Suprachiasmatic nucleus-dependent and independent outputs driving rhythmic activity in hypothalamic and thalamic neurons
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RESEARCH ARTICLE
Open Access
Suprachiasmatic nucleus-dependent and independent outputs driving rhythmic activity in hypothalamic and thalamic neurons Court Harding, David A. Bechtold and Timothy M. Brown*
Abstract Background: Daily variations in mammalian physiology are under control of a central clock in the suprachiasmatic nucleus (SCN). SCN timing signals are essential for coordinating cellular clocks and associated circadian variations in cell and tissue function across the body; however, direct SCN projections primarily target a restricted set of hypothalamic and thalamic nuclei involved in physiological and behavioural control. The role of the SCN in driving rhythmic activity in these targets remains largely unclear. Here, we address this issue via multielectrode recording and manipulations of SCN output in adult mouse brain slices. Results: Electrical stimulation identifies cells across the midline hypothalamus and ventral thalamus that receive inhibitory input from the SCN and/or excitatory input from the retina. Optogenetic manipulations confirm that SCN outputs arise from both VIP and, more frequently, non-VIP expressing cells and that both SCN and retinal projections almost exclusively target GABAergic downstream neurons. The majority of midline hypothalamic and ventral thalamic neurons exhibit circadian variation in firing and those receiving inhibitory SCN projections consistently exhibit peak activity during epochs when SCN output is low. Physical removal of the SCN confirms that neuronal rhythms in ~ 20% of the recorded neurons rely on central clock input but also reveals many neurons that can express circadian variation in firing independent of any SCN input. Conclusions: We identify cell populations across the midline hypothalamus and ventral thalamus exhibiting SCNdependent and independent rhythms in neural activity, providing new insight into the mechanisms by which the circadian system generates daily physiological rhythms. Keywords: Electrophysiology, Circadian, Paraventricular nucleus, Subparaventricular zone, Channelrhodopsin
Background Most aspects of mammalian physiology and behaviour exhibit pronounced daily variations under control of an internal circadian timing system [1, 2]. While there are local clocks across the brain and body that contribute to these processes, the maintenance of robust whole animal * Correspondence: [email protected] Centre for Biological Timing, Faculty of Medicine, Biology and Health, University of Manchester, Manchester, UK
physiological timing and its coordination with environmental cycles relies on a master clock located in the hypothalamic suprachiasmatic nuclei (SCN) [3–5]. Hence, the molecular clock in SCN neurons drives circadian variation in membrane excitability and electrical output, and retinal inputs to the SCN align these neuronal oscillators to transmit high amplitude timing signals to their downstream targets [6, 7]. By contrast with our relatively advanced understanding of timekeeping within the SCN, the mechanism by which
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