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Neuron Dec 2018Response to danger needs to be rapid and appropriate. In humans, nocifensive behaviors often precede conscious pain perception. Much is known about local spinal cord...
Response to danger needs to be rapid and appropriate. In humans, nocifensive behaviors often precede conscious pain perception. Much is known about local spinal cord circuits for simple reflexive responses, but the mechanisms underlying more complex behaviors remain poorly understood. We now describe a brainstem circuit that controls escape responses to select noxious stimuli. Tracing experiments characterized a highly interconnected excitatory circuit involving the dorsal spinal cord, parabrachial nucleus (PBNl), and reticular formation (MdD). A combination of chemogenetic, optogenetic, and genetic ablation approaches revealed that PBNl neurons are activated by noxious stimuli and trigger robust escape responses to heat through connections to the MdD. Remarkably, MdD neurons receive excitatory input from the PBN and target both the spinal cord and PBN; activation of these neurons phenocopies the behavioral effects of PBNl neuron stimulation. These findings identify a substrate for controlling appropriate behavioral responses to painful stimuli.
Topics: Adenosine Triphosphate; Animals; Brain Stem; Calcitonin Gene-Related Peptide; Decerebrate State; Luminescent Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nerve Tissue Proteins; Neural Pathways; Nociceptors; Optogenetics; Pain; Pain Perception; Spinal Cord; Tachykinins; Transduction, Genetic
PubMed: 30449655
DOI: 10.1016/j.neuron.2018.10.037 -
Neurology International Sep 2019A 69-year-old man who had been bedridden in nursing home because of a 5- year history of progressive supranuclear palsy (PSP) was admitted due to aspiration pneumonia....
A 69-year-old man who had been bedridden in nursing home because of a 5- year history of progressive supranuclear palsy (PSP) was admitted due to aspiration pneumonia. Besides neck dystonia in extension, he showed "alternating flexed-extended posturing", in which the arm was flexed on one side and extended on the other. Magnetic resonance imaging of the brain revealed global cerebral atrophy that predominantly affected the cortex and midbrain. The mechanisms of complex posturing in late-stage PSP may sometimes be related to decortication and decerebration as well as dystonia, and "alternating flexed- extended posturing" might be one of the phenotypes of pathological progression in PSP.
PubMed: 31579148
DOI: 10.4081/ni.2019.8257 -
The Journal of Physiology Jul 2019We investigated the cardiovascular and respiratory responses of the normotensive Wistar-Kyoto (WKY) rat and the spontaneously hypertensive (SH) rat to inhalation and...
KEY POINTS
We investigated the cardiovascular and respiratory responses of the normotensive Wistar-Kyoto (WKY) rat and the spontaneously hypertensive (SH) rat to inhalation and intravenous injection of the noxious stimuli allyl isothiocyanate (AITC). AITC inhalation evoked atropine-sensitive bradycardia in conscious WKY rats, and evoked atropine-sensitive bradycardia and atenolol-sensitive tachycardia with premature ventricular contractions (PVCs) in conscious SH rats. Intravenous injection of AITC evoked bradycardia but no tachycardia/PVCs in conscious SHs, while inhalation and injection of AITC caused similar bradypnoea in conscious SH and WKY rats. Anaesthesia (inhaled isoflurane) inhibited the cardiac reflexes evoked by inhaled AITC but not injected AITC. Data indicate the presence of a de novo nociceptive pulmonary-cardiac reflex triggering sympathoexcitation in SH rats, and this reflex is dependent on vagal afferents but is not due to steady state blood pressure or due to remodelling of vagal efferent function.
ABSTRACT
Inhalation of noxious irritants/pollutants activates airway nociceptive afferents resulting in reflex bradycardia in healthy animals. Nevertheless, noxious pollutants evoke sympathoexcitation (tachycardia, hypertension) in cardiovascular disease patients. We hypothesize that cardiovascular disease alters nociceptive pulmonary-cardiac reflexes. Here, we studied reflex responses to irritants in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive (SH) rats. Inhaled allyl isothiocyanate (AITC) evoked atropine-sensitive bradycardia with atrial-ventricular (AV) block in conscious WKY rats, thus indicating a parasympathetic reflex. Conversely, inhaled AITC in conscious SH rats evoked complex brady-tachycardia with both AV block and premature ventricular contractions (PVCs). Atropine abolished the bradycardia and AV block, but the atropine-insensitive tachycardia and PVCs were abolished by the β -adrenoceptor antagonist atenolol. The aberrant AITC-evoked reflex in SH rats was not reduced by acute blood pressure reduction by captopril. Surprisingly, intravenous AITC only evoked bradycardia in conscious SH and WKY rats. Furthermore, anaesthesia reduced the cardiac reflexes evoked by inhaled but not injected AITC. Nevertheless, anaesthesia had little effect on AITC-evoked respiratory reflexes. Such data suggest distinct differences in nociceptive reflex pathways dependent on cardiovascular disease, administration route and downstream effector. AITC-evoked tachycardia in decerebrate SH rats was abolished by vagotomy. Finally, there was no difference in the cardiac responses of WKY and SH rats to vagal efferent electrical stimulation. Our data suggest that AITC inhalation in SH rats evokes de novo adrenergic reflexes following vagal afferent activation. This aberrant reflex is independent of steady state hypertension and is not evoked by intravenous AITC. We conclude that pre-existing hypertension aberrantly shifts nociceptive pulmonary-cardiac reflexes towards sympathoexcitation.
Topics: Animals; Blood Pressure; Bradycardia; Captopril; Heart; Heart Rate; Hypertension; Isothiocyanates; Lung; Male; Nociceptors; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reflex; Tachycardia; Vagus Nerve
PubMed: 31077371
DOI: 10.1113/JP278085 -
The Journal of Physiology Aug 2020The decerebrate mouse provides a novel working model of the exercise pressor reflex (EPR). The decerebrate mouse model of the EPR is similar to the previously described...
KEY POINTS
The decerebrate mouse provides a novel working model of the exercise pressor reflex (EPR). The decerebrate mouse model of the EPR is similar to the previously described decerebrate rat model. Studying the EPR in transgenic mouse models can define exact mechanisms of the EPR in health and disease.
ABSTRACT
The exercise pressor reflex (EPR) is defined by a rise in mean arterial pressure (MAP) and heart rate (HR) in response to exercise and is necessary to match metabolic demand and prevent premature fatigue. While this reflex is readily tested in humans, mechanistic studies are largely infeasible. Here, we have developed a novel murine model of the EPR to allow for mechanistic studies in various mouse models. We observed that ventral root stimulation (VRS) in an anaesthetized mouse causes a depressor response and a reduction in HR. In contrast, the same stimulation in a decerebrate mouse causes a rise in MAP and HR which is abolished by dorsal rhizotomy or by neuromuscular blockade. Moreover, we demonstrate a reduced MAP response to VRS using TRPV1 antagonism or in Trpv1 null mice while the response to passive stretch remains intact. Additionally, we demonstrate that intra-arterial infusion of capsaicin results in a dose-related rise in MAP and HR that is significantly reduced by a selective and potent TRPV1 antagonist or is completely abolished in Trpv1 null mice. These data serve to validate the development of a decerebrate mouse model for the study of cardiovascular responses to exercise and further define the role of the TRPV1 receptor in mediating the EPR. This novel model will allow for extensive study of the EPR in unlimited transgenic and mutant mouse lines, and for an unprecedented exploration of the molecular mechanisms that control cardiovascular responses to exercise in health and disease.
Topics: Animals; Blood Pressure; Decerebrate State; Disease Models, Animal; Heart Rate; Mice; Muscle Contraction; Muscle, Skeletal; Rats; Rats, Sprague-Dawley; Reflex
PubMed: 32406099
DOI: 10.1113/JP277602 -
Journal of Neurophysiology Apr 2021We recently demonstrated in decerebrate and conscious cat preparations that hindlimb somatosensory inputs converge with vestibular afferent input onto neurons in...
We recently demonstrated in decerebrate and conscious cat preparations that hindlimb somatosensory inputs converge with vestibular afferent input onto neurons in multiple central nervous system (CNS) locations that participate in balance control. Although it is known that head position and limb state modulate postural reflexes, presumably through vestibulospinal and reticulospinal pathways, the combined influence of the two inputs on the activity of neurons in these brainstem regions is unknown. In the present study, we evaluated the responses of vestibular nucleus (VN) neurons to vestibular and hindlimb stimuli delivered separately and together in conscious cats. We hypothesized that VN neuronal firing during activation of vestibular and limb proprioceptive inputs would be well fit by an additive model. Extracellular single-unit recordings were obtained from VN neurons. Sinusoidal whole body rotation in the roll plane was used as the search stimulus. Units responding to the search stimulus were tested for their responses to 10° ramp-and-hold roll body rotation, 60° extension hindlimb movement, and both movements delivered simultaneously. Composite response histograms were fit by a model of low- and high-pass filtered limb and body position signals using least squares nonlinear regression. We found that VN neuronal activity during combined vestibular and hindlimb proprioceptive stimulation in the conscious cat is well fit by a simple additive model for signals with similar temporal dynamics. The mean value for goodness of fit across all units was 0.74 ± 0.17. It is likely that VN neurons that exhibit these integrative properties participate in adjusting vestibulospinal outflow in response to limb state. Vestibular nucleus neurons receive convergent information from hindlimb somatosensory inputs and vestibular inputs. In this study, extracellular single-unit recordings of vestibular nucleus neurons during conditions of passively applied limb movement, passive whole body rotations, and combined stimulation were well fit by an additive model. The integration of hindlimb somatosensory inputs with vestibular inputs at the first stage of vestibular processing suggests that vestibular nucleus neurons account for limb position in determining vestibulospinal responses to postural perturbations.
Topics: Afferent Pathways; Animals; Behavior, Animal; Cats; Electrophysiological Phenomena; Female; Hindlimb; Movement; Neurons; Physical Stimulation; Postural Balance; Proprioception; Vestibular Nuclei; Vestibule, Labyrinth
PubMed: 33534649
DOI: 10.1152/jn.00350.2019 -
The Journal of Neuroscience : the... Apr 2022Higher vertebrates are capable not only of forward but also backward and sideways locomotion. Also, single steps in different directions are generated for postural...
Higher vertebrates are capable not only of forward but also backward and sideways locomotion. Also, single steps in different directions are generated for postural corrections. While the networks responsible for the control of forward walking (FW) have been studied in considerable detail, the networks controlling steps in other directions are mostly unknown. Here, to characterize the operation of the spinal locomotor network during FW and backward walking (BW), we recorded the activity of individual spinal interneurons from L4 to L6 during both FW and BW evoked by epidural stimulation (ES) of the spinal cord at L5-L6 in decerebrate cats of either sex. Three groups of neurons were revealed. Group 1 (45%) had a similar phase of modulation during both FW and BW. Group 2 (27%) changed the phase of modulation in the locomotor cycle depending on the direction of locomotion. Group 3 neurons were modulated during FW only (Group 3a, 21%) or during BW only (Group 3b, 7%). We suggest that Group 1 neurons belong to the network generating the vertical component of steps (the limb elevation and lowering) because it should operate similarly during locomotion in any direction, while Groups 2 and 3 neurons belong to the networks controlling the direction of stepping. Results of this study provide new insights into the organization of the spinal locomotor circuits, advance our understanding of ES therapeutic effects, and can potentially be used for the development of novel strategies for recuperation of impaired balance control, which requires the generation of corrective steps in different directions. Animals and humans can perform locomotion in different directions in relation to the body axis (forward, backward, sideways). While the networks that control forward walking have been studied in considerable detail, the networks controlling steps in other directions are unknown. Here, by recording the activity of the same spinal neurons during forward and backward walking, we revealed three groups of neurons forming, respectively, the network operating similarly during stepping in different directions, the network changing its operation with a change in the direction of stepping, and the network operating only during locomotion in a specific direction. These networks presumably control different aspects of the step. The obtained results provide new insights into the organization of the spinal locomotor networks.
Topics: Animals; Epidural Space; Interneurons; Locomotion; Spinal Cord; Walking
PubMed: 35296546
DOI: 10.1523/JNEUROSCI.1884-21.2022 -
American Journal of Physiology. Heart... Oct 2017Previous studies have shown that diabetic peripheral neuropathy affects both unmyelinated and myelinated afferents, similar to those evoking the exercise pressor reflex....
Previous studies have shown that diabetic peripheral neuropathy affects both unmyelinated and myelinated afferents, similar to those evoking the exercise pressor reflex. However, the effect of type 1 diabetes (T1DM) on this reflex is not known. We examined, in decerebrate male and female T1DM [streptozotocin (STZ)] and healthy control (CTL) rats, pressor and cardioaccelerator responses to isometric contraction of the hindlimb muscles during the early and late stages of the disease. STZ (50 mg/kg) was injected to induce diabetes, and experiments were conducted at 1, 3, and 6 wk after injection. On the day of the experiment, we statically contracted the hindlimb muscles by stimulating the sciatic nerve and measured changes in mean arterial pressure and heart rate. We found that the pressor but not cardioaccelerator response was exaggerated in STZ rats at 1 wk (STZ: 21 ± 3 mmHg, = 10, and CTL: 14 ± 2 mmHg, = 10, < 0.05) and at 3 wk (STZ: 26 ± 5 mmHg, = 10, and CTL: 17 ± 3 mmHg, = 11, < 0.05) after injection. However, at 6 wk, and only in male rats, both the pressor (STZ: 13 ± 3 mmHg, = 12, and CTL: 17 ± 3 mmHg, = 13, < 0.05) and cardioaccelerator responses (STZ: 7 ± 3 beats/min, = 12, and CTL: 10 ± 3 beats/min, = 13, < 0.05) to contraction were significantly attenuated in STZ rats compared with CTL rats. These data indicate that T1DM exaggerates the exercise pressor reflex during the early stages of the disease in both male and female rats. Conversely, T1DM attenuates this reflex in the late stage of the disease in male but not female rats. This is the first study to provide evidence that the pressor and cardioaccelerator responses to skeletal muscle contraction vary depending on the duration of type 1 diabetes.
Topics: Animals; Arterial Pressure; Case-Control Studies; Decerebrate State; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Electric Stimulation; Female; Heart Rate; Hindlimb; Male; Muscle Contraction; Muscle, Skeletal; Physical Conditioning, Animal; Rats; Rats, Sprague-Dawley; Reflex; Reflex, Abnormal; Sciatic Nerve; Sex Factors; Vasoconstriction
PubMed: 28778915
DOI: 10.1152/ajpheart.00399.2017 -
Frontiers in Neural Circuits 2020: The spinal cord's central pattern generators (CPGs) have been explained by the symmetrical half-center hypothesis, the bursts generator, computational models, and more...
: The spinal cord's central pattern generators (CPGs) have been explained by the symmetrical half-center hypothesis, the bursts generator, computational models, and more recently by connectome circuits. Asymmetrical models, at odds with the half-center paradigm, are composed of extensor and flexor CPG modules. Other models include not only flexor and extensor motoneurons but also motoneuron pools controlling biarticular muscles. It is unknown whether a preferred model can explain some particularities that fictive scratching (FS) in the cat presents. The first aim of this study was to investigate FS patterns considering the aiming and the rhythmic periods, and second, to examine the effects of serotonin (5HT) on and segmental inputs to FS. : The experiments were carried out first in brain cortex-ablated cats (BCAC), then spinalized (SC), and for the midcollicular (MCC) preparation. Subjects were immobilized and the peripheral nerves were used to elicit the Monosynaptic reflex (MR), to modify the scratching patterns and for electroneurogram recordings. : In BCAC, FS was produced by pinna stimulation and, in some cases, by serotonin. The scratching aiming phase (AP) initiates with the activation of either flexor or extensor motoneurons. Serotonin application during the AP produced simultaneous extensor and flexor bursts. Furthermore, WAY 100635 (5HT1A antagonist) produced a brief burst in the tibialis anterior (TA) nerve, followed by a reduction in its electroneurogram (ENG), while the soleus ENG remained silent. In SC, rhythmic phase (RP) activity was recorded in the soleus motoneurons. Serotonin or WAY produced FS bouts. The electrical stimulation of Ia afferent fibers produced heteronymous MRes waxing and waning during the scratch cycle. In MCC, FS began with flexor activity. Electrical stimulation of either deep peroneus (DP) or superficial peroneus (SP) nerves increased the duration of the TA electroneurogram. Medial gastrocnemius (MG) stretching or MG nerve electrical stimulation produced a reduction in the TA electroneurogram and an initial MG extensor burst. MRes waxed and waned during the scratch cycle. : Descending pathways and segmental afferent fibers, as well as 5-HT and WAY, can change the FS pattern. To our understanding, the half-center hypothesis is the most suitable for explaining the AP in MCC.
Topics: Ablation Techniques; Animals; Brain; Cats; Cerebral Cortex; Decerebrate State; Electric Stimulation; Motor Neurons; Peripheral Nerves; Reflex, Monosynaptic; Serotonin; Serotonin Antagonists; Spinal Cord; Superior Colliculi
PubMed: 32174815
DOI: 10.3389/fncir.2020.00001 -
Frontiers in Neuroscience 2017Sympathetic nerve activity (SNA) contributes appreciably to the control of physiological function, such that pathological alterations in SNA can lead to a variety of... (Review)
Review
Sympathetic nerve activity (SNA) contributes appreciably to the control of physiological function, such that pathological alterations in SNA can lead to a variety of diseases. The goal of this review is to discuss the characteristics of SNA, briefly review the methodology that has been used to assess SNA and its control, and to describe the essential role of neurophysiological studies in conscious animals to provide additional insights into the regulation of SNA. Studies in both humans and animals have shown that SNA is rhythmic or organized into bursts whose frequency varies depending on experimental conditions and the species. These rhythms are generated by brainstem neurons, and conveyed to sympathetic preganglionic neurons through several pathways, including those emanating from the rostral ventrolateral medulla. Although rhythmic SNA is present in decerebrate animals (indicating that neurons in the brainstem and spinal cord are adequate to generate this activity), there is considerable evidence that a variety of supratentorial structures including the insular and prefrontal cortices, amygdala, and hypothalamic subnuclei provide inputs to the brainstem regions that regulate SNA. It is also known that the characteristics of SNA are altered during stress and particular behaviors such as the defense response and exercise. While it is a certainty that supratentorial structures contribute to changes in SNA during these behaviors, the neural underpinnings of the responses are yet to be established. Understanding how SNA is modified during affective responses and particular behaviors will require neurophysiological studies in awake, behaving animals, including those that entail recording activity from neurons that generate SNA. Recent studies have shown that responses of neurons in the central nervous system to most sensory inputs are context-specific. Future neurophysiological studies in conscious animals should also ascertain whether this general rule also applies to sensory signals that modify SNA.
PubMed: 29311801
DOI: 10.3389/fnins.2017.00730 -
Journal of Clinical and Diagnostic... Jul 2016Malaria is the most important parasitic disease of humans causes clinical illness over 300-500 million people globally and over one million death every year globally....
INTRODUCTION
Malaria is the most important parasitic disease of humans causes clinical illness over 300-500 million people globally and over one million death every year globally. The involvement of the nervous system in malaria is studied in this paper, to help formulate a strategy for better malaria management.
AIM
To study the Neuropsychiatric manifestation in malaria.
MATERIALS AND METHODS
This was a prospective observational study in 170 patients with a clinical diagnosis of malaria admitted in various medical wards of medicine department of PBM Hospital, Bikaner during epidemic of malaria. It included both sexes of all age groups except the paediatric range. The diagnosis of malaria was confirmed by examination of thick and thin smear/optimal test/strip test. Only those cases that had asexual form of parasite of malaria in the blood by smear examination or optimal test were included in the study.
RESULTS
Out of total 170 patients 104 (62%) reported Plasmodium falciparum (PF), Plasmodium vivax (PV) were 57 (33.5%) followed by mixed (PF+PV) 9 (5.3%) cases. The total PBF-MP test positivity was 84.5%. Maximum patients were belonging to the age range of 21-40 year with male predominance. Neuropsychiatric manifestation seen in falciparum malaria (n=111) as follow: altered consciousness 20 (18.01%), headache 17 (15.32%), neck rigidity 5 (4.5%), convulsion 5 (4.55%), extra pyramidal rigidity 2 (1.8%), decorticate rigidity 1 (0.90%), decerebrate rigidity 1 (0.90%), cerebellar ataxia 3 (2.7%), subarachnoid haemorrhage 1 (0.90%), aphasia 2 (1.8%), subconjunctival haemorrhage 1 (0.90%), conjugate deviation of eye 1 (0.90%) and psychosis 6 (5.40%). Twenty one patients presented with cerebral malaria out of 111 patients. Most patients of cerebral malaria presented with altered level of consciousness followed by headache and psychosis. Acute confusional state with clouding of consciousness was the most common presentation of psychosis (50%).
CONCLUSION
Neuropsychiatric manifestations are not an uncommon presentation of malaria. Most commonly caused by PF malaria. Malaria should be thought as a differential diagnosis in pyrexia with neuropsychiatric manifestation. Observation obtained in the study will be highly useful for the diagnosis and management of patients suffering from malaria.
PubMed: 27630883
DOI: 10.7860/JCDR/2016/19035.8169