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

Sarah Simmons,Fereshteh S Nugent,Ludovic D Langlois,T John Wu,Mario G Oyola,Shawn Gouty

doi:10.3389/fnsyn.2021.804898

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.

Highlights

Traumatic brain injury (TBI) accounts for almost 3 million hospitalizations or admissions into the emergency room in the United States with the incidence rate increasing annually (Taylor et al, 2017; GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators, 2019)
Given our prior observations suggesting region-specific paraventricular nucleus (PVN) corticotropin-releasing factor (CRF) dysregulation, we first investigated the effects of mbTBI on PVN CRF depolarization-induced neuronal excitability and intrinsic membrane properties in intact synaptic transmission from dorsal PVN (dPVN) and ventral PVN (vPVN) CRF neurons in PVN slices from sham and mbTBI male adult CRF:tdTomato mice 7 days post-injury (Figure 1 and Table 1)
We found that mbTBI did not affect neuronal excitability of dPVN or vPVN CRF neurons (Figure 1B: dPVN, n = 22/5 per group, 2-way ANOVA, effect of mbTBI: F(1, 420) = 0.28, P = 0.59; effect of current: F(9, 420) = 8.03, P < 0.0001; mbTBIxcurrent interaction: F(9, 420) = 0.47, P = 0.89; Figure 1C: vPVN, n = 15–17/5/group, 2-way ANOVA, effect of mbTBI: F(1, 300) = 2.11, P = 0.14; effect of current: F(9, 300) = 2.32, P < 0.05; mbTBIxcurrent interaction: F(9, 300) = 0.55, P = 0.83 )

Summary

INTRODUCTION

Traumatic brain injury (TBI) accounts for almost 3 million hospitalizations or admissions into the emergency room in the United States with the incidence rate increasing annually (Taylor et al, 2017; GBD 2016 Traumatic Brain Injury and Spinal Cord Injury Collaborators, 2019). When PVN CRF projection neurons were distinguished using FG staining, we observed that mbTBI only decreased c-Fos+ immunoreactivity in PVN non-neuroendocrine CRF neurons of females in response to restraint stress without any alterations in males (Russell et al, 2018a). Given that the activity of distinct CRF neurons in these anatomical subregions of the PVN is shown to be differentially modulated by some of the neurotransmitters and bioactive substances (Mukai et al, 2020) and mediates endocrine vs non-neuroendocrine components of PVN CRF signaling (Russell et al, 2018a,b), our data suggest that mbTBI-induced persistent dPVN CRF dysfunction may primarily contribute to stress-related psychopathology following mbTBI

METHODS

RESULTS

DATA AVAILABILITY STATEMENT