Rostral Medulla Research Articles

Sympathetic hyperactivity, hypertension, and tachycardia induced by stimulation of the ponto-medullary junction in humans

ObjectiveThe purpose of this study is to investigate changes in autonomic activities and systemic circulation generated by surgical manipulation or electrical stimulation to the human brain stem. MethodsWe constructed a system that simultaneously recorded microsurgical field videos and heart rate variability (HRV) that represent autonomic activities. In 20 brain stem surgeries recorded, HRV features and sites of surgical manipulation were analyzed in 19 hypertensive epochs, defined as the periods with transient increases in the blood pressure. We analyzed the period during electrical stimulation to the ponto-medullary junction, performed for the purpose of monitoring a cranial nerve function. ResultsIn the hypertensive epoch, HRV analysis showed that sympathetic activity predominated over the parasympathetic activity. The hypertensive epoch was more associated with surgical manipulation of the area in the caudal pons or the rostral medulla oblongata compared to controls. During the period of electrical stimulation, there were significant increases in blood pressures and heart rates, accompanied by sympathetic overdrive. ConclusionsOur results provide physiological evidence that there is an important autonomic center located adjacent to the ponto-medullary junction. SignificanceA large study would reveal a candidate target of neuromodulation for disorders with autonomic imbalances such as drug-resistant hypertension.

Nicotinic Receptors in the Brainstem Ascending Arousal System in SIDS With Analysis of Pre-natal Exposures to Maternal Smoking and Alcohol in High-Risk Populations of the Safe Passage Study.

Pre-natal exposures to nicotine and alcohol are known risk factors for sudden infant death syndrome (SIDS), the leading cause of post-neonatal infant mortality. Here, we present data on nicotinic receptor binding, as determined by 125I-epibatidine receptor autoradiography, in the brainstems of infants dying of SIDS and of other known causes of death collected from the Safe Passage Study, a prospective, multicenter study with clinical sites in Cape Town, South Africa and 5 United States sites, including 2 American Indian Reservations. We examined 15 pons and medulla regions related to cardiovascular control and arousal in infants dying of SIDS (n = 12) and infants dying from known causes (n = 20, 10 pre-discharge from time of birth, 10 post-discharge). Overall, there was a developmental decrease in 125I-epibatidine binding with increasing postconceptional age in 5 medullary sites [raphe obscurus, gigantocellularis, paragigantocellularis, centralis, and dorsal accessory olive (p = 0.0002–0.03)], three of which are nuclei containing serotonin cells. Comparing SIDS with post-discharge known cause of death (post-KCOD) controls, we found significant decreased binding in SIDS in the nucleus pontis oralis (p = 0.02), a critical component of the cholinergic ascending arousal system of the rostral pons (post-KCOD, 12.1 ± 0.9 fmol/mg and SIDS, 9.1 ± 0.78 fmol/mg). In addition, we found an effect of maternal smoking in SIDS (n = 11) combined with post-KCOD controls (n = 8) on the raphe obscurus (p = 0.01), gigantocellularis (p = 0.02), and the paragigantocellularis (p = 0.002), three medullary sites found in this study to have decreased binding with age and found in previous studies to have abnormal indices of serotonin neurotransmission in SIDS infants. At these sites, 125I-epibatidine binding increased with increasing cigarettes per week. We found no effect of maternal drinking on 125I-epibatidine binding at any site measured. Taken together, these data support changes in nicotinic receptor binding related to development, cause of death, and exposure to maternal cigarette smoking. These data present new evidence in a prospective study supporting the roles of developmental factors, as well as adverse exposure on nicotinic receptors, in serotonergic nuclei of the rostral medulla—a finding that highlights the interwoven and complex relationship between acetylcholine (via nicotinic receptors) and serotonergic neurotransmission in the medulla.

Nociception alterations precede motor symptoms in a progressive model of parkinsonism induced by reserpine in middle-aged rats

Nociception alterations are frequent non-motor symptoms of the prodromal phase of Parkinson’s disease (PD). The period for the onset of symptoms and the pathophysiological mechanisms underlying these alterations remain unclear. We investigated the course of nociception alterations in a progressive model of parkinsonism induced by reserpine (RES) in rats. Male Wistar rats (6–7 months) received 5 or 10 subcutaneous injections of RES (0.1 mg/kg) or vehicle daily for 20 days. Motor evaluation and nociceptive assessment were performed throughout the treatment. At the end of the treatment rats were euthanized, the brains removed and processed for immunohistochemical analysis (TH and c-Fos). The RES-treated rats exhibited an increased nociceptive response to mechanical and chemical stimulation in the electronic von Frey and formalin tests, respectively. Moreover, these alterations preceded the motor impairment observed in the catalepsy test. In addition, the RES treatment reduced the TH-immunoreactivity in the ventral tegmental area (VTA) and increased the c-Fos expression in the ventral-lateral periaqueductal gray (vlPAG), rostral ventral medulla (RVM) and dorsal raphe nucleus (DRN) after noxious stimuli induced by formalin. Taken together, our results reinforce that nociceptive changes are one of the early signs of PD and monoamine depletion in basal ganglia can be involved in the abnormal processing of nociceptive information in PD.

Displaying the autonomic processing network in humans – a global tractography approach

Regulation of the internal homeostasis is modulated by the central autonomic system. So far, the view of this system is determined by animal and human research focusing on cortical and subcortical grey substance regions. To provide an overview based on white matter architecture, we used a global tractography approach to reconstruct a network of tracts interconnecting brain regions that are known to be involved in autonomic processing. Diffusion weighted imaging data were obtained from subjects of the human connectome project (HCP) database. Resulting tracts are in good agreement with previous studies assuming a division of the central autonomic system into a cortical (CAN) and a subcortical network (SAN): the CAN consist of three subsystems that encompass all cerebral lobes and overlap within the insular cortex: a parieto-anterior-temporal pathway (PATP), an occipito-posterior-temporo-frontal pathway (OPTFP) and a limbic pathway. The SAN on the other hand connects the hypothalamus to the periaqueductal grey and locus coeruleus, before it branches into a dorsal and a lateral part that target autonomic nuclei in the rostral medulla oblongata. Our approach furthermore reveals how the CAN and SAN are interconnected: the hypothalamus can be considered as the interface-structure of the SAN, whereas the insula is the central hub of the CAN. The hypothalamus receives input from prefrontal cortical fields but is also connected to the ventral apex of the insular cortex. Thus, a holistic view of the central autonomic system could be created that may promote the understanding of autonomic signaling under physiological and pathophysiological conditions.

A functional map for diverse forelimb actions within brainstem circuitry.

The brainstem is a key centre in the control of body movements. Although the precise nature of brainstem cell types and circuits that are central to full-body locomotion are becoming known1-5, efforts to understand the neuronal underpinnings of skilled forelimb movements have focused predominantly on supra-brainstem centres and the spinal cord6-12. Here we define the logic of a functional map for skilled forelimb movements within the lateral rostral medulla (latRM) of the brainstem. Using in vivo electrophysiology in freely moving mice, we reveal a neuronal code with tuning of latRM populations to distinct forelimb actions. These include reaching and food handling, both of which are impaired by perturbation of excitatory latRM neurons. Through the combinatorial use of genetics and viral tracing, we demonstrate that excitatory latRM neurons segregate into distinct populations by axonal target, and act through the differential recruitment of intra-brainstem and spinal circuits. Investigating the behavioural potential of projection-stratified latRM populations, we find that the optogenetic stimulation of these populations can elicit diverse forelimb movements, with each behaviour stably expressed by individual mice. In summary, projection-stratified brainstem populations encode action phases and together serve as putative building blocks for regulating key features of complex forelimb movements, identifying substrates of the brainstem for skilled forelimb behaviours.

Optogenetic Approach to Local Neuron Network Analysis of the Medullary Respiratory Center.

Using an optogenetic approach, we analyzed a local neuron network of the respiratory center in the medulla of a brainstem-spinal cord preparation isolated from neonatal rat. We developed a transgenic (Tg) rat line in which Phox2b-positive cells expressed archaerhodopsin-3 (Arch) or one of the step-function channelrhodopsin variants (ChRFR) under the control of Phox2b promoter-enhancer regions. Then, in en bloc preparations from 0- to 2-day-old Tg neonatal rats, we analyzed membrane potential changes of medullary respiratory-related neurons in response to photostimulation of the rostral ventral medulla. The photostimulation-induced inhibition or facilitation of the respiratory rhythm in Arch-expressing or ChRFR-expressing Tg rat preparations, respectively. Selective photoactivation of Phox2b-positive neurons expressing ChRFR in the rostral ventrolateral medulla of a neonatal rat en bloc preparation induced membrane potential changes of respiratory-related neurons that were dependent on heterogeneous properties of synaptic connections in the respiratory center. We concluded that the optogenetic approach is a powerful method of verifying a hypothetical model of local networks among respiratory-related neurons in the rostral ventrolateral medulla of neonatal rat.

Network Localization of Central Hypoventilation Syndrome in Lateral Medullary Infarction.

The brainstem plays a key role in the control of respiration. Strokes involving the lateral medulla can rarely produce a central hypoventilation syndrome (CHS) characterized by loss of automatic respiration called Ondine's curse. In this study, we investigated the neuroanatomical correlates of CHS in patients with lateral medullary infarction (LMI). Cases of CHS following LMI were identified from searching our medical records and literature. Voxel-based lesion-symptom mapping and lesion network-symptom-mapping (LNSM) analysis was performed to identify the regions connected to the lesion sites based on normative functional connectome data. Sixteen patients with CHS and 32 controls were included. The ventro-lateral region of the rostral medulla showed a significant association with CHS. LNSM analysis showed connections of this region to the rostral ventro-lateral medulla and caudal pons. In patients with LMI, disruption of the respiratory control network, at the level of ventro-lateral region of the rostral medulla, could result in CHS.

Microglia in the human infant brain and factors that affect expression

The present study reports on the microglial populations present in 34 regions of the human infant brain (1–11 months), and whether developmental parameters or extrinsic factors such as cigarette smoke exposure, prone sleeping and an upper respiratory tract infection (URTI) influence their expression. Further, we compare microglia populations amongst three sudden unexpected death in infancy (SUDI) sub-groups: explained SUDI (eSUDI, n ​= ​7), sudden infant death syndrome (SIDS) I (n ​= ​8) and SIDS II (n ​= ​13). Ionised calcium binding adaptor molecule-1 (Iba1) was used to determine the morphology and area covered by microglia in a given brain region. Activation was explored using cluster-of-differentiation factor 68 (CD68) and human leukocyte antigen-DP,DQ,DR (HLA). We found regional heterogeneity in the area covered and activation status of microglia across the infant brain. The hippocampus, basal ganglia, white matter and dentate nucleus of the cerebellum showed larger areas of Iba1, while the brainstem had the smallest. Microglia in regions of the basal ganglia and cortex demonstrated positive correlations with infant developmental parameters, while in nuclei of the rostral medulla, negative correlations between microglia parameters were seen. URTI and cigarette smoke exposure were associated with a reduced microglial area in regions of the hippocampus and cortex (parietal and occipital), respectively. In the context of SIDS, a reduced microglial area was seen in SIDS II and fewer SIDS I infants demonstrated activated phenotypes in the hippocampus. Overall, we identify the distribution of microglia in the infant brain to be heterogenous, and influenced by intrinsic and extrinsic factors, and that the SIDS I group is a useful control group for future research into other infant CNS pathologies.

MRI and pathology correlations in the medulla in sudden unexpected death in epilepsy (SUDEP): a postmortem study.

Sudden unexpected death in epilepsy (SUDEP) likely arises as a result of autonomic dysfunction around the time of a seizure. In vivo MRI studies report volume reduction in the medulla and other brainstem autonomic regions. Our aim, in a pathology series, is to correlate regional quantitative features on 9.4T MRI with pathology measures in medullary regions. Forty-seven medullae from 18 SUDEP, 18 nonepilepsy controls and 11 epilepsy controls were studied. In 16 cases, representing all three groups, ex vivo 9.4T MRI of the brainstem was carried out. Five regions of interest (ROI) were delineated, including the reticular formation zone (RtZ), and actual and relative volumes (RV), as well as T1, T2, T2* and magnetization transfer ratio (MTR) measurements were evaluated on MRI. On serial sections, actual and RV estimates using Cavalieri stereological method and immunolabelling indices for myelin basic protein, synaptophysin and Microtubule associated protein 2 (MAP2) were carried out in similar ROI. Lower relative RtZ volumes in the rostral medulla but higher actual volumes in the caudal medulla were observed in SUDEP (P<0.05). No differences between groups for T1, T2, T2* and MTR values in any region was seen but a positive correlation between T1 values and MAP2 labelling index in RtZ (P<0.05). Significantly lower MAP2 LI were noted in the rostral medulla RtZ in epilepsy cases (P<0.05). Rostro-caudal alterations of medullary volume in SUDEP localize with regions containing respiratory regulatory nuclei. They may represent seizure-related alterations, relevant to the pathophysiology of SUDEP.

Neuronal Networks in Hypertension: Recent Advances.

Neurogenic hypertension is associated with excessive sympathetic nerve activity to the kidneys and portions of the cardiovascular system. Here we examine the brain regions that cause heightened sympathetic nerve activity in animal models of neurogenic hypertension, and we discuss the triggers responsible for the changes in neuronal activity within these regions. We highlight the limitations of the evidence and, whenever possible, we briefly address the pertinence of the findings to human hypertension. The arterial baroreflex reduces arterial blood pressure variability and contributes to the arterial blood pressure set point. This set point can also be elevated by a newly described cerebral blood flow-dependent and astrocyte-mediated sympathetic reflex. Both reflexes converge on the presympathetic neurons of the rostral medulla oblongata, and both are plausible causes of neurogenic hypertension. Sensory afferent dysfunction (reduced baroreceptor activity, increased renal, or carotid body afferent) contributes to many forms of neurogenic hypertension. Neurogenic hypertension can also result from activation of brain nuclei or sensory afferents by excess circulating hormones (leptin, insulin, Ang II [angiotensin II]) or sodium. Leptin raises blood vessel sympathetic nerve activity by activating the carotid bodies and subsets of arcuate neurons. Ang II works in the lamina terminalis and probably throughout the brain stem and hypothalamus. Sodium is sensed primarily in the lamina terminalis. Regardless of its cause, the excess sympathetic nerve activity is mediated to some extent by activation of presympathetic neurons located in the rostral ventrolateral medulla or the paraventricular nucleus of the hypothalamus. Increased activity of the orexinergic neurons also contributes to hypertension in selected models.

Vestibular and Ocular Motor Properties in Lateral Medullary Stroke Critically Depend on the Level of the Medullary Lesion

Background: Lateral medullary stroke (LMS) results in a characteristic pattern of brainstem signs including ocular motor and vestibular deficits. Thus, an impaired angular vestibulo-ocular reflex (aVOR) may be found if the vestibular nuclei are affected.Objective: We aimed to characterize the frequency and pattern of vestibular and ocular-motor deficits in patients with LMS.Methods: Patients with MR-confirmed acute/subacute unilateral LMS from a stroke registry were included and a bedside neuro-otological examination was performed. Video-oculography and video-based head-impulse testing (vHIT) was obtained and semicircular canal function was determined. The lesion location/extension as seen on MRI was rated and involvement of the vestibular nuclei was judged.Results: Seventeen patients with LMS (age = 59.4 ± 14.3 years) were included. All patients had positive H.I.N.T.S. vHIT showed mild-to-moderate aVOR impairments in three patients (ipsilesional = 1; ipsilesional and contralesional = 1; contralesional = 1). Spontaneous nystagmus (n = 10/15 patients) was more often beating contralesionally than ipsilesionally (6 vs. 3) and was accompanied by upbeat nystagmus in four patients. Head-shaking nystagmus was noted in seven subjects, ipsilesionally beating in six and down-beating in one. On brain MRI, damage of the most caudal parts of the medial and/or inferior vestibular nucleus was noted in 13 patients. Only those two patients with lesions affecting the rostral medulla oblongata demonstrated an ipsilaterally impaired aVOR.Conclusions: While subtle ocular motor signs pointed to damage of the central–vestibular pathways in all 17 patients, aVOR deficits were infrequent, restricted to those patients with rostral medullary lesions and, if present, mild to moderate only. This can be explained by lesions located too far caudally and too far ventrally to substantially affect the vestibular nuclei.

Sex-steroid-dependent plasticity of brain-stem autonomic circuits.

In the central nervous system (CNS), nuclei of the brain stem play a critical role in the integration of peripheral sensory information and the regulation of autonomic output in mammalian physiology. The nucleus tractus solitarius of the brain stem acts as a relay center that receives peripheral sensory input from vagal afferents of the nodose ganglia, integrates information from within the brain stem and higher central centers, and then transmits autonomic efferent output through downstream premotor nuclei, such as the nucleus ambiguus, the dorsal motor nucleus of the vagus, and the rostral ventral lateral medulla. Although there is mounting evidence that sex and sex hormones modulate autonomic physiology at the level of the CNS, the mechanisms and neurocircuitry involved in producing these functional consequences are poorly understood. Of particular interest in this review is the role of estrogen, progesterone, and 5α-reductase-dependent neurosteroid metabolites of progesterone (e.g., allopregnanolone) in the modulation of neurotransmission within brain-stem autonomic neurocircuits. This review will discuss our understanding of the actions and mechanisms of estrogen, progesterone, and neurosteroids at the cellular level of brain-stem nuclei. Understanding the complex interaction between sex hormones and neural signaling plasticity of the autonomic nervous system is essential to elucidating the role of sex in overall physiology and disease.

Modulation of Cannabinoid System and Proinflammatory Cytokine mRNAs in Central and Peripheral Tissue in a Rodent E. coli Sepsis Model

Cytokine production is regulated by the endogenous cannabinoid system (ECS) in many pro‐inflammatory conditions. Sepsis is a highly morbid condition that results from a dysregulated host response to infection. Our previous work showed that ventilatory pattern variability (VPV) decreased concomitantly with increased pro‐inflammatory cytokine production. However, the ECS has not been integrated with transcriptional regulation of pro‐inflammatory cytokines nor with VPV during the progression to sepsis. We hypothesized that decreases in VPV correlate with increased cannabinoid receptor (Cnr) 1 &amp; 2 and pro‐inflammatory cytokine mRNAs. We implanted a fibrin clot that contained either 0 or 25×106E. coli in the peritoneal cavity of adult, male rats (n=24). Respiratory measures were obtained prior to clot implantation and again 1 hour (h) prior to euthanasia. At 3, 6, or 12 h following the clot implantation the rostral and caudal medulla, lung, heart and liver were harvested. VPV was computed with a group of linear and nonlinear dynamic measurements. Total RNA was extracted using Trizol reagent, and cDNA was synthesized using reverse transcription PCR. Quantitative real‐time PCR was performed in duplicate for each sample using TaqMan Gene® Expression Assays specific for 18S ribosomal RNA (18S), Glyceraldehyde 3‐phosphate dehydrogenase (Gapdh), beta actin (Actb), Cnr1 &amp; 2, interleukin (IL) 1‐beta (Il1b) &amp; Il6 and tumor necrosis factor‐alpha (Tnfa). The most stable reference gene combination was determined using NormFinder software and each target gene was normalized to the geometric mean of these reference genes. Relative quantitation of gene expression was performed using the comparative CT method (2−ΔΔCT method) with the 0 E. coli fibrin clot groups (n=4/group) at each time point as the comparative control. At 12 h after inoculation, expiratory duration decreased [F(2,18) = 4.01, p = 0.036] and the ventilatory waveform became more predictable (increased mutual information [F(2,18) = 5.56, p = 0.013] and decreased sample entropy [F(2,18) = 4.25, p = 0.031]). The fold change in cytokine and ECS gene expression varied with tissue. At 12 h after inoculation gene expression increased in heart and rostral medulla, while gene expression decreased in lung, caudal medulla and liver. These preliminary data and analyses support our hypothesis that decreased VPV observed at 12 h is associated with increased expression of ECS and pro‐inflammatory cytokines in heart and rostral medulla. In lung and caudal medulla, however, expression of pro‐inflammatory cytokines decreased, while Cnr1 increased in caudal medulla and Cnr2 increased in lung tissue. Further research is needed to determine how modulation of the ECS can effectively regulate proinflammatory cytokine production and changes in VPV.Support or Funding InformationNIH 5T32HL007913‐18, NIH U01 EB021960, VA Research Service I01BX004197

Sodium pumps, ouabain and aldosterone in the brain: A neuromodulatory pathway underlying salt-sensitive hypertension and heart failure

Accumulating evidence obtained over the last three decades has revealed a neuroendocrine system in the brain that mediates long term increases in blood pressure. The system involves distinct ion transport pathways including the alpha-2 isoform of the Na,K pump and epithelial sodium channels, as well as critical hormone elements such as angiotensin II, aldosterone, mineralocorticoid receptors and endogenous ouabain. Activation of this system either by circulating or central sodium ions and/or angiotensin II leads to a cascading sequence of events that begins in the hypothalamus and involves the participation of several brain nuclei including the subfornical organ, supraoptic and paraventricular nuclei and the rostral ventral medulla. Key events include heightened aldosterone synthesis and mineralocorticoid receptor activation, upregulation of epithelial sodium channels, augmented synthesis and secretion of endogenous ouabain from hypothalamic magnocellular neurons, and sustained increases in sympathetic outflow. The latter step depends upon increased production of angiotensin II and the primary amplification of angiotensin II type I receptor signaling from the paraventricular nucleus to the rostral ventral lateral medulla. The transmission of sympathetic traffic is secondarily amplified in the periphery by increased short- and long-term potentiation in sympathetic ganglia and by sustained actions of endogenous ouabain in the vascular wall that augment expression of sodium calcium exchange, increase cytosolic Ca2+ and heighten myogenic tone and contractility. Upregulation of this multi-amplifier system participates in forms of hypertension where salt, angiotensin and/or aldosterone are elevated and contributes to adverse outcomes in heart failure.

Optogenetic analysis of respiratory neuronal networks in the ventral medulla of neonatal rats producing channelrhodopsin in Phox2b-positive cells.

Paired-like homeobox gene Phox2b is predominantly expressed in pre-inspiratory neurons in the parafacial respiratory group (pFRG) in newborn rat rostral ventrolateral medulla. To analyse detailed local networks of the respiratory centre using optogenetics, the effects of selective activation of Phox2b-positive neurons in the ventral medulla on respiratory rhythm generation were examined in brainstem-spinal cord preparations isolated from transgenic newborn rats with Phox2b-positive cells expressing channelrhodopsin variant ChRFR(C167A). Photostimulation up to 43 s increased the respiratory rate > 200% of control, whereas short photostimulation (1.5 s) of the rostral pFRG reset the respiratory rhythm. At the cellular level, photostimulation depolarised Phox2b-positive pre-inspiratory, inspiratory and respiratory-modulated tonic neurons and Phox2b-negative pre-inspiratory neurons. In contrast, changes in membrane potential of Phox2b-negative inspiratory and expiratory neurons varied depending on characteristics of ongoing synaptic connections in local respiratory networks in the rostral medulla. In the presence of tetrodotoxin, photostimulation depolarised Phox2b-positive cells, but caused no significant changes in membrane potential of Phox2b-negative cells. We concluded that depolarisation of Phox2b-positive neurons was due to cell-autonomous photo-activation and summation of excitatory postsynaptic potentials, whereas membrane potential changes of Phox2b-negative neurons depended on the network configuration. Our findings shed further light on local networks among respiratory-related neurons in the rostral ventrolateral medulla and emphasise the important role of pre-inspiratory neurons in respiratory rhythm generation in the neonatal rat en bloc preparation.

Visualizing the trigeminovagal complex in the human medulla by combining ex-vivo ultra-high resolution structural MRI and polarized light imaging microscopy

A trigeminovagal complex, as described in some animals, could help to explain the effect of vagus nerve stimulation as a treatment for headache disorders. However, the existence of a trigeminovagal complex in humans remains unclear. This study, therefore investigated the existence of the trigeminovagal complex in humans. One post-mortem human brainstem was scanned at 11.7T to obtain structural (T1-weighted) and diffusion magnetic resonance images ((d)MR images). Post-processing of dMRI data provided track density imaging (TDI) maps to investigate white matter at a smaller resolution than the imaging resolution. To evaluate the reconstructed tracts, the MR-scanned brainstem and three additional brainstems were sectioned for polarized light imaging (PLI) microscopy. T1-weighted images showed hyperintense vagus medullar striae, coursing towards the dorsomedial aspect of the medulla. dMRI-, TDI- and PLI-images showed these striae to intersect the trigeminal spinal tract (sp5) in the lateral medulla. In addition, PLI images showed that a minority of vagus fibers separated from the vagus trajectory and joined the trigeminal spinal nucleus (Sp5) and the sp5. The course of the vagus tract in the rostral medulla was demonstrated in this study. This study shows that the trigeminal- and vagus systems interconnect anatomically at the level of the rostral medulla where the vagus fibers intersect with the Sp5 and sp5. Physiological and clinical utility of this newly identified interconnection is a topic for further research.

CORRIGENDUM.

CorrigendumCORRIGENDUMPublished Online:13 Jun 2019https://doi.org/10.1152/jn.z9k-5111-corr.2019Original articleMoreSectionsPDF (52 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Shadmehr R. Distinct neural circuits for control of movement vs. holding still. J Neurophysiol 117: 1431–1460, 2017. First published January 4, 2017; doi:10.1152/jn.00840.2016.The author issues a correction to his review article “Distinct neural circuits for control of movement vs. holding still.” This correction does not affect any conclusions of the article and has arisen because the author was made aware of an important publication (Cheron et al. 1986) that was not cited in the review.On page 1435, first column, it should read “Cheron et al. (1986), and subsequently Cannon and Robinson (1987), discovered one such circuit in the dorsal rostral medulla, a region where neurons project onto the abducens nucleus.”On page 1442, second column, it should read “Kaneko (1997) had confirmed Cheron et al. (1986) and Cannon and Robinson’s (1987) finding that damage to the prepositus impaired the animal’s ability to hold the eyes steady following the saccade.”REFERENCE Cheron G, Godaux E, Laune JM, Vanderkelen B. Lesions in the cat prepositus complex: effects on the vestibulo-ocular reflex and saccades. J Physiol 372: 75–94, 1986. doi:10.1113/jphysiol.1986.sp015998. Crossref | PubMed | ISI | Google Scholar Download PDF Previous Back to Top FiguresReferencesRelatedInformation Related ArticlesDistinct neural circuits for control of movement vs. holding still 01 Apr 2017Journal of Neurophysiology More from this issue > Volume 121Issue 6June 2019Pages 2433-2433 Copyright & PermissionsCopyright © 2019 the American Physiological Societyhttps://doi.org/10.1152/jn.z9k-5111-corr.2019PubMed31194623History Published online 13 June 2019 Published in print 1 June 2019 Metrics

Neuropathology of Spontaneous Hypertensive Encephalopathy in Cats.

Pathologic features of 12 cats with naturally acquired systemic hypertension and concomitant hypertensive encephalopathy were analyzed. All cats demonstrated acute onset of signs localized to the forebrain and/or brainstem, including stupor, coma, and seizures. All cats had systemic hypertension, ranging from 160 to 300 mm Hg. Gross lesions were identified in 4 of 12 cases, including caudal herniation of the cerebrum and cerebellum, sometimes with compression of the rostral colliculus and medulla. Histologically, all cases featured bilaterally symmetrical edema of the cerebral white matter. Associated vascular lesions, especially arteriolar hyalinosis, were also observed. Concurrent lesions were chronic tubulointerstitial nephritis (11/12 cases), adenomatous hyperplasia of the thyroid gland (4 cases), hypertensive choroidal arteriopathy (6 cases), and left ventricular hypertrophy (5 cases). This study demonstrates that the typical histologic manifestation of spontaneous hypertensive encephalopathy in cats is bilaterally symmetrical edema of the subcortical cerebral white matter.

Cardiovascular Effects Of Acute Optogenetic Modulation Of Oxytocin‐PVN Neurons

The actions of oxytocin (OT), a neuropeptide that is largely synthesized in the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus, has been implicated in a variety of homeostatic processes. Recent studies have demonstrated that chronic activation of OT neurons in the PVN prevents hypertension that is a consequence of intermittent hypoxia/hypercapnia. The present study combines genetically‐modified mice with in vivo optogenetics to determine the cardiovascular consequences of selective inhibition or excitation of OT neurons residing in the PVN. Male mice engineered to direct the expression of Cre recombinase to the OT gene had adenoassociated virus synthesizing an inhibitory opsin (Switch), an excitatory opsin (ChR2), or enhanced yellow fluorescent protein (eYFP) bilaterally injected into the PVN. Subsequently, mice were implanted with fiber optics targeting the PVN. One month later, mice were anesthetized with isoflurane and were implanted with a Millar catheter into their left common carotid artery for continuous recording of blood pressure and heart rate. Relative to the eYFP control group, OT‐Cre mice expressing Switch exhibited reduced blood pressure (−24±6 mmHg) and heart rate (−21±9 BPM) in response to optogenetic inhibition when compared with the eYFP group (4±2 mmHg and 5±4 bpm; n=3, p&lt;0.05). In contrast, in the ChR2‐injected group, blue light stimulation (1 min; 30 Hz; 20ms pulse width) significantly increased blood pressure by 15±2 mmHg while decreasing heart rate by −27±10 bpm when compared to controls (0±1mmHg and 9±5 bpm; n=5, p&lt;0.01. Neuroanatomical experiments revealed that neurons in the PVN that synthesize OT send dense axonal projections to the median eminence, the nucleus of the solitary tract, and the rostral ventral lateral medulla. Collectively, the results suggest that OT synthesizing neurons in the PVN mediate cardiovascular function possibly by affecting autonomic outflow and/or the activity of neuroendocrine axes.Support or Funding InformationNIH Funding supported the present studyThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

(237) Periaqueductal Gray Dopaminergic Neurons Modulate Peripheral Inflammatory Hyperalgesia

Neural dopamine (DA) modulators such as ᴅ-amphetamine and methylphenidate provide a promising new approach to treating pain. Though the mechanism by which they produce analgesia is poorly understood, these psychostimulants are antinociceptive and counteract the opioid-induced side effects of respiratory depression and sedation. Despite their potential, DA-modulating drugs have never been adopted clinically for pain relief, possibly due to a lack of understanding their mechanism of action. Considering previous evidence of a role of DA neurons from the periaqueductal gray (PAG) in pain modulation, we hypothesized that PAG DA neurons are antinociceptive and contribute significantly to the analgesic effect of ᴅ-amphetamine via descending spinal cord inhibition at the rostral ventral medulla (RVM). Male C57BL/6 mice that had received carrageenan in the hind paw were treated intraperitoneally with ᴅ-amphetamine, and its analgesic effect was compared with the analgesia produced by morphine. Separate groups of mice were stereotaxically prepared with infusion cannula targeted to either the PAG or RVM. We observed that the inhibition of thermal hyperalgesia in the mouse model of carrageenan-induced inflammatory pain by systemic ᴅ-amphetamine (6mg/kg) was similar to that produced by morphine (3mg/kg), and that ᴅ-amphetamine increased cFOS expression in PAG DA neurons. Targeted microinfusion of ᴅ-amphetamine, L-DOPA, or a selective D2 receptor agonist, but not a D1 agonist, into the PAG also attenuated thermal hyperalgesia, suggesting a role for D2 receptors in PAG-mediated analgesia. Finally, systemic ᴅ-amphetamine-mediated analgesia was prevented when neural transmission through the RVM was inhibited by local pretreatment with the GABAA receptor agonist muscimol. These findings indicate a modulatory role of D2 receptors and descending inhibition through GABAergic receptors at the RVM in ᴅ-amphetamine-mediated analgesia. Importantly, they indicate that the use of stimulants could enhance pain control, potentially as an alternative to opioids, avoiding the deleterious side-effects responsible for the current opioid crisis.