Nicotine enhances inhibition of mouse vagal motor neurons by modulating excitability of premotor GABAergic neurons in the nucleus tractus solitarii

Abstract

The caudal nucleus of the solitary tract (NTS) serves as the site of the first synapse for visceral sensory inputs to the central nervous system. The NTS sends functional projections to multiple brain nuclei, with gastric-related projections primarily targeting the dorsal motor nucleus of the vagus (DMV). Previous studies have demonstrated that the majority of caudal NTS neurons that project to the DMV respond robustly to nicotine and express nicotinic acetylcholine receptors (nAChRs). However, the cytochemical identity and relationship with specific viscera of DMV-projecting, nicotine-responsive caudal NTS neurons have not been determined. The present study used transgenic mice that express enhanced green fluorescent protein (EGFP) under a GAD67 promoter in a subset of GABAergic neurons, in vivo retrograde pseudorabies viral labeling to identify gastric-related vagal complex neurons, and patch-clamp electrophysiology in acute brain stem slices to test the hypothesis that gastric-related and GABAergic inhibitory synaptic input to the DMV from the caudal NTS is under a robust modulatory control by nAChRs. Our results suggest that activation of nAChRs in the caudal NTS, but not DMV, potentiates GABAergic, but not glutamatergic, input to the DMV. Gastric-related caudal NTS and DMV neurons are directly involved in this nicotinesensitive circuitry. Understanding the central patterns of nicotinic modulation of visceral sensory-motor circuitry may help develop therapeutic interventions to restore autonomic homeostasis in patients with autonomic impairments.GABA; nicotine receptor; nucleus tractus solitarii; parasympathetic reflex; vagal reflex THE DORSAL VAGAL COMPLEX (DVC) of the caudal brain stem consists of the nucleus tractus solitarii (NTS), the dorsal motor nucleus of the vagus (DMV), and the area postrema. A functional DVC is critical for maintenance of autonomic homeostasis, including gastrointestinal, cardiovascular, and respiratory reflexes. The caudal NTS is the site of the first synapse and a key integration center for autonomic visceral sensory input to the central nervous system (CNS) from the thoracic and most subdiaphragmatic viscera (Saper 2002). The caudal NTS sends excitatory (e.g., glutamatergic) and inhibitory (e.g., GABAergic) projections to preganglionic brain stem sites that modulate both parasympathetic and sympathetic reflexes (Bailey et al. 2006a;

EA at PC6 Promotes Gastric Motility: Role of Brainstem Vagovagal Neurocircuits

“…Furthermore, GABA is the major inhibitory transmitter in the brain. Studies by Xu et al showed that nicotinic acetylcholine receptors (nAChRs) activate GABAergic neurons in the tail of the NTS and enhance the inhibition of mouse vagal motor neurons [29]. Previous studies have shown that the microinjection of nonselective ionotropic glutamate receptor antagonist canine uridine into the dorsal vagus complex (i.e., NTS, DMV, and AP) has little effect on gastric motility, whereas microinjection of the GABAA antagonist bicuculline increases gastric motility [30].…”

Effects of acute and chronic nicotine on catecholamine neurons of the nucleus of the solitary tract

“…Interestingly, we found that nicotine has broad effects on non-CA neurons, suggesting a wide influence of nicotine on NTS function. Our response rate is higher than that reported for neurons in the rat NTS (48,87), as well as among mouse NTS GABAergic neurons projecting to the dorsal motor nucleus of the vagus (DMNV) (101). The variance may reflect differences in slice preparation, since we use a horizontal brain slice as opposed to a coronal slice, and may therefore record from slightly different regions of the NTS.…”

“…Nicotine preferentially activates DMNV-projecting NTS neurons compared with those that project to the parabrachial nucleus (27). NTS-CA neurons have been shown to project to both regions (8,79,80) and presumably represent some of the nicotinesensitive neurons in both groups, in addition to the GABA neurons identified by Xu et al (101).…”

“…Here, we show that NTS-CA neurons are uniformly activated by nicotine, directly, through nAChR␣4␤2, and indirectly, through increased glutamate release via nAChR␣7, presumably through a presynaptic mechanism as the nAChR␣7 agonist AR-R17779 increases mEPSC frequency but not amplitude. Nicotine was previously shown to increase glutamate inputs (48) and induce postsynaptic currents in approximately one-half of NTS neurons through nAChR␣7 and nAChR␣4␤2, respectively (48,87), some of which are GABAergic (101). However, the neurotransmitter phenotype of the other neurons was not known.…”

“…It also induces a postsynaptic current in a subpopulation of NTS neurons (27,28,48,96). Nicotine has been shown to activate GABAergic NTS neurons (101), however, the other phenotypes of NTS neurons activated by nicotine are not known.…”