Interactions of Traumatic Brain Injury and Epilepsy Gene Expression on Thalamocortical Dysfunction and Sensory Processing

About This Grant

Mild traumatic brain injuries (mTBIs), those that do not cause gross anatomical damage and produce only brief periods of altered awareness, have affected countless veterans. Despite being classified as “mild,” a significant number of mTBI patients experience chronic somatosensory dysfunction, especially headaches. Although post-mTBI symptoms are influenced by various factors, recent studies indicate that certain individuals may have a genetic vulnerability that increases their risk. A critical unmet need exists for the development of more effective treatments for chronic somatosensory symptoms following mTBI, as well as reliable biomarkers to identify patients who are most likely to benefit from these interventions. Therapeutic brain stimulation has shown promise in treating certain chronic pain syndromes and could also be applied to post-mTBI sensory dysfunction. To develop effective mTBI neuromodulation therapies, a fundamental understanding of how mTBI alters somatosensory circuit physiology in both susceptible and non- susceptible individuals is essential. While previous studies have investigated histological changes associated with mTBI, a comprehensive understanding of how mTBI impacts sensory circuit function remains elusive. Recently, basic neuroscience experiments revealed many aspects of somatosensory circuit physiology and thereby laid the groundwork for studies of how mTBI can alter these connections. In the current model, somatosensory data is relayed and modulated in connections between thalamic ventral posterior nuclei (VPN) and primary somatosensory cortex (S1). Sensory information is conveyed from S1-layer 5 to secondary somatosensory cortex (S2), a region that performs higher order processing. Importantly, layer 5 S1→S2 signaling mediates antinociceptive effects and may be an attractive target for future therapeutic neuromodulation studies for post mTBI somatosensory disorders. This project aims to test the overarching hypothesis that mTBI causes sensory dysfunction by altering neuronal physiology in S1, S2, and layer 5 S1→S2 signaling, and that individuals with pre-existing thalamocortical/ corticocortical dysfunction are more susceptible to these changes. The research will utilize a military-type repetitive mTBI (RmTBI) model in both wild-type mice and mice expressing the human epilepsy gene Gabra1A322D/+ (Het mice), which exhibit spontaneous thalamocortical reverberations and preexisting thalamocortical dysfunction. Aim 1 will use the investigators’ innovative, minimally invasive high density electrode arrays to determine how RmTBI affects long-range VPN→S1 signaling and related somatosensory behaviors in wild-type and Het mice. The effects of RmTBI and the Gabra1 mutation on somatosensory evoked potentials (SSEP) and event-related somatosensory oscillations will be elucidated and these findings will be correlated with MRI, histology, and behavioral data. Aim 2 will uncover the impact of RmTBI and the Gabra1 mutation on layer-specific neuronal activity in S1 and S2. The team’s novel flexible transcortical electrode arrays will be used to measure cortical layer-specific S1 and S2 field potentials in WT and Het mice and network statistical methods will calculate information flow among the layers in the somatosensory cortex. Aim 3 will investigate how optogenetic stimulation of antinociceptive layer 5 S1→S2 signaling modifies RmTBI mediated effects on mechanical and noxious stimulation responses and textured object exploration. This aim will causally manipulate this antinociceptive connectivity and thus directly test a possible mechanism of altered somatosensory function after RmTBI. In addition, this aim will lay the groundwork for future translational studies to test targeted neuromodulation therapies for veterans with mTBI and somatosensory disorders. Upon completion, this project will identify genetic influences on the neurophysiological mechanisms by which RmTBI disrupts somatosensory function which will lead to the development of targeted neuromodulation and other therapies for mTBI patients suffering from chronic sensory dysfunction.