Glucocorticoids impair memory inference through noradrenergic disruption of GABAergic regulation in hippocampal CA3

The integration of separate memories sharing overlapping elements allows for inferring relationships between events that have never been experienced together. Recent findings indicate that stress impairs this process of mnemonic inference, which may have important implications for stress-related psychopathologies. However, the mechanisms underlying such impairments remain largely unknown. To elucidate the neuroendocrine mechanisms by which stress affects mnemonic inference, mice were first trained on two sets of auditory-visual cue associations. Afterwards, one of the visual cues was paired with reward. Mnemonic inference was probed by examining reward-seeking behavior in response to the auditory cues alone. Control mice successfully inferred the auditory cue-outcome association, selectively seeking reward in response to the auditory cue associated with the rewarded visual cue. In contrast, systemic administration of the stress hormone corticosterone before testing impaired inference accuracy, leading mice to seek reward to both auditory cues. Corticosterone administration was accompanied by increased noradrenergic activity, and stimulation of noradrenergic signaling with yohimbine similarly disrupted inference accuracy. Conversely, the β-adrenoceptor antagonist propranolol prevented the corticosterone-induced impairment, indicating that corticosterone effects depend on concurrent noradrenergic activation. At the neural level, the corticosterone-induced mnemonic inference impairment was associated with enhanced GABAergic inhibition of pyramidal neurons in the hippocampal CA3 region. Furthermore, hippocampal administration of the GABA _A receptor antagonist bicuculline prevented the corticosterone-induced impairment in mnemonic inference. Together, these findings identify a glucocorticoid–noradrenergic mechanism that disrupts mnemonic inference through enhanced GABAergic inhibition in hippocampal CA3, providing an account of how stress hormones impair inferential memory.