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1.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919862

RESUMO

The Shenmen point (acupuncture point heart 7: HT7), located in the heart meridian, is frequently used to treat mental disorders, including drug addiction, anxiety, and depression. This study aimed to determine how HT7 regulates anxiety and negative emotions caused by repeated alcohol administration, focusing on the amygdala and paraventricular nucleus (PVN). Repeated administration of alcohol (ETOH; 2 g/kg, i.p. injection, 16% v/v) for 14 days increased the corticosterone (CORT) levels, and HT7 stimulation reduced the plasma CORT levels. HT7 stimulation mitigated anxiety-like behaviors and reduced 22-kHz ultrasonic vocalizations in rats receiving repeated ETOH injections. HT7 stimulation increased the amygdala expression of mature brain-derived neurotropic factor (mBDNF) and phosphorylated tropomyosin receptor kinase B (pTrkB) and decreased the PVN corticotropin-releasing hormone (CRH) expression. Amygdala microinjections of the TrkB antagonist ANA-12 (0.1 pmol/1 µL) reversed the increase in PVN CRH levels. The reduced PVN CRH levels were regulated by CRH-expressing neurons in the amygdala, and the increased amygdala CRH levels were affected by the HT7-stimulation induced increases in mBDNF. HT7 stimulation alleviates increased stress hormone levels and mitigates anxiety and negative emotions caused by repeated ETOH administration. These results provide scientific support for the clinical use of acupuncture to treat various alcoholism-induced diseases.


Assuntos
Terapia por Acupuntura , Ansiedade/fisiopatologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Hormônio Liberador da Corticotropina/metabolismo , Etanol/administração & dosagem , Transdução de Sinais , Ultrassom , Vocalização Animal , Pontos de Acupuntura , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/sangue , Comportamento Animal , Corticosterona/sangue , Etanol/sangue , Masculino , Núcleo Hipotalâmico Paraventricular/metabolismo , Fosforilação , Ratos Wistar , Receptor trkB/metabolismo
2.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33671048

RESUMO

Previous studies have shown that genetically selected Marchigian Sardinian alcohol-preferring (msP) rats consume excessive amounts of ethanol to self-medicate from negative moods and to relieve innate hypersensitivity to stress. This phenotype resembling a subset of alcohol use disorder (AUD) patients, appears to be linked to a dysregulation of the equilibrium between stress and antistress mechanisms in the extended amygdala. Here, comparing water and alcohol exposed msP and Wistar rats we evaluate the transcript expression of the anti-stress opioid-like peptide nociceptin/orphanin FQ (N/OFQ) and its receptor NOP as well as of dynorphin (DYN) and its cognate κ-opioid receptor (KOP). In addition, we measured the transcript levels of corticotropin-releasing factor (CRF), CRF receptor 1 (CRF1R), brain-derived neurotrophic factor (BDNF) and of the tropomyosin receptor kinase B receptor (Trk-B). Results showed an innately up-regulation of the CRFergic system, mediating negative mood and stress responses, as well as an inherent up-regulation of the anti-stress N/OFQ system, both in the amygdala (AMY) and bed nucleus of the stria terminalis (BNST) of msP rats. The up-regulation of this latter system may reflect an attempt to buffer the negative condition elicited by the hyperactivity of pro-stress mechanisms since results showed that voluntary alcohol consumption dampened N/OFQ. Alcohol exposure also reduced the expression of dynorphin and CRF transmissions in the AMY of msP rats. In the BNST, alcohol intake led to a more complex reorganization of these systems increasing receptor transcripts in msP rats, along with an increase of CRF and a decrease of N/OFQ transcripts, respectively. Moreover, mimicking the effects of alcohol in the AMY we observed that the activation of NOP receptor by intracerebroventricular administration of N/OFQ in msP rats caused an increase of BDNF and a decrease of CRF transcripts. Our study indicates that both stress and anti-stress mechanisms are dysregulated in the extended AMY of msP rats. The voluntary alcohol drinking, as well as NOP agonism, have a significant impact on neuropeptidergic systems arrangement, bringing the systems back to normalization.


Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Alcoolismo/patologia , Tonsila do Cerebelo/patologia , Dinorfinas/farmacologia , Etanol/toxicidade , Peptídeos Opioides/farmacologia , Fragmentos de Peptídeos/farmacologia , Receptores Opioides/metabolismo , Alcoolismo/etiologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal , Masculino , Neurotransmissores/farmacologia , Ratos , Ratos Wistar , Receptores Opioides/genética
3.
Eur J Pharmacol ; 896: 173883, 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33513334

RESUMO

The lesions induced by Ibotenic acid (IA) emulate some of the symptoms associated with schizophrenia, such as impaired working memory that is predominantly organized by the medial prefrontal cortex (mPFC), or difficulties in social interactions that aremainly organized by the amygdala (AMG). The plastic capacity of dendritic spines in neurons of the mPFC and AMG is modulated by molecules that participate in the known deterioration of working memory, although the influence of these on the socialization of schizophrenic patients is unknown. Here, the effect of a neonatal IA induced lesion on social behavior and working memory was evaluated in adult rats, along with the changes in cytoarchitecture of dendritic spines and their protein content, specifically the postsynaptic density protein 95 (PSD-95), Synaptophysin (Syn), AMPA receptors, and brain-derived neurotrophic factor (BDNF). Both working memory and social behavior were impaired, and the density of the spines, as well as their PSD-95, Syn, AMPA receptor and BDNF content was lower in IA lesioned animals. The proportional density of thin, mushroom, stubby and wide spines resulted in plastic changes that suggest the activation of compensatory processes in the face of the adverse effects of the lesion. In addition, the reduction in the levels of the modulating factors also suggests that the signaling pathways in which such factors are implicated would be altered in the brains of patients with schizophrenia. Accordingly, the experimental study of such signaling pathways is likely to aid the development of more effective pharmacological strategies for the treatment of schizophrenia.


Assuntos
Tonsila do Cerebelo/patologia , Comportamento Animal , Espinhas Dendríticas/patologia , Plasticidade Neuronal , Córtex Pré-Frontal/patologia , Esquizofrenia/patologia , Psicologia do Esquizofrênico , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiopatologia , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Espinhas Dendríticas/metabolismo , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large/metabolismo , Ácido Ibotênico , Masculino , Aprendizagem em Labirinto , Memória de Curto Prazo , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos Sprague-Dawley , Receptores de AMPA/metabolismo , Esquizofrenia/induzido quimicamente , Esquizofrenia/metabolismo , Esquizofrenia/fisiopatologia , Comportamento Social , Sinaptofisina/metabolismo
4.
Int J Mol Sci ; 22(2)2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33467450

RESUMO

Fear extinction requires coordinated neural activity within the amygdala and medial prefrontal cortex (mPFC). Any behavior has a transcriptomic signature that is modified by environmental experiences, and specific genes are involved in functional plasticity and synaptic wiring during fear extinction. Here, we investigated the effects of optogenetic manipulations of prelimbic (PrL) pyramidal neurons and amygdala gene expression to analyze the specific transcriptional pathways associated to adaptive and maladaptive fear extinction. To this aim, transgenic mice were (or not) fear-conditioned and during the extinction phase they received optogenetic (or sham) stimulations over photo-activable PrL pyramidal neurons. At the end of behavioral testing, electrophysiological (neural cellular excitability and Excitatory Post-Synaptic Currents) and morphological (spinogenesis) correlates were evaluated in the PrL pyramidal neurons. Furthermore, transcriptomic cell-specific RNA-analyses (differential gene expression profiling and functional enrichment analyses) were performed in amygdala pyramidal neurons. Our results show that the optogenetic activation of PrL pyramidal neurons in fear-conditioned mice induces fear extinction deficits, reflected in an increase of cellular excitability, excitatory neurotransmission, and spinogenesis of PrL pyramidal neurons, and associated to strong modifications of the transcriptome of amygdala pyramidal neurons. Understanding the electrophysiological, morphological, and transcriptomic architecture of fear extinction may facilitate the comprehension of fear-related disorders.


Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Extinção Psicológica/fisiologia , Medo/fisiologia , Células Piramidais/fisiologia , Transcriptoma/genética , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/metabolismo , Animais , Fenômenos Eletrofisiológicos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Medo/psicologia , Masculino , Memória/fisiologia , Camundongos Transgênicos , Vias Neurais/citologia , Vias Neurais/metabolismo , Vias Neurais/fisiologia , Optogenética/métodos , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiologia , Células Piramidais/metabolismo , Transmissão Sináptica/fisiologia
5.
Cell Mol Life Sci ; 78(6): 3045-3055, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33313982

RESUMO

Excess maternal fat intake and obesity increase offspring susceptibility to conditions such as chronic anxiety and substance abuse. We hypothesised that environmentally modulated DNA methylation changes (5mC/5hmC) in regulatory regions of the genome that modulate mood and consumptive behaviours could contribute to susceptibility to these conditions. We explored the effects of environmental factors on 5mC/5hmC levels within the GAL5.1 enhancer that controls anxiety-related behaviours and alcohol intake. We first observed that 5mC/5hmC levels within the GAL5.1 enhancer differed significantly in different parts of the brain. Moreover, we noted that early life stress had no significant effect of 5mC/5hmC levels within GAL5.1. In contrast, we identified that allowing access of pregnant mothers to high-fat diet (> 60% calories from fat) had a significant effect on 5mC/5hmC levels within GAL5.1 in hypothalamus and amygdala of resulting male offspring. Cell transfection-based studies using GAL5.1 reporter plasmids showed that 5mC has a significant repressive effect on GAL5.1 activity and its response to known stimuli, such as EGR1 transcription factor expression and PKC agonism. Intriguingly, CRISPR-driven disruption of GAL5.1 from the mouse genome, although having negligible effects on metabolism or general appetite, significantly decreased intake of high-fat diet suggesting that GAL5.1, in addition to being epigenetically modulated by high-fat diet, also actively contributes to the consumption of high-fat diet suggesting its involvement in an environmentally influenced regulatory loop. Furthermore, considering that GAL5.1 also controls alcohol preference and anxiety these studies may provide a first glimpse into an epigenetically controlled mechanism that links maternal high-fat diet with transgenerational susceptibility to alcohol abuse and anxiety.


Assuntos
Alcoolismo/patologia , Ansiedade/patologia , Dieta Hiperlipídica , Elementos Facilitadores Genéticos/genética , 5-Metilcitosina/metabolismo , Alcoolismo/genética , Tonsila do Cerebelo/metabolismo , Animais , Ansiedade/genética , Linhagem Celular Tumoral , Metilação de DNA , Modelos Animais de Doenças , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Epigênese Genética , Feminino , Humanos , Hipotálamo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Quinase C/química , Proteína Quinase C/metabolismo
6.
J Pharmacol Sci ; 145(1): 140-149, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33357772

RESUMO

Inochinohaha White (IHW) is a Japanese herbal medicine for treating women with anxiety associated with premenstrual syndrome (PMS). In this study, we examined the effects of IHW on anxiety-like behavior in rats undergoing progesterone withdrawal (PWD), a model for PMS. Female rats were injected daily with progesterone for 21 days. Water and ethanol extracts of IHW (WE-IHW and EE-IHW, respectively) were administered orally 15 days after the initiation of progesterone injections. Anxiety-like behavior in an elevated plus maze was evaluated 48 h after the final injection of progesterone. PWD induced anxiety-like behavior, and EE-IHW (300 mg/kg), but not WE-IHW, significantly attenuated this behavior. Administration of the GABA agonists, diazepam or muscimol, significantly attenuated PWD-induced anxiety-like behavior. To investigate the underlying mechanisms of IHW action, we analyzed GABAA receptor expression in the amygdala of these rats. EE-IHW ameliorated the PWD-induced decrease in GABAA receptor ß2-subunit mRNA, although ß2-subunit protein was unchanged. Brain-derived neurotrophic factor (BDNF) has been reported to have anxiolytic effects and enhance GABAergic synaptic transmission. We found that EE-IHW increased BDNF levels in a dose-dependent manner. Our results suggest that EE-IHW attenuates PWD-induced anxiety-like behavior by increasing GABAA receptor-mediated signaling via increases in ß2-subunit and BDNF in the amygdala.


Assuntos
Ansiedade/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Expressão Gênica/efeitos dos fármacos , Fitoterapia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Síndrome Pré-Menstrual/tratamento farmacológico , Síndrome Pré-Menstrual/psicologia , Receptores de GABA-A/genética , Receptores de GABA-A/metabolismo , Administração Oral , Tonsila do Cerebelo/metabolismo , Animais , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Injeções , Síndrome Pré-Menstrual/genética , Progesterona/administração & dosagem , Ratos Wistar
7.
Proc Natl Acad Sci U S A ; 117(37): 22962-22966, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32868418

RESUMO

Gonadal hormones are linked to mechanisms that govern appetitive behavior and its suppression. Estrogens are synthesized from androgens by the enzyme aromatase, highly expressed in the ovaries of reproductive-aged women and in the brains of men and women of all ages. We measured aromatase availability in the amygdala using positron emission tomography (PET) with the aromatase inhibitor [11C]vorozole in a sample of 43 adult, normal-weight, overweight, or obese men and women. A subsample of 27 also completed personality measures to examine the relationship between aromatase and personality traits related to self-regulation and inhibitory control. Results indicated that aromatase availability in the amygdala was negatively associated with body mass index (BMI) (in kilograms per square meter) and positively correlated with scores of the personality trait constraint independent of sex or age. Individual variations in the brain's capacity to synthesize estrogen may influence the risk of obesity and self-control in men and women.


Assuntos
Apetite/fisiologia , Estrogênios/metabolismo , Obesidade/metabolismo , Adulto , Idoso , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/metabolismo , Androgênios , Aromatase/análise , Inibidores da Aromatase , Índice de Massa Corporal , Encéfalo/metabolismo , Estrogênios/fisiologia , Feminino , Humanos , Lipogênese , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/métodos , Autocontrole
8.
Mol Pharmacol ; 98(4): 454-461, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32606204

RESUMO

Endogenous opioid peptides in the amygdala regulate many of our behaviors and emotional responses. In particular, the endogenous opioid enkephalin plays a significant role in regulating amygdala activity, but its action is strongly limited by peptidases, which degrade enkephalin into inactive fragments. Inhibiting peptidases may be an attractive method to enhance endogenous opioid signaling; however, we do not know which specific peptidase(s) to target. Using inhibition of glutamate release onto the intercalated cells of the amygdala as an assay for enkephalin activity, we applied specific peptidase inhibitors to determine which peptidase(s) regulate enkephalin signaling in this region. Thiorphan (10 µM), captopril (1 µM), or bestatin (10 µM) were used to inhibit the activity of neprilysin, angiotensin-converting enzyme, or aminopeptidase N, respectively. In rat brain slices containing the intercalated cells, we found that inhibition of glutamate release by a submaximal concentration of enkephalin was doubled by application of all three peptidase inhibitors combined. Then, we tested inhibitors individually and found that inhibition of neprilysin alone could enhance enkephalin responses to the same extent as inhibitors of all three peptidases combined. This indicates neprilysin is the predominant peptidase responsible for degrading enkephalins in the intercalated cells of the amygdala. This differs from the striatum, locus coeruleus, and spinal cord, where multiple peptidases metabolize enkephalin. These data highlight the importance of knowing which specific peptidase(s) control opioid actions in the relevant neural circuit and how they change in disease states to allow rational choices of drugs targeting the specific peptidase of interest. SIGNIFICANCE STATEMENT: Endogenous opioids modulate many of our emotional and behavioral responses. In the amygdala, they modulate our pain, fear, and addictive behaviors. Their actions are terminated when they are catabolized into inactive fragments by at least three different peptidases. In this study, we found that neprilysin selectively controls endogenous opioid concentrations at synapses in the intercalated cells of the amygdala. This peptidase may be a target for regulation of endogenous opioid modulation of amygdala-mediated emotional and behavioral responses.


Assuntos
Tonsila do Cerebelo/metabolismo , Encefalinas/metabolismo , Neprilisina/metabolismo , Inibidores de Proteases/farmacologia , Animais , Captopril/farmacologia , Sinapses Elétricas/efeitos dos fármacos , Sinapses Elétricas/metabolismo , Ácido Glutâmico/metabolismo , Leucina/análogos & derivados , Leucina/farmacologia , Masculino , Neprilisina/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Tiorfano/farmacologia
9.
J Pharmacol Sci ; 144(1): 57-59, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32624301

RESUMO

Some psychiatric diseases are associated with disruptions in the circadian clock system. Ziprasidone (ZIP), a second-generation antipsychotic, is widely used for psychiatry-related pharmacotherapy but its mechanism has not been clearly elucidated. We measured clock gene fluctuation patterns in the hippocampus and the amygdala in ZIP-treated mice. ZIP significantly increased Per1, Per2, and Bmal1 mRNA 2 h after the lights were turned off (ZT14) in the hippocampus, but not in the amygdala. These results suggest that ZIP might affect clock gene regulation, which could represent the pathway underlying symptom amelioration.


Assuntos
Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Antipsicóticos/farmacologia , Relógios Biológicos/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Expressão Gênica/efeitos dos fármacos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , Piperazinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tiazóis/farmacologia , Tonsila do Cerebelo/metabolismo , Animais , Hipocampo/metabolismo , Luz , Masculino , Camundongos Endogâmicos C57BL
10.
Nat Commun ; 11(1): 3492, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661319

RESUMO

Ventral hippocampal CA1 (vCA1) projections to the amygdala are necessary for contextual fear memory. Here we used in vivo Ca2+ imaging in mice to assess the temporal dynamics by which ensembles of vCA1 neurons mediate encoding and retrieval of contextual fear memories. We found that a subset of vCA1 neurons were responsive to the aversive shock during context conditioning, their activity was necessary for memory encoding, and these shock-responsive neurons were enriched in the vCA1 projection to the amygdala. During memory retrieval, a population of vCA1 neurons became correlated with shock-encoding neurons, and the magnitude of synchronized activity within this population was proportional to memory strength. The emergence of these correlated networks was disrupted by inhibiting vCA1 shock responses during memory encoding. Thus, our findings suggest that networks of cells that become correlated with shock-responsive neurons in vCA1 are essential components of contextual fear memory ensembles.


Assuntos
Região CA1 Hipocampal/metabolismo , Medo/fisiologia , Memória/fisiologia , Algoritmos , Tonsila do Cerebelo/metabolismo , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
Braz J Med Biol Res ; 53(8): e9950, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32578721

RESUMO

Pathophysiological mechanisms involved in orofacial pain and their relationship with emotional disorders have emerged as an important research area for multidisciplinary studies. In particular, temporomandibular disorders (TMD) have been evaluated clinically from both physiological and psychological perspectives. We hypothesized that an altered neuronal activity occurs in the amygdala and the dorsal raphe nucleus (DR), encephalic regions involved in the modulation of painful and emotional information. Adult male Wistar rats were used in an experimental complete Freund's adjuvant (CFA)-induced temporomandibular joint (TMJ) inflammation model. CFA was applied for 1 or 10 days, and the animals were euthanized for brain samples dissection for FosB/ΔFosB and parvalbumin (PV) immunostaining. Our results were consistent in showing that the amygdala and DR were activated in the persistent inflammatory phase (10 days) and that the expression of PV+ interneurons in the amygdala was decreased. In contrast, in the DR, the expression of PV+ interneurons was increased in persistent states of CFA-induced TMJ inflammation. Moreover, at 10 days of inflammation, there was an increased co-localization of PV+ and FosB/ΔFosB+ neurons in the basolateral and central nucleus of the amygdala. Different nuclei of the amygdala, as well as portions of the DR, were activated in the persistent phase (10 days) of TMJ inflammation. In conclusion, altered activity of the amygdala and DR was detected during persistent inflammatory nociception in the temporomandibular joint. These regions may be essential for both sensory and affective dimensions of orofacial pain.


Assuntos
Tonsila do Cerebelo/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Parvalbuminas/metabolismo , Articulação Temporomandibular/fisiologia , Animais , Inflamação , Masculino , Neurônios , Ratos , Ratos Sprague-Dawley , Ratos Wistar
12.
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
13.
Exp Anim ; 69(4): 382-387, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-32350170

RESUMO

Our early weaning schedule was associated with the emergence of trait anxiety in male rodents performing an elevated plus maze but not an open-field test. We previously reported that early weaning weakened excitatory neurotransmission to the amygdala from the prefrontal cortex, where the mesocorticolimbic dopaminergic (DAergic) fiber terminates on each. In this study, we investigated DAergic transmission in both these brain regions. The extracellular levels of amygdalar DA in adulthood were two times higher in rats weaned at 16 days compared to those weaned at 30 days in both the home cage and the open-field. This difference in extracellular DA levels was not apparent in the prefrontal cortex. The concurrently measured locomotor and rearing behaviors did not vary according to the weaning period and the probe-implanted region, respectively. These results suggest that the effects of early weaning on DA tone appear to be specific to the amygdala and do not represent ubiquitous upregulation as these changes were not observed in the prefrontal cortex.


Assuntos
Tonsila do Cerebelo/metabolismo , Dopamina/metabolismo , Microdiálise , Córtex Pré-Frontal , Desmame , Animais , Feminino , Masculino , Especificidade de Órgãos , Ratos Sprague-Dawley
14.
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
15.
J Neurosci ; 40(24): 4739-4749, 2020 06 10.
Artigo em Inglês | MEDLINE | ID: mdl-32393533

RESUMO

High trait anxiety is associated with altered activity across emotion regulation circuitry and a higher risk of developing anxiety disorders and depression. This circuitry is extensively modulated by serotonin. Here, to understand why some people may be more vulnerable to developing affective disorders, we investigated whether serotonin-related gene expression across the brain's emotion regulation circuitry may underlie individual differences in trait anxiety using the common marmoset (Callithrix jacchus, mixed sexes) as a model. First, we assessed the association of region-specific expression of the serotonin transporter (SLC6A4) and serotonin receptor (HTR1A, HTR2A, HTR2C) genes with anxiety-like behavior; and second, we investigated their causal role in two key features of the high trait anxious phenotype: high responsivity to anxiety-provoking stimuli and an exaggerated conditioned threat response. While the expression of the serotonin receptors did not show a significant relationship with anxiety-like behavior in any of the targeted brain regions, serotonin transporter expression, specifically within the right ventrolateral prefrontal cortex (vlPFC) and most strongly in the right amygdala, was associated positively with anxiety-like behavior. The causal relationship between amygdala serotonin levels and an animal's sensitivity to threat was confirmed via direct amygdala infusions of a selective serotonin reuptake inhibitor (SSRI), citalopram. Both anxiety-like behaviors, and conditioned threat-induced responses were reduced by the blockade of serotonin reuptake in the amygdala. Together, these findings provide evidence that high amygdala serotonin transporter expression contributes to the high trait anxious phenotype and suggest that reduction of threat reactivity by SSRIs may be mediated by their actions in the amygdala.SIGNIFICANCE STATEMENT Findings here contribute to our understanding of how the serotonin system underlies an individual's expression of threat-elicited negative emotions such as anxiety and fear within nonhuman primates. Exploration of serotonergic gene expression across brain regions implicated in emotion regulation revealed that serotonin transporter gene expression in the ventrolateral prefrontal cortex (vlPFC) and most strongly in the amygdala, but none of the serotonin receptor genes, were predictive of interindividual differences in anxiety-like behavior. Targeting of amygdala serotonin reuptake with selective serotonin reuptake inhibitors (SSRIs) confirmed the causal relationship between amygdala serotonin transporter and an animal's sensitivity to threat by reversing expression of two key features of the high trait-like anxiety phenotype: high responsivity to anxiety-provoking uncertain threat and responsivity to certain conditioned threat.


Assuntos
Tonsila do Cerebelo/metabolismo , Ansiedade/metabolismo , Emoções/fisiologia , Comportamento Exploratório/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Ansiedade/genética , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Callithrix , Citalopram/farmacologia , Emoções/efeitos dos fármacos , Comportamento Exploratório/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/fisiologia , Feminino , Humanos , Masculino , Receptores de Serotonina/genética , Receptores de Serotonina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Inibidores de Captação de Serotonina/farmacologia
16.
Neurobiol Aging ; 91: 160-166, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32280031

RESUMO

Brain aging is accompanied by an accumulation of damaged proteins, which results from deterioration of cellular quality control mechanisms and decreased protein degradation. The ubiquitin-proteasome system (UPS) is the primary proteolytic mechanism responsible for targeted degradation. Recent work has established a critical role of the UPS in memory and synaptic plasticity, but the role of the UPS in age-related cognitive decline remains poorly understood. Here, we measured markers of UPS function and related them to fear memory in rats. Our results show that age-related memory deficits are associated with reductions in phosphorylation of the Rpt6 proteasome regulatory subunit and corresponding increases in lysine-48 (K48)-linked ubiquitin tagging within the basolateral amygdala. Increases in K48 polyubiquitination were also observed in the medial prefrontal cortex and dorsal hippocampus. These data suggest that protein degradation is a critical component of age-related memory deficits. This extends our understanding of the relationship between the UPS, aging, and memory, which is an important step toward the prevention and treatment of deficits associated with normal cognitive aging and memory-related neurodegenerative diseases.


Assuntos
Tonsila do Cerebelo/metabolismo , Envelhecimento Cognitivo/psicologia , Condicionamento Clássico , Medo/fisiologia , Hipocampo/metabolismo , Transtornos da Memória/etiologia , Memória/fisiologia , Córtex Pré-Frontal/metabolismo , Complexo de Endopeptidases do Proteassoma/fisiologia , Proteólise , Ubiquitina/fisiologia , Animais , Masculino , Fosforilação , Complexo de Endopeptidases do Proteassoma/metabolismo , Ratos Endogâmicos F344 , Ubiquitina/metabolismo
18.
Cell Mol Life Sci ; 77(19): 3745-3768, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32172301

RESUMO

Risk of relapse is a major challenge in the treatment of substance use disorders. Several types of learning and memory mechanisms are involved in substance use and have implications for relapse. Associative memories form between the effects of drugs and the surrounding environmental stimuli, and exposure to these stimuli during abstinence causes stress and triggers drug craving, which can lead to relapse. Understanding the neural underpinnings of how these associations are formed and maintained will inform future advances in treatment practices. A large body of research has expanded our knowledge of how associative memories are acquired and consolidated, how they are updated through reactivation and reconsolidation, and how competing extinction memories are formed. This review will focus on the vast literature examining the mechanisms of cocaine Pavlovian associative memories with an emphasis on the molecular memory mechanisms and circuits involved in the consolidation, reconsolidation, and extinction of these memories. Additional research elucidating the specific signaling pathways, mechanisms of synaptic plasticity, and epigenetic regulation of gene expression in the circuits involved in associative learning will reveal more distinctions between consolidation, reconsolidation, and extinction learning that can be applied to the treatment of substance use disorders.


Assuntos
Cocaína/farmacologia , Memória/efeitos dos fármacos , Transtornos Relacionados ao Uso de Substâncias/patologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Humanos , Interocepção/efeitos dos fármacos , Memória/fisiologia , Transtornos Relacionados ao Uso de Substâncias/metabolismo
19.
J Clin Neurosci ; 74: 180-186, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32111564

RESUMO

Mesial temporal lobe epilepsy with hippocampal sclerosis is the most frequent form of focal epilepsy in adults, and it is often refractory to drug treatment. Regardless of the efforts on developing new antiepileptic drugs for refractory cases, studies suggest a need for better understanding the molecular bases of epilepsy. The microRNAs have been progressively investigated as potential targets for both epilepsy mechanisms elucidation and treatment. Therefore, the goal of this study was to evaluate the differential expression of miR-219, miR-181b, and miR-195, previously described as regulators of the excitatory neurotransmitter receptors NMDA-R1 and AMPA-GluR2 and inhibitory neurotransmitter GABAA (α2, ß3, and γ2 subunits) in the amygdala and hippocampus of patients with mesial temporal lobe epilepsy. Based on genes and miRNAs' quantitative Polymerase Chain Reaction (qPCR) from 18 patients with epilepsy, our results showed an inverse relationship between miR-219 and NMDA-NR1 expression in both the amygdala and hippocampus in comparison to their expression in controls. NR1 and GluR2 were upregulated in the amygdala of epileptic patients. Low miR-195 expression was observed in the amygdala of patients with epilepsy. Our findings indicate that miR-219 has a possible regulatory role in excitatory neurotransmission in patients with epilepsy, contributing to the new avenue of miRNA biology in drug-resistant epilepsy, reserving huge potential for future applications and clinical interventions in conjunction with existing therapies.


Assuntos
Epilepsia do Lobo Temporal/metabolismo , MicroRNAs/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Tonsila do Cerebelo/metabolismo , Epilepsia do Lobo Temporal/genética , Regulação da Expressão Gênica/genética , Hipocampo/metabolismo , Humanos , Regulação para Cima
20.
Sci Rep ; 10(1): 3969, 2020 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-32123192

RESUMO

Neurodevelopment and mature brain function are spatiotemporally regulated by various cytokines and chemokines. The chemokine-like neuropeptide FAM19A1 is a member of family with sequence similarity 19 (FAM19), which is predominantly expressed in the brain. Its highly conserved amino acid sequence among vertebrates suggests that FAM19A1 may play important physiological roles in neurodevelopment and brain function. Here we used a LacZ reporter gene system to map the expression pattern of the FAM19A1 gene in the mouse brain. The FAM19A1 expression was observed in several brain regions starting during embryonic brain development. As the brain matured, the FAM19A1 expression was detected in the pyramidal cells of cortical layers 2/3 and 5 and in several limbic areas, including the hippocampus and the amygdala. FAM19A1-deficient mice were used to evaluate the physiological contribution of FAM19A1 to various brain functions. In behavior analysis, FAM19A1-deficient mice exhibited several abnormal behaviors, including hyperactive locomotor behavior, long-term memory deficits and fear acquisition failure. These findings provide insight into the potential contributions of FAM19A1 to neurodevelopment and mature brain function.


Assuntos
Comportamento Animal , Encéfalo/metabolismo , Quimiocinas/fisiologia , Condicionamento Psicológico , Medo/fisiologia , Hipercinese/fisiopatologia , Memória de Longo Prazo/fisiologia , Tonsila do Cerebelo/metabolismo , Animais , Feminino , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Knockout
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