How brain activity evolves from fear to anxiety: Implications for today’s mental well-being

 
Post-traumatic stress syndrome (PTSD) is predicted to be a long-term outcome from today’s frightening turbulence. Life-threatening fear is traumatic and can have enduring effects on mental health. Yet we still need to understand the brain’s response to fear and how that response changes with recovery or progression to anxiety states like PTSD.

While inducing fear in humans for research is not feasible, fear can be provoked in rodents by exposure to a predator, like a cat or fox. We use this paradigm to witness how the mammalian brain responds to life-threatening fear and, by imaging over time, discover how this response evolves to anxiety (Uselman et al., 2020). For the first time, we couple brain imaging with fearful behavior over time to learn how neural activity and behavior intertwine in the long run.

Deregulation of the serotonergic system through disruption of the serotonin transporter (SERT) leaves mice abnormally vulnerable to prolonged anxiety after predator stress. SERT plays a big role in human mental health, as it is a target of psychoactive drugs, like cocaine and Prozac, a commonly prescribed anti-depressant. SERT-knockout mice (SERT-KO) provide a unique animal model to learn how anxiety transpires from frightening experiences.

We compared behavior and brain activity of wild type mice with littermates lacking SERT to identify the neural correlates of anxiety–those regions active in the SERT-KOs and not in wild type. To acquire maps of brain-wide activity during transition to anxiety, we performed longitudinal MRI of mice before and at successive time points after fear. To highlight active neurons, we dosed the mice with manganese, a non-toxic ion that lights up active neurons in MRI. Advanced computational analyses of these images yielded maps of activity throughout the brain before, during, and long after acute fear in vulnerable and resilient individuals.

Wild type mice displayed little neural activity during normal exploratory behavior in their home cage. However, after exposure to a predator odor, the mice ran and hid in the dark, a defensive behavior indicative of fear. The activity across the brain spiked in more than a dozen regions, including sub-regions in the extended amygdala, hippocampus, and hypothalamus–areas involved in fear, memory and hormonal release. Wild type mice returned to natural explorations at nine days, but SERT-KO did not. In tandem with this resilient behavior, wild type brain activity decreased, while activity in brains of SERT-KO mice continued at a high level, persisting in lateral amygdala, thalamic nuclei and hypothalamus, and increasing in the ventral tegmental area, a region involved in reward circuitry.

What does this mean in the time of COVID? Many of the same brain regions we identified in anxious SERT-KO mice are also active in anxious humans. Our data shows the importance of the serotonergic system in regulating fear-anxiety responses, as well as a curious involvement of the reward circuitry in the anxiety state. Finally, the time lag for resilient or anxious outcomes suggests that with early containment of fearful responses, progression to anxiety may be less likely. Meditation, music, poetry, exercise and other stress-reducing activities that engage the reward circuitry will likely help. Early interventions will have lasting benefits.