Examination of diurnal variation and sex differences in hippocampal neurophysiology and spatial memory

Abstract

Circadian rhythms are biological processes that cycle across 24 hours and regulate many facets of neurophysiology, including learning and memory. Circadian variation in spatial memory task performance is well-documented; however, the effect of sex across circadian time remains unclear. Additionally, little is known regarding the impact of time-of-day on hippocampal neuronal physiology. Here, we investigated the influence of both sex and time-of-day on hippocampal neurophysiology and memory in mice. Performance on the object location memory (OLM) task depended on both circadian time and sex, with memory enhanced at night in males but during the day in females. Long-term synaptic potentiation (LTP) magnitude at CA3-CA1 synapses was greater at night compared to day in both sexes. Next, we measured spontaneous synaptic excitation and inhibition onto CA1 pyramidal neurons. Frequency and amplitude of inhibition was greater during the day compared to night, regardless of sex. Frequency and amplitude of excitation was larger in females, compared to males, independent of time-of-day, although both time-of-day and sex influenced presynaptic release probability. At night, CA1 pyramidal neurons showed enhanced excitability (action potential firing and/or baseline potential) that was dependent on synaptic excitation and inhibition, regardless of sex. This study emphasizes the importance of sex and time-of-day in hippocampal physiology, especially given that many neurological disorders impacting the hippocampus are linked to circadian disruption and present differently in men and women. Knowledge about how sex and circadian rhythms affect hippocampal physiology can improve the translational relevancy of therapeutics and inform the appropriate timing of existing treatments.

Significance Statement

Circadian rhythms regulate many aspects of neurophysiology, including cognition. However, the impact of time-of-day and sex on hippocampal neurophysiology and hippocampus-dependent memory remains largely unexplored. Here, we report that circadian regulation of object location memory is sex dependent. Furthermore, examination of hippocampal physiology across time-of-day in both sexes revealed: enhanced long-term synaptic potentiation at night, greater daytime inhibitory synaptic transmission onto CA1 pyramidal neurons, effects of both sex and time-of-day on excitatory synaptic transmission onto CA1 pyramidal neurons, and enhanced nighttime excitability of CA1 pyramidal neurons that is dependent on both synaptic input and position along anterior-posterior hippocampal axis. These results underscore the importance of accounting for sex, regional location, and time-of-day in the study of hippocampal physiology.