LHb hyperactivity and mTBI-induced self-grooming deficits 39 . TBI patients also experience neuroendocrine dysfunction [41][42][43][44] with dysregulation of the hypothalamic pituitary axis (HPA) stress neuromodulator, corticotropin releasing factor (CRF), that has significant impact on stress neuronal responses and affective states following mTBI [45][46][47][48][49] . Our previous studies have demonstrated that the rodent LHb is highly responsive to CRF 50,51 .…”