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The Cannabinoid System Regulates Circadian Clock Function
- Publication Year :
- 2023
-
Abstract
- Environmental light information is the main stimulus that synchronizes an organisms’ circadian rhythms, which are approximately 24-hour oscillations in physiology and behavior. In mammals, circadian rhythms are driven by a central pacemaker in the suprachiasmatic nucleus (SCN) of the hypothalamus. A neuromodulatory system within the SCN, the endocannabinoid system (ECS), plays a role in clock function; however, little is known about the bidirectional effects each system exerts on one another. Therefore, we investigated the temporal and spatial architecture of the ECS in the SCN and examined the effects of acute administration of exogenous cannabinoids on circadian behavior. To investigate the temporal molecular landscape of ECS components in the SCN we excised the SCN of male and female C57BL/6J mice that were housed under 12:12 light/dark and constant dark conditions. SCN tissue was then processed to examine ECS gene expression across the 24-hour day. Data from these experiments suggest that a considerable number of ECS genes are under control of the circadian clock, and further suggests that they have a time-of-day specific role in SCN clock function. Out of six ECS receptors we examined, only one was detected, cannabinoid receptor 1 (Cnr1/CB1), which is the primary ECS receptor in the central nervous system, along with several genes involved in synthesis, degradation, and transport of endocannabinoids. Next, we investigated the spatial layout of the ECS in the SCN with RNAscope in situ hybridization. Analysis of these data shows most of the inspected ECS components are in a higher percentage of cells in male compared to female animals. All genes were present in both neurons and astrocytes, but only two genes, Mgll and fatty acid binding protein 7 (Fabp7), exhibited higher levels in astrocytes. We also characterized ECS components in cells expressing the neuropeptides Vip, Avp, or neither neuropeptide; there were equal or the highest levels of expression in the neuronal category which lacked Vip or Avp. These results suggest that endocannabinoids are synthesized, degraded, and signal through multiple cell types within the SCN, but primarily signal through neuronally located CB1. We then tested the effects of the exogenous cannabinoids CP 55,940 (a CB1 receptor agonist) and cannabidiol (CBD) (a constituent of marijuana) on circadian wheel-running behavior. Acute injections of CP 55,940 early in the active period paired with a light pulse 30 minutes after intraperitoneal injections reduces the phase shifting effects on clock output in male animals, but not in females. Increasing doses of CP 55,940 increased the amount of wheel-running suppression on the day of injection but did so in both males and females. This suggests that the sex difference in phase delay effects are circadian clock specific. No effects of CBD administration on photic phase shifts were observed. These behavioral data imply that cannabinoids mainly act through CB1 to affect the circadian clock. Taken together, our results support a time-of-day dependent modulation of the ECS in SCN clock function, where endocannabinoid signaling is regulated via neurons and astrocytes. Additionally, our data support the idea that cannabinoids primarily act on the circadian clock by signaling through CB1 and that a sex difference in circadian behavior occurs with its activation.
- Subjects :
- Neurobiology
Circadian Rhythms
Endocannabinoids
Wheel-running
Sex-differences
Subjects
Details
- Language :
- English
- Database :
- OpenDissertations
- Publication Type :
- Dissertation/ Thesis
- Accession number :
- ddu.oai.etd.ohiolink.edu.kent1685630282566922