Abstract
The suprachiasmatic nucleus (SCN) is the principal pacemaker driving the circadian rhythms of physiological behaviors. The SCN consists of distinct neurons expressing neuropeptides, including arginine vasopressin (AVP), vasoactive intestinal polypeptide (VIP), gastrin-releasing peptide (GRP), cholecystokinin (CCK), and so on. AVP, VIP, and GRP neurons receive light stimulation from the retina to synchronize endogenous circadian clocks with the solar day, whereas CCK neurons are not directly innervated by retinal ganglion cells and may be involved in the non-photic regulation of the circadian clock. To better understand the function of CCK neurons in non-photic circadian rhythm, it is vital to clarify the direct afferent inputs to CCK neurons in the SCN. Here, we utilized a recently developed rabies virus- and Cre/loxP-based, cell type-specific, retrograde tracing system to map and quantitatively analyze the whole-brain monosynaptic inputs to SCN CCK neurons. We found that SCN CCK neurons received direct inputs from 29 brain nuclei. Among these nuclei, paraventricular nucleus of the hypothalamus (PVH), paraventricular nucleus of the thalamus (PVT), supraoptic nucleus (SON), ventromedial nucleus of the hypothalamus, and seven other nuclei sent numerous inputs to CCK neurons. Moderate inputs originated from the zona incerta, periventricular hypothalamic nucleus, and five other nuclei. A few inputs to CCK neurons originated from the orbital frontal cortex, prelimbic cortex, cingulate cortex, claustrum, and seven other nuclei. In addition, SCN CCK neurons were preferentially innervated by AVP neurons of the ipsilateral PVH and SON rather than their contralateral counterpart, whereas the contralateral PVT sent more projections to CCK neurons than to its ipsilateral counterpart. Taken together, these results expand our knowledge of the specific innervation to mouse SCN CCK neurons and provide an important indication for further investigations on the function of CCK neurons.
Highlights
The suprachiasmatic nucleus (SCN) has been widely known as a central pacemaker that orchestrates physiological and behavioral circadian rhythms that need daily synchronization to stay in phase with the 24-h solar cycle
We found that the starter neurons were restricted to the ventral part of the rostral and middle SCN, ipsilateral to the injection site (Figures 1F,H)
We found that SCN CCK neurons integrated the majority of their inputs (91.97%) from the diencephalon, from the ventromedial nucleus of the hypothalamus (VMH) (16.47%), paraventricular nucleus of the hypothalamus (PVH) (11.78%), arcuate nucleus of the hypothalamus (Arc) (9.37%), ventromedial preoptic nucleus (VMPO) (7.66%), paraventricular nucleus of the thalamus (PVT) (6.16%), medial preoptic nucleus (MPO) (6.23%), and supraoptic nucleus (SON) (4.67%) (Figures 3, 4)
Summary
The suprachiasmatic nucleus (SCN) has been widely known as a central pacemaker that orchestrates physiological and behavioral circadian rhythms that need daily synchronization to stay in phase with the 24-h solar cycle. Previous studies have shown that feeding and temperature signals were mediated by the diencephalon, including the preoptic area, dorsomedial nucleus of the hypothalamus (DMH), arcuate nucleus of the hypothalamus (Arc), and paraventricular nucleus of the thalamus (PVT) (Tan et al, 2016; Hume et al, 2017; Zhao et al, 2017). It is not clear whether these nuclei send direct projections to CCK neurons of the SCN to entrain the circadian clock. Identifying the afferent circuits of SCN CCK neurons is critical to comprehensively understand the function of these neurons
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