Opioidergic neurotransmission in the nucleus of the solitary tract brainstem circuitry

Abstract

The nucleus of the solitary tract (NTS) is the first central site for integration of autonomic sensory input arriving from the vagus. NTS neurons excite preganglionic cardiac vagal neurons (CVNs) in the nucleus ambiguus (NA), to slow the heart and reduce cardiac output. This cardioinhibitory response is sensitive to exogenous and endogenous opioids such as β-endorphin, a product of the precursor proopiomelanocortin (POMC). The NTS contains POMC neurons which project toward the NA. Activation of these neurons evokes a rapid bradycardia which is abolished by opioid receptor antagonism. This establishes an apparent paradox where the rapid excitation of CVNs involves a slowly acting inhibitory opioid.
This thesis aimed to test the hypothesis that NTS POMC neurons are 2nd order glutamatergic neurons, that form monosynaptic connections locally and with vagal motor neurons in the medulla. Additionally, β-endorphin modulates NTS POMC glutamatergic neurotransmission.
An optogenetic approach was employed to selectively activate NTS POMC neurons using Cre-dependent Adeno-Associated Viral vectors injected into the NTS of genetically modified POMC-Cre mice. Intrinsic properties of NTS POMC neurons and their neurotransmission within vagal circuits was investigated.
The NTS POMC neurons act as 2nd order NTS neurons in vago-vagal reflexes, mediating fast excitation of vagal motor nuclei. NTS POMC neurons are primarily glutamatergic but form sparse GABAergic synapses within the NTS. NTS POMC neurons show spontaneous activity making them a likely source of an inhibitory μ-opioid receptor-mediated tone in dorsal vagal motor (DMV) neurons. In contrast the NTS POMC neurons do not generate the inhibitory GABAergic tone previously reported in DMV. Activation of NTS POMC neurons evoked the release of β-endorphin in the NA, increasing NTS POMC excitatory drive to putative CVNs. A mechanism is proposed involving β-endorphin mediated disinhibition of excitatory POMC terminals, via inhibitory interneurons, and likely accounting for the apparently paradoxical, rapid, opioid-sensitive bradycardia.

Date of Award	12 May 2022
Original language	English
Awarding Institution	University of Bristol
Supervisor	Anthony Edward Pickering (Supervisor) & Graeme Henderson (Supervisor)