SummaryThe suprachiasmatic nucleus (SCN) of the hypothalamus orchestrates daily rhythms of physiology and behavior in mammals. Its circadian (∼24 hr) oscillations of gene expression and electrical activity are generated intrinsically and can persist indefinitely in temporal isolation. This robust and resilient timekeeping is generally regarded as a product of the intrinsic connectivity of its neurons. Here we show that neurons constitute only one “half” of the SCN clock, the one metabolically active during circadian daytime. In contrast, SCN astrocytes are active during circadian nighttime, when they suppress the activity of SCN neurons by regulating extracellular glutamate levels. This glutamatergic gliotransmission is sensed by neurons of the dorsal SCN via specific pre-synaptic NMDA receptor assemblies containing NR2C subunits. Remarkably, somatic genetic re-programming of intracellular clocks in SCN astrocytes was capable of remodeling circadian behavioral rhythms in adult mice. Thus, SCN circuit-level timekeeping arises from interdependent and mutually supportive astrocytic-neuronal signaling.
Circadian (~24h) rhythms depend on intra-cellular transcription-translation negative feedback loops (TTFLs). How these self-sustained cellular clocks achieve multi-cellular integration and thereby direct daily rhythms of behavior in animals is largely obscure. The suprachiasmatic nucleus (SCN) is the fulcrum of this gene-to-cell-to-circuit-to-behavior pathway in mammals. We describe cell-type-specific, functionally distinct, TTFLs in neurons and astrocytes of the SCN and show that- in the absence of other cellular clocks- the cell autonomous astrocytic TTFL alone can drive molecular oscillations in the SCN and circadian behavior in mice. Astrocytic clocks achieve this by reinstating clock gene expression and circadian function of SCN neurons via glutamatergic signals. These results provide a first demonstration that astrocytes can autonomously initiate and sustain complex mammalian behavior.
Dendritic spine remodelling involves regulated actin dynamics and is essential for synaptic plasticity. The Arp2/3 inhibitor PICK1 is here shown to regulate spine size: inducing shrinkage during long-term depression.
The hypothalamic suprachiasmatic nuclei (SCN) are the principal mammalian circadian timekeeper, coordinating organism-wide daily and seasonal rhythms. To achieve this, cellautonomous circadian timing by the~20,000 SCN cells is welded into a tight circuit-wide ensemble oscillation. This creates essential, network-level emergent properties of precise, high-amplitude oscillation with tightly defined ensemble period and phase. Although synchronised, regional cell groups exhibit differentially phased activity, creating stereotypical spatiotemporal circadian waves of cellular activation across the circuit. The cellular circuit pacemaking components that generate these critical emergent properties are unknown. Using intersectional genetics and real-time imaging, we show that SCN cells expressing vasoactive intestinal polypeptide (VIP) or its cognate receptor, VPAC2, are neurochemically and electrophysiologically distinct, but together they control de novo rhythmicity, setting ensemble period and phase with circuit-level spatiotemporal complexity. The VIP/VPAC2 cellular axis is therefore a neurochemically and topologically specific pacemaker hub that determines the emergent properties of the SCN timekeeper.
Circadian rhythms in mammals are governed by the hypothalamic suprachiasmatic nucleus (SCN), in which 20,000 clock cells are connected together into a powerful time‐keeping network. In the absence of network‐level cellular interactions, the SCN fails as a clock. The topology and specific roles of its distinct cell populations (nodes) that direct network functions are, however, not understood. To characterise its component cells and network structure, we conducted single‐cell sequencing of SCN organotypic slices and identified eleven distinct neuronal sub‐populations across circadian day and night. We defined neuropeptidergic signalling axes between these nodes, and built neuropeptide‐specific network topologies. This revealed their temporal plasticity, being up‐regulated in circadian day. Through intersectional genetics and real‐time imaging, we interrogated the contribution of the Prok2‐ProkR2 neuropeptidergic axis to network‐wide time‐keeping. We showed that Prok2‐ProkR2 signalling acts as a key regulator of SCN period and rhythmicity and contributes to defining the network‐level properties that underpin robust circadian co‐ordination. These results highlight the diverse and distinct contributions of neuropeptide‐modulated communication of temporal information across the SCN.
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