Neurons In Medulla Research Articles

Medullary neuronal loss is not associated with α-synuclein burden in multiple system atrophy.

Accumulation of α-synuclein in multiple system atrophy (MSA) affects medullary autonomic and respiratory control areas, including the rostral ventrolateral medulla and raphe nuclei. Relative neuronal vulnerability and its relationship to α-synuclein accumulation in these areas are unknown. The aim of this study was to determine the extent of loss of adrenergic neurons in the rostral ventrolateral medulla and serotonergic neurons in the ventrolateral medulla and raphe nuclei and its relationship with α-synuclein accumulation. Medullary sections from 7 MSA and 6 control subjects were processed for tyrosine hydroxylase, tryptophan hydroxylase, and α-synuclein immunoreactivity. Neuronal counts were performed stereologically, whereas α-synuclein burden in oligodendrocytes and neurons was quantified using object detection density (area/mm2). All MSA cases had orthostatic hypotension; 5 had laryngeal stridor. There was marked neuronal loss in the rostral ventrolateral medulla and medullary raphe in all cases. Most severely affected were tyrosine hydroxylase ventrolateral medulla (C1) neurons (83% reduction), followed by tryptophan hydroxylase neurons in the ventrolateral medulla (70%), raphe obscurus (56%), pallidus (57%), and magnus (47%). α-Synuclein accumulation occurred predominantly as glial cytoplasmic inclusions with rare α-synuclein accumulation occurring within the remaining neurons. Density of α-synuclein did not correlate with neuronal loss in any of the areas analyzed, and there was no correlation between α-synuclein density and disease duration for any regions of interest. These findings indicate that in MSA adrenergic neurons are more susceptible than serotonergic neurons in the medulla. Further, loss of medullary monoaminergic neurons may progress independently from α-synuclein accumulation in MSA. © 2016 International Parkinson and Movement Disorder Society.

Analysis of morphine-induced changes in the activity of periaqueductal gray neurons in the intact rat

Microinjection of morphine into the periaqueductal gray (PAG) produces antinociception. In vitro slice recordings indicate that all PAG neurons are sensitive to morphine either by direct inhibition or indirect disinhibition. We tested the hypothesis that all PAG neurons respond to opioids in vivo by examining the extracellular activity of PAG neurons recorded in lightly anesthetized and awake rats. Spontaneous activity was less than 1Hz in most neurons. Noxious stimuli (heat, pinch) caused an increase in activity in 57% and 75% of the neurons recorded in anesthetized and awake rats, respectively. The same noxious stimuli caused a decrease in activity in only 17% and 6% of neurons recorded in anesthetized and awake rats. Systemic administration of morphine caused approximately equal numbers of neurons to increase, decrease, or show no change in activity in lightly anesthetized rats. In contrast, administration of morphine caused an increase in the activity of 22 of the 27 neurons recorded in awake rats. No change in activity was evident in the remaining five neurons. Changes in activity caused by morphine were surprisingly modest (a median increase from 0.7 to 1.3Hz). The small inconsistent effects of morphine are in stark contrast to the large changes produced by morphine on the activity of rostral ventromedial medulla (RVM) neurons or the widespread inhibition and excitation of PAG neurons treated with opioids in in vitro slice experiments. The relatively modest effects of morphine in the present study suggest that morphine produces antinociception by causing small changes in the activity of many PAG neurons.

Imidazoleacetic acid-ribotide in vestibulo-sympathetic pathway neurons.

Imidazole-4-acetic acid-ribotide (IAARP) is a putative neurotransmitter/modulator and an endogenous regulator of sympathetic drive, notably systemic blood pressure, through binding to imidazoline receptors. IAARP is present in neurons and processes throughout the CNS, but is particularly prevalent in regions that are involved in blood pressure control. The goal of this study was to determine whether IAARP is present in neurons in the caudal vestibular nuclei that participate in the vestibulo-sympathetic reflex (VSR) pathway. This pathway is important in modulating blood pressure upon changes in head position with regard to gravity, as occurs when humans rise from a supine position and when quadrupeds climb or rear. Sinusoidal galvanic vestibular stimulation was used to activate the VSR and cfos gene expression in VSR pathway neurons of rats. These subjects had previously received a unilateral FluoroGold tracer injection in the rostral or caudal ventrolateral medullary region. The tracer was transported retrogradely and filled vestibular neuronal somata with direct projections to the injected region. Brainstem sections through the caudal vestibular nuclei were immunostained to visualize FluoroGold, cFos protein, IAARP and glutamate immunofluorescence. The results demonstrate that IAARP is present in vestibular neurons of the VSR pathway, where it often co-localizes with intense glutamate immunofluorescence. The co-localization of IAARP and intense glutamate immunofluorescence in VSR neurons may represent an efficient chemoanatomical configuration, allowing the vestibular system to rapidly up- and down-modulate the activity of presympathetic neurons in the ventrolateral medulla, thereby altering blood pressure.

Catecholaminergic neurons in synaptic connections with pre-Bötzinger complex neurons in the rostral ventrolateral medulla in normoxic and daily acute intermittent hypoxic rats

The rostral ventrolateral medulla (RVLM) contains cardiovascular-related catecholaminergic neurons and respiratory-related pre-Bötzinger complex (pre-BötC) neurons, which are intermingled and functionally connected for coordinating cardiorespiratory activities. Daily acute intermittent hypoxia (dAIH) is known to elicit respiratory plasticity. However, it is unclear if the catecholaminergic neurons directly synapse onto pre-BötC neurons, and if the local circuitry exhibits plasticity when exposed to dAIH. The present study was aimed to determine the synaptic phenotypes between dopamine-β-hydroxylase (DβH)-immunoreactive (ir) catecholaminergic neurons and neurokinin 1 receptor (NK1R)-ir pre-BötC neurons, and the effect of dAIH on the neuronal network. Immunofluorescence histochemistry was used to reveal immunoreactivities of DβH and NK1R in the RVLM of normoxic and dAIH rats. Synaptic phenotypes were examined with double-labeling immunoelectron microscopy. We found that DβH immunoreactivity was expressed in somata and processes, some of which were in close apposition to NK1R-ir pre-BötC neurons. DβH-ir gold particles were localized to somata, dendrites, and axonal terminals. DβH-ir terminals formed asymmetric synapses, and occasionally, symmetric synapses in the pre-BötC, featuring the local circuitry. Of the synapses, 28% in normoxic and 29.6% in dAIH groups were apposed to NK1R-ir dendrites. Significant increases in DβH expression and NK1R-ir processes were found in the dAIH group. Moreover, the area and number of processes in close appositions were significantly elevated, strongly suggesting that dAIH induced plasticity with increased connections and interactions between the cardiovascular- and respiratory-related neurons in the local circuitry. In conclusion, asymmetric synapses are predominant in the crosstalk between catecholaminergic and pre-BötC neurons in the RVLM, elaborating excitatory transmission driving the coupling of cardiorespiratory activities. The neural network manifests plasticity in response to dAIH challenge.

Microglial number is related to the number of tyrosine hydroxylase neurons in SHR and normotensive rats.

Microglia are ubiquitously distributed throughout the central nervous system (CNS) and play a critical role in the maintenance of neuronal homeostasis. Recent advances have shown that microglia, never resting cells of the CNS, continuously monitor and influence neuronal/synaptic activity levels, by communicating with neurons with the aid of their dynamic processes. The brainstem contains many catecholaminergic nuclei that are key to many aspects of brain function. This includes C1 neurons of the ventrolateral medulla that are thought to play a critical role in control of the circulation. Despite the role of catecholaminergic brainstem neurons in normal physiology, the presence of microglia that surrounds them is poorly understood. Here, we investigate the spatial distribution and morphology of microglia in catecholaminergic nuclei of the brainstem in 3 strains of rat: Sprague-Dawley (SD), Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Our data reveal that microglia are heterogeneously distributed within and across different strains of rats. Interestingly, intra-strain comparison of tyrosine hydroxylase-immunoreactive (TH-ir) neuronal and microglial number reveals that microglial number varies with the TH-ir neuronal number in the brainstem. Even though microglial spatial distribution varies across brainstem nuclei, microglial morphology (% area covered, number of end point processes and branch length) does not differ significantly. This work provides the first evidence that even though microglia, in their surveilling state, do not vary appreciably in their morphology across brainstem areas, they do have a heterogeneous pattern of distribution that may be influenced by their local environment.

Blockade of orexin receptors reduces glutamatergic excitation of adrenal premotor neurons in the rostral ventrolateral medulla

Excitation of adrenal sympathetic premotor neurons in the rostral ventrolateral medulla (RVLM) elicits epinephrine release as part of the glucose counter‐regulatory response to hypoglycemia. It is known that this response is partly mediated by excitatory inputs from hypothalamic orexin neurons. Although some orexin neurons co‐express glutamate, whether orexin and glutamate interact in order to facilitate adrenal sympathetic premotor neurons is unknown. In pentobarbitone‐anesthetized male Sprague‐Dawley rats, we show tested whether glutamatergic activation of adrenal premotor neurons depends on activation of orexin receptors (Ox‐R). Microinjection of glutamate (50 mM/50 nl) into the RVLM, where adrenal premotor neurons are found, increased adrenal sympathetic nerve activity (ASNA). The increase in ASNA was reduced following non‐selective blockade of orexin receptors. RVLM orexin receptors were blocked by microinjecting a combination of SB334867 (Ox1‐R antagonist) and TCS OX2 29 (Ox2‐R antagonist) into the RVLM. The reduction in ASNA in response to glutamate microinjection into the RVLM was dose dependent (0.1–10 mM/50 nl), and the response was abolished with 1 mM of the combined antagonists (P<0.05). The results suggest that the counter‐regulatory release of epinephrine during hypoglycemia depends on the interaction between glutamate and orexin receptors located on the adrenal sympathetic premotor neurons.Support or Funding InformationNHMRC AustraliaAustin Medical Research Foundation

Mapping projections of excitatory and inhibitory preBötzinger Complex neurons

Understanding the neural control of breathing requires a detailed neuroanatomical and functional map of the breathing central pattern generator (CPG). The logical entry point in constructing such a map is the “engine” of respiratory rhythm, the preBötzinger Complex (preBötC), a bilateral microcircuit of ~3000 interconnected neurons in the ventrolateral medulla. The preBötC generates respiratory rhythm in rodents (and presumably all mammals, including humans); rhythmic activity in the preBötC is required to produce inspiratory movements. To delineate the breathing CPG circuit in mice, we used a viral strategy to identify projections from molecularly‐defined populations of preBötC neurons. Using stereotaxic delivery of Cre‐dependent AAV expressing EGFP (AAV‐flex‐EGFP) into the preBötC of somatostatin‐Cre or GlyT2‐Cre mice, we located efferent projections emanating from two broad, functionally distinct classes of neurons: excitatory neurons that express somatostatin (SST) and inhibitory neurons that express the glycine transporter GlyT2. Critically, we optimized the viral delivery method to restrict viral transfections within the preBötC, while sufficiently labeling neurons to visualize long distance projections, enabling reliable identification of preBötC projections. Glutamatergic SST+ preBötC neurons project to brainstem nuclei implicated in the control of breathing including the contralateral preBötC, parahypo‐glossal/nucleus of the solitary tract, ventral respiratory group, and parabrachial/Kölliker‐Fuse nuclei, similar to efferent projections in rats; these neurons also had suprapontine projections to multiple hypothalamic nuclei, periaquaductal grey, as well as sparse projections to amygdala, suggesting that the preBötC relays respiratory information to higher brain regions that may modulate physiological or behavioral processes. Strikingly, glycinergic preBötC neurons send projections in parallel with glutamatergic SST+ neurons to the same brainstem and suprapontine targets.Support or Funding InformationA.P. Giannini Foundation, NIH T32 NS007101, NIH F32 HL126522‐01, NIH RO1 HL070029‐13

A possible neural mechanism for photosensitivity in chronic pain.

Patients with functional pain disorders often complain of generalized sensory hypersensitivity, finding sounds, smells, or even everyday light aversive. The neural basis for this aversion is unknown, but it cannot be attributed to a general increase in cortical sensory processing. Here, we quantified the threshold for aversion to light in patients with fibromyalgia, a pain disorder thought to reflect dysregulation of pain-modulating systems in the brain. These individuals expressed discomfort at light levels substantially lower than that of healthy control subjects. Complementary studies in lightly anesthetized rat demonstrated that a subset of identified pain-modulating neurons in the rostral ventromedial medulla unexpectedly responds to light. Approximately half of the pain-facilitating "ON-cells" and pain-inhibiting "OFF-cells" sampled exhibited a change in firing with light exposure, shifting the system to a pronociceptive state with the activation of ON-cells and suppression of OFF-cell firing. The change in neuronal firing did not require a trigeminal or posterior thalamic relay, but it was blocked by the inactivation of the olivary pretectal nucleus. Light exposure also resulted in a measurable but modest decrease in the threshold for heat-evoked paw withdrawal, as would be expected with engagement of this pain-modulating circuitry. These data demonstrate integration of information about light intensity with somatic input at the level of single pain-modulating neurons in the brain stem of the rat under basal conditions. Taken together, our findings in rodents and humans provide a novel mechanism for abnormal photosensitivity and suggest that light has the potential to engage pain-modulating systems such that normally innocuous inputs are perceived as aversive or even painful.

Intermittent severe hypoxia induces plasticity within serotonergic and catecholaminergic neurons in the neonatal rat ventrolateral medulla.

5-HT neurons contribute to autoresuscitation and survival during intermittent severe hypoxia (IsH). In adults, catecholaminergic neurons in the ventrolateral medulla (VLM) contribute to the autonomic response to hypoxia. We hypothesized that 1) catecholaminergic neurons in the neonatal VLM are activated following IsH, 2) this activation is compromised following an acute loss of brain stem 5-HT, and 3) IsH induces cellular and/or transcriptomic plasticity within catecholaminergic and serotonergic neurons that are within or project to the VLM, respectively. To test these hypotheses, we treated rat pups with 6-fluorotryptophan, a tryptophan hydroxylase (TPH) inhibitor, and then exposed treated and vehicle controls to IsH or air. Along with immunohistochemistry to detect tyrosine hydroxylase (TH)- or Fos-positive neurons, we used RNA sequencing to resolve the effects of IsH and 5-HT deficiency on the expression of serotonergic and catecholaminergic system genes in the VLM. 5-HT deficiency compromised autoresuscitation and survival. IsH significantly increased the number of identifiable TH-positive VLM neurons, an effect enhanced by 5-HT deficiency (P = 0.003). Contrary to our hypothesis, 5-HT-deficient pups had significantly more Fos-positive neurons following IsH (P = 0.008) and more activated TH-positive neurons following IsH or air (P = 0.04). In both groups the expression of the 5-HT transporter and TPH2 was increased following IsH. In 5-HT-deficient pups, the expression of the inhibitory 5-HT1A receptor was decreased following IsH, while the expression of DOPA decarboxylase was increased. These data show that the serotonergic and catecholaminergic systems in the VLM of the neonatal rat are dynamically upregulated by IsH, potentially adapting cardiorespiratory responses to severe hypoxia.

Adrenaline: insights into its metabolic roles in hypoglycaemia and diabetes.

Adrenaline is a hormone that has profound actions on the cardiovascular system and is also a mediator of the fight-or-flight response. Adrenaline is now increasingly recognized as an important metabolic hormone that helps mobilize energy stores in the form of glucose and free fatty acids in preparation for physical activity or for recovery from hypoglycaemia. Recovery from hypoglycaemia is termed counter-regulation and involves the suppression of endogenous insulin secretion, activation of glucagon secretion from pancreatic α-cells and activation of adrenaline secretion. Secretion of adrenaline is controlled by presympathetic neurons in the rostroventrolateral medulla, which are, in turn, under the control of central and/or peripheral glucose-sensing neurons. Adrenaline is particularly important for counter-regulation in individuals with type 1 (insulin-dependent) diabetes because these patients do not produce endogenous insulin and also lose their ability to secrete glucagon soon after diagnosis. Type 1 diabetic patients are therefore critically dependent on adrenaline for restoration of normoglycaemia and attenuation or loss of this response in the hypoglycaemia unawareness condition can have serious, sometimes fatal, consequences. Understanding the neural control of hypoglycaemia-induced adrenaline secretion is likely to identify new therapeutic targets for treating this potentially life-threatening condition.

Central neural control of thermoregulation and brown adipose tissue.

Central neural circuits orchestrate the homeostatic repertoire that maintains body temperature during environmental temperature challenges and alters body temperature during the inflammatory response. This review summarizes the experimental underpinnings of our current model of the CNS pathways controlling the principal thermoeffectors for body temperature regulation: cutaneous vasoconstriction controlling heat loss, and shivering and brown adipose tissue for thermogenesis. The activation of these effectors is regulated by parallel but distinct, effector-specific, core efferent pathways within the CNS that share a common peripheral thermal sensory input. Via the lateral parabrachial nucleus, skin thermal afferent input reaches the hypothalamic preoptic area to inhibit warm-sensitive, inhibitory output neurons which control heat production by inhibiting thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to thermogenesis-controlling premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation of spinal circuits necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus sympathetic premotor neurons controlling cutaneous vasoconstriction. The model proposed for central thermoregulatory control provides a useful platform for further understanding of the functional organization of central thermoregulation and elucidating the hypothalamic circuitry and neurotransmitters involved in body temperature regulation.

Dysfunctional Relationship Between the Prefrontal Cortex and Amygdala for Explaining Posttraumatic CRPS Syndrome.

Dear Editor, After limb trauma, the first short lasting response corresponds to a facilitatory supraspinal influence exerted at the spinal cord with sympathoexcitation. A descending sympathoexcitatory response with analgesia, peripheral vasoconstriction, and facilitated motor reflexes could be an active adaptive response for helping to maintain the capacity to use an injured body part for flight or fight in case of emergency. After that, a descending sympathoinhibitory response with hyperalgesia, vasodilatation, and muscle weakness could be a passive adaptive response, where facilitation of pain might promote protection from new injury and vasodilatation and immobilization might help the healing process of the injured region. Persistent sympathoinhibition has been implicated for developing posttraumatic complex regional pain syndrome (CRPS). However, there is little known about the underlying neuroanatomical pathways involved in persistent sympathoinhibition in CRPS patients. Periaqueductal gray (PAG) has been seen as a center for defensive reactions that is capable of coordinating the sensory, motor, and autonomic outputs of the stress response. According to Vianna [1], four main longitudinal cell-rich subdivisions exist in the PAG, namely the dorsomedial (dmPAG), dorsolateral (dlPAG), lateral, and ventrolateral (vlPAG) subdivisions. Activation of neurons in the lateral/dorsolateral column of the PAG (l/dlPAG) results in sympathoexcitation that accompany the fight-or-flight response [2,3]. Activation of neurons in the vlPAG results in the sympathoinhibition that can accompany deep pain [2,3]. These PAG columns have extensive, viscerotopically organized, descending projections to sympathetic premotor neurons in the rostroventral medulla (RVM) [4]. Differential activation of l/dlPAG columns and vlPAG columns could provide a substrate for the parallel activation or inhibition of premotor neurons in the RVM and Locus Coeruleus thus explaining different patterns of autonomic activity supporting active and passive coping behaviors. Afferent signals from the autonomic nervous system terminating in lamina …

Seizure-Induced Sympathoexcitation Is Caused by Activation of Glutamatergic Receptors in RVLM That Also Causes Proarrhythmogenic Changes Mediated by PACAP and Microglia in Rats.

Sudden unexpected death in epilepsy is a major cause of death in epilepsy. Generally, seizures are accompanied by changes in brain function leading to uncontrolled nerve activity causing high blood pressure, rapid heart rate, and abnormal heart rhythm. Nevertheless, the brain chemicals causing these cardiovascular changes are unknown. Chemicals, such as glutamate and pituitary adenylate cyclase activating polypeptide, whose expression is increased after seizures, act on specific cardiovascular nuclei in the brain and influence the activity of the heart, and blood vessels. Microglia, which manage excitation in the brain, are commonly activated after seizure and produce pro- and/or anti-inflammatory factors. Hence, we aimed to determine the effects of blocking glutamate, pituitary adenylate cyclase activating polypeptide, and microglia in the RVLM and their contribution to cardiovascular autonomic dysfunction in seizure.

Clinical Implications

HomeHypertensionVol. 66, No. 6Clinical Implications Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBClinical Implications Originally published1 Dec 2015https://doi.org/10.1161/HYPERTENSIONAHA.115.06698Hypertension. 2015;66:1089Systolic Blood Pressure Trajectories (p 1108)Download figureDownload PowerPointIdentifying people in early life who are at the greatest risk of developing adult hypertension might permit effective risk reduction via age-appropriate prevention and intervention strategies, thereby reducing the burden of blood pressure-related disease in later life. There are conflicting recommendations on routine screening for primary hypertension in children, and better information is needed for medical decision-making around risk assessment. In this issue of Hypertension, results from the Dunedin Multidisciplinary Health and Development Study, a longitudinal representative birth cohort study (n=975), show that subgroups within the population who are on trajectories toward developing prehypertension or hypertension by early midlife can be identified as early as 7 years of age. Early life risk factors for high blood pressure trajectory group membership were identified, including male sex, having a family history of hypertension, being the first born, and lower birth weight. Having a higher body mass index and cigarette smoking over time resulted in increasing blood pressure levels, especially among individuals in the higher blood pressure groups. Many early midlife cardiovascular correlates, including a composite index of metabolic abnormalities, were associated with prehypertensive and hypertensive blood pressure trajectory group membership, demonstrating the broader clinical utility of these trajectories. These data suggest that estimating risk for future hypertension (and cardiovascular disease more generally) can begin in childhood before blood pressure reaches prehypertensive or hypertensive levels in adulthood.Cerebrospinal Fluid NaCl Increases Sympathetic Nerve Activity via Rostral Ventrolateral Medulla (p 1184)Download figureDownload PowerPointEvidence from both salt-sensitive humans and animal models indicates that the ingestion of excess dietary salt produces discrete increases in cerebrospinal fluid NaCl concentrations by ≈2 to 5 mmol/L. This central hypernatremia subsequently activates the sympathetic nervous system to raise arterial blood pressure. Although changes in cerebrospinal fluid NaCl concentrations are sensed by specialized neurons in the hypothalamus, it is not clear how these changes translate into activation of the sympathetic nervous system and hypertension. In this issue of Hypertension, Stocker et al identified several novel mechanisms, including a distinct population of hindbrain neurons that mediate the sympathoexcitatory actions of NaCl. The authors demonstrated for the first time that intracerebroventricular infusion of hypertonic NaCl increases sympathetic outflow to the hindlimb vasculature and adrenal gland but decreases renal or does not alter splanchnic sympathetic nerve activity. This pattern results in a sympathetically mediated increase in blood pressure. Additional neurophysiological recordings suggest that these complex responses to central hypernatremia are mediated by a glutamatergic activation of bulbospinal, and likely C1 (or catecholaminergic), neurons of the rostral ventrolateral medulla (Figure). These findings have several important implications: (1) the brain selectively regulates sympathetic outflow to various end organs, (2) a discrete population of hindbrain neurons via glutamatergic input mediates the sympathoexcitatory response to central hypernatremia, and (3) both findings may represent future clinical targets for the treatment of salt-sensitive hypertension.Soluble fms-Like Tyrosine Kinase-1 e15a: Serum Levels and Bioactivity (p 1251)Download figureDownload PowerPointIn preeclampsia, there is excess secretion of the antiangiogenic factor soluble fms-like tyrosine kinase (sFLT-1) into the maternal circulation, leading to endothelial dysfunction, hypertension, and multiorgan injury. sFLT-1 e15 is by far the dominant placental sFLT-1 variant, and given preeclampsia is undoubtedly a placental disease (because delivery resolves the condition), sFLT-1 e15a may be the main sFLT-1 variant causing preeclampsia. Surprisingly, sFLT-1 e15a protein has been poorly characterized. In this issue of Hypertension, Palmer et al characterized sFLT-1 e15a protein bioactivity and reported circulating levels in pregnant women. It is conceivable that an sFLT-1 e15a ELISA may be better at predicting preeclampsia than the existing sFLT-1 ELISA (which indiscriminately detects all sFLT-1 variants). The team raised antibodies and developed a sFLT-1 e15a ELISA. Using this, they reported that circulating sFLT-1 e15a concentrations increased across gestation and were 10-fold higher in women with preterm preeclampsia compared with controls (Figure). They also showed that sFLT-1 e15a is bioactive. sFLT-1 e15a blocked vascular endothelial growth factor activation of its own receptor, decreased endothelial cell migration and invasion, and decreased endothelial tube formation. Furthermore, sFLT-1 e15a blocked vascular endothelial growth factor–induced sprouting from mouse aortic rings. The development of therapeutics should take sFLT-1 e15a into account. Identifying medications that decrease placental sFLT-1 e15a secretion or neutralize its biological activity may be a therapeutic strategy. Furthermore, it is possible that an sFLT-1 e15a ELISA has potential as a biomarker test to predict preeclampsia. Previous Back to top Next FiguresReferencesRelatedDetails December 2015Vol 66, Issue 6 Advertisement Article InformationMetrics © 2015 American Heart Association, Inc.https://doi.org/10.1161/HYPERTENSIONAHA.115.06698 Originally publishedDecember 1, 2015 PDF download Advertisement

A Class of Visual Neurons with Wide-Field Properties Is Required for Local Motion Detection

Visual motion cues are used by many animals to guide navigation across a wide range of environments. Long-standing theoretical models have made predictions about the computations that compare light signals across space and time to detect motion. Using connectomic and physiological approaches, candidate circuits that can implement various algorithmic steps have been proposed in the Drosophila visual system. These pathways connect photoreceptors, via interneurons in the lamina and the medulla, to direction-selective cells in the lobula and lobula plate. However, the functional architecture of these circuits remains incompletely understood. Here, we use a forward genetic approach to identify the medulla neuron Tm9 as critical for motion-evoked behavioral responses. Using in vivo calcium imaging combined with genetic silencing, we place Tm9 within motion-detecting circuitry. Tm9 receives functional inputs from the lamina neurons L3 and, unexpectedly, L1 and passes information onto the direction-selective T5 neuron. Whereas the morphology of Tm9 suggested that this cell would inform circuits about local points in space, we found that the Tm9 spatial receptive field is large. Thus, this circuit informs elementary motion detectors about a wide region of the visual scene. In addition, Tm9 exhibits sustained responses that provide a tonic signal about incoming light patterns. Silencing Tm9 dramatically reduces the response amplitude of T5 neurons under a broad range of different motion conditions. Thus, our data demonstrate that sustained and wide-field signals are essential for elementary motion processing.

What do we understand from clinical and mechanistic studies on acupuncture treatment for hypertension?

The outcome of acupuncture on hypertension treatment is inconclusive. This study aims to evaluate the influence of acupuncture on hypertension, based on findings from mechanistic studies over the course of decades particularly those conducted at the University of California, Irvine. Low-current and low-frequency electroacupuncture (EA) at P5–6 (overlying the median nerve) and S36–37 (overlying the deep peroneal nerve) reduced high blood pressure in a subset of patients (~70 %) with mild-to-moderate hypertension, in a slow-onset (4–8 weeks) but long-lasting (1–2 months) manner. EA inhibited cardiovascular sympathoexcitatory neurons through activation of neurons in the arcuate nucleus of the hypothalamus, the ventrolateral periaqueductal gray in the midbrain and the nucleus raphe pallidus in the medulla, through inhibiting the activity of premotor sympathetic neurons in the rostral ventrolateral medulla (rVLM). Several neurotransmitters such as glutamate, acetylcholine, opioids, GABA, nociceptin, serotonin and endocannabinoids were involved in this EA-induced hypotensive response. The long-lasting inhibition of hypertension induced by EA was related to opioids and GABA in the rVLM, neural circuitry between the arcuate and ventrolateral periaqueductal gray, and prolongation of the increase in preproenkephalin mRNA levels and enkephalin levels in the rVLM and arcuate. Moreover, the long-lasting inhibition of sympathetic activity by EA was confirmed in EA-treated hypertensive patients with decreased levels of norepinephrine, renin and aldosterone.

Afferent and efferent connections of C1 cells with spinal cord or hypothalamic projections in mice.

The axonal projections and synaptic input of the C1 adrenergic neurons of the rostral ventrolateral medulla (VLM) were examined using transgenic dopamine-beta hydroxylase Cre mice and modified rabies virus. Cre-dependent viral vectors expressing TVA (receptor for envelopeA) and rabies glycoprotein were injected into the left VLM. EnvelopeA-pseudotyped rabies-EGFP glycoprotein-deficient virus (rabies-EGFP) was injected 4-6weeks later in either thoracic spinal cord (SC) or hypothalamus. TVA immunoreactivity was detected almost exclusively (95%) in VLM C1 neurons. In mice with SC injections of rabies-EGFP, starter cells (expressing TVA+EGFP) were found at the rostral end of the VLM; in mice with hypothalamic injections starter C1 cells were located more caudally. C1 neurons innervating SC or hypothalamus had other terminal fields in common (e.g., dorsal vagal complex, locus coeruleus, raphe pallidus and periaqueductal gray matter). Putative inputs to C1 cells with SC or hypothalamic projections originated from the same brain regions, especially the lower brainstem reticular core from spinomedullary border to rostral pons. Putative input neurons to C1 cells were also observed in the nucleus of the solitary tract, caudal VLM, caudal spinal trigeminal nucleus, cerebellum, periaqueductal gray matter and inferior and superior colliculi. In sum, regardless of whether they innervate SC or hypothalamus, VLM C1 neurons receive input from the same general brain regions. One interpretation is that many types of somatic or internal stimuli recruit these neurons en bloc to produce a stereotyped acute stress response with sympathetic, parasympathetic, vigilance and neuroendocrine components.

Descending Command Neurons in the Brainstem that Halt Locomotion

The episodic nature of locomotion is thought to be controlled by descending inputs from the brainstem. Most studies have largely attributed this control to initiating excitatory signals, but little is known about putative commands that may specifically determine locomotor offset. To link identifiable brainstem populations to a potential locomotor stop signal, we used developmental genetics and considered a discrete neuronal population in the reticular formation: the V2a neurons. We find that those neurons constitute a major excitatory pathway to locomotor areas of the ventral spinal cord. Selective activation of V2a neurons of the rostral medulla stops ongoing locomotor activity, owing to an inhibition of premotor locomotor networks in the spinal cord. Moreover, inactivation of such neurons decreases spontaneous stopping in vivo. Therefore, the V2a "stop neurons" represent a glutamatergic descending pathway that favors immobility and may thus help control the episodic nature of locomotion.

Medullary neuronal loss and alpha-synuclein burden in Multiple System Atrophy

Spinally projecting neurons in the rostral ventrolateral medulla (RVLM) are thought to play a critical role in the generation of vasomotor sympathetic tone and represent a major site of convergence for multiple descending and reflex pathways that co-ordinate sympathetic nerve activity. Elucidating the organization of the circuits that drive these neurons is a key research objective. Here we present brain-wide connectomic maps of neurons that provide monosynaptic drive to putative RVLM sympathetic premotor neurons, generated using a two-step restricted trans-synaptic viral tracing strategy. We made focal microinjections of a genetically restricted reporter-expressing rabies vector, SADΔG(EnvA)-RFP, into the RVLM, and restricted its entry to neurons that project to the T2 spinal cord by first transducing them with a cassette required for rabies entry and trans-synapsis, YTB. By precisely targeting rabies injections to the core of the RVLM bulbospinal population we were able to restrict rabies ‘seeding’ to small numbers (as low as one single neuron) of RVLM presympathetic neurons immediately caudal to the facial nucleus, and then map the locations of neurons that provide monosynaptic input to the seed population. We observed reproducible patterns of inputs arising from the dorsal, contralateral, and midline medulla, and local RVLM interneurons including catecholaminergic non-bulbospinal neurons and neurons likely to reside within the ventral respiratory column. Distant inputs were identified in the pons, cerebellum and midbrain, and included previously suspected sites of monosynaptic drive such as the paraventricular nucleus of the hypothalamus.

The connectome of rostral ventrolateral medulla sympathetic premotor neurons

Spinally projecting neurons in the rostral ventrolateral medulla (RVLM) are thought to play a critical role in the generation of vasomotor sympathetic tone and represent a major site of convergence for multiple descending and reflex pathways that co-ordinate sympathetic nerve activity. Elucidating the organization of the circuits that drive these neurons is a key research objective. Here we present brain-wide connectomic maps of neurons that provide monosynaptic drive to putative RVLM sympathetic premotor neurons, generated using a two-step restricted trans-synaptic viral tracing strategy. We made focal microinjections of a genetically restricted reporter-expressing rabies vector, SADΔG(EnvA)-RFP, into the RVLM, and restricted its entry to neurons that project to the T2 spinal cord by first transducing them with a cassette required for rabies entry and trans-synapsis, YTB. By precisely targeting rabies injections to the core of the RVLM bulbospinal population we were able to restrict rabies ‘seeding’ to small numbers (as low as one single neuron) of RVLM presympathetic neurons immediately caudal to the facial nucleus, and then map the locations of neurons that provide monosynaptic input to the seed population. We observed reproducible patterns of inputs arising from the dorsal, contralateral, and midline medulla, and local RVLM interneurons including catecholaminergic non-bulbospinal neurons and neurons likely to reside within the ventral respiratory column. Distant inputs were identified in the pons, cerebellum and midbrain, and included previously suspected sites of monosynaptic drive such as the paraventricular nucleus of the hypothalamus.