A stressed mind is made more prone to rigid thinking, mouse study finds

University of California, Los Angeles researchers have discovered that chronic stress flips brain activity between two amygdala-striatal pathways, disrupting flexible decision-making and promoting inflexible habits.

The research identifies distinct roles for the basolateral amygdala–dorsomedial striatum (BLA→DMS) and central amygdala–dorsomedial striatum (CeA→DMS) circuits in action-outcome learning and habit formation.

Chronic stress impairs goal-directed decision-making, often leading to rigid, habitual behaviors that underpin several psychiatric conditions. Understanding the neuronal circuits involved could illuminate vulnerabilities in disorders like substance use, obsessive-compulsive disorder, and depression.

In the study, “A dual-pathway architecture for stress to disrupt agency and promote habit,” published in Nature, researchers used a systems neuroscience approach in male and female mice to uncover the underlying brain activity mechanisms.

Chronic mild unpredictable stress was induced through pseudo-random unexpected exposure to stressors, including damp bedding, cage tilting, white noise, continuous illumination, physical restraint, and footshock over 14 days.

While the intentionally mild stress level did not produce pronounced anxiety or depression-like phenotypes in classic tests, blood corticosterone levels were elevated, and body weight decreased in stressed mice compared to controls, confirming stress induction. Controls received handling only.

Cohorts underwent short training sessions in which lever presses earned food pellets. Fiber photometry recorded neuronal signals in distinct amygdala–striatal projections. Optogenetic and chemogenetic manipulations pinpointed how these circuits control goal-directed learning or habit formation.

Behavioral assessments involved lever-press tasks under random-ratio and random-interval reinforcement schedules. Outcome-specific devaluation and contingency degradation tests measured action-outcome learning and habit formation.

Control mice reduced lever pressing when the reward was devalued, indicating preserved agency. Stressed mice displayed insensitivity to devaluation, indicating disrupted action-outcome learning and premature habit formation.

Neuronal activity in BLA→DMS and CeA→DMS pathways were recorded using fiber photometry. BLA→DMS projections were activated by rewards during learning in control mice but suppressed in stressed mice, disrupting action-outcome associations.

Conversely, CeA→DMS projections, typically inactive during early learning, became progressively engaged following stress, facilitating habit formation.

Optogenetic and chemogenetic manipulations further clarified these pathways’ functions. Inhibiting BLA→DMS activity during learning in unstressed mice disrupted agency.

Activating BLA→DMS projections during learning restored agency in stressed mice. In contrast, inhibiting CeA→DMS projections during learning prevented stress-induced habits, while activating this pathway in mildly stressed mice promoted habit formation. Neither manipulation affected instrumental learning acquisition.

The findings reveal that chronic stress diminishes BLA→DMS-mediated flexible decision-making and recruits CeA→DMS circuitry to promote inflexible habits. These results highlight the amygdala’s dual influence on the dorsomedial striatum in balancing goal-directed and habitual behaviors under stress.

It also suggests that stress-induced vulnerabilities to compulsive behaviors, including those linked to substance use and other psychiatric conditions, might have targetable brain circuitry for therapeutic interventions.

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