Examination of Diurnal Variation and Sex Differences in Hippocampal Neurophysiology and Spatial Memory

Abstract

Circadian rhythms are biological processes that cycle across 24 h 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 (CT) 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 with 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 with night, regardless of sex. Frequency and amplitude of excitation was larger in females, compared with 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 neurologic 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.

Evaluating the daily modulation of FADD and related molecular markers in different brain regions in male rats

“…Prior studies that evaluated the regulation of circadian genes by components of the MAPK pathway (e.g., Akashi et al., 2008; Eckel‐Mahan et al., 2008; reviewed by Wang et al., 2020) also showed that their activity peaked in certain brain regions during the day (inactive period for the mice evaluated; Eckel‐Mahan et al., 2008). Moreover, since this disruption of p‐ERK oscillations was linked to an impaired memory persistence (Eckel‐Mahan et al., 2008), the 24‐h modulation of p‐ERK/t‐ERK observed in association with FADD fluctuations might be key for normal physiological activities (e.g., Gaspar et al., 2019; Goode et al., 2022; McCauley et al., 2020; Patke et al., 2020).…”

Control of circadian rhythm on cortical excitability and synaptic plasticity

“…Indeed, studies performed in nocturnal rodents show that hippocampal LTP is remarkably affected by the time of the day and that this modulation stands even after rearing the animals in darkness for a few days, thus demonstrating the dependency on the intrinsic circadian clock rather than on the light cycle. Surprisingly, there is no complete agreement on the direction of the effect: while several studies indicate that hippocampal LTP measured in CA1 is stronger at night, during the active phase of nocturnal animals ( Chaudhury et al, 2005 ; Bowden et al, 2012 ; Nakatsuka and Natsume, 2014 ; Besing et al, 2017 ; Davis et al, 2020 ; Goode et al, 2022 ), other studies provide a different picture, with the peak of LTP during the day ( Raghavan et al, 1999 ; McCauley et al, 2020 ). These differences underline the complexity of the problem of linking circadian rhythm with models of synaptic plasticity and behavioral assays.…”

“…(C) mTOR is the converging point between the environmental stimuli and the autonomous circadian clock. Goode et al, 2022), other studies provide a different picture, with the peak of LTP during the day (Raghavan et al, 1999;McCauley et al, 2020). These differences underline the complexity of the problem of linking circadian rhythm with models of synaptic plasticity and behavioral assays.…”

“…The authors concluded that this result “probably reflects a 24-h rhythm in some aspects of learning or retention.” Other studies in nocturnal rodents confirm that learning assays involving negative stimuli peaks during the day ( Chaudhury and Colwell, 2002 ; Eckel-Mahan et al, 2008 ; Wang et al, 2009 ), thus suggesting a increased plasticity of the pathways processing negative emotions. In contrast, behavioral assays of memory and learning involving positive or neutral stimuli peaked at night (reviewed in Snider et al, 2018 ; Goode et al, 2022 ). From this body of evidence, we can expect that long-term potentiation (LTP), a correlate to memory and learning, should also be modulated through the day-night cycle.…”

On-demand low-frequency stimulation for seizure control: efficacy and behavioral implications

“…Third, cognitive function includes not only the abilities of learning and memory but also attention, behavioral flexibility, problem-solving, and action planning 88 and hence should not be disregarded. A fourth limitation concerns the diurnal variations and sex differences in hippocampal physiology and behavior 89…”