Gamma frequency oscillations improve pathological and emotional outcomes in a mouse model of repetitive mild TBI

Approximately 20% of U.S. veterans in wars following 9/11 have experienced one or more traumatic brain injury (TBI), including repetitive mild exposures. The risk of sustaining TBI during military service is doubled in veterans who sustain a TBI prior to enlistment. Repetitive mild TBI (rmTBI) clinical symptoms can emerge years to decades after exposure to injury and include motor and cognitive dysfunction, anxiety, and depression. Furthermore, rmTBI neuropathology is characterized by select neuroinflammatory, vasculature, and degenerative responses in brain regions such as the cortex and hippocampus, contributing to cognitive and emotional alterations. Few treatments are available for rmTBI to address pathological and behavioral outcomes, highlighting the importance of an animal model of rmTBI to allow development of new therapies for the Veteran population. Here, we will first employ a rmTBI model protocol in the mouse and evaluate the ability of therapeutic exposure to stimuli presented at ~40Hz (gamma frequency) to improve rmTBI model-induced pathological and behavioral alterations. Neural gamma band oscillations play a major role in cognition, and exogenous application of simultaneous light and sound stimuli at gamma frequency entrains neural gamma oscillations (referred to as Gamma Entrainment Using Sensory Stimuli; GENUS). GENUS treatment has been shown to alter pathological markers of inflammation and neurodegeneration, as well as improve behavioral/cognitive outcomes, in animal models of Alzheimer’s disease (AD) and in humans with AD. We will apply GENUS daily (or control treatment) in mice starting 6 weeks after rmTBI exposure until a chronic 6-month timepoint, and predict improvement of both pathological and emotional outcomes. Behavioral evaluation (one week following rmTBI model exposure, then every two months until 6-month timepoint) will include measures of motor coordination (rotorod) and mood disturbance, including the elevated plus and open field mazes (anxiety and risk-taking/impulsivity) and tail suspension test (anhedonia/depression). Chronic neuroinflammation seen in rmTBI includes alterations in brain astroglia and microglia, vascular abnormalities, and resulting altered cerebral blood flow which most likely contribute to increased levels of cis-phosphorylated tau and possibly to later neurodegeneration. At the 6-month time point following rmTBI exposure, we will perform immunohistochemistry stains on brain tissue, allowing simultaneous histological labeling of markers including vasculature abnormalities, neurodegeneration, and markers of neuroinflammation. Brain regions to be analyzed include the medial prefrontal cortex (mPFC), hippocampus, and amygdala, which are chief neural players in cognition, anxiety, and mood. GENUS treatment has previously been shown to induce gamma oscillations in several neural structures and improves some of the cognitive dysfunction and histopathological alterations in mPFC and hippocampus in the AD mouse model. We will evaluate here whether GENUS treatment improves the neuropathological changes and behavioral impairments induced by rmTBI in a clinically relevant mouse model. Delaying GENUS treatment until 6 weeks after rmTBI model exposure is translationally significant, modeling the delayed timing from injury to when the Veteran seeks treatment at the VA. If successful, these studies will support the development of a noninvasive therapeutic treatment for rmTBI experienced by Veterans. Project Number: 1I21RX005145-01A1 | Fiscal Year: 2026 | NIH Institute/Center: Veterans Affairs (VA) | Principal Investigator: JAMES MCNALLY | Institution: VA BOSTON HEALTH CARE SYSTEM, BOSTON, MA | Activity Code: I21 | Study Section: Rehabilitation Research and Development SPiRE Program[RRDS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11046079