Subcortical-hippocampal circuits for mediating impaired contextual fear memory after an acute shift of the light/dark phase

Acute disturbances of the light-dark cycle may lead to cognitive impairments associated with disturbances in hippocampal functions in humans and rodent models that are potentially governed by subcortical modulation. In this study, we applied a jet-lag-like model in mice by introducing a six-hour delay of the switch towards the light, inactive phase of mice following a contextual fear conditioning training. Phase delay (PD) resulted in a reduced fear memory expression in male but not female, associated with a sex-specific activation of orexinergic neurons in the lateral hypothalamus (LH) as well as of cells in the supramammillary nucleus (SuM) and in the hilus of the dorsal hippocampal dentate gyrus (DG), as assessed by immunolabelling for the activity marker c-Fos. Mimicking the overactivation of SuM and DG by chemogenetic stimulation before contextual fear memory retrieval replicated the PD-induced phenotype, suggesting a direct contribution of the SuM and the DG on modulating fear expression after PD. Further circuit analysis by c-Fos revealed a reciprocal interaction between the SuM and the DG. In addition, orexinergic neurons in the LH were activated by chemogenetic stimulation of the SuM. Together, our results reveal that an acute, jet-lag-like phase shift applied during late consolidation stages induced deficits in fear memory expression associated with an overactivation of the SuM-DG pathway and the orexinergic system. These findings may provide insights into the subcortical modulation of memory-relevant circuits, with relevance for acute light-dark rhythm disruptions prevalent in modern societies as well as for disorders associated with memory disturbances. Significance statementAcute disturbances of the light-dark cycle, as experienced during jet lag or shift work, are increasingly common and can impair memory and cognitive function. Here, we identify a brain circuit underlying jet-lag-induced fear memory deficits that occurs selectively in male, but not female mice. A six-hour delay of the dark phase impaired recall of a previously learned fear memory in males, associated with overactivation of two interconnected brain regions, the supramammillary nucleus and the dentate gyrus of the hippocampus, as well as neurons producing the wake-promoting signal orexin. Artificially mimicking this overactivation was sufficient to reproduce the memory impairment, revealing a hypothalamo-hippocampal circuit that translates circadian disruption into memory deficits, with implications for cognitive disorders and sex-specific vulnerability.