Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior

Abstract

Up to 50% of traumatic brain injury (TBI) survivors demonstrate persisting and late-onset anxiety disorders indicative of limbic system dysregulation, yet the pathophysiology underlying the symptoms is unclear. We hypothesize that the development of TBIinduced anxiety-like behavior in an experimental model of TBI is mediated by changes in glutamate neurotransmission within the amygdala. Adult, male Sprague-Dawley rats underwent midline fluid percussion injury or sham surgery. Anxiety-like behavior was assessed at 7 and 28 days post-injury (DPI) followed by assessment of real-time glutamate neurotransmission in the basolateral amygdala (BLA) and central nucleus of the amygdala (CeA) using glutamate-selective microelectrode arrays. The expression of anxiety-like behavior at 28 DPI coincided with decreased evoked glutamate release and slower glutamate clearance in the CeA, not BLA. Numerous factors contribute to the changes in glutamate neurotransmission over time. In two additional animal cohorts, protein levels of glutamatergic transporters (Glt-1 and GLAST) and presynaptic modulators of glutamate release (mGluR2, TrkB, BDNF, and glucocorticoid receptors) were quantified using automated capillary western techniques at 28 DPI. Astrocytosis and microglial activation have been shown to drive maladaptive glutamate signaling and were histologically assessed over 28 DPI. Alterations in glutamate neurotransmission could not be explained by changes in protein levels for glutamate transporters, mGluR2 receptors, astrocytosis, and microglial activation. Presynaptic modulators, BDNF and TrkB, were significantly decreased at 28 DPI in the amygdala. Dysfunction in presynaptic regulation of glutamate neurotransmission may contribute to anxiety-related behavior and serve as a therapeutic target to improve circuit function.

Approaches to Monitor Circuit Disruption after Traumatic Brain Injury: Frontiers in Preclinical Research

“…The assays provide for the sensitive, objective, and quantifiable behavioral measures with the use of video tracking, automated recordings, and detection technologies to record and analyze the behaviors. The assays include neurobehavioral assessment [39], exploratory behavior [40,41], learning and memory [42], and sensory sensitivity [43,44]. These behavioral models have a high degree of face validity, wherein the observable phenotype in the animal reproduces the human TBI condition.…”

Neural markers of vulnerability to anxiety outcomes following traumatic brain injury

“…In the mPFC, whereas E-I signaling changes linked to cognitive and fear dysfunction following injury have been explored (Kobori and Dash, 2006, Schneider et al, 2016), those associated with anxiety behaviors are less clear. In the BLA, results regarding GABAergic and glutamatergic signaling are contradictory, with some studies reporting increases and other reporting decreases following injury (Ajao et al, 2012, Reger et al, 2012, Malkesman et al, 2013, Almeida-Suhett et al, 2014, Palmer et al, 2016, Popovitz et al, 2019, Beitchman et al, 2020). In the hippocampus, dysfunction of inhibitory synapses and reduction in glutamate precursors have been reported following injury (Witgen et al, 2005, Cole et al, 2010).…”

Sex-Dependent Pathology in the HPA Axis at a Sub-acute Period After Experimental Traumatic Brain Injury

“…Midline fluid percussion injury (mFPI) surgery was carried out similarly to previously published methods from this laboratory (52,53). Each cage of rats (2/cage) was randomized into either injured or sham groups following acclimation to the vivarium facility.…”

“…After regaining the righting reflex, injured rats require little to no medical intervention in the post-operative period, similar to mild TBI as defined by a Glasgow Coma Score of 13-15. More detailed discussion of the clinical relevance of mFPI have been published (53,59). At 3-4 months of age, rats are roughly estimated to translationally represent late adolescent-young adult humans (60).…”