Suprachiasmatic VIP neurons are required for normal circadian rhythmicity and comprised of molecularly distinct subpopulations

Abstract

The hypothalamic suprachiasmatic (SCN) clock contains several neurochemically defined cell groups that contribute to the genesis of circadian rhythms. Using cell-specific and genetically targeted approaches we have confirmed an indispensable role for vasoactive intestinal polypeptide-expressing SCN (SCN VIP) neurons, including their molecular clock, in generating the mammalian locomotor activity (LMA) circadian rhythm. Optogenetic-assisted circuit mapping revealed functional, di-synaptic connectivity between SCN VIP neurons and dorsomedial hypothalamic neurons, providing a circuit substrate by which SCN VIP neurons may regulate LMA rhythms. In vivo photometry revealed that while SCN VIP neurons are acutely responsive to light, their activity is otherwise behavioral state invariant. Single-nuclei RNAsequencing revealed that SCN VIP neurons comprise two transcriptionally distinct subtypes, including putative pacemaker and non-pacemaker populations. Altogether, our work establishes necessity of SCN VIP neurons for the LMA circadian rhythm, elucidates organization of circadian outflow from and modulatory input to SCN VIP cells, and demonstrates a subpopulation-level molecular heterogeneity that suggests distinct functions for specific SCN VIP subtypes.

Time-restricted feeding near dawn entrains long-term behavioral changes through the suprachiasmatic nucleus

“…SCN VIP neurons represent integration points for both photic and non-photic sensory inputs (Acosta-Galvan et al, 2011). The activation of SCN VIP neurons by bilateral injections of Cre-dependent hM3Dq into the SCN of heterozygous VIP-Cre mice at ZT4 and ZT13 does not change locomotor or sleep-wake cycle phenotypes (Todd et al, 2020). Hence, we asked whether selective inhibition of SCN VIP neurons may be able to simulate the effect of ZT0-4 TRF entrainment (i.e., delay the offset of activity).…”

Genesis of the Master Circadian Pacemaker in Mice

“…The SCN is a pair of nuclei located in the anterior hypothalamus, situated directly dorsal to the optic chiasm and lateral to the third ventricle. It is comprised of approximately 20,000 heterogenous neurons that secrete dozens of neuropeptides, neurotransmitters, and cytokines, many of which can be at least partially co-expressed by certain populations of SCN neurons ( Figure 2 ; Abrahamson and Moore, 2001 ; Cheng et al, 2002 ; Antle and Silver, 2005 ; Todd et al, 2020 ; Wen et al, 2020 ). The SCN is classically divided into two subregions, a light-responsive ventrolateral “core” and a rhythmic dorsomedial “shell,” based on the neurochemical nature of cells in each area and its physiological function ( Aton et al, 2005 ).…”

“…GRP can also act as a secondary synchronizing neuropeptide when VIP-VPAC2 signaling is defective, since addition of GRP to Vpac2 –/– SCN explants can transiently restore network synchrony ( Brown et al, 2005 ; Maywood et al, 2011 ). Recent single cell RNAseq studies have found that GRP-expressing neurons are a subpopulation of VIP neurons: approximately one-quarter of VIP + cells in the SCN co-express GRP ( Todd et al, 2020 ; Wen et al, 2020 ).…”

Potential Pathways for Circadian Dysfunction and Sundowning-Related Behavioral Aggression in Alzheimer’s Disease and Related Dementias

“…These VIP core neurons then appear to entrain the rhythmicity of AVP shell neurons and other SCN neuronal cell types in order to establish SCN-level synchrony (Aton et al, 2005;Maywood et al, 2006). The subpopulation of SCN neurons expressing NMS have also been implicated as playing a crucial role in circadian pacemaking (Lee et al, 2015), however, more recent work suggests that the critical neurons in this role belong to a molecularly distinct subpopulation that expresses both NMS and VIP together (Todd et al, 2020). Interestingly, Todd et al (2020) found that SCN VIP neurons that also contain NMS are enriched with the transcript Per2 associated with a core clock gene, whereas the non-NMS subpopulation of SCN VIP neurons that also contain GRP did not have such transcripts.…”

“…The subpopulation of SCN neurons expressing NMS have also been implicated as playing a crucial role in circadian pacemaking (Lee et al, 2015), however, more recent work suggests that the critical neurons in this role belong to a molecularly distinct subpopulation that expresses both NMS and VIP together (Todd et al, 2020). Interestingly, Todd et al (2020) found that SCN VIP neurons that also contain NMS are enriched with the transcript Per2 associated with a core clock gene, whereas the non-NMS subpopulation of SCN VIP neurons that also contain GRP did not have such transcripts. Altogether, this suggests that SCN VIP neurons are composed of both pacemaker and non-pacemaker subpopulations, which is supported by previous work demonstrating that SCN VIP neurons can be divided into two groups based on the lightinducibility of clock genes, innervation of retinal afferents, day-night variability of VIP mRNA, and coexpression of GRP (Kawamoto et al, 2003).…”