Pde4b deficiency in female mice leads to enhanced extinction learning and blunted stress reactivity

Fear extinction is a critical adaptive process that is disrupted in stress-induced disorders. Phosphodiesterase-4B (PDE4B), a regulator of intracellular cyclic adenosine monophosphate (cAMP) signaling, has been implicated in fear learning and stress responsivity in males; however, its role in females remains poorly understood. Here, we investigated the behavioural and physiological consequences of Pde4b knockout in adult female mice using a novel genetic model targeting the catalytic domain shared by multiple PDE4B isoforms. Pde4b knockout did not alter baseline innate (i.e., unconditioned) avoidance-like behaviour to a novel environment in the open field or elevated plus maze, nor did it affect fear acquisition. In contrast, Pde4b knockout significantly facilitated fear extinction learning and extinction recall. In addition, Pde4b knockout blunted corticosterone responses to acute restraint stress and was associated with reduced thymus weight, indicating altered stress responsivity. Estrous cycle stage did not significantly influence extinction behaviour. Together, these findings identify Pde4b as a regulator of fear recovery or extinction as well as stress physiology in female mice. Our results broadly extend prior work in males while suggesting sex-specific considerations in Pde4b function, underscoring the importance of examining females in preclinical models of stress-related psychopathology. These data support further investigation of Pde4b targeted strategies for disorders characterized by impaired fear extinction such as PTSD.