Central Neuronal Circuits Research Articles

Endogenous cannabinoids in the piriform cortex tune olfactory perception

Sensory perception depends on interactions between external inputs transduced by peripheral sensory organs and internal network dynamics generated by central neuronal circuits. In the sensory cortex, desynchronized network states associate with high signal-to-noise ratio stimulus-evoked responses and heightened perception. Cannabinoid-type-1-receptors (CB1Rs) - which influence network coordination in the hippocampus - are present in anterior piriform cortex (aPC), a sensory paleocortex supporting olfactory perception. Yet, how CB1Rs shape aPC network activity and affect odor perception is unknown. Using pharmacological manipulations coupled with multi-electrode recordings or fiber photometry in the aPC of freely moving male mice, we show that systemic CB1R blockade as well as local drug infusion increases the amplitude of gamma oscillations in aPC, while simultaneously reducing the occurrence of synchronized population events involving aPC excitatory neurons. In animals exposed to odor sources, blockade of CB1Rs reduces correlation among aPC excitatory units and lowers behavioral olfactory detection thresholds. These results suggest that endogenous endocannabinoid signaling promotes synchronized population events and dampen gamma oscillations in the aPC which results in a reduced sensitivity to external sensory inputs.

Central sensitization mechanisms in chronic migraine with medication overuse headache: a study of thalamocortical activation and lateral cortical inhibition.

It is unclear whether cortical hyperexcitability in chronic migraine with medication overuse headache (CM-MOH) is due to increased thalamocortical drive or aberrant cortical inhibitory mechanisms. Somatosensory evoked potentials (SSEP) were performed by electrical stimulation of the median nerve (M), ulnar nerve (U) and simultaneous stimulation of both nerves (MU) in 27 patients with CM-MOH and, for comparison, in 23 healthy volunteers (HVs) of a comparable age distribution. We calculated the degree of cortical lateral inhibition using the formula: 100 - [MU/(M + U) × 100] and the level of thalamocortical activation by analyzing the high frequency oscillations (HFOs) embedded in parietal N20 median SSEPs. Compared to HV, CM-MOH patients showed higher lateral inhibition (CM-MOH 52.2% ± 15.4 vs. HV 40.4% ± 13.3; p = 0.005), which positively correlated with monthly headache days, and greater amplitude of pre-synaptic HFOs (p = 0.010) but normal post-synaptic HFOs (p = 0.122). Our findings suggest that central neuronal circuits are highly sensitized in CM-MOH patients, at both thalamocortical and cortical levels. The observed changes could be due to the combination of dysfunctional central pain control mechanisms, hypersensitivity and hyperresponsiveness directly linked to the chronic intake of acute migraine drugs.

Controlled activation of cortical astrocytes modulates neuropathic pain-like behaviour

Chronic pain is a major public health problem that currently lacks effective treatment options. Here, a method that can modulate chronic pain-like behaviour induced by nerve injury in mice is described. By combining a transient nerve block to inhibit noxious afferent input from injured peripheral nerves, with concurrent activation of astrocytes in the somatosensory cortex (S1) by either low intensity transcranial direct current stimulation (tDCS) or via the chemogenetic DREADD system, we could reverse allodynia-like behaviour previously established by partial sciatic nerve ligation (PSL). Such activation of astrocytes initiated spine plasticity to reduce those synapses formed shortly after PSL. This reversal from allodynia-like behaviour persisted well beyond the active treatment period. Thus, our study demonstrates a robust and potentially translational approach for modulating pain, that capitalizes on the interplay between noxious afferents, sensitized central neuronal circuits, and astrocyte-activation induced synaptic plasticity.

Contribution of Afferent Feedback to Adaptive Hindlimb Walking in Cats: A Neuromusculoskeletal Modeling Study

Mammalian locomotion is generated by central pattern generators (CPGs) in the spinal cord, which produce alternating flexor and extensor activities controlling the locomotor movements of each limb. Afferent feedback signals from the limbs are integrated by the CPGs to provide adaptive control of locomotion. Responses of CPG-generated neural activity to afferent feedback stimulation have been previously studied during fictive locomotion in immobilized cats. Yet, locomotion in awake, behaving animals involves dynamic interactions between central neuronal circuits, afferent feedback, musculoskeletal system, and environment. To study these complex interactions, we developed a model simulating interactions between a half-center CPG and the musculoskeletal system of a cat hindlimb. Then, we analyzed the role of afferent feedback in the locomotor adaptation from a dynamic viewpoint using the methods of dynamical systems theory and nullcline analysis. Our model reproduced limb movements during regular cat walking as well as adaptive changes of these movements when the foot steps into a hole. The model generates important insights into the mechanism for adaptive locomotion resulting from dynamic interactions between the CPG-based neural circuits, the musculoskeletal system, and the environment.

Odor sampling strategies in mice with genetically altered olfactory responses.

Peripheral sensory cells and the central neuronal circuits that monitor environmental changes to drive behaviors should be adapted to match the behaviorally relevant kinetics of incoming stimuli, be it the detection of sound frequencies, the speed of moving objects or local temperature changes. Detection of odorants begins with the activation of olfactory receptor neurons in the nasal cavity following inhalation of air and airborne odorants carried therein. Thus, olfactory receptor neurons are stimulated in a rhythmic and repeated fashion that is determined by the breathing or sniffing frequency that can be controlled and altered by the animal. This raises the question of how the response kinetics of olfactory receptor neurons are matched to the imposed stimulation frequency and if, vice versa, the kinetics of olfactory receptor neuron responses determine the sniffing frequency. We addressed this question by using a mouse model that lacks the K+-dependent Na+/Ca2+ exchanger 4 (NCKX4), which results in markedly slowed response termination of olfactory receptor neuron responses and hence changes the temporal response kinetics of these neurons. We monitored sniffing behaviors of freely moving wildtype and NCKX4 knockout mice while they performed olfactory Go/NoGo discrimination tasks. Knockout mice performed with similar or, surprisingly, better accuracy compared to wildtype mice, but chose, depending on the task, different odorant sampling durations depending on the behavioral demands of the odorant identification task. Similarly, depending on the demands of the behavioral task, knockout mice displayed a lower basal breathing frequency prior to odorant sampling, a possible mechanism to increase the dynamic range for changes in sniffing frequency during odorant sampling. Overall, changes in sniffing behavior between wildtype and NCKX4 knockout mice were subtle, suggesting that, at least for the particular odorant-driven task we used, slowed response termination of the odorant-induced receptor neuron response either has a limited detrimental effect on odorant-driven behavior or mice are able to compensate via an as yet unknown mechanism.

Kappa Opioid Receptor Ligands and Pharmacology: Diphenethylamines, a Class of Structurally Distinct, Selective Kappa Opioid Ligands.

The kappa opioid receptor (KOR), a G protein-coupled receptor, and its endogenous ligands, the dynorphins, are prominent members of the opioid neuromodulatory system. The endogenous kappa opioid system is expressed in the central and peripheral nervous systems, and has a key role in modulating pain in central and peripheral neuronal circuits and a wide array of physiological functions and neuropsychiatric behaviors (e.g., stress, reward, emotion, motivation, cognition, epileptic seizures, itch, and diuresis). We review the latest advances in pharmacology of the KOR, chemical developments on KOR ligands with advances and challenges, and therapeutic and potential applications of KOR ligands. Diverse discovery strategies of KOR ligands targeting natural, naturally derived, and synthetic compounds with different scaffolds, as small molecules or peptides, with short or long-acting pharmacokinetics, and central or peripheral site of action, are discussed. These research efforts led to ligands with distinct pharmacological properties, as agonists, partial agonists, biased agonists, and antagonists. Differential modulation of KOR signaling represents a promising strategy for developing pharmacotherapies for several human diseases, either by activating (treatment of pain, pruritus, and epilepsy) or blocking (treatment of depression, anxiety, and addiction) the receptor. We focus on the recent chemical and pharmacological advances on diphenethylamines, a new class of structurally distinct, selective KOR ligands. Design strategies and investigations to define structure-activity relationships together with in vivo pharmacology of diphenethylamines as agonists, biased agonists, and antagonists and their potential use as therapeutics are discussed.

LA RISPECIFICAZIONE DEL TRASMETTITORE E DEL RECETTORE È UNA NUOVA FORMA DI PLASTICITÀ DEL SISTEMA NERVOSO NELL’ADULTO

After some words on the scientific role of Professor Paolo Mantegazza atthe University of Milan (4, 5, 6), I briefly illustrate some studies related to the occurrence of neurotransmitter and receptor re-specification in the adult animals. The greatdiscoveries of the early twentieth century on neuronal communication have established that the majority of communication between nerve cells occurs through a special structure, the synapse, allowing the one-way transfer of information between twocells through the release of a neurotransmitter from the presynaptic cell and its recognition by receptors localized in the postsynaptic cell. According to H. Dale axiom (9) each neuron could be identified on the basis of the neurotransmitter released and theinnervated cell by the type of receptors expressed; then neurons could be classified asexcitatory if they release acetylcholine, glutamate or other transmitters, or inhibitory ifthey release GABA or glycine. However, in recent years many studies have shown that, especially during development, a neuron could release and co-release several neuro-transmitters, sometimes even simultaneously, changing its classification from excitatory to inhibitory and vice versa(7). This researches opened a new field of study onsynaptic plasticity: the neurotransmitter and receptor re-specification. Our group, together with Prof. Mantegazza, tried to “force” it through experiments of denervation and heterologous re-innervation in the autonomic nervous system and at the neuromuscular junction. In a first series of experiments we studied the regenerative capabilities of the peripheral nervous system in three experimental models: a) re-innervation of the denervated superior cervical ganglion (SCG) (14, 15, 22) by cholinergicefferent vagal fibers, b) re-innervation of peripheral effectors smooth muscles (nicti-tating membrane) by the cholinergic preganglionic fibers; c) re-innervation in an in vivo transplant model of peripheral organs by the SCG. In these researches we haveestablished: 1) that a sympathetic ganglion could be re-innervated by vagal fibersforming normal ganglionic synapses, but with a strong reshaping, in vivo, of the cen-tral neural circuits so that sympathetic stimuli occurred through a vagal excitation; 2) preganglionic cholinergic fibers innervate the smooth muscle of the nictitating mem-brane releasing catecholamines instead of acetylcholine; 3) that in an in vivo model ofSCG transplant together with iris or adrenal medulla fragments, the SCG was able todistinguish between organs that required a postsynaptic innervation, iris, which wasinnervated, and organs that require a presynaptic innervation, the adrenal medulla,that was not innervated. We were then in the presence, even in the adult animal, of anew nervous plasticity with re-specification the neurotransmitter. These resultsdemonstrate that heterologous innervation could “force” plasticity in adult peripheralnervous system, alters the biological properties of neurons, upsets central neuronal circuits, but continues to maintain in experimental transplants basic rules of innervation between neurons and peripheral organs. Thirty years later, the group of prof. Brunelliin Brescia (23), along with pharmacologists and physiologists, had highlighted the pos-sibility of re-innervate striated muscles in a functional way with nerve fibers derivedfrom the red nucleus of the vestibular complex. The interest was, once again, in thefact that the re-innervating fibers were of glutamatergic type, and not cholinergic likethose of normal motor neurons, and that neuromuscular transmission was transformedfrom nicotinic cholinergic in glutamatergic. A new type of plasticity: the receptor re-specification had occurred also in this experimenal model. In close cooperationbetween our Milan and the Brescia group we could reconfirm with more appropriateexperiments that the re-innervation occurred; that neuromuscular junction had a glutamatergic transmission; that new re-innervating fibers made synapses at the same sitesof the previous neuromuscular junctions; that the new fibers release glutamate; andthat muscle cells expressed new glutamate receptors (24). Once again we were in thepresence of an extraordinary phenomenon of synaptic plasticity, in this case a receptorre-specification, and again with a strong impact on the central nervous system circuits.These experiences, along with many others now available in the literature, show thatthe adult peripheral nervous system, both autonomous and musculoskeletal, has aplasticity unthinkable before and open a field of great interest aiming at the understanding how neuronal specificity is regulated and at the investigation of non-canonical, but perhaps functional, re-innervation experiments in transplants and in post-traumatic surgery.

Leptin and brain-adipose crosstalks.

Interactions between the brain and distinct adipose depots have a key role in maintaining energy balance, thereby promoting survival in response to metabolic challenges such as cold exposure and starvation. Recently, there has been renewed interest in the specific central neuronal circuits that regulate adipose depots. Here, we review anatomical, genetic and pharmacological studies on the neural regulation of adipose function, including lipolysis, non-shivering thermogenesis, browning and leptin secretion. In particular, we emphasize the role of leptin-sensitive neurons and the sympathetic nervous system in modulating the activity of brown, white and beige adipose tissues. We provide an overview of advances in the understanding of the heterogeneity of the brain regulation of adipose tissues and offer a perspective on the challenges and paradoxes that the community is facing regarding the actions of leptin on this system.

P295 Effects of functional electric stimulation and task specific training on gait recovery in patients with stroke: Randomized controlled trial

Objectives This work was designed to assess the effects of functional electrical stimulation (FES) combined with task specific training on gait recovery in stroke patients. Methods Thirty hemiparetic stroke patients aged 40–58 years old were randomly assigned into two equal groups; the control group had received conventional physiotherapy program while the study group had received the same program in addition to FES therapy during treadmill training. Two dimensional (2D) gait analysis was used to assess gait parameters before and after completion of the treatment sessions. Results A statistically significant improvement had been reported in all gait parameters in the post-treatment assessment of the study group as compared to the control group including the gait velocity (P = 0.048), cadence (P = 0.030), ten meters walking time (P = 0.043), step length (P = 0.033), stride length (P = 0.015) and the instantaneous angles of knee and ankle of the affected lower limb during gait cycle sub-phases. Discussion These results may be attributed to physiological effect of FES during treadmill training. It induces afferent-efferent stimulation which results in limb movement. It provides task-oriented practice of walking and active repetitive movement training. It activates sensory inputs and central neuronal circuits that allow optimal motor learning. It stimulates neuronal recovery and neuroplasticity. Conclusion FES therapy combined with conventional stroke rehabilitation program improves gait parameters when compared to conventional therapy alone in hemiparetic stroke patients. Significance The beneficial effects of FES on gait encourage the corporation of its use in the rehabilitation programs for patients with hemiparetic stroke.

Selective κ receptor partial agonist HS666 produces potent antinociception without inducing aversion after i.c.v. administration in mice.

Background and purposeThe κ receptor has a central role in modulating neurotransmission in central and peripheral neuronal circuits that subserve pain and other behavioural responses. Although κ receptor agonists do not produce euphoria or lead to respiratory suppression, they induce dysphoria and sedation. We hypothesized that brain‐penetrant κ receptor ligands possessing biased agonism towards G protein signalling over β‐arrestin2 recruitment would produce robust antinociception with fewer associated liabilities.Experimental approachTwo new diphenethylamines with high κ receptor selectivity, HS665 and HS666, were assessed following i.c.v. administration in mouse assays of antinociception with the 55°C warm‐water tail withdrawal test, locomotor activity in the rotorod and conditioned place preference. The [35S]‐GTPγS binding and β‐arrestin2 recruitment in vitro assays were used to characterize biased agonism.Key resultsHS665 (κ receptor agonist) and HS666 (κ receptor partial agonist) demonstrated dose‐dependent antinociception after i.c.v. administration mediated by the κ receptor. These highly selective κ receptor ligands displayed varying biased signalling towards G protein coupling in vitro, consistent with a reduced liability profile, reflected by reduced sedation and absence of conditioned place aversion for HS666.Conclusions and implicationsHS665 and HS666 activate central κ receptors to produce potent antinociception, with HS666 displaying pharmacological characteristics of a κ receptor analgesic with reduced liability for aversive effects correlating with its low efficacy in the β‐arrestin2 signalling pathway. Our data provide further understanding of the contribution of central κ receptors in pain suppression, and the prospect of dissociating the antinociceptive effects of HS665 and HS666 from κ receptor‐mediated adverse effects.

Nitric Oxide Synthase in the Central Nervous System and Peripheral Organs of Stramonita haemastoma: Protein Distribution and Gene Expression in Response to Thermal Stress.

Nitric oxide (NO) is generated via the oxidation of l-arginine by the enzyme NO synthase (NOS) both in vertebrates and invertebrates. Three NOS isoforms, nNOS, iNOS and eNOS, are known in vertebrates, whereas a single NOS isoform is usually expressed in invertebrates, sharing structural and functional characteristics with nNOS or iNOS depending on the species. The present paper is focused on the constitutive Ca2+/calmodulin-dependent nNOS recently sequenced by our group in the neogastropod Stramonita haemastoma (ShNOS). In this paper we provide new data on cellular distribution of ShNOS in the CNS (pedal ganglion) and peripheral organs (osphradium, tentacle, eye and foot) obtained by WB, IF, CM and NADPHd. Results demonstrated that NOS-like proteins are widely expressed in sensory receptor elements, neurons and epithelial cells. The detailed study of NOS distribution in peripheral and central neurons suggested that NOS is both intracellular and presynaptically located. Present findings confirm that NO may have a key role in the central neuronal circuits of gastropods and in sensory perception. The physiological relevance of NOS enzymes in the same organs was suggested by thermal stress experiments demonstrating that the constitutive expression of ShNOS is modulated in a time- and organ-dependent manner in response to environmental stressors.

Abstracts From the 36th Annual Scientific Meeting of the HBPRCA

### CONTRIBUTION OF THE AREA POSTREMA TO THE INCREASED CARDIAC SYMPATHETIC NERVE ACTIVITY IN OVINE HEART FAILURE Abukar Y, Ramchandra R, May CN The Florey Institute of Neuroscience and Mental Health, Melbourne, Victoria, Australia Background : Heart failure (HF) is associated with an increase in cardiac sympathetic nerve activity (CSNA), which is directly linked to mortality in HF patients. The mechanisms responsible for the elevated CSNA remain unclear. Previous studies indicate that the area postrema (AP), a circumventricular organ in the brainstem, plays a role in the control of sympathetic nerve activity. We hypothesized that the elevated CSNA in HF is mediated by the AP and lesioning this region would reduce the increased CSNA in sheep with HF. Aims : To determine the effect of sham lesion or lesion of the AP on CSNA and hemodynamics in conscious sheep with HF. Methods : Studies were conducted in 2 groups of sheep with pacing-induced HF: sham (n=6) and AP lesion (n=6) sheep. Mean arterial blood pressure (MAP), heart rate (HR) and CSNA were recorded simultaneously in conscious sheep at least 4 days after surgery. Results : Heart failure was associated with a significant decrease in ejection fraction (from 74±2 % to 38±1 %; P<0.001), which was similar in both groups. There was a significant reduction in CSNA burst incidence in the AP lesion group compared with the sham group (45±10 and 89±3 bursts/100 heartbeats, respectively; P<0.01). Conclusions : In sheep with HF, the group with lesion of the AP had a significantly lower CSNA compared with the sham group. These data suggest that the AP plays a role in setting the detrimental high levels of CSNA in HF. ### G PROTEIN-COUPLED ESTROGEN RECEPTOR SIGNALING IMPROVES STROKE OUTCOME IN FEMALE MICE Broughton BRS, Jansen GL, Sobey CG Department of Pharmacology, Monash University, Clayton, Victoria, Australia Background: Estrogen has been assumed to provide neuroprotection following stroke entirely via classical estrogen receptors. Interestingly, there is recent evidence that activation of a novel G …

Role of the Renal Nerves in a Conscious Rabbit Model of Chronic Kidney Disease

Chronic kidney disease (CKD) contributes substantially to the global burden of cardiovascular disease. The renal nerves are likely to play a major role in CKD-induced hypertension since renal injury stimulates afferent sensory nerve fibers which modulate central neuronal circuits and thus sympathetic outflow. We investigated a novel conscious rabbit model of CKD by lesioning 5/6th of the renal cortex in one kidney and removing the contralateral kidney. We examined the role of the renal nerves by denervating the kidneys. Blood pressure (BP) and renal sympathetic nerve activity (RSNA), autonomic reflexes and noradrenaline spillover were examined after 3 weeks CKD. Plasma creatinine and urea were 44% and 38% higher in CKD than controls. BP and RSNA were 8% and 33% higher but total noradrenaline spillover was 32% lower in CKD rabbits (P<0.05). Responses to hypoxia were attenuated by CKD and RSNA baroreflexes were shifted to the higher BP level. Renal denervation reduced RSNA in both CKD and control rabbits (30%) but only lowered BP in controls. Noradrenaline spillover was unaltered by denervation but RSNA baroreflexes in both groups were shifted downwards. The hypertension to airjet was enhanced in both groups after denervation but the hypertension to hypoxia was attenuated in the control animals only. Blood parameters were not altered by renal denervation. Thus, while RSNA is elevated in CKD, there is sympathoinhibition in other beds. Renal denervation did not alter the renal impairment or hypertension suggesting that the renal nerves play a minor role in maintaining hypertension in this model of CKD.

Stress-induced dendritic internalization and nuclear translocation of the neurokinin-3 (NK3) receptor in vasopressinergic profiles of the rat paraventricular nucleus of the hypothalamus

Central neuronal circuits that relay stress information include vasopressin- (AVP) and oxytocin- (OC) containing neurons of the paraventricular nucleus of the hypothalamus (PVN). These neurons are potentially modulated by neurokinin-3 receptors (NK3Rs) of the tachykinin family of neuropeptides. NK3Rs have been localized in PVN neurons and have showed nuclear translocation following an osmotic challenge in rodents. However, their subcellular distribution in AVP or OC neurons of the PVN and plasticity following restraint stress in rats are unknown. In the present study, densities of NK3Rs in PVN AVP- or OC-labeled somatodendritic profiles were measured by quantitative immunoelectron microscopy in control or stressed rats. In resting conditions, NK3Rs were predominantly located in AVP neurons, however sparsely distributed in OC neurons of the PVN. All NK3-labeled somata of the PVN in control rats showed cytoplasmic but no nuclear immunolabeling. An acute restraint stress session of 30min significantly increased nuclear NK3R density in AVP-labeled somata but not in OC-labeled somata. These changes were accompanied by a respective decrease and increase in plasmalemmal and cytoplamic NK3R densities in AVP-labeled but not in OC-labeled dendrites. The results of this study suggest that in the rat PVN 1) NK3R distribution is conducive to modulation of systemic and/or central AVP release through PVN inputs to the posterior pituitary and/or the amygdala and 2) acute restraint stress activates (internalizes) NK3Rs on surface and evokes nuclear NK3R translocation exclusively in AVP neurons. This trafficking might contribute to neurochemical imbalances observed in neuronal circuits involved in stress-related disorders such as anxiety.

Protocol for a prospective neuroimaging study investigating the supraspinal control of lower urinary tract function in healthy controls and patients with non-neurogenic lower urinary tract symptoms

IntroductionLower urinary tract symptoms (LUTS) are highly prevalent, cause an enormous economic burden on healthcare systems and significantly impair the quality of life (QoL) of affected patients. The dependence of...

Impaired neural drive in patients with low back pain.

Control of trunk movement relies on the integration between central neuronal circuits and peripheral skeletomuscular activities and it can be altered by pain. There is increasing evidence that there are deficits within the central nervous system controlling the trunk muscles in people with low back pain (LBP). However, it is unclear how LBP impacts upon neural drive to back muscles at different levels of voluntary contraction. Therefore, the purpose of this study was to investigate if neural drive is impaired in these patients. Seventeen patients with LBP and 11 healthy controls were recruited. Bilateral electromyographic (EMG) recordings were obtained from the erector spinae (ES) muscles at two vertebral levels (T12 and L4). Participants performed a series of brief isometric back extensions (50-100% maximum voluntary contraction - MVC), during which transcranial magnetic stimulation was delivered. The size of the evoked (superimposed) twitch was measured using dynamometry. The size of the superimposed twitch decreased linearly with increasing contraction strength in the controls; however, this linear relationship was not observed in the patients. Additionally, patients had larger superimposed twitches and longer time-to-peak amplitudes during MVCs than those observed in controls. Furthermore, patients had lower MVC and root-mean-square EMG activity of ES muscles during MVCs. A decline of central neural drive to the back muscles at high level of voluntary contraction was observed in patients with LBP. These results suggest that it might be pertinent to include neuromuscular facilitation programmes and therapeutic exercise utilizing high voluntary contractions for patients with LBP.

Three-Dimensional Computer Model of Brainstem Respiratory Neuronal Circuits - Application for Research in Respirology

Abstract Methods that had been applied to study central neuronal circuits regulating cough and respiratory reflexes so far rely on recording performed in vivo, ex vivo, micro injecting and lesion methods. Based on the available data it is clear that this network is complicated, multilevel, holarchical, undergoing reconfiguration under afferent inputs. For many students and researchers it is complicated to get a virtual spatial image of these cooperating neuronal populations. The project was aimed to create graphical three-dimensional computer model of the brainstem using environment MATLAB and the matrix algebra to visualize neuron localization within the brainstem. Relevant data for the model had been taken from recent and also former research papers published in particular areas. This model may help scientists to visualize groups of neurons, help them to find targets for microinjecting or lesion studies together with stereotaxic positioning. The model is upgradeable and highly flexible for future use, research and teaching applications in MATLAB environment. MATLAB is a high-level language and interactive environment that enables you to perform computationally intensive tasks faster than with traditional programming languages

Hindbrain Ghrelin Receptor Signaling Is Sufficient to Maintain Fasting Glucose

The neuronal coordination of metabolic homeostasis requires the integration of hormonal signals with multiple interrelated central neuronal circuits to produce appropriate levels of food intake, energy expenditure and fuel availability. Ghrelin, a peripherally produced peptide hormone, circulates at high concentrations during nutrient scarcity. Ghrelin promotes food intake, an action lost in ghrelin receptor null mice and also helps maintain fasting blood glucose levels, ensuring an adequate supply of nutrients to the central nervous system. To better understand mechanisms of ghrelin action, we have examined the roles of ghrelin receptor (GHSR) expression in the mouse hindbrain. Notably, selective hindbrain ghrelin receptor expression was not sufficient to restore ghrelin-stimulated food intake. In contrast, the lowered fasting blood glucose levels observed in ghrelin receptor-deficient mice were returned to wild-type levels by selective re-expression of the ghrelin receptor in the hindbrain. Our results demonstrate the distributed nature of the neurons mediating ghrelin action.

Muscles bring breathing alive

Increases in ventilation, heart rate and systolic blood pressure accompany muscle exercise. Two neural mechanisms contribute to these effects. One of these is centrally mediated motor command, in which there is parallel activation of locomotor and autonomic brain circuits, while the other is feedback from muscle afferent receptors. The relative influence of the latter has been the focus of much attention in recent years.The population of afferent fibres in skeletal muscle is dominated by the small myelinated group III and unmyelinated group IV nerve fibres. Many of these thin fibre muscle afferents are sensitive to metabolites of muscle contraction, and it is well accepted that they play a significant role in the cardiovascular and respiratory response to exercise. Amongst the group III afferents are those that respond to mechanical deformation, and in the last 10 years good evidence has been provided to show that they also play a role in the cardiovascular changes associated with exercise (Hayes & Kaufman, 2001; Gladwell & Coote, 2002). Surprisingly, the role of these thin fibre muscle mechanoreceptors in respiratory control during exercise has been somewhat neglected, although it would be expected that cardiovascular and ventilatory changes are tightly integrated. The paper by Bruce & White (2011) in this issue of Experimental Physiology addresses this issue. In the early 1960s, Kao and colleagues published a series of papers describing cross-perfusion experiments in anaesthetized dogs in order to isolate potential sources of respiratory stimuli. They concluded that ‘It seems necessary to postulate a receptor in skeletal muscle which is responsible for the great intensity of ventilation during muscle exercise’ (see Kao, 1963). In human studies it is less clear, there being evidence for and against an effect of muscle contractions on ventilation. In particular, the close linear relationship between the work of muscles and oxygen consumption argues against a significant role for skeletal muscle mechanoreceptors. This would not be the case for muscle metaboreceptors. In humans, the metaboreceptors can be studied without the presence of command signals, by trapping metabolites produced during contraction with circulatory occlusion of the limb. In the last 10 years, a method has been developed that enables the muscle mechanoreceptor reflex to be studied, also in isolation of central command. This is achieved by passive stretch of a muscle group by dorsiflexion of the foot (Gladwell & Coote, 2002). These techniques are cleverly exploited in the paper by Bruce & White (2011), in which the influence on ventilation, the heart and blood pressure of either metaboreceptors or mechanoreceptors and both together are tested. The ingenious part of the study was to increase the subliminal fringe of the central neuronal circuits by increasing the excitability of central respiratory and other autonomic neurones by raising the inspired carbon dioxide concentration. This enabled the central synaptic effects to summate sufficiently to activate the respiratory and cardiovascular effectors so they could be observed and measured. The experiments controlled for the effects of metabolite sensitization of muscle afferents, hypercapnia-induced elevation of central respiratory drive and central command. The results convincingly show that facilitation of central neurones by hypercapnia results in a significant increase in ventilation when either muscle mechanoreceptors alone or muscle metaboreceptors alone are activated. The cardiovascular responses were also enhanced. This is the first clear indication that, during natural exercise, it is likely that thin fibre mechanoreceptors in skeletal muscles provide a significant signal to central autonomic pools of neurones that act together with the metaboreceptors and central command signals to ensure that the oxygen demands of exercise are precisely met. These results are not only important to the understanding of normal cardiorespiratory control during exercise but may also help to explain the reduced exercise capacity in patients with heart failure, hypertension and chronic obstructive pulmonary disease. In these patients, abnormal cardiorespiratory responses and intolerance of exercise may be linked to inappropriate reflex information generated by the muscle, as recently highlighted by Koba et al. (2009). The paper by Bruce & White (2011) adds weight to the conclusion of the study by Koba et al. (2009) that in these patients, accentuation of muscle mechanoreceptor signals is responsible for the enhanced cardiorespiratory responses in these disease states.

Prrxl1 is required for the generation of a subset of nociceptive glutamatergic superficial spinal dorsal horn neurons

Perception of noxious events relies on activation of complex central neuronal circuits. The spinal cord dorsal horn plays a pivotal role in the process relaying to the brain various types of somatosensory input. These functions are accomplished by distinct sensory neurons specifically organized in different laminae. They differentiate during development in a spatial-temporal order due to the expression of combinatorial sets of homeodomain transcription factors. Here we demonstrate that the differential expression of the homeodomain transcription factors Prrxl1 (DRG11), Tlx3, and Lmx1b defines various subpopulations of spinal cord dorsal horn glutamatergic early born and late born neurons. Accordingly, in the superficial dorsal horn of Prrxl1(-/-) mice, the number of glutamatergic neurons is reduced by 70%, while the number of Golgi-impregnated and noxious-induced Fos immunoreactive neurons is reduced by 85%. These results suggest a crucial role for Prrxl1 in the generation of various subpopulations of nociceptive glutamatergic superficial dorsal horn neurons.