Disruption of circadian timing increases synaptic inhibition and reduces cholinergic responsiveness in the dentate gyrus

Abstract

We investigated synaptic mechanisms in the hippocampus that could explain how loss of circadian timing leads to impairments in spatial and recognition memory. Experiments were performed in hippocampal slices from Siberian hamsters (Phodopus sungorus) because, unlike mice and rats, their circadian rhythms are easily eliminated without modifications to their genome and without surgical manipulations, thereby leaving neuronal circuits intact. Recordings of excitatory postsynaptic field potentials and population spikes in area CA1 and dentate gyrus granule cells revealed no effect of circadian arrhythmia on basic functions of synaptic circuitry, including long-term potentiation. However, dentate granule cells from circadian-arrhythmic animals maintained a more depolarized resting membrane potential than cells from circadian-intact animals; a significantly greater proportion of these cells depolarized in response to the cholinergic agonist carbachol (10 μM), and did so by increasing their membrane potential threefold greater than cells from the control (entrained) group. Dentate granule cells from arrhythmic animals also exhibited higher levels of tonic inhibition, as measured by the frequency of spontaneous inhibitory postsynaptic potentials. Carbachol also decreased stimulus-evoked synaptic excitation in dentate granule cells from both intact and arrhythmic animals as expected, but reduced stimulus-evoked synaptic inhibition only in cells from control hamsters. These findings show that loss of circadian timing is accompanied by greater tonic inhibition, and increased synaptic inhibition in response to muscarinic receptor activation in dentate granule cells. Increased inhibition would likely attenuate excitation in dentate-CA3 microcircuits, which in turn might explain the spatial memory deficits previously observed in circadian-arrhythmic hamsters.

Impaired Morris water task retention following T21 light dark cycle exposure is not due to reduced hippocampal c-FOS expression

“…We might have found differing effects on neuronal activation if other immediate early genes were assessed. Related to this, a recent report suggests that the excitation/inhibition state in the circuitry of the dentate gyrus leans more toward inhibition in circadian disrupted animals, without there being any deficit in long term potentiation ( McMartin et al, 2021 ).…”

“…When paired with Ruby et al (2017) , it appears that memory impairments induced by photic circadian rhythm manipulations are not a result of attenuated hippocampal c-FOS expression. On the contrary, it does appear that a bias for synaptic inhibition in the dentate gyrus occurs with circadian arrhythmicity ( McMartin et al, 2021 ). But it remains to be seen if this applies to the current data because our animals remained rhythmic during the T21, they were just not entrained to the light dark cycle ( Ruby et al, 2008 ; Fernandez et al, 2014 ; Shimizu et al, 2016 ; Kwapis et al, 2018 ; Hasegawa et al, 2019 ; Lehr et al, 2021 ).…”

Circadian activities of the brain MNK‐eIF4E signalling axis contribute to diurnal rhythms of some cognitive functions

“…SCN lesion in mice impairs contextual fear memory and spatial memory (Phan et al, 2011). In the disruptive phase shift (DPS) model, where circadian rhythm in the SCN is disrupted by shifted ambient lighting in hamsters, severe deficits in object recognition and spatial memory are found but LTP in hippocampal DG and CA1 remains intact (McMartin et al, 2021). Interestingly, SCN lesion can rescue these memory deficits in the DPS hamsters (Fernandez et al, 2014).…”

Circadian desynchronization attenuates information throughput of prefrontal cortex pyramidal neurons in mice

“…A major hypothesis in the field is that these extra-SCN clocks and the SCN operate synergistically to drive daily rhythms in nearly all components of physiology and behavior, which is why their disruption has numerous physiological and psychological consequences, including exacerbated metabolic and mood disorders (Otsuka et al 2020; McCarthy and Welsh 2012; Morris et al 2015; Bechtold, Gibbs, and Loudon 2010; Karatsoreos 2012). While there have been several well executed studies that demonstrate the importance of circadian rhythms on neurophysiological function in the hippocampus and brainstem, none have included the PFC, and all have largely focused on extracellular field recordings (Chaudhury, Wang, and Colwell 2005; Loh et al 2015; Paul et al 2020; Chrobok et al 2021; McMartin et al 2021). Thus, previous studies have not shed light on the fundamental electrophysiological processes at the cellular level that are affected by time-of-day.…”