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

Abstract

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 mice, associated with an 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) in male mice, 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.