Behavioral, Biochemical, and Physiological Components of Stress-Enhanced Fear Learning in an Animal Model of Post-Traumatic Stress Disorder
- Author(s): Meyer, Edward
- Advisor(s): Spigelman, Igor
- et al.
Major anxiety disorders, such as post-traumatic stress disorder (PTSD), have a devastating social impact. PTSD can lead to high rates of substance use disorders, such as alcoholism. Previous investigations show strong interplay between stress and alcohol use, but have yet to characterize precise brain mechanisms involved. Evidence points to the basolateral amygdala (BLA) as playing a central role in the acquisition and storage of emotional memory.
Recently, an animal model of stress enhanced fear learning (SEFL) that mimics specific characteristics of PTSD has been developed to study behavioral and physiological components of PTSD-like stress in rodents. In PTSD, enhanced fear after a traumatic experience is manifested as an inappropriately exaggerated response to stimuli that are reminders of the trauma, as well as an increased propensity to acquire new fears. In SEFL, enhanced fear after an initial stressor is manifest as a sensitized fear response and enhanced fear learning after exposure to subsequent mild stressors. This work shows that the SEFL model leads to increased voluntary alcohol consumption in stressed rats compared to unstressed rats. Interestingly, however, SEFL does not alter previously acquired alcohol drinking behavior.
Biochemical analysis of BLA tissue and electrophysiological recordings in pyramidal neurons from the lateral nucleus of the BLA were done to identify the cellular mechanisms by which SEFL induces enhanced freezing and increased alcohol intake. This work shows that SEFL increased BLA expression of the α-amino-3-hydroxy-5-methy-4-isoxazole propionic acid receptor (AMPAR) subunit, GluA1, and the γ-aminobutyric acid type-A receptor (GABAAR) subunits α1, α2, and α3. SEFL also produced long-term increases in AMPAR-mediated excitatory postsynaptic currents and changes in voltage-sensitive inward rectifying depolarizing currents that regulate the excitability of pyramidal neurons. Together these data demonstrate long-lasting biochemical and functional changes in the intrinsic and synaptic excitability of the BLA pyramidal neurons. Since the BLA is necessary for the induction and expression of SEFL, it is likely that these biochemical and functional changes represent the brain mechanisms responsible for the behavioral manifestations of SEFL.