Dopamine Rebound-Excitation Theory: Putting Brakes on PTSD

It is not uncommon for humans or animals to experience traumatic events in their lifetimes. However, the majority of individuals are resilient to long-term detrimental changes turning into anxiety and depression, such as post-traumatic stress disorder (PTSD). What underlying neural mechanism accounts for individual variability in stress resilience? Hyperactivity in fear circuits, such as the amygdalar system, is well-known to be the major pathophysiological basis for PTSD, much like a “stuck accelerator.” Interestingly, increasing evidence demonstrates that dopamine (DA) – traditionally known for its role in motivation, reward prediction, and addiction – is also crucial in regulating fear learning and anxiety. Yet, how dopaminergic (DAergic) neurons control stress resilience is unclear, especially given that DAergic neurons have multiple subtypes with distinct temporal dynamics. Here, we propose the Rebound-Excitation Theory, which posits that DAergic neurons’ rebound-excitation at the termination of fearful experiences serves as an important “brake” by providing intrinsic safety-signals to fear-processing neural circuits in a spatially and temporally controlled manner. We discuss how DAergic neuron rebound-excitation may be regulated by genetics and experiences, and how such physiological properties may be used as a brain-activity biomarker to predict and confer individual resilience to stress and anxiety.