Development and Connectivity of the Circadian Clock Neuron Network

About This Grant

Abstract/Summary: The Fernández Lab seeks to understand how environmental cues and internal physiological states are processed by the nervous system to drive behavior. Our current research focuses on the circadian clock, which allows organisms to maintain internal temporal order and anticipate daily changes in their environment. While the molecular mechanisms underlying the circadian clock are well characterized, the processes by which clock neurons develop and establish connections with each other and with downstream pathways remain poorly understood. Drosophila is an excellent model due to the conservation of the molecular circadian clock and the presence of network motifs resembling those in mammals. Emerging evidence from both mammalian and invertebrate models suggest that core circadian clock genes, some of which are expressed prior to the initiation of the molecular clock, play critical in neuronal development and physiology beyond their established functions in molecular timekeeping mechanism. We recently showed that this is the case for the Drosophila clock gene cycle. When downregulated exclusively during development, cycle leads to altered clock neuron morphology and the loss of adult behavioral rhythms. Our ongoing and future research is aimed at understanding how clock neurons establish their connectivity patterns during development to form a synchronized network of neurons that drives rhythmicity, from gene expression to complex behaviors. Specifically, we will examine the developmental roles of the clock genes cycle and Clock in shaping the connectivity of the main circadian pacemaker neurons and other early-born clock neurons. Notably, these genes are expressed in clock neurons before molecular oscillations can be detected, and we will assess how their downregulation impacts gene expression pathways that influence early-developmental neuronal morphology and connectivity. Additionally, we will examine how various groups of clock neurons respond to key synchronizing signals throughout development, as well as to stimulation of other clock neuron classes. Our recent findings indicate that female circadian rhythms are more resilient to loss of synchronizing factors and suggest that the relative hierarchy of circadian oscillators is sexually dimorphic. We aim to determine the extent to which sexual dimorphism in circadian timekeeping emerges during development and the contributions of sex determination genes in establishing sex differences. Our research program aims to understand how clock neurons develop, communicate, and form precise connections to generate a functional network that drives timekeeping. Our results will contribute to a broader understanding of the mechanisms underlying neuronal development and behavioral plasticity.