Somatostatin-GABA neurons regulate vago-vagal circuitry
Lewin, Amanda Elizabeth
Parasympathetic regulation of the gastric antrum is mediated through the vago-vagal circuitry in which glutamatergic afferents relay peripheral information to the CNS and cholinergic efferents transmit the compensatory response back to the periphery. Within the CNS, the DVC, which encompasses the NTS and DMV, is responsible for the modulation and integration of both peripheral and central signals in order to regulate the gastric antrum. GABAergic regulation within these nuclei is critical for the control of the vago-vagal circuit regulating the gastric antrum, however the source of GABA that is responsible for this regulation remains unknown. The most likely source of GABAergic regulation is somatostatin (SST) containing interneurons, due to their regulatory contributions throughout the CNS, the presence of the SST peptide and receptors in the DVC, and the effects of the SST peptide on gastric function. For these reasons, SST-GABA neuron regulation in the DVC was the focus of this dissertation.In order to investigate the contribution of SST-GABA neurons in the regulation of the DVC, Cre-Lox technology was used which allowed for selective ‘reporter’ expression in SST-GABA neurons. These ‘reporters’ made it possible to visually identify (TdTomato), selectively excite (ChR2), or selectively inhibit (ArchT) SST-GABA neurons. Utilizing these transgenics, along with neuronal tracers, I was able to establish that SST-GABA neurons in the DVC are: (1) anatomically connected to vagal efferents that innervate the gastric antrum; (2) functionally connected to DMV output neurons that innervate the gastric antrum; (3) functionally connected to neurons within the NTS; (4) an important source of tonic inhibition of DMV output neurons that innervate the antrum; (5) and important source of tonic inhibition within the NTS; (6) themselves under tonic inhibitory drive and, (7) inhibited by agonists of melanocortin, µ-opioid, and GRP receptors whose activation is known to alter the activity of the DVC in a manner that mimics GABAergic blockade.The findings presented in this dissertation demonstrate that SST-GABA neurons are integral in the regulation of the vagal circuitry responsible for gastric motility. These neurons likely shape network dynamics and represent a target by which other brain regions homeostatically regulate vagal circuitry.
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