title: Increased Cortical Gamma-Aminobutyric Acid Precedes Incomplete Extinction of Conditioned Fear and Increased Hippocampal Excitatory Tone in a Mouse Model of Mild Traumatic Brain Injury.
abstract: Mild traumatic brain injury (mTBI) contributes to development of affective disorders, including post-traumatic stress disorder (PTSD). Psychiatric symptoms typically emerge in a tardive fashion post-TBI, with negative effects on recovery. Patients with PTSD, as well as rodent models of PTSD, demonstrate structural and functional changes in brain regions mediating fear learning, including prefrontal cortex (PFC), amygdala (AMYG), and hippocampus (HC). These changes may reflect loss of top-down control by which PFC normally exhibits inhibitory influence over AMYG reactivity to fearful stimuli, with HC contribution. Considering the susceptibility of these regions to injury, we examined fear conditioning (FC) in the delayed post-injury period, using a mouse model of mTBI. Mice with mTBI displayed enhanced acquisition and delayed extinction of FC. Using proton magnetic resonance spectroscopy ex vivo, we examined PFC, AMYG, and HC levels of gamma-aminobutyric acid (GABA) and glutamate as surrogate measures of inhibitory and excitatory neurotransmission, respectively. Eight days post-injury, GABA was increased in PFC, with no significant changes in AMYG. In animals receiving FC and mTBI, glutamate trended toward an increase and the GABA/glutamate ratio decreased in ventral HC at 25 days post-injury, whereas GABA decreased and GABA/glutamate decreased in dorsal HC. These neurochemical changes are consistent with early TBI-induced PFC hypoactivation facilitating the fear learning circuit and exacerbating behavioral fear responses. The latent emergence of overall increased excitatory tone in the HC, despite distinct plasticity in dorsal and ventral HC fields, may be associated with disordered memory function, manifested as incomplete extinction and enhanced FC recall.
authors.affiliation: 1 Research and Development Service, John D. Dingell Veterans Affairs Medical Center , Detroit, Michigan.|2 Department of Neurosurgery, Wayne State University School of Medicine , Detroit, Michigan.
authors.forename: Brandy L
authors.initials: BL
authors.lastname: Schneider
authors.affiliation: 3 Department of Anesthesiology, Wayne State University School of Medicine , Detroit, Michigan.|5 Magnetic Resonance Core (MRC), Wayne State University School of Medicine , Detroit, Michigan.
authors.forename: Farhad
authors.initials: F
authors.lastname: Ghoddoussi
authors.affiliation: 1 Research and Development Service, John D. Dingell Veterans Affairs Medical Center , Detroit, Michigan.|2 Department of Neurosurgery, Wayne State University School of Medicine , Detroit, Michigan.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Charlton
authors.affiliation: 4 Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine , Detroit, Michigan.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Kohler
authors.affiliation: 3 Department of Anesthesiology, Wayne State University School of Medicine , Detroit, Michigan.|4 Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine , Detroit, Michigan.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Galloway
authors.affiliation: 4 Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine , Detroit, Michigan.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Perrine
authors.affiliation: 1 Research and Development Service, John D. Dingell Veterans Affairs Medical Center , Detroit, Michigan.|2 Department of Neurosurgery, Wayne State University School of Medicine , Detroit, Michigan.
authors.forename: Alana C
authors.initials: AC
authors.lastname: Conti
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D001924:Brain Concussion / Q000503:physiopathology* / Q000523:psychology; D003214:Conditioning, Classical; D005108:Extinction, Psychological / Q000502:physiology*; D005239:Fear; D006624:Hippocampus / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013313:Stress Disorders, Post-Traumatic / Q000209:etiology / Q000503:physiopathology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D005680:gamma-Aminobutyric Acid
keywords: GABA; fear conditioning; glutamate; post-traumatic stress disorder; traumatic brain injury