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1.
Life Sci ; 260: 118338, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-32841662

RESUMO

AIMS: Fluoxetine (FLX) is a common selective serotonin reuptake inhibitor, which is used in adolescents with psychiatric disorders. Controversial results have been obtained in different studies about the effects of FLX on cognitive functions. The present study was designed to examine the effects of chronic FLX exposure during adolescence on cognitive function, anxiety-like behaviors, and hippocampal brain-derived neurotrophic factor (BDNF) mRNA expression among adult male and female rats. MAIN METHODS: The sex-dependent effects of FLX chronic administration during adolescence (5 mg/kg/day, gavage) on short-term novel object recognition memory (NORM), anxiety-like behaviors, and BDNF mRNA expression in the hippocampus were examined. NORM and anxiety-like behaviors were assessed by novel object recognition, open field, and elevated plus-maze (EPM) tests, respectively. The expression of BDNF mRNA was also evaluated by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). KEY FINDINGS: The present findings revealed the dysfunction of short-term NORM among the adolescent male and female rats exposed to FLX, while the mRNA expression of BDNF was significantly higher among the males. Moreover, adolescent FLX administration had different effects on the anxiety-like behaviors of the male and female rats. Adolescent FLX treatment also decreased the body weight of the male animals. SIGNIFICANCE: In conclusion, adolescent FLX treatment impairs cognitive functions in both sexes and increases BDNF mRNA expression in the hippocampus of the male animals. FLX administration during adolescence has sex-dependent effects on anxiety-like behaviors. These findings indicate that the impairment of cognitive functions can occur following the adolescent manipulation of the serotonergic system. Therefore, the side effects of chronic FLX administration during adolescence should be more considered.


Assuntos
Ansiedade/tratamento farmacológico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Fluoxetina/administração & dosagem , Hipocampo/metabolismo , Transtornos da Memória/tratamento farmacológico , Reconhecimento Psicológico/efeitos dos fármacos , Inibidores de Captação de Serotonina/administração & dosagem , Animais , Ansiedade/patologia , Fator Neurotrófico Derivado do Encéfalo/genética , Feminino , Fluoxetina/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Transtornos da Memória/metabolismo , Transtornos da Memória/patologia , Ratos , Inibidores de Captação de Serotonina/farmacologia
2.
Proc Natl Acad Sci U S A ; 117(21): 11788-11798, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32393630

RESUMO

Down syndrome (DS) is the most common form of intellectual disability. The cognitive alterations in DS are thought to depend on brain regions critical for learning and memory such as the prefrontal cortex (PFC) and the hippocampus (HPC). Neuroimaging studies suggest that increased brain connectivity correlates with lower intelligence quotients (IQ) in individuals with DS; however, its contribution to cognitive impairment is unresolved. We recorded neural activity in the PFC and HPC of the trisomic Ts65Dn mouse model of DS during quiet wakefulness, natural sleep, and the performance of a memory test. During rest, trisomic mice showed increased theta oscillations and cross-frequency coupling in the PFC and HPC while prefrontal-hippocampal synchronization was strengthened, suggesting hypersynchronous local and cross-regional processing. During sleep, slow waves were reduced, and gamma oscillations amplified in Ts65Dn mice, likely reflecting prolonged light sleep. Moreover, hippocampal sharp-wave ripples were disrupted, which may have further contributed to deficient memory consolidation. Memory performance in euploid mice correlated strongly with functional connectivity measures that indicated a hippocampal control over memory acquisition and retrieval at theta and gamma frequencies, respectively. By contrast, trisomic mice exhibited poor memory abilities and disordered prefrontal-hippocampal functional connectivity. Memory performance and key neurophysiological alterations were rescued after 1 month of chronic administration of a green tea extract containing epigallocatequin-3-gallate (EGCG), which improves executive function in young adults with DS and Ts65Dn mice. Our findings suggest that abnormal prefrontal-hippocampal circuit dynamics are candidate neural mechanisms for memory impairment in DS.


Assuntos
Síndrome de Down/fisiopatologia , Hipocampo/fisiologia , Córtex Pré-Frontal/fisiologia , Reconhecimento Psicológico/fisiologia , Animais , Catequina/análogos & derivados , Catequina/farmacologia , Modelos Animais de Doenças , Função Executiva/efeitos dos fármacos , Feminino , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Fármacos Neuroprotetores/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos
3.
Toxicology ; 436: 152437, 2020 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-32169474

RESUMO

Mild cognitive impairment in Parkinson's disease (PD-MCI) is considered as a nonmotor clinical symptom in Parkinson's disease (PD). Microglia-mediated inflammation contributes to cognitive function impairment. Poloxamer 188 (P188) is an amphipathic polymer which has cytoprotective effect in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced dopaminergic (DA) neurons degeneration in PD. But whether P188 could ameliorate cognitive impairment in PD is still illusive. In the present study, we showed in a mouse model that paraquat (10 mg/kg) and maneb (30 mg/kg) (P + M) treatment intraperitoneally twice a week for 6 consecutive weeks resulted in cognitive deficits and synapse loss in hippocampus, together with DA neuron damage in the substantia nigra pars compacta (SNpc). P188 (0.8 g/kg) injection via tail vein 30 min after P + M administration significantly restored DA neuron numbers in SNpc and synapse density in hippocampus, and alleviated P + M-mediated cognitive function impairment in novel object recognition task and morris water maze task (MWM). Pathological synapse loss might be attributed to increased microglial phagocytic activity and cell density, and P188 prevented P + M-induced phagocytic state changes of microglia, such as increase in cell body size and decrease in process length, and upregulated microglia abundance in hippocampus. Consistently, P188 attenuated P + M-mediated increased mRNA levels of microglia proliferation related CSF1r and CSF2ra, microglial engulfment associated CD68, ICAM1, and ICAM2, and pro-inflammatory IL-6, IL-1ß, CD11b, and TNF-α in hippocampus. Together, these findings suggest that the biocompatible polymer P188 blunts microglia activation which may promote synaptic loss and exacerbate cognitive function in a mouse model of PD-MCI.


Assuntos
Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Hipocampo/efeitos dos fármacos , Mediadores da Inflamação/metabolismo , Transtornos Parkinsonianos/tratamento farmacológico , Parte Compacta da Substância Negra/efeitos dos fármacos , Poloxâmero/farmacologia , Animais , Proliferação de Células/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/metabolismo , Neurônios Dopaminérgicos/patologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Maneb , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Microglia/patologia , Degeneração Neural , Paraquat , Transtornos Parkinsonianos/induzido quimicamente , Transtornos Parkinsonianos/metabolismo , Transtornos Parkinsonianos/psicologia , Parte Compacta da Substância Negra/metabolismo , Parte Compacta da Substância Negra/patologia , Fagocitose/efeitos dos fármacos , Poloxâmero/farmacocinética , Reconhecimento Psicológico/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/patologia
4.
Toxicol Appl Pharmacol ; 394: 114954, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32171570

RESUMO

Learning and memory deficits are obvious symptoms that develop over time in patients with poorly controlled diabetes. Hyperactivity of the renin-angiotensin system (RAS) is directly associated with ß-cell dysfunction and diabetic complications, including cognitive impairment. Here, we investigated the protective and molecular effects of two RAS modifiers, aliskiren; renin inhibitor and captopril; angiotensin converting enzyme inhibitor, on cognitive deficits in the rat hippocampus. Injection of low dose streptozotocin for 4 days resulted in type 1 diabetes. Then, poorly controlled diabetes was mimicked with ineffective daily doses of insulin for 4 weeks. The hyperglycaemia and pancreatic atrophy caused memory disturbance that were identifiable in behavioural tests, hippocampal neurodegeneration, and the following significant changes in the hippocampus, increases in the inflammatory marker interleukin 1ß, cholinesterase, the oxidative stress marker malondialdehyde and protein expression of phosphorylated extracellular-signal-regulated kinase and glycogen synthase kinase-3 beta versus decrease in the antioxidant reduced glutathione and protein expression of phosphorylated glycogen synthase kinase-3 beta. Blocking RAS with either drugs along with insulin amended all previously mentioned parameters. Aliskiren stabilized the blood glucose level and restored normal pancreatic integrity and hippocampal malondialdehyde level. Aliskiren showed superior protection against the hippocampal degeneration displayed in the earlier behavioural modification in the passive avoidance test, and the aliskiren group outperformed the control group in the novel object recognition test. We therefore conclude that aliskiren and captopril reversed the diabetic state and cognitive deficits in rats with poorly controlled STZ-induced diabetes through reducing oxidative stress and inflammation and modulating protein expression.


Assuntos
Amidas/uso terapêutico , Captopril/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/psicologia , Diabetes Mellitus Experimental/psicologia , Fumaratos/uso terapêutico , Quinase 3 da Glicogênio Sintase/antagonistas & inibidores , Hipocampo/efeitos dos fármacos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Encéfalo/patologia , Colinesterases/metabolismo , Disfunção Cognitiva/etiologia , Diabetes Mellitus Experimental/patologia , Hipocampo/enzimologia , Hipocampo/patologia , Interleucina-1beta/biossíntese , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Pâncreas/patologia , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos
5.
Brain Behav Immun ; 87: 645-659, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32097763

RESUMO

Glioblastoma is a kind of malignant tumour and originates from the central nervous system. In the last century, some researchers and clinician have noticed that the psychosocial and neurocognitive functioning of patients with malignant gliomas can be impaired. Many clinical studies have demonstrated that part of patients, adults or children, diagnosed with glioblastoma will suffer from cognitive deficiency during their clinical course, especially in long-term survivors. Many nanoparticles (NPs) can inhibit the biological functions of tumours by modulating tumour-associated inflammation, which provokes angiogenesis and tumour growth. As one of the best antiviral nanoparticles (AVNPs), AVNP2 is the 2nd generation of AVNP2 that have been conjugated to graphite-graphene for improving physiochemical performance and reducing toxicity. AVNP2 inactivates viruses, such as the H1N1 and H5N1influenza viruses and even the SARS coronavirus, while it inhibits bacteria, such as MRSA and E. coli. As antimicrobials, nanoparticles are considered to be one of the vectors for the administration of therapeutic compounds. Yet, little is known about their potential functionalities and toxicities to the neurotoxic effects of cancer. Herein, we explored the functionality of AVNP2 on inhibiting C6 in glioma-bearing rats. The novel object-recognition test and open-field test showed that AVNP2 significantly improved the neuro-behaviour affected by C6 glioma. AVNP2 also alleviated the decline of long-term potentiation (LTP) and the decreased density of dendritic spines in the CA1 region induced by C6. Western blot assay and immunofluorescence staining showed that the expressions of synaptic-related proteins (PSD-95 and SYP) were increased, and these findings were in accordance with the results mentioned above. It revealed that the sizes of tumours in C6 glioma-bearing rats were smaller after treatment with AVNP2. The decreased expression of inflammatory factors (IL-1ß, IL-6 and TNF-α) by Western blotting assay and ELISA, angiogenesis protein (VEGF) by Western blotting assay and other related proteins (BDNF, NF-ĸB, iNOS and COX-2) by Western blotting assay in peri-tumour tissue indicated that AVNP2 could control tumour-associated inflammation, thus efficiently ameliorating the local inflammatory condition and, to some extent, inhibiting angiogenesis in C6-bearing rats. In conclusion, our results suggested that AVNP2 could have an effect on the peri-tumor environment, obviously restraining the growth progress of gliomas, and eventually improving cognitive levels in C6-bearing rats.


Assuntos
Antivirais/uso terapêutico , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/psicologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Encefalite/etiologia , Encefalite/prevenção & controle , Glioma/complicações , Glioma/psicologia , Nanopartículas/uso terapêutico , Animais , Comportamento Animal , Peso Corporal/efeitos dos fármacos , Região CA1 Hipocampal/efeitos dos fármacos , Região CA1 Hipocampal/patologia , Disfunção Cognitiva/psicologia , Citocinas/biossíntese , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Humanos , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Transplante de Neoplasias , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/biossíntese , Fator A de Crescimento do Endotélio Vascular/genética
6.
Psychopharmacology (Berl) ; 237(6): 1577-1593, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32076746

RESUMO

RATIONALE: Schizophrenia is a mental illness which is characterised by positive and negative symptoms and by cognitive impairments. While the major prevailing hypothesis is that altered dopaminergic and/or glutamatergic transmission contributes to this disease, there is evidence that the noradrenergic system also plays a role in its major symptoms. OBJECTIVES: In the present paper, we investigated the pro-cognitive effect of 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) an endogenous neuroprotective compound, on ketamine-modelled schizophrenia in rats. METHODS: We used an antagonist of NMDA receptors (ketamine) to model memory deficit symptoms in rats. Using the novel object recognition (NOR) test, we investigated the pro-cognitive effect of 1MeTIQ. Additionally, olanzapine, an atypical antipsychotic drug, was used as a standard to compare the pro-cognitive effects of the substances. In vivo microdialysis studies allowed us to verify the changes in the release of monoamines and their metabolites in the rat striatum. RESULTS: Our study demonstrated that 1MeTIQ, similarly to olanzapine, exhibits a pro-cognitive effect in NOR test and enhances memory disturbed by ketamine treatment. Additionally, in vivo microdialysis studies have shown that ketamine powerfully increased noradrenaline release in the rat striatum, while 1MeTIQ and olanzapine completely antagonised this neurochemical effect. CONCLUSIONS: 1MeTIQ, as a possible pro-cognitive drug, in contrast to olanzapine, expresses beneficial neuroprotective activity in the brain, increasing concentration of the extraneuronal dopamine metabolite, 3-methoxytyramine (3-MT), which plays an important physiological role in the brain as an inhibitory regulator of catecholaminergic activity. Moreover, we first demonstrated the essential role of noradrenaline release in memory disturbances observed in the ketamine-model of schizophrenia, and its possible participation in negative symptoms of the schizophrenia.


Assuntos
Ketamina/toxicidade , Atividade Motora/efeitos dos fármacos , Nootrópicos/uso terapêutico , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Tetra-Hidroisoquinolinas/uso terapêutico , Animais , Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Corpo Estriado/efeitos dos fármacos , Dopamina/análogos & derivados , Dopamina/metabolismo , Antagonistas de Aminoácidos Excitatórios/toxicidade , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Masculino , Microdiálise , Atividade Motora/fisiologia , Nootrópicos/farmacologia , Norepinefrina/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Tetra-Hidroisoquinolinas/farmacologia , Resultado do Tratamento
7.
Psychopharmacology (Berl) ; 237(6): 1607-1619, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32088834

RESUMO

RATIONALE: Cortical and hippocampal neuronal apoptosis and neuroinflammation are associated with behavioral deficits following traumatic brain injury (TBI). OBJECTIVES: The present study was designed to investigate the potential protective effects of flavonoid chrysin against TBI-induced vestibulomotor impairment, exploratory/locomotor dysfunctions, recognition memory decline, and anxiety/depression-like behaviors, as well as the verified possible involved mechanisms. METHODS: Chrysin (25, 50, or 100 mg/kg/day; P.O.) was administered to rats immediately after diffuse TBI induction, and it was continued for 3 or 14 days. Behavioral functions were assessed by employing standard behavioral paradigms at scheduled points in time. Three days post-TBI, inflammation status was assayed in both cerebral cortex and hippocampus using ELISA kits. Moreover, apoptosis and expression of Bcl-2 family proteins were examined by TUNEL staining and immunohistochemistry, respectively. RESULTS: The results indicated that treatment with chrysin improved vestibulomotor dysfunction, ameliorated recognition memory deficit, and attenuated anxiety/depression-like behaviors in the rats with TBI. Chrysin treatment also modulated inflammation status, reduced apoptotic index, and regulated Bcl-2 family proteins expression in the brains of rats with TBI. CONCLUSIONS: In conclusion, the results suggest that chrysin could be beneficial for protection against TBI-associated behavioral deficits, owing to its anti-apoptotic and anti-inflammatory properties.


Assuntos
Ansiedade/tratamento farmacológico , Lesões Encefálicas Traumáticas/tratamento farmacológico , Depressão/tratamento farmacológico , Flavonoides/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Ansiedade/etiologia , Ansiedade/psicologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/psicologia , Depressão/etiologia , Depressão/psicologia , Flavonoides/farmacologia , Masculino , Transtornos da Memória/etiologia , Transtornos da Memória/metabolismo , Transtornos da Memória/psicologia , Ratos , Ratos Wistar
8.
Psychopharmacology (Berl) ; 237(4): 1209-1221, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31912193

RESUMO

RATIONALE: Parental drug use around or before conception can have adverse consequences for offspring. Historically, this research has focused on the effects of maternal substance use on future generations but less is known about the influence of the paternal lineage. This study focused on the impact of chronic paternal morphine exposure prior to conception on behavioral outcomes in male and female progeny. OBJECTIVES: This study sought to investigate the impact of paternal morphine self-administration on anxiety-like behavior, the stress response, and memory in male and female offspring. METHODS: Adult, drug-naïve male and female progeny of morphine-treated sires and controls were evaluated for anxiety-like behavior using defensive probe burying and novelty-induced hypophagia paradigms. Hypothalamic-pituitary-adrenal (HPA) axis function was assessed by measuring plasma corticosterone levels following a restraint stressor in male and female progeny. Memory was probed using a battery of tests including object location memory, novel object recognition, and contextual fear conditioning. RESULTS: Paternal morphine exposure did not alter anxiety-like behavior or stress-induced HPA axis activation in male or female offspring. Morphine-sired male and female offspring showed intact hippocampus-dependent memory: they performed normally on the long-term fear conditioning and object location memory tests. In contrast, paternal morphine exposure selectively disrupted novel object recognition in female, but not male, progeny. CONCLUSIONS: Our findings demonstrate that paternal morphine taking produces sex-specific and selective impairments in object recognition memory while leaving hippocampal function largely intact.


Assuntos
Analgésicos Opioides/administração & dosagem , Transtornos da Memória/induzido quimicamente , Morfina/administração & dosagem , Exposição Paterna/efeitos adversos , Reconhecimento Psicológico/efeitos dos fármacos , Caracteres Sexuais , Animais , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Transtornos da Memória/psicologia , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/fisiologia , Autoadministração
9.
Brain ; 143(1): 359-373, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31782760

RESUMO

Failure of Alzheimer's disease clinical trials to improve or stabilize cognition has led to the need for a better understanding of the driving forces behind cognitive decline in the presence of active disease processes. To dissect contributions of individual pathologies to cognitive function, we used the TgF344-AD rat model, which recapitulates the salient hallmarks of Alzheimer's disease pathology observed in patient populations (amyloid, tau inclusions, frank neuronal loss, and cognitive deficits). scyllo-Inositol treatment attenuated amyloid-ß peptide in disease-bearing TgF344-AD rats, which rescued pattern separation in the novel object recognition task and executive function in the reversal learning phase of the Barnes maze. Interestingly, neither activities of daily living in the burrowing task nor spatial memory in the Barnes maze were rescued by attenuating amyloid-ß peptide. To understand the pathological correlates leading to behavioural rescue, we examined the neuropathology and in vivo electrophysiological signature of the hippocampus. Amyloid-ß peptide attenuation reduced hippocampal tau pathology and rescued adult hippocampal neurogenesis and neuronal function, via improvements in cross-frequency coupling between theta and gamma bands. To investigate mechanisms underlying the persistence of spatial memory deficits, we next examined neuropathology in the entorhinal cortex, a region whose input to the hippocampus is required for spatial memory. Reduction of amyloid-ß peptide in the entorhinal cortex had no effect on entorhinal tau pathology or entorhinal-hippocampal neuronal network dysfunction, as measured by an impairment in hippocampal response to entorhinal stimulation. Thus, rescue or not of cognitive function is dependent on regional differences of amyloid-ß, tau and neuronal network dysfunction, demonstrating the importance of staging disease in patients prior to enrolment in clinical trials. These results further emphasize the need for combination therapeutic approaches across disease progression.


Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/efeitos dos fármacos , Cognição/efeitos dos fármacos , Córtex Entorrinal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Inositol/farmacologia , Memória Espacial/efeitos dos fármacos , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/psicologia , Peptídeos beta-Amiloides/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Córtex Entorrinal/metabolismo , Córtex Entorrinal/patologia , Função Executiva/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Aprendizagem em Labirinto , Vias Neurais , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/patologia , Neurogênese/efeitos dos fármacos , Ratos , Ratos Transgênicos , Reconhecimento Psicológico/efeitos dos fármacos , Reversão de Aprendizagem/efeitos dos fármacos
10.
Horm Behav ; 119: 104647, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31778719

RESUMO

Relatively little is known about the effects of endogenous and exogenous steroid hormones on ecologically relevant behavioral and cognitive phenotypes in women, such as emotion recognition, despite the widespread use of steroid hormone-altering hormonal contraceptives (HCs). Though some previous studies have examined the effect of HC use, estradiol, progesterone, and testosterone on emotion recognition in women, they have been limited by cross-sectional designs, small sample sizes (total n < 100), and compromised statistical power to detect significant effects. Using data from two test sessions in a large sample of naturally cycling women (NC; n = 192) and women on HCs (n = 203), we found no group differences in emotion recognition; further, the lack of group differences in emotion recognition was not modulated by item difficulty or emotional valence. Among NC women who provided saliva samples across two sessions that were assayed for estradiol and progesterone concentrations, we found no compelling evidence across models that between-subject differences and within-subject fluctuations in these ovarian hormones predicted emotion recognition accuracy, with the exception that between-subjects estradiol negatively predicted emotion recognition for emotions of neutral valence (p = .042). Among HC women who provided saliva samples across two sessions that were assayed for testosterone, we found no compelling evidence that between-subjects differences and within-subject fluctuations in testosterone predicted emotion recognition accuracy. Overall, our analyses provide little support for the idea that circulating endogenous or exogenous ovarian hormones influence emotion recognition in women.


Assuntos
Anticoncepcionais Orais Hormonais/farmacologia , Inteligência Emocional/efeitos dos fármacos , Hormônios Esteroides Gonadais/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Adulto , Estudos Transversais , Inteligência Emocional/fisiologia , Emoções , Estradiol/análise , Estradiol/metabolismo , Feminino , Hormônios Esteroides Gonadais/análise , Humanos , Ovário/efeitos dos fármacos , Ovário/metabolismo , Progesterona/análise , Progesterona/metabolismo , Reconhecimento Psicológico/fisiologia , Saliva/química , Saliva/metabolismo , Testosterona/análise , Testosterona/metabolismo , Adulto Jovem
11.
Horm Behav ; 119: 104638, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31765660

RESUMO

Social behavior plays a significant role in the formation of social structure and population regulation in both animals and humans. Oxytocin (OXT) and its receptor (OXTR) are well known for regulating social behaviors, but their upstream regulating factors are rarely investigated. We hypothesized that the phosphorylation of the signal transducer and activator of transcription 3 (p-Stat3) may regulate social and aggressive behaviors via the OXT system in the nucleus accumbens (NAc). To test this hypothesis, OXT, p-Stat3 inhibitor, OXTR antagonist, and OXT plus p-Stat3 inhibitor were infused, respectively, into the NAc in the brain of male Brandt's voles (Lasiopodomys brandtii) - a social rodent species in grassland of Inner Mongolia, China. Our data showed that blockage of p-Stat3-Tyr705 signaling pathway in the NAc not only increased aggressive behavior but also impaired social recognition of male Brandt's voles via its effects on the expression of local OXT and OXTR. These results have illustrated a novel signaling pathway of p-Stat3-Tyr705 in regulating social behaviors via the OXT system.


Assuntos
Arvicolinae/fisiologia , Núcleo Accumbens/metabolismo , Ocitocina/fisiologia , Receptores de Ocitocina/fisiologia , Fator de Transcrição STAT3/metabolismo , Comportamento Social , Agressão/efeitos dos fármacos , Agressão/fisiologia , Animais , Arvicolinae/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiologia , Células HeLa , Humanos , Masculino , Núcleo Accumbens/efeitos dos fármacos , Ocitocina/farmacologia , Fosforilação/efeitos dos fármacos , Proteínas Quinases/metabolismo , Piridinas/farmacologia , Receptores de Ocitocina/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Tirfostinas/farmacologia
12.
Toxicology ; 429: 152327, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31704166

RESUMO

Diazinon is a widely-used organophosphate pesticide. Pulsatile exposure to diazinon during neonatal development has previously been shown cause long-term neurobehavioral impairments in rats. However, the effects of chronic low concentration exposures during perinatal development remain unclear. This experiment evaluated such effects in Sprague-Dawley rats by implanting osmotic pumps in breeder females prior to conception (N = 13-15 litters per condition) which then delivered chronic, zero order kinetic low-level infusions of 0, 114 or 228 ug/day of diazinon throughout pregnancy. One male and one female from each litter was assessed with a battery of behavioral tests that continued from four weeks of age into adulthood. Litter was used as the unit of variance for the analysis of variance test of significance, with sex as a within litter factor. Diazinon treatment condition was the between subjects factor and time or sessions were repeated measures. Chronic diazinon exposure from pre-mating until the neonatal period caused a significant (p < 0.05) increase in percent of time spent on the open arms of the elevated plus maze, an index of risk-taking behavior. Gestational and lactational diazinon exposure also caused a significant (p < 0.05) degree of hyperactivity in the Figure-8 apparatus during adolescence, specifically affecting the early part of the hour-long test session. This effect had dissipated by the time the rats reached adulthood. Diazinon exposure also caused a significant impairment in novel object recognition, a test of cognitive function. Offspring exposed to 228 ug/day diazinon (p < 0.05) showed significantly less preference for the novel vs. familiar object than controls during the first five minutes of the novel object recognition test.


Assuntos
Comportamento Animal/efeitos dos fármacos , Diazinon/toxicidade , Inseticidas/toxicidade , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Animais , Cognição/efeitos dos fármacos , Diazinon/administração & dosagem , Feminino , Inseticidas/administração & dosagem , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Gravidez , Ratos , Ratos Sprague-Dawley , Reconhecimento Psicológico/efeitos dos fármacos
13.
Biol Pharm Bull ; 43(2): 272-283, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31748466

RESUMO

Accumulating evidence suggests that the inhibition of neuroinflammation is a potential target for therapeutic or preventive strategies for Alzheimer's disease (AD). Chemerin has attracted particular attention for its role in the regulation of inflammation. In addition, amyloid ß1-42 (Aß1-42) can interact with chemokine-like receptor 1 (CMKLR1), the receptor for chemerin, and induce microglial chemotaxis. Meanwhile, CMKLR1 is expressed in the brain, and both chemerin and Aß1-42 share the same receptor. Thus, we hypothesized that chemerin (C9), a chemerin-derived nonapeptide, may have the potential to ameliorate Aß1-42 mediated AD disease progression. The results showed that an intracerebroventricular (i.c.v.) injection of C9 (8 µg/kg) facilitated memory formation and improved memory retention, as evidenced by the results of both the novel object recognition test (NOR) and object location recognition (OLR) tasks. These memory-enhancing effects of C9 were also observed after C9 (2 µg/kg) was infused into the hippocampus. Moreover, we found that treatment with C9 reversed the deficits in memory and learning ability induced by oligomeric Aß1-42. Meanwhile, C9 also significantly inhibited Aß1-42-induced increases in the levels of pro-inflammatory cytokines such as interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the hippocampus. The same results were obtained for Western blotting and enzyme-linked immunosorbent assay (ELISA) experiments. Finally, we observed that C9 did not affect locomotor activity, suggesting that its improvement of memory is not a false positive induced by hypolocomotion. In conclusion, C9 may facilitate memory formation, prolong memory retention, and ameliorate Aß1-42-induced memory impairment, suggesting that C9 may potentially represent a novel strategy for the treatment of AD.


Assuntos
Peptídeos beta-Amiloides , Quimiocinas/farmacologia , Quimiocinas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Transtornos da Memória/induzido quimicamente , Fragmentos de Peptídeos , Reconhecimento Psicológico/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Animais , Citocinas/metabolismo , Hipocampo/efeitos dos fármacos , Inflamação , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Receptores de Quimiocinas/metabolismo
14.
Horm Behav ; 117: 104589, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593697

RESUMO

Studies have shown that the evolutionarily conserved neuropeptide oxytocin (OT) promotes various prosocial behaviors, yet there are few studies of the effect of OT on social judgments, especially on judgments when the actor's intention and the final outcome are incongruent. In a double-blind, placebo-controlled experiment, participants were asked to play the role of the recipient in a dictator game and to make social judgments about the dictator after intranasal OT administration. To isolate the outcome and the intention of the dictator's allocation, we developed a novel social judgment task in which recipients were told that 50% of the dictators' proposals would be reversed. The results showed that the effect of OT on social judgment was modulated by intention: OT increased goodness ratings only towards dictators with hyperfair intention. Our findings support the affiliative-motivation theory which states that OT enhances the affiliative motivation and recognition of positive-valence social stimuli.


Assuntos
Intenção , Julgamento/efeitos dos fármacos , Ocitocina/farmacologia , Administração Intranasal , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Motivação/efeitos dos fármacos , Ocitocina/administração & dosagem , Placebos , Reconhecimento Psicológico/efeitos dos fármacos , Comportamento Social , Adulto Jovem
15.
J Pharm Pharmacol ; 72(1): 149-160, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31713882

RESUMO

OBJECTIVES: A botanical drug derived from the ethanolic extract composed of Clematis chinensis Osbeck (Ranunculaceae), Trichosanthes kirilowii Maximowicz (Cucurbitaceae) and Prunella vulgaris Linné (Lamiaceae) has been used to ameliorate rheumatoid arthritis as an ethical drug in Korea. In our study, we investigated the effect of this herbal complex extract (HCE) on schizophrenia-like behaviours induced by MK-801. METHODS: HCE (30, 100 or 300 mg/kg, p.o) was orally administered to male ICR mice to a schizophrenia-like animal model induced by MK-801. We conducted an acoustic startle response task, an open-field task, a novel object recognition task and a social novelty preference task. KEY FINDINGS: We found that a single administration of HCE (100 or 300 mg/kg) ameliorated MK-801-induced abnormal behaviours including sensorimotor gating deficits and social or object recognition memory deficits. In addition, MK-801-induced increases in phosphorylated Akt and GSK-3ß expression levels in the prefrontal cortex were reversed by HCE (30, 100 or 300 mg/kg). CONCLUSIONS: These results imply that HCE ameliorates MK-801-induced dysfunctions in prepulse inhibition, social interactions and cognitive function, partly by regulating the Akt and GSK-3ß signalling pathways.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Disfunção Cognitiva/prevenção & controle , Transtornos Neurológicos da Marcha/prevenção & controle , Extratos Vegetais/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Esquizofrenia/prevenção & controle , Filtro Sensorial/efeitos dos fármacos , Animais , Clematis , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/fisiopatologia , Disfunção Cognitiva/psicologia , Modelos Animais de Doenças , Maleato de Dizocilpina , Transtornos Neurológicos da Marcha/induzido quimicamente , Transtornos Neurológicos da Marcha/fisiopatologia , Transtornos Neurológicos da Marcha/psicologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Locomoção/efeitos dos fármacos , Masculino , Camundongos Endogâmicos ICR , Fosforilação , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Prunella , Reconhecimento Psicológico/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Esquizofrenia/induzido quimicamente , Psicologia do Esquizofrênico , Comportamento Social , Trichosanthes
16.
Int J Neurosci ; 130(3): 262-269, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31544572

RESUMO

Aim of the study: High-fat diet (HFD) consumption and insufficient vitamin D levels are globally increasing phenomena. The present study assessed the effect of chronic HFD feeding with and without vitamin D supplementation on recognition memory and prefrontal cortex expression of choline acetyltransferase (CAT) and acetylcholinesterase (Achase).Materials and methods: Forty male Wistar rats were subjected to four dietary regimens (n = 10); control diet (10% fat), control + vitamin D3, high-fat diet (HFD 45% fat) and HFD + vitamin D3 for 6 months. Rats were tested for the novel object recognition test, and their prefrontal cortices were assessed for expression of CAT and Achase.Results: Recognition memory was impaired in HFD-fed rats compared to control rats as evidenced by significantly decreased discrimination index in the novel object recognition test. Moreover, CAT expression was significantly decreased while Achase expression was significantly increased in the prefrontal cortex of HFD-fed rats. Vitamin D3 supplementation with HFD significantly increased the exploration of the novel object and the discrimination index and attenuated the alterations in the prefrontal cortex CAT and Achase expression.Conclusions: The present findings support the potential effect of vitamin D on recognition memory and cholinergic transmission in the prefrontal cortex and add to the pathophysiology of HFD consumption.


Assuntos
Acetilcolinesterase/metabolismo , Comportamento Animal/efeitos dos fármacos , Colecalciferol/farmacologia , Colina O-Acetiltransferase/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/etiologia , Dieta Hiperlipídica/efeitos adversos , Memória Episódica , Córtex Pré-Frontal/enzimologia , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Colecalciferol/administração & dosagem , Suplementos Nutricionais , Modelos Animais de Doenças , Masculino , Ratos , Ratos Wistar
17.
Lasers Med Sci ; 35(3): 573-584, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31372913

RESUMO

The effectiveness of transcranial photobiomodulation (tPBM) and methylene Blue (MB) in treating learning and memory impairments is previously reported. In this study, we investigated the effect of tPBM and MB in combination or alone on unpredictable chronic mild stress (UCMS)-induced learning and memory impairments in mice. Fifty-five male BALB/c mice were randomly allocated to five groups: control, laser sham + normal saline (NS), tPBM + NS, laser sham + MB, and tPBM + MB. All groups except the control underwent UCMS and were treated simultaneously for 4 weeks. Elevated plus maze (EPM) was used to evaluate anxiety-like behaviors. Novel object recognition (NOR) test and Barnes maze tests were used to evaluate learning and memory function. The serum cortisol and brain nitric oxide (NO), reactive oxygen species (ROS), total antioxidant capacity (TAC), glutathione peroxidase (GPx), and superoxide dismutase (SOD) levels were measured by spectrophotometric methods. Behavioral tests revealed that UCMS impaired learning and memory, and treatment with PBM, MB, and their combination reversed these impairments. Levels of NO, ROS, SOD activity in brain, and serum cortisol levels significantly increased while brain GPx activity and total antioxidant capacity significantly decreased in the sham + NS animals when compared with the controls. A significant improvement was observed in treatment groups due to reversion of the aforementioned molecular analysis caused by UCMS when it was compared with control levels. Both tPBM and MB in combination or alone have significant therapeutic effects on learning and memory impairments in UCMS-received animals.


Assuntos
Comportamento Animal/efeitos dos fármacos , Comportamento Animal/efeitos da radiação , Terapia com Luz de Baixa Intensidade , Azul de Metileno/farmacologia , Crânio , Animais , Antioxidantes/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiologia , Encéfalo/efeitos da radiação , Modelos Animais de Doenças , Glutationa Peroxidase/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/efeitos da radiação , Memória/efeitos dos fármacos , Memória/efeitos da radiação , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/efeitos da radiação , Superóxido Dismutase/metabolismo
18.
Acta Pharmacol Sin ; 41(2): 145-153, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31213670

RESUMO

Type 2 diabetes (T2D) and Alzheimer's disease (AD) share several common pathophysiological features. Huperzine A (Hup A), a Lycopodium alkaloid extracted from the Chinese herb moss Huperzia serrata, is a specific and reversible inhibitor of acetylcholinesterase, which is clinically used for the treatment of AD. In this study, we investigated whether Hup A improved the metabolic and cognitive functions in the high fat-induced (HFD) obese mice and genetic ob/ob mice. HFD and ob/ob mice were treated with Hup A (0.1, 0.3 mg · kg-1 · d-1, ig) for 3 months. Body weight was monitored and glucose tolerance tests were performed. Novel object recognition test and Morris water maze assay were conducted to evaluate the cognitive functions. We found that the Hup A treatment had no significant effect on peripheral metabolism of obese mice, whereas Hup A (0.1, mg · kg-1 · d-1) improved both the abilities of object recognition and spatial memory in HFD-fed mice, but not in ob/ob mice. Furthermore, Hup A treatment significantly upregulated the insulin and phosphorylated Akt levels in the cortex of HFD-fed mice, but not ob/ob mice. In addition, Hup A (0.3, mg · kg-1 · d-1) significantly decreased cortical ß-secretase (BACE1) expression. In conclusion, these results demonstrate that treatment with Hup A (0.1, mg · kg-1 · d-1) can effectively improve the cognitive functions, at least in diet-induced obese mice.


Assuntos
Alcaloides/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Insulina/metabolismo , Obesidade/complicações , Sesquiterpenos/farmacologia , Alcaloides/administração & dosagem , Animais , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/farmacologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Obesidade/tratamento farmacológico , Reconhecimento Psicológico/efeitos dos fármacos , Sesquiterpenos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacos
19.
Mol Neurobiol ; 57(1): 315-330, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31332763

RESUMO

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by cognitive decline and dementia with no effective treatment. Here, we investigated a novel compound from oats named avenanthramide-C (Avn-C), on AD-related memory impairment and behavioral deficits in transgenic mouse models. Acute hippocampal slices of wild-type or AD transgenic mice were treated with Avn-C in the presence or absence of oligomeric Aß42. LTP analyses and immunoblotting were performed to assess the effect of Avn-C on Aß-induced memory impairment. To further investigate the effect of Avn-C on impaired memory and Aß pathology, two different AD transgenic mice (Tg2576 and 5XFAD) models were orally treated with either Avn-C or vehicle for 2 weeks. They were then assessed for the effect of the treatment on neuropathologies and behavioral impairments. Avn-C reversed impaired LTP in both ex vivo- and in vivo-treated AD mice hippocampus. Oral administration (6 mg/kg per day) for 2 weeks in AD mice leads to improved recognition and spatial memory, reduced caspase-3 cleavage, reversed neuroinflammation, and to accelerated glycogen synthase kinase-3ß (pS9GSK-3ß) and interleukin (IL-10) levels. Avn-C exerts its beneficial effects by binding to α1A adrenergic receptors to stimulate adenosine monophosphate-activated kinase (AMPK). All of the beneficial effects of Avn-C on LTP retrieval could be blocked by prazosin hydrochloride, a specific inhibitor of α1A adrenergic receptors. Our findings provide evidence, for the first time, that oats' Avn-C reverses the AD-related memory and behavioral impairments, and establish it as a potential candidate for Alzheimer's disease drug development.


Assuntos
Doença de Alzheimer/fisiopatologia , Cognição/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , ortoaminobenzoatos/farmacologia , Adenilato Quinase/metabolismo , Administração Oral , Doença de Alzheimer/enzimologia , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/patologia , Encéfalo/fisiopatologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Inflamação/patologia , Potenciação de Longa Duração/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Modelos Biológicos , Receptores Adrenérgicos alfa 1/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Memória Espacial , ortoaminobenzoatos/administração & dosagem
20.
Brain ; 143(1): 266-288, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31848580

RESUMO

Huntington's disease is associated with a reactive microglial response and consequent inflammation. To address the role of these cells in disease pathogenesis, we depleted microglia from R6/2 mice, a rapidly progressing model of Huntington's disease marked by behavioural impairment, mutant huntingtin (mHTT) accumulation, and early death, through colony-stimulating factor 1 receptor inhibition (CSF1Ri) with pexidartinib (PLX3397) for the duration of disease. Although we observed an interferon gene signature in addition to downregulated neuritogenic and synaptic gene pathways with disease, overt inflammation was not evident by microglial morphology or cytokine transcript levels in R6/2 mice. Nonetheless, CSF1Ri-induced microglial elimination reduced or prevented disease-related grip strength and object recognition deficits, mHTT accumulation, astrogliosis, and striatal volume loss, the latter of which was not associated with reductions in cell number but with the extracellular accumulation of chondroitin sulphate proteoglycans (CSPGs)-a primary component of glial scars. A concurrent loss of proteoglycan-containing perineuronal nets was also evident in R6/2 mice, and microglial elimination not only prevented this but also strikingly increased perineuronal nets in the brains of naïve littermates, suggesting a new role for microglia as homeostatic regulators of perineuronal net formation and integrity.


Assuntos
Aminopiridinas/farmacologia , Matriz Extracelular/efeitos dos fármacos , Proteína Huntingtina/efeitos dos fármacos , Doença de Huntington/metabolismo , Microglia/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Pirróis/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Animais , Astrócitos/efeitos dos fármacos , Proteoglicanas de Sulfatos de Condroitina/efeitos dos fármacos , Proteoglicanas de Sulfatos de Condroitina/metabolismo , Citocinas/efeitos dos fármacos , Citocinas/genética , Modelos Animais de Doenças , Regulação para Baixo , Matriz Extracelular/metabolismo , Força da Mão , Humanos , Proteína Huntingtina/genética , Proteína Huntingtina/metabolismo , Doença de Huntington/genética , Doença de Huntington/patologia , Doença de Huntington/fisiopatologia , Inflamação , Camundongos , Camundongos Transgênicos , Neostriado/patologia , Neuritos/efeitos dos fármacos , RNA Mensageiro/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Sinapses/efeitos dos fármacos , Transcriptoma
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