Assuntos
Dor Crônica , Adenosina , Animais , Anti-Inflamatórios , Masculino , Piperidinas , Ratos , Nervo IsquiáticoRESUMO
The possibility that immunological changes might contribute to symptom severity in fibromyalgia (FM) prompted this proof-of-concept study to determine whether differences in monocyte subpopulations might be present in persons with FM compared with healthy controls. Relationships were assessed by comparing specific symptoms in those with FM (n = 20) and patterns of monocyte subpopulations with healthy age-matched and gender-matched controls (n = 20). Within the same time frame, all participants provided a blood sample and completed measures related to pain, fatigue, sleep disturbances, perceived stress, positive and negative affect and depressed mood (and the Fibromyalgia Impact Questionnaire for those with FM). Monocyte subpopulations were assessed using flow cytometry. No differences were observed in total percentages of circulating monocytes between the groups; however, pain was inversely correlated with percentages of circulating classical (r = -0.568, p = 0.011) and intermediate (r = -0.511, p = 0.025) monocytes in the FM group. Stress and pain were highly correlated (r = 0.608, p = 0.004) in the FM group. The emerging pattern of changes in the percentages of circulating monocyte subpopulations concomitant with higher ratings of perceived pain and the correlation between stress and pain found in the FM group warrant further investigation. Copyright © 2015 John Wiley & Sons, Ltd.
Assuntos
Fibromialgia/sangue , Fibromialgia/fisiopatologia , Inflamação/sangue , Monócitos , Dor/sangue , Estresse Psicológico/sangue , Adulto , Comorbidade , Estudos Transversais , Feminino , Fibromialgia/epidemiologia , Humanos , Inflamação/epidemiologia , Masculino , Pessoa de Meia-Idade , Dor/epidemiologia , Índice de Gravidade de Doença , Estresse Psicológico/epidemiologiaRESUMO
Neuronal activity in the nucleus of the solitary tract, ventrolateral medulla, area postrema, and parabrachial nucleus was studied in rats with intraperitoneal or subcutaneous tumors on the 7th, 14th, 21st, and 28th day after injection of fibrosarcoma tumor cells. We found that the number of Fos and dopamine ß-hydroxylase immunopositive neurons differs between animals with intraperitoneal and subcutaneous tumors and also between tumor-bearing rats at different times following injection. Our data indicate that responses of the brainstem structures to peripheral tumor growth depend on the localization as well as the stage of the tumor growth.
Assuntos
Fibrossarcoma/fisiopatologia , Neoplasias Peritoneais/fisiopatologia , Rombencéfalo/fisiopatologia , Neoplasias de Tecidos Moles/fisiopatologia , Tela Subcutânea/fisiopatologia , Animais , Área Postrema/enzimologia , Área Postrema/fisiopatologia , Biomarcadores/metabolismo , Dopamina beta-Hidroxilase/metabolismo , Fibrossarcoma/patologia , Imuno-Histoquímica , Interleucina-1beta/sangue , Masculino , Bulbo/enzimologia , Bulbo/fisiopatologia , Transplante de Neoplasias , Neoplasias Peritoneais/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Rombencéfalo/enzimologia , Transdução de Sinais/fisiologia , Neoplasias de Tecidos Moles/patologia , Núcleo Solitário/enzimologia , Núcleo Solitário/fisiopatologia , Tela Subcutânea/patologia , Fatores de Tempo , Carga Tumoral , Fator de Necrose Tumoral alfa/sangueRESUMO
Immune challenges can lead to marked behavioral changes, including fatigue, reduced social interest, anorexia, and somnolence, but the precise neuronal mechanisms that underlie sickness behavior remain elusive. Part of the neurocircuitry influencing behavior associated with illness likely includes viscerosensory nuclei located in the caudal brainstem, based on findings that inactivation of the dorsal vagal complex (DVC) can prevent social withdrawal. These brainstem nuclei contribute multiple neuronal projections that target different components of autonomic and stress-related neurocircuitry. In particular, catecholaminergic neurons in the ventrolateral medulla (VLM) and DVC target the hypothalamus and drive neuroendocrine responses to immune challenge, but their particular role in sickness behavior is not known. To test whether this catecholamine pathway also mediates sickness behavior, we compared effects of DVC inactivation with targeted lesion of the catecholamine pathway on exploratory behavior, which provides an index of motivation and fatigue, and associated patterns of brain activation assessed by immunohistochemical detection of c-Fos protein. LPS treatment dramatically reduced exploratory behavior, and produced a pattern of increased c-Fos expression in brain regions associated with stress and autonomic adjustments paraventricular hypothalamus (PVN), bed nucleus of the stria terminalis (BST), central amygdala (CEA), whereas activation was reduced in regions involved in exploratory behavior (hippocampus, dorsal striatum, ventral tuberomammillary nucleus, and ventral tegmental area). Both DVC inactivation and catecholamine lesion prevented reductions in exploratory behavior and completely blocked the inhibitory LPS effects on c-Fos expression in the behavior-associated regions. In contrast, LPS-induced activation in the CEA and BST was inhibited by DVC inactivation but not by catecholamine lesion. The findings support the idea that parallel pathways from immune-sensory caudal brainstem sources target distinct populations of forebrain neurons that likely mediate different aspects of sickness. The caudal medullary catecholaminergic projections to the hypothalamus may significantly contribute to brain mechanisms that induce behavioral "fatigue" in the context of physiological stressors.
Assuntos
Epinefrina/metabolismo , Comportamento Exploratório/fisiologia , Comportamento de Doença/fisiologia , Bulbo/metabolismo , Neurônios/metabolismo , Norepinefrina/metabolismo , Tonsila do Cerebelo/imunologia , Tonsila do Cerebelo/metabolismo , Análise de Variância , Animais , Nível de Alerta/fisiologia , Cateteres de Demora , Dopamina beta-Hidroxilase/imunologia , Dopamina beta-Hidroxilase/metabolismo , Hipotálamo/imunologia , Hipotálamo/metabolismo , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Bulbo/imunologia , Vias Neurais/imunologia , Vias Neurais/metabolismo , Neurônios/imunologia , Neuropeptídeos/imunologia , Neuropeptídeos/metabolismo , Orexinas , Proteínas Proto-Oncogênicas c-fos/imunologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
The autonomic nervous system plays a central role in regulation of host defense and in physiological responses to sepsis, including changes in heart rate and heart rate variability. The cholinergic anti-inflammatory response, whereby infection triggers vagal efferent signals that dampen production of proinflammatory cytokines, would be predicted to result in increased vagal signaling to the heart and increased heart rate variability. In fact, decreased heart rate variability is widely described in humans with sepsis. Our studies elucidate this apparent paradox by showing that mice injected with pathogens demonstrate transient bradyarrhythmias of vagal origin in a background of decreased heart rate variability (HRV). Intraperitoneal injection of a large inoculum of Gram-positive or Gram-negative bacteria or Candida albicans rapidly induced bradyarrhythmias of sinus and AV nodal block, characteristic of cardiac vagal firing and dramatically increased short-term HRV. These pathogen-induced bradycardias were immediately terminated by atropine, an antagonist of muscarinic cholinergic receptors, demonstrating the role of vagal efferent signaling in this response. Vagal afferent signaling following pathogen injection was demonstrated by intense nuclear c-Fos activity in neurons of the vagal sensory ganglia and brain stem. Surprisingly, pathogen-induced bradycardia demonstrated rapid and prolonged desensitization and did not recur on repeat injection of the same organism 3 h or 3 days after the initial exposure. After recovery from the initial bradycardia, depressed heart rate variability developed in some mice and was correlated with elevated plasma cytokine levels and mortality. Our findings of decreased HRV and transient heart rate decelerations in infected mice are similar to heart rate changes described by our group in preterm neonates with sepsis. Pathogen sensing and signaling via the vagus nerve, and the desensitization of this response, may account for periods of both increased and decreased heart rate variability in sepsis.
Assuntos
Fibras Colinérgicas/fisiologia , Frequência Cardíaca/fisiologia , Infecções/fisiopatologia , Nervo Vago/fisiologia , Animais , Atropina/farmacologia , Vias Autônomas/fisiologia , Bradicardia/etiologia , Bradicardia/fisiopatologia , Tronco Encefálico/fisiologia , Candida albicans , Candidíase/sangue , Candidíase/complicações , Candidíase/fisiopatologia , Fibras Colinérgicas/efeitos dos fármacos , Citocinas/sangue , Vias Eferentes/efeitos dos fármacos , Vias Eferentes/fisiologia , Eletrocardiografia , Gânglios Sensitivos/fisiologia , Coração/efeitos dos fármacos , Coração/fisiopatologia , Infecções/sangue , Infecções/complicações , Infecções por Klebsiella/sangue , Infecções por Klebsiella/complicações , Infecções por Klebsiella/fisiopatologia , Klebsiella pneumoniae , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Proto-Oncogênicas c-fos/metabolismo , Sepse/mortalidade , Sepse/fisiopatologia , Infecções Estafilocócicas/sangue , Infecções Estafilocócicas/complicações , Infecções Estafilocócicas/fisiopatologia , Staphylococcus aureus , Telemetria , Nervo Vago/efeitos dos fármacosRESUMO
Caudal brainstem viscerosensory nuclei convey information about the body's internal state to forebrain regions implicated in feeding behavior and responses to immune challenge, and may modulate ingestive behavior following immune activation. Illness-induced appetite loss might be attributed to accentuated "satiety" pathways, activation of a distinct "danger channel" separate from satiety pathways, or both. To evaluate neural substrates that could mediate the effects of illness on ingestive behavior, we analyzed the pattern and phenotypes of medullary neurons responsive to consumption of a preferred food, sweetened milk, and to intraperitoneal lipopolysaccharide challenge that reduced sweetened milk intake. Brainstem sections were stained for c-Fos, dopamine beta-hydroxylase, phenylethanolamine-N-methyltransferase, and glucagon-like peptide-1 (GLP-1) immunoreactivity. Sweetened milk intake activated many neurons throughout the nucleus of the solitary tract (NTS), including A2 noradrenergic neurons in the caudal half of the NTS. LPS challenge activated a similar population of neurons in the NTS, in addition to rostral C2 adrenergic and mid-level A2 noradrenergic neurons in the NTS, many C1 and A1 neurons in the ventrolateral medulla, and in GLP-1 neurons in the dorsal medullary reticular nucleus. Increased numbers of activated GLP-1 neurons in the NTS were only associated with sweetened milk ingestion. Evidence for parallel processing was reflected in the parabrachial nucleus, where sweetened milk intake resulted in activation of the inner external lateral, ventrolateral and central medial portions, whereas LPS challenge induced c-Fos expression in the outer external lateral portions. Thus, signals generated in response to potentially dangerous physiological conditions seem to be propagated via specific populations of catecholaminergic neurons in the NTS and VLM, and likely include a pathway through the external lateral PBN. The data indicate that immune challenge engages multiple ascending neural pathways including both a distinct catecholaminergic "danger" pathway, and a possibly multimodal pathway derived from the NTS.
Assuntos
Bulbo/imunologia , Bulbo/fisiologia , Neurônios/imunologia , Neurônios/fisiologia , Percepção/fisiologia , Saciação/fisiologia , Animais , Contagem de Células , Comportamento de Ingestão de Líquido/fisiologia , Epinefrina/metabolismo , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Lipopolissacarídeos/toxicidade , Masculino , Vias Neurais/imunologia , Vias Neurais/fisiologia , Norepinefrina/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Núcleo Solitário/imunologia , Núcleo Solitário/fisiologiaRESUMO
Orexin neurons in the lateral hypothalamus constitute a critical component in regulation of waking, feeding, and reward-related behaviors. In this study we examined the effects of lipopolysaccharide (LPS) challenge on Fos expression in orexin neurons in rats, to determine changes during sickness in two different behavioral contexts. One cohort of rats was treated with saline or LPS during the daytime, and then tested on an elevated plus maze (EPM) or left in their home cage until sacrifice. Another cohort received LPS or saline shortly before dark onset and was sacrificed 90min into the dark period. The brains were double-stained for Fos and orexin-A immunoreactivity (both cohorts) and for Fos and histidine decarboxylase (dark period cohort). Orexin neurons were strongly activated in context of exploratory behavior (double-labeled for Fos in both medial and lateral portions). LPS challenge prior to maze exposure diminished this activation, most notably among the lateral orexin neurons. In home cage controls, LPS challenge lead to increased Fos expression, most notably in the medial orexin neurons, when compared to saline-injected home cage controls that show little or no Fos during the daytime. In the dark period, Fos expression in both orexin and histaminergic neurons was abundant, which LPS challenge strongly suppressed. These findings are consistent with the hypothesis that the orexin neurons, in conjunction with the histaminergic system, represent a potential target of the neurocircuitry that drives sickness behavior due to peripheral inflammation, likely through functional inhibition of these hypothalamic cell groups.
Assuntos
Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/toxicidade , Neurônios/metabolismo , Neuropeptídeos/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Análise de Variância , Animais , Contagem de Células , Comportamento Exploratório , Histidina Descarboxilase/metabolismo , Hipotálamo/efeitos dos fármacos , Comportamento de Doença , Imuno-Histoquímica , Masculino , Neuroimunomodulação , Neurônios/efeitos dos fármacos , Neurotransmissores/metabolismo , Orexinas , Fotoperíodo , Ratos , Ratos Sprague-DawleyRESUMO
Immune challenge induces behavioral changes including reduced ingestion of palatable food. Multiple pathways likely contribute to this effect, including viscerosensory pathways controlling hypothalamic feeding circuits or by influence on "reward" circuitry previously established to control ingestive behavior. To investigate whether the effects of immune challenge may influence this network, we compared brain activation patterns in animals trained to drink a palatable sweetened milk solution and treated systemically with either the immune stimulant lipopolysaccharide (LPS) or saline. Brain sections were processed for localization of the activation marker c-Fos in neurons of regions implicated in regulation of feeding behavior. Sweetened milk ingestion was associated with increased numbers of c-Fos positive neurons in the caudal core and shell of the nucleus accumbens (NAc), the paraventricular thalamus (PVT), central nucleus of the amygdala (CEA), the basal lateral amygdala (BLA), in orexin-A containing neurons of the lateral hypothalamus (LH), and in cocaine and amphetamine regulated transcript (CART) neurons of the arcuate hypothalamus. In LPS-treated animals sweetened milk consumption was significantly reduced, as was c-Fos induction in the hypothalamic orexin-A and CART neurons, and in the BLA. In addition, induction of c-Fos in the rostral regions of the NAc, the PVT, and CEA was increased following LPS treatment, compared to controls. The findings from this study point to a network of brain regions (LH, PVT, NAc, and BLA) previously implicated in the modulation of feeding behavior, reward, and arousal that may also contribute to neural substrates involved in the reorganization of behavioral priorities that occurs during sickness.
Assuntos
Tonsila do Cerebelo/imunologia , Ingestão de Alimentos/imunologia , Hipotálamo/imunologia , Lipopolissacarídeos/imunologia , Núcleo Accumbens/imunologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Tonsila do Cerebelo/metabolismo , Análise de Variância , Animais , Contagem de Células , Ingestão de Alimentos/efeitos dos fármacos , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/metabolismo , Imuno-Histoquímica , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Melaninas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuropeptídeos/metabolismo , Núcleo Accumbens/metabolismo , Orexinas , Hormônios Hipofisários/metabolismo , Ratos , Ratos Sprague-DawleyRESUMO
The presence of certain bacteria in the gastrointestinal tract influences behavior and brain function. For example, challenge with live Campylobacter jejuni (C. jejuni), a common food-born pathogen, reduces exploration of open arms of the plus maze, consistent with anxiety-like behavior, and activates brain regions associated with autonomic function, likely via a vagal pathway. As yet, however, little is known regarding the interface of immune sensory signals with brain substrates that mediate changes in behavioral states. To address this issue, we challenged mice with either C. jejuni or saline, and 7-8h later assessed anxiety-like behavior using the open holeboard, and used immunohistochemical detection of the protein c-Fos as an activation marker in the brain. C. jejuni treatment was associated with increased avoidance of the center regions of the holeboard, compared to saline-treated controls. Exposure to the holeboard induced activation in multiple brain regions previously implicated in anxiety-like behavior, including the lateral septum (LS), paraventricular (PVN) and dorsomedial hypothalamic nuclei (DMH), basolateral and central nuclei of the amygdala (BLA, CEA), bed nucleus of the stria terminalis (BST) and periaquiductal grey (PAG), compared to homecage controls. In C. jejuni-treated animals c-Fos induction also occurred in autonomic regions, as previously reported. The PVN, BLA, parts of the BST, medial prefrontal (mPFC) and anterior cingulate responded to both C. jejuni treatment and the holeboard, suggesting a role for these regions in the enhanced anxiety-like behavior observed. In saline-treated animals, anxiety-like behavior was predicted by activation in the CEA and BLA, whereas in C. jejuni-treated animals, c-Fos expression in the BST predicted the degree of anxiety-like behavior. These findings implicate the PVN, amygdala and BST as interfaces between gastrointestinal pathogenic challenge and brain regions that mediate behavioral responses to stress, and reinforce these nuclei as anatomical substrates by which viscerosensory stimuli can influence behavior.
Assuntos
Ansiedade , Infecções por Campylobacter/psicologia , Campylobacter jejuni , Comportamento Exploratório , Tonsila do Cerebelo/fisiopatologia , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Infecções por Campylobacter/fisiopatologia , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos , Núcleo Hipotalâmico Paraventricular/fisiopatologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Núcleos Septais/fisiopatologia , Distribuição TecidualRESUMO
Infection is associated with activation in central autonomic nuclei involved in mediating coordinated host defense responses. Aged mice showed exaggerated sickness behavior following peripheral injection of pro-inflammatory bacterial lipopolysaccharide (LPS), but is unknown whether central autonomic network responses are concomitantly increased. To assess whether aged mice exhibit enhanced neural response to LPS, we compared neural responses using c-Fos immunohistochemistry in aged BALB/c mice (22-24 months) with those of young adult peers (3-6 months). Intraperitoneal LPS challenge induced robust expression of c-Fos protein in central autonomic regions, including catecholaminergic neurons in the pons and brainstem, as well as in barrier-associated areas including the circumventricular organs. The numbers of c-Fos positive neurons were significantly greater in the aged compared to the young adult mice. These findings show age-associated enhancement of response to inflammation in the blood-brain chemosensory interfaces as well the central autonomic pathways involved in the elaboration of sickness symptoms, which may contribute to exaggerated sickness and poorer outcomes of infectious disease in the elderly.
Assuntos
Envelhecimento/fisiologia , Tronco Encefálico/citologia , Lipopolissacarídeos/administração & dosagem , Neurônios/efeitos dos fármacos , Fatores Etários , Animais , Tronco Encefálico/efeitos dos fármacos , Contagem de Células/métodos , Vias de Administração de Medicamentos , Imuno-Histoquímica/métodos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neurônios/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Immune-responsive neurons in the brainstem, primarily in the nucleus of the solitary tract (NTS) and ventrolateral medulla (VLM), contribute to a significant drive on forebrain nuclei responsible for brain-mediated host defense responses. The current study investigated the relative contribution of brainstem-derived ascending pathways to forebrain immune-responsive nuclei in the rat by means of retrograde tract tracing and c-Fos immunohistochemistry. Fluorogold was iontophoresed into the bed nucleus of stria terminalis (BST), central nucleus of the amygdala (CEA), paraventricular nucleus of the hypothalamus (PVN), and the pontine lateral parabrachial nucleus (PBL; an important component of ascending viscerosensensory pathways) followed 2 weeks later by intraperitoneal injection of lipopolysaccharide (LPS, 0.1 mg/kg) or saline. The NTS and VLM provide immune-responsive input to all four regions, via direct, predominantly catecholaminergic, projections to the PVN, the lateral BST, and the CEA, and mostly non-catecholaminergic projections to the PBL. The PBL provides a major LPS-activated input to the BST and CEA. The pattern of LPS-activated catecholaminergic projections from the VLM and NTS to the forebrain is characterized by a strong predominance of VLM input to the PVN, whereas the NTS provides a greater contribution to the BST. These findings indicate that direct and indirect pathways originate in the caudal brainstem that propagate immune-related information from the periphery with multiple levels of processing en route to the forebrain nuclei, which may allow for integration of brain responses to infection.
Assuntos
Tonsila do Cerebelo/citologia , Bulbo/citologia , Vias Neurais/citologia , Núcleo Hipotalâmico Paraventricular/citologia , Núcleos Septais/citologia , Tonsila do Cerebelo/imunologia , Tonsila do Cerebelo/metabolismo , Animais , Corantes Fluorescentes/metabolismo , Imuno-Histoquímica , Lipopolissacarídeos/imunologia , Masculino , Bulbo/imunologia , Bulbo/metabolismo , Vias Neurais/imunologia , Vias Neurais/metabolismo , Neuroimunomodulação/imunologia , Neuroimunomodulação/fisiologia , Núcleo Hipotalâmico Paraventricular/imunologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Núcleos Septais/imunologia , Núcleos Septais/metabolismo , Fibras Aferentes Viscerais/citologia , Fibras Aferentes Viscerais/imunologia , Fibras Aferentes Viscerais/metabolismoRESUMO
Symptoms of anxiety frequently occur concomitant to the development and persistence of inflammatory bowel disease (IBD) in patients. In the present study, we utilized an animal model of IBD, infection with Citrobacter rodentium, to determine whether the infection per se can drive anxiety-like behavior. Nine-week-old CF-1 male mice were challenged orally with either saline or C. rodentium. Early in the infective process (7-8 h later), mice were tested on a hole-board open field apparatus for anxiety-like behavior measurement. Immediately following behavioral testing, plasma samples were obtained for immune cytokine analysis and colons were excised for histological analysis. In additional animals, vagal ganglia were removed and processed for c-Fos protein detection. Challenge with C. rodentium significantly increased anxiety-like behavior as evidenced by avoidance of the center area and increased risk assessment behavior. Plasma levels of the cytokines IFN-gamma, TNF-alpha and IL-12 were not different. However vagal sensory ganglia from C. rodentium-treated animals evinced significantly more c-Fos protein-positive neurons, consistent with vagal afferent transmission of C. rodentium-related signals from gut to brain. Histological examination of the colon indicated a lack of overt inflammation at the 8 h post-challenge time point, indicating that the differences in behavior were unlikely to follow from inflammation-related stress. The results of the present study demonstrate that infection with C. rodentium can induce anxiety-like symptoms that are likely mediated via vagal sensory neurons.
Assuntos
Transtornos de Ansiedade/etiologia , Citrobacter rodentium , Colite/complicações , Infecções por Enterobacteriaceae/complicações , Administração Oral , Animais , Transtornos de Ansiedade/microbiologia , Comportamento Animal , Colite/microbiologia , Colo/microbiologia , Colo/patologia , Infecções por Enterobacteriaceae/microbiologia , Comportamento Exploratório/fisiologia , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Abundant evidence now supports the idea that multiple pathways or mechanisms underlie communication from the immune system to the brain. The presence of a variety of mechanisms suggests that they may each contribute something different to immunosensory signaling. For instance, brain mediated immune signal transduction is dependent upon the presence of circulating mediators whereas peripheral sensory nerves are more likely to be important early on in an infection, prior to elevation of circulating cytokines, or in local infections within the terminal fields of these nerves. To test the hypothesis that local infection in the gut activates vagal sensory neurons, we assessed expression of the neuronal activation marker c-Fos in neurons in the vagal sensory ganglia and in the primary sensory relay nucleus for the vagus, the nucleus of the solitary tract (nTS) in mice treated orally either with saline or live Campylobacter jejuni (C. jejuni). Male CF1 mice were inoculated orally with either C. jejuni or saline, and c-Fos expression in the vagal sensory neurons and brain 4-12 h later was assessed via immunohistochemistry. Oral inoculation with C. jejuni led to a significant increase in c-Fos expression in neurons bilaterally in the vagal ganglia, in the absence of elevated levels of circulating pro-inflammatory cytokines. C. jejuni treatment activated neurons in the nTS, as well as in brain regions associated with primary viscerosensory pathways and the central autonomic network. These findings provide evidence that peripheral sensory neurons contribute an early signal to the brain regarding potential pathogens.
Assuntos
Infecções por Campylobacter/imunologia , Campylobacter jejuni/imunologia , Ceco/imunologia , Neuroimunomodulação/fisiologia , Nervo Vago/fisiologia , Fibras Aferentes Viscerais/fisiologia , Animais , Encéfalo/metabolismo , Infecções por Campylobacter/sangue , Ceco/inervação , Ceco/microbiologia , Citocinas/sangue , Sistema Nervoso Entérico/fisiologia , Gânglios Autônomos/fisiologia , Masculino , Camundongos , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Infections with bacterial pathogens can induce increased anxiety-like behaviors in rodents without otherwise noticeable behavioral or physiological symptoms of sickness, as shown with the food-borne pathogen Campylobacter jejuni. This observation implicates the ability of the brain to sense, and respond to, such an infection. We tested our hypothesis that intestinal infection with the gram-negative bacterium C. jejuni leads to activation of certain brain regions that process gastro-intestinal sensory information. The induction of c-Fos protein as a marker for neuronal activation was assessed in the brains of mice inoculated orally with live C. jejuni, as compared to saline-treated controls. Upon colonization of the intestines, C. jejuni activated visceral sensory nuclei in the brainstem (the nucleus of the solitary tract and the lateral parabrachial nucleus) both one and two days after the oral challenge. In addition, increased c-Fos expression occurred in the hypothalamic paraventricular nucleus on the second day. This neural response occurred in the absence of measurable systemic immune activation, as serum levels of tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 were undetectable and/or unchanged. These findings support the notion that information about infection with C. jejuni in the gut is indeed relayed to the visceral sensory structures in the brain. The brain responses observed could contribute to changes in behavior observed after infection.
Assuntos
Encéfalo/imunologia , Infecções por Campylobacter/imunologia , Campylobacter jejuni/imunologia , Ceco/microbiologia , Neuroimunomodulação/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Análise de Variância , Animais , Biomarcadores/análise , Encéfalo/metabolismo , Ceco/imunologia , Citocinas/sangue , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos , Núcleo Hipotalâmico Paraventricular/imunologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Solitário/imunologia , Núcleo Solitário/metabolismo , Tegmento Mesencefálico/imunologia , Tegmento Mesencefálico/metabolismoRESUMO
Peripheral administration of lipopolysaccharide (LPS), a potent activator of the immune system, induces symptoms of behavioral depression, such as social withdrawal, concommitant with increases in c-Fos expression in central autonomic network nuclei. Previous studies implicated vagal visceral sensory nerves in transduction of immune-related signals relevant to for the induction of social withdrawal, a symptom of behavioral depression. Vagal sensory nerves terminate in the dorsal vagal complex (DVC) of the brainstem, a region that functions to integrate visceral signals and may also play a role in modulating arousal and affect. The objective of the current study was to determine whether the DVC contributes to immunosensory pathways driving symptoms of social withdrawal associated with LPS-induced behavioral depression, using a reversible lesion technique to temporarily inactivate the DVC. To assess the effects of DVC inactivation on LPS-induced social withdrawal and the subsequent changes in brain activation, we used behavioral assessment of social withdrawal, and analyzed c-Fos expression, a marker of neuronal activation, in the central nucleus of the amygdala (CEA), bed nucleus of the stria terminalis (BST), hypothalamic paraventricular nucleus (PVN), and ventromendial preoptic area (VMPO). Two hours following intraperitoneal LPS injection, there was a significant increase in c-Fos immunoreactivity in forebrain regions in animals treated with LPS. DVC inactivation completely blocked LPS-induced social withdrawal and dramatically reduced LPS-induced Fos expression in all four forebrain regions assessed. Collectively, these findings support the idea that the DVC acts as an immune-behavior interface between the peripheral stimuli and brain areas involved in modulating social behavior.
Assuntos
Vias Autônomas/metabolismo , Comportamento Animal/fisiologia , Bulbo/imunologia , Neuroimunomodulação/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Comportamento Social , Nervo Vago/imunologia , Reação de Fase Aguda/imunologia , Reação de Fase Aguda/metabolismo , Tonsila do Cerebelo/metabolismo , Análise de Variância , Anestésicos Locais/farmacologia , Animais , Área Postrema/citologia , Área Postrema/efeitos dos fármacos , Área Postrema/imunologia , Vias Autônomas/imunologia , Comportamento Animal/efeitos dos fármacos , Bupivacaína/farmacologia , Relação Dose-Resposta a Droga , Lipopolissacarídeos , Masculino , Bulbo/citologia , Bulbo/efeitos dos fármacos , Neurônios Aferentes/citologia , Neurônios Aferentes/efeitos dos fármacos , Neurônios Aferentes/imunologia , Núcleo Hipotalâmico Paraventricular/metabolismo , Área Pré-Óptica/metabolismo , Proteínas Proto-Oncogênicas c-fos/genética , RNA Mensageiro/análise , Ratos , Ratos Sprague-Dawley , Núcleos Septais/citologia , Núcleos Septais/efeitos dos fármacos , Núcleos Septais/imunologia , Alienação Social , Núcleo Solitário/citologia , Núcleo Solitário/efeitos dos fármacos , Núcleo Solitário/imunologia , Nervo Vago/citologia , Nervo Vago/efeitos dos fármacosRESUMO
It has recently become accepted that the activated immune system communicates to brain via release of pro-inflammatory cytokines. This review examines the possibility that pro-inflammatory cytokines (interleukins and/or tumor necrosis factor) mediate a variety of commonly studied hyperalgesic states. We will first briefly review basic immune responses and inflammation. We will then develop the concept of illness responses and provide evidence for their existence and for the dramatic changes in neural functioning that they cause. Lastly, we will examine the potential roles that both pro-inflammatory cytokines and the neural circuits that they activate may play in the hyperalgesic states produced by irritants, inflammatory agents, and nerve damage. The possibility is raised that apparently diverse hyperalgesic states may converge in the central nervous system and activate similar or identical neural circuitry.