Summary: When anxiety develops, many specific brain regions become more active and the normal coordination between those regions breaks down.
Source: University of New Mexico
Overview: The global stressors of the COVID-19 pandemic, economic uncertainty and social unrest have heightened fear and distress for millions. Understanding how acute fear can evolve into long-lasting anxiety in vulnerable people is essential for improving prevention and treatment.
A research team at the University of New Mexico, led by Elaine L. Bearer, MD, PhD, Harvey Family Professor in Pathology, with graduate student Taylor W. Uselman, has identified brain-wide neural patterns that mark the transition from a fear response to sustained anxiety for the first time.
“Psychiatry has had limited information about the brain changes that follow a fearful event and why some people fail to recover,” Bearer explains. “Our study maps how brain activity evolves after an acute threat and pinpoints differences associated with long-term anxiety.”
The team modeled fear and anxiety in mice using a predator-like odor that reliably provokes a defensive reaction. While exposing humans to such stimuli is not feasible, this rodent model allowed researchers to track behavior and whole-brain activity before, during and after the brief threat.
To create a vulnerable group, the researchers used mice lacking the serotonin transporter gene (SERT-KO). The serotonin transporter is a primary target of many psychoactive substances and antidepressant medications. Deleting this gene increases susceptibility to anxiety, providing a useful model for studying the biological steps that make fear persist.
The study compared normal (wild-type) mice with SERT-KO mice to identify neural correlates of anxiety — brain regions and networks that remain active in anxious animals but not in resilient ones.
Neuronal activity was visualized using manganese-enhanced magnetic resonance imaging (MEMRI). Manganese ions accumulate in active neurons and produce a clear signal on MRI scans, allowing the researchers to create time-lapse maps of brain activity across the awake, behaving animal. Computational analyses then quantified where and when activity changed.
Across the whole brain, the team found differences in 45 subregions. Some areas responded immediately to the threat, while other regions became active later during the recovery period. Importantly, anxiety vulnerability in SERT-KO mice correlated with greater and more widespread activation: more regions lit up and the active volumes within regions were larger compared with wild-type mice.
Several implicated regions are well known for their role in stress and emotion, such as the amygdala and hypothalamus. Unexpectedly, components of the reward circuitry, including parts of the striatum and ventral pallidum, were also more active in anxious mice, suggesting that anxiety alters networks beyond classical fear centers.
Network coordination changed as well. In anxious mice, the normal patterns of coordination between brain regions were disrupted, indicating that anxiety involves not just elevated local activity but a breakdown in the brain’s typical communication and integration.
Bearer summarizes: “Anxiety is not just a prolonged acute fear response. It is characterized by increased activity across many specific regions and a loss of the brain’s normal coordination. These findings define a brain-wide signature of anxiety.”
Clinical implications are immediate. The delayed emergence of either resilient recovery or persistent anxiety suggests that early interventions after traumatic or frightening events may prevent the transition to chronic anxiety or post-traumatic stress. Because the serotonin transporter was central to vulnerability in this model, pharmacologic strategies that target serotonergic systems may reduce the risk of long-term anxiety. Equally, nonpharmacologic approaches — meditation, music, poetry, exercise and other stress-reducing activities that engage reward and regulatory circuits — are likely to support recovery.
About this research:
Source: University of New Mexico
Media Contact: Mark Rudi, University of New Mexico
Image: Public domain
Original research: Open access. “Evolution of brain-wide activity in the awake behaving mouse after acute fear by longitudinal manganese-enhanced MRI” by Elaine L. Bearer et al., published in NeuroImage.
Abstract
Evolution of brain-wide activity in the awake behaving mouse after acute fear by longitudinal manganese-enhanced MRI
A single, life-threatening fear can produce long-lasting anxiety in a subset of vulnerable individuals, but how whole-brain activity changes from acute fear to persistent anxiety is not well understood. Using predator stress to provoke fear and comparing wild-type mice with serotonin transporter knockout (SERT-KO) mice, researchers tracked behavior and brain activity over time. Both genotypes showed immediate defensive behavior after the stressor, but SERT-KO mice retained defensive behavior for 23 days while wild-type animals returned to baseline by nine days. Manganese-enhanced MRI (MEMRI) was used longitudinally to map activity in awake, behaving animals. Results showed widespread Mn2+ accumulation immediately after fear in both genotypes, which evolved into distinct activity patterns by day nine. SERT-KO mice exhibited activity in more brain regions and larger active volumes within regions than wild-type mice. Computational segmentation using an in vivo atlas identified dynamic changes across 45 of 87 regions, with the striatum and ventral pallidum notably more active in anxious mice. Additional markers of neural activation confirmed MEMRI findings. Together, these results reveal how a single acute fear exposure produces brain-wide changes that evolve differently in vulnerable individuals and demonstrate the value of longitudinal MEMRI for studying the progression from fear to anxiety.