Dedicated C‐fibre viscerosensory pathways to central nucleus of the amygdala
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Emotions are accompanied by concordant changes in visceral function, including cardiac output, respiration and digestion. One major forebrain integrator of emotional responses, the amygdala, is considered to rely on embedded visceral afferent information, although few details are known. In the present study, we retrogradely transported dye from the central nucleus of the amygdala (CeA) to identify CeA-projecting nucleus of the solitary tract (NTS) neurons for synaptic characterization and compared them with unlabelled, near-neighboor NTS neurons. Solitary tract (ST) afferents converged onto NTS-CeA second-order sensory neurons in greater numbers, as well as indirectly via polysynaptic pathways. Unexpectedly, all mono- and polysynaptic ST afferent pathways to NTS-CeA neurons were organized exclusively as either transient receptor potential cation channel subfamily V member 1 (TRPV1)-sensitive or TRPV1-resistant, regardless of whether intervening neurons were excitatory or inhibitory. This strict sorting provides viscerosensory signals to CeA about visceral conditions with respect to being either 'normal' via A-fibres or 'alarm' via TRPV1 expressing C-fibres and, accordingly, this pathway organization probably encodes interoceptive status.Emotional state is impacted by changes in visceral function, including blood pressure, breathing and digestion. A main line of viscerosensory information processing occurs first in the nucleus of the solitary tract (NTS). In the present study conducted in rats, we examined the synaptic characteristics of visceral afferent pathways to the central nucleus of the amygdala (CeA) in brainstem slices by recording from retrogradely labelled NTS projection neurons. We simultaneously recorded neuron pairs: one dye positive (i.e. NTS-CeA) and a second unlabelled neighbour. Graded shocks to the solitary tract (ST) always (93%) triggered EPSCs at CeA projecting NTS neurons. Half of the NTS-CeA neurons received at least one primary afferent input (classed 'second order') indicating that viscerosensory information arrives at the CeA conveyed via a pathway involving as few as two synapses. The remaining NTS-CeA neurons received viscerosensory input only via polysynaptic pathways. By contrast, ∼3/4 of unlabelled neighbouring neurons were directly connected to ST. NTS-CeA neurons received greater numbers of ST-related inputs compared to unlabelled NTS neurons, indicating that highly convergent viscerosensory signals reach the CeA. Remarkably, despite multifibre convergence, all single NTS-CeA neurons received inputs derived from only unmyelinated afferents [transient receptor potential cation channel subfamily V member 1 (TRPV1) expressing C-fibres] or only non-TRPV1 ST afferent inputs, and never a combination of both. Such segregation means that visceral afferent information followed separate lines to reach the CeA. Their very different physiological activation profiles mean that these parallel visceral afferent pathways encode viscerosensory signals to the amygdala that may provide interoceptive assessments to impact on behaviours.Keywords:
Solitary tract
Solitary nucleus
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Rostral ventrolateral medulla
Medulla
Catecholaminergic cell groups
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SUMMARY 1. One of the key areas that links psychologically induced stress with the blood pressure‐regulatory system is the central nucleus of the amygdala (CeA). This is an integratory forebrain nucleus that receives input from higher centres in the forebrain and has extensive connections with the hypothalamus and the medulla oblongata, areas involved in the regulation of the cardiovascular reflexes. 2. Based on studies using electrical or chemical stimulation or electrolytic lesions of the CeA, it has become clear that the CeA plays an important role in the regulation of blood pressure in response to stressful or fearful stimuli. 3. Two important medullary areas known to receive projections from the CeA are the nucleus tractus solitarius (NTS) and the rostral ventrolateral medulla (RVLM). The NTS is the site of the first synapse for afferent fibres originating from baroreceptors, chemoreceptors and the heart, whereas the RVLM contains neurons that maintain resting blood pressure and sympathetic nerve activity via projections to sympathetic preganglionic neurons in the intermediolateral cell column of the thoracolumbar spinal cord. 4. Electron microscopic studies using combined anterograde tracing and pre‐ and post‐embedding immunogold labelling have shown that the pathways originating from the CeA to the NTS are inhibitory and may use GABA as a neurotransmitter. The results of these studies suggest that blood pressure changes produced by activation of the CeA may be mediated by attenuation of baroreceptor reflexes through a GABAergic mechanism at the level of the NTS. 5. Neuronal tract tracing combined with neurofunctional studies using the Fos protein as a marker of activated neurons indicate that the CeA projects directly to baroreceptive neurons in the NTS and RVLM that are activated by changes in blood pressure. 6. In conclusion, studies that have examined the efferent pathways of the CeA suggest that CeA neurons with projections to medullary baroreceptive neurons may play a vital role in the reflex changes in sympathetic nerve activity that are involved in blood pressure regulation in response to stress or anxiety.
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Emotions are accompanied by concordant changes in visceral function, including cardiac output, respiration and digestion. One major forebrain integrator of emotional responses, the amygdala, is considered to rely on embedded visceral afferent information, although few details are known. In the present study, we retrogradely transported dye from the central nucleus of the amygdala (CeA) to identify CeA-projecting nucleus of the solitary tract (NTS) neurons for synaptic characterization and compared them with unlabelled, near-neighboor NTS neurons. Solitary tract (ST) afferents converged onto NTS-CeA second-order sensory neurons in greater numbers, as well as indirectly via polysynaptic pathways. Unexpectedly, all mono- and polysynaptic ST afferent pathways to NTS-CeA neurons were organized exclusively as either transient receptor potential cation channel subfamily V member 1 (TRPV1)-sensitive or TRPV1-resistant, regardless of whether intervening neurons were excitatory or inhibitory. This strict sorting provides viscerosensory signals to CeA about visceral conditions with respect to being either 'normal' via A-fibres or 'alarm' via TRPV1 expressing C-fibres and, accordingly, this pathway organization probably encodes interoceptive status.Emotional state is impacted by changes in visceral function, including blood pressure, breathing and digestion. A main line of viscerosensory information processing occurs first in the nucleus of the solitary tract (NTS). In the present study conducted in rats, we examined the synaptic characteristics of visceral afferent pathways to the central nucleus of the amygdala (CeA) in brainstem slices by recording from retrogradely labelled NTS projection neurons. We simultaneously recorded neuron pairs: one dye positive (i.e. NTS-CeA) and a second unlabelled neighbour. Graded shocks to the solitary tract (ST) always (93%) triggered EPSCs at CeA projecting NTS neurons. Half of the NTS-CeA neurons received at least one primary afferent input (classed 'second order') indicating that viscerosensory information arrives at the CeA conveyed via a pathway involving as few as two synapses. The remaining NTS-CeA neurons received viscerosensory input only via polysynaptic pathways. By contrast, ∼3/4 of unlabelled neighbouring neurons were directly connected to ST. NTS-CeA neurons received greater numbers of ST-related inputs compared to unlabelled NTS neurons, indicating that highly convergent viscerosensory signals reach the CeA. Remarkably, despite multifibre convergence, all single NTS-CeA neurons received inputs derived from only unmyelinated afferents [transient receptor potential cation channel subfamily V member 1 (TRPV1) expressing C-fibres] or only non-TRPV1 ST afferent inputs, and never a combination of both. Such segregation means that visceral afferent information followed separate lines to reach the CeA. Their very different physiological activation profiles mean that these parallel visceral afferent pathways encode viscerosensory signals to the amygdala that may provide interoceptive assessments to impact on behaviours.
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The nucleus of the solitary tract (NTS) regulates life-sustaining functions ranging from appetite and digestion to heart rate and breathing. It is also the brain's primary sensory nucleus for visceral sensations relevant to symptoms in medical and psychiatric disorders. To better understand which neurons may exert top-down control over the NTS, here we provide a brain-wide map of all neurons that project axons directly to the caudal, viscerosensory NTS, focusing on a medial subregion with aldosterone-sensitive HSD2 neurons. Injecting an axonal tracer (cholera toxin b) into the NTS produces a similar pattern of retrograde labeling in rats and mice. The paraventricular hypothalamic nucleus (PVH), lateral hypothalamic area, and central nucleus of the amygdala (CeA) contain the densest concentrations of NTS-projecting neurons. PVH afferents are glutamatergic (express Slc17a6/Vglut2) and are distinct from neuroendocrine PVH neurons. CeA afferents are GABAergic (express Slc32a1/Vgat) and are distributed largely in the medial CeA subdivision. Other retrogradely labeled neurons are located in a variety of brain regions, including the cerebral cortex (insular and infralimbic areas), bed nucleus of the stria terminalis, periaqueductal gray, Barrington's nucleus, Kölliker-Fuse nucleus, hindbrain reticular formation, and rostral NTS. Similar patterns of retrograde labeling result from tracer injections into different NTS subdivisions, with dual retrograde tracing revealing that many afferent neurons project axon collaterals to both the lateral and medial NTS subdivisions. This information provides a roadmap for studying descending axonal projections that may influence visceromotor systems and visceral "mind-body" symptoms.
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G protein-coupled receptors that signal bitter taste (T2Rs) are expressed in the mucosal lining of the oral cavity and gastrointestinal (GI) tract. In mice, intragastric infusion of T2R ligands activates Fos expression within the caudal viscerosensory portion of the nucleus of the solitary tract (NTS) through a vagal pathway (Hao S, Sternini C, Raybould HE. Am J Physiol Regul Integr Comp Physiol 294: R33-R38, 2008). The present study was performed in rats to further characterize the distribution and chemical phenotypes of brain stem and forebrain neurons activated to express Fos after intragastric gavage of T2R ligands, and to determine a potential behavioral correlate of this central neural activation. Compared with relatively low brain stem and forebrain Fos expression in control rats gavaged intragastrically with water, rats gavaged intragastrically with T2R ligands displayed significantly increased activation of neurons within the caudal medial (visceral) NTS and caudal ventrolateral medulla, including noradrenergic neurons, and within the lateral parabrachial nucleus, central nucleus of the amygdala, and paraventricular nucleus of the hypothalamus. A behavioral correlate of this Fos activation was evidenced when rats avoided consuming flavors that previously were paired with intragastric gavage of T2R ligands. While unconditioned aversive responses to bitter tastants in the oral cavity are often sufficient to inhibit further consumption, a second line of defense may be provided postingestively by ligand-induced signaling at GI T2Rs that signal the brain via vagal sensory inputs to the caudal medulla.
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Abstract The HSD2 (11‐β‐hydroxysteroid dehydrogenase type 2‐expressing) neurons in the nucleus of the solitary tract (NTS) of the rat are aldosterone‐sensitive and have been implicated in sodium appetite. The central nucleus of the amygdala (CeA) has been shown to modulate salt intake in response to aldosterone, so we investigated the connections between these two sites. A prior retrograde tracing study revealed only a minor projection from the HSD2 neurons directly to the CeA, but these experiments suggested that a more substantial projection may be relayed through the parabrachial nucleus. Small injections of cholera toxin beta subunit (CTb) into the external lateral parabrachial subnucleus (PBel) produced both retrograde cell body labeling in the HSD2 neurons and anterograde axonal labeling in the lateral subdivision of the CeA. Also, injections of either CTb or Phaseolus vulgaris leucoagglutinin into the medial subdivision of the CeA labeled a descending projection from the amygdala to the medial NTS. Axons from the medial CeA formed numerous varicosities and terminals enveloping the HSD2 neurons. Complementary CTb injections, centered in the HSD2 subregion of the NTS, retrogradely labeled neurons in the medial CeA. These bidirectional projections could form a functional circuit between the HSD2 neurons and the CeA. The HSD2 neurons may represent one of the functional inputs to the lateral CeA, and their activity may be modulated by a return projection from the medial CeA. This circuit could provide a neuroanatomical basis for the modulation of salt intake by the CeA. J. Comp. Neurol. 497:646–657, 2006. © 2006 Wiley‐Liss, Inc.
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Biotinylated dextran amine
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Using retrograde tract-tracing and electrophysiological methods, we characterized the anatomical and functional relationship between the central nucleus of the amygdala and the dorsal vagal complex. Retrograde tract-tracing techniques revealed that the central nucleus of the amygdala projects to the dorsal vagal complex with a topographic distribution. Following injection of retrograde tracer into the vagal complex, retrogradely labelled neurons in the central nucleus of the amygdala were clustered in the central portion at the rostral level and in the medial part at the middle level of the nucleus. Few labelled neurons were seen at the caudal level. Electrical stimulation of the central nucleus of the amygdala altered the basal firing rates of 65 % of gut-related neurons in the nucleus of the solitary tract and in the dorsal motor nucleus of the vagus. Eighty-one percent of the neurons in the nucleus of the solitary tract and 47 % of the neurons in the dorsal motor nucleus were inhibited. Electrical stimulation of the central nucleus of the amygdala also modulated the response of neurons in the dorsal vagal complex to gastrointestinal stimuli. The predominant effect on the neurons of the nucleus of the solitary tract was inhibition. These results suggest that the central nucleus of the amygdala influences gut-related neurons in the dorsal vagal complex and provides a neuronal circuitry that explains the regulation of gastrointestinal activity by the amygdala.
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