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1.
Bratisl Lek Listy ; 120(12): 881-886, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31855045

RESUMO

BACKGROUND: Galangin, a flavonoid compound with acetylcholinesterase inhibitory activity, may improve cognitive functions by enhancing cholinergic transmission. OBJECTIVES: We aimed to investigate the effects of galangin on spatial memory impairment in rats. METHODS: The effects of galangin (50 and 100 mg/kg) and reference anti-dementia drug donepezil (1mg/kg) administrations were examined on memory impairment induced by the muscarinic cholinergic receptor antagonist scopolamine or the nicotinic cholinergic receptor antagonist mecamylamine in the Morris water maze (MWM) test. Hippocampal acetylcholine concentrations were also determined. RESULTS: Galangin 50 and 100 mg/kg significantly decreased the mean distance to platform and increased the time spent in the escape platform quadrant in scopolamine-treated rats. Galangin 100 mg/kg significantly decreased the mean distance to platform and increased the time spent in the escape platform quadrant in mecamylamine-treated rats. The effects of galangin in the MWM were comparable with donepezil. Scopolamine and mecamylamine decreased acetylcholine concentrations, whereas galangin both alone and with mecamylamine or scopolamine administration increased acetylcholine concentrations. CONCLUSION: Galangin improved memory impairment comparable to donepezil and nicotinic and muscarinic receptors may be involved in this effect. Galangin may be considered as a promising flavonoid in the prevention and treatment of memory impairment in Alzheimer's disease and other dementias (Fig. 7,Ref. 37).


Assuntos
Aprendizagem da Esquiva/efeitos dos fármacos , Flavonoides/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Mecamilamina/toxicidade , Escopolamina/toxicidade , Memória Espacial/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/fisiologia , Inibidores da Colinesterase , Donepezila , Flavonoides/administração & dosagem , Aprendizagem em Labirinto/fisiologia , Mecamilamina/efeitos adversos , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Escopolamina/efeitos adversos
2.
Nat Neurosci ; 22(11): 1806-1819, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31636448

RESUMO

Prediabetes and Alzheimer's disease both increase in prevalence with age. The former is a risk factor for the latter, but a mechanistic linkage between them remains elusive. We show that prediabetic serum hyperinsulinemia is reflected in the cerebrospinal fluid and that this chronically elevated insulin renders neurons resistant to insulin. This leads to abnormal electrophysiological activity and other defects. In addition, neuronal insulin resistance reduces hexokinase 2, thus impairing glycolysis. This hampers the ubiquitination and degradation of p35, favoring its cleavage to p25, which hyperactivates CDK5 and interferes with the GSK3ß-induced degradation of ß-catenin. CDK5 contributes to neuronal cell death while ß-catenin enters the neuronal nucleus and re-activates the cell cycle machinery. Unable to successfully divide, the neuron instead enters a senescent-like state. These findings offer a direct connection between peripheral hyperinsulinemia, as found in prediabetes, age-related neurodegeneration and cognitive decline. The implications for neurodegenerative conditions such as Alzheimer's disease are described.


Assuntos
Envelhecimento/fisiologia , Ciclo Celular/fisiologia , Senescência Celular/fisiologia , Hiperinsulinismo/fisiopatologia , Resistência à Insulina/fisiologia , Neurônios/fisiologia , Animais , Morte Celular/fisiologia , Senescência Celular/efeitos dos fármacos , Quinase 5 Dependente de Ciclina/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Expressão Gênica/efeitos dos fármacos , Glicólise/efeitos dos fármacos , Hexoquinase/metabolismo , Hiperinsulinismo/líquido cefalorraquidiano , Potenciais Pós-Sinápticos Inibidores/fisiologia , Insulina/farmacologia , Liraglutida/farmacologia , Masculino , Aprendizagem em Labirinto/fisiologia , Metformina/farmacologia , Camundongos , Neurônios/metabolismo , Fosfotransferases/metabolismo , Cultura Primária de Células , Proteínas Serina-Treonina Quinases/metabolismo , Ubiquitinação/fisiologia , beta Catenina/metabolismo
3.
Braz J Med Biol Res ; 52(11): e8899, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31664307

RESUMO

Few behavioral tests allow measuring several characteristics and most require training, complex analyses, and/or are time-consuming. We present an apparatus based on rat exploratory behavior. Composed of three different environments, it allows the assessment of more than one behavioral characteristic in a short 3-min session. Factorial analyses have defined three behavioral dimensions, which we named Exploration, Impulsivity, and Self-protection. Behaviors composing the Exploration factor were increased by chlordiazepoxide and apomorphine and decreased by pentylenetetrazole. Behaviors composing the Impulsivity factor were increased by chlordiazepoxide, apomorphine, and both acute and chronic imipramine treatments. Behaviors composing the Self-protection factor were decreased by apomorphine. We submitted Wistar rats to the open-field test, the elevated-plus maze, and to the apparatus we are proposing. Measures related to exploratory behavior in all three tests were correlated. Measures composing the factors Impulsivity and Self-protection did not correlate with any measures from the two standard tests. Also, compared with existing impulsivity tests, the one we proposed did not require previous learning, training, or sophisticated analysis. Exploration measures from our test are as easy to obtain as the ones from other standard tests. Thus, we have proposed an apparatus that measured three different behavioral characteristics, was simple and fast, did not require subjects to be submitted to previous learning or training, was sensitive to drug treatments, and did not require sophisticated data analyses.


Assuntos
Ansiedade/psicologia , Comportamento Animal/fisiologia , Pesquisa Comportamental/instrumentação , Comportamento Exploratório/fisiologia , Medo/fisiologia , Comportamento Impulsivo/fisiologia , Animais , Ansiolíticos/farmacologia , Antidepressivos Tricíclicos/farmacologia , Apomorfina/farmacologia , Comportamento Animal/efeitos dos fármacos , Clordiazepóxido/farmacologia , Agonistas de Dopamina/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Medo/efeitos dos fármacos , Antagonistas GABAérgicos/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Modelos Animais , Pentilenotetrazol/farmacologia , Ratos Wistar , Fatores de Tempo
4.
Nat Commun ; 10(1): 4266, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31537781

RESUMO

Decreased expression of 4-hydroxyphenylpyruvic acid dioxygenase (HPD), a key enzyme for tyrosine metabolism, is a cause of human tyrosinemia. However, the regulation of HPD expression remains largely unknown. Here, we demonstrate that molecular chaperone TTC36, which is highly expressed in liver, is associated with HPD and reduces the binding of protein kinase STK33 to HPD, thereby inhibiting STK33-mediated HPD T382 phosphorylation. The reduction of HPD T382 phosphorylation results in impaired recruitment of FHA domain-containing PELI1 and PELI1-mediated HPD polyubiquitylation and degradation. Conversely, deficiency or depletion of TTC36 results in enhanced STK33-mediated HPD T382 phosphorylation and binding of PELI1 to HPD and subsequent PELI1-mediated HPD downregulation. Ttc36-/- mice have reduced HPD expression in the liver and exhibit tyrosinemia, damage to hippocampal neurons, and deficits of learning and memory. These findings reveal a previously unknown regulation of HPD expression and highlight the physiological significance of TTC36-STK33-PELI1-regulated HPD expression in tyrosinemia and tyrosinemia-associated neurological disorders.


Assuntos
Proteínas de Membrana/metabolismo , Proteínas Mitocondriais/metabolismo , Proteínas Nucleares/metabolismo , Oxirredutases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Tirosinemias/patologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Linhagem Celular , Células HEK293 , Hipocampo/patologia , Humanos , Masculino , Aprendizagem em Labirinto/fisiologia , Proteínas de Membrana/genética , Memória/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Mitocondriais/genética , Fosforilação , Transdução de Sinais/fisiologia , Ubiquitinação
5.
Neurochem Res ; 44(11): 2631-2642, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31564017

RESUMO

Preterm birth and hypoxia-ischemia (HI) are major causes of neonatal death and neurological disabilities in newborns. The widely used preclinical HI model combines carotid occlusion with hypoxia exposure; however, the relationship between different hypoxia exposure periods with brain tissue loss, astrocyte reactivity and behavioral impairments following HI is lacking. Present study evaluated HI-induced behavioral and morphological consequences in rats exposed to different periods of hypoxia at postnatal day 3. Wistar rats of both sexes were assigned into four groups: control group, HI-120 min, HI-180 min and HI-210 min. Neurodevelopmental reflexes, exploratory abilities and cognitive function were assessed. At adulthood, tissue damage and reactive astrogliosis were measured. Animals exposed to HI-180 and HI-210 min had delayed neurodevelopmental reflexes compared to control group. Histological assessment showed tissue loss that was restricted to the ipsilateral hemisphere in lower periods of hypoxia exposure (120 and 180 min) but affected both hemispheres when 210 min was used. Reactive astrogliosis was increased only after 210 min of hypoxia. Interestingly, cognitive deficits were induced regardless the duration of hypoxia and there were correlations between behavioral parameters and cortex, hippocampus and corpus callosum volumes. These results show the duration of hypoxia has a close relationship with astrocytic response and tissue damage progression. Furthermore, the long-lasting cognitive memory deficit and its association with brain structures beyond the hippocampus suggests that complex anatomical changes should be involved in functional alterations taking place as hypoxia duration is increased, even when the cognitive impairment limit is achieved.


Assuntos
Astrócitos/fisiologia , Hipóxia-Isquemia Encefálica/fisiopatologia , Animais , Animais Recém-Nascidos , Encéfalo/patologia , Disfunção Cognitiva/fisiopatologia , Feminino , Gliose/fisiopatologia , Hipóxia-Isquemia Encefálica/patologia , Masculino , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/fisiopatologia , Ratos Wistar , Análise de Regressão , Fatores de Tempo
6.
Life Sci ; 235: 116835, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31493480

RESUMO

Sleep is crucial to improve athlete performance and their circadian rhythm, but sleep patterns may be disturbed because athletes participate in several competitions. In addition, intensive training programs can cause muscle pain and psychological stress in athletes, resulting in a lack of sleep. Sleep also plays a critical role in the recovery of muscle injury induced by exercise. The current study evaluated the effect of sleep deprivation on the recovery of muscle injury induced by high-intensity exercise in a mouse model. In this study, 28 mice were randomly assigned to four groups (N = 7): control (Control), exercise (EX), sleep deprivation (SD), and sleep deprivation with exercise (EX+SD). The mice from the EX and EX+SD groups were subjected to high-intensity swimming. The results showed that 72-h sleep deprivation increased food intake and reduced body weight. However, the manipulation of 8-week exercise and/or 72-h sleep deprivation did not have any effect in the elevated plus maze task and tail suspension test. Interestingly, the EX+SD group exhibited improved memory performance in the Morris water maze and impaired motor activity in the open field test. According to the TNF-α level and aspartate aminotransferase (AST), and creatine phosphokinase (CK) activities, only the EX+SD group exhibited muscle impairment. Overall, high-intensity exercise may cause muscle injury, and adequate sleep can recover muscle damage. However, sleep deprivation reduces protein synthesis, which decreases the ability to restore muscle damage and aggravates the harmful effect of high-intensity exercise.


Assuntos
Músculos/lesões , Músculos/fisiopatologia , Condicionamento Físico Animal/fisiologia , Recuperação de Função Fisiológica/fisiologia , Privação do Sono/fisiopatologia , Animais , Aspartato Aminotransferases/metabolismo , Creatina Quinase/metabolismo , Resposta de Imobilidade Tônica/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Atividade Motora/fisiologia , Músculos/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
7.
Acta Psychol (Amst) ; 199: 102895, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31377309

RESUMO

Spatial abilities associated with success in educational and occupational fields of Science, Technology, Engineering, and Mathematics (STEM) have been repeatedly shown to be gendered, with males demonstrating measurably better spatial abilities than females. Less is known about why this is, or about how experience with spatial systems (videogames, for example) affects these abilities. We conducted two experiments with 82 participants with varying degrees of videogame experience on measures of mental rotation, spatial learning, and spatial memory. Spatial learning and memory were tested in a Virtual Morris Water Maze. In the first experiment, the maze lacked proximal landmarks. Males proved faster and more accurate than females in learning the location of the hidden platform. As predicted males also outperformed females in mental rotation abilities. Mental rotation correlated with performance in the virtual maze, indicating that in the absence of proximal landmarks, participants relied on strategies requiring mental rotation. Experienced 3D videogame players did not demonstrate superior spatial learning and memory, but performed better than novices in mental rotation. In the second experiment, the maze had proximal cues, in the form of landmarks on the circumference of the virtual pool, and gender-based differences in navigational performance significantly diminished. Under these changed environmental conditions, mental rotation ability did not correlate with performance in the VMWM, suggesting that given proximal cues, the need for mental rotation diminishes. Differences between videogame novices and experts also decreased when proximal cues were provided. Females in particular obtained more discernible benefits from videogame experience. Together, these experiments reveal how the spatial abilities and strategies used to solve the Morris maze task vary with environmental design. Given the structural similarities between the virtual maze and videogame environments, these results offer insight into how spatial experience gained through videogame playing can affect aspects of spatial cognition, and can help identify design elements that contribute to their improvement.


Assuntos
Percepção Espacial/fisiologia , Aprendizagem Espacial/fisiologia , Jogos de Vídeo/psicologia , Realidade Virtual , Adolescente , Adulto , Feminino , Humanos , Masculino , Aprendizagem em Labirinto/fisiologia , Fatores Sexuais , Memória Espacial/fisiologia , Navegação Espacial/fisiologia , Adulto Jovem
8.
Neuron ; 103(3): 506-519.e4, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31201123

RESUMO

In motor neocortex, preparatory activity predictive of specific movements is maintained by a positive feedback loop with the thalamus. Motor thalamus receives excitatory input from the cerebellum, which learns to generate predictive signals for motor control. The contribution of this pathway to neocortical preparatory signals remains poorly understood. Here, we show that, in a virtual reality conditioning task, cerebellar output neurons in the dentate nucleus exhibit preparatory activity similar to that in anterolateral motor cortex prior to reward acquisition. Silencing activity in dentate nucleus by photoactivating inhibitory Purkinje cells in the cerebellar cortex caused robust, short-latency suppression of preparatory activity in anterolateral motor cortex. Our results suggest that preparatory activity is controlled by a learned decrease of Purkinje cell firing in advance of reward under supervision of climbing fiber inputs signaling reward delivery. Thus, cerebellar computations exert a powerful influence on preparatory activity in motor neocortex.


Assuntos
Córtex Cerebelar/fisiologia , Núcleos Cerebelares/fisiologia , Córtex Motor/fisiologia , Movimento/fisiologia , Rede Nervosa/fisiologia , Animais , Condicionamento Operante/fisiologia , Sinais (Psicologia) , Retroalimentação Fisiológica , Feminino , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos Endogâmicos C57BL , Células de Purkinje/fisiologia , Tempo de Reação/fisiologia , Recompensa , Tálamo/fisiologia , Fatores de Tempo , Realidade Virtual
9.
Nat Commun ; 10(1): 2554, 2019 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-31186425

RESUMO

Representations of our future environment are essential for planning and decision making. Previous research in humans has demonstrated that the hippocampus is a critical region for forming and retrieving associations, while the medial orbitofrontal cortex (OFC) is an important region for representing information about recent states. However, it is not clear how the brain acquires predictive representations during goal-directed learning. Here, we show using fMRI that while participants learned to find rewards in multiple different Y-maze environments, hippocampal activity was highest during initial exposure and then decayed across the remaining repetitions of each maze, consistent with a role in rapid encoding. Importantly, multivariate patterns in the OFC-VPFC came to represent predictive information about upcoming states approximately 30 s in the future. Our findings provide a mechanism by which the brain can build models of the world that span long-timescales to make predictions.


Assuntos
Aprendizagem em Labirinto/fisiologia , Córtex Pré-Frontal/fisiologia , Recompensa , Adulto , Feminino , Previsões , Hipocampo/fisiologia , Humanos , Imagem por Ressonância Magnética , Masculino
10.
Behav Processes ; 166: 103893, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31252072

RESUMO

One neglected aspect of research on foraging behavior is that of the effect of obstacles that increase habitat complexity on foraging efficiency. Here, we explored how long it takes individually foraging desert ant workers (Cataglyphis niger) to reach a food reward in a maze, and examined whether maze complexity affects maze-solving time (the time elapsed till the first worker reached the food reward). The test mazes differed in their complexity level, or the relative number of correct paths leading to the food reward, vs. wrong paths leading to dead-ends. Maze-solving time steeply increased with maze complexity, but was unaffected by colony size, despite the positive correlation between colony size and the number of workers that searched for food. The number of workers observed feeding on the food reward 10 min after its discovery decreased with complexity level but not colony size. We compared our experimental results to three simulation models, applying different search methods, ranked them according to their fit to the data and found the self-avoiding random search to fit the best. We suggest possible reasons for the model deviations from the observational findings. Our data emphasize the necessity to refer to habitat complexity when studying foraging behavior.


Assuntos
Formigas/fisiologia , Comportamento Exploratório/fisiologia , Aprendizagem em Labirinto/fisiologia , Animais , Comportamento Alimentar/fisiologia , Alimentos , Recompensa , Fatores de Tempo
11.
Int J Neurosci ; 129(10): 1024-1038, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31215278

RESUMO

Aim: The effect of peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist pioglitazone on the brain tissues oxidative damage and learning and memory impairment in the juvenile hypothyroid rats was evaluated. Main methods: Rats were classified as: ( 1 ) Control; (2) Propylthiouracil (PTU); (3) PTU-Pio 10 and (4) PTU-Pio 20. PTU was given in drinking water (0.05%) during 6 weeks. Pioglitazone (10 or 20 mg/kg) was daily injected intraperitoneally. Passive avoidance (PA) and Morris water maze (MMW) were conducted. Later, the animals were sacrificed and the brain tissues were removed for biochemical measurements. Key funding: The results indicated that in the MWM escape latency as well as traveled path increased in the PTU group as compared to the control group. Also, the time spent in the target quadrant in the probe test of MWM and step-through latency in the PA test were decreased in the PTU group as compared to the control group. Pioglitazone reversed all the negative behavioral effects of hypothyroidism. Administration of PTU attenuated thiol and superoxide dismutase (SOD), and catalase (CAT) activities in the brain tissues, whereas increased malondialdehyde (MDA) and nitric oxide (NO) metabolites. PPARγ agonist improved thiol, SOD and CAT, while diminished MDA concentration. Significance: Our finding in the present study indicated that PPARγ agonist pioglitazone prevented the brain tissues from oxidative damage and learning and memory impairments in juvenile hypothyroid rats.


Assuntos
Lesões Encefálicas/tratamento farmacológico , Hipotireoidismo/tratamento farmacológico , Transtornos da Memória/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , PPAR gama/agonistas , Pioglitazona/farmacologia , Fatores Etários , Animais , Lesões Encefálicas/metabolismo , Relação Dose-Resposta a Droga , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Hipotireoidismo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Transtornos da Memória/metabolismo , Estresse Oxidativo/fisiologia , Pioglitazona/uso terapêutico , Ratos , Ratos Wistar , Resultado do Tratamento
12.
Neural Plast ; 2019: 2823679, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31223308

RESUMO

Increased amyloid-ß (Aß) plaque deposition is thought to be the main cause of Alzheimer's disease (AD). ß-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is the key protein involved in Aß peptide generation. Excessive expression of BACE1 might cause overproduction of neurotoxins in the central nervous system. Previous studies indicated that BACE1 initially cleaves the amyloid precursor protein (APP) and may subsequently interfere with physiological functions of proteins such as PKA, which is recognized to be closely associated with long-term potentiation (LTP) level and can effectively ameliorate cognitive impairments. Therefore, revealing the underlying mechanism of BACE1 in the pathogenesis of AD might have a significant impact on the future development of therapeutic agents targeting dementia. This study examined the effects of electroacupuncture (EA) stimulation on BACE1, APP, and p-PKA protein levels in hippocampal tissue samples. Memory and learning abilities were assessed using the Morris water maze test after EA intervention. Immunofluorescence, immunohistochemistry, and western blot were employed to assess the distribution patterns and expression levels of BACE1, APP, and p-PKA, respectively. The results showed the downregulation of BACE1 and APP and the activation of PKA by EA. In summary, EA treatment might reduce BACE1 deposition in APP/PS1 transgenic mice and regulate PKA and its associated substrates, such as LTP to change memory and learning abilities.


Assuntos
Secretases da Proteína Precursora do Amiloide/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Disfunção Cognitiva/terapia , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Eletroacupuntura , Hipocampo/metabolismo , Precursor de Proteína beta-Amiloide/genética , Animais , Disfunção Cognitiva/metabolismo , Modelos Animais de Doenças , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Transgênicos , Presenilina-1/genética
13.
Neuron ; 103(4): 673-685.e5, 2019 08 21.
Artigo em Inglês | MEDLINE | ID: mdl-31230762

RESUMO

Autism spectrum disorder (ASD) is strongly associated with de novo gene mutations. One of the most commonly affected genes is SCN2A. ASD-associated SCN2A mutations impair the encoded protein NaV1.2, a sodium channel important for action potential initiation and propagation in developing excitatory cortical neurons. The link between an axonal sodium channel and ASD, a disorder typically attributed to synaptic or transcriptional dysfunction, is unclear. Here we show that NaV1.2 is unexpectedly critical for dendritic excitability and synaptic function in mature pyramidal neurons in addition to regulating early developmental axonal excitability. NaV1.2 loss reduced action potential backpropagation into dendrites, impairing synaptic plasticity and synaptic strength, even when NaV1.2 expression was disrupted in a cell-autonomous fashion late in development. These results reveal a novel dendritic function for NaV1.2, providing insight into cellular mechanisms probably underlying circuit and behavioral dysfunction in ASD.


Assuntos
Transtorno do Espectro Autista/genética , Dendritos/fisiologia , Canal de Sódio Disparado por Voltagem NAV1.2/fisiologia , Córtex Pré-Frontal/fisiologia , Células Piramidais/fisiologia , Potenciais de Ação , Animais , Sinalização do Cálcio , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Heterozigoto , Hipocampo/citologia , Hipocampo/crescimento & desenvolvimento , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Potenciais Pós-Sinápticos em Miniatura/fisiologia , N-Metilaspartato/análise , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Neocórtex/citologia , Neocórtex/crescimento & desenvolvimento , Neocórtex/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/crescimento & desenvolvimento , Engenharia de Proteínas , Comportamento Social , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/análise
14.
Neurotox Res ; 36(2): 334-346, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31055771

RESUMO

Aluminum (Al) exposure impairs learning and memory function in humans and in animal models. Several studies have shown that the neurotoxicity of Al is associated with damage to mitochondrial morphology and mitochondrial dysfunction, but the molecular mechanism is unclear. The present study was performed to elucidate the possible molecular mechanism related to the Al-induced abnormal mitochondrial dynamics that lead to learning and memory disorders. SD rats were exposed to Al-maltolate complex (Al(mal)3) (blank, 0, 0.41, 0.81, or 1.62 mg/kg) for 30, 60, or 90 days, and neurobehavior, mitochondrial morphology, mitochondrial function, the levels of fission proteins such as dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1), and the levels of fusion proteins such as optic atrophy 1 (Opa1), mitofusin 1 (Mfn1), and mitofusin 2 (Mfn2) were explored. The results indicated that exposure to Al(mal)3 increased the concentration of Al in the brain in a time- and dose-dependent manner and impaired spatial learning and memory. Al(mal)3 damaged mitochondrial morphology and impaired mitochondrial function in the hippocampus. Dose-dependent elevations in the levels of mitochondrial fission (Drp1 and Fis1) and fusion (Opa1, Mfn1, and Mfn2) proteins were observed. In addition, the upregulation of calcineurin (CaN) and the reduced phosphorylation of Drp1 (s637) may have disturbed the balance of mitochondrial fission and fusion in the hippocampus. These results showed that Al-induced learning and memory impairment may be related to mitochondrial fission and fusion disorders.


Assuntos
Alumínio/toxicidade , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Aprendizagem em Labirinto/efeitos dos fármacos , Dinâmica Mitocondrial/efeitos dos fármacos , Animais , Relação Dose-Resposta a Droga , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Dinâmica Mitocondrial/fisiologia , Ratos , Ratos Sprague-Dawley
15.
Psychopharmacology (Berl) ; 236(9): 2797-2810, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31049607

RESUMO

RATIONALE: Previous studies have demonstrated that repeated social defeat (RSD) stress only induces cognitive deficits when experienced during adulthood. However, RSD increases cocaine-rewarding effects in adult and adolescent mice, inducing different expressions of proBDNF in the ventral tegmental area. OBJECTIVE: The aim of the present study was to evaluate the effect of cocaine administration in socially defeated adult or adolescent mice on learning, memory, and anxiety. Additionally, the role of BDNF was also studied. METHODS: Adolescent and young adult mice were exposed to four episodes of social defeat or exploration (control), being treated with a daily injection of four doses of saline or 1 mg/kg of cocaine 3 weeks after the last social defeat. Other groups were treated with the TrkB receptor antagonist ANA-12 during this 21-day period. After this treatment, their cognitive and anxiogenic profiles were evaluated, along with the expression of BDNF, pCREB, and pERK1/2 in the dentate gyrus (DG) and basolateral amygdala (BLA). RESULTS: Cocaine induced an increased expression of pCREB and BDNF in the DG and BLA only in defeated animals. Although RSD did not affect memory, the administration of cocaine induced memory impairments only in defeated animals. Defeated adult mice needed more time to complete the mazes, and this effect was counteracted by cocaine administration. RSD induced anxiogenic effects only when experienced during adulthood and cocaine induced a general anxiolytic effect. Blockade of Trkb decreased memory retention without affecting spatial learning and modified anxiety on non-stressed mice depending on their age. CONCLUSION: Our results demonstrate that the long-lasting effects of social defeat on anxiety and cognition are modulated by cocaine administration. Our results highlight that the BDNF signaling pathway could be a target to counteract the effects of cocaine on socially stressed subjects.


Assuntos
Azepinas/administração & dosagem , Benzamidas/administração & dosagem , Cocaína/administração & dosagem , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Comportamento Social , Estresse Psicológico/psicologia , Animais , Ansiedade/tratamento farmacológico , Ansiedade/psicologia , Inibidores da Captação de Dopamina/administração & dosagem , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Camundongos , Camundongos Endogâmicos , Receptor trkB/antagonistas & inibidores , Estresse Psicológico/tratamento farmacológico
16.
J Neuroinflammation ; 16(1): 104, 2019 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-31103039

RESUMO

BACKGROUND: Hypoxia-ischemia (HI) during the perinatal period is one of the most common causes of acute mortality and chronic neurologic morbidity. Hydrogen-rich saline (HS) treatment in neonatal mice has been reported to alleviate brain injury following HI, but the mechanisms involved are not known. METHODS: A modified version of the Rice-Vannucci method for the induction of neonatal HI brain injury was performed on postnatal day 7 mouse pups. Animals or BV2-cells received HS and an AMPK inhibitor at indicative time post-injury. RESULTS: In the current study, we show that HS treatment attenuated the accumulation of CD11b+/CD45high cells, suppressed HI-induced neuro-inflammation, induced microglial anti-inflammatory M2 polarization, was associated with promoting AMPK activation, and inhibited nuclear factor-κB activation as demonstrated both in vivo and in vitro. In addition, HS treatment reversed HI-induced neurological disabilities, was associated with improving damaged synapses, and restored the expression levels of synaptophysin and postsynaptic density protein 95 following HI insult. Furthermore, HI insult which increased levels of complement component C1q, C3, and C3aR1 was observed. Importantly, C1q deposited in the infarct core and lesion boundary zone following HI injury, was found to co-localize within regions of synapse loss, whereas HS treatment reversed these effects of HI on synapse loss and complement component levels. Notably, the AMPK inhibitor reversed the beneficial effects of HS as described above. CONCLUSIONS: These results demonstrate that HS restored behavioral deficits after HI in neonatal mice. These beneficial effects, in part, involve promoting microglia M2 polarization and complement-mediated synapse loss via AMPK activation.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas do Sistema Complemento/metabolismo , Hipóxia-Isquemia Encefálica/metabolismo , Microglia/metabolismo , Solução Salina/administração & dosagem , Sinapses/metabolismo , Animais , Animais Recém-Nascidos , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Linhagem Celular , Polaridade Celular/efeitos dos fármacos , Polaridade Celular/fisiologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/fisiologia , Feminino , Hidrogênio/administração & dosagem , Hipóxia-Isquemia Encefálica/tratamento farmacológico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Gravidez , Distribuição Aleatória , Sinapses/efeitos dos fármacos
17.
Exp Brain Res ; 237(7): 1881-1888, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31093716

RESUMO

Numerous mental health disorders are characterized by cognitive impairments that result in poor vocational and social outcomes. Among the cognitive domains commonly affected, working memory deficits have been noted in patients with attention-deficit/hyperactivity disorder (Martinussen et al. in J Am Acad Child Adolesc Psychiatry 44:377-384, 2005), post-traumatic stress disorder (Honzel et al. in Cogn Affect Behav Neurosci 14:792-804, 2014), and consistently with schizophrenia patients (Callicott et al. in Cereb Cortex 10:1078-1092, 2000; Lewis et al. in Front Hum Neurosci 10:85, 2005; Amann et al. in Brain Res Bull 83:147-161, 2010; Limongi et al. in Schizophr Res 197:386-391, 2018). Oscillations in neural activity from electroencephalogram (EEG) recordings are decomposed by frequency, and band-specific decreases in gamma power (> 30 Hz) have been correlated with working memory ability. This study examined within-subject changes in power of frequency-specific bands during sample versus choice trials during a spatial working memory paradigm (T-maze). EEG was recorded using a relatively novel wireless EEG telemetry system fully implanted within the mouse, enabling uninhibited movement during behavioral tasks. No significant differences were found between sample and correct choice phases in the alpha, theta or gamma frequency ranges. Evoked power was significantly higher during the choice phase than the sample phase in the high-beta/low-gamma frequency range. This frequency range has been implicated in the propagation of cortical predictions to lower levels of stimuli encoding in a top-down hierarchical manner. Results suggest there is an increase in brain activity during correct trials when the mouse enters the opposite arm during the choice phase compared to the sample phase, likely due to prediction error resulting from a discrepancy between present and prior experience. Future studies should identify specific cortical networks involved and investigate neural activity at the neuronal level.


Assuntos
Ritmo beta/fisiologia , Ritmo Gama/fisiologia , Aprendizagem em Labirinto/fisiologia , Memória de Curto Prazo/fisiologia , Memória Espacial/fisiologia , Animais , Previsões , Camundongos , Camundongos Endogâmicos C57BL
18.
Psychopharmacology (Berl) ; 236(11): 3135-3146, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31079161

RESUMO

RATIONALE: The basolateral amygdala (BLA) plays important roles in the cognitive control in human and non-human animals. However, inconsistent findings between species have been observed and there have been relatively few detailed investigations of the cognitive properties of BLA, especially in mice. OBJECTIVE: Our aim was to determine the role of BLA in cognition by using optogenetic manipulations. METHODS: Male C57BL/six mice were trained and tested on the five-choice serial reaction time task (5-CSRTT), open-field test (OFT), elevated plus maze (EPM), Y-maze, and novel object recognition (NOR) test during optogenetic stimulation and inhibition of the BLA. RESULTS: Optogenetic activation of the BLA decreased the impulsivity and increased the compulsivity of mice, whereas optogenetic inhibition of BLA had the opposite effect. Similarly, anxiety-like behaviours and spatial working memory were increased in BLA activation mice, whereas BLA inhibition decreased these behaviours. However, both BLA activation and inhibition decreased the motivation of the mice. CONCLUSIONS: These data demonstrate that the BLA regulates impulsive action and spatial working memory, and plays a critical role in anxiety-like behaviours.


Assuntos
Complexo Nuclear Basolateral da Amígdala/química , Complexo Nuclear Basolateral da Amígdala/fisiologia , Comportamento de Escolha/fisiologia , Tempo de Reação/fisiologia , Animais , Ansiedade/psicologia , Complexo Nuclear Basolateral da Amígdala/efeitos dos fármacos , Cognição/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Optogenética/métodos
19.
Pharmacol Rep ; 71(3): 449-456, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003156

RESUMO

BACKGROUND: Hippocampus and entorhinal cortex are key players of learning and memory. Despite their established role in memory processes, the contribution of muscarinic receptor activity in these brain regions during memory retrieval remains elusive. This study was aimed to assess the role of hippocampal CA1 and medial entorhinal cortex muscarinic receptors in memory retrieval. METHOD: Mice were implanted with bilateral cannulas in the hippocampus CA1 and medial entorhinal cortex. After recovery they were trained for Morris water maze test, novel object recognition test and contextual fear conditioning. Scopolamine was infused 10 min prior to retrieval test. RESULTS: Pre-test scopolamine infusion in hippocampal CA1 and medial entorhinal cortex significantly reduced overall exploration of objects (p<0.001). Similarly, pre-retrieval inactivation dorsal hippocampal CA1 and medial entorhinal cortex muscarinic activity caused significant impairment of spatial and fear memories retrieval (p<0.05). CONCLUSION: These findings showed vital role of muscarinic activity in retrieving hippocampal and entorhinal cortex dependent memories and suggest a possible target for treating retrograde amnesia.


Assuntos
Córtex Entorrinal/metabolismo , Medo/fisiologia , Hipocampo/metabolismo , Memória/fisiologia , Rememoração Mental/fisiologia , Receptores Muscarínicos/metabolismo , Animais , Região CA1 Hipocampal/metabolismo , Córtex Entorrinal/fisiologia , Hipocampo/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos BALB C , Escopolamina/metabolismo
20.
Biomed Pharmacother ; 114: 108833, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30978525

RESUMO

Age-related changes such as increased oxidative stress and DNA damage are important risk factors for Alzheimer's disease (AD). This study aimed to clarify the role of POLD1, the catalytic subunit of DNA polymerase δ, in neurodegeneration symptoms of AD. POLD1 expression levels were evaluated in patients with different neurodegenerative diseases by ELISA, RT-PCR and Western blot analysis. The impairment of cognitive ability in AD patients and senescence-accelerated mouse prone 8 (SAMP8) mice were evaluated by MMSE/MoCA score and Morris water maze (MWM) test. We found that serum concentration and expression levels of POLD1 in lymphocytes were reduced in AD patients. The cognitive impairment in AD patients and SAMP8 mice was associated with reduced POLD1 expression. In addition, POLD1 knockdown led to premature senescence and increased DNA damage in primary neuronal cells of SAMP8 mice. In conclusion, this is the first study suggesting that the deficiency of POLD1 may aggravate AD progression, and POLD1 is a potential diagnostic marker and therapeutic target for AD.


Assuntos
Doença de Alzheimer/genética , Transtornos Cognitivos/genética , Cognição/fisiologia , Disfunção Cognitiva/genética , DNA Polimerase III/deficiência , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/genética , Animais , Modelos Animais de Doenças , Feminino , Humanos , Linfócitos/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Pessoa de Meia-Idade , Estresse Oxidativo/genética
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