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Direct current stimulation (DCS) is a non-invasive approach to stimulate the nervous system that is now considered a powerful tool for treating neurological diseases such as those affecting cognitive or locomotor functions. DCS, as applied clinically today, is an approach built on early uses in antiquity and knowledge gained over time. Its current use makes use of specific devices and takes into account knowledge of the mechanisms by which this approach modulates functioning of the nervous system at the cellular level. Over the last 20 years, although there are few studies, it has been shown that DCS can also modulate the breathing autonomic function. In this narrative review, after briefly providing the historical perspective and describing the principles and the main cellular and molecular effects, we summarize the currently available data regarding the modulation of ventilation, and propose that DCS could be used to treat autonomic or non-autonomic neurological disorders affecting breathing.
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Doenças do Sistema Nervoso Autônomo , Humanos , Doenças do Sistema Nervoso Autônomo/terapia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Terapia por Estimulação Elétrica/métodos , Transtornos Respiratórios/terapia , Transtornos Respiratórios/fisiopatologia , Doenças do Sistema Nervoso/terapia , Animais , Respiração , Sistema Nervoso Autônomo/fisiopatologiaRESUMO
The gut-brain peptide neuromedin U (NMU) decreases food intake and body weight and improves glucose tolerance. Here, we characterized NMU as an enteropeptide and determined how it impacts glucose excursion. NMU was expressed predominantly in the proximal small intestine, and its secretion was triggered by ingestion of a mixed meal. Although a single peripheral injection of NMU in C57BL/6NRj mice prevented the rise of glycemia upon an oral but not an intraperitoneal load of glucose, it unexpectedly prevented insulin secretion, only slightly improved peripheral insulin sensitivity, and barely reduced intestinal glucose absorption. Interestingly, peripheral administration of NMU abrogated gastric emptying. NMU receptors 1 and 2 were detected in pyloric muscles and NMU was able to directly induce pyloric contraction in a dose-dependent manner ex vivo in isometric chambers. Using a modified glucose tolerance test, we demonstrate that improvement of oral glucose tolerance by NMU was essentially, if not exclusively, because of its impact on gastric emptying. Part of this effect was abolished in vagotomized (VagoX) mice, suggesting implication of the vagus tone. Accordingly, peripheral injection of NMU was associated with increased number of c-FOS-positive neurons in the nucleus of the solitary tract, which was partly prevented in VagoX mice. Finally, NMU kept its ability to improve oral glucose tolerance in obese and diabetic murine models. Together, these data demonstrate that NMU is an enteropeptide that prevents gastric emptying directly by triggering pylorus contraction and indirectly through vagal afferent neurons. This blockade consequently reduces intestinal nutrient absorption and thereby results in an apparent improved tolerance to oral glucose challenge.-Jarry, A.-C., Merah, N., Cisse, F., Cayetanot, F., Fiamma, M.-N., Willemetz, A., Gueddouri, D., Barka, B., Valet, P., Guilmeau, S., Bado, A., Le Beyec, J., Bodineau, L., Le Gall, M. Neuromedin U is a gut peptide that alters oral glucose tolerance by delaying gastric emptying via direct contraction of the pylorus and vagal-dependent mechanisms.
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Glicemia/efeitos dos fármacos , Esvaziamento Gástrico/efeitos dos fármacos , Glucose/metabolismo , Neuropeptídeos/farmacologia , Peptídeos/farmacologia , Piloro/efeitos dos fármacos , Nervo Vago/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Ingestão de Alimentos/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Teste de Tolerância a Glucose/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
Cannabis is one of the most commonly used recreational drugs at ages highly correlated with potential pregnancy. Endocannabinoid signalling regulates important stages of neuronal development. When cannabinoid receptors, which are widely distributed through the nervous system, are activated by exogenous cannabinoids, breathing in adult rats is depressed. Here, we show that, in newborn mice, endocannabinoids, through the activation of cannabinoid receptor type 1 (CB1 R), participate in the modulation of respiration and its control. Blocking CB1 Rs at birth suppressed the brake exerted by endocannabinoids on ventilation in basal and in hypoxic conditions. The number of apnoeas and their duration were also minimized by activation of CB1 Rs in normoxic and in hypoxic conditions. However, prenatal cannabis intoxication, caused by a daily injection of WIN55,212-2, in pregnant mice durably modified respiration of the offspring, as shown by hyperventilation in basal conditions, an altered chemoreflex in response to hypoxia, and longer apnoeas. When CB1 Rs were blocked in WIN55,212-2 treated newborns, persistent hyperventilation was still observed, which could partly be explained by a perturbation of the central respiratory network. In fact, in vitro medullary preparations from WIN55,212-2 treated pups, free of peripheral or of supramedullary structures, showed an altered fictive breathing frequency. In conclusion, the endocannabinoid pathway at birth seems to modulate breathing and protect the newborn against apnoeas. However, when exposed prenatally to an excess of cannabinoid, the breathing neuronal network in development seems to be modified, probably rendering the newborn more vulnerable in the face of an unstable environment.
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Benzoxazinas/efeitos adversos , Agonistas de Receptores de Canabinoides/efeitos adversos , Hipóxia/fisiopatologia , Morfolinas/efeitos adversos , Naftalenos/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal , Respiração , Animais , Animais Recém-Nascidos , Apneia/tratamento farmacológico , Apneia/fisiopatologia , Antagonistas de Receptores de Canabinoides/farmacologia , Feminino , Hipóxia/tratamento farmacológico , Imuno-Histoquímica , Bulbo/efeitos dos fármacos , Bulbo/crescimento & desenvolvimento , Bulbo/fisiopatologia , Camundongos Endogâmicos C57BL , Periodicidade , Piperidinas/farmacologia , Pletismografia , Gravidez , Pirazóis/farmacologia , Receptor CB1 de Canabinoide/metabolismo , Respiração/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Low birth weight (LBW) increases the risk of neurodevelopmental disorders (NDDs) such as attention-deficit/hyperactive disorder and autism spectrum disorder, as well as cerebral palsy, for which no prophylactic measure exists. Neuroinflammation in fetuses and neonates plays a major pathogenic role in NDDs. Meanwhile, umbilical cord-derived mesenchymal stromal cells (UC-MSCs) exhibit immunomodulatory properties. Therefore, we hypothesized that systemic administration of UC-MSCs in the early postnatal period may attenuate neuroinflammation and thereby prevent the emergence of NDDs. The LBW pups born to dams subjected to mild intrauterine hypoperfusion exhibited a significantly lesser decrease in the monosynaptic response with increased frequency of stimulation to the spinal cord preparation from postnatal day 4 (P4) to P6, suggesting hyperexcitability, which was improved by intravenous administration of human UC-MSCs (1 × 105 cells) on P1. Three-chamber sociability tests at adolescence revealed that only LBW males exhibited disturbed sociability, which tended to be ameliorated by UC-MSC treatment. Other parameters, including those determined via open-field tests, were not significantly improved by UC-MSC treatment. Serum or cerebrospinal fluid levels of pro-inflammatory cytokines were not elevated in the LBW pups, and UC-MSC treatment did not decrease these levels. In conclusion, although UC-MSC treatment prevents hyperexcitability in LBW pups, beneficial effects for NDDs are marginal.
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Transtorno do Espectro Autista , Células-Tronco Mesenquimais , Transtornos do Neurodesenvolvimento , Adolescente , Humanos , Masculino , Recém-Nascido , Transtorno do Espectro Autista/terapia , Doenças Neuroinflamatórias , Cordão Umbilical , Transtornos do Neurodesenvolvimento/etiologia , Transtornos do Neurodesenvolvimento/prevenção & controleRESUMO
Introduction: Congenital Central Hypoventilation Syndrome, a rare disease caused by PHOX2B mutation, is associated with absent or blunted CO2/H+ chemosensitivity due to the dysfunction of PHOX2B neurons of the retrotrapezoid nucleus. No pharmacological treatment is available. Clinical observations have reported non-systematic CO2/H+ chemosensitivity recovery under desogestrel. Methods: Here, we used a preclinical model of Congenital Central Hypoventilation Syndrome, the retrotrapezoid nucleus conditional Phox2b mutant mouse, to investigate whether etonogestrel, the active metabolite of desogestrel, led to a restoration of chemosensitivity by acting on serotonin neurons known to be sensitive to etonogestrel, or retrotrapezoid nucleus PHOX2B residual cells that persist despite the mutation. The influence of etonogestrel on respiratory variables under hypercapnia was investigated using whole-body plethysmographic recording. The effect of etonogestrel, alone or combined with serotonin drugs, on the respiratory rhythm of medullary-spinal cord preparations from Phox2b mutants and wildtype mice was analyzed under metabolic acidosis. c-FOS, serotonin and PHOX2B were immunodetected. Serotonin metabolic pathways were characterized in the medulla oblongata by ultra-high-performance liquid chromatography. Results: We observed etonogestrel restored chemosensitivity in Phox2b mutants in a non-systematic way. Histological differences between Phox2b mutants with restored chemosensitivity and Phox2b mutant without restored chemosensitivity indicated greater activation of serotonin neurons of the raphe obscurus nucleus but no effect on retrotrapezoid nucleus PHOX2B residual cells. Finally, the increase in serotonergic signaling by the fluoxetine application modulated the respiratory effect of etonogestrel differently between Phox2b mutant mice and their WT littermates or WT OF1 mice, a result which parallels with differences in the functional state of serotonergic metabolic pathways between these different mice. Discussion: Our work thus highlights that serotonin systems were critically important for the occurrence of an etonogestrel-restoration, an element to consider in potential therapeutic intervention in Congenital Central Hypoventilation Syndrome patients.
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Desogestrel , Progestinas , Animais , Camundongos , Desogestrel/farmacologia , Desogestrel/uso terapêutico , Progestinas/farmacologia , Serotonina , Gonanos , Dióxido de Carbono , Modelos Animais de Doenças , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Fatores de Transcrição/metabolismo , Congêneres da ProgesteronaRESUMO
Spinal cord injury is associated with damage in descending and ascending pathways between brainstem/cortex and spinal neurons, leading to loss in sensory-motor functions. This leads not only to locomotor reduction but also to important respiratory impairments, both reducing cardiorespiratory engagement, and increasing cardiovascular risk and mortality. Moreover, individuals with high-level injuries suffer from sleep-disordered breathing in a greater proportion than the general population. Although no current treatments exist to restore motor function in spinal cord injury (SCI), serotoninergic (5-HT) 1A receptor agonists appear as pharmacologic neuromodulators that could be important players in inducing functional improvements by increasing the activation of spared motoneurons. Indeed, single therapies of serotoninergic 1A (5-HT1A) agonists allow for acute and temporary recovery of locomotor function. Moreover, the 5-HT1A agonist could be even more promising when combined with other pharmacotherapies, exercise training, and/or spinal stimulation, rather than administered alone. In this review, we discuss previous and emerging evidence showing the value of the 5HT1A receptor agonist therapies for motor and respiratory limitations in SCI. Moreover, we provide mechanistic hypotheses and clinical impact for the potential benefit of 5-HT1A agonist pharmacology in inducing neuroplasticity and improving locomotor and respiratory functions in SCI.
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The majority of spinal cord injuries (SCIs) are cervical (cSCI), leading to a marked reduction in respiratory capacity. We aimed to investigate the effect of hemicontusion models of cSCI on both diaphragm activity and respiratory function to serve as preclinical models of cervical SCI. Since phrenic motoneuron pools are located at the C3-C5 spinal level, we investigated two models of preclinical cSCI mimicking human forms of injury, namely, one above (C3 hemicontusion-C3HC) and one below phrenic motoneuron pools (C6HC) in wild-type swiss OF-1 mice, and we compared their effects on respiratory function using whole-body plethysmography and on diaphragm activity using electromyography (EMG). At 7 days post-surgery, both C3HC and C6HC damaged spinal cord integrity above the lesion level, suggesting that C6HC potentially alters C5 motoneurons. Although both models led to decreased diaphragmatic EMG activity in the injured hemidiaphragm compared to the intact one (-46% and -26% in C3HC and C6HC, respectively, both p = 0.02), only C3HC led to a significant reduction in tidal volume and minute ventilation compared to sham surgery (-25% and -20% vs. baseline). Moreover, changes in EMG amplitude between respiratory bursts were observed post-C3HC, reflecting a change in phrenic motoneuronal excitability. Hence, C3HC and C6HC models induced alteration in respiratory function proportionally to injury level, and the C3HC model is a more appropriate model for interventional studies aiming to restore respiratory function in cSCI.
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Prenatal hypoxia is a recognised risk factor for neurodevelopmental disorders associated with both membrane proteins involved in neuron homeostasis, e.g., chloride (Cl-) cotransporters, and alterations in brain neurotransmitter systems, e.g., catecholamines, dopamine, and GABA. Our study aimed to determine whether prenatal hypoxia alters central respiratory drive by disrupting the development of Cl- cotransporters KCC2 and NKCC1. Cl- homeostasis seems critical for the strength and efficiency of inhibition mediated by GABAA and glycine receptors within the respiratory network, and we searched for alterations of GABAergic and glycinergic respiratory influences after prenatal hypoxia. We measured fictive breathing from brainstem in ex vivo preparations during pharmacological blockade of KCC2 and NKCC1 Cl- cotransporters, GABAA, and glycine receptors. We also evaluated the membrane expression of Cl- cotransporters in the brainstem by Western blot and the expression of Cl- cotransporter regulators brain-derived neurotrophic factor (BDNF) and calpain. First, pharmacological experiments showed that prenatal hypoxia altered the regulation of fictive breathing by NKCC1 and KCC2 Cl- cotransporters, GABA/GABAA, and glycin. NKCC1 inhibition decreased fictive breathing at birth in control mice while it decreased at 4 days after birth in pups exposed to prenatal hypoxia. On the other hand, inhibition of KCC2 decreased fictive breathing 4 days after birth in control mice without any change in prenatal hypoxia pups. The GABAergic system appeared to be more effective in prenatal hypoxic pups whereas the glycinergic system increased its effectiveness later. Second, we observed a decrease in the expression of the Cl- cotransporter KCC2, and a decrease with age in NKCC1, as well as an increase in the expression of BDNF and calpain after prenatal hypoxia exposure. Altogether, our data support the idea that prenatal hypoxia alters the functioning of GABAA and glycinergic systems in the respiratory network by disrupting maturation of Cl- homeostasis, thereby contributing to long-term effects by disrupting ventilation.
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Cerebral palsy (CP) is a complex syndrome of various sensory, motor and cognitive deficits. Its prevalence has recently decreased in some developed countries and its symptoms have also shifted since the 1960s. From the 1990s, CP has been associated with prematurity, but recent epidemiologic studies show reduced or absent brain damage, which recapitulates developmental coordination disorder (DCD). In previous studies, we developed a rat model based on mild intrauterine hypoperfusion (MIUH) that recapitulated the diversity of symptoms observed in preterm survivors. Briefly, MIUH led to early inflammatory processes, diffuse brain damage, minor locomotor deficits, musculoskeletal pathologies, neuroanatomical and functional disorganization of the primary somatosensory (S1) cortex but not in the motor cortex (M1), delayed sensorimotor reflexes, spontaneous hyperactivity, deficits in sensory information processing, and memory and learning impairments in adult rats. Adult MIUH rats also exhibited changes in muscle contractile properties and phenotype, enduring hyperreflexia and spasticity, as well as hyperexcitability in the sensorimotor cortex. We recently developed a rat model of DCD based on postnatal sensorimotor restriction (SMR) without brain damage. Briefly, SMR led to digitigrade locomotion (i.e., "toe walking") related to ankle-knee overextension, degraded musculoskeletal tissues (e.g., gastrocnemius atrophy), and lumbar hyperreflexia. The postnatal SMR then led to secondary degradation of the hind-limb maps in S1 and M1 cortices, altered cortical response properties and cortical hyperexcitability, but no brain damage. Thus, our 2 rat models appear to recapitulate the diversity of symptoms ranging from CP to DCD and contribute to understanding the emergence and mechanisms underlying the corresponding neurodevelopmental disorders. These preclinical models seem promising for testing strategies of rehabilitation based on both physical and cognitive training to promote adaptive brain plasticity and to improve physical body conditions.
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Paralisia Cerebral , Transtornos das Habilidades Motoras , Córtex Sensório-Motor , Animais , Paralisia Cerebral/etiologia , Marcha , Humanos , Locomoção , RatosRESUMO
Dysfunction of central respiratory CO2/H+ chemosensitivity is a pivotal factor that elicits deep hypoventilation in patients suffering from central hypoventilation syndromes. No pharmacological treatment is currently available. The progestin desogestrel has been suggested to allow recovery of respiratory response to CO2/H+ in patients suffering from central hypoventilation, but except the fact that supramedullary regions may be involved, mechanisms are still unknown. Here, we tested in neonates whether orexin systems contribute to desogestrel's central effects on respiratory function. Using isolated ex vivo central nervous system preparations from newborn rats, we show orexin and almorexant, an antagonist of orexin receptors, supressed strengthening of the increase in respiratory frequency induced by prolonged metabolic acidosis under exposure to etonogestrel, the active metabolite of desogestrel. In parallel, almorexant suppressed the increase and enhanced increase in c-fos expression in respiratory-related brainstem structures induced by etonogestrel. These results suggest orexin signalisation is a key component of acidosis reinforcement of respiratory drive by etonogestrel in neonates. Although stage of development used is different as that for progestin clinical observations, presents results provide clues about conditions under which desogestrel or etonogestrel may enhance ventilation in patients suffering from central hypoventilation syndromes.
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BACKGROUND: Central alveolar hypoventilation syndromes (CHS) encompass neurorespiratory diseases resulting from congenital or acquired neurological disorders. Hypercapnia, acidosis, and hypoxemia resulting from CHS negatively affect physiological functions and can be lifethreatening. To date, the absence of pharmacological treatment implies that the patients must receive assisted ventilation throughout their lives. OBJECTIVE: To highlight the relevance of determining conditions in which using gonane synthetic progestins could be of potential clinical interest for the treatment of CHS. METHODS: The mechanisms by which gonanes modulate the respiratory drive were put into the context of those established for natural progesterone and other synthetic progestins. RESULTS: The clinical benefits of synthetic progestins to treat respiratory diseases are mixed with either positive outcomes or no improvement. A benefit for CHS patients has only recently been proposed. We incidentally observed restoration of CO2 chemosensitivity, the functional deficit of this disease, in two adult CHS women by desogestrel, a gonane progestin, used for contraception. This effect was not observed by another group, studying a single patient. These contradictory findings are probably due to the complex nature of the action of desogestrel on breathing and led us to carry out mechanistic studies in rodents. Our results show that desogestrel influences the respiratory command by modulating the GABAA and NMDA signaling in the respiratory network, medullary serotoninergic systems, and supramedullary areas. CONCLUSION: Gonanes show promise for improving ventilation of CHS patients, although the conditions of their use need to be better understood.
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Gonanos/farmacologia , Gonanos/uso terapêutico , Progesterona/análogos & derivados , Apneia do Sono Tipo Central/tratamento farmacológico , Animais , Desogestrel/farmacologia , Desogestrel/uso terapêutico , Humanos , Progestinas/farmacologiaRESUMO
Motor control and body representations in the central nervous system are built, i.e., patterned, during development by sensorimotor experience and somatosensory feedback/reafference. Yet, early emergence of locomotor disorders remains a matter of debate, especially in the absence of brain damage. For instance, children with developmental coordination disorders (DCD) display deficits in planning, executing and controlling movements, concomitant with deficits in executive functions. Thus, are early sensorimotor atypicalities at the origin of long-lasting abnormal development of brain anatomy and functions? We hypothesize that degraded locomotor outcomes in adulthood originate as a consequence of early atypical sensorimotor experiences that induce developmental disorganization of sensorimotor circuitry. We showed recently that postnatal sensorimotor restriction (SMR), through hind limb immobilization from birth to one month, led to enduring digitigrade locomotion with ankle-knee overextension, degraded musculoskeletal tissues (e.g., gastrocnemius atrophy), and clear signs of spinal hyperreflexia in adult rats, suggestive of spasticity; each individual disorder likely interplaying in self-perpetuating cycles. In the present study, we investigated the impact of postnatal SMR on the anatomical and functional organization of hind limb representations in the sensorimotor cortex and processes representative of maladaptive neuroplasticity. We found that 28 days of daily SMR degraded the topographical organization of somatosensory hind limb maps, reduced both somatosensory and motor map areas devoted to the hind limb representation and altered neuronal response properties in the sensorimotor cortex several weeks after the cessation of SMR. We found no neuroanatomical histopathology in hind limb sensorimotor cortex, yet increased glutamatergic neurotransmission that matched clear signs of spasticity and hyperexcitability in the adult lumbar spinal network. Thus, even in the absence of a brain insult, movement disorders and brain dysfunction can emerge as a consequence of reduced and atypical patterns of motor outputs and somatosensory feedback that induce maladaptive neuroplasticity. Our results may contribute to understanding the inception and mechanisms underlying neurodevelopmental disorders, such as DCD.
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Adaptação Fisiológica/fisiologia , Elevação dos Membros Posteriores/efeitos adversos , Transtornos dos Movimentos/fisiopatologia , Plasticidade Neuronal , Córtex Sensório-Motor/fisiopatologia , Animais , Feminino , Elevação dos Membros Posteriores/fisiologia , Masculino , Transtornos dos Movimentos/patologia , Neurônios/patologia , Análise de Componente Principal , RatosRESUMO
Motor control and body representation in the central nervous system (CNS) as well as musculoskeletal architecture and physiology are shaped during development by sensorimotor experience and feedback, but the emergence of locomotor disorders during maturation and their persistence over time remain a matter of debate in the absence of brain damage. By using transient immobilization of the hind limbs, we investigated the enduring impact of postnatal sensorimotor restriction (SMR) on gait and posture on treadmill, age-related changes in locomotion, musculoskeletal histopathology and Hoffmann reflex in adult rats without brain damage. SMR degrades most gait parameters and induces overextended knees and ankles, leading to digitigrade locomotion that resembles equinus. Based on variations in gait parameters, SMR appears to alter age-dependent plasticity of treadmill locomotion. SMR also leads to small but significantly decreased tibial bone length, chondromalacia, degenerative changes in the knee joint, gastrocnemius myofiber atrophy and muscle hyperreflexia, suggestive of spasticity. We showed that reduced and atypical patterns of motor outputs, and somatosensory inputs and feedback to the immature CNS, even in the absence of perinatal brain damage, play a pivotal role in the emergence of movement disorders and musculoskeletal pathologies, and in their persistence over time. Understanding how atypical sensorimotor development likely contributes to these degradations may guide effective rehabilitation treatments in children with either acquired (ie, with brain damage) or developmental (ie, without brain injury) motor disabilities.
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Transtornos Neurológicos da Marcha/etiologia , Transtornos Neurológicos da Marcha/fisiopatologia , Locomoção , Músculo Esquelético/fisiopatologia , Fatores Etários , Animais , Peso Corporal , Paralisia Cerebral , Teste de Esforço , Feminino , Marcha , Elevação dos Membros Posteriores , Masculino , Ratos , Ratos Sprague-Dawley , Reflexo AnormalRESUMO
Intrauterine ischemia-hypoxia is detrimental to the developing brain and leads to white matter injury (WMI), encephalopathy of prematurity (EP), and often to cerebral palsy (CP), but the related pathophysiological mechanisms remain unclear. In prior studies, we used mild intrauterine hypoperfusion (MIUH) in rats to successfully reproduce the diversity of clinical signs of EP, and some CP symptoms. Briefly, MIUH led to inflammatory processes, diffuse gray and WMI, minor locomotor deficits, musculoskeletal pathologies, neuroanatomical and functional disorganization of the primary somatosensory and motor cortices, delayed sensorimotor reflexes, spontaneous hyperactivity, deficits in sensory information processing, memory and learning impairments. In the present study, we investigated the early and long-lasting mechanisms of pathophysiology that may be responsible for the various symptoms induced by MIUH. We found early hyperreflexia, spasticity and reduced expression of KCC2 (a chloride cotransporter that regulates chloride homeostasis and cell excitability). Adult MIUH rats exhibited changes in muscle contractile properties and phenotype, enduring hyperreflexia and spasticity, as well as hyperexcitability in the sensorimotor cortex. Taken together, these results show that reduced expression of KCC2, lumbar hyperreflexia, spasticity, altered properties of the soleus muscle, as well as cortical hyperexcitability may likely interplay into a self-perpetuating cycle, leading to the emergence, and persistence of neurodevelopmental disorders (NDD) in EP and CP, such as sensorimotor impairments, and probably hyperactivity, attention, and learning disorders.
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Adaptation of physiological and behavioral functions to seasonal changes in daylength is of major relevance for optimal fitness and survival. Because aging is characterized by changes in biological rhythms, it may be hypothesized that old animals fall short of showing a full adaptation to prolonged changes in the duration of daily light exposure, as naturally occurring in relation to season in younger individuals. To test this hypothesis, we analyzed changes in the patterns of daily locomotor activity and body temperature rhythms of young and old mouse lemurs (Microcebus murinus, Primates) exposed to short and long daylengths. The effect of an increase in the duration of daily light exposure was attenuated in old animals, as compared to younger lemurs. Although some age-related differences in the locomotor activity rhythm could be seen under exposure to short daylength, they were predominant under long daylength. Some mechanisms allowing adaptation to changing daylength thus seem to be impaired at old age. Changes in coupling of circadian oscillators to the light-dark cycle and disturbances in the physiological responses to change in light duration should be further investigated.
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Envelhecimento/fisiologia , Temperatura Corporal/fisiologia , Cheirogaleidae/fisiologia , Atividade Motora , Fotoperíodo , Adaptação Fisiológica , Animais , Relógios Biológicos , MasculinoRESUMO
In humans, activity rhythms become fragmented and attenuated in the elderly. This suggests an alteration of the circadian system per se that could in turn affect the expression of biological rhythms. In primates, very few studies have analyzed the effect of aging on the circadian system. The mouse lemur provides a unique model of aging in non-human primates. To assess the effect of aging on the circadian system of this primate, we recorded the circadian and daily rhythms of locomotor activity of mouse lemurs of various ages. We also examined age-related changes in the daily rhythm of immunoreactivities for vasoactive intestinal polypeptide (VIP) and arginine-vasopressin (AVP) in suprachiasmatic nucleus neurons (SCN), two major peptides of the biological clock. Compared to adult animals, aged mouse lemurs showed a significant increase in daytime activity and an advanced activity onset. Moreover, when maintained in constant dim red light, aged animals exhibited a shortening of the free-running period compared to adult animals. In adults, AVP immunoreactivity (ir) peaked during the second part of the day, and VIP ir peaked during the night. In aged mouse lemurs, the peaks of AVP ir and VIP ir were significantly shifted with no change in amplitude. AVP ir was most intense at the beginning of the night; whereas, VIP ir peaked at the beginning of the daytime. A weakened oscillator could account for the rhythmic disorders often observed in the elderly. Changes in the daily rhythms of AVP ir and VIP ir may affect the ability of the SCN to transmit rhythmic information to other neural target sites, and thereby modify the expression of some biological rhythms.
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Envelhecimento , Comportamento Animal , Relógios Biológicos , Cheirogaleidae/anatomia & histologia , Animais , Arginina/metabolismo , Ritmo Circadiano , Neuropeptídeos/química , Peptídeos/química , Primatas , Núcleo Supraquiasmático/metabolismo , Fatores de Tempo , Peptídeo Intestinal Vasoativo/metabolismo , Vasopressinas/metabolismoRESUMO
We mapped and characterized changes in the activity of brainstem cell groups under hypoxia in one-day-old newborn mice, an animal model in which the central nervous system at birth is particularly immature. The classical biphasic respiratory response characterized by transient hyperventilation, followed by severe ventilation decline, was associated with increased c-FOS immunoreactivity in brainstem cell groups: the nucleus of the solitary tract, ventral reticular nucleus of the medulla, retrotrapezoid/parafacial region, parapyramidal group, raphe magnus nucleus, lateral, and medial parabrachial nucleus, and dorsal subcoeruleus nucleus. In contrast, the hypoglossal nucleus displayed decreased c-FOS immunoreactivity. There were fewer or no activated catecholaminergic cells activated in the medulla oblongata, whereas ~45% of the c-FOS-positive cells in the dorsal subcoeruleus were co-labeled. Approximately 30% of the c-FOS-positive cells in the parapyramidal group were serotoninergic, whereas only a small portion were labeled for serotonin in the raphe magnus nucleus. None of the c-FOS-positive cells in the retrotrapezoid/parafacial region were co-labeled for PHOX2B. Thus, the hypoxia-activated brainstem neuronal network of one-day-old mice is characterized by (i) the activation of catecholaminergic cells of the dorsal subcoeruleus nucleus, a structure implicated in the strong depressive pontine influence previously reported in the fetus but not in newborns, (ii) the weak activation of catecholaminergic cells of the ventral reticular nucleus of the medulla, an area involved in hypoxic hyperventilation, and (iii) the absence of PHOX2B-positive cells activated in the retrotrapezoid/parafacial region. Based on these results, one-day-old mice could highlight characteristics for modeling the breathing network of premature infants.
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In the gray mouse lemur, a prosimian primate, aging is associated with a reduction of olfactory behaviors and sexual stimulation. To assess the effect of aging on the central response to pheromone stimulation in this primate, we measured the c-fos expression in the main and accessory olfactory bulbs of adult and aged male mouse lemurs, following exposure to the volatile phase of urine from proestrous females. In adults, pheromone exposure increased the number of Fos-positive neurons in the main olfactory bulb without changes in the accessory olfactory bulb. Fos expression was not increased by the odorant stimulation in aged mouse lemurs. Our results may explain the age-related decrease in behaviors associated with olfactory stimulation in this primate.
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Envelhecimento/metabolismo , Cheirogaleidae/metabolismo , Genes fos/fisiologia , Bulbo Olfatório/metabolismo , Atrativos Sexuais/metabolismo , Envelhecimento/efeitos dos fármacos , Animais , Feminino , Genes fos/efeitos dos fármacos , Masculino , Bulbo Olfatório/efeitos dos fármacos , Atrativos Sexuais/administração & dosagemRESUMO
The influence on the breathing pattern of the activation of serotonin receptors belonging to the subtypes 2(A) and 2(C) (5-HT(2A/2C)) has been assessed in newborn and adult conscious rats. Rats were given an acute intraperitoneal dose of the agonist DOI (1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane; 5 mg/kg). In newborns, DOI elicited a long-lasting respiratory depression by decreasing both tidal volume and respiratory frequency. In adults, DOI retained a depressant influence, although attenuated, on tidal volume. In contrast, it elicited an increase in respiratory frequency. In separate subsets of newborn and adult rats, immunohistochemistry has been used to monitor c-fos expression induced by DOI in the medullary and pontine regions involved in respiratory control. Counts of immunoreactive neurons indicated a marked increase in the neuronal populations activated in the adult compared to the newborn rat. The response to both experimental factors (newborn vs. adult controls) and drug (injected vs. control age-matched rats) were more pronounced in mature animals. Among developmental changes in the pattern of labeling, DOI elicited Fos expression in the adult but not in the neonate in the ventrolateral subnucleus of the nucleus of the solitary tract, the parabrachial area and the Kölliker-Fuse nucleus. This finding suggested that changes in the respiratory response to DOI might at least partly depend on maturational events within networks involved in the modulation of respiratory timing.
Assuntos
Envelhecimento/metabolismo , Tronco Encefálico/crescimento & desenvolvimento , Indofenol/análogos & derivados , Neurônios/metabolismo , Receptores de Serotonina/metabolismo , Centro Respiratório/crescimento & desenvolvimento , Fenômenos Fisiológicos Respiratórios/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Tronco Encefálico/citologia , Tronco Encefálico/metabolismo , Contagem de Células , Estado de Consciência/efeitos dos fármacos , Estado de Consciência/fisiologia , Feminino , Imuno-Histoquímica , Indofenol/farmacologia , Masculino , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor 5-HT2A de Serotonina , Receptor 5-HT2C de Serotonina , Receptores de Serotonina/efeitos dos fármacos , Centro Respiratório/citologia , Centro Respiratório/metabolismo , Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/fisiologiaRESUMO
Consequences of 5-HT(1/2) systems blockade by methysergide on newborn rats respiratory drive were evaluated in vivo with unrestrained animals and in vitro using brainstem-spinal cord preparations. A decrease in respiratory frequency until a plateau level was observed under both in vivo (82.8 +/- 0.6% of control values) and in vitro (76.8 +/- 0.8% of control values) conditions whereas an increase in inspiratory amplitude (135.1 +/- 2.1% of control values) was only retrieved in vivo. By the use of the c-fos expression analysis, we correlated these effects with neuronal activity changes, particularly, in vivo in two key structures between the respiratory ponto-medullary network and the peripheral or suprapontine afferences, namely the commissural subnucleus of the nucleus of the solitary tract and the lateral parabrachial nucleus. Thus, peripheral and suprapontine inputs seem to be of a primeval importance in the respiratory influence of endogenous 5-HT. Besides, as 5-HT is involved in the respiratory perturbations that occur in sudden infant death syndrome (SIDS), our results suggest a participation of peripheral and suprapontine inputs in these disorders.