Research reportSynaptic activation of cardiac vagal neurons by capsaicin sensitive and insensitive sensory neurons
Introduction
The activity of cardioinhibitory vagal neurons (CVNs) is a major determinant of heart rate. Resting heart rate is normally dominated by the tonic activity of cardioinhibitory CVNs and is influenced to a lesser extent by excitatory sympathetic cardiac activity [11]. CVNs have been found to be localized in the dorsal motor nucleus (DMNX) and the nucleus ambiguus (NA) in the brainstem [13], [22]. CVNs are intrinsically silent and therefore must rely on synaptic input to become activated [16].
Two major reflex pathways that control CVN activity are the baroreflex and the Bezold-Jarisch reflex. Baroreceptors, located in the carotid sinus and the aortic arch respond to increases in arterial pressure, and through a polysynaptic pathway, excite CVNs [14], [15]. Similarly, CVNs are activated via a polysynaptic pathway upon activation of cardiac afferent neurons originating from the myocardium in the Bezold-Jarisch reflex. This reflex is thought to be responsible for the bradycardia that occurs during cardiac ischemia [19].
Although the physiological activation of CVNs is well established, the full circuitry of these reflexes is unknown. The first synapse of both the Bezold-Jarisch reflex and the baroreflex is located in the nucleus tractus solitarius (NTS). Aortic baroreceptor sensory fibers within the aortic depressor nerve (ADN) merge into the vagus nerve and synapse upon neurons in the NTS [5], [9]. Sensory neurons involved with the Bezold-Jarisch reflex originate mostly from the cardiac ventricles and like aortic baroreceptors, their afferent fibers are located within the vagus nerve and synapse in the NTS [2], [12], [20]. However, the complete circuitry from sensory neurons to NTS neurons, and finally the pathway to CVNs, is unknown. Although previous work has shown that stimulation of the NTS evokes both monosynaptic GABAergic and glutamatergic synaptic pathways in CVNs [17], [23], [24] there are a number of limitations in these studies. Stimulation of the NTS excites not only postsensory neurons, but also neurons that may not be activated by sensory pathways. Evoking synaptic responses in CVNs upon stimulation of NTS cannot provide information about the number of potential synapses within the NTS in this reflex pathway. Furthermore these studies cannot address whether activation of sensory neurons activates the glutamatergic, GABAergic or both synaptic pathways from the NTS. This work examines the neurotransmitters, receptors, and latencies that are involved in the polysynaptic activation of CVNs upon stimulation of afferent fibers in the vagus nerve as well as the relative roles of A and C-fiber stimulation in the activation of CVNs.
Section snippets
Labeling of cardiac vagal neurons (CVNs)
An initial surgery was performed in Sprague–Dawley rats (6–10 days old). Animals were anaesthetized with halothane and hypothermia and the heart was exposed with a right thoracotomy between the 2nd and 3rd ribs and rhodamine (XRITC; Molecular Probes, Eugene, OR, USA) was injected into the pericardial sac and applied to the synaptic terminals of CVNs. The rats were allowed to recover for 3–7 days to allow the retrograde fluorescent tracer to label the cell bodies of CVNs in the brainstem. All
Results
Cardiac vagal neurons responded to vagal stimulation with both excitatory postsynaptic currents (EPSCs) as well as inhibitory postsynaptic currents (IPSCs). To isolate the excitatory glutamatergic synaptic events strychnine (1 μM) and gabazine (25 μM) were focally applied to the patch clamped CVN. Under these conditions, stimulation of the vagus nerve consistently evoked glutamatergic postsynaptic currents that occurred with a latency of 44±3 ms and amplitude of −245±31 pA, see Fig. 1. In the
Discussion
There are three major findings in this study. Stimulation of the vagus nerve evokes both GABAergic and glutamatergic, but not glycinergic pathways to CVNs in the DMNX. Both GABAergic and glutamatergic synaptic responses were greatly diminished in the presence of 1 μM capsaicin. The latency of glutamatergic synaptic events were not significantly increased by capsaicin, whereas capsaicin significantly increased the latency of the GABAergic pathway to CVNs.
Since stimulation of baroreceptors and
Acknowledgements
This work was supported by NIH grants HL59895 and HL49965 to D.M.
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