RESUMO
Pattern separation is a hippocampal process in which highly similar stimuli are recognized as separate representations, and deficits could lead to memory impairments in neuropsychiatric disorders such as schizophrenia. The 5-HT1A receptor (5-HT1AR) is believed to be involved in these hippocampal pattern separation processes. However, in the dorsal raphe nucleus (DRN), the 5-HT1AR is expressed as a somatodendritic autoreceptor, negatively regulates serotonergic signaling, and could thereby counteract the effects of hippocampal postsynaptic 5-HT1A receptors. Therefore, this study aims to identify how pre- and post-synaptic 5-HT1AR activity affects pattern separation. Object pattern separation (OPS) performance was measured in male Wistar rats after both acute and chronic treatment (i.p.) with 5-HT1AR biased agonists F13714 (0.0025 mg/kg acutely, 0.02 mg/kg/day chronically) or NLX-101 (0.08 mg/kg acutely, 0.32 mg/kg/day chronically), which preferentially activate autoreceptors or postsynaptic receptors respectively, for 14 days. Body temperature - a functional correlate of hypothalamic 5-HT1AR stimulation - was measured daily. Additionally, 5-HT1AR density (DRN) and plasticity markers (hippocampus) were assessed. Acute treatment with F13714 impaired OPS performance, whereas chronic treatment normalized this, and a drop in body temperature was found from day 4 onwards. NLX-101 enhanced OPS performance acutely and chronically, and caused an acute drop in body temperature. Chronic NLX-101 treatment increased doublecortin positive neurons in the dorsal hippocampus, while chronic treatment with F13714 resulted in a downregulation of 5-HT1A autoreceptors, which likely reversed the acute impairment in OPS performance. Chronic treatment with NLX-101 appears to have therapeutic potential to improve brain plasticity and OPS performance.
Assuntos
Aminopiridinas , Autorreceptores , Hipocampo , Plasticidade Neuronal , Reconhecimento Fisiológico de Modelo , Piperidinas , Pirimidinas , Receptor 5-HT1A de Serotonina , Reconhecimento Psicológico , Agonistas do Receptor 5-HT1 de Serotonina , Aminopiridinas/farmacologia , Animais , Autorreceptores/fisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/fisiologia , Piperidinas/farmacologia , Pirimidinas/farmacologia , Ratos , Ratos Wistar , Receptor 5-HT1A de Serotonina/fisiologia , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Agonistas do Receptor 5-HT1 de Serotonina/farmacologia , Agonistas do Receptor 5-HT1 de Serotonina/uso terapêuticoRESUMO
Comparison of the cognition-stimulating effects of Dimebon in a wide dose range revealed a non-monotonic and nontrivial wave-like dose-dependence of its activity. Positive results were obtained at low (0.02-0.05 mg/kg) or high (5-10 mg/kg) doses of Dimebon, while intermediate doses were ineffective. This type of the dose dependence of the pharmacological effect can indicate that the substance has several targets. This fact should be taken into consideration when selecting the doses and concentrations of the substance and its analogues for further studies, and for planning treatment schemes and administration doses in clinical studies.
Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Cognição/efeitos dos fármacos , Indóis/farmacologia , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Animais , Aziridinas , Relógios Biológicos/efeitos dos fármacos , Colina/análogos & derivados , Cognição/fisiologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Ratos , Ratos WistarRESUMO
Objective: To evaluate the effects of Hypericum perforatum (hypericum) on cognitive behavior and neurotrophic factor levels in the brain of male and female rats. Methods: Male and female Wistar rats were treated with hypericum or water during 28 days by gavage. The animals were then subjected to the open-field test, novel object recognition and step-down inhibitory avoidance test. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-line derived neurotrophic factor (GDNF) levels were evaluated in the hippocampus and frontal cortex. Results: Hypericum impaired the acquisition of short- and long-term aversive memory in male rats, evaluated in the inhibitory avoidance test. Female rats had no immediate memory acquisition and decreased short-term memory acquisition in the inhibitory avoidance test. Hypericum also decreased the recognition index of male rats in the object recognition test. Female rats did not recognize the new object in either the short-term or the long-term memory tasks. Hypericum decreased BDNF in the hippocampus of male and female rats. Hypericum also decreased NGF in the hippocampus of female rats. Conclusions: The long-term administration of hypericum appears to cause significant cognitive impairment in rats, possibly through a reduction in the levels of neurotrophic factors. This effect was more expressive in females than in males.
Assuntos
Animais , Masculino , Feminino , Extratos Vegetais/farmacologia , Cognição/efeitos dos fármacos , Hypericum , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Fatores de Crescimento Neural/análise , Extratos Vegetais/administração & dosagem , Distribuição Aleatória , Fatores Sexuais , Resultado do Tratamento , Ratos Wistar , Modelos Animais , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Memória/efeitos dos fármacos , Fatores de Crescimento Neural/efeitos dos fármacosRESUMO
OBJECTIVE: To evaluate the effects of Hypericum perforatum (hypericum) on cognitive behavior and neurotrophic factor levels in the brain of male and female rats. METHODS: Male and female Wistar rats were treated with hypericum or water during 28 days by gavage. The animals were then subjected to the open-field test, novel object recognition and step-down inhibitory avoidance test. Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell-line derived neurotrophic factor (GDNF) levels were evaluated in the hippocampus and frontal cortex. RESULTS: Hypericum impaired the acquisition of short- and long-term aversive memory in male rats, evaluated in the inhibitory avoidance test. Female rats had no immediate memory acquisition and decreased short-term memory acquisition in the inhibitory avoidance test. Hypericum also decreased the recognition index of male rats in the object recognition test. Female rats did not recognize the new object in either the short-term or the long-term memory tasks. Hypericum decreased BDNF in the hippocampus of male and female rats. Hypericum also decreased NGF in the hippocampus of female rats. CONCLUSIONS: The long-term administration of hypericum appears to cause significant cognitive impairment in rats, possibly through a reduction in the levels of neurotrophic factors. This effect was more expressive in females than in males.
Assuntos
Cognição/efeitos dos fármacos , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Hypericum , Fatores de Crescimento Neural/análise , Extratos Vegetais/farmacologia , Animais , Relação Dose-Resposta a Droga , Feminino , Lobo Frontal/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Modelos Animais , Fatores de Crescimento Neural/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Distribuição Aleatória , Ratos Wistar , Fatores Sexuais , Resultado do TratamentoRESUMO
Reconsolidation theory has supported the notion that active memory is vulnerable to the effects of an amnesic agent. An extension of reconsolidation theory posits that active memory, while necessary for creating vulnerability in memory, is not sufficient. Prediction error (i.e., when expectation is inconsistent with reality) may be a key factor in the destabilization of memory. The present study examined the role of prediction error in appetitive memory reconsolidation. Rats learned to dig in cups of scented sand to retrieve buried sweet cereal rewards. Forty-eight hours following acquisition, a single reactivation trial was given during which a prediction error or no prediction error was included. The prediction error consisted of a single extinction trial, while the no prediction error condition consisted of an additional reinforced trial. Cycloheximide (CHX; 1 mg/kg) or vehicle (VEH: distilled water; 1 mg/kg) was administered intraperitoneally immediately following reactivation. One week following reactivation, rats received 2 nonreinforced test trials. Results showed longer latencies to dig for rats that received CHX following a prediction error (CHX/PE) compared to rats that received VEH (VEH/PE) or did not receive a prediction error (CHX/NoPE or VEH/NoPE). These results add to a growing literature demonstrating that protein synthesis is necessary in appetitive memory reconsolidation only when reactivation includes a prediction error. (PsycINFO Database Record
Assuntos
Comportamento Apetitivo/fisiologia , Discriminação Psicológica/fisiologia , Consolidação da Memória/fisiologia , Percepção Olfatória/fisiologia , Reconhecimento Fisiológico de Modelo/fisiologia , Animais , Comportamento Apetitivo/efeitos dos fármacos , Cicloeximida/farmacologia , Discriminação Psicológica/efeitos dos fármacos , Alimentos , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Masculino , Consolidação da Memória/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Percepção Olfatória/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Inibidores da Síntese de Proteínas/farmacologia , Ratos Long-Evans , RecompensaRESUMO
Nonassociative learning is considered simple because it depends on presentation of a single stimulus, but it likely reflects complex molecular signaling. To advance understanding of the molecular mechanisms of one form of nonassociative learning, habituation, for ethologically relevant signals we examined song recognition learning in adult zebra finches. These colonial songbirds learn the unique song of individuals, which helps establish and maintain mate and other social bonds, and informs appropriate behavioral interactions with specific birds. We leveraged prior work demonstrating behavioral habituation for individual songs, and extended the molecular framework correlated with this behavior by investigating the mechanistic Target of Rapamycin (mTOR) signaling cascade. We hypothesized that mTOR may contribute to habituation because it integrates a variety of upstream signals and enhances associative learning, and it crosstalks with another cascade previously associated with habituation, ERK/ZENK. To begin probing for a possible role for mTOR in song recognition learning, we used a combination of song playback paradigms and bidirectional dysregulation of mTORC1 activation. We found that mTOR demonstrates the molecular signatures of a habituation mechanism, and that its manipulation reveals the complexity of processes that may be invoked during nonassociative learning. These results thus expand the molecular targets for habituation studies and raise new questions about neural processing of complex natural signals.
Assuntos
Percepção Auditiva/fisiologia , Proteínas Aviárias/metabolismo , Habituação Psicofisiológica/fisiologia , Reconhecimento Fisiológico de Modelo/fisiologia , Serina-Treonina Quinases TOR/metabolismo , Vocalização Animal , Animais , Vias Auditivas/efeitos dos fármacos , Vias Auditivas/enzimologia , Percepção Auditiva/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Feminino , Tentilhões , Habituação Psicofisiológica/efeitos dos fármacos , Masculino , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/enzimologia , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidoresRESUMO
INTRODUCTION: The polyphenol resveratrol has been suggested to exert beneficial effects on memory and the aging hippocampus due to calorie-restriction mimicking effects. However, the evidence based on human interventional studies is scarce. We therefore aimed to determine the effects of resveratrol on memory performance, and to identify potential underlying mechanisms using a broad array of blood-based biomarkers as well as hippocampus connectivity and microstructure assessed with ultra-high field magnetic resonance imaging (UHF-MRI). METHODS: In this double-blind, randomized controlled trial, 60 elderly participants (60-79 years) with a wide body-mass index (BMI) range of 21-37 kg/m2 were randomized to receive either resveratrol (200â¯mg/day) or placebo for 26 weeks (registered at ClinicalTrials.gov: NCT02621554). Baseline and follow-up assessments included the California Verbal Learning Task (CVLT, main outcome), the ModBent task, anthropometry, markers of glucose and lipid metabolism, inflammation and neurotrophins derived from fasting blood, multimodal neuroimaging at 3 and 7â¯T, and questionnaires to assess confounding factors. RESULTS: Multivariate repeated-measures ANOVA did not detect significant time by group effects for CVLT performance. There was a trend for preserved pattern recognition memory after resveratrol, while performance decreased in the placebo group (n.s., pâ¯=â¯0.07). Further exploratory analyses showed increases in both groups over time in body fat, cholesterol, fasting glucose, interleukin 6, high sensitive C-reactive protein, tumor necrosis factor alpha and in mean diffusivity of the subiculum and presubiculum, as well as decreases in physical activity, brain-derived neurotrophic factor and insulin-like growth factor 1â¯at follow-up, which were partly more pronounced after resveratrol. DISCUSSION: This interventional study failed to show significant improvements in verbal memory after 6 months of resveratrol in healthy elderly with a wide BMI range. A non-significant trend emerged for positive effects on pattern recognition memory, while possible confounding effects of unfavorable changes in lifestyle behavior, neurotrophins and inflammatory markers occurred. Our findings also indicate the feasibility to detect (un)healthy aging-related changes in measures of hippocampus microstructure after 6 months using 7T diffusion MRI. More studies incorporating a longer duration and larger sample size are needed to determine if resveratrol enhances memory performance in healthy older adults.
Assuntos
Hipocampo/efeitos dos fármacos , Memória/efeitos dos fármacos , Resveratrol/administração & dosagem , Idoso , Mapeamento Encefálico , Método Duplo-Cego , Feminino , Hipocampo/anatomia & histologia , Hipocampo/fisiologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória/fisiologia , Pessoa de Meia-Idade , Vias Neurais/anatomia & histologia , Vias Neurais/fisiologia , Testes Neuropsicológicos , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/fisiologiaRESUMO
The olfactory system participates in many sensory processes, and olfactory endophenotypes appear in a variety of neurological disorders such as Alzheimer's and Parkinson's disease, depression and schizophrenia. Social withdrawal is a core negative symptom of schizophrenia and animal models have proven to be invaluable for studying the neurobiological mechanisms and cognitive processes behind the formation of social relationships. The subchronic phencyclidine (PCP) rat model is a validated model for negative symptoms of schizophrenia, such as impaired sociability. However, the complete range of social behaviour and deficits in the model are still not fully understood. Intact rodent olfaction is essential for a wide range of social behaviour and disrupted olfactory function could have severe effects on social communication and recognition. In order to examine the olfactory ability of male rats treated with subchronic PCP, we conducted an olfactory habituation/dishabituation test including both non-social and social odours. The subchronic PCP-treated rats successfully recognized and discriminated among the odours, indicative of intact olfaction. Interestingly, the subchronic PCP-treated rats showed greater interest for a novel social odour compared to the saline-treated rats and the rationale remains to be elucidated. Our data indicate that subchronic PCP treatment does not disrupt olfactory function in male rats. By ruling out impaired olfaction as cause for the poor social interaction performance in subchronic PCP-treated rats, our data supports the use of NMDA receptor antagonists to model the negative symptoms of schizophrenia.
Assuntos
Antagonistas de Aminoácidos Excitatórios/farmacologia , Percepção Olfatória/efeitos dos fármacos , Fenciclidina/farmacologia , Comportamento Social , Animais , Discriminação Psicológica/efeitos dos fármacos , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Habituação Psicofisiológica/efeitos dos fármacos , Masculino , Motivação/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Testes Psicológicos , Distribuição Aleatória , Ratos Sprague-Dawley , Esquizofrenia , Fatores de TempoRESUMO
Working memory (WM) is the ability to temporarily store information for use and manipulation. Working memory is thought to depend on a distributed set of higher cortical areas including the prefrontal and parietal cortex in primates while relatively little research has been conducted in rodents to elucidate the exact role of the parietal cortex (PC) in WM, particularly in relation to the construct of WM capacity. Previous work in our lab demonstrates that performance of the odour span task (OST), an olfactory incremental delayed nonmatching-to-sample task, relies on the medial prefrontal cortex (mPFC). However, the effects of inactivating the PC on the OST have not been studied. Therefore, the present experiment assessed the effects of inactivating the PC with the GABA receptor agonists muscimol/baclofen on performance of the OST. Infusions of muscimol/baclofen did not disrupt working memory performance, assessed by the mean number of odours each rat could remember before making an error on each day of testing. In contrast, performance of a positive control task, spontaneous cross-modal object recognition, was impaired by inactivating the PC. These results suggest that performance of the OST does not depend on the PC in rats. Our results are notable given past research demonstrating the importance of the parietal cortex for attentional processes and working memory in other tasks.
Assuntos
Memória de Curto Prazo/fisiologia , Percepção Olfatória/fisiologia , Lobo Parietal/fisiologia , Animais , Baclofeno/farmacologia , Agonistas GABAérgicos/farmacologia , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Muscimol/farmacologia , Testes Neuropsicológicos , Percepção Olfatória/efeitos dos fármacos , Lobo Parietal/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/fisiologia , Ratos Long-Evans , Reconhecimento Psicológico/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Percepção Visual/efeitos dos fármacos , Percepção Visual/fisiologiaRESUMO
Aging is associated with impaired performance in behavioral pattern separation (PS) tasks based on similarities in object features and in object location. These deficits have been attributed to functional alterations in the dentate gyrus (DG)-CA3 region. Animal studies suggested a role of adult-born DG neurons in PS performance. The present study investigated the effect of aging in C57BL/6J mice performing PS tasks based on either object features or object location. At the age of 18 months or more, performance was severely impaired in both tasks. Spatial PS performance declined gradually over adult lifespan from 3 to 21 months. Subchronic treatment with the cognitive enhancer D-serine fully rescued spatial PS performance in 18-month-old mice and induced a modest increase in the number of 4-week-old adult-born cells in the DG. Performance of mice in these PS tasks shows an age dependence, which appears to translate well to that found in humans. This model should help in deciphering physiological changes underlying PS deficits and in identifying future therapeutic targets.
Assuntos
Região CA3 Hipocampal/fisiologia , Envelhecimento Cognitivo/psicologia , Giro Denteado/fisiologia , Reconhecimento Fisiológico de Modelo/fisiologia , Animais , Masculino , Camundongos Endogâmicos C57BL , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Serina/farmacologiaRESUMO
BACKGROUND: Anticholinergic challenge can induce odor identification impairment that indicates Alzheimer's disease pathology. OBJECTIVE: To determine if decline in odor identification ability with anticholinergic challenge can predict improvement with donepezil, a cholinesterase inhibitor (ChEI), in patients with mild cognitive impairment (MCI). METHODS: At baseline, the University of Pennsylvania Smell identification Test (UPSIT) was administered before and after an anticholinergic atropine nasal spray challenge. Donepezil was started at 5âmg daily, increased to 10âmg daily if tolerated, and then the dose was kept constant for 52 weeks. Main outcomes were change in Selective Reminding Test (SRT) total immediate recall and ADAS-Cog total score from baseline to 26 and 52 weeks. RESULTS: In 37 participants, mean age 70.4 (SD 9.8) y, greater atropine-induced decrease in UPSIT score at baseline was associated with greater improvement in SRT total recall score from baseline to 26 and 52 weeks (pâ<â0.03). This effect remained after adjusting for time, age, education, gender, APOE É4 status, and baseline cognitive score (pâ<â0.05). Decrease in UPSIT score was associated with global improvement (CIBIC-plus) over 52 weeks (pâ<â0.02). After excluding patients with congential anosmia, increase in UPSIT score from 0 to 8 weeks showed a trend-level association with improvement on the ADAS-Cog (pâ=â0.07). CONCLUSIONS: Anticholinergic challenge-induced odor identification decline was associated with cognitive improvement, and short-term improvement in odor identification tended to predict longer term cognitive improvement. These simple inexpensive strategies have the potential to improve selection of patients with MCI for ChEI treatment.
Assuntos
Atropina/administração & dosagem , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/diagnóstico , Indanos/uso terapêutico , Antagonistas Muscarínicos/administração & dosagem , Percepção Olfatória/efeitos dos fármacos , Piperidinas/uso terapêutico , Idoso , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/fisiopatologia , Donepezila , Feminino , Humanos , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Testes Neuropsicológicos , Odorantes , Transtornos do Olfato/tratamento farmacológico , Transtornos do Olfato/fisiopatologia , Percepção Olfatória/fisiologia , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/fisiologia , Prognóstico , Psicotrópicos/uso terapêutico , Resultado do TratamentoRESUMO
Learning to associate a stimulus with reinforcement causes plasticity in primary sensory cortex. Neural activity caused by the associated stimulus is paired with reinforcement, but population analyses have not found a selective increase in response to that stimulus. Responses to other stimuli increase as much as, or more than, responses to the associated stimulus. Here, we applied population analysis at a new time point and additionally evaluated whether cholinergic receptor blockers interacted with the plastic changes in cortex. Three days of tone identification behavior caused responsiveness to increase broadly across primary auditory cortex, and target responses strengthened less than overall responsiveness. In pharmacology studies, behaviorally impairing doses of selective acetylcholine receptor blockers were administered during behavior. Neural responses were evaluated on the following day, while the blockers were absent. The muscarinic group, blocked by scopolamine, showed lower responsiveness and an increased response to the tone identification target that exceeded both the 3-day control group and task-naïve controls. Also, a selective increase in the late phase of the response to the tone identification stimulus emerged. Nicotinic receptor antagonism, with mecamylamine, more modestly lowered responses the following day and lowered target responses more than overall responses. Control acute studies demonstrated the muscarinic block did not acutely alter response rates, but the nicotinic block did. These results lead to the hypothesis that the decrease in the proportion of the population spiking response that is selective for the target may be explained by the balance between effects modulated by muscarinic and nicotinic receptors.
Assuntos
Córtex Auditivo/metabolismo , Percepção Auditiva/fisiologia , Neurônios/metabolismo , Reconhecimento Fisiológico de Modelo/fisiologia , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo , Estimulação Acústica , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Córtex Auditivo/efeitos dos fármacos , Percepção Auditiva/efeitos dos fármacos , Mapeamento Encefálico , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Masculino , Mecamilamina/farmacologia , Microeletrodos , Antagonistas Muscarínicos/farmacologia , Neurônios/efeitos dos fármacos , Antagonistas Nicotínicos/farmacologia , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Ratos Sprague-Dawley , Escopolamina/farmacologiaRESUMO
OBJECTIVES: In the present study, effects of 3',4'-dihydroxyflavonol (DiOHF) on anxiety-like behavior, and learning and memory were investigated in a model of transient global cerebral ischemia and reperfusion. METHODS: The animals were assigned to sham-operated, ischemia, and two DiOHF-treated (10 mg/kg i.p.) groups. DiOHF was administered at 1 hour before and immediately after the ischemia. Male rats were subjected to bilateral common carotid artery occlusion to induce acute cerebral ischemia for 20 minutes, followed by reperfusion for 7 days. The openfield, elevated plus maze (EPM), and Morris water maze tests were used to evaluate the effects of DiOHF treatment on ischemia-induced locomotor activity, anxiety-like behavior, and spatial and recognition memory impairments, respectively. RESULTS: In the open field test, locomotor activity in the ischemic rats was not altered 6 days after the ischemia, nor was anxiety-like behavior, which was evaluated with the EPM (P > 0.05). In the water-maze test, cerebral ischemia significantly decreased the exploration time in the target quadrant, and the platform crossing counts were lower (P < 0.05) in the probe trial test; this memory impairment was significantly improved by DiOHF applied 1 hour before and immediately after ischemia (P < 0.05). DISCUSSION: All together, these findings suggest that DiOHF reverses spatial learning and memory deficits resulting from transient global ischemia but has no significant effect on anxiety-like behavior.
Assuntos
Antioxidantes/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Flavonóis/uso terapêutico , Deficiências da Aprendizagem/prevenção & controle , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Traumatismo por Reperfusão/prevenção & controle , Animais , Ansiolíticos/administração & dosagem , Ansiolíticos/uso terapêutico , Antioxidantes/administração & dosagem , Ansiedade/etiologia , Ansiedade/prevenção & controle , Comportamento Animal/efeitos dos fármacos , Isquemia Encefálica/fisiopatologia , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Flavonóis/administração & dosagem , Injeções Intraperitoneais , Deficiências da Aprendizagem/etiologia , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/etiologia , Fármacos Neuroprotetores/administração & dosagem , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Distribuição Aleatória , Ratos Wistar , Traumatismo por Reperfusão/etiologia , Traumatismo por Reperfusão/fisiopatologia , Aprendizagem Espacial/efeitos dos fármacos , Fatores de TempoRESUMO
Repeated exposure to sub-anesthetic doses of ketamine in rats has been shown to induce cognitive deficits, as well as behavioral changes akin to the negative symptoms of schizophrenia, giving much face validity to the use of ketamine administration as a pharmacological model of schizophrenia. This study sought to further characterize the behavioral effects of two different ketamine pre-treatment regimens, focusing primarily on the effects of repeated ketamine administration on novelty processing, a capacity that is disrupted in schizophrenia. Rats received 5 or 14 intra-peritoneal injections of 30mg/kg ketamine or saline across 5 or 7days, respectively. They were then tested in an associative mismatch detection task to examine their ability to detect novel configurations of familiar audio-visual sequences. Furthermore, rats underwent a sequential novel object and novel object location exploration task. Subsequently, rats were also tested on the delayed matching to place T-maze task, sucrose preference task and locomotor tests involving administering a challenge dose of amphetamine (AMPH). The high-dose ketamine pre-treatment regimen elicited impairments in mismatch detection and working memory. In contrast, the low-dose ketamine pre-treatment regimen improved performance of novelty detection. In addition, low-dose ketamine pre-treated rats showed locomotor sensitization following an AMPH challenge, while the high-dose ketamine pre-treated rats showed an attenuated locomotor response to AMPH, compared to control rats. These findings demonstrate that different regimens of repeated ketamine administration induce alterations in novelty processing in opposite directions, and that differential neural adaptations occurring in the mesolimbic dopamine system may underlie these effects.
Assuntos
Atenção/efeitos dos fármacos , Ketamina/administração & dosagem , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Psicotrópicos/administração & dosagem , Anfetamina/administração & dosagem , Animais , Aprendizagem por Associação/efeitos dos fármacos , Percepção Auditiva/efeitos dos fármacos , Sacarose Alimentar , Relação Dose-Resposta a Droga , Comportamento Exploratório/efeitos dos fármacos , Injeções Intraperitoneais , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Atividade Motora/efeitos dos fármacos , Testes Psicológicos , Ratos Long-Evans , Percepção Gustatória/efeitos dos fármacos , Percepção Visual/efeitos dos fármacosRESUMO
It is commonly assumed that neural systems efficiently process natural sensory input. However, the mechanisms by which such efficient processing is achieved, and the consequences for perception and behaviour remain poorly understood. Here we show that small conductance calcium-activated potassium (SK) channels enable efficient neural processing and perception of natural stimuli. Specifically, these channels allow for the high-pass filtering of sensory input, thereby removing temporal correlations or, equivalently, whitening frequency response power. Varying the degree of adaptation through pharmacological manipulation of SK channels reduced efficiency of coding of natural stimuli, which in turn gave rise to predictable changes in behavioural responses that were no longer matched to natural stimulus statistics. Our results thus demonstrate a novel mechanism by which the nervous system can implement efficient processing and perception of natural sensory input that is likely to be shared across systems and species.
Assuntos
Peixe Elétrico/fisiologia , Sistema da Linha Lateral/fisiologia , Reconhecimento Fisiológico de Modelo/fisiologia , Células Piramidais/fisiologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Alcanos/farmacologia , Animais , Benzimidazóis/farmacologia , Agonistas dos Canais de Cálcio/farmacologia , Estimulação Elétrica , Eletrodos Implantados , Peixes , Ácido Glutâmico/farmacologia , Sistema da Linha Lateral/efeitos dos fármacos , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Células Piramidais/citologia , Células Piramidais/efeitos dos fármacos , Compostos de Quinolínio/farmacologia , Canais de Potássio Ativados por Cálcio de Condutância Baixa/agonistas , Canais de Potássio Ativados por Cálcio de Condutância Baixa/antagonistas & inibidores , Fatores de TempoRESUMO
Recent studies suggest that direct mortality and physiological effects caused by pollutants are major contributing factors to global amphibian decline. However, even sublethal concentrations of pollutants could be harmful if they combined with other factors to cause high mortality in amphibians. Here we show that sublethal concentrations of pollutants can disrupt the ability of amphibian larvae to recognize predators, hence increasing their risk of predation. This effect is indeed much more important since very low amounts of pollutants are ubiquitous, and environmental efforts are mostly directed towards preventing lethal spills. We analyzed the effects of two common contaminants (humic acid and ammonium nitrate) on the ability of tadpoles of the western spadefoot toad (Pelobates cultripes) to recognize chemical cues from a common predator, nymphs of the dragonfly Anax imperator. We compared the swimming activity of tadpoles in the presence and absence of water-borne chemical cues from dragonflies at different concentrations of humic acid and ammonium nitrate. Tadpoles reduced swimming activity in response to predator cues in the absence of pollutants, whereas they remained unresponsive to these cues when either humic acid or ammonium nitrate was added to the water, even at low concentrations. Moreover, changes in tadpole activity associated with the pollutants themselves were non-significant, indicating no toxic effect. Alteration of the natural chemical environment of aquatic systems by pollutants may be an important contributing cause for declines in amphibian populations, even at sublethal concentrations.
Assuntos
Anuros/fisiologia , Exposição Ambiental , Comportamento Predatório/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Substâncias Húmicas/toxicidade , Larva/efeitos dos fármacos , Nitratos/toxicidade , Odonatos , Reconhecimento Fisiológico de Modelo/efeitos dos fármacosRESUMO
Rats, humans, and monkeys demonstrate robust crossmodal object recognition (CMOR), identifying objects across sensory modalities. We have shown that rats' performance of a spontaneous tactile-to-visual CMOR task requires functional integration of perirhinal (PRh) and posterior parietal (PPC) cortices, which seemingly provide visual and tactile object feature processing, respectively. However, research with primates has suggested that PRh is sufficient for multisensory object representation. We tested this hypothesis in rats using a modification of the CMOR task in which multimodal preexposure to the to-be-remembered objects significantly facilitates performance. In the original CMOR task, with no preexposure, reversible lesions of PRh or PPC produced patterns of impairment consistent with modality-specific contributions. Conversely, in the CMOR task with preexposure, PPC lesions had no effect, whereas PRh involvement was robust, proving necessary for phases of the task that did not require PRh activity when rats did not have preexposure; this pattern was supported by results from c-fos imaging. We suggest that multimodal preexposure alters the circuitry responsible for object recognition, in this case obviating the need for PPC contributions and expanding PRh involvement, consistent with the polymodal nature of PRh connections and results from primates indicating a key role for PRh in multisensory object representation. These findings have significant implications for our understanding of multisensory information processing, suggesting that the nature of an individual's past experience with an object strongly determines the brain circuitry involved in representing that object's multisensory features in memory. SIGNIFICANCE STATEMENT: The ability to integrate information from multiple sensory modalities is crucial to the survival of organisms living in complex environments. Appropriate responses to behaviorally relevant objects are informed by integration of multisensory object features. We used crossmodal object recognition tasks in rats to study the neurobiological basis of multisensory object representation. When rats had no prior exposure to the to-be-remembered objects, the spontaneous ability to recognize objects across sensory modalities relied on functional interaction between multiple cortical regions. However, prior multisensory exploration of the task-relevant objects remapped cortical contributions, negating the involvement of one region and significantly expanding the role of another. This finding emphasizes the dynamic nature of cortical representation of objects in relation to past experience.
Assuntos
Córtex Cerebral/fisiologia , Reconhecimento Fisiológico de Modelo/fisiologia , Reconhecimento Visual de Modelos/fisiologia , Reconhecimento Psicológico/fisiologia , Análise de Variância , Anestésicos Locais/farmacologia , Animais , Córtex Cerebral/citologia , Córtex Cerebral/efeitos dos fármacos , Lidocaína/farmacologia , Masculino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Reconhecimento Visual de Modelos/efeitos dos fármacos , Estimulação Luminosa , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Long-Evans , Tato/fisiologiaRESUMO
Successful memory involves not only remembering information over time, but also keeping memories distinct and less confusable. The computational process for making representations for similar input patterns more distinct from each other has been referred to as "pattern separation." In this work, we developed a set of behavioral conditions that allowed us to manipulate the load for pattern separation at different stages of memory. Thus, we provide experimental evidence that a brain-derived neurotrophic factor (BDNF)-dependent pattern separation process occurs during the encoding/storage/consolidation, but not the retrieval stage of memory processing. We also found that a spontaneous increase in BDNF in the dentate gyrus of the hippocampus is associated with exposure to landmarks delineating similar, but not dissimilar, spatial locations, suggesting that BDNF is expressed on an "as-needed" basis for pattern separation.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Giro Denteado/metabolismo , Memória/fisiologia , Reconhecimento Fisiológico de Modelo/fisiologia , Animais , Mapeamento Encefálico , Fator Neurotrófico Derivado do Encéfalo/farmacologia , Giro Denteado/efeitos dos fármacos , Humanos , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Ratos , Proteínas Recombinantes/farmacologiaRESUMO
Preclinical data suggest that the 5-hydroxytryptamine (serotonin) 6 (5-HT6) receptor may be a potential target for the development of new therapies for treating cognitive dysfunctions in schizophrenia and other central nervous system disorders. Recent evidence indicates that not only blockade but also activation of 5-HT6 receptors exerts procognitive effects. Nevertheless, little is known about the potential efficacy of 5-HT6 receptor agonists in models of schizophrenia-like cognitive deficits. The aim of the present study was to evaluate the effects of the 5-HT6 receptor agonist, EMD 386088, on the ketamine-induced deficits in the attentional set-shifting task (ASST), novel object recognition (NOR) task and prepulse inhibition (PPI) task in rats. Acute administration of EMD 386088 (2.5 and 5 mg/kg, intraperitoneally) to Sprague-Dawley rats reversed the deficit in the ASST induced by repeated ketamine administration. Moreover, the ketamine-induced deficit in the NOR task was ameliorated by EMD 386088 at a dose of 5 mg/kg. However, in contrast to the antipsychotic drug clozapine, the 5-HT6 agonist did not affect PPI disrupted by ketamine. The present study demonstrated the beneficial effects of the 5-HT6 agonist in ameliorating some of the ketamine-induced deficits relevant to schizophrenia. It thus seems likely that the 5-HT6 receptor activation may represent a useful pharmacological approach to the treatment of cognitive disturbances observed in this disorder.
Assuntos
Atenção/efeitos dos fármacos , Indóis/farmacologia , Ketamina/farmacologia , Reconhecimento Fisiológico de Modelo/efeitos dos fármacos , Piridinas/farmacologia , Receptores de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/farmacologia , Animais , Antipsicóticos/farmacologia , Clozapina/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Esquizofrenia/tratamento farmacológico , Esquizofrenia/metabolismo , Serotonina/metabolismoRESUMO
In this article, we present a new view on the nature of cognitive processes suggesting that there is a common core, viz., automatic sensory-cognitive processes that form the basis for higher-order cognitive processes. It has been shown that automatic sensory-cognitive processes are shared by humans and various other species and occur at different developmental stages and even in different states of consciousness. This evidence, based on the automatic electrophysiological change-detection response mismatch negativity (MMN), its magnetoencephalographic equivalent MMNm, and behavioral data, indicates that in audition surprisingly complex processes occur automatically and mainly in the sensory-specific cortical regions. These processes include, e.g. stimulus anticipation and extrapolation, sequential stimulus-rule extraction, and pattern and pitch-interval encoding. Furthermore, these complex perceptual-cognitive processes, first found in waking adults, occur similarly even in sleeping newborns, anesthetized animals, and deeply sedated adult humans, suggesting that they form the common perceptual-cognitive core of cognitive processes in general. Although the present evidence originates mainly from the auditory modality, it is likely that analogous evidence could be obtained from other sensory modalities when measures corresponding to those used in the study of the auditory modality become available.