Tanja Babic

The role of vagal neurocircuits in the regulation of nausea and vomiting

Nausea and vomiting are among the most frequently occurring symptoms observed by clinicians. While advances have been made in understanding both the physiological as well as the neurophysiological pathways involved in nausea and vomiting, the final common pathway(s) for emesis have yet to be defined. Regardless of the difficulties in elucidating the precise neurocircuitry involved in nausea and vomiting, it has been accepted for over a century that the locus for these neurocircuits encompasses several structures within the medullary reticular formation of the hindbrain and that the role of vagal neurocircuits in particular are of critical importance. The afferent vagus nerve is responsible for relaying a vast amount of sensory information from thoracic and abdominal organs to the central nervous system. Neurons within the nucleus of the tractus solitarius not only receive these peripheral sensory inputs but have direct or indirect connections with several other hindbrain, midbrain and forebrain structures responsible for the co-ordination of the multiple organ systems. The efferent vagus nerve relays the integrated and co-ordinated output response to several peripheral organs responsible for emesis. The important role of both sensory and motor vagus nerves, and the available nature of peripheral vagal afferent and efferent nerve terminals, provides extensive and readily accessible targets for the development of drugs to combat nausea and vomiting.

A critical re-evaluation of the specificity of action of perivagal capsaicin

Perivagal application of capsaicin (1% solution) is considered to cause selective degeneration of vagal afferent (sensory) C fibres and has been used extensively to examine the site of action of many gastrointestinal (GI) neuropeptides. The actions of both capsaicin and GI neuropeptides may not be restricted to vagal afferent fibres, however, as other non‐sensory neurones displayed sensitivity to capsaicin and brainstem microinjections of these neuropeptides induce GI effects similar to those obtained upon systemic application. The present study used immunohistochemical, biophysical and functional approaches to test the hypothesis that perivagal capsaicin induces degeneration of vagal efferents controlling GI functions. Our data indicate that perivagal application of capsaicin induces degeneration of vagal efferent motoneurones and decreased vagal motor responses. Treatment with perivagal capsaicin cannot therefore be considered selective for vagal afferent C fibres and, consequently, care is needed when using perivagal capsaicin to assess the mechanism of action of GI neuropeptides.

Differential organization of excitatory and inhibitory synapses within the rat dorsal vagal complex

The dorsal motor nucleus of the vagus (DMV) is pivotal in the regulation of upper gastrointestinal functions, including motility and both gastric and pancreatic secretion. DMV neurons receive robust GABA- and glutamatergic inputs. Microinjection of the GABA(A) antagonist bicuculline (BIC) into the DMV increases pancreatic secretion and gastric motility, whereas the glutamatergic antagonist kynurenic acid (KYN) is ineffective unless preceded by microinjection of BIC. We used whole cell patch-clamp recordings with the aim of unveiling the brain stem neurocircuitry that uses tonic GABA- and glutamatergic synapses to control the activity of DMV neurons in a brain stem slice preparation. Perfusion with BIC altered the firing frequency of 71% of DMV neurons, increasing firing frequency in 80% of the responsive neurons and decreasing firing frequency in 20%. Addition of KYN to the perfusate either decreased (52%) or increased (25%) the firing frequency of BIC-sensitive neurons. When KYN was applied first, the firing rate was decreased in 43% and increased in 21% of the neurons; further perfusion with BIC had no additional effect in the majority of neurons. Our results indicate that there are several permutations in the arrangements of GABA- and glutamatergic inputs controlling the activity of DMV neurons. Our data support the concept of brain stem neuronal circuitry that may be wired in a finely tuned organ- or function-specific manner that permits precise and discrete modulation of the vagal motor output to the gastrointestinal tract.

Vagal afferent fibres determine the oxytocin-induced modulation of gastric tone

•u2002 Oxytocin (OXT) inputs to the brainstem modulate cardiorespiratory, feeding and gastric functions. •u2002 Vagal afferent (sensory) inputs are known to modulate brainstem synapses involved in visceral reflexes; however, the neurocircuits through which OXT exerts its actions are still unknown. •u2002 In this study we elucidate these mechanisms of actions and report that vagal sensory fibres control these neurocircuits in a conditionally controlled manner such that brainstem synapses can prepare the neurocircuits to allow appropriate modulation of digestive processes. •u2002 The results presented here improve our understanding of the central regulation of gastrointestinal functions and have the potential of being extended to the understanding of cardiorespiratory and feeding functions controlled by adjacent brainstem centres.

Pancreatic insulin and exocrine secretion are under the modulatory control of distinct subpopulations of vagal motoneurones in the rat

•u2002 The pancreas consists of two functional parts, exocrine, which releases digestive enzymes, and endocrine, which releases hormones, such as insulin. •u2002 Both parts are under neural regulatory control by the vagus nerve. Vago‐vagal neurocircuits integrate the sensory information, chemical or mechanical, from the gastrointestinal tract with the motor output back to the gastrointestinal system, including the pancreas. •u2002 Both excitatory and inhibitory vago‐vagal neural circuits are regulated by many neurotransmitters, including glutamate acting on different types of metabotropic glutamate receptors. •u2002 In this study, we show that different subtypes of metabotropic glutamate receptors regulate differentially exocrine and endocrine pancreatic functions by affecting different neurocircuits. •u2002 The present study provides the physiological basis to develop pharmacological strategies aimed to provide a better understanding of pathophysiological conditions, such as pancreatitis or diabetes, that affect selectively the exocrine or endocrine pancreas.

Glucose-dependent trafficking of 5-HT3 receptors in rat gastrointestinal vagal afferent neurons

Backgroundu2002 Intestinal glucose induces gastric relaxation via vagally mediated sensory‐motor reflexes. Glucose can alter the activity of gastrointestinal (GI) vagal afferent (sensory) neurons directly, via closure of ATP‐sensitive potassium channels, and indirectly, via the release of 5‐hydroxytryptamine (5‐HT) from mucosal enteroendocrine cells. We hypothesized that glucose may also be able to modulate the ability of GI vagal afferent neurons to respond to the released 5‐HT, via regulation of neuronal 5‐HT3 receptors.

Plasticity in the brainstem vagal circuits controlling gastric motor function triggered by corticotropin releasing factor

The prototypical stress hormone, corticotropin releasing factor (CRF), and the prototypical anti‐stressor hormone, oxytocin (OXT), are known to modulate brainstem neurocircuits involved in visceral reflexes. We demonstrated recently that the brainstem neurocircuits through which OXT exerts its actions are modulated by vagal afferent fibres; however, it is unknown whether the OXT‐induced modulation of brainstem vagal neurocircuits is also regulated differentially by CRF. Here we elucidate the cellular mechanisms and the effects on gastric tone of OXT following exposure of vagal brainstem neurones to CRF and report that CRF induces short‐term plastic changes in OXT‐sensitive vagal neurocircuits. The results presented may represent a possible mechanism through which stress alters the central regulation of gastrointestinal functions and may reflect the vagal dysregulation occurring as a consequence of stress‐exacerbated functional dyspepsia.

Innervation of skeletal muscle by leptin receptor-containing neurons.

In addition to suppressing food intake, leptin reduces body adiposity by altering metabolism within peripheral tissues such as adipose tissue and muscle. Recent work indicates that leptin action within the brain is sufficient to promote glucose uptake and increase fat oxidation within skeletal muscle, and that these effects are dependent on the sympathetic nervous system. To identify neuronal circuits through which leptin impacts skeletal muscle metabolism, we used LepRb-GFP reporter mice in combination with muscle-specific injection of an mRFP-expressing pseudorabies virus (PRV), which acts as a transsynaptic retrograde tracer. Consistent with previous observations in the rat, muscle-specific PRV injection lead to labeling within multiple areas of the hypothalamus and brainstem. However, the only areas in which PRV and LepRb colocalization was detected were within the brainstem nucleus of the solitary tract (NTS) and the hypothalamic retrochiasmatic area. Within the NTS 28.5+/-9.4% of PRV-positive neurons contained LepRb-GFP, while in the RCH 37+/-1.7% of PRV neurons also contained LepRb. In summary, these data clearly implicate the NTS and RCH as key sites through which brain leptin impacts skeletal muscle, and as such provide an anatomical framework within which to interpret physiological data indicating that leptin acts in the brain to influence metabolism within skeletal muscle.

Role of the vagus in the reduced pancreatic exocrine function in copper-deficient rats

Copper plays an essential role in the function and development of the central nervous system and exocrine pancreas. Dietary copper limitation is known to result in noninflammatory atrophy of pancreatic acinar tissue. Our recent studies have suggested that vagal motoneurons regulate pancreatic exocrine secretion (PES) by activating selective subpopulations of neurons within vagovagal reflexive neurocircuits. We used a combination of in vivo, in vitro, and immunohistochemistry techniques in a rat model of copper deficiency to investigate the effects of a copper-deficient diet on the neural pathways controlling PES. Duodenal infusions of Ensure or casein, as well as microinjections of sulfated CCK-8, into the dorsal vagal complex resulted in an attenuated stimulation of PES in copper-deficient animals compared with controls. Immunohistochemistry of brain stem slices revealed that copper deficiency reduced the number of tyrosine hydroxylase-immunoreactive, but not neuronal nitric oxide synthase- or choline acetyltransferase-immunoreactive, neurons in the dorsal motor nucleus of the vagus (DMV). Moreover, a copper-deficient diet reduced the number of large (>11 neurons), but not small, intrapancreatic ganglia. Electrophysiological recordings showed that DMV neurons from copper-deficient rats are less responsive to CCK-8 or pancreatic polypeptide than are DMV neurons from control rats. Our results demonstrate that copper deficiency decreases efferent vagal outflow to the exocrine pancreas. These data indicate that the combined selective loss of acinar pancreatic tissue and the decreased excitability of efferent vagal neurons induce a deficit in the vagal modulation of PES.

Acute pancreatitis decreases the sensitivity of pancreas‐projecting dorsal motor nucleus of the vagus neurones to group II metabotropic glutamate receptor agonists in rats

Acute pancreatitis is one of the most severe disorders of the exocrine pancreas. Pancreatic exocrine secretions (PES) are under regulatory control of dorsal motor nucleus of the vagus (DMV) neurones and their activity is regulated by inhibitory GABAergic and excitatory glutamatergic synaptic inputs. Group II metabotropic glutamate receptors (mGluR) decrease synaptic transmission to pancreas‐projecting DMV neurones and modulate PES. In this study, we show that acute pancreatitis induces a long‐lasting increase in excitatory synaptic transmission to pancreas‐projecting neurones by decreasing the response of excitatory synaptic terminals to group II mGluR agonists. These data suggest that changes in group II mGluR expression in the DMV may underlie short‐ and long‐term changes in PES in acute pancreatitis.