Circadian regulation of glutamate release pathways shapes synaptic throughput in the brainstem nucleus of the solitary tract (NTS)

Abstract

Circadian regulation of autonomic reflex pathways pairs physiological function with the daily light cycle. The brainstem nucleus of the solitary tract (NTS) is a key candidate for rhythmic control of the autonomic nervous system. Here we investigated circadian regulation of NTS neurotransmission and synaptic throughput using patch‐clamp electrophysiology in brainstem slices from mice. We found that spontaneous quantal glutamate release onto NTS neurons showed strong circadian rhythmicity, with the highest rate of release during the light phase and the lowest in the dark, that were sufficient to drive day/night differences in constitutive postsynaptic action potential firing. In contrast, afferent evoked action potential throughput was enhanced during the dark and diminished in the light. Afferent‐driven synchronous release pathways showed a similar decrease in release probability that did not explain the enhanced synaptic throughput during the night. However, analysis of postsynaptic membrane properties revealed diurnal changes in conductance, which, when coupled with the circadian changes in glutamate release pathways, tuned synaptic throughput between the light and dark phases. These coordinated pre‐/postsynaptic changes encode nuanced control over synaptic performance and pair NTS action potential firing and vagal throughput with time of day. Key points Vagal afferent neurons relay information from peripheral organs to the brainstem nucleus of the solitary tract (NTS) to initiate autonomic reflex pathways as well as providing important controls of food intake, digestive function and energy balance. Vagally mediated reflexes and behaviours are under strong circadian regulation. Diurnal fluctuations in presynaptic vesicle release pathways and postsynaptic membrane conductances provide nuanced control over NTS action potential firing and vagal synaptic throughput. Coordinated pre‐/postsynaptic changes represent a fundamental mechanism mediating daily changes in vagal afferent signalling and autonomic function.

Interrogating synaptic transmission at circadian time scales

“…The NTS, in turn, impacts various autonomic reflex pathways, feeding, satiety and the resulting gastrointestinal physiological responses. Importantly, all these physiological functions that are influenced by the NTS show robust circadian rhythmicity (Ragozzino et al., 2023).…”

“…In the initial set of experiments, Ragozzino et al. (2023) showed that the NTS and nodose ganglia have strongly rhythmic clock gene expression. For instance, canonical gene regulatory components, such as Per1, Per2 and NR1D1 (Rev‐erbα), that underlie cellular circadian rhythmicity showed significantly diurnal expression patterns in both the NTS and the nodose ganglia (Takahashi, 2017).…”

“…Next, using high‐resolution whole‐cell recordings to isolate synaptic responses, Ragozzino et al. (2023) observed strong circadian rhythmicity of spontaneous quantal glutamatergic neurotransmission onto NTS neurons. In these experiments, the highest rate of spontaneous glutamate release occurred during the light phase, and lowest levels prevailed in the dark.…”

“…Ragozzino et al. (2023) also observed that the regulation of action potential‐evoked release was completely the opposite, in that it was enhanced through the night and diminished during the day. The presynaptic changes that regulate evoked release were also coupled with alterations in neuronal conductance.…”

“…The systematic study by Ragozzino et al. (2023) presents a great road map for future investigations into these poorly understood aspects of synaptic biology.…”