Motor Nucleus Research Articles

Targeted stimulation of the vagus nerve reduces renal injury in female mice with systemic lupus erythematosus

Pharmacological stimulation of the vagus nerve has been shown to suppress inflammation and reduce blood pressure in a murine model of systemic lupus erythematosus (SLE) that is characterized by hypertension, inflammation, renal injury and dysautonomia. The present study aims to directly stimulate vagal nerves at the level of the dorsal motor nucleus of the vagus (DMV) using designer receptors exclusively activated by designer drugs (DREADDs) to determine if there is similar protection and confirm mechanism. Female NZBWF1/J (SLE) mice and NZW/LacJ mice (controls, labeled as NZW throughout) received bilateral microinjections of pAAV-hSyn-hM3D(Gq)-mCherry or control virus into the DMV at 31 weeks of age. After two weeks of recovery and viral transfection, the DREADD agonist clozapine-N-oxide (CNO; 3 mg/kg) was injected subcutaneously for an additional 14 days. At 35 weeks, mean arterial pressure (MAP; mmHg) was increased in SLE mice compared to NZW mice, but selective activation of DMV neurons did not significantly alter MAP in either group. SLE mice had higher indices of renal injury including albumin excretion rate (μg/day), glomerulosclerosis index, interstitial fibrosis, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) compared to NZW mice. Selective DMV neuronal activation reduced albumin excretion rate, glomerulosclerosis, interstitial fibrosis, and NGAL in SLE mice but not NZW mice. Together, these data indicate that selective activation of neurons within the DMV by DREADD protects the kidney suggesting an important role of vagus-mediated pathways in the progression of renal injury in SLE.

A rare case report: isolated midbrain lacunar infarct affecting the ipsilateral medial longitudinal fasciculus causing internuclear ophthalmoplegia effect

Isolated medial longitudinal fasciculus infarct is rare and can also be associated with cranial nerve nuclei or extra-nuclear regions leading to respective neurological deficit. We report a case of 73-year-old woman presenting with a 24 hour of confusion, abnormal eye movement and unsteady gait on a background history of uncontrolled diabetes mellitus (DM), hypertension and Alzheimer’s disease. Her examination found to have dysdiadokinesia in left upper limb and inability to adduct right eyeball on left lateral gaze, without affecting the pupil. She was not oriented to time and place while before this event she could. Her examination found to have normal power in limbs and sensation. Her computed tomography (CT) brain showed no evidence of acute infarction or intracranial bleed. Magnetic resonance imaging (MRI) brain demonstrated acute lacunar infarct involving the ipsilateral medial longitudinal fasciculus. This case demonstrates rare brainstem infarct affecting medial longitudinal fasciculus region below the IIIrd cranial nerve nucleus giving features of internuclear ophthalmoplegia affecting medial rectus muscle without affecting autonomic fibres of IIIrd cranial nerve due to which the pupil is not affected. We recommend strict control of predisposing conditions, mainly diabetes and hypertension to reduce the incidence of brainstem stroke.

Evaluation of cellular activity in response to sleep deprivation by a comprehensive analysis of the whole mouse brain.

Sleep deprivation (SD) causes several adverse functional outcomes, and understanding the associated processes can improve quality of life. Although the effects of SD on neuronal activity in several brain regions have been identified, a comprehensive evaluation of the whole brain is still lacking. Hence, we performed SD using two different methods, gentle handling and a dedicated chamber, in targeted recombination in active populations 2 (TRAP2) mice crossed with Rosa-ZsGreen reporter mice and visualized cellular activity in the whole brain. Using the semi-automated post-imaging analysis tool Slice Histology Alignment, Registration, and Cell Quantification (SHARCQ), the number of activated cells was quantified. From the analysis of 14 brain regions, cellular activity was significantly increased in the olfactory areas and decreased in the medulla by the two SD methods. From the analysis of the further subdivided 348 regions, cellular activity was significantly increased in the vascular organ of the lamina terminalis, lateral hypothalamic area, parabigeminal nucleus, ventral tegmental area, and magnocellular reticular nucleus, and decreased in the anterior part of the basolateral amygdalar nucleus, nucleus accumbens, septohippocampal nucleus, reticular nucleus of the thalamus, preoptic part of the periventricular hypothalamic nucleus, ventromedial preoptic nucleus, rostral linear nucleus raphe, facial motor nucleus, vestibular nuclei, and some fiber tracts (oculomotor nerve, genu of corpus callosum, and rubrospinal tract) by the two SD methods. Two subdivided regions of the striatum (caudoputamen and other striatum), epithalamus, vascular organ of the lamina terminalis, anteroventral preoptic nucleus, superior colliculus optic layer, medial terminal nucleus of the accessory optic tract, pontine gray, and fiber tracts (medial lemniscus, columns of the fornix, brachium of the inferior colliculus, and mammillary peduncle) were differentially affected by the two SD methods. Most brain regions detected from these analyses have been reported to be involved in regulating sleep/wake regulatory circuits. Moreover, the results from the connectivity analysis indicated that the connectivity of cellular activity among brain regions was altered by SD. Together, such a comprehensive analysis of the whole brain is useful for understanding the mechanisms by which SD and/or sleep disruption affects brain function.

The spectrum of central nervous system manifestations in leprosy: a systematic review of published case reports and case series.

This systematic review aimed to investigate central nervous system (CNS) involvement in leprosy by analysing multiple cohort studies, individual cases and case series. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. PubMed, Scopus and Embase databases were searched up to 8 July 2023, using a predefined search strategy. Inclusion criteria included patients diagnosed with leprosy with evidence of CNS involvement. The quality of the included cases was evaluated using the Joanna Briggs Institute checklist. A total of 34 records were identified, including 18 cohort studies and 16 reports describing 27 isolated cases. Autopsies revealed macroscopic changes in the spinal cord, neurofibrillary tangles and senile plaques. Mycobacterium leprae was detected in neurons of the medulla oblongata and spinal cord using PCR and phenolic glycolipid 1 staining. Cerebrospinal fluid (CSF) analysis showed inflammatory changes, increased gamma globulins and detection of Mycobacterium leprae antigens and antibodies. In 21 patients (78%), spinal cord/brachial plexus abnormities were detected. In the majority, MRI revealed T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity in the cervical cord. In patients with brainstem involvement, T2/FLAIR hyperintensity was noted in the cerebellar peduncles, facial nerve nuclei and/or other cranial nerve nuclei. Brain parenchymal involvement was noted in three patients. This systematic review provides evidence of CNS involvement in leprosy, based on autopsy findings, neuroimaging, CSF analysis and neurophysiological studies.

Comparative localization of colorectal sensory afferent central projections in the mouse spinal cord dorsal horn and caudal medulla dorsal vagal complex.

The distal colon and rectum (colorectum) are innervated by spinal and vagal afferent pathways. The central circuits into which vagal and spinal afferents relay colorectal nociceptive information remain to be comparatively assessed. To address this, regional colorectal retrograde tracing and colorectal distension (CRD)-evoked neuronal activation were used to compare the circuits within the dorsal vagal complex (DVC) and dorsal horn (thoracolumbar [TL] and lumbosacral [LS] spinal levels) into which vagal and spinal colorectal afferents project. Vagal afferent projections were observed in the nucleus tractus solitarius (NTS), area postrema (AP), and dorsal motor nucleus of the vagus (DMV), labeled from the rostral colorectum. In the NTS, projections were opposed to catecholamine and pontine parabrachial nuclei (PbN)-projecting neurons. Spinal afferent projections were labeled from rostral through to caudal aspects of the colorectum. In the dorsal horn, the number of neurons activated by CRD was linked to pressure intensity, unlike in the DVC. In the NTS, 13%±0.6% of CRD-activated neurons projected to the PbN. In the dorsal horn, at the TL spinal level, afferent input was associated with PbN-projecting neurons in lamina I (LI), with 63%±3.15% of CRD-activated neurons in LI projecting to the PbN. On the other hand, at the LS spinal level, only 18%±0.6% of CRD-activated neurons in LI projected to the PbN. The collective data identify differences in the central neuroanatomy that support the disparate roles of vagal and spinal afferent signaling in the facilitation and modulation of colorectal nociceptive responses.

The effects of laser acupuncture dosage at PC6 (Neiguan) on brain reactivity: a pilot resting-state fMRI study.

Previous studies indicated that laser acupuncture (LA) may effectively treat various medical conditions. However, brain responses associated with LA intervention have not been fully investigated. This study is focused on the effect of LA with different energy density (ED) in brain using resting-state functional magnetic resonance imaging (fMRI). We hypothesized that different ED would elicit various brain responses. We enrolled healthy adults participants and selected bilateral PC6 (Neiguan) as the intervention points. LA was applied, respectively, with ED of 0, 7.96, or 23.87 J/cm2. Two 500-s resting-state fMRI scans were acquired before and after intervention, respectively. The functional connectivity (FC) was calculated between autonomic nerve system-regulation associated brainstem structures and other brain regions. Compared to other dosages, the FC between rostral ventrolateral medulla and orbitofrontal cortex has more enhanced; the FC between caudal ventrolateral medulla, nucleus of the solitary tract/nucleus ambiguus, and dorsal motor nucleus of the vagus and somatosensory area has more weakened when ED was 23.87 J/cm2. Different dosages of LA have demonstrated varied regions of FC changes between regions of interest and other brain areas, which indicated that variations in EDs might influence the clinical efficacy and subsequent impacts through distinct neural pathways within the brain.

Feeding during the resting phase causes gastrointestinal tract dysfunction and desynchronization of metabolic and neuronal rhythms in rats.

Disrupted circadian rhythms may result from a misalignment between the environmental cycles (due to shift work, sleep restriction, feeding at an unusual time of day) and endogenous rhythms or by physiological aging. Among the numerous adverse effects, disrupted rhythms affect the brain-gut axis, contributing to the pathogenesis of several diseases in the gastrointestinal tract, for example, abdominal pain, constipation, gastric dyspepsia, inflammatory bowel disease, irritable bowel syndrome, and others. This study evaluated the rat gastric emptying, gastrointestinal motility, a clock gene, gut hormones, and the neuron activity on the nucleus of tractus solitarius (NTS), area postrema (AP), and the dorsal motor nucleus of the vagus (DMV) in rats with restricted food access to the rest phase for 4 weeks. Our results show that food restricted to the rest light period disturbed the expression pattern of a series of transcripts, including metabolic and circadian regulation. Also, the secretion of gastrointestinal hormones, gastric emptying, intestinal motility, and NTS, AP, and DMV activity were altered. These data indicate the importance of the time of the day food is ingested on the regulation of energy balance and the endocrine activity of the stomach and small intestine, emphasizing the importance of food as a powerful circadian synchronizer and an essential factor for the triggering of gastrointestinal diseases and metabolic problems. These findings offer a novel clue regarding the obesity-promoting effect attributed to feeding time and open the possibility of treating this and other intestinal disorders.

Choline-acetyltransferase (ChAT) and acetylcholinesterase (AChE) in the human infant dorsal motor nucleus of the Vagus (DMNV), and alterations according to sudden infant death syndrome (SIDS) category

Amongst other molecules, the cholinergic system consists of choline-acetyltransferase (ChAT, − synthesis enzyme), acetylcholinesterase (AChE – primary hydrolysis enzyme), and butyrylcholinesterase (BuChE – secondary hydrolysis enzyme). In the brainstem, the Dorsal Motor Nucleus of The Vagus (DMNV) has high cholinergic expression and is a region of interest in the neuropathology of sudden infant death syndrome (SIDS). SIDS is the unexpected death of a seemingly healthy infant, but postmortem brainstem abnormalities suggesting altered cholinergic regulation have been found.This study aimed to determine the percentage of positive ChAT and AChE neurons within the infant DMNV through immunohistochemistry at the three levels of the brainstem medulla (caudal, intermediate, and rostral), to investigate whether the proportion of neurons positive for these enzymes differs amongst the diagnostic subgroups of SIDS compared to those with an explained cause of Sudden unexpected death in infancy (eSUDI), and whether there were any associations with SIDS risk factors (male gender, cigarette smoke exposure, co-sleeping/bed sharing, and prone sleeping). Results showed that ChAT-positive neurons were lower in the rostral DMNV in the SIDS II cohort, and within the caudal and intermediate DMNV of infants who were exposed to cigarette smoke. These findings suggest altered cholinergic regulation in the brainstem of SIDS infants, with potential contribution of cigarette smoke exposure, presumably via the nicotinic acetylcholinergic receptor system.

MORPHOMETRIC PARAMETERS OF THE HUMAN FETUS PONS 17-18 WEEKS OF INTRAUTERINE DEVELOPMENT

Relevance. Currently, increased interest is observed in the early stages of postnatal ontogenesis in research of age-related changes in the systems of the human body.
 Aim: To define the macrometric parameters of the pons of human fetuses of 17-18 weeks of fetal development, the sizes and area of the cranial nerve nuclei contained in pons, as well as the size and area of the nerve cells that form these nuclei.
 Materials and methods: We performed an anatomical and histological examination of 10 human fetuses at the stage of 17-18 weeks of intrauterine development.
 Results: The boundaries of the nucleus of the abductor nerve are unclear, the neurons of the nucleus are spherical or rounded in shape. The vestibular nucleus of the vestibulocochlear nerve has an indeterminate shape, the boundaries of the nucleus are not clear, neurons with different areas of the nucleus are noted, from large to small. The motor nucleus of the facial nerve has an elongated shape, with not clear outer edges, the nerve cells are dome-shaped. The principal nucleus of the trigeminal nerve has a rounded shape.
 Conclusions: We established that at 17-18 weeks of intrauterine development of human fetuses, the nucleus of the abductor nerve, the motor nucleus of the facial nerve, the principal nucleus of the trigeminal nerve, and the vestibular nucleus of the vestibulocochlear nerve were visualized. Nucleus of the abductor nerve has the largest area, the smallest -has the vestibular nucleus of the vestibulocochlear nerve. The largest area of neurons of the vestibular nucleus was established in comparison with the area of the nucleus of the facial, trigeminal and abductor nerves. The diameter and area of the nuclei of the cells of the abductor nerve, the motor nucleus of the facial nerve, and the principal nucleus of the trigeminal nerve have almost the same size, while the area of the neurons of the vestibulocochlear nerve is different, there is a group of neurons with a large area, and there is a group with a much smaller area of neurons.

The substantia nigra modulates proximal colon tone and motility in a vagally-dependent manner in the rat.

A monosynaptic pathway connects the substantia nigra pars compacta (SNpc) to neurons of the dorsal motor nucleus of the vagus (DMV). This monosynaptic pathway modulates the vagal control of gastric motility. It is not known, however, whether this nigro-vagal pathway also modulates the tone and motility of the proximal colon. In rats, microinjection of retrograde tracers in the proximal colon and of anterograde tracers in SNpc showed that bilaterally labelled colonic-projecting neurons in the DMV received inputs from SNpc neurons. Microinjections of the ionotropic glutamate receptor agonist, NMDA, in the SNpc increased proximal colonic motility and tone, as measured via a strain gauge aligned with the colonic circular smooth muscle; the motility increase was inhibited by acute subdiaphragmatic vagotomy. Upon transfection of SNpc with pAAV-hSyn-hM3D(Gq)-mCherry, chemogenetic activation of nigro-vagal nerve terminals by brainstem application of clozapine-N-oxide increased the firing rate of DMV neurons and proximal colon motility; both responses were abolished by brainstem pretreatment with the dopaminergic D1-like antagonist SCH23390. Chemogenetic inhibition of nigro-vagal nerve terminals following SNpc transfection with pAAV-hSyn-hM4D(Gi)-mCherry decreased the firing rate of DMV neurons and inhibited proximal colon motility. These data suggest that a nigro-vagal pathway modulates activity of the proximal colon motility tonically via a discrete dopaminergic synapse in a manner dependent on vagal efferent nerve activity. Impairment of this nigro-vagal pathway may contribute to the severely reduced colonic transit and prominent constipation observed in both patients and animal models of parkinsonism. KEY POINTS: Substantia nigra pars compacta (SNpc) neurons are connected to the dorsal motor nucleus of the vagus (DMV) neurons via a presumed direct pathway. Brainstem neurons in the lateral DMV innervate the proximal colon. Colonic-projecting DMV neurons receive inputs from neurons of the SNpc. The nigro-vagal pathway modulates tone and motility of the proximal colon via D1-like receptors in the DMV. The present study provides the mechanistic basis for explaining how SNpc alterations may lead to a high rate of constipation in patients with Parkinson's Disease.

Selective efferent vagal stimulation in heart failure.

Patients diagnosed with heart failure have high rates of mortality and morbidity. Based on promising preclinical studies, vagal nerve stimulation has been trialled in these patients using whole nerve electrical stimulation, but the results have been mixed. This is, at least in part, due to an inability to selectively recruit the activity of specific fibres within the vagus with whole nerve electrical stimulation, as well as not knowing which the 'therapeutic' fibres are. This symposium review focuses on a population of cardiac-projecting efferent vagal fibres with cell bodies located within the dorsal motor nucleus of the vagus nerve and a new method of selectively targeting these projections as a potential treatment in heart failure. NEW FINDINGS: What is the topic of this review? Selective efferent vagal stimulation in heart failure. What advances does it highlight? Selectively targeting a population of cardiac-projecting efferent vagal fibres with cell bodies within the dorsal motor nucleus of the vagus using optogenetics slows the progression of heart failure in rats.

Insulin Preferentially Regulates the Activity of Parasympathetic Preganglionic Neurons over Sympathetic Preganglionic Neurons.

Insulin is a peptide hormone that regulates post-prandial physiology, and it is well known that insulin controls homeostasis at least in part via the central nervous system. In particular, insulin alters the activity of neurons within the autonomic nervous system. However, currently available data are mostly from unidentified brainstem neurons of the dorsal motor nucleus of the vagus nerve (DMV). In this study, we used several genetically engineered mouse models to label distinct populations of neurons within the brainstem and the spinal cord for whole-cell patch clamp recordings and to assess several in vivo metabolic functions. We first confirmed that insulin directly inhibited cholinergic (parasympathetic preganglionic) neurons in the DMV. We also found inhibitory effects of insulin on both the excitatory and inhibitory postsynaptic currents recorded in DMV cholinergic neurons. In addition, GABAergic neurons of the DMV and nucleus tractus solitarius were inhibited by insulin. However, insulin had no effects on the cholinergic sympathetic preganglionic neurons of the spinal cord. Finally, we obtained results suggesting that the insulininduced inhibition of parasympathetic preganglionic neurons may not play a critical role in the regulation of glucose homeostasis and gastrointestinal motility. Our results demonstrate that insulin inhibits parasympathetic neuronal circuitry in the brainstem, while not affecting sympathetic neuronal activity in the spinal cord.

Intraoperative Neurophysiologic Monitoring in Predicting Dysphagia After Brainstem and Fourth Ventricle Surgery

Dysphagia represents the main complication of posterior fossa neurosurgery. Adequate diagnosis of this complication is warranted to prevent untimely extubation with subsequent aspiration. Intraoperative neurophysiologic monitoring (IONM) modalities may be used for this purpose. However, it is not known which IONM modality may be significant for diagnosis. This study aimed to define the most significant IONM modality for dysphagia prognostication after posterior fossa neurosurgery. The analysis included 46 patients (34 with tumors of the fourth ventricle and 12 with brainstem localization) who underwent surgical excision of the tumor. Neurologic symptoms before and after neurosurgery were noted and magnetic resonance imaging with the subsequent volume estimation of the removed mass was performed, followed by an IONM findings analysis (mapping of the nucleus of the caudal cranial nerves [CN] and corticobulbar motor-evoked potentials [CoMEP]). Aggravation of dysphagia was noted in 24% of the patients, more often in patients with tumor localization in the fourth ventricle (26%) than in those with brainstem mass lesions (16%). Mapping of the caudal cranial nerve nuclei did not correlate with the dysfunction of these structures. CoMEP was significantly associated with the neurologic state of the CN. The decrease in CoMEP is a significant prognostic factor for postoperative bulbar symptoms appearance or aggravation. Mapping the CN is an important identification tool. The CoMEP modality should be used intraoperatively to determine the functional state of the CN and predict postoperative dysphagia.

The Infratrigeminal Suprafloccular Approach to Intrapontine Lesions: An Anatomical Overview and Relevance for the Approach to Intrapontine Lesions.

Background and objectives Brainstem lesions have long been considered complex pathologies that may lead to permanent deficits or life-threatening complications, posing significant challenges for surgical removal. Among these lesions, intrapontine lesions are particularly challenging in the field of neurosurgery. However, with advancements in microsurgical anatomy knowledge and technology, these lesions have become more amenable to surgical treatment. In this study, the authors examine an infratrigeminal suprafloccular approach, which has been shown to be a safe surgical route, resulting in fewer postoperative complications, while evaluating the anatomical nuances of the approach and route. Methods Twenty cadaveric brainstem specimens were analyzed to assess the anatomy, focusing on the lateral aspect of the pons as a potential safe entry zone for intrapontine lesions. The authors consistently analyzed twenty brainstem specimens, carefully examining the pontine microsurgical anatomy. A triangular area of entrance was measured, with three sides or walls (X, Y, and Z) aiming to identify the safe zone that would spare the distinct pontine nuclei, ascending sensory pathways, corticospinal, corticonuclear, and corticopontine tracts of the brainstem. An illustrative case was adapted to the described safe entry zone for corroboration purposes. Results The authors measured three distinct lines on the lateral surface of the pons, named X, Y, and Z, forming a triangle in shape. Line X extended from the midpoint anteroposteriorly of the flocculus of the cerebellum to the apparent trigeminal exit in the lateral aspect of the pons. Line Y ran from the trigeminal exit in the pons to the apparent exit of the facial-vestibulocochlear complex in the far lateral aspect of the pontomedullary sulcus in the cerebellopontine fissure. Line Z represented the measurement from the vestibulocochlear complex to the midpoint anteroposteriorly of the flocculus of the cerebellum. The mean measurements were as follows: X = 14.41mm (range: 10mm to 20mm), Y = 13.1mm (range: 10mm to 21mm), and Z = 3mm (range: 2mm to 5mm). The mean surface area of the analyzed specimens within the triangle (formed by X, Y, and Z) was 20.1mm² (range: 10mm² to 40mm²). This area was identified as a safe zone for the entry of microsurgical approaches to intrapontine lesions, involving less retraction of the anterior pons and potentially sparing critical structures, such as the corticospinal tracts, pontine perforating arteries, tegmentum pontis, cranial nerve nuclei, substantia reticulata dorsally, and transverse pontine fibers. Microsurgical anatomical findings, combined with intraoperative monitoring in an illustrative case, consistently demonstrated that this entry area predicted less functional instability of the analyzed tracts and resulted in fewer postoperative complications. Conclusion Deep-seated pontine lesions present a complex range of pathologies with a high potential for devastating outcomes, particularly those involving hemorrhage. This study identifies and describes a presumed safe entry zone that allows for the creation of a surgical corridor for biopsy or microsurgical resection of these lesions, reducing morbidity in a previously considered impenetrable region.

GABA-immunoreactive neurons in the Central Nervous System of the viviparous teleost Poecilia sphenops

Gamma-aminobutyric acid (GABA) functions as the primary inhibitory neurotransmitter within the central nervous system (CNS) of vertebrates. In this study, we examined the distribution pattern of GABA-immunoreactive (GABA-ir) cells and fibres in the CNS of the viviparous teleost Poecilia sphenops using immunofluorescence method. GABA immunoreactivity was seen in the glomerular, mitral, and granular layers of the olfactory bulbs, as well as in most parts of the dorsal and ventral telencephalon. The preoptic area consisted of a small cluster of GABA-ir cells, whereas extensively labelled GABA-ir neurons were observed in the hypothalamic areas, including the paraventricular organ, tuberal hypothalamus, nucleus recessus lateralis, nucleus recessus posterioris, and inferior lobes. In the thalamus, GABA-positive neurons were only found in the ventral thalamic and central posterior thalamic nuclei, whereas the dorsal part of the nucleus pretectalis periventricularis consisted of a few GABA-ir cells. GABA-immunoreactivity was extensively seen in the alar and basal subdivisions of the midbrain, whereas in the rhombencephalon, GABA-ir cells and fibres were found in the cerebellum, motor nucleus of glossopharyngeal and vagal nerves, nucleus commissuralis of Cajal, and reticular formation. In the spinal cord, GABA-ir cells and fibres were observed in the dorsal horn, ventral horn, and around the central canal. Overall, the extensive distribution of GABA-ir cells and fibres throughout the CNS suggests several roles for GABA, including the neuroendocrine, viscerosensory, and somatosensory functions, for the first time in a viviparous teleost.

A brainstem circuit for the expression of defensive facial reactions in rat

The brainstem houses neuronal circuits that control homeostasis of vital functions. These include the depth and rate of breathing1,2 and, critically, apnea, a transient cessation of breathing that prevents noxious vapors from entering further into the respiratory tract. Current thinking is that this reflex is mediated by two sensory pathways. One known pathway involves vagal and glossopharyngeal afferents that project to the nucleus of the solitary tract.3,4,5 Yet, apnea induced by electrical stimulation of the nasal epithelium or delivery of ammonia vapors to the nose persists after brainstem transection at the pontomedullary junction, indicating that the circuitry that mediates this reflex is intrinsic to the medulla.6 A second potential pathway, consistent with this observation, involves trigeminal afferents from the nasal cavity that project to the muralis subnucleus of the spinal trigeminal complex.7,8 Notably, the apneic reflex is not dependent on olfaction as it can be initiated even after disruption of olfactory pathways.9 We investigated how subnucleus muralis cells mediate apnea in rat. By means of electrophysiological recordings and lesions in anesthetized rats, we identified a pathway from chemosensors in the nostrils through the muralis subnucleus and onto both the preBötzinger and facial motor nuclei. We then monitored breathing and orofacial reactions upon ammonia delivery near the nostril of alert, head-restrained rats. The apneic reaction was associated with a grimace, characterized by vibrissa protraction, wrinkling of the nose, and squinting of the eyes. Our results show that a brainstem circuit can control facial expressions for nocifensive and potentially pain-inducing stimuli.

Abstract P409: Angiotensin Ii Activates At1a Receptors In Sfo-pvn-dmv To Modulate The Autonomic Nervous System And Immune System In Hypertension

Angiotensin II (AngII) modulates the autonomic nervous system (ANS) and we have previously found that it activates a vagal-splenic reflex that in turn promotes lymphocytes priming and blood pressure increase. AngII binds type 1a receptors (AT1aR) expressed in the neuronal centers of the cardiovascular control, among which the dorsal motor nucleus of the vagus nerve (DMV). Here we hypothesize that AngII signaling in the DMV activates the vagal-splenic pathway elicited by hypertension. To investigate whether circulating AngII targets the DMV, we intravenously injected fluorescent AngII in mice implanted with osmotic minipumps (AngII or veh), finding it in the DMV complex of AngII mice . To target DMV AT1aR signaling, we utilized AT1aRflox crossed with mice expressing cre-recombinase in PHOX2B neurons. We verified gene deletion by RNAscope and infused AngII, finding no protection from HTN (SBP 147±4 vs 146±2 mmHg in AT1aR-KO-DMV vs WT, p=0.797). Hence we investigated whether upstream brain areas relevant for AngII signaling, the paraventricular nucleus of the hypothalamus (PVN) and the subfornical organ (SFO), modulate DMV complex. Interestingly, AngII was able to cross BBB of PVN and SFO of hypertensive mice. Mechanistically, we targeted AT1aR gene in PVN and SFO, finding protection from AngII-HTN in both cases (SBP 109±1 vs 144±1 mmHg in AT1aR-KO-PVNvsWT, p<0.001; SBP 140±2 vs 160±2 mmHg, in AT1aR-KO-SFOvsWT, p<0.001). Consequently, to test whether the SFO might be the first sensor of hypertension-induced vagus-splenic activity, we measured the SSNA in AT1aR- SFO KO finding it significantly reduced (107±10vs323±57 in AngII AT1aR-SFO KOvsWT, as number of spikes by microneurography, p<0.01), as immune cell egression was (splenic CD3+area 120±10 vs 64±7 mm 2 *10 3 in AngII AT1aR-SFO KOvsWT, p<0.001). These results suggest that AT1aRs in the SFO-PVN axis modulates the DMV function and in turn the vagal-splenic reflex in HTN.

The Cortical and Subcortical Neural Control of Swallowing: A Narrative Review.

Swallowing is a sophisticated process involving the precise and timely coordination of the central and peripheral nervous systems, along with the musculatures of the oral cavity, pharynx, and airway. The role of the infratentorial neural structure, including the swallowing central pattern generator and cranial nerve nuclei, has been described in greater detail compared with both the cortical and subcortical neural structures. Nonetheless, accumulated data from analysis of swallowing performance in patients with different neurological diseases and conditions, along with results from neurophysiological studies of normal swallowing have gradually enhanced understanding of the role of cortical and subcortical neural structures in swallowing, potentially leading to the development of treatment modalities for patients suffering from dysphagia. This review article summarizes findings about the role of both cortical and subcortical neural structures in swallowing based on results from neurophysiological studies and studies of various neurological diseases. In sum, cortical regions are mainly in charge of initiation and coordination of swallowing after receiving afferent information, while subcortical structures including basal ganglia and thalamus are responsible for movement control and regulation during swallowing through the cortico-basal ganglia-thalamo-cortical loop. This article also presents how cortical and subcortical neural structures interact with each other to generate the swallowing response. In addition, we provided the updated evidence about the clinical applications and efficacy of neuromodulation techniques, including both non-invasive brain stimulation and deep brain stimulation on dysphagia.

Brain regulation of gastric dysfunction induced by stress.

Psychological and physical stressors have been implicated in gastric disorders in humans. The mechanism coupling the brain to the stomach underlying stress-induced gastric dysfunction has remained elusive. Here, we show that the stomach directly receives acetylcholinergic inputs from the dorsal motor nucleus of the vagus (AChDMV), which are innervated by serotonergic neurons in the dorsal raphe nucleus (5-HTDRN). Microendoscopic calcium imaging and multi-tetrode electrophysiological recordings reveal that the 5-HTDRN → AChDMV → stomach circuit is inhibited with chronic stress accompanied by hypoactivate gastric function. Artificial activation of this circuit reverses the gastric dysfunction induced by chronic stress in both male and female mice. Our study demonstrates that this 5-HTDRN → AChDMV → stomach axis drives gastric dysfunction associated with stress, thus providing insights into the circuit basis for brain regulation of the stomach.

Cerebellar and basal ganglia inputs define three main nuclei in the mouse ventral motor thalamus.

The thalamus is a central link between cortical and subcortical brain motor systems. Axons from the deep nuclei of the cerebellum (DCN), or the output nuclei of the basal ganglia system (substantia nigra reticulata, SNr; and internal pallidum GPi/ENT) monosynaptically innervate the thalamus, prominently some nuclei of the ventral nuclear group. In turn, axons from these ventral nuclei innervate the motor and premotor areas of the cortex, where their input is critical for planning, execution and learning of rapid and precise movements. Mice have in recent years become a widely used model in motor system research. However, information on the distribution of cerebellar and basal ganglia inputs in the rodent thalamus remains poorly defined. Here, we mapped the distribution of inputs from DCN, SNr, and GPi/ENT to the ventral nuclei of the mouse thalamus. Immunolabeling for glutamatergic and GABAergic neurotransmission markers delineated two distinct main territories, characterized each by the presence of large vesicular glutamate transporter type 2 (vGLUT2) puncta or vesicular GABA transporter (vGAT) puncta. Anterograde labeling of axons from DCN revealed that they reach virtually all parts of the ventral nuclei, albeit its axonal varicosities (putative boutons) in the vGAT-rich sector are consistently smaller than those in the vGLUT2-rich sector. In contrast, the SNr axons innervate the whole vGAT-rich sector, but not the vGLUT2-rich sector. The GPi/ENT axons were found to innervate only a small zone of the vGAT-rich sector which is also targeted by the other two input systems. Because inputs fundamentally define thalamic cell functioning, we propose a new delineation of the mouse ventral motor nuclei that is consistent with the distribution of DCN, SNr and GPi/ENT inputs and resembles the general layout of the ventral motor nuclei in primates.