INTERGENERATIONAL INHERITANCE OF STRESS AND UNPREDICTABILITY LEARNING: A PUTATIVE BIOPHYSICAL MECHANISM

Stress can induce long-lasting changes in neural function that extend beyond the exposed individual, yet the neuronal mechanisms supporting intergenerational transmission remain unclear. We investigated how predictable versus unpredictable stress alters intrinsic excitability in the anterior insular cortex and shapes fear-related behavior across generations. Adult mice underwent tone–shock fear conditioning under predictable, unpredictable, or naïve conditions, followed two weeks later by three days of tone-only exposure. Unpredictably stressed mice exhibited persistently elevated freezing across extinction sessions, consistent with heightened fear expression and impaired extinction learning. At the cellular level, this behavioral phenotype was accompanied by a marked reduction in post-burst after-hyperpolarization (AHP) amplitude in insular cortex pyramidal neurons, indicating increased intrinsic excitability.
To examine intergenerational effects, animals from each group were bred and first-generation offspring were exposed to a single tone–mild shock pairing followed by tone-only exposure. Offspring of stressed parents showed enhanced freezing compared to offspring of naïve controls, with the strongest effects observed in offspring of unpredictably stressed parents. Importantly, offspring of unpredictably stressed parents also exhibited reduced AHP amplitude in insular pyramidal neurons, mirroring parental intrinsic excitability changes.
Pharmacological blockade of the M-current using the Kv7 channel antagonist reduced AHP amplitude in naïve animals and predictably stressed parents, but not in offspring of predictably stressed parents, whose AHP was already reduced at baseline. These findings identify stress-pattern–dependent modulation of intrinsic neuronal excitability in the insular cortex, mediated in part by M-current–related mechanisms, as a candidate biophysical substrate for intergenerational transmission of heightened fear.