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 TBI-induced 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.
Highlights
Affective disorders, including generalized anxiety disorder and post-traumatic stress disorder (PTSD), develop and persist in up to 50% of traumatic brain injury (TBI) survivors, few common biological mechanisms between TBI and non-TBI patients have been elucidated (Kessler et al, 2005; Scholten et al, 2016)
Glutamate Neurotransmission in the basolateral amygdala (BLA) Does Not Change Over 1-Month Following diffuse TBIs (dTBI)
Multifactorial mental illnesses are the result of poorly understood pathophysiology that confounds treatment approaches leading to poor symptom control. These are the first experiments that demonstrate dTBI initiates a cascade of molecular events in the amygdala capable of contributing to the expression of anxietylike behavior
Summary
Affective disorders, including generalized anxiety disorder and post-traumatic stress disorder (PTSD), develop and persist in up to 50% of traumatic brain injury (TBI) survivors, few common biological mechanisms between TBI and non-TBI patients have been elucidated (Kessler et al, 2005; Scholten et al, 2016). The pathophysiology contributing to affective symptoms following dTBI is poorly understood, resulting in misdiagnosis and ineffective treatments (Van der Kolk, 2002; Collins et al, 2004; Hoge et al, 2014). Diffuse and focal experimental models of TBI identify alterations in amygdala circuitry, including increased neuronal hyperexcitability and GABA production proteins in the absence of overt neuropathology (Hallam et al, 2004; Meyer et al, 2012). Pyramidal and stellate neurons in the basolateral amygdala (BLA)
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