Modulation of Cough Reflex by Gaba-Ergic Inhibition in Medullary Raphé of the Cat

We studied the effects of GABA receptor agonists microinjections in medullary raphé on the mechanically induced tracheobronchial cough response in anesthetized, unparalyzed, spontaneously breathing cats. The results suggest that GABA-ergic inhibition significantly contributes to the regulation of cough reflex by action of both GABAA and GABAB receptors. The data are consistent with inhomogeneous occurrence of GABA-ergic neurons in medullary raphé and their different involvement in the cough reflex control. Cells within rostral nucleus raphé obscurus with dominant role of GABAA receptors and neurons of rostral nucleus raphé pallidus and caudal nucleus raphé magnus with dominant role of GABAB receptors participate in regulation of cough expiratory efforts. These cough control elements are distinct from cough gating mechanism. GABA-ergic inhibition in the raphé caudal to obex had insignificant effect on cough. Contradictory findings for GABA, muscimol and baclofen administration in medullary raphé suggest involvement of coordinated activity of GABA on multiple receptors affecting raphé neurons and/or the local neuronal circuits in the raphé modulating cough motor drive.

Enhancing GABAergic Tone in the Rostral Nucleus of the Solitary Tract Reconfigures Sensorimotor Neural Activity

ABSTRACTRecent work has shown that most cells in the rostral, gustatory portion of the nucleus tractus solitarius (rNTS) in awake, freely licking rats show lick-related firing. However, the relationship between taste-related and lick-related activity in rNTS remains unclear. Here, we tested if GABA-derived inhibitory activity regulates the balance of lick- and taste-driven neuronal activity. Combinatorial viral tools were used to restrict expression of ChR2-EYFP to GAD1+ GABAergic neurons. Viral infusions were bilateral in rNTS. 2-4wks later, an optical fiber attached to 8-16 drivable microwires was implanted into the rNTS. After recovery, water-deprived rats were presented with taste stimuli in an experimental chamber. Trials were 5 consecutive taste licks [NaCl, KCl, NH4Cl, sucrose, MSG/IMP, citric acid, quinine, or artificial saliva (AS)] separated by 5 AS licks on a VR5 schedule. Each taste lick triggered a 1s train of laser light (25Hz; 473nm; 8-10mW) in a random half of the trials. In all, 113 cells were recorded in the rNTS, 50 responded to one or more taste stimuli without GABA enhancement. Selective changes in response magnitude (spike count) within cells shifted across unit patterns but preserved inter-stimulus relationships. Cells where enhanced GABAergic tone increased lick coherence conveyed more information distinguishing basic taste qualities and different salts than other cells. In addition, GABA activation significantly amplified the amount of information that discriminated palatable vs. unpalatable tastants. By dynamically regulating lick coherence and remodeling the across-unit response patterns to taste, enhancing GABAergic tone in rNTS reconfigures the neural activity reflecting sensation and movement.Significance StatementThe rostral nucleus tractus solitarius (rNTS) is the first structure in the central gustatory pathway. Electrophysiological recordings from the rNTS in awake, freely-licking animals show that cells in this area have lick- as well as taste-related activity, but the relationship between these characteristics is not well understood. Here, we showed evidence that GABA activation can dynamically regulate both of these two properties in rNTS cells to enhance the information conveyed, especially about palatable vs. unpalatable tastants. These data provide insights into the role of inhibitory activity in the rNTS.

A computational analysis of signal fidelity in the rostral nucleus of the solitary tract

Neurons in the rostral nucleus of the solitary tract (rNST) convey taste information to both local circuits and pathways destined for forebrain structures. This nucleus is more than a simple relay, however, because rNST neurons differ in response rates and tuning curves relative to primary afferent fibers. To systematically study the impact of convergence and inhibition on firing frequency and breadth of tuning (BOT) in rNST, we constructed a mathematical model of its two major cell types: projection neurons and inhibitory neurons. First, we fit a conductance-based neuronal model to data derived from whole cell patch-clamp recordings of inhibitory and noninhibitory neurons in a mouse expressing Venus under the control of the VGAT promoter. We then used in vivo chorda tympani (CT) taste responses as afferent input to modeled neurons and assessed how the degree and type of convergence influenced model cell output frequency and BOT for comparison with in vivo gustatory responses from the rNST. Finally, we assessed how presynaptic and postsynaptic inhibition impacted model cell output. The results of our simulations demonstrated 1) increasing numbers of convergent afferents (2–10) result in a proportional increase in best-stimulus firing frequency but only a modest increase in BOT, 2) convergence of afferent input selected from the same best-stimulus class of CT afferents produced a better fit to real data from the rNST compared with convergence of randomly selected afferent input, and 3) inhibition narrowed the BOT to more realistically model the in vivo rNST data. NEW & NOTEWORTHY Using a combination of in vivo and in vitro neurophysiology together with conductance-based modeling, we show how patterns of convergence and inhibition interact in the rostral (gustatory) solitary nucleus to maintain signal fidelity. Although increasing convergence led to a systematic increase in firing frequency, tuning specificity was maintained with a pattern of afferent inputs sharing the best-stimulus compared with random inputs. Tonic inhibition further enhanced response fidelity.

Microcircuitry of the Rostral Nucleus of the Solitary Tract

Gustatory and somatosensory information from the oral cavity is carried by afferent fibers in the fifth, seventh, and ninth cranial nerves to synapse in the rostral nucleus of the solitary tract (rNST). Incoming taste afferents from the three cranial nerves follow a rostral-caudal gradient within the nucleus, characterized by a gradual transition from neurons with anterior-to-posterior mouth receptive fields. This organization predisposes a pattern of convergence onto second-order neurons of afferents innervating adjacent or apposing receptors, while maintaining an orotopic representation. Although evidence for convergence between the seventh and ninth nerves is relatively infrequent in extracellular recordings, high-magnification confocal microscopy and patch recordings suggest the potential for considerable interaction between these cranial nerves. Overall, the convergence of afferent input functions to increase the overall firing rate, receptive field size, and responsiveness to a wider range of taste stimuli of second-order neurons than peripheral fibers.