High-intensity fear engrams extend beyond threat processing to drive cognitive and affective dysfunction

Abstract

Maladaptive fear memories are a core feature of stress-related disorders and are often accompanied by cognitive and affective disturbances; yet, it remains unclear whether the same neuronal ensembles link maladaptive fear to these behavioural alterations. Here, we show that activity of fear engrams causally contributes to behavioural consequences of intense fear beyond threat processing. Using activity-dependent tagging in the dorsal dentate gyrus (dDG) of mice, we identify neuronal ensembles recruited during high-intensity fear conditioning and show that chemogenetic inhibition of these neurons restores cognitive performance and reduces behavioural despair. These effects are specific to fear-associated ensembles, as inhibition of randomly tagged neurons fails to reproduce them, and depend on persistence of the fear memory, as they are abolished following extinction. Cell-type-specific manipulations revealed that glutamatergic, but not GABAergic, HI-tagged neurons drive fear expression and the associated cognitive and affective alterations, whereas GABAergic neurons exert an opposing influence on fear expression. Consistent with these findings, high-intensity fear was associated with increased reactivation of excitatory fear-tagged neurons and reduced reactivation of GABAergic fear-tagged neurons during behavioural despair. Together, these findings identify high-intensity fear engrams as a causal substrate linking threat-related experiences to cognitive and affective dysfunction and implicate altered excitatory-inhibitory recruitment within a single memory ensemble in the emergence of multi-domain behavioural alterations associated with stress-related disorders.