Abstract
Oscillations are a ubiquitous dynamic state in living systems that arise at all biological scales,from gene regulatory networks to animal behaviours, and across disparate timescales, from
milliseconds to years. The coordination between many oscillators is a fundamental process that
generates complex and emergent dynamics and endows rhythms with a biological function. This
thesis examines a number of oscillating neural circuits from the brainstem to the hypothalamus
and studies how oscillatory function arises and how it is coordinated.
The first system investigated is a collection of three circadian oscillators in the dorsal
vagal complex (DVC) in the mouse brainstem. This network presents an accessible setting for
investigating the fundamental principles via which multiple circadian oscillators communicate
and synchronise with one another. Time-frequency analysis and phenomenological modelling
of circadian gene expression data in the DVC are used to understand how a spatiotemporal
wave emerges among the three oscillators. Furthermore, a network topology of circadian phase
communication in the DVC is proposed and is used to show how the coupling between clocks
may be tuned to a subcritical state.
In the hypothalamus, the tuberoinfundibular dopaminergic (TIDA) neurones that regulate
the release of the reproductive hormone prolactin, are the site of multiple oscillatory phenomena.
The dopamine output of the population follows a circadian cycle, and TIDA neurones regularly
burst on the scale of seconds. A novel algorithm to detect extracellular TIDA activity is
developed to assess TIDA electrical activity in multielectrode array recordings. It is found that
TIDA cells are excited and burst with a shorter period during the night, compared to the day.
Furthermore, the neuropeptides vasoactive-intestinal polypeptide (VIP) and gastrin-releasing
peptide, which potentially signals the internal time of an organism, excite TIDA neurones. In
the case of VIP, this excitation only occurs during the night. The results suggest that both
intrinsic TIDA timekeeping and signalling from the master biological clock coordinate the daily
changes in this network.
The bursting activity rhythm of the TIDA population occurs on the scale of seconds and
is relevant for prolactin regulation, yet its generation remains elusive. A minimal model of
the ionic mechanisms hypothesised to cause TIDA bursting is constructed and fitted to data.
A slow oscillation driven by persistent Na+ and Ca2+-activated K+ currents is proposed to
underly TIDA bursting and the viability of this mechanism is confirmed by comparing it
to experimental manipulations of the rat TIDA network. Furthermore, the role of electrical
coupling in coordinating the collective activity of a TIDA network is investigated in a two-cell
network. Such coupling is found to synchronise the TIDA network and influence the network
frequency. Additionally, it is shown that bursting can be forced upon a non-bursting cell via
coupling to a bursting cell. The conclusions highlight the capacity for future work in this neural
population, which is discussed in detail.
| Date of Award | 19 Mar 2024 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Alan R Champneys (Supervisor) & Hugh D Piggins (Supervisor) |