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1.
Life Sci ; 253: 117692, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32376271

RESUMO

BACKGROUND: Depression is the most significant cause of suicide among neuropsychiatric illnesses. Major depression further affects the quality of life in an individual with epilepsy. The treatment of depression in an epileptic patient could be very challenging because of drug selection or the fact that some antiepileptic drugs are known to cause depression. It has been shown that in addition to the known involvement of the serotonergic pathway in depression, the glutamatergic system is also involved in the evolution of the disease, but this knowledge is limited. This study assessed if induction of epilepsy in rats will cause depressive-like behavior, alters the concentrations of metabotropic receptor 5 (mGluR5), glutamate transport protein (GLAST), glutamate synthase (GS) and brain derived neurotrophic factor (BDNF). MATERIALS AND METHOD: Epilepsy was induced in rats by injecting Pentylenetetrazole at 35 mg/kg every other day. At kindle, rats were subjected to sucrose preference test (SPT) and forced swim test (FST) and decapitated 4 h later. Hippocampal tissue was collected and the BDNF concentration was measured with ELISA; mGluR5 and GS protein expression was measured using western blot while amygdala tissue was used for GLAST expression with flow cytometry. RESULTS: Our results showed that epilepsy leads to depressive-like behavior in rats and alters the glutamatergic system. CONCLUSION: Therefore, we conclude that targeting the glutamate pathway may be a good strategy to alleviate depressive-like behavior associated with epilepsy.


Assuntos
Depressão/fisiopatologia , Epilepsia/fisiopatologia , Ácido Glutâmico/metabolismo , Convulsões Febris/fisiopatologia , Tonsila do Cerebelo/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transportador 1 de Aminoácido Excitatório/metabolismo , Glutamato Sintase/metabolismo , Hipocampo/metabolismo , Masculino , Pentilenotetrazol/administração & dosagem , Ratos , Ratos Sprague-Dawley , Receptor de Glutamato Metabotrópico 5/metabolismo
2.
Nature ; 581(7807): 204-208, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32405000

RESUMO

It has been speculated that brain activities might directly control adaptive immune responses in lymphoid organs, although there is little evidence for this. Here we show that splenic denervation in mice specifically compromises the formation of plasma cells during a T cell-dependent but not T cell-independent immune response. Splenic nerve activity enhances plasma cell production in a manner that requires B-cell responsiveness to acetylcholine mediated by the α9 nicotinic receptor, and T cells that express choline acetyl transferase1,2 probably act as a relay between the noradrenergic nerve and acetylcholine-responding B cells. We show that neurons in the central nucleus of the amygdala (CeA) and the paraventricular nucleus (PVN) that express corticotropin-releasing hormone (CRH) are connected to the splenic nerve; ablation or pharmacogenetic inhibition of these neurons reduces plasma cell formation, whereas pharmacogenetic activation of these neurons increases plasma cell abundance after immunization. In a newly developed behaviour regimen, mice are made to stand on an elevated platform, leading to activation of CeA and PVN CRH neurons and increased plasma cell formation. In immunized mice, the elevated platform regimen induces an increase in antigen-specific IgG antibodies in a manner that depends on CRH neurons in the CeA and PVN, an intact splenic nerve, and B cell expression of the α9 acetylcholine receptor. By identifying a specific brain-spleen neural connection that autonomically enhances humoral responses and demonstrating immune stimulation by a bodily behaviour, our study reveals brain control of adaptive immunity and suggests the possibility to enhance immunocompetency by behavioural intervention.


Assuntos
Comportamento Animal/fisiologia , Encéfalo/fisiologia , Imunidade Humoral/imunologia , Baço/imunologia , Baço/inervação , Acetilcolina/metabolismo , Acetilcolina/farmacologia , Neurônios Adrenérgicos/metabolismo , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Colina O-Acetiltransferase/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Hemocianinas/imunologia , Imunoglobulina G/imunologia , Ativação Linfocitária , Masculino , Camundongos , Núcleo Hipotalâmico Paraventricular/citologia , Núcleo Hipotalâmico Paraventricular/efeitos dos fármacos , Núcleo Hipotalâmico Paraventricular/metabolismo , Plasmócitos/citologia , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Receptores Nicotínicos/deficiência , Receptores Nicotínicos/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Estresse Psicológico/imunologia , Estresse Psicológico/metabolismo , Linfócitos T/imunologia
3.
PLoS One ; 15(1): e0226486, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31931515

RESUMO

Treatment-resistant depression (TRD) occurs in many patients and causes high morbidity and mortality. Because TRD subjects are particularly difficult to study especially longitudinally, biological data remain very limited. In a preliminary study to judge feasibility and power, 25 TRD patients were referred from specialty psychiatric practices. All were severely and chronically depressed and mostly had comorbid psychiatric disorders as is typical in TRD. Nine patients were able to complete all required components of the protocol that included diagnostic interview; rating scales; clinical magnetic resonance imaging; medication washout; treatment with maximally tolerated olanzapine-fluoxetine combination for 8 weeks; and pre- and post-treatment fluorodeoxyglucose positron emission tomography. This drug combination is an accepted standard of treatment for TRD. Dropouts arose from worsening depression, insomnia, and anxiety. One patient remitted; three responded. A priori regions of interest included the amygdala and subgenual cingulate cortex (sgACC; Brodmann area BA25). Responders showed decreased metabolism with treatment in the right amygdala that correlated with clinical response; no significant changes in BA25; better response to treatment the higher the baseline BA25 metabolism; and decreased right ventromedial prefrontal metabolism (VMPFC; broader than BA25) with treatment which did not correlate with depression scores. The baseline metabolism of all individuals showed heterogeneous patterns when compared to a normative metabolic database. Although preliminary given the sample size, this study highlights several issues important for future work: marked dropout rate in this study design; need for large sample size for adequate power; baseline metabolic heterogeneity of TRD requiring careful subject characterization for future studies of interventions; relationship of amygdala activity decreases with response; and the relationship between baseline sgACC and VMPFC activity with response. Successful treatment of TRD with olanzapine-fluoxetine combination shows changes in cerebral metabolism like those seen in treatment-responsive major depression.


Assuntos
Benzodiazepinas/uso terapêutico , Encéfalo/metabolismo , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Fluoxetina/uso terapêutico , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/metabolismo , Encéfalo/diagnóstico por imagem , Transtorno Depressivo Resistente a Tratamento/metabolismo , Transtorno Depressivo Resistente a Tratamento/patologia , Combinação de Medicamentos , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/metabolismo , Índice de Gravidade de Doença
4.
Proc Natl Acad Sci U S A ; 117(4): 2140-2148, 2020 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-31932450

RESUMO

Approximately 25% of patients who are prescribed opioids for chronic pain misuse them, and 5 to 10% develop an opioid use disorder. Although the neurobiological target of opioids is well known, the molecular mechanisms that are responsible for the development of addiction-like behaviors in some but not all individuals are poorly known. To address this issue, we used a unique outbred rat population (heterogeneous stock) that better models the behavioral and genetic diversity that is found in humans. We characterized individual differences in addiction-like behaviors using an addiction index that incorporates the key criteria of opioid use disorder: escalated intake, highly motivated responding, and hyperalgesia. Using in vitro electrophysiological recordings in the central nucleus of the amygdala (CeA), we found that rats with high addiction-like behaviors (HA) exhibited a significant increase in γ-aminobutyric acid (GABA) transmission compared with rats with low addiction-like behaviors (LA) and naive rats. The superfusion of CeA slices with nociceptin/orphanin FQ peptide (N/OFQ; 500 nM), an endogenous opioid-like peptide, normalized GABA transmission in HA rats. Intra-CeA levels of N/OFQ were lower in HA rats than in LA rats. Intra-CeA infusions of N/OFQ (1 µg per site) reversed the escalation of oxycodone self-administration in HA rats but not in LA rats. These results demonstrate that the downregulation of N/OFQ levels in the CeA may be responsible for hyper-GABAergic tone in the CeA that is observed in individuals who develop addiction-like behaviors. Based on these results, we hypothesize that small molecules that target the N/OFQ system might be useful for the treatment of opioid use disorder.


Assuntos
Tonsila do Cerebelo/metabolismo , Peptídeos Opioides/administração & dosagem , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Oxicodona/efeitos adversos , Ácido gama-Aminobutírico/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Humanos , Masculino , Transtornos Relacionados ao Uso de Opioides/etiologia , Transtornos Relacionados ao Uso de Opioides/metabolismo , Ratos , Autoadministração
5.
Biol Pharm Bull ; 42(12): 2009-2015, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787717

RESUMO

The traditional herbal medicines yokukansan (YKS) and yokukansankachimpihange (YKSCH) are prescribed for neurosis, insomnia or night crying and irritability in children. YKSCH comprises YKS and two additional herbs, a chimpi and a hange, and is used to treat digestive function deficiencies. However, the differences between the effects of YKS and YKSCH on brain function are unclear. The present study examined the effects of YKS and YKSCH on aggressive behavior in mice reared under a social isolation (SI) condition. Mice were housed individually for 6 weeks. YKS and YKSCH were administered orally for 2 weeks before aggression tests. SI increased aggressive behavior against naïve mice, and YKS, but not YKSCH, significantly attenuated this aggressive behavior. Because serotonin (5-HT)2A and 5-HT3A receptor antagonists are reported to have anti-aggressive effects, the mRNA levels of these receptors were examined. YKS attenuated the SI-induced increase in 5-HT2A and 5-HT3A receptor mRNA in the amygdala. On the other hand, YKSCH attenuated the SI-induced increase in 5-HT1A receptor mRNA. YKS and YKSCH did not affect 5-HT and its metabolite 5-hydroxyindoleacetic acid content in the amygdala. However, YKSCH increased the mRNA level of arginine vasopressin (AVP), which is a neuropeptide that has been implicated in aggression, in the amygdala. These results suggest that YKS ameliorates aggressive behavior by decreasing 5-HT2A and 5-HT3A receptor expression. The YKSCH-induced increase in AVP may disrupt the anti-aggressive effect of YKS. YKS may be more effective than YKSCH for treating irritability if digestive function deficiencies are not considered.


Assuntos
Agressão/efeitos dos fármacos , Arginina Vasopressina/genética , Comportamento Animal/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Receptores de Serotonina/genética , Isolamento Social , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Ácido Hidroxi-Indolacético/metabolismo , Masculino , Camundongos , RNA Mensageiro/metabolismo , Serotonina/metabolismo
6.
Semin Reprod Med ; 37(2): 64-70, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31847026

RESUMO

The hypothalamic hormone kisspeptin (encoded by the KISS1/kiss1 gene) is the master regulator of the reproductive axis with its role in controlling gonadotrophin hormone secretion now well characterized. However, identification of kisspeptin and its cognate receptor expression within the amygdala, a key limbic brain region whose functions contribute to a broad range of physiological and behavioral processes, has heightened interest concerning kisspeptins' role in the broader aspects of reproductive physiology. In this review, we detail the important developments and key studies examining the emerging functions of this kisspeptin population. These studies provide novel advances in our understanding of the mechanisms controlling reproductive neuroendocrinology by defining the crucial role of the amygdala kisspeptin system in modulating pubertal timing, reproductive hormone secretion, and pulsatility, as well as its influence in governing-related behaviors. To this end, the role of the amygdala kisspeptin system in integrating reproductive hormone secretion with behavior sheds new light onto the potential use of kisspeptin-based therapeutics for reproductive and related psychosexual disorders.


Assuntos
Tonsila do Cerebelo/metabolismo , Kisspeptinas/metabolismo , Comportamento Reprodutivo/fisiologia , Animais , Feminino , Hormônios Esteroides Gonadais/metabolismo , Hormônio Liberador de Gonadotropina/metabolismo , Humanos , Masculino , Puberdade/metabolismo , Transdução de Sinais
7.
Ann Palliat Med ; 8(5): 660-666, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31865727

RESUMO

BACKGROUND: Protein kinase Mζ (PKMζ), a typical brain-specific PKC isoform, has been shown to be critical in the maintenance of long-term potentiation and memory storage. Zeta inhibitory peptide (ZIP), a peptide with selective inhibition of PKMζ, has been used in relieving experimental neuropathic pain and disrupting memory. The aim of this study was to investigate the effects of intra-amygdalar infusion of ZIP on neuropathic pain induced by chronic constriction injury (CCI), and inflammatory pain induced by complete Freund's adjuvant (CFA) in adult rats. METHODS: (I) ZIP was infused into the amygdala 30 minutes (min) before CCI was performed. Mechanical withdrawal threshold (MWT) was determined prior to the infusion of ZIP, and 30, 60, 90, 120, 150, 180 min after CCI (n=8 per group). (II) ZIP was infused into the amygdala 3, 7, 14 days after CCI (n=8 per group). MWT was measured 30 min before the infusion and 2, 12, 24 h after the infusion. (III) Three days after CCI, ZIP was infused into the amygdala repeatedly once a day for 2 days. MWT was measured before each infusion and 2 or 24 h after each infusion (n=8 per group). (IV) ZIP was infused into the amygdala 24 h after the establishment of inflammatory pain induced by complete Freund's adjuvant (CFA). MWT was determined 30 min before the infusion and 30, 60, 90, 120 and 150 min after the infusion (n=8 per group). RESULTS: As shown in figures, (I) amygdalar infusion of ZIP prior to the CCI produced no effect on CCI-induced hyperalgesia when compared to scr-ZIP or saline infusion [n=8, interaction effect, F (7.312, 76.776) =1.237, P>0.05; time as main factor, F (3.656, 76.776) =115.346, P<0.001; group as main factor, F (2, 21) =0.648, P>0.05]. (II) BLA infusion of ZIP significantly increased mechanical withdrawal threshold 7 days after CCI [n=8, interaction effect, F (5.476, 57.500) =15.279, P<0.001; time as main factor, F (2.738, 57.500) = 242.357, P<0.001; group as main factor, F (2,21) =4.786, P<0.05], just the same as 3 and 14 days after CCI (data not shown). (III) Bilateral injection of ZIP into the BLA significantly reduced mechanical hyperalgesia 2 h after the administration [n=8, paired t-test, t (0.05,7) =-5.561, P<0.05; n=8, paired t-test, t (0.05,7) =-4.745, P<0.05], and returned to baseline 24 h after the administration [n=8, paired t-test, t (0.05,7) =1.039, P>0.05; n=8, paired t-test, t (0.05,7) =-1.173, P>0.05]. (IV) ZIP produced no effect on mechanical withdrawal thresholds at all time points examined after the infusion, compared with scr-ZIP or saline control groups (n=8, interaction effect, F (6.135, 126) =1.724, P>0.05; group as main factor, F (2,21) =0.608, P>0.05). CONCLUSIONS: Intra-amygdala infusion of ZIP attenuates mechanical hyperalgesia induced by CCI but has no effect on inflammatory pain induced by CFA in rats, suggesting that amygdala PKMζ may be a therapeutic target in the treatment of neuropathic pain.


Assuntos
Tonsila do Cerebelo/metabolismo , Inflamação/tratamento farmacológico , Lipopeptídeos/administração & dosagem , Lipopeptídeos/uso terapêutico , Neuralgia/tratamento farmacológico , Animais , Ratos
8.
Int J Mol Sci ; 20(22)2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31766245

RESUMO

The amygdala is a cerebral region whose function is compromised in temporal lobe epilepsy (TLE). Patients with TLE present cognitive and emotional dysfunctions, of which impairments in recognizing facial expressions have been clearly attributed to amygdala damage. However, damage to the amygdala has been scarcely addressed, with the majority of studies focusing on the hippocampus. The aim of this study was to evaluate epilepsy-related plasticity of cholinergic projections to the basolateral nucleus (BL) of the amygdala. Adult rats received kainic acid (KA) injections and developed status epilepticus. Weeks later, they showed spontaneous recurrent seizures documented by behavioral observations. Changes in cholinergic innervation of the BL were investigated by using an antibody against the vesicular acetylcholine transporter (VAChT). In KA-treated rats, it was found that (i) the BL shrunk to 25% of its original size (p < 0.01 vs. controls, Student's t-test), (ii) the density of vesicular acetylcholine transporter-immunoreactive (VAChT-IR) varicosities was unchanged, (iii) the volumes of VAChT-IR cell bodies projecting to the BL from the horizontal limb of the diagonal band of Broca, ventral pallidum, and subcommissural part of the substantia innominata were significantly increased (p < 0.05, Bonferroni correction). These results illustrate significant changes in the basal forebrain cholinergic cells projecting to the BL in the presence of spontaneous recurrent seizures.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Prosencéfalo Basal/fisiopatologia , Epilepsia do Lobo Temporal/fisiopatologia , Plasticidade Neuronal , Acetilcolina/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Prosencéfalo Basal/metabolismo , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/patologia , Modelos Animais de Doenças , Epilepsia do Lobo Temporal/induzido quimicamente , Epilepsia do Lobo Temporal/metabolismo , Ácido Caínico , Masculino , Ratos Wistar , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo
9.
Proc Natl Acad Sci U S A ; 116(43): 21659-21665, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31591201

RESUMO

Autism spectrum disorder (ASD) does not have a distinct pathogenesis or effective treatment. Increasing evidence supports the presence of immune dysfunction and inflammation in the brains of children with ASD. In this report, we present data that gene expression of the antiinflammatory cytokine IL-37, as well as of the proinflammatory cytokines IL-18 and TNF, is increased in the amygdala and dorsolateral prefrontal cortex of children with ASD as compared to non-ASD controls. Gene expression of IL-18R, which is a receptor for both IL-18 and IL-37, is also increased in the same brain areas of children with ASD. Interestingly, gene expression of the NTR3/sortilin receptor is reduced in the amygdala and dorsolateral prefrontal cortex. Pretreatment of cultured human microglia from normal adult brains with human recombinant IL-37 (1 to 100 ng/mL) inhibits neurotensin (NT)-stimulated secretion and gene expression of IL-1ß and CXCL8. Another key finding is that NT, as well as the proinflammatory cytokines IL-1ß and TNF increase IL-37 gene expression in cultured human microglia. The data presented here highlight the connection between inflammation and ASD, supporting the development of IL-37 as a potential therapeutic agent of ASD.


Assuntos
Tonsila do Cerebelo/metabolismo , Transtorno do Espectro Autista/metabolismo , Interleucina-1/metabolismo , Microglia/metabolismo , Neurotensina/metabolismo , Córtex Pré-Frontal/metabolismo , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Células Cultivadas , Criança , Humanos , Interleucina-18/metabolismo , Subunidade alfa de Receptor de Interleucina-18/metabolismo , Interleucina-1beta/biossíntese , Interleucina-8/biossíntese , Fator de Necrose Tumoral alfa/metabolismo
10.
Acta Neurobiol Exp (Wars) ; 79(3): 309-317, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31587023

RESUMO

We determined CA1 hippocampal field to be involved in self-exposure, a type of novelty­seeking behaviour that has also been associated with short 22 kHz and flat 50 kHz ultrasonic vocalizations (USV) in adult male Long-Evans rats. Rats were habituated for three days to a self-exposure cage with two nose-poke holes. On day four, the animals from the experimental group were allowed to turn the cage light off for 5 s with a nose­poke (test/self­exposure session), while rats from control-yoked group had changing light conditions coupled and identical to the experimental animals. The experimental rats performed more nose-pokes during self-exposure session than animals from the control group. This effect was accompanied by a higher density of c-Fos-positive nuclei in the hippocampal CA1. There were no significant group differences in c-Fos expression in other brain regions analysed. However, possible involvement of several other structures in self-exposure (i.e., CA3, the dentate gyrus, amygdala, prefrontal cortex, and nucleus accumbens) is also discussed, as their correlational activity, reflected by c-Fos immunoactivity, was observed in the experimental rats. During test sessions, there were more nose-pokes accompanied by short 22 kHz calls and 50 kHz calls performed by the rats of the experimental group than of the control group. The CA1 region has previously been associated with novelty; short 22 kHz USV and flat 50 kHz USV could be associated with self-exposure, also they appear to be emitted correlatively.


Assuntos
Comportamento Exploratório/fisiologia , Hipocampo/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Vocalização Animal/fisiologia , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Masculino , Núcleo Accumbens/metabolismo , Ratos Long-Evans
11.
Behav Neurosci ; 133(6): 614-623, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31599608

RESUMO

In Pavlovian renewal paradigms, intact female rats have previously failed to exhibit renewal of appetitive behavior after extinction. However, when treated with exogenous estradiol, female rats exhibit robust renewal behavior. The current study aims to investigate whether the estrous cycle can influence renewal of appetitive behaviors and activity in brain areas known to support the renewal effect. We further aimed to examine whether the estrous cycle would similarly affect renewal of two different types of appetitive behaviors. We first establish that rats in the proestrous stage of the estrous cycle during extinction exhibit elevated renewal behavior compared with rats in either metestrous/diestrous stages, and only rats in proestrus during extinction training (but not during the renewal test) exhibit elevated renewal behavior. Furthermore, we show that this estrous cycle dependent effect on renewal only applies to the conditioned approach behavior toward the food delivery site but not the conditioned approach behavior toward the light cue associated with food delivery. Finally, we examined FOS activity within the prelimbic and infralimbic areas of the medial prefrontal cortex, the dorsal and ventral hippocampal formation, the paraventricular nucleus of the thalamus, the nucleus accumbens, and areas of the amygdala. Particularly in the hippocampus and amygdala, FOS expression which corresponded to the behavioral differences between groups was observed. Results from this study suggest that context information processing may vary as a function of endogenous female hormones across the gonadal hormone cycle and that encoding and retrieval of this information is accomplished in a state-specific manner. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Comportamento Apetitivo/efeitos dos fármacos , Ciclo Estral/fisiologia , Extinção Psicológica/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Condicionamento Clássico/efeitos dos fármacos , Estradiol/farmacologia , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Feminino , Hipocampo/metabolismo , Memória/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Tálamo/metabolismo
12.
Bull Exp Biol Med ; 167(5): 610-615, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31606808

RESUMO

The severity and specificity of CNS disturbances resulting from negative psychoemotional experience are determined by not only genetically determined stress sensitivity, but also epigenetic factors; among the latter, the context of stress exposure, e.g. stress controllability is considered. We examined the effect of controllability factor on behavioral and neurochemical parameters of acute stress in the elevated plus maze test. The situations of controllable and uncontrollable stress were modeled by allowing or restricting mice in their choice for closed arms during testing in the maze. The anxiety level of inbred BALB/c and C57Bl/6N mice was assessed and the levels and monoamine turnover in the medial prefrontal cortex, hippocampus, amygdala, and hypothalamus were measured. It was found that the decrease in stress controllability suppresses explorative activity in mice; the behavioral and neurochemical differences between the two strains are not constant feature and depend on stress controllability; serotoninergic and dopaminerigic neurotransmission in the hypothalamus can be a signal to discriminate stress controllability in the brain.


Assuntos
Ansiedade/metabolismo , Dopamina/metabolismo , Hipotálamo/metabolismo , Norepinefrina/metabolismo , Serotonina/metabolismo , Estresse Psicológico/metabolismo , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiopatologia , Animais , Ansiedade/fisiopatologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Hipotálamo/fisiopatologia , Aprendizagem em Labirinto , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Estresse Psicológico/fisiopatologia , Transmissão Sináptica
13.
Proc Natl Acad Sci U S A ; 116(42): 21176-21184, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31575739

RESUMO

As the inhibitory γ-aminobutyric acid-ergic (GABAergic) transmission has a pivotal role in the central nervous system (CNS) and defective forms of its synapses are associated with serious neurological disorders, numerous versions of caged GABA and, more recently, photoswitchable ligands have been developed to investigate such transmission. While the complementary nature of these probes is evident, the mechanisms by which the GABA receptors can be photocontrolled have not been fully exploited. In fact, the ultimate need for specificity is critical for the proper synaptic exploration. No caged allosteric modulators of the GABAA receptor have been reported so far; to introduce such an investigational approach, we exploited the structural motifs of the benzodiazepinic scaffold to develop a photocaged version of diazepam (CD) that was tested on basolateral amygdala (BLa) pyramidal cells in mouse brain slices. CD is devoid of any intrinsic activity toward the GABAA receptor before irradiation. Importantly, CD is a photoreleasable GABAA receptor-positive allosteric modulator that offers a different probing mechanism compared to caged GABA and photoswitchable ligands. CD potentiates the inhibitory signaling by prolonging the decay time of postsynaptic GABAergic currents upon photoactivation. Additionally, no effect on presynaptic GABA release was recorded. We developed a photochemical technology to individually study the GABAA receptor, which specifically expands the toolbox available to study GABAergic synapses.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Diazepam/farmacologia , Receptores de GABA-A/metabolismo , Sinapses/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Camundongos , Camundongos Endogâmicos C57BL , Células Piramidais/efeitos dos fármacos , Células Piramidais/metabolismo , Potenciais Sinápticos/efeitos dos fármacos , Transmissão Sináptica/efeitos dos fármacos , Ácido gama-Aminobutírico/metabolismo
14.
Proc Natl Acad Sci U S A ; 116(42): 21213-21218, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31575746

RESUMO

The gap between predicted brain age using magnetic resonance imaging (MRI) and chronological age may serve as a biomarker for early-stage neurodegeneration. However, owing to the lack of large longitudinal studies, it has been challenging to validate this link. We aimed to investigate the utility of such a gap as a risk biomarker for incident dementia using a deep learning approach for predicting brain age based on MRI-derived gray matter (GM). We built a convolutional neural network (CNN) model to predict brain age trained on 3,688 dementia-free participants of the Rotterdam Study (mean age 66 ± 11 y, 55% women). Logistic regressions and Cox proportional hazards were used to assess the association of the age gap with incident dementia, adjusted for age, sex, intracranial volume, GM volume, hippocampal volume, white matter hyperintensities, years of education, and APOE ε4 allele carriership. Additionally, we computed the attention maps, which shows which regions are important for age prediction. Logistic regression and Cox proportional hazard models showed that the age gap was significantly related to incident dementia (odds ratio [OR] = 1.11 and 95% confidence intervals [CI] = 1.05-1.16; hazard ratio [HR] = 1.11, and 95% CI = 1.06-1.15, respectively). Attention maps indicated that GM density around the amygdala and hippocampi primarily drove the age estimation. We showed that the gap between predicted and chronological brain age is a biomarker, complimentary to those that are known, associated with risk of dementia, and could possibly be used for early-stage dementia risk screening.


Assuntos
Biomarcadores/metabolismo , Demência/patologia , Substância Cinzenta/patologia , Idoso , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/patologia , Demência/metabolismo , Feminino , Substância Cinzenta/metabolismo , Hipocampo/metabolismo , Hipocampo/patologia , Humanos , Estudos Longitudinais , Imagem por Ressonância Magnética/métodos , Masculino , Modelos de Riscos Proporcionais , Risco , Substância Branca/metabolismo , Substância Branca/patologia
15.
Front Neuroendocrinol ; 55: 100791, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31542287

RESUMO

Adolescence marks a key developmental window during which emotion dysregulation increases, along with risk for the onset of anxiety and other affect-related pathologies. Although emotion dysregulation and related pathologies normatively decline during the transition into adulthood, this does not occur for a sizable minority of individuals. Finally, sex differences in anxiety emerge during adolescence, with females developing a 2-fold increase in risk relative to males. Unfortunately, a neurobiological model of the mechanisms that cause these changes during adolescence has yet to be proposed. In the present work, we first provide brief reviews of relevant literature. Next, we outline a dual-mechanism model focused on (i) the influence of pubertal testosterone on key emotion-regulation circuitry (i.e., orbitofrontal cortex-amygdala coupling) and (ii) myelination of the fiber bundles connecting such circuitry (i.e., uncinate fasciculus). The proposed model offers a set of specific, testable hypotheses that will hopefully spur much needed cross-disciplinary research.


Assuntos
Sintomas Afetivos , Tonsila do Cerebelo , Transtornos de Ansiedade , Rede Nervosa , Sistemas Neurossecretores/metabolismo , Córtex Pré-Frontal , Puberdade/metabolismo , Caracteres Sexuais , Testosterona/metabolismo , Adolescente , Adulto , Sintomas Afetivos/metabolismo , Sintomas Afetivos/fisiopatologia , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiopatologia , Animais , Transtornos de Ansiedade/metabolismo , Transtornos de Ansiedade/fisiopatologia , Feminino , Humanos , Masculino , Rede Nervosa/crescimento & desenvolvimento , Rede Nervosa/metabolismo , Rede Nervosa/fisiopatologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Adulto Jovem
16.
Int J Mol Sci ; 20(18)2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31489921

RESUMO

The amygdala plays a key role in emotional-affective aspects of pain and in pain modulation. The central nucleus (CeA) serves major amygdala output functions related to emotional-affective behaviors and pain modulation. Our previous studies implicated the corticotropin-releasing factor (CRF) system in amygdala plasticity and pain behaviors in an arthritis model. We also showed that serotonin (5-HT) receptor subtype 5-HT2CR in the basolateral amygdala (BLA) contributes to increased CeA output and neuropathic pain-like behaviors. Here, we tested the novel hypothesis that 5-HT2CR in the BLA drives CRF1 receptor activation to increase CeA neuronal activity in neuropathic pain. Extracellular single-unit recordings of CeA neurons in anesthetized adult male rats detected increased activity in neuropathic rats (spinal nerve ligation model) compared to sham controls. Increased CeA activity was blocked by local knockdown or pharmacological blockade of 5-HT2CR in the BLA, using stereotaxic administration of 5-HT2CR short hairpin RNA (shRNA) viral vector or a 5-HT2CR antagonist (SB242084), respectively. Stereotaxic administration of a CRF1 receptor antagonist (NBI27914) into the BLA also decreased CeA activity in neuropathic rats and blocked the facilitatory effects of a 5-HT2CR agonist (WAY161503) administered stereotaxically into the BLA. Conversely, local (BLA) knockdown of 5-HT2CR eliminated the inhibitory effect of NBI27914 and the facilitatory effect of WAY161503 in neuropathic rats. The data suggest that 5-HT2CR activation in the BLA contributes to neuropathic pain-related amygdala (CeA) activity by engaging CRF1 receptor signaling.


Assuntos
Tonsila do Cerebelo/metabolismo , Neuralgia/etiologia , Neuralgia/metabolismo , Neurônios/metabolismo , Receptor 5-HT2C de Serotonina/genética , Receptores de Hormônio Liberador da Corticotropina/genética , Tonsila do Cerebelo/fisiopatologia , Animais , Modelos Animais de Doenças , Técnicas de Silenciamento de Genes , Masculino , Neuralgia/fisiopatologia , Ratos , Receptor 5-HT2C de Serotonina/metabolismo , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Receptores de Hormônio Liberador da Corticotropina/metabolismo , Antagonistas do Receptor 5-HT2 de Serotonina/farmacologia
17.
Int J Mol Sci ; 20(17)2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31484392

RESUMO

Brain-derived neurotrophic factor (BDNF) has previously been shown to play an important role in glutamatergic synaptic plasticity in the amygdala, correlating with cued fear learning. While glutamatergic neurotransmission is facilitated by BDNF signaling in the amygdala, its mechanism of action at inhibitory synapses in this nucleus is far less understood. We therefore analyzed the impact of chronic BDNF depletion on GABAA-mediated synaptic transmission in BDNF heterozygous knockout mice (BDNF+/-). Analysis of miniature and evoked inhibitory postsynaptic currents (IPSCs) in the lateral amygdala (LA) revealed neither pre- nor postsynaptic differences in BDNF+/- mice compared to wild-type littermates. In addition, long-term potentiation (LTP) of IPSCs was similar in both genotypes. In contrast, facilitation of spontaneous IPSCs (sIPSCs) by norepinephrine (NE) was significantly reduced in BDNF+/- mice. These results argue against a generally impaired efficacy and plasticity at GABAergic synapses due to a chronic BDNF deficit. Importantly, the increase in GABAergic tone mediated by NE is reduced in BDNF+/- mice. As release of NE is elevated during aversive behavioral states in the amygdala, effects of a chronic BDNF deficit on GABAergic inhibition may become evident in response to states of high arousal, leading to amygdala hyper-excitability and impaired amygdala function.


Assuntos
Tonsila do Cerebelo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Potenciação de Longa Duração/fisiologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Potenciação de Longa Duração/genética , Camundongos , Camundongos Knockout , Plasticidade Neuronal/genética , Plasticidade Neuronal/fisiologia , Técnicas de Patch-Clamp , Transmissão Sináptica/genética , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/metabolismo
18.
Curr Cardiol Rep ; 21(10): 121, 2019 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-31473817

RESUMO

PURPOSE OF REVIEW: Recently, an association between cannabis use and Takotsubo (stress) cardiomyopathy (TTC) has been shown. With the current trend of legalization of cannabis, it is important to understand brain effects of cannabis use that could lead to cardiac disease, such as TTC. Here we review recent brain imaging studies in order to search for the evidence supporting the association between cannabis use, stress, and TTC. RECENT FINDINGS: There exist brain imaging studies showing similar findings across TTC, stress, and cannabis use. These similar findings are mainly centered on a key central autonomic network region amygdala, i.e., amygdala hyperactivity/hyperconnectivity when exposed to challenge, stress, or negative stimuli. This similarity supports a close association among cannabis use, stress, and TTC. Amygdala-centered neuronal circuits could underlie cannabis use as risk factor to TTC. Based on the findings, several directions for future studies are proposed.


Assuntos
Tonsila do Cerebelo/metabolismo , Cannabis/efeitos adversos , Estresse Psicológico/complicações , Cardiomiopatia de Takotsubo/metabolismo , Tonsila do Cerebelo/fisiopatologia , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Cardiomiopatias , Humanos , Fatores de Risco , Cardiomiopatia de Takotsubo/etiologia
19.
Neurobiol Learn Mem ; 164: 107065, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31400468

RESUMO

The aim of the present study was to assess thealterations of corticolimbic microRNAs and protein expressions in the effect of scopolamine with or without stress on passive-avoidance memory in male Wistar rats. The expressions of miR-1, miR-10 and miR-26 and also the levels of p-CREB, CREB, C-FOS and BDNF in the prefrontal cortex (PFC), the hippocampus and the amygdala were evaluated using RT-qPCR and Western blotting techniques. The data showed that the administration of a muscarinic receptor antagonist, scopolamine or the exposure to 30 min stress significantly induced memory loss. Interestingly, the injection of an ineffective dose of scopolamine (0.5 mg/kg) alongside with exposure to an ineffective time of stress (10 min) impaired memory formation, suggesting a potentiative effect of stress on scopolamine response. Our results showed that memory formation was associated with the down-regulated expression of miR-1, miR-10 and miR-26 in the PFC and the hippocampus, but not the amygdala. The relative expression increase of miR-1 and miR-10 in the PFC and the hippocampus was shown in memory loss induced by scopolamine administration or 30-min stress. The PFC level of miR-10 and also hippocampal level of miR-1 and miR-10 were significantly up-regulated, while amygdala miR-1 and miR-26 were down-regulated in scopolamine-induced memory loss under stress. Memory formation increased BDNF, C-FOS and p-CREB/CREB in the PFC, the hippocampus and the amygdala. In contrast, the PFC, hippocampal and amygdala protein expressions were significantly decreased in memory loss induced by scopolamine administration (2 mg/kg), stress exposure (for 30 min) or scopolamine (0.5 mg/kg) plus stress (10 min). One of the most significant findings to emerge from this study is that the stress exposure potentiated the amnesic effect of scopolamine may via affecting the expressions of miRs and proteins in the PFC, the hippocampus and the amygdala. It is possible to hypothesis that corticolimbic signaling pathways play a critical role in relationship between stress and Alzheimer's disease.


Assuntos
Sistema Límbico/metabolismo , Transtornos da Memória/metabolismo , MicroRNAs/metabolismo , Córtex Pré-Frontal/metabolismo , Estresse Psicológico/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Aprendizagem da Esquiva/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Sistema Límbico/efeitos dos fármacos , Masculino , Transtornos da Memória/induzido quimicamente , Antagonistas Muscarínicos/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos Wistar , Escopolamina/administração & dosagem , Estresse Psicológico/induzido quimicamente
20.
RNA Biol ; 16(12): 1764-1774, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31432767

RESUMO

With the advance of high-throughput sequencing technology numerous new regulatory small RNAs have been identified, that broaden the variety of processing mechanisms and functions of non-coding RNA. Here we explore small non-coding RNA (sncRNA) expression in central parts of the physiological stress and anxiety response system. Therefore, we characterize the sncRNA profile of tissue samples from Amygdala, Hippocampus, Hypothalamus and Adrenal Gland, obtained from 20 pigs. Our analysis reveals that all tissues but Amygdala and Hippocampus possess distinct, tissue-specific expression pattern of miRNA that are associated with Hypoxia, stress responses as well as memory and fear conditioning. In particular, we observe marked differences in the expression profile of limbic tissues compared to those associated to the HPA/stress axis, with a surprisingly high aggregation of 3´-tRNA halves in Amygdala and Hippocampus. Since regulation of sncRNA and RNA cleavage plays a pivotal role in the central nervous system, our work provides seminal insights in the role/involvement of sncRNA in the transcriptional and post-transcriptional regulation of negative emotion, stress and coping behaviour in pigs, and mammals in general.


Assuntos
Adaptação Fisiológica/genética , Regulação da Expressão Gênica , Genoma , Pequeno RNA não Traduzido/genética , Estresse Fisiológico/genética , Glândulas Suprarrenais/metabolismo , Tonsila do Cerebelo/metabolismo , Animais , Condicionamento Operante , Medo/fisiologia , Sequenciamento de Nucleotídeos em Larga Escala , Hipocampo/metabolismo , Hipotálamo/metabolismo , Hipóxia/genética , Hipóxia/metabolismo , Memória/fisiologia , Anotação de Sequência Molecular , Especificidade de Órgãos , Clivagem do RNA , Pequeno RNA não Traduzido/classificação , Pequeno RNA não Traduzido/metabolismo , Suínos
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