Year: 2017
Type: dissertation
Abstract: The mammalian central circadian clock is localized in the suprachiasmatic nucleus (SCN), and is responsible for orchestrating ~24-hour rhythms in behavior and physiology. An additional property of timekeeping in organisms is seasonal adaptation, or adaptation to seasonal variations in environmental conditions. Melatonin signaling has been studied for its role in adapting physiology to seasonal light/dark variations, yet the SCN is responsible for encoding and relaying daylength information by unknown mechanisms. MicroRNAs are small non-coding RNAs that regulate gene expression post-transcriptionally. MicroRNA-132 is part of a microRNA cluster, miR-132/212, that is often expressed in tandem, with well-characterized roles in neuronal plasticity. MiR-132 has been shown to modulate photic entrainment in acute paradigms; however, the role of miR-132/212 in acute and long-term circadian plasticity has not been explored. I aimed to do so in this study using a loss-of-function approach. I found that miR-132/212 ablation alters entrainment to non-24 hour cycles and seasonal photoperiods, and is accompanied by heightened clock protein rhythm amplitude and altered photoperiod-dependent clock protein expression patterns in the SCN. MiR-132/212-deficient SCN neurons show decreased dendritic spine density, which could potentially underlie the perturbed rhythmicity in clock gene expression and behavioral phenotypes. In the seasonal mammal Mesocricetus auratus, adaptation to winter-like photoperiods correlates with decreased dendritic spine density in SCN neurons, and is independent from melatonin signaling. MeCP2 (methyl-CpG binding protein 2) is a miR-132/212 target with roles in brain development and plasticity. MeCP2 expression is altered in miR-132/212-deficient SCN, as is its downstream gene BDNF (brain derived neurotrophic factor) and mTOR (mammalian target of rapamycin) signaling. I used in vitro and in vivo approaches to explore how MeCP2 modulates dendritic morphology phenotypes, and propose that the interaction between miR-132/212-regulated MeCP2, its downstream target BDNF, and the mTOR signaling pathway, is responsible for modulating SCN neuronal plasticity, which could be the basis for encoding seasonal time.
Source: TSpace (University of Toronto)
Author: Lucia Mendoza Viveros
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2908489336