Circadian rhythms are ubiquitous throughout biology. In mammals, these rhythms are centrally orchestrated by the master pacemaker, the suprachiasmatic nuclei (SCN), which aligns rhythms in internal physiology with the external geophysical time. In addition, there are other brain structures outside of the SCN which are also capable of generating endogenous oscillations in gene expression and neuronal activity, and thus control the timing of diverse processes such as mood regulation, rest-activity cycles, feeding behaviour and other aspects of the brainâs reward system. Interestingly, accumulating evidence suggests that smoking behaviours are also modulated by the time of day, indicating that the circadian system might be controlling the endogenous cholinergic pathways underlying these behaviours. Therefore, to investigate this possibility, the overall aim of this thesis was to explore how the time of day impacts the key brain circuitry mediating nicotineâs effects, specifically within the medial habenula (MHb). We began by investigating daily variation in behavioural responses to nicotine in rats. We found that there was significant diurnal variation in nicotine-evoked changes in locomotor behaviour which appeared to be dependent on the level of arousal of the animal. These experiments support the idea that there is a rhythmic component to the circuitry underlying nicotine responses. The next aim was to explore circadian variation in cholinergic signalling at the network level. These studies focussed specifically on the MHb, a small structure of the epithalamus, which is implicated both as a critical mediator of smoking behaviours and has also been identified as a potential circadian oscillator. We explored circadian variation in mouse MHb neuronal activity and cholinergic signalling through the use of both ex- and in vivo electrophysiological approaches. Ex vivo, we found evidence of rhythmicity in spontaneous firing activity, even in the absence of SCN input, and diurnal variation in responses to nicotine. We further confirmed rhythmicity in MHb neuronal activity in vivo, and revealed that MHb cholinergic neurons integrate both circadian and photic information, which could contribute to the rhythmic drive in nicotine addiction behaviours. Finally, we investigated the molecular mechanisms driving the diurnal variation in MHb properties. We generated a diurnal transcriptomic profile of mouse MHb tissue, and whilst we did not find evidence for robust rhythms in molecular clock gene expression, we did however find a group of rhythmic transcripts which were associated with hormone signalling and mechanisms regulating synaptic plasticity that may underlie rhythms in MHb function. Overall the results presented in this thesis indicate that there is certainly rhythmic control of rodent MHb activity, response to nicotine and cholinergic output. This highlights the MHb as a potential site for diurnal modulation of goal-directed behaviours including those related to nicotine addiction, which has implications both for the treatment of nicotine addiction as well as other mood disorders which might be modulated through this structure.
|Date of Award||1 Aug 2022|
- The University of Manchester
|Supervisor||Hugh Piggins (Supervisor), Timothy Brown (Supervisor) & Joanna Neill (Supervisor)|