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1.
Eur J Neurosci ; 50(5): 2773-2785, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31231836

RESUMO

Chronic stress is a major risk factor for developing Alzheimer's disease (AD) and promotes the processing of amyloid precursor protein (APP) to ß-amyloid (Aß). However, the precise relationship of stress and disease-typical cognitive decline is presently not well understood. The aim of this study was to investigate how early life stress may affect cognition in adult mice with and without soluble Aß pathology typical for the early stages of the disease. We focussed on sustained attention and response control, aspects of cognition mediated by the prefrontal cortex that are consistently impaired both in early AD and after chronic stress exposure. Young wild-type mice as well as transgenic arcAß mice overexpressing the hAPParc/swe transgene were exposed to a chronic unpredictable stress paradigm (age 3-8 weeks). At 15 weeks, these mice were tested on the 5-choice serial reaction time task, a test of sustained attention and executive control. We found that, expectedly, chronic stress increased impulsive choices and impaired sustained attention in wild-type mice. However, the same treatment reduced impulsivity and did not interfere with sustained attention in arcAß mice. These findings suggest an unexpected interaction between chronic stress and Aß whereby Aß-pathology caused by the hAPParc/swe mutation prevented and/or reversed stress-induced cognitive changes through mechanisms that deserve further investigation. They also indicate that Aß, in modest amounts, may have a beneficial role for cognitive stability, for example by protecting neural networks from the impact of further physiological or behavioural stress.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Cognição/fisiologia , Função Executiva/fisiologia , Estresse Psicológico/genética , Doença de Alzheimer/genética , Animais , Atenção/fisiologia , Comportamento Animal/fisiologia , Modelos Animais de Doenças , Comportamento Impulsivo/fisiologia , Masculino , Camundongos , Mutação , Tempo de Reação/fisiologia
2.
Psychopharmacology (Berl) ; 235(12): 3495-3508, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30327842

RESUMO

RATIONALE: Muscarinic acetylcholine receptors are known to play key roles in mediating cognitive processes, and impaired muscarinic cholinergic neurotransmission is associated with normal ageing processes and Alzheimer's disease. However, the specific contributions of the individual muscarinic receptor subtypes (M1-M5) to cognition are presently not well understood. OBJECTIVES: The aim of this study was to investigate the contribution of M2-type muscarinic receptor signalling to sustained attention, executive control and learning and memory. METHODS: M2 receptor-deficient (M2-/-) mice were tested on a touchscreen-operated task battery testing visual discrimination, behavioural flexibility, object-location associative learning, attention and response control. Spontaneous recognition memory for real-world objects was also assessed. RESULTS: We found that M2-/- mice showed an enhancement of attentional performance, but significant deficits on some tests of learning and memory. Executive control and visual discrimination were unaffected by M2-depletion. CONCLUSIONS: These findings suggest that M2 activation has heterogeneous effects across cognitive domains, and provide insights into how acetylcholine may support multiple specific cognitive processes through functionally distinct cholinergic receptor subtypes. They also suggest that therapeutics involving M2 receptor-active compounds should be assessed across a broad range of cognitive domains, as they may enhance some cognitive functions, but impair others.


Assuntos
Atenção/fisiologia , Aprendizagem/fisiologia , Receptor Muscarínico M2/deficiência , Reconhecimento Psicológico/fisiologia , Animais , Condicionamento Operante/fisiologia , Masculino , Memória/fisiologia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estimulação Luminosa/métodos , Percepção Visual/fisiologia
3.
Psychopharmacology (Berl) ; 232(21-22): 3935-45, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26173611

RESUMO

RATIONALE: The hippocampus is implicated in many of the cognitive impairments observed in conditions such as Alzheimer's disease (AD) and schizophrenia (SCZ). Often, mice are the species of choice for models of these diseases and the study of the relationship between brain and behaviour more generally. Thus, automated and efficient hippocampal-sensitive cognitive tests for the mouse are important for developing therapeutic targets for these diseases, and understanding brain-behaviour relationships. One promising option is to adapt the touchscreen-based trial-unique nonmatching-to-location (TUNL) task that has been shown to be sensitive to hippocampal dysfunction in the rat. OBJECTIVES: This study aims to adapt the TUNL task for use in mice and to test for hippocampus-dependency of the task. METHODS: TUNL training protocols were altered such that C57BL/6 mice were able to acquire the task. Following acquisition, dysfunction of the dorsal hippocampus (dHp) was induced using a fibre-sparing excitotoxin, and the effects of manipulation of several task parameters were examined. RESULTS: Mice could acquire the TUNL task using training optimised for the mouse (experiments 1). TUNL was found to be sensitive to dHp dysfunction in the mouse (experiments 2, 3 and 4). In addition, we observed that performance of dHp dysfunction group was somewhat consistently lower when sample locations were presented in the centre of the screen. CONCLUSIONS: This study opens up the possibility of testing both mouse and rat models on this flexible and hippocampus-sensitive touchscreen task.


Assuntos
Cognição/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Animais , Automação , Comportamento de Escolha/efeitos dos fármacos , Masculino , Meloxicam , Camundongos , Camundongos Endogâmicos C57BL , N-Metilaspartato/farmacologia , Neurotoxinas/farmacologia , Tiazinas/farmacologia , Tiazóis/farmacologia
4.
J Neurosci ; 33(16): 7057-65, 2013 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-23595763

RESUMO

Perineuronal nets (PNNs) are extracellular matrix structures surrounding cortical neuronal cell bodies and proximal dendrites and are involved in the control of brain plasticity and the closure of critical periods. Expression of the link protein Crtl1/Hapln1 in neurons has recently been identified as the key event triggering the formation of PNNs. Here we show that the genetic attenuation of PNNs in adult brain Crtl1 knock-out mice enhances long-term object recognition memory and facilitates long-term depression in the perirhinal cortex, a neural correlate of object recognition memory. Identical prolongation of memory follows localized digestion of PNNs with chondroitinase ABC, an enzyme that degrades the chondroitin sulfate proteoglycan components of PNNs. The memory-enhancing effect of chondroitinase ABC treatment attenuated over time, suggesting that the regeneration of PNNs gradually restored control plasticity levels. Our findings indicate that PNNs regulate both memory and experience-driven synaptic plasticity in adulthood.


Assuntos
Córtex Cerebral/fisiologia , Matriz Extracelular/metabolismo , Depressão Sináptica de Longo Prazo/fisiologia , Neurônios/fisiologia , Reconhecimento Psicológico/fisiologia , Análise de Variância , Animais , Animais Recém-Nascidos , Condroitina ABC Liase/farmacologia , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Proteínas da Matriz Extracelular/deficiência , Genótipo , Depressão Sináptica de Longo Prazo/efeitos dos fármacos , Depressão Sináptica de Longo Prazo/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Neurônios/efeitos dos fármacos , Penicilinase/farmacologia , Proteoglicanas/deficiência , Reconhecimento Psicológico/efeitos dos fármacos , Fatores de Tempo
5.
Neurobiol Aging ; 34(3): 731-44, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22959727

RESUMO

Transgenic mouse models of Alzheimer's disease (AD) with abundant ß-amyloid develop memory impairments. However, multiple nonmnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals, but have not been routinely assessed in animal models. Here, we assessed the cognitive abilities of TgCRND8 mice-a widely used model of ß-amyloid pathology-with a touch screen-based automated test battery. The test battery comprises highly translatable tests of multiple cognitive constructs impaired in human AD, such as memory, attention, and response control, as well as appropriate control tasks. We found that familial AD mutations affect not only memory, but also cause significant alterations of sustained attention and behavioral flexibility. Because changes in attention and response inhibition may affect performance on tests of other cognitive abilities including memory, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD. A more comprehensive phenotyping with specialized, multicomponent cognitive test batteries for mice might significantly advance translation from preclinical mouse studies to the clinic.


Assuntos
Doença de Alzheimer/fisiopatologia , Atenção , Inibição Psicológica , Transtornos da Memória/fisiopatologia , Testes Neuropsicológicos , Doença de Alzheimer/genética , Animais , Modelos Animais de Doenças , Masculino , Transtornos da Memória/genética , Camundongos , Camundongos Transgênicos , Interface Usuário-Computador
6.
Brain Res Bull ; 92: 49-55, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22390982

RESUMO

The cognitive phenotyping of mouse models of Alzheimer's disease (AD) currently focuses on impairments in learning and memory. However, AD is not simply a memory disorder, but other cognitive domains, and in particular attention, can also be impaired even at very early stages of the disease. In this review we argue for the benefits of including other constructs, and in particular attention, in preclinical studies to identify drug targets and disease mechanisms of AD in mouse models. First we give a brief account of the evidence for attentional deficits in AD; we then summarise methods to assess equivalent aspects of attention in mice, followed by a review of recent evidence for attentional impairments in widely used mouse models of AD. We conclude by suggesting that a multidimensional approach to cognitive assessment in preclinical models, in which a number of aspects of cognition are investigated while confounding factors are minimized, is becoming increasingly feasible and may contribute significantly towards the development of more targeted therapeutic interventions.


Assuntos
Doença de Alzheimer/complicações , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Transtornos Cognitivos/etiologia , Compreensão/fisiologia , Animais , Modelos Animais de Doenças , Humanos , Camundongos
7.
Brain ; 135(Pt 7): 2103-14, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22466291

RESUMO

Alzheimer's disease is commonly regarded as a loss of memory for past events. However, patients with Alzheimer's disease seem not only to forget events but also to express false confidence in remembering events that have never happened. How and why false recognition occurs in such patients is currently unknown, and treatments targeting this specific mnemonic abnormality have not been attempted. Here, we used a modified object recognition paradigm to show that the tgCRND8 mouse-which overexpresses amyloid ß and develops amyloid plaques similar to those in the brains of patients with Alzheimer's disease-exhibits false recognition. Furthermore, we found that false recognition did not occur when tgCRND8 mice were kept in a dark, quiet chamber during the delay, paralleling previous findings in patients with mild cognitive impairment, which is often considered to be prodromal Alzheimer's disease. Additionally, false recognition did not occur when mice were treated with the partial N-methyl-d-aspartic acid receptor antagonist memantine. In a subsequent experiment, we found abnormally enhanced N-methyl-d-aspartic acid receptor-dependent long-term depression in these mice, which could be normalized by treatment with memantine. We suggest that Alzheimer's disease typical amyloid ß pathology leads to aberrant synaptic plasticity, thereby making memory representations more susceptible to interfering sensory input, thus increasing the likelihood of false recognition. Parallels between these findings and those from the literature on Alzheimer's disease and mild cognitive impairment suggest a mechanism underlying false recognition in these patients. The false recognition phenomenon may provide a novel paradigm for the discovery of potential therapies to treat the mnemonic dysfunction characteristic of this disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/psicologia , Memantina/farmacologia , Reconhecimento Psicológico/efeitos dos fármacos , Privação Sensorial/fisiologia , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Precursor de Proteína beta-Amiloide/genética , Animais , Modelos Animais de Doenças , Estimulação Elétrica/métodos , Depressão Sináptica de Longo Prazo/fisiologia , Depressão Sináptica de Longo Prazo/efeitos da radiação , Memantina/uso terapêutico , Camundongos , Camundongos Transgênicos , Placa Amiloide/patologia , Reconhecimento Psicológico/fisiologia , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/patologia , Lobo Temporal/fisiopatologia
8.
Neuropharmacology ; 61(8): 1366-78, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21903112

RESUMO

Cholinergic receptors have been implicated in schizophrenia, Alzheimer's disease, Parkinson's disease, and Huntington's disease. However, to better target therapeutically the appropriate receptor subsystems, we need to understand more about the functions of those subsystems. In the current series of experiments, we assessed the functional role of M(1) receptors in cognition by testing M(1) receptor-deficient mice (M1R(-/-)) on the five-choice serial reaction time test of attentional and response functions, carried out using a computer-automated touchscreen test system. In addition, we tested these mice on several tasks featuring learning, memory and perceptual challenges. An advantage of the touchscreen method is that each test in the battery is carried out in the same task setting, using the same types of stimuli, responses and feedback, thus providing a high level of control and task comparability. The surprising finding, given the predominance of the M(1) receptor in cortex, was the complete lack of effect of M(1) deletion on measures of attentional function per se. Moreover, M1R(-/-) mice performed relatively normally on tests of learning, memory and perception, although they were impaired in object recognition memory with, but not without an interposed delay interval. They did, however, show clear abnormalities on a variety of response measures: M1R(-/-) mice displayed fewer omissions, more premature responses, and increased perseverative responding compared to wild-types. These data suggest that M1R(-/-) mice display abnormal responding in the face of relatively preserved attention, learning and perception.


Assuntos
Atenção/fisiologia , Condicionamento Clássico/fisiologia , Tempo de Reação/genética , Receptor Muscarínico M1/deficiência , Percepção Visual/genética , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estimulação Luminosa/métodos , Tempo de Reação/fisiologia
9.
J Neurosci ; 31(9): 3500-7, 2011 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-21368062

RESUMO

Several mouse models of Alzheimer's disease (AD) with abundant ß-amyloid and/or aberrantly phosphorylated tau develop memory impairments. However, multiple non-mnemonic cognitive domains such as attention and executive control are also compromised early in AD individuals. Currently, it is unclear whether mutations in the ß-amyloid precursor protein (APP) and tau are sufficient to cause similar, AD-like attention deficits in mouse models of the disease. To address this question, we tested 3xTgAD mice (which express APPswe, PS1M146V, and tauP301L mutations) and wild-type control mice on a newly developed touchscreen-based 5-choice serial reaction time test of attention and response control. The 3xTgAD mice attended less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild-type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects: first, although 3xTgAD mice initially responded as accurately as wild-type mice, they subsequently failed to sustain their attention over the duration of the task; second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Atenção/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Indanos/uso terapêutico , Piperidinas/uso terapêutico , Doença de Alzheimer/genética , Animais , Atenção/fisiologia , Condicionamento Operante/fisiologia , Donepezila , Humanos , Indanos/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Piperidinas/administração & dosagem
10.
Proc Natl Acad Sci U S A ; 107(5): 2367-72, 2010 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-20133882

RESUMO

Increasing evidence suggests that regular exercise improves brain health and promotes synaptic plasticity and hippocampal neurogenesis. Exercise improves learning, but specific mechanisms of information processing influenced by physical activity are unknown. Here, we report that voluntary running enhanced the ability of adult (3 months old) male C57BL/6 mice to discriminate between the locations of two adjacent identical stimuli. Improved spatial pattern separation in adult runners was tightly correlated with increased neurogenesis. In contrast, very aged (22 months old) mice had impaired spatial discrimination and low basal cell genesis that was refractory to running. These findings suggest that the addition of newly born neurons may bolster dentate gyrus-mediated encoding of fine spatial distinctions.


Assuntos
Aprendizagem por Discriminação/fisiologia , Atividade Motora/fisiologia , Animais , Bromodesoxiuridina/metabolismo , Contagem de Células , Giro Denteado/irrigação sanguínea , Giro Denteado/citologia , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese , Corrida/fisiologia
11.
Neuroreport ; 20(9): 881-5, 2009 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-19421077

RESUMO

Researchers are becoming increasingly interested in the role of the hippocampus in pattern separation, a process which keeps items distinct in memory. In this study, we develop and test a new automated touchscreen-based method for studying pattern separation in rodents. Rats were trained to discriminate locations on a computer screen that varied in their similarity, that is, their distance apart on the screen. Animals with lesions of the dorsal hippocampus were impaired when the locations discriminated were close together but not when they were far apart, indicating impaired pattern separation. This test provides an automated test of pattern separation, which adds to an expanding battery of cognitive tests that can be carried out using the touchscreen testing method.


Assuntos
Ciências do Comportamento/métodos , Aprendizagem por Discriminação/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Testes Neuropsicológicos , Neuropsicologia/métodos , Animais , Aprendizagem por Associação/fisiologia , Ciências do Comportamento/instrumentação , Cognição/fisiologia , Computadores/tendências , Condicionamento Clássico/fisiologia , Denervação , Comportamento Exploratório/fisiologia , Masculino , Rememoração Mental/fisiologia , Modelos Neurológicos , Neuropsicologia/instrumentação , Orientação/fisiologia , Reconhecimento Automatizado de Padrão/métodos , Reconhecimento Visual de Modelos/fisiologia , Valor Preditivo dos Testes , Resolução de Problemas/fisiologia , Ratos , Sensibilidade e Especificidade , Aprendizagem Seriada/fisiologia , Percepção Espacial/fisiologia , Comportamento Espacial/fisiologia , Tato/fisiologia , Interface Usuário-Computador , Percepção Visual
12.
Eur J Neurosci ; 29(6): 1141-52, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19302150

RESUMO

Long-term potentiation (LTP) at hippocampal CA3-CA1 synapses is thought to be mediated, at least in part, by an increase in the postsynaptic surface expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) receptors induced by N-methyl-d-aspartate (NMDA) receptor activation. While this process was originally attributed to the regulated synaptic insertion of GluA1 (GluR-A) subunit-containing AMPA receptors, recent evidence suggests that regulated synaptic trafficking of GluA2 subunits might also contribute to one or several phases of potentiation. However, it has so far been difficult to separate these two mechanisms experimentally. Here we used genetically modified mice lacking the GluA1 subunit (Gria1(-/-) mice) to investigate GluA1-independent mechanisms of LTP at CA3-CA1 synapses in transverse hippocampal slices. An extracellular, paired theta-burst stimulation paradigm induced a robust GluA1-independent form of LTP lacking the early, rapidly decaying component characteristic of LTP in wild-type mice. This GluA1-independent form of LTP was attenuated by inhibitors of neuronal nitric oxide synthase and protein kinase C (PKC), two enzymes known to regulate GluA2 surface expression. Furthermore, the induction of GluA1-independent potentiation required the activation of GluN2B (NR2B) subunit-containing NMDA receptors. Our findings support and extend the evidence that LTP at hippocampal CA3-CA1 synapses comprises a rapidly decaying, GluA1-dependent component and a more sustained, GluA1-independent component, induced and expressed via a separate mechanism involving GluN2B-containing NMDA receptors, neuronal nitric oxide synthase and PKC.


Assuntos
Expressão Gênica/fisiologia , Hipocampo/metabolismo , Potenciação de Longa Duração/genética , Receptores de AMPA/metabolismo , Análise de Variância , Animais , Biofísica , Estimulação Elétrica/métodos , Inibidores Enzimáticos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/genética , Expressão Gênica/efeitos dos fármacos , Técnicas In Vitro , Potenciação de Longa Duração/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Rede Nervosa/efeitos dos fármacos , Rede Nervosa/fisiologia , Óxido Nítrico Sintase Tipo I/metabolismo , Proteína Quinase C/metabolismo , Receptores de AMPA/antagonistas & inibidores , Receptores de AMPA/deficiência
13.
J Neurosci ; 28(14): 3623-30, 2008 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-18385321

RESUMO

NMDA receptors (NMDARs) containing NR2A (epsilon1) subunits are key contributors to hippocampal long-term potentiation (LTP) induction in adult animals and have therefore been widely implicated in hippocampus-dependent spatial learning. Here we show that mice lacking the NR2A subunit or its C-terminal intracellular domain exhibit impaired spatial working memory (SWM) but normal spatial reference memory (SRM). Both NR2A mutants acquired the SRM version of the water maze task, and the SRM component of the radial maze, as well as controls. They were, however, impaired on a non-matching-to-place T-maze task, and on the SWM component of the radial maze. In addition, NR2A knock-out mice displayed a diminished spatial novelty preference in a spontaneous exploration Y-maze task, and were impaired on a T-maze task in which distinctive inserts present on the floor of the maze determined which goal arm contained the reward, but only if there was a discontiguity between the conditional cue and the place at which the reward was delivered. This dissociation of spatial memory into distinctive components is strikingly similar to results obtained with mice lacking glutamate receptor-A (GluR-A)-containing AMPA receptors, which support long-term potentiation expression. These results identify a specific role for a NMDAR-dependent signaling pathway that leads to the activation of a GluR-A-dependent expression mechanism in a rapidly acquired, flexible form of spatial memory. This mechanism depends on the C-terminal intracellular domain of the NR2A subunit. In contrast, the ability to associate a particular spatial location with the water maze escape platform or food reward is NR2A independent, as well as GluR-A independent.


Assuntos
Memória de Curto Prazo/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Percepção Espacial/fisiologia , Análise de Variância , Animais , Comportamento Animal , Condicionamento Psicológico/fisiologia , Comportamento Exploratório/fisiologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação/fisiologia , Receptores de N-Metil-D-Aspartato/deficiência , Fatores de Tempo
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