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The connectome of medullary sympathetic premotor neurons

Dempsey, BR;

The basal and evoked activity of sympathetic nerves, and therefore the physiological
consequences of sympathetic nerve activity (e.g. cardiovascular homeostasis), are
directly dependent on synaptic drive arising from groups of sympathetic premotor
neurons in the medulla and hypothalamus. The central theme of this thesis is the
employment of genetic tools, primarily viral based tracing strategies, to map the
locations of neurons distributed throughout out the brain that provide synaptic drive to
sympathetic premotor neurons in the ventral medulla.
Genetic tools grant researchers the ability to selectively manipulate neuronal
populations based on either anatomical criteria or the constitutive expression of specific
promoters. In Chapter 2 of this thesis we developed a novel technique that permits the
genetic manipulation of single neurons in the rat, based on functional
(electrophysiological) criteria. The work described in this chapter is foundational for
future experiments that intend to map functionally relevant circuits in combination with
tran-synaptic viral tracing strategies.
Sympathetic premotor neurons within the rostral ventrolateral medulla (RVLM) are
essential for the generation of vasomotor tone. However, key questions regarding the
architecture of the circuits that control their activity remain. In Chapter 3 we address
this topic by employing a trans-synaptic viral tracing strategy to identify neurons
monosynaptically connected to bulbospinal RVLM neurons. The anatomical data
acquired using this approach has allowed us to generate a brainwide map of the neurons
that provide monosynaptic input to bulbospinal RVLM neurons, and therefore
determine major sources of synaptic drive likely to underlie the generation of SNA. We
describe an arrangement for afferent input to RVLM bulbospinal neurons that
emphasises input from hitherto unappreciated local medullary sources, but is overall
qualitatively similar to currently held circuit schemes.
In Chapter 4 we examine the anatomical substrates that underlie the recruitment of
autonomic and motor responses to alerting stimuli. Using an anterograde viral tracing
strategy we identify a previously undescribed direct efferent projection from the
superior and inferior colliculi to the ventral brainstem. We describe termination of
axons originating from the colliculi to regions of the brainstem previously associated
with sympathetic, respiratory, and motor functions, and observe putative synaptic
contacts in close apposition to bulbospinal neurons in the rostral ventromedial medulla
and medullary raphe nuclei. These observations characterize a potential pathway via
which sympathetic, respiratory and motor outflows are coordinated by higher order
sensory systems.
The application of genetic approaches in the context of autonomic systems provides an
unprecedented opportunity to examine the structure of discrete neural circuits that
drive a defined, measurable output. The experiments conducted in this thesis provide a
greater understanding of the neuroanatomy that underlies the central control of
physiological behaviours, specifically the basal control of blood pressure and the
coordination of sympathetic outputs as component of motor responses to the
environment.