RESUMO
Calcyon regulates activity-dependent internalization of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) glutamate receptors and long-term depression of excitatory synapses. Elevated levels of calcyon are consistently observed in brains from schizophrenic patients, and the calcyon gene is associated with attention-deficit hyperactivity disorder. Executive function deficits are common to both disorders, and at least for schizophrenia, the etiology appears to involve both heritable and neurodevelopmental factors. Here, we show with calcyon-overexpressing Cal(OE) transgenic mice that lifelong calcyon upregulation impairs executive functions including response inhibition and working memory, without producing learning and memory deficits in general. As response inhibition and working memory, as well as the underlying neural circuitry, continue to mature into early adulthood, we functionally silenced the transgene during postnatal days 28-49, a period corresponding to adolescence. Remarkably, the response inhibition and working memory deficits including perseverative behavior were absent in adult Cal(OE) mice with the transgene silenced in adolescence. Suppressing the calcyon transgene in adulthood only partially rescued the deficits, suggesting calcyon upregulation in adolescence irreversibly alters development of neural circuits supporting mature response inhibition and working memory. Brain regional immunoblots revealed a prominent downregulation of AMPA GluR1 subunits in hippocampus and GluR2/3 subunits in hippocampus and prefrontal cortex of the Cal(OE) mice. Silencing the transgene in adolescence prevented the decrease in hippocampal GluR1, further implicating altered fronto-hippocampal connectivity in the executive function deficits observed in the Cal(OE) mice. Treatments that mitigate the effects of high levels of calcyon during adolescence could preempt adult deficits in executive functions in individuals at risk for serious mental illness.
Assuntos
Inibição Psicológica , Proteínas de Membrana/metabolismo , Transtornos da Memória/fisiopatologia , Memória de Curto Prazo/fisiologia , Regulação para Cima/fisiologia , Animais , Animais Recém-Nascidos , Quinase da Proteína Quinase Dependente de Cálcio-Calmodulina/genética , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Modelos Animais de Doenças , Doxiciclina/metabolismo , Doxiciclina/farmacologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/efeitos dos fármacos , Medo/fisiologia , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Proteínas de Membrana/genética , Transtornos da Memória/genética , Camundongos , Camundongos Transgênicos , Receptores de AMPA/metabolismo , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Understanding how the hippocampus processes episodic memory information during neuropathological conditions is important for treatment and prevention applications. Previous data have shown that during chronic neuroinflammation the expression of the plasticity related behaviourally-induced immediate early gene Arc is altered within the CA3 and the dentate gyrus; both of these hippocampal regions show a pronounced increase in activated microglia. Low doses of memantine, a low to moderate affinity open channel uncompetitive N-Methyl-d-aspartate receptor antagonist, reduce neuroinflammation, return Arc expression to control levels and attenuate cognitive deficits induced by lipopolysaccharide. Here we investigate whether neuroinflammation affects the accuracy of information processing in the CA3 and CA1 hippocampal regions and if this is modified by memantine treatment. Using the immediate early gene-based brain-imaging method called cellular analysis of temporal activity by fluorescence in situ hybridization, it is possible to detect primary transcripts at the genomic alleles; this provides exceptional temporal and cellular resolution and facilitates the mapping of neuronal activity. Here, we use this method to compare the neuronal populations activated by two separate experiences in CA1 and CA3 and evaluate the accuracy of information processing during chronic neuroinflammation. Our results show that the CA3 pyramidal neuron activity is not stable between two exposures to the same environment context or two different contexts. CA1 networks, however, do not differ from control conditions. These data suggest that during chronic neuroinflammation, the CA3 networks show a disrupted ability to encode spatial information, and that CA1 neurons can work independently of CA3. Importantly, memantine treatment is able to partially normalize information processing in the hippocampus, suggesting that when given early during the development of the pathology memantine confers neuronal and cognitive protection while indirectly prevents pathological microglial activation.
Assuntos
Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Hipocampo/fisiopatologia , Memantina/uso terapêutico , Inflamação Neurogênica/fisiopatologia , Animais , Mapeamento Encefálico/métodos , Células Cultivadas , Doença Crônica , Proteínas do Citoesqueleto/biossíntese , Proteínas do Citoesqueleto/genética , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Expressão Gênica , Genes Precoces , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hibridização in Situ Fluorescente , Lipopolissacarídeos , Masculino , Memantina/farmacologia , Microglia/efeitos dos fármacos , Rede Nervosa/fisiopatologia , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Inflamação Neurogênica/tratamento farmacológico , Inflamação Neurogênica/psicologia , Neurônios/metabolismo , RNA Mensageiro/genética , Ratos , Ratos Endogâmicos F344 , Receptores de N-Metil-D-Aspartato/antagonistas & inibidoresRESUMO
Neuroinflammation is reliably associated with the pathogenesis of a number of neurodegenerative diseases, and can be detected by the presence of activated microglia. Neuroinflammation can be induced by chronic lipopolysaccharide (LPS) infusion into the 4th ventricle of the rat resulting in region-selective microglia activation and impaired hippocampal-dependent memory. Furthermore, this treatment results in altered behaviorally-induced expression of the immediate early gene Arc, indicating altered network activity. LPS is known to activate microglia directly, leading to increased glutamate release, and in enhanced N-methyl-d-aspartate (NMDA) -dependent signaling. Taken together, the foregoing suggests that decreasing NMDA receptor activation during early stages of chronic neuroinflammation should reduce a) microglia activation, b) overexpression of Arc, and c) spatial memory deficits. Memantine, a low to moderate affinity open channel uncompetitive NMDA receptor antagonist, at low doses was used here to test these hypotheses. Rats were chronically infused into the 4th ventricle for 28 days with LPS alone, vehicle alone (via osmotic minipump) or LPS and memantine (10 mg/kg/day memantine s.c.). The results reported here demonstrate that memantine reduces OX6-immunolabeling for activated microglia, spares resident microglia, returns Arc (activity-regulated cytoskeletal associated protein, protein) -expressing neuronal populations to control levels (as revealed by Arc immunolabeling and fluorescence in situ hybridization), and ameliorates the spatial memory impairments produced by LPS alone. These data indicate that memantine therapy at low doses, recreating plasma levels similar to those of therapeutic doses in human, acts in part through its ability to reduce the effects of neuroinflammation, resulting in normal gene expression patterns and spatial learning. Combined, these findings suggest that low, therapeutically relevant doses of memantine delivered early in the development of neuroinflammation-influenced diseases may confer neural and cognitive protection.
Assuntos
Encefalite/tratamento farmacológico , Regulação da Expressão Gênica/efeitos dos fármacos , Memantina/farmacologia , Transtornos da Memória/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Proteínas do Citoesqueleto/efeitos dos fármacos , Proteínas do Citoesqueleto/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Encefalite/genética , Encefalite/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Regulação da Expressão Gênica/fisiologia , Gliose/tratamento farmacológico , Gliose/fisiopatologia , Gliose/prevenção & controle , Mediadores da Inflamação/farmacologia , Lipopolissacarídeos/farmacologia , Masculino , Memória , Transtornos da Memória/genética , Transtornos da Memória/metabolismo , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteínas do Tecido Nervoso/efeitos dos fármacos , Proteínas do Tecido Nervoso/metabolismo , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Endogâmicos F344 , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Lesions of the lateral/basolateral amygdala nuclei (BLC) disrupt freezing behaviour in response to explicit or contextual cues (conditioned stimuli--CS) paired previously with footshock (unconditioned stimulus). This deficit in expression of defensive behaviour in response to conditioned stimuli is often interpreted as inability of lesioned rats to learn CS-US associations. However, findings of several studies indicate that BLC-lesioned rats can rapidly learn CS-US associations. Such findings suggest that lesioned rats can learn CS-US associations but are impaired in the expression of freezing behaviour. In the present study we report that both temporary inactivation (lidocaine) and permanent excitotoxic (NMDA) lesions of the BLC impair the unconditioned freezing and avoidance behaviours of rats in response to a novel fear-eliciting stimulus, a ball of cat hair. These findings suggest that the BLC influences the expression of freezing and avoidance behaviours, and/or that it potentiates rats' experience of fear. Along with prior evidence of spared memory for aversive learning after BLC lesions, these findings suggest that disrupted freezing to conditioned cues in BLC-lesioned rats does not necessarily reflect inability to form CS-US associations.
Assuntos
Tonsila do Cerebelo/fisiologia , Aprendizagem da Esquiva/fisiologia , Comportamento Animal/fisiologia , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/efeitos dos fármacos , Anestésicos Locais/farmacologia , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Denervação , Agonistas de Aminoácidos Excitatórios/farmacologia , Medo/efeitos dos fármacos , Lidocaína/farmacologia , Masculino , N-Metilaspartato/farmacologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/fisiopatologia , Vias Neurais/citologia , Vias Neurais/efeitos dos fármacos , Vias Neurais/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Neurotoxinas/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
BACKGROUND: As the unitary theory of anesthesia gives way to the "multiple sites, multiple mechanisms" concept, the sites involved in mediating the components of anesthesia must be identified. In the current study, we test the hypothesis that the basolateral amygdala complex (BLAC) is a brain site involved with mediating propofol-induced amnesia. METHODS: Male Sprague-Dawley rats were divided into two groups, sham-operated control animals and rats given bilateral excitotoxic N-methyl-D-aspartate lesions of the BLAC. For each group, animals were given intraperitoneal saline or propofol (25 mg/kg) 5 min before inhibitory avoidance learning. Rats were given a foot shock (0.4 mA) upon entering the dark side of a two-sided apparatus. Rats could escape additional shock by returning to and staying in the light side. Training ended after shock avoidance for greater than 60 s. Memory was tested at 24 h. Longer latencies to enter the dark side 24 h after training imply better memory. RESULTS: Sham-saline-treated animals had a robust memory latency (median latency [interquartile range] = 300 [163-567] s). Sham-propofo-treated animals exhibited a significant anterograde amnesia (latency = 63 [14-111] s) (P < 0.05 vs. sham-saline-treated animal). Both the saline-injected and propofol-injected animals with BLAC lesions showed robust memory (latency = 300 [264-485] and 323 [143480] s, respectively). These latencies did not differ from performance in the sham-saline-treated group and were significantly higher than the latency of the sham-propofol-treated group (both P < 0.05). CONCLUSIONS: Discrete BLAC lesions blocked the amnestic effect of propofol. BLAC activity appears to be a requirement for propofol-induced amnesia. This finding suggests that the BLAC is a key brain site mediating anesthetic-induced amnesia.
Assuntos
Amnésia/induzido quimicamente , Tonsila do Cerebelo/efeitos dos fármacos , Anestésicos Intravenosos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Propofol/farmacologia , Tonsila do Cerebelo/fisiologia , Animais , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
A major hypothesis about lateral/basolateral amygdala complex (BLC) function in memory proposes that the BLC is the site where conditioned stimulus-unconditioned stimulus (CS-US) associations are formed and permanently stored during Pavlovian 'fear conditioning.' Thus, according to this hypothesis, the BLC is necessary for the acquisition and expression of both discrete-cue and contextual Pavlovian fear conditioning. This hypothesis clearly requires that animals with complete lesions of the BLC be completely unable to acquire Pavlovian fear conditioning. In this experiment, distribution of training and testing trials over three sessions revealed that rats with complete BLC lesions rapidly acquired a contextual CS-US association (as assessed with freezing behaviour), although their performance, as expected, did not equal that of sham operated controls. Irrespective of the nature of the freezing deficit relative to controls, the learning in the BLC-lesioned rats strongly indicates that Pavlovian fear conditioning CS-US associations can be rapidly acquired in the absence of the BLC, and that the BLC cannot therefore be necessary for their acquisition.
Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Animais , Comportamento Animal/fisiologia , Denervação , Agonistas de Aminoácidos Excitatórios , Masculino , Memória/fisiologia , N-Metilaspartato , Neurotoxinas , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/fisiologiaRESUMO
Previous findings indicate that the basolateral amygdala complex of nuclei (BLC) is involved in modulating (i.e., enhancing or impairing) memory consolidation for aversive training such as inhibitory avoidance. The present study examined whether the BLC also modulates the consolidation of memory for classical fear conditioning in which a specific context is paired with footshock. Adult male rats with bilateral cannulae targeting the BLC were allowed, first, to habituate in a Y maze that had differently shaped and textured arms. On the next day the rats were placed in one maze arm (shock arm), and they received four unsignaled footshocks. In Experiment 1, immediately after the training some rats received BLC inactivation with lidocaine (10 microgram/0.2 microliter per side), and control rats received buffered saline. In Experiment 2, rats received immediate post-training intra-BLC infusions of the muscarinic receptor agonist oxotremorine (10 ng/0.2 microliter per side) or saline. On a 24 hr retention test each rat was placed in a "safe" arm of the maze and allowed to access all maze arms. Lidocaine-treated rats had impaired memory for the classical fear conditioning when they were compared with the saline-treated controls: they spent less time freezing, entered the shock arm more readily and more often, and spent more time in it. In contrast, oxotremorine-treated rats had a stronger memory for the context-footshock association as assessed by all measures of memory. Thus, post-training treatments affecting BLC function modulate memory for Pavlovian contextual fear conditioning in a manner similar to that found with other types of training.
Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Medo/fisiologia , Memória/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Anestésicos Locais/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Eletrochoque , Lidocaína/farmacologia , Masculino , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Oxotremorina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Extensive evidence indicates that benzodiazepine receptors in the amygdala are involved in regulating memory consolidation. Recent findings indicate that many other drugs and hormones influence memory through selective activation of the basolateral amygdala nucleus (BLA). This experiment examined whether the memory-modulatory effect of flumazenil, a benzodiazepine receptor antagonist, selectively involves the BLA. Bilateral microinfusions of flumazenil (12 nmol in 0.2 microl) into the BLA of rats administered immediately after training in an inhibitory avoidance task significantly enhanced 48-h retention performance whereas infusions into the central nucleus were ineffective. These findings indicate that the BLA is selectively involved in mediating flumazenil's influence on memory storage and are thus consistent with extensive evidence indicating that the BLA is involved in regulating memory consolidation.
Assuntos
Tonsila do Cerebelo/fisiologia , Aprendizagem da Esquiva/fisiologia , Flumazenil/farmacologia , Antagonistas de Receptores de GABA-A , Memória/fisiologia , Receptores de GABA-A/fisiologia , Tonsila do Cerebelo/patologia , Análise de Variância , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Masculino , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Estatísticas não ParamétricasRESUMO
Evidence that lesions of the basolateral amygdala complex (BLC) impair memory for fear conditioning in rats, measured by lack of "freezing" behavior in the presence of cues previously paired with footshocks, has suggested that the BLC may be a critical locus for the memory of fear conditioning. However, evidence that BLC lesions may impair unlearned as well as conditioned freezing makes it difficult to interpret the findings of studies assessing conditioned fear with freezing. The present study investigated whether such lesions prevent the expression of several measures of memory for contextual fear conditioning in addition to freezing. On day 1, rats with sham lesions or BLC lesions explored a Y maze. The BLC-lesioned rats (BLC rats) displayed a greater exploratory activity. On day 2, each of the rats was placed in the "shock" arm of the maze, and all of the sham and half of the BLC rats received footshocks. A 24-hr retention test assessed the freezing, time spent per arm, entries per arm, and initial entry into the shock arm. As previously reported, shocked BLC rats displayed little freezing. However, the other measures indicated that the shocked BLC rats remembered the fear conditioning. They entered less readily and less often and spent less time in the shock arm than did the control nonshocked BLC rats. Compared with the sham rats, the shocked BLC rats entered more quickly and more often and spent more time in the shock arm. These findings indicate that an intact BLC is not essential for the formation and expression of long-term cognitive/explicit memory of contextual fear conditioning.