RESUMO
The nervous and immune systems are intricately linked1. Although psychological stress is known to modulate immune function, mechanistic pathways linking stress networks in the brain to peripheral leukocytes remain poorly understood2. Here we show that distinct brain regions shape leukocyte distribution and function throughout the body during acute stress in mice. Using optogenetics and chemogenetics, we demonstrate that motor circuits induce rapid neutrophil mobilization from the bone marrow to peripheral tissues through skeletal-muscle-derived neutrophil-attracting chemokines. Conversely, the paraventricular hypothalamus controls monocyte and lymphocyte egress from secondary lymphoid organs and blood to the bone marrow through direct, cell-intrinsic glucocorticoid signalling. These stress-induced, counter-directional, population-wide leukocyte shifts are associated with altered disease susceptibility. On the one hand, acute stress changes innate immunity by reprogramming neutrophils and directing their recruitment to sites of injury. On the other hand, corticotropin-releasing hormone neuron-mediated leukocyte shifts protect against the acquisition of autoimmunity, but impair immunity to SARS-CoV-2 and influenza infection. Collectively, these data show that distinct brain regions differentially and rapidly tailor the leukocyte landscape during psychological stress, therefore calibrating the ability of the immune system to respond to physical threats.
Assuntos
Encéfalo , Medo , Leucócitos , Neurônios Motores , Vias Neurais , Estresse Psicológico , Animais , Células da Medula Óssea/citologia , Células da Medula Óssea/imunologia , Encéfalo/citologia , Encéfalo/fisiologia , COVID-19/imunologia , Quimiocinas/imunologia , Suscetibilidade a Doenças , Medo/fisiologia , Glucocorticoides/metabolismo , Humanos , Leucócitos/citologia , Leucócitos/imunologia , Linfócitos/citologia , Linfócitos/imunologia , Tecido Linfoide/citologia , Tecido Linfoide/imunologia , Camundongos , Monócitos/citologia , Monócitos/imunologia , Neurônios Motores/citologia , Neurônios Motores/fisiologia , Neutrófilos/citologia , Neutrófilos/imunologia , Optogenética , Infecções por Orthomyxoviridae/imunologia , Núcleo Hipotalâmico Paraventricular/fisiologia , SARS-CoV-2/imunologia , Estresse Psicológico/imunologia , Estresse Psicológico/fisiopatologiaRESUMO
Tumor necrosis factor-α (TNFα) in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA) in cardiovascular disease models, but mechanisms are incompletely understood. As previously reported, bilateral PVN TNFα (0.6 pmol, 50 nL) induced acute ramping of splanchnic SNA (SSNA) that averaged +64 ± 7% after 60 min and +109 ± 17% after 120 min (P < 0.0001, n = 10). Given that TNFα can rapidly strengthen glutamatergic transmission, we hypothesized that progressive activation of ionotropic glutamate receptors is critically involved. When compared with that of vehicle (n = 5), prior blockade of PVN AMPA or NMDA receptors in anesthetized (urethane/α-chloralose) adult male Sprague-Dawley rats dose-dependently (ED50: 2,3-dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide (NBQX), 2.48 nmol; D-(-)-2-amino-5-phosphonopentanoic acid (APV), 12.33 nmol), but incompletely (Emax: NBQX, 64%; APV, 41%), attenuated TNFα-induced SSNA ramping (n = 5/dose). By contrast, combined receptor blockade prevented ramping (1.3 ± 2.1%, P < 0.0001, n = 5). Whereas separate blockade of PVN AMPA or NMDA receptors (n = 5/group) had little effect on continued SSNA ramping when performed 60 min after TNFα injection, combined blockade (n = 5) or PVN inhibition with the GABA-A receptor agonist muscimol (n = 5) effectively stalled, without reversing, the SSNA ramp. Notably, PVN TNFα increased local TNFα immunofluorescence after 120, but not 60 min. Findings indicate that AMPA and NMDA receptors each contribute to SSNA ramping to PVN TNFα, and that their collective availability and ongoing activity are required to initiate and sustain the ramping response. We conclude that acute sympathetic activation by PVN TNFα involves progressive local glutamatergic excitation that recruits downstream neurons capable of maintaining heightened SSNA, but incapable of sustaining SSNA ramping.NEW & NOTEWORTHY The proinflammatory cytokine TNFα contributes to heightened SNA in cardiovascular disease models, but mechanisms remain obscure. Here, we demonstrate that TNFα injection into the hypothalamic PVN triggers SNA ramping by mechanisms dependent on local ionotropic glutamate receptor availability, but largely independent of TNFα autoinduction. Continued SNA ramping depends on ionotropic glutamate receptor and neuronal activity in PVN, indicating that strengthening and/or increased efficacy of glutamatergic transmission is necessary for acute sympathoexcitation by PVN TNFα.
Assuntos
Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Nervos Esplâncnicos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Antagonistas de Aminoácidos Excitatórios/farmacologia , Agonistas de Receptores de GABA-A/farmacologia , Masculino , Muscimol/farmacologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Nervos Esplâncnicos/efeitos dos fármacos , Nervos Esplâncnicos/fisiologiaRESUMO
Relaxin, an ovarian polypeptide hormone, is found in the hypothalamic paraventricular nucleus (PVN) which is an important central integrative site for the control of blood pressure and sympathetic outflow. The aim of this study was to determine if superoxide anions modulate the effects of relaxin in the PVN. Experiments were performed in normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Relaxin mRNA and protein, and its receptor, relaxin family peptide receptor 1 (RXFP1) levels in PVN were 3.24, 3.17, and 3.64 times higher in SHRs than in WKY rats, respectively. Microinjection of relaxin-2 into the PVN dose-dependently increased mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA) and heart rate (HR) in both WKY rats and SHRs, although the effects on MAP (16.87⯱â¯1.99 vs. 8.97⯱â¯1.48â¯mm Hg in 100â¯nmol), RSNA (22.60⯱â¯2.15 vs. 11.77⯱â¯1.43 % in 100â¯nmol) and HR (22.85⯱â¯3.13 vs. 12.62⯱â¯2.83 beats/min in 100â¯nmol) were greater in SHRs. Oxidative stress level was enhanced after relaxin-2 microinjection into the PVN. Pretreatment with superoxide anion scavengers or NADPH oxidase inhibitor blocked, and superoxide dismutase inhibitor potentiated the effects of relaxin-2 on MAP, RSNA and HR. RXFP1 knockdown significantly attenuated the blood pressure of SHRs, and inhibited the increases of atrial natriuretic peptide, brain natriuretic peptide, collagen I, collagen III and fibronectin in the heart of SHRs. These results demonstrated that relaxin is expressed in the PVN, and contributes to hypertension and sympathetic overdrive via oxidative stress. Down-regulation of RXFP1 in the PVN could attenuate hypertension and cardiac remodeling.
Assuntos
Pressão Sanguínea/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Relaxina/farmacologia , Animais , Eletrocardiografia , Sequestradores de Radicais Livres/farmacologia , Expressão Gênica , Frequência Cardíaca/efeitos dos fármacos , Masculino , NADPH Oxidases/antagonistas & inibidores , Núcleo Hipotalâmico Paraventricular/fisiologia , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Receptores Acoplados a Proteínas G/genética , Receptores de Peptídeos/genética , Relaxina/genética , Superóxido Dismutase/antagonistas & inibidoresRESUMO
It is the heterogeneous changes of hypothalamic functions that determine the chronological sequence of aging in mammals. Recently, it was hypothesized by Cai the decrease in slow-wave sleep (SWS) resulting from skin aging as responsible for the degeneration of hypothalamic suprachiasmatic nucleus (SCN). It was soon hypothesized by the European people in television that the increase in body fat as responsible for the degeneration of male preoptic sexually dimorphic nucleus (SDN-POA), via the aromatase converting testosterone to estradiol as proposed by Cohen. It is the hypothalamic paraventricular nucleus (PVN) that remains unchanged in neuron number during aging for psychological stress. In this chapter, it is briefly reviewed more manifestations of hypothalamic related mammalian aging processes, including (1) the aging of ovary by lipid, estradiol and hypothalamus; (2) the aging of muscle, stomach, intestine, thymus, and the later aging of brain, regulated by growth hormone/insulin-like growth factor 1(GH/IGF1); (3) the cardiovascular hypertension from PVN activation, the bone and other peripheral aging by psychological stress, and that of kidney by vasopressin. It is classified these aging processes by the primary regulation from one of the three hypothalamic nuclei, although still necessary to investigate and supplement their secondary regulation by the hypothalamic nuclei in future. It is the hypothalamic structural changes that shift the functional balance among these three hypothalamic systems toward aging.
Assuntos
Hipotálamo , Núcleo Supraquiasmático , Envelhecimento/fisiologia , Animais , Estradiol , Feminino , Humanos , Hipotálamo/fisiologia , Masculino , Núcleo Hipotalâmico Paraventricular/fisiologia , Núcleo Supraquiasmático/fisiologiaRESUMO
Chemical stimulation of kidney causes sympathetic activation and pressor responses in rats. The excitatory renal reflex (ERR) is mediated by angiotensin type 1 receptor (AT1R) and superoxide anions in hypothalamic paraventricular nucleus (PVN). The aim of this study is to determine whether interleukin-1ß (IL-1ß) in the PVN mediates the ERR, and whether the IL-1ß production in the PVN is dependent on the AT1R-superoxide anion signaling. Experiments were performed in adult rats under anesthesia. The ERR was induced by renal infusion of capsaicin, and evaluated by the responses of the contralateral renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP). Inhibition of IL-1ß production with MCC950 in the PVN dose-dependently inhibited the capsaicin-induced ERR and sympathetic activation. The PVN microinjection of IL-1 receptor antagonist IL-1Ra or specific IL-1ß antibody abolished the capsaicin-induced ERR, while IL-1ß enhanced the ERR. Renal infusion of capsaicin promoted p65-NFκB phosphorylation and IL-1ß production in the PVN, which were prevented by PVN microinjection of NADPH oxidase inhibitor apocynin or the superoxide anion scavenger tempol. The PVN microinjection of NFκB inhibitor BMS-345541 abolished the capsaicin induced-ERR and IL-1ß production, but not the NADPH oxidase activation and superoxide anion production. Furthermore, capsaicin-induced p65-NFκB phosphorylation and IL-1ß production in the PVN were prevented by AT1R antagonist losartan, or angiotensin converting enzyme inhibitor captopril. These results indicate that capsaicin-induced ERR and sympathetic activation are mediated by IL-1ß in the PVN. The IL-1ß production in the PVN is dependent on the AT1R-mediated superoxide anion generation and NFκB activation.
Assuntos
Interleucina-1beta/metabolismo , Rim/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Reflexo , Acetofenonas/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Animais , Pressão Sanguínea , Capsaicina/farmacologia , Inibidores Enzimáticos/farmacologia , Furanos/farmacologia , Imidazóis/farmacologia , Indenos/farmacologia , Rim/inervação , Losartan/farmacologia , Masculino , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Quinoxalinas/farmacologia , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Angiotensina/metabolismo , Sulfonamidas/farmacologia , Superóxidos/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiologia , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/metabolismoRESUMO
Estradiol derived from neural aromatization of testosterone plays a key role in the organization and activation of neural structures underlying male behaviors. This study evaluated the contribution of the estrogen receptor (ER) ß in estradiol-induced modulation of social and mood-related behaviors by using mice lacking the ERß gene in the nervous system. Mutant males exhibited reduced social interaction with same-sex congeners and impaired aggressive behavior. They also displayed increased locomotor activity, and reduced or unaffected anxiety-state level in three paradigms. However, when mice were exposed to unescapable stress in the forced swim and tail suspension tests, they spent more time immobile and a reduced time in swimming and climbing. These behavioral alterations were associated with unaffected circadian and restraint stress-induced corticosterone levels, and unchanged number of tryptophan hydroxylase 2-immunoreactive neurons in the dorsal raphe. By contrast, reduced mRNA levels of oxytocin and arginine-vasopressin were observed in the bed nucleus of stria terminalis, whereas no changes were detected in the hypothalamic paraventricular nucleus. The neural ERß is thus involved to different extent levels in social and mood-related behaviors, with a particular action on oxytocin and arginine-vasopressin signaling pathways of the bed nucleus of stria terminalis, yet the involvement of other brain areas cannot be excluded.
Assuntos
Afeto/fisiologia , Agressão/fisiologia , Ansiedade/genética , Receptor beta de Estrogênio/deficiência , Animais , Ansiedade/psicologia , Arginina Vasopressina/metabolismo , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Estradiol/metabolismo , Receptor beta de Estrogênio/genética , Humanos , Locomoção/genética , Masculino , Camundongos , Camundongos Knockout , Mutação , Neurônios/metabolismo , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Núcleos Septais/citologia , Núcleos Septais/fisiologia , Transdução de Sinais/fisiologia , Testosterona/metabolismoRESUMO
Myocardial infarction (MI) is a leading cause of death worldwide. For those who survive the acute insult, the progressive dilation of the ventricle associated with chronic heart failure is driven by an adverse increase in circulating levels of the antidiuretic hormone, vasopressin, which is secreted from hypothalamic supraoptic (SON) and paraventricular nuclei (PVN) nerve terminals. Although increased vasopressin neuronal activity has been demonstrated in the latter stages of chronic heart failure, we hypothesised that vasopressin neurones become activated immediately following an acute MI. Male Sprague-Dawley rats were anaesthetised and an acute MI was induced by ligation of the left anterior descending coronary artery. After 90 minutes of myocardial ischaemia, brains were collected. Dual-label immunohistochemistry was used to quantify the expression of Fos protein, a marker of neuronal activation, within vasopressin- or oxytocin-labelled neurones of the hypothalamic PVN and SON. Fos protein and tyrosine hydroxylase within the brainstem were also quantified. The results obtained show that the expression of Fos in both vasopressin and oxytocin neurones of the PVN and SON was significantly elevated as soon as 90 minutes post-MI compared to sham rats. Moreover, Fos protein was also elevated in tyrosine hydroxylase neurones in the nucleus tractus solitarius and rostral ventrolateral medulla of MI rats than sham rats. We conclude that magnocellular vasopressin and oxytocin neuronal activation occurs immediately following acute MI, rather than in the later stages of chronic heart failure. Therefore, prompt vasopressin antagonist therapy as an adjunct treatment for acute MI may impede the progression of ventricular dilatation, which remains a key adverse hallmark of chronic heart failure.
Assuntos
Infarto do Miocárdio/fisiopatologia , Neurônios/fisiologia , Ocitocina/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Núcleo Supraóptico/fisiologia , Vasopressinas/fisiologia , Animais , Tronco Encefálico/fisiologia , Oclusão Coronária/fisiopatologia , Masculino , Proteínas Proto-Oncogênicas c-fos/biossíntese , Ratos , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
Activation of corticotropin-releasing hormone (CRH) type 2 receptors (CRHR2) in the nucleus of the solitary tract (NTS) contributes to the development of hypertension, but the source of CRH inputs to the NTS that increases blood pressure remains unknown. This study tested the hypothesis that activation of CRH-containing projections from the paraventricular nucleus of the hypothalamus (PVN) to the NTS increase blood pressure. We expressed channelrhodopsin 2 (ChR2), a light-sensitive ion channel, into CRH-containing neurons in the PVN. This was achieved by injecting Cre-inducible virus expressing ChR2 into the PVN of CRH-Cre mice. CRH-Cre mice are genetically modified mice expressing Cre recombinase only in neurons producing CRH. We found that optogenetic stimulation of CRH-containing somas in the PVN or CRH-containing fibers in the NTS originating from the PVN significantly increased blood pressure and heart rate. Microinjection of K-41498 (CRHR2 antagonist) into the NTS attenuated the pressor and tachycardiac responses induced by optogenetic stimulation of CRH-containing somas in the PVN. In vitro loose-patch recordings revealed that optogenetic stimulation of CRH-containing fibers in the NTS originating from the PVN significantly increased the discharge frequency of NTS neurons. This effect was attenuated by pretreatment of K-41498 and was abolished by pretreatment of kynurenic acid (nonselective glutamate receptor antagonist). These results suggest that activation of PVN-NTS CRH-containing projections increases blood pressure and heart rate. The cardiovascular responses may be mediated at least in part by the corelease of CRH and glutamate from NTS CRH-containing axons originating from the PVN. NEW & NOTEWORTHY Optogenetic stimulation of paraventricular nucleus of the hypothalamus (PVN) corticotropin-releasing hormone (CRH)-containing somas or nucleus of the solitary tract (NTS) CRH-containing fibers originating from the PVN increased blood pressure and heart rate. Corelease of CRH and glutamate from NTS CRH-containing axons originating from the PVN may contribute to the pressor and tachycardiac responses elicited by optogenetic stimulation of PVN CRH-containing somas.
Assuntos
Pressão Sanguínea , Hormônio Liberador da Corticotropina/metabolismo , Neurônios/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Núcleo Solitário/fisiologia , Proteínas de Anfíbios/farmacologia , Animais , Channelrhodopsins/antagonistas & inibidores , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Frequência Cardíaca , Ácido Cinurênico/farmacologia , Masculino , Camundongos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Optogenética , Núcleo Hipotalâmico Paraventricular/citologia , Hormônios Peptídicos/farmacologia , Núcleo Solitário/citologiaRESUMO
Anxiety disorders represent one of the most prevalent mental disorders in today's society and early adversity has been identified as major contributor to anxiety-related pathologies. Serotonin (5-hydroxytryptamine, 5-HT) is implicated in mediating the effects of early-life events on anxiety-like behaviours. In order to further elucidate the interaction of genetic predisposition and adversity in early, developmental stages on anxiety-related behaviours, the current study employed tryptophan hydroxylase 2 (Tph2)-deficient female mice, as a model for lifelong brain 5-HT synthesis deficiency. Offspring of this line were exposed to maternal separation (MS) and tested, in the open-field (OF) or the dark-light box (DLB). Subsequently, neural activity was assessed, using c-Fos immunohistochemistry. In the DLB, MS rescued the observed decrease in activity in the light compartment of homozygous Tph2-deficient mice and furthermore increased the incidence of escape-related jumps in animals of the same genotype. In the OF, MS increased escape-related behaviours in homo- and heterozygous Tph2-deficient offspring. On the neural level, both behavioural tests evoked a distinct activation pattern, as shown by c-Fos immunohistochemistry. Exposure to the DLB resulted in Tph2-dependent activation of paraventricular nucleus and basolateral amygdala, while OF exposure led to a specific activation in lateral amygdala of maternally separated animals and a Tph2 genotype- and MS-dependent activation of the ventrolateral and dorsolateral periaqueductal grey. Taken together, our findings suggest that MS promotes active responses to aversive stimuli, dependent on the availability of brain 5-HT. These effects might be mediated by the distinct activation of anxiety-relevant brain regions, due to the behavioural testing.
Assuntos
Ansiedade/fisiopatologia , Privação Materna , Triptofano Hidroxilase/fisiologia , Tonsila do Cerebelo/fisiologia , Animais , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Feminino , Camundongos , Camundongos Knockout , Núcleo Hipotalâmico Paraventricular/fisiologia , Substância Cinzenta Periaquedutal/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Serotonina/deficiência , Serotonina/fisiologia , Triptofano Hidroxilase/genéticaRESUMO
KEY POINTS: Causal relationships between central cardiovascular pathways and sympathetic vasomotor tone have not been evidenced. This study aimed to verify the sympathoexcitatory role of hypothalamic paraventricular nucleus neurons that project to the rostral ventrolateral medulla (PVN-RVLM neurons). By using optogenetic techniques, we demonstrated that stimulation of PVN-RVLM glutamatergic neurons increased renal sympathetic nerve activity and arterial pressure via, at least in part, stimulation of RVLM C1 neurons in rats. This monosynaptic pathway may function in acute sympathetic adjustments to stressors and/or be a component of chronic sympathetic hyperactivity in pathological conditions such as heart failure. ABSTRACT: The rostral ventrolateral medulla (RVLM), which is known to play an important role in regulating sympathetic vasomotor tone, receives axonal projections from the hypothalamic paraventricular nucleus (PVN). However, no studies have proved that excitation of the PVN neurons that send axonal projections to the RVLM (PVN-RVLM neurons) causes sympathoexcitation. This study aimed to directly examine the sympathoexcitatory role of PVN-RVLM neurons. Male rats received microinjections into the PVN with an adeno-associated virus (AAV) vector that encoded a hybrid of channelrhodopsin-2/1 with the reporter tdTomato (ChIEF-tdTomato), or into the RVLM with a retrograde AAV vector that encoded a channelrhodopsin with green fluorescent protein (ChR2-GFPretro ). Under anaesthesia with urethane and α-chloralose, photostimulation (473 nm wavelength) of PVN-RVLM neurons, achieved by laser illumination of either RVLM of ChIEF-tdTomato rats (n = 8) or PVN of ChR2-GFPretro rats (n = 4), elicited significant renal sympathoexcitation. Immunofluorescence confocal microscopy showed that RVLM adrenergic C1 neurons of ChIEF-tdTomato rats were closely associated with tdTomato-labelled, PVN-derived axons that contained vesicular glutamate transporter 2. In another subset of anaesthetized ChIEF-tdTomato rats (n = 6), the renal sympathoexcitation elicited by photostimulation of the PVN was suppressed by administering ionotropic glutamate receptor blockers into the RVLM. These results demonstrate that excitation of PVN-RVLM glutamatergic neurons leads to sympathoexcitation via, at least in part, stimulation of RVLM C1 neurons.
Assuntos
Bulbo/fisiologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Sistema Nervoso Simpático/fisiologia , Animais , Axônios/fisiologia , Pressão Sanguínea , Ácido Glutâmico/metabolismo , Rim/fisiologia , Masculino , Optogenética , Ratos , Ratos Sprague-DawleyRESUMO
'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZGABA) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZGABA neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZGABA transmission phase-dependently increases aggression. Finally, SPZGABA-recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression.
Assuntos
Agressão/fisiologia , Ritmo Circadiano/fisiologia , Hipotálamo/fisiologia , Vias Neurais/fisiologia , Animais , Mapeamento Encefálico , Corticosterona/sangue , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipotálamo/citologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Vias Neurais/citologia , Optogenética , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Núcleo Supraquiasmático/fisiologia , Peptídeo Intestinal Vasoativo/fisiologia , Núcleo Hipotalâmico Ventromedial/citologia , Núcleo Hipotalâmico Ventromedial/fisiologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
Apelin is a novel endogenous active peptide. The aim of this study is to investigate whether apelin in the paraventricular nucleus (PVN) can improve the cardiac function in rats subjected to thoracic surgery trauma, and whether it is involved in the protective effect of electro-acupuncture (EA). Sprague-Dawley rats were randomly divided into non-stressed group (control), thoracic surgical trauma stressed group (trauma) and bilateral Neiguan EA applied on thoracic surgical trauma stressed group (trauma + EA-PC 6). The mRNA expressions of apelin receptor (APJR) and apelin in the PVN were detected by real time-PCR. The exogenous apelin-13 (6 mmol/L, 0.1 µL) was microinjected into the rat PVN in the thoracic trauma group, and the effects of apelin-13 on the blood pressure (BP), heart rate (HR) and the discharge of rostral ventrolateral medulla (RVLM) neurons were observed through the simultaneous recording technology by polygraph. The results showed that the APJR mRNA expression was significantly decreased in the rats of trauma group as compared with that in the control group (P < 0.05), and a decline trend of apelin mRNA expression was also observed. EA application at bilateral Neiguan acupoints partially recovered the decline of APJR and apelin mRNA expression by the treatment of thoracic trauma. Both mean arterial pressure and HR in the thoracic surgical trauma group were significantly increased by the microinjection of exogenous apelin-13 into the PVN (P < 0.05), and the single-unit discharge rate of RVLM neurons also had an increasing trend. These results suggest that apelin in the PVN can improve the cardiac function of thoracic surgical trauma rats, and may be involved in the protective effects of EA.
Assuntos
Apelina/fisiologia , Eletroacupuntura , Núcleo Hipotalâmico Paraventricular/fisiologia , Procedimentos Cirúrgicos Torácicos , Animais , Receptores de Apelina/fisiologia , Pressão Sanguínea , Frequência Cardíaca , Peptídeos e Proteínas de Sinalização Intercelular/administração & dosagem , Bulbo/fisiologia , Neurônios , Ratos , Ratos Sprague-DawleyRESUMO
Light synchronizes the body's circadian rhythms by modulating the master clock located in the suprachiasmatic nucleus (SCN) of the hypothalamus. In modern lifestyles that run counter to normal circadian rhythms, the extended and/or irregular light exposure impairs circadian rhythms and, consequently, promotes feeding and metabolic disorders. However, the neuronal pathway through which light is coupled to feeding behavior is less elucidated. The present study employed the light exposure during the dark phase of the day in rats and observed its effect on neuronal activity and feeding behavior. Light exposure acutely suppressed food intake and elevated c-Fos expression in the AVP neurons of SCN and the oxytocin (Oxt) neurons of paraventricular nucleus (PVN) in the hypothalamus. The light-induced suppression of food intake was abolished by blockade of the Oxt receptor in the brain. Retrograde tracer analysis demonstrated the projection of SCN AVP neurons to the PVN. Furthermore, intracerebroventricular injection of AVP suppressed food intake and increased c-Fos in PVN Oxt neurons. Intra-PVN injection of AVP exerted a stronger anorexigenic effect than intracerebroventriclar injection. AVP also induced intracellular Ca2+ signaling and increased firing frequency in Oxt neurons in PVN slices. These results reveal the novel neurocircuit from SCN AVP to PVN Oxt that relays light reception to inhibition of feeding behavior. This light-induced neurocircuit may serve as a pathway for forming the circadian feeding rhythm and linking irregular light exposure to arrhythmic feeding and, consequently, obesity and metabolic diseases.
Assuntos
Arginina Vasopressina/metabolismo , Comportamento Alimentar/fisiologia , Luz , Ocitocina/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Núcleo Supraquiasmático/metabolismo , Animais , Arginina Vasopressina/farmacologia , Arginina Vasopressina/fisiologia , Sinalização do Cálcio/efeitos dos fármacos , Sinalização do Cálcio/fisiologia , Ritmo Circadiano/fisiologia , Comportamento Alimentar/efeitos dos fármacos , Hipotálamo/metabolismo , Hipotálamo/fisiologia , Inibição Psicológica , Masculino , Vias Neurais , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ocitocina/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Wistar , Receptores de Ocitocina , Núcleo Supraquiasmático/fisiologiaRESUMO
BACKGROUND AND PURPOSE: Neuromedin U (NmU) may be a novel target for obesity treatment owing to its anorectic and energy expenditure enhancing effects. Although two receptors, NMU1 and NMU2, are both responsible for the NmU-mediated anti-obesity effects, the receptor agonist with the most appropriate profiles for treating obesity and diabetes in terms of efficacy and safety is as yet unknown. Thus, we developed and evaluated novel NMU1/2 receptor-selective agonists. EXPERIMENTAL APPROACH: Efficacy and safety were assessed in mice with diet-induced obesity (DIO) and those with leptin-deficient diabetes (ob/ob) through repeated peripheral administration of selective agonists to NMU1 (NMU-6102) and NMU2 (NMU-2084), along with non-selective NMU1/2 agonists (NMU-0002 and NMU-6014). We also performed immunohistochemistry for c-Fos protein expression in the brain to probe their mechanisms of action. KEY RESULTS: Although both non-selective NMU1/2 agonists and the NMU2-selective agonist had high efficacy compared with the NMU1-selective agonist, only the NMU2-selective agonist led to relatively low adverse effects, such as diarrhoea, in DIO mice. However, the non-selective NMU1/2 agonist and the NMU1-selective agonist, but not the NMU2-selective agonist, were effective in diabetic ob/ob mice. Mechanistically, NMU2-selective agonists preferentially activate pro-opiomelanocortin neurons in the hypothalamic arcuate nucleus but not in the paraventricular nucleus. CONCLUSIONS AND IMPLICATIONS: These results suggest that an NMU2 receptor-selective agonist may be a well-balanced drug for the treatment of obesity and that an NMU1 receptor-selective agonist may also be beneficial for treating obesity and diabetes once its side effects are minimized.
Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Obesidade/tratamento farmacológico , Oligopeptídeos/efeitos adversos , Oligopeptídeos/uso terapêutico , Receptores de Neurotransmissores/agonistas , Animais , Núcleo Arqueado do Hipotálamo/fisiologia , Encéfalo/metabolismo , Masculino , Camundongos , Núcleo Hipotalâmico Paraventricular/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
OBJECTIVE: Leptin is a cytokine produced by adipose tissue that acts mainly on the hypothalamus to regulate appetite and energy homeostasis. Previous studies revealed that the leptin receptor is expressed not only in neurons, but also in glial cells. Microglia are resident immune cells in the brain that play an essential role in immune defense and neural network development. Previously we reported that microglial morphology and cytokine production are changed in the leptin receptor deficient db/db mouse, suggesting that leptin's central effects on metabolic control might involve signaling through microglia. In the current study, we aimed to uncover the role of leptin signaling in microglia in systemic metabolic control. METHODS: We generated a mouse model with leptin receptor deficiency, specifically in the myeloid cells, to determine the role of microglial leptin signaling in the development of metabolic disease and to investigate microglial functions. RESULTS: We discovered that these mice have increased body weight with hyperphagia. In the hypothalamus, pro-opiomelanocortin neuron numbers in the arcuate nucleus (ARC) and α-MSH projections from the ARC to the paraventricular nucleus (PVN) decreased, which was accompanied by the presence of less ramified microglia with impaired phagocytic capacity in the PVN. CONCLUSIONS: Myeloid cell leptin receptor deficient mice partially replicate the db/db phenotype. Leptin signaling in hypothalamic microglia is important for microglial function and a correct formation of the hypothalamic neuronal circuit regulating metabolism.
Assuntos
Núcleo Arqueado do Hipotálamo/metabolismo , Hiperfagia/genética , Células Mieloides/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Receptores para Leptina/deficiência , Aumento de Peso , Animais , Núcleo Arqueado do Hipotálamo/citologia , Núcleo Arqueado do Hipotálamo/fisiologia , Células Cultivadas , Camundongos , Microglia/metabolismo , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Fagocitose , Receptores para Leptina/genética , Receptores para Leptina/metabolismoRESUMO
Neuropeptides, such as neuropeptide S (NPS) and oxytocin (OXT), represent potential options for the treatment of anxiety disorders due to their potent anxiolytic profile. In this study, we aimed to reveal the mechanisms underlying the behavioral action of NPS, and present a chain of evidence that the effects of NPS within the hypothalamic paraventricular nucleus (PVN) are mediated via actions on local OXT neurons in male Wistar rats. First, retrograde studies identified NPS fibers originating in the brainstem locus coeruleus, and projecting to the PVN. FACS identified prominent NPS receptor expression in PVN-OXT neurons. Using genetically encoded calcium indicators, we further demonstrated that NPS reliably induces a transient increase in intracellular Ca2+ concentration in a subpopulation of OXT neurons, an effect mediated by NPS receptor. In addition, intracerebroventricular (i.c.v.) NPS evoked a significant somatodendritic release of OXT within the PVN as assessed by microdialysis in combination with a highly sensitive radioimmunoassay. Finally, we could show that the anxiolytic effect of NPS seen after i.c.v. or intra-PVN infusion requires responsive OXT neurons of the PVN and locally released OXT. Thus, pharmacological blockade of OXT receptors as well as chemogenetic silencing of OXT neurons within the PVN prevented the effect of synthetic NPS. In conclusion, our results indicate a significant role of the OXT system in mediating the effects of NPS on anxiety, and fill an important gap in our understanding of brain neuropeptide interactions in the context of regulation of emotional behavior within the hypothalamus.SIGNIFICANCE STATEMENT Given the rising scientific interest in neuropeptide research in the context of emotional and stress-related behaviors, our findings demonstrate a novel intrahypothalamic mechanism involving paraventricular oxytocin neurons that express the neuropeptide S receptor. These neurons respond with transient Ca2+ increase and somatodendritic oxytocin release following neuropeptide S stimulation. Thereby, oxytocin neurons seem essential for neuropeptide S-induced anxiolysis, as this effect was blocked by pharmacological and chemogenetic inhibition of the oxytocin system.
Assuntos
Ansiedade/fisiopatologia , Neuropeptídeos/fisiologia , Ocitocina/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Receptores de Ocitocina/fisiologia , Animais , Transporte Axonal , Proteínas de Bactérias/análise , Sinalização do Cálcio/fisiologia , Dependovirus/genética , Comportamento Exploratório/efeitos dos fármacos , Genes Reporter , Vetores Genéticos , Proteínas Luminescentes/análise , Masculino , Microdiálise , Atividade Motora/efeitos dos fármacos , Neuropeptídeos/farmacologia , Ocitocina/agonistas , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Ratos , Ratos Wistar , Receptores de Neuropeptídeos/efeitos dos fármacos , Receptores de Neuropeptídeos/fisiologia , Receptores de Ocitocina/antagonistas & inibidores , Transmissão Sináptica/efeitos dos fármacos , Proteína Vermelha FluorescenteRESUMO
Glucagon-like Peptide 1 (GLP-1)-expressing neurons in the hindbrain send robust projections to the paraventricular nucleus of the hypothalamus (PVN), which is involved in the regulation of food intake. Here, we describe that stimulation of GLP-1 afferent fibers within the PVN is sufficient to suppress food intake independent of glutamate release. We also show that GLP-1 receptor (GLP-1R) activation augments excitatory synaptic strength in PVN corticotropin-releasing hormone (CRH) neurons, with GLP-1R activation promoting a protein kinase A (PKA)-dependent signaling cascade leading to phosphorylation of serine S845 on GluA1 AMPA receptors and their trafficking to the plasma membrane. Finally, we show that postnatal depletion of GLP-1R in the PVN increases food intake and causes obesity. This study provides a comprehensive multi-level (circuit, synaptic, and molecular) explanation of how food intake behavior and body weight are regulated by endogenous central GLP-1. VIDEO ABSTRACT.
Assuntos
Hormônio Liberador da Corticotropina/fisiologia , Ingestão de Alimentos/fisiologia , Peptídeo 1 Semelhante ao Glucagon/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Receptores de AMPA/fisiologia , Animais , Células Cultivadas , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Receptor do Peptídeo Semelhante ao Glucagon 1/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/fisiologia , Fosforilação , Receptores de AMPA/metabolismo , Transdução de Sinais/fisiologiaRESUMO
Stress-induced hyperglycemia is a fundamental adaptive response that mobilizes energy stores in response to threats. Here, our examination of the contributions of the central catecholaminergic (CA) neuronal system to this adaptive response revealed that CA neurons in the ventrolateral medulla (VLM) control stress-induced hyperglycemia. Ablation of VLM CA neurons abolished the hyperglycemic response to both physical and psychological stress, whereas chemogenetic activation of these neurons was sufficient to induce hyperglycemia. We further found that CA neurons in the rostral VLM, but not those in the caudal VLM, cause hyperglycemia via descending projections to the spinal cord. Monosynaptic tracing experiments showed that VLM CA neurons receive direct inputs from multiple stress-responsive brain areas. Optogenetic studies identified an excitatory PVN-VLM circuit that induces hyperglycemia. This study establishes the central role of VLM CA neurons in stress-induced hyperglycemia and substantially expands our understanding of the central mechanism that controls glucose metabolism.
Assuntos
Glicemia/metabolismo , Catecolaminas/metabolismo , Hiperglicemia/metabolismo , Bulbo/metabolismo , Núcleo Hipotalâmico Paraventricular/metabolismo , Estresse Fisiológico/fisiologia , Estresse Psicológico/metabolismo , Animais , Lipopolissacarídeos , Bulbo/fisiologia , Camundongos , Vias Neurais/fisiologia , Núcleo Hipotalâmico Paraventricular/fisiologia , Proteínas Proto-Oncogênicas c-fos/metabolismoRESUMO
Abstract Background: Isotonic blood volume expansion (BVE) induced alterations of sympathetic and parasympathetic activity in the heart and blood vessels, which can be modulated by serotonergic pathways. Objective: To evaluate the effect of saline or serotonergic agonist (DOI) administration in the hypothalamic paraventricular nucleus (PVN) on cardiovascular responses after BVE. Methods: We recorded pulsatile blood pressure through the femoral artery to obtain the mean arterial pressure (MAP), systolic (SBP) and diastolic blood pressure (DBP), heart rate (HR) and the sympathetic-vagal ratio (LF/HF) of Wistar rats before and after they received bilateral microinjections of saline or DOI into the PVN, followed by BVE. Results: No significant differences were observed in the values of the studied variables in the different treatments from the control group. However, when animals are treated with DOI followed by BVE there is a significant increase in relation to the BE control group in all the studied variables: MBP (114.42±7.85 vs 101.34±9.17); SBP (147.23±14.31 vs 129.39±10.70); DBP (98.01 ±4.91 vs 87.31±8.61); HR (421.02±43.32 vs 356.35±41.99); and LF/HF ratio (2.32±0.80 vs 0.27±0.32). Discussion: The present study showed that the induction of isotonic BVE did not promote alterations in MAP, HR and LF/HF ratio. On the other hand, the injection of DOI into PVN of the hypothalamus followed by isotonic BVE resulted in a significant increase of all variables. Conclusion: These results suggest that serotonin induced a neuromodulation in the PVN level, which promotes an inhibition of the baroreflex response to BVE. Therefore, the present study suggests the involvement of the serotonergic system in the modulation of vagal reflex response at PVN in the normotensive rats.
Resumo Fundamento: Expansão de volume extracelular (EVEC) promove alterações da atividade simpática e parassimpática no coração e vasos sanguíneos, os quais podem ser moduladas por vias serotoninérgicas. Objetivo: Avaliar o efeito da administração de salina ou agonista serotoninérgico (DOI) nos núcleos paraventriculares hipotalâmico (NPV) sobre respostas cardiovasculares após EVEC. Métodos: Foram obtidos registros da pressão arterial pulsátil, por meio da artéria femoral, para obtenção dos valores da pressão arterial média (PAM), sistólica (PAS), diastólica (PAD), frequência cardíaca (FC) e razão simpático-vagal (LF/HF) de ratos Wistar antes e após receberem microinjeções bilaterais no NPV de salina ou DOI seguida de EVEC. Resultados: Não foram observadas diferenças significativas dos valores das variáveis estudadas nos diferentes tratamentos do grupo controle. Entretanto, quando os animais são tratados com DOI seguida de EVEC ocorre aumento significativo em relação ao grupo controle com EVEC em todas as variáveis estudadas: PAM (114,42±7,85 vs 101,34±9,17), PAS (147,23±14,31 vs 129,39±10,70), PAD (98,01 ±4,91 vs 87,31±8,61), FC (421,02±43,32 vs 356,35±41,99) e LF/HF (2,32±0,80 vs 0,27±0,32). Discussão: O presente estudo mostrou que a indução de EVEC isotônica não promoveu alterações na PAM, PAD, PAS, FC e LF/HF. Por outro lado, os animais que receberam microinjeção de DOI no NPV seguida de EVEC apresentaram aumento significativo de todas as variáveis. Conclusão: Esses resultados sugerem que a serotonina exerce uma neuromodulação em nivel do NPV, e essa promove uma inibição da resposta barorreflexa frente à EVEC. Assim, o presente trabalho sugere o envolvimento serotoninérgico na neuromodulação no nivel do NPV na resposta reflexa vagal em ratos normotensos.
Assuntos
Animais , Masculino , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/fisiologia , Volume Sanguíneo/efeitos dos fármacos , Cloreto de Sódio/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Valores de Referência , Fatores de Tempo , Pressão Sanguínea/efeitos dos fármacos , Pressão Sanguínea/fisiologia , Volume Sanguíneo/fisiologia , Fenômenos Fisiológicos Cardiovasculares , Reprodutibilidade dos Testes , Ratos Wistar , Barorreflexo/efeitos dos fármacos , Barorreflexo/fisiologia , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologiaRESUMO
Adropin is a peptide hormone with cardiovascular and metabolic roles in the periphery, including effects on glucose and lipid homeostasis. Central administration of adropin has been shown to inhibit water intake in rats; however, the site at which central adropin acts has yet to be elucidated. The hypothalamic paraventricular nucleus (PVN), a critical autonomic control center, plays essential roles in the control of fluid balance, energy homeostasis, and cardiovascular regulation, and is, therefore, a potential target for centrally acting adropin. In the present study, we used whole cell patch-clamp techniques to examine the effects of adropin on the excitability of neurons within the PVN. All three neuronal subpopulations (magnocellular, preautonomic, and neuroendocrine) in the PVN were found to be responsive to bath-application of 10 nM adropin, which elicited responses in 68% of cells tested (n = 57/84). The majority of cells (58%) depolarized (5.2 ± 0.3 mV; n = 49) in response to adropin, whereas the remaining responsive cells (10%) hyperpolarized (-3.4 ± 0.5 mV; n = 8), effects that were shown to be concentration-dependent. Additionally, responses were maintained in the presence of 1 µM TTX in 75% of cells tested (n = 9/12), and voltage-clamp analysis revealed that adropin had no effect on the amplitude or frequency of excitatory or inhibitory postsynaptic currents (EPSCs and IPSCs) in PVN neurons, suggesting the peptide exerts direct, postsynaptic actions on these neurons. Collectively, these findings suggest central adropin may exert its physiological effects through direct actions on neurons in the PVN.