Biology subjects

Goode, L. K.

Publications and source records attributed to Goode, L. K..

3 recordsLinked to original sources

bioRxiv2022

Circadian regulation of dentate gyrus excitability mediated by G-protein signaling

The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm that is driven by intrinsic activity of molecular clock genes controlling membrane excitability. Most brain regions, including the hippocampus, harbor similar intrinsic circadian transcriptional machinery but whether these molecular programs generate oscillations of membrane properties is unexplored. Here, we show that intrinsic excitability of mouse dentate granule neurons exhibits a 24-hour oscillation that controls spiking probability. Diurnal changes in excitability are mediated by antiphase G-protein regulation of potassium and sodium conductances to reduce excitability during the light phase. Disruption of the circadian transcriptional machinery by conditional deletion of Bmal1 enhances excitability selectively during the light phase, increasing engram recruitment and spatial discrimination memory. These results reveal that circadian transcriptional machinery regulates intrinsic excitability, highlighting the role of cell-autonomous oscillations in hippocampal function and behavior. HighlightsDentate neurons exhibit a 24-hour oscillation of excitability with low excitability during the Light phase Reduced excitability results from G-protein regulation of passive and active properties Bmal1 deletion disrupts G-protein regulation to enhance excitability during the Light Bmal1 deletion enhances the size of memory engrams and spatial discrimination

neuroscience↗

bioRxiv2022

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

Circadian rhythms are biological processes that cycle across 24 hours and regulate many facets of neurophysiology, including learning and memory. Circadian variation in performance on spatial memory tasks 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. 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.

neuroscience↗

bioRxiv2021

Impaired clock gene expression and abnormal diurnal regulation of hippocampal inhibitory transmission and spatial memory in a mouse model of Alzheimers disease

Patients with Alzheimers disease (AD) often have fragmentation of sleep/wake cycles and disrupted 24-h (circadian) activity. Despite this, little work has investigated the potential underlying day/night disruptions in cognition and neuronal physiology in the hippocampus. The molecular clock, an intrinsic transcription-translation feedback loop that regulates circadian behavior, may also regulate hippocampal neurophysiological activity. We hypothesized that disrupted diurnal variation in clock gene expression in the hippocampus corresponds with loss of normal day/night differences in membrane excitability, synaptic physiology, and cognition. We previously reported that the Tg-SwDI mouse model of AD has disrupted circadian locomotor rhythms and neurophysiological output of the suprachiasmatic nucleus (the primary circadian clock). Here, we report that Tg-SwDI mice failed to show day-night differences in a spatial working memory task, unlike wild-type controls that exhibited enhanced spatial working memory at night. Moreover, Tg-SwDI mice had lower levels of Per2, one of the core components of the molecular clock, at both mRNA and protein levels when compared to age-matched controls. Interestingly, we discovered neurophysiological impairments in area CA1 of the Tg-SwDI hippocampus. In controls, spontaneous inhibitory post-synaptic currents (sIPSCs) in pyramidal cells showed greater amplitude and lower inter-event interval during the day than the night. However, the normal day/night differences in sIPSCs were absent (amplitude) or reversed (inter-event interval) in pyramidal cells from Tg-SwDI mice. In control mice, current injection into CA1 pyramidal cells produced more firing during the night than during the day, but no day/night difference in excitability was observed in Tg-SwDI mice. The normal day/night difference in excitability in controls was blocked by GABA receptor inhibition. Together, these results demonstrate that the normal diurnal regulation of inhibitory transmission in the hippocampus is diminished in a mouse model of AD, leading to decreased daytime inhibition onto hippocampal CA1 pyramidal cells. Uncovering disrupted day/night differences in circadian gene regulation, hippocampal physiology, and memory in AD mouse models may provide insight into possible chronotherapeutic strategies to ameliorate Alzheimers disease symptoms or delay pathological onset.

neuroscience↗