RESUMO
The endogenous opioid system has been implicated in alcohol consumption and preference in both humans and animals. The mu opioid receptor (MOR) is expressed on multiple cells in the striatum, however little is known about the contributions of specific MOR populations to alcohol drinking behaviors. The current study used mice with a genetic deletion of MOR in cholinergic cells (ChAT-Cre/Oprm1fl/fl) to examine the role of MORs expressed in cholinergic interneurons (CINs) in home cage self-administration paradigms. Male and female ChAT-Cre/Oprm1fl/fl mice were generated and heterozygous Cre+ (knockout) and Cre- (control) mice were tested for alcohol consumption in two drinking paradigms: limited access "Drinking in the Dark" and intermittent access. Quinine was added to the drinking bottles in the DID experiment to test aversion-resistant, "compulsive" drinking. Nicotine and sucrose drinking were also assessed so comparisons could be made with other rewarding substances. Cholinergic MOR deletion did not influence consumption or preference for ethanol (EtOH) in either drinking task. Differences were observed in aversion-resistance in males with Cre + mice tolerating lower concentrations of quinine than Cre-. In contrast to EtOH, preference for nicotine was reduced following cholinergic MOR deletion while sucrose consumption and preference was increased in Cre+ (vs. Cre-) females. Locomotor activity was also greater in females following the deletion. These results suggest that cholinergic MORs participate in preference for rewarding substances. Further, while they are not required for consumption of alcohol alone, cholinergic MORs may influence the tendency to drink despite negative consequences.
Assuntos
Consumo de Bebidas Alcoólicas , Camundongos Knockout , Quinina , Receptores Opioides mu , Recompensa , Animais , Receptores Opioides mu/genética , Receptores Opioides mu/metabolismo , Masculino , Feminino , Camundongos , Quinina/farmacologia , Quinina/administração & dosagem , Consumo de Bebidas Alcoólicas/genética , Consumo de Bebidas Alcoólicas/psicologia , Nicotina/farmacologia , Etanol/farmacologia , Etanol/administração & dosagem , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/fisiologia , Neurônios Colinérgicos/metabolismo , Autoadministração , Sacarose/administração & dosagem , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Interneurônios/efeitos dos fármacos , Interneurônios/fisiologia , Interneurônios/metabolismoRESUMO
Intestinal barrier dysfunction, leaky gut, is implicated in various diseases, including irritable bowel syndrome (IBS) and neurodegenerative conditions like Alzheimer's disease. Our recent investigation revealed that basal forebrain cholinergic neurons (BFCNs), critical for cognitive function, receive signals from butyrate and orexin, playing a role in regulating intestinal barrier function through adenosine A2B signaling and the vagus. This study explores the involvement and function of brain histamine, linked to BFCNs, in the regulation of intestinal barrier function. Colonic permeability, assessed by quantifying absorbed Evans blue in rat colonic tissue, showed that histamine did not affect increased colonic permeability induced by LPS when administered subcutaneously. However, intracisternal histamine administration improved colonic hyperpermeability. Elevating endogenous histamine levels in the brain with SKF91488, a histamine N-methyltransferase inhibitor, also improved colonic hyperpermeability. This effect was abolished by intracisternal chlorpheniramine, an histamine H1 receptor antagonist, not ranitidine, an H2 receptor antagonist. The SKF91488-induced improvement in colonic hyperpermeability was blocked by vagotomy, intracisternal pirenzepine (suppressing BFCNs activity), or alloxazine (an adenosine A2B receptor antagonist). Additionally, intracisternal chlorpheniramine injection eliminated butyrate-induced improvement in colonic hyperpermeability. These findings suggest that brain histamine, acting via the histamine H1 receptor, regulates intestinal barrier function involving BFCNs, adenosine A2B signaling, and the vagus. Brain histamine appears to centrally regulate intestinal barrier function influenced by butyrate, differentiating its actions from peripheral histamine in conditions like IBS, where mast cell-derived histamine induces leaky gut. Brain histamine emerges as a potential pharmacological target for diseases associated with leaky gut, such as dementia and IBS.
Assuntos
Neurônios Colinérgicos , Colo , Histamina , Permeabilidade , Ratos Sprague-Dawley , Receptor A2B de Adenosina , Nervo Vago , Animais , Histamina/metabolismo , Histamina/farmacologia , Ratos , Masculino , Receptor A2B de Adenosina/metabolismo , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/fisiologia , Nervo Vago/efeitos dos fármacos , Nervo Vago/fisiologia , Nervo Vago/metabolismo , Colo/metabolismo , Colo/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/metabolismoRESUMO
The development of human brain is shaped by both genetic and environmental factors. Sex differences in cognitive function have been found in humans as a result of sexual dimorphism in neural information transmission. Numerous studies have reported the positive effects of education on cognitive functions. However, little work has investigated the effect of education on attenuating cognitive sex differences and the neural mechanisms behind it based on healthy population. In this study, the Wisconsin Card Sorting Test (WCST) was employed to examine sex differences in cognitive function in 135 Thai healthy subjects, and label-free quantitative proteomic method and bioinformatic analysis were used to study sex-specific neurotransmission-related protein expression profiles. The results showed sex differences in two WCST sub-scores: percentage of Total corrects and Total errors in the primary education group (Bayes factor>100) with males performed better, while such differences eliminated in secondary and tertiary education levels. Moreover, 11 differentially expressed proteins (DEPs) between men and women (FDR<0.1) were presented in both education groups, with majority of them upregulated in females. Half of those DEPs interacted directly with nAChR3, whereas the other DEPs were indirectly connected to the cholinergic pathways through interaction with estrogen. These findings provided a preliminary indication that a cholinergic-estrogen interaction relates to, and might underpin, the effect of education on attenuating cognitive sex differences in a Thai healthy population.
Assuntos
Encéfalo , Neurônios Colinérgicos , Cognição , Escolaridade , Estrogênios , Caracteres Sexuais , Feminino , Humanos , Masculino , Teorema de Bayes , Cognição/fisiologia , Testes Neuropsicológicos , Proteômica , População do Sudeste Asiático , Fatores Sexuais , Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Voluntários Saudáveis , Estrogênios/fisiologia , Neurônios Colinérgicos/fisiologiaRESUMO
The loss of neurons in parafascicular thalamus (Pf) and their inputs to dorsomedial striatum (DMS) in Lewy body disease (LBD) and Parkinson's disease dementia (PDD) have been linked to the effects of neuroinflammation. We found that, in rats, these inputs were necessary for both the function of striatal cholinergic interneurons (CINs) and the flexible encoding of the action-outcome (AO) associations necessary for goal-directed action, producing a burst-pause pattern of CIN firing but only during the remapping elicited by a shift in AO contingency. Neuroinflammation in the Pf abolished these changes in CIN activity and goal-directed control after the shift in contingency. However, both effects were rescued by either the peripheral or the intra-DMS administration of selegiline, a monoamine oxidase B inhibitor that we found also enhances adenosine triphosphatase activity in CINs. These findings suggest a potential treatment for the cognitive deficits associated with neuroinflammation affecting the function of the Pf and related structures.
Assuntos
Demência , Doença de Parkinson , Ratos , Animais , Doenças Neuroinflamatórias , Neurônios Colinérgicos/fisiologia , Doença de Parkinson/tratamento farmacológico , Corpo Estriado/fisiologia , Colinérgicos , CogniçãoRESUMO
Cholinergic interneurons are central hubs of the striatal neuronal network, controlling information processing in a behavioral-state-dependent manner. It remains unknown, however, how such state transitions influence the integrative properties of these neurons. To address this, we made simultaneous somato-dendritic recordings from identified rodent cholinergic interneurons, revealing that action potentials are initiated at dendritic sites because of a dendritic axonal origin. Functionally, this anatomical arrangement ensured that the action potential initiation threshold was lowest at axon-bearing dendritic sites, a privilege efficacy powerfully accentuated at the hyperpolarized membrane potentials achieved in cholinergic interneurons following salient behavioral stimuli. Experimental analysis revealed the voltage-dependent attenuation of the efficacy of non-axon-bearing dendritic excitatory input was mediated by the recruitment of dendritic potassium channels, a regulatory mechanism that, in turn, was controlled by the pharmacological activation of neurokinin receptors. Together, these results indicate that the neuropeptide microenvironment dynamically controls state- and compartment-dependent dendritic information processing in striatal cholinergic interneurons.
Assuntos
Colinérgicos , Corpo Estriado , Colinérgicos/farmacologia , Potenciais da Membrana/fisiologia , Potenciais de Ação/fisiologia , Peptídeos , Interneurônios/fisiologia , Neurônios Colinérgicos/fisiologiaRESUMO
Cholinergic interneurons (CINs) are essential elements of striatal circuits and functions. Although acetylcholine signaling via muscarinic receptors (mAChRs) has been well studied, more recent data indicate that postsynaptic nicotinic receptors (nAChRs) located on striatal GABAergic interneurons (GINs) are equally critical. One example is that CIN stimulation induces large disynaptic inhibition of striatal projection neurons (SPNs) mediated by nAChR activation of GINs. Although these circuits are ideally positioned to modulate striatal output, the neurons involved are not definitively identified because of an incomplete mapping of CINs-GINs interconnections. Here, we show that CINs modulate four GINs populations via an intricate mechanism involving co-activation of presynaptic and postsynaptic mAChRs and nAChRs. Using optogenetics, we demonstrate the participation of tyrosine hydroxylase-expressing GINs in the disynaptic inhibition of SPNs via heterotypic electrical coupling with neurogliaform interneurons. Altogether, our results highlight the importance of CINs in regulating GINs microcircuits via complex synaptic/heterosynaptic mechanisms.
Assuntos
Acetilcolina , Receptores Nicotínicos , Tirosina 3-Mono-Oxigenase , Corpo Estriado/fisiologia , Interneurônios/fisiologia , Colinérgicos/farmacologia , Receptores Muscarínicos , Neurônios Colinérgicos/fisiologiaRESUMO
The striatum is an essential component of the basal ganglia that is involved in motor control, action selection and motor learning. The pathophysiological changes of the striatum are present in several neurological and psychiatric disorder including Parkinson's and Huntington's diseases. The striatal cholinergic neurons are the main regulators of striatal microcircuitry. It has been demonstrated that estrogen exerts various effects on neuronal functions in dopaminergic and medium spiny neurons (MSN), however little is known about how the activity of cholinergic interneurons are influenced by estrogens. In this study we examined the acute effect of 17ß-estradiol on the function of striatal cholinergic neurons in adult mice in vitro. We also tested the effect of estrus cycle and sex on the spontaneous activity of cholinergic interneurons in the striatum. Our RNAscope experiments showed that ERα, ERß, and GPER1 receptor mRNAs are expressed in some striatal cholinergic neurons at a very low level. In cell-attached patch clamp experiments, we found that a high dose of 17ß-estradiol (100 nM) affected the spontaneous firing rate of these neurons only in old males. Our findings did not demonstrate any acute effect of a low concentration of 17ß-estradiol (100 pM) or show any association of estrus cycle or sex with the activity of striatal cholinergic neurons. Although estrogen did not induce changes in the intrinsic properties of neurons, indirect effects via modulation of the synaptic inputs of striatal cholinergic interneurons cannot be excluded.
Assuntos
Colinérgicos , Interneurônios , Masculino , Feminino , Camundongos , Animais , Interneurônios/fisiologia , Colinérgicos/farmacologia , Neurônios Colinérgicos/fisiologia , Estradiol/farmacologia , EstrogêniosRESUMO
The ability to make predictions based on stored information is a general coding strategy. A prediction error (PE) is a mismatch between expected and current events. Our memories, like ourselves, are subject to change. Thus, an acquired memory can become active and update its content or strength by a labilization-reconsolidation process. Within the reconsolidation framework, PE drives the updating of consolidated memories. In the past our lab has made key progresses showing that a blockade in the central cholinergic system during reconsolidation can cause memory impairment, while reinforcement of cholinergic activity enhances it. In the present work we determined that PE is a necessary condition for memory to reconsolidate in an inhibitory avoidance task using both male and female mice. Depending on the intensity of the unconditioned stimulus (US) used during training, a negative (higher US intensity) or positive (lower US intensity/no US) PE on a retrieval session modified the behavioral response on a subsequent testing session. Furthermore, we demonstrated that the cholinergic system modulates memory reconsolidation only when PE is detected. In this scenario administration of oxotremorine, scopolamine or nicotine after memory reactivation either enhanced or impaired memory reconsolidation in a sex-specific manner.
Assuntos
Neurônios Colinérgicos/fisiologia , Consolidação da Memória , Animais , Aprendizagem da Esquiva/fisiologia , Neurônios Colinérgicos/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Feminino , Masculino , Consolidação da Memória/efeitos dos fármacos , Consolidação da Memória/fisiologia , Camundongos , Nicotina/farmacologia , Oxotremorina/análogos & derivados , Oxotremorina/farmacologia , Receptores Colinérgicos/efeitos dos fármacos , Receptores Colinérgicos/fisiologia , Escopolamina/farmacologiaRESUMO
Human menstrual blood-derived mesenchymal stromal cells (MenSCs) have become not only an important source of stromal cells for cell therapy but also a cellular source for neurologic disorders in vitro modeling. By using culture protocols originally developed in our laboratory, we show that MenSCs can be converted into floating neurospheres (NSs) using the Fast-N-Spheres medium for 24-72 h and can be transdifferentiated into functional dopaminergic-like (DALNs, ~ 26% TH + /DAT + flow cytometry) and cholinergic-like neurons (ChLNs, ~ 46% ChAT + /VAChT flow cytometry) which responded to dopamine- and acetylcholine-triggered neuronal Ca2+ inward stimuli when cultured with the NeuroForsk and the Cholinergic-N-Run medium, respectively in a timely fashion (i.e., 4-7 days). Here, we also report a direct transdifferentiation method to induce MenSCs into functional astrocyte-like cells (ALCs) by incubation of MenSCs in commercial Gibco® Astrocyte medium in 7 days. The MSC-derived ALCs (~ 59% GFAP + /S100ß +) were found to respond to glutamate-induced Ca2+ inward stimuli. Altogether, these results show that MenSCs are a reliable source to obtain functional neurogenic cells to further investigate the neurobiology of neurologic disorders.
Assuntos
Linhagem da Célula/fisiologia , Transdiferenciação Celular/fisiologia , Neurônios Colinérgicos/fisiologia , Neurônios Dopaminérgicos/fisiologia , Menstruação/fisiologia , Células-Tronco Mesenquimais/fisiologia , Adolescente , Adulto , Células Cultivadas , Feminino , Humanos , Adulto JovemRESUMO
OBJECTIVE: Patients with myasthenia gravis associated with muscle-specific tyrosine kinase antibodies (MuSK-MG) often manifest signs of cholinergic hyperactivity with standard doses of acetylcholinesterase inhibitors (AChE-Is). Aim of the study was to investigate whether repetitive compound muscle action potential (R-CMAP), the neurophysiological correlate of cholinergic hyperactivity, was present in MuSK-MG irrespective of AChE-I treatment. METHODS: Patients with confirmed diagnosis of MuSK-MG were consecutively enrolled during follow-up visits, from January 2019 to April 2020. All these subjects underwent the same neurophysiological protocol, including motor nerve conduction studies and repetitive nerve stimulation. In patients taking pyridostigmine, neurophysiological testing was performed at least 12 hours after the last dose. For comparison, the presence of R-CMAP was investigated in 20 consecutive acetylcholine receptor antibody positive myasthenia gravis (AChR-MG) patients. RESULTS: We enrolled 25 MuSK-MG patients (20 females), aged 16-79 years at the study time, with disease duration ranging 0.6-48.8 years (median: 17.7 years). R-CMAP was detected in 12/25 (48%) MuSK-MG cases and in none of the AChR-MG controls (p = 0.0003). In the MuSK-MG population, a history of muscle cramps and fasciculations, during low-dose pyridostigmine therapy, was significantly more frequent in R-CMAP positive than in R-CMAP negative patients (100% vs 31%, p = 0.001). At the time of the study, the proportion of patients still symptomatic for MG was higher among R-CMAP positive cases (92% vs 23%, p = 0.0005). CONCLUSIONS: Cholinergic hyperactivity is a relatively common finding in MuSK-MG patients, independent of AChE-I treatment, and may constitute an intrinsic feature of the disease. SIGNIFICANCE: R-CMAP detection can represent a useful diagnostic clue for MuSK-MG and predicts poor tolerance to AChE-Is.
Assuntos
Autoanticorpos/sangue , Neurônios Colinérgicos/fisiologia , Miastenia Gravis/sangue , Miastenia Gravis/fisiopatologia , Receptores Proteína Tirosina Quinases/sangue , Receptores Colinérgicos/sangue , Acetilcolinesterase/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neurônios Colinérgicos/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Eletromiografia/métodos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/tratamento farmacológico , Estudos Retrospectivos , Adulto JovemRESUMO
Osteoarthritis (OA) poses a major health and economic burden worldwide due to an increasing number of patients and the unavailability of disease-modifying drugs. In this review, the latest understanding of the involvement of the cholinergic system in joint homeostasis and OA will be outlined. First of all, the current evidence on the presence of the cholinergic system in the normal and OA joint will be described. Cholinergic innervation as well as the non-neuronal cholinergic system are detected. In a variety of inflammatory diseases, the classic cholinergic anti-inflammatory pathway lately received a lot of attention as via this pathway cholinergic agonists can reduce inflammation. The role of this cholinergic anti-inflammatory pathway in the context of OA will be discussed. Activation of this pathway improved the progression of the disease. Secondly, chondrocyte hypertrophy plays a pivotal role in osteophyte formation and OA development; the impact of the cholinergic system on hypertrophic chondroblasts and endochondral ossification will be evaluated. Cholinergic stimulation increased chondrocyte proliferation, delayed chondrocyte differentiation and caused early mineralisation. Moreover, acetylcholinesterase and butyrylcholinesterase affect the endochondral ossification via an acetylcholine-independent pathway. Thirdly, subchondral bone is critical for cartilage homeostasis and metabolism; the cholinergic system in subchondral bone homeostasis and disorders will be explored. An increase in osteoblast proliferation and osteoclast apoptosis is observed. Lastly, current therapeutic strategies for OA are limited to symptom relief; here the impact of smoking on disease progression and the potential of acetylcholinesterase inhibitors as candidate disease-modifying drug for OA will be discussed.
Assuntos
Acetilcolina/metabolismo , Neurônios Colinérgicos/fisiologia , Articulações , Osteoartrite/metabolismo , Osteoartrite/terapia , Cistos Ósseos/patologia , Cartilagem Articular/metabolismo , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Condrócitos/patologia , Progressão da Doença , Humanos , Hipertrofia , Inflamação/patologia , Articulações/inervação , Articulações/metabolismo , Esclerose , Fumar , Membrana Sinovial/inervação , Membrana Sinovial/metabolismo , Sinovite/patologiaRESUMO
Breathing is regulated by a host of arousal and sleep-wake state-dependent neuromodulators to maintain respiratory homeostasis. Modulators such as acetylcholine, norepinephrine, histamine, serotonin (5-HT), adenosine triphosphate (ATP), substance P, somatostatin, bombesin, orexin, and leptin can serve complementary or off-setting functions depending on the target cell type and signaling mechanisms engaged. Abnormalities in any of these modulatory mechanisms can destabilize breathing, suggesting that modulatory mechanisms are not overly redundant but rather work in concert to maintain stable respiratory output. The present review focuses on the modulation of a specific cluster of neurons located in the ventral medullary surface, named retrotrapezoid nucleus, that are activated by changes in tissue CO2/H+ and regulate several aspects of breathing, including inspiration and active expiration.
Assuntos
Células Quimiorreceptoras/fisiologia , Bulbo/fisiologia , Receptores de Neurotransmissores/fisiologia , Mecânica Respiratória/fisiologia , Trifosfato de Adenosina/fisiologia , Animais , Neurônios Colinérgicos/fisiologia , Humanos , Bulbo/citologia , Receptores Purinérgicos/fisiologia , Respiração , Neurônios Serotoninérgicos/fisiologiaRESUMO
A network of cholinergic neurons in the basal forebrain innerve the forebrain and are proposed to contribute to a variety of functions including cortical plasticity, attention, and sensorimotor behavior. This study examined the contribution of the nucleus basalis cholinergic projection to the sensorimotor cortex on recovery on a skilled reach-to-eat task following photothrombotic stroke in the forelimb region of the somatosensory cortex. Mice were trained to perform a single pellet skilled reaching task and their pre and poststroke performance, from Day 4 to Day 28 poststroke, was assessed frame-by-frame by video analysis with endpoint, movement and sensorimotor integration measures. Somatosensory forelimb lesions produced impairments in endpoint and movement component measures of reaching and increased the incidence of fictive eating, a sensory impairment in mistaking a missed reach for a successful reach. Upregulated acetylcholine (ACh) release, as measured by local field potential recording, elicited via optogenetic stimulation of the nucleus basalis improved recovery of reaching and improved movement scores but did not affect sensorimotor integration impairment poststroke. The results show that the mouse cortical forelimb somatosensory region contributes to forelimb motor behavior and suggest that ACh upregulation could serve as an adjunct to behavioral therapy for acute treatment of stroke.
Assuntos
Neurônios Colinérgicos/fisiologia , Córtex Motor/fisiopatologia , Destreza Motora/fisiologia , Optogenética , Recuperação de Função Fisiológica , Córtex Somatossensorial/fisiopatologia , AVC Trombótico/fisiopatologia , Animais , Gânglios da Base/fisiologia , Comportamento Animal/fisiologia , Fenômenos Biomecânicos , Feminino , Alimentos , Membro Anterior/fisiopatologia , Luz/efeitos adversos , Masculino , CamundongosRESUMO
BACKGROUND: A pre-existing neurocognitive disorder (NCD) is a relevant factor for the outcome of surgical patients. To improve understanding of these conditions, we investigated the association between parameters of the cholinergic system and NCD. METHOD: This investigation is part of the BioCog project (www.biocog.eu), which is a prospective multicenter observational study including patients aged 65 years and older scheduled for elective surgery. Patients with a Mini-Mental State Examination (MMSE) score ≤23 points were excluded. Neurocognitive disorder was assessed according to the fifth Diagnostic and Statistical Manual of Mental Disorders criteria. The basal forebrain cholinergic system volume (BFCSV) was assessed with magnetic resonance imaging, the peripheral cholinesterase (ChE) activities with point-of-care measurements, and anticholinergic load by analyzing the long-term medication with anticholinergic scales (Anticholinergic Drug Scale [ADS], Anticholinergic Risk Scale [ARS], Anticholinergic Cognitive Burden Scale [ACBS]). The associations of BFCSV, ChE activities, and anticholinergic scales with NCD were studied with logistic regression analysis, adjusting for confounding factors. RESULTS: A total of 797 participants (mean age 72 years, 42% females) were included. One hundred and eleven patients (13.9%) fulfilled criteria for mild NCD and 82 patients (10.3%) for major NCD criteria. We found that AcetylChE activity was associated with major NCD (odds ratio [95% confidence interval]: [U/gHB] 1.061 [1.010, 1.115]), as well as ADS score ([points] 1.353 [1.063, 1.723]) or ARS score, respectively ([points] 1.623 [1.100, 2.397]) with major NCD. However, we found no association between BFCSV or ButyrylChE activity with mild or major NCD. CONCLUSIONS: AcetylChE activity and anticholinergic load were associated with major NCD. Future research should focus on the association of the cholinergic system and the development of postoperative delirium and postoperative NCD.
Assuntos
Antagonistas Colinérgicos/uso terapêutico , Neurônios Colinérgicos/fisiologia , Transtornos Neurocognitivos/fisiopatologia , Período Pré-Operatório , Acetilcolinesterase/metabolismo , Idoso , Prosencéfalo Basal/diagnóstico por imagem , Prosencéfalo Basal/efeitos dos fármacos , Prosencéfalo Basal/metabolismo , Antagonistas Colinérgicos/efeitos adversos , Neurônios Colinérgicos/efeitos dos fármacos , Neurônios Colinérgicos/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Transtornos Neurocognitivos/induzido quimicamente , Transtornos Neurocognitivos/etiologia , Transtornos Neurocognitivos/patologia , Neuroimagem , Estudos ProspectivosRESUMO
The nervous system plays an important role in cancer initiation and progression. Accumulated evidences clearly show that the sympathetic nervous system exerts stimulatory effects on carcinogenesis and cancer growth. However, the role of the parasympathetic nervous system in cancer has been much less elucidated. Whereas retrospective studies in vagotomized patients and experiments employing vagotomized animals indicate the parasympathetic nervous system has an inhibitory effect on cancer, clinical studies in patients with prostate cancer indicate it has stimulatory effects. Therefore, the aim of this paper is a critical evaluation of the available data related to the role of the parasympathetic nervous system in cancer.
Assuntos
Progressão da Doença , Neoplasias/etiologia , Sistema Nervoso Parassimpático/fisiologia , Animais , Neurônios Colinérgicos/fisiologia , Cães , Frequência Cardíaca/fisiologia , Humanos , Masculino , Camundongos , Neoplasias da Próstata/etiologia , Ratos , Estudos Retrospectivos , Sistema Nervoso Simpático/fisiologia , Vagotomia/efeitos adversos , Vagotomia/métodos , Nervo Vago/fisiologiaRESUMO
OBJECTIVE: Pediatric obsessive-compulsive disorder (OCD) sometimes appears rapidly, even overnight, often after an infection. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, or PANDAS, describes such a situation after infection with Streptococcus pyogenes. PANDAS may result from induced autoimmunity against brain antigens, although this remains unproven. Pilot work suggests that IgG antibodies from children with PANDAS bind to cholinergic interneurons (CINs) in the striatum. CIN deficiency has been independently associated with tics in humans and with repetitive behavioral pathology in mice, making it a plausible locus of pathology. The authors sought to replicate and extend earlier work and to investigate the cellular effects of PANDAS antibodies on cholinergic interneurons. METHODS: Binding of IgG to specific neurons in human and mouse brain slices was evaluated ex vivo after incubation with serum from 27 children with rigorously characterized PANDAS, both at baseline and after intravenous immunoglobulin (IVIG) treatment, and 23 matched control subjects. Binding was correlated with symptom measures. Neural activity after serum incubation was assessed in mouse slices using molecular markers and electrophysiological recording. RESULTS: IgG from children with PANDAS bound to CINs, but not to several other neuron types, more than IgG from control subjects, in three independent cohorts of patients. Post-IVIG serum had reduced IgG binding to CINs, and this reduction correlated with symptom improvement. Baseline PANDAS sera decreased activity of striatal CINs, but not of parvalbumin-expressing GABAergic interneurons, and altered their electrophysiological responses, in acute mouse brain slices. Post-IVIG PANDAS sera and IgG-depleted baseline sera did not alter the activity of striatal CINs. CONCLUSIONS: These findings provide strong evidence for striatal CINs as a critical cellular target that may contribute to pathophysiology in children with rapid-onset OCD symptoms, and perhaps in other conditions.
Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Neurônios Colinérgicos/imunologia , Corpo Estriado/imunologia , Transtorno Obsessivo-Compulsivo/imunologia , Infecções Estreptocócicas/imunologia , Animais , Doenças Autoimunes/complicações , Estudos de Casos e Controles , Criança , Pré-Escolar , Neurônios Colinérgicos/fisiologia , Corpo Estriado/fisiopatologia , Feminino , Humanos , Imunoglobulina G/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Transtorno Obsessivo-Compulsivo/complicações , Transtorno Obsessivo-Compulsivo/etiologia , Infecções Estreptocócicas/complicaçõesRESUMO
Cholinergic neurons control numerous primate-specific and sexually dimorphic brain functions. Here, we present our differentiation protocol for the closely related human female and male neuroblastoma-originated cell lines LA-N-2 and LA-N-5. Pro-cholinergic differentiation (with upregulation of choline acetyltransferase) of both lines can be achieved using neurokines such as ciliary neurotrophic factor (CNTF). Comparative RNA sequencing and mass spectrometry analyses between those two cell lines, supported by experimental intervention, will deepen our understanding of cholinergic systems in human psychiatric and neurologic disease. For complete details on the use and execution of this protocol, please refer to Lobentanzer et al. (2019).
Assuntos
Técnicas de Cultura de Células/métodos , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/fisiologia , Acetilcolina/fisiologia , Diferenciação Celular/fisiologia , Linhagem Celular Tumoral , Células Cultivadas , Colina O-Acetiltransferase/metabolismo , Fator Neurotrófico Ciliar/metabolismo , Feminino , Humanos , Masculino , Proteínas do Tecido Nervoso/fisiologia , Células-Tronco Neurais/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/fisiopatologia , Células Tumorais CultivadasRESUMO
In the brain, compact clusters of neuron cell bodies, termed nuclei, are essential for maintaining parameters of host physiology within a narrow range optimal for health. Neurons residing in the brainstem dorsal motor nucleus (DMN) project in the vagus nerve to communicate with the lungs, liver, gastrointestinal tract, and other organs. Vagus nerve-mediated reflexes also control immune system responses to infection and injury by inhibiting the production of tumor necrosis factor (TNF) and other cytokines in the spleen, although the function of DMN neurons in regulating TNF release is not known. Here, optogenetics and functional mapping reveal cholinergic neurons in the DMN, which project to the celiac-superior mesenteric ganglia, significantly increase splenic nerve activity and inhibit TNF production. Efferent vagus nerve fibers terminating in the celiac-superior mesenteric ganglia form varicose-like structures surrounding individual nerve cell bodies innervating the spleen. Selective optogenetic activation of DMN cholinergic neurons or electrical activation of the cervical vagus nerve evokes action potentials in the splenic nerve. Pharmacological blockade and surgical transection of the vagus nerve inhibit vagus nerve-evoked splenic nerve responses. These results indicate that cholinergic neurons residing in the brainstem DMN control TNF production, revealing a role for brainstem coordination of immunity.
Assuntos
Endotoxemia/fisiopatologia , Inflamação/patologia , Bulbo/fisiologia , Baço/inervação , Fatores de Necrose Tumoral/metabolismo , Nervo Vago/fisiologia , Potenciais de Ação/imunologia , Animais , Neurônios Colinérgicos/fisiologia , Modelos Animais de Doenças , Endotoxemia/imunologia , Gânglios Simpáticos/fisiologia , Humanos , Inflamação/imunologia , Lipopolissacarídeos/administração & dosagem , Lipopolissacarídeos/imunologia , Masculino , Bulbo/citologia , Camundongos , Camundongos Transgênicos , Optogenética , Ratos , Transdução de Sinais/imunologia , Baço/metabolismo , Técnicas EstereotáxicasRESUMO
Cognitive impairment of obstructive sleep apnea syndrome (OSAS) patients is related to the basal forebrain (BF) cholinergic neurons. To further investigate the effect of the excitation or inhibition of BF cholinergic neurons on cognitive ability, we employed a chronic intermittent hypoxia (CIH) mice model and implanted microinjection cannulas in the BFs for targeted intervention, finally performed the behavioral experiments and examined immunohistochemistry and biochemical changes in the BFs. The results showed that (1) CIH induced cognitive decline in mice. (2) The excitation of BF cholinergic neurons attenuated cognitive decline, while the inhibition of these neurons aggravated cognitive impairment. (3) Microinjection of adenosine into the BF aggravated cognitive decline, while caffeine improved cognitive ability. (4) CIH induced BF cholinergic neuron injury in mice. (5) The excitation of BF cholinergic neurons alleviated cholinergic neuron injury, while the inhibition of these neurons aggravated this injury. (6) Microinjection of adenosine into the BF aggravated cholinergic neuron injury, while caffeine alleviated this injury. (7) CIH induced endoplasmic reticulum stress, oxidative stress and inflammatory responses in the BFs of mice. (8) The excitation of BF cholinergic neurons mitigated endoplasmic reticulum stress, oxidative stress and inflammatory responses in the BF in mice, while the inhibition of BF cholinergic neurons worsened these responses in the BF. (9) Microinjection of adenosine into the BF aggravated endoplasmic reticulum stress, oxidative stress and the inflammatory response, while caffeine alleviated these responses. This work indicates that CIH induces BF cholinergic neuron injury through multiple pathways, including endoplasmic reticulum stress, oxidative stress and the inflammatory response, thereby leading to cognitive dysfunction in mice. BF cholinergic neurons play a vital role in these pathways, thus reducing cholinergic neuron injury and restoring cognitive function in mice. Adenosine, which is an upstream modifier of acetylcholine, also plays an important role in altering cognitive ability.
Assuntos
Neurônios Colinérgicos/fisiologia , Cognição/fisiologia , Hipóxia Encefálica/fisiopatologia , Aprendizagem em Labirinto/fisiologia , Acetilcolina/farmacologia , Adenosina/farmacologia , Animais , Apoptose/efeitos dos fármacos , Cafeína/farmacologia , Neurônios Colinérgicos/efeitos dos fármacos , Cognição/efeitos dos fármacos , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Estresse do Retículo Endoplasmático/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/fisiologiaRESUMO
As for many other adult stem cells, the behavior of hematopoietic stem and progenitor cells (HSPCs) is subjected to circadian regulatory patterns. Multiple HSPC functions, such as proliferation, differentiation or trafficking exhibit time-dependent patterns that require a tight coordination to ensure daily blood cell production. The autonomic nervous system, together with circulating hormones, relay circadian signals from the central clock-the suprachiasmatic nucleus in the brain-to synchronize HSC niche physiology according to light/darkness cycles. Research over the last 20 years has revealed how specific neural signals modulate certain aspects of circadian HSC biology. However, only recently some studies have started to decipher the cellular and molecular mechanisms that orchestrate this complex regulation in a time-dependent fashion. Here we firstly review some of the recent key findings illustrating how different neural signals (catecholaminergic or cholinergic) regulate circadian HSC egress, homing, maintenance, proliferation, and differentiation. In particular, we highlight the critical role of different neurotransmitter receptors in the bone marrow microenvironment to channel these neural signals and regulate antagonistic processes according to circadian cues and organismal demands. Then, we discuss the potential biological meaning of HSC circadian regulation and its possible utility for clinical purposes. Finally, we offer our perspective on emerging concepts in HSC chronobiology.