RESUMO
Arc (Activity-regulated cytoskeleton-associated protein) is an effector neuronal immediate-early gene (IEG) and has been closely linked to behaviorally-induced neuronal plasticity. The present studies examined the regionally-selective, dissociable patterns of Arc expression induced by Pavlovian trace fear conditioning, delay fear conditioning, and contextual fear conditioning as well as novel context exposure. This research was guided by anatomical studies identifying heterogeneity of connectivity across the transverse (CA1, CA3) and septo-temporal (dorsal vs. ventral) axes of the hippocampus; companion neuropsychological experiments suggest that these subregions likely play functionally dissociable roles in different forms of hippocampal-dependent learning. Hence the primary goal of the present study was to characterize the expression of Arc protein across both the septotemporal and transverse axes of the hippocampus induced by hippocampal dependent trace fear conditioning and compare these expression patterns to those induced by other fear conditioning paradigms. A second goal of these studies was to explore which specific paradigmatic features of the fear conditioning task itself are responsible for the observed patterns of Arc expression. The results of these studies suggest that, within the dorsal hippocampus, Arc expression in CA3 induced by trace fear conditioning may play a unique role in representing the context, while Arc protein expression within ventral CA3 may reflect CS processing. Arc protein expression in dorsal and ventral CA1 are likely not meaningfully involved in trace fear conditioning as there is either a lack of significant enhancement (dorsal CA1) or enhancement is not unique to subjects trained in trace fear conditioning (ventral CA1). The specific regional pattern of Arc protein enhancement induced by trace fear conditioning may reflect the unique temporal parameters of the task which critically engages the hippocampus in processing both contextual representations as well as the explicit CS. This additional hippocampal processing may account for the greater enhancement in Arc protein in dorsal and ventral CA3 for subjects trained in trace fear conditioning compared to novel context exposure, or contextual and delay fear conditioning.
Assuntos
Região CA1 Hipocampal/metabolismo , Região CA3 Hipocampal/metabolismo , Condicionamento Clássico/fisiologia , Proteínas do Citoesqueleto/metabolismo , Medo/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Animais , Comportamento Animal/fisiologia , Expressão Gênica/fisiologia , Masculino , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
A common source of variance (i.e., "general intelligence") underlies an individual's performance across diverse tests of cognitive ability, and evidence indicates that the processing efficacy of working memory may serve as one such source of common variance. One component of working memory, selective attention, has been reported to co-vary with general intelligence, and dopamine D1 signaling in prefrontal cortex can modulate attentional abilities. Based on their aggregate performance across five diverse tests of learning, here we characterized the general cognitive ability (GCA) of CD-1 outbred mice. In response to a D1 agonist (SKF82958, 1 mg/kg), we then assessed the relationship between GCA and activation of D1 receptor (D1R)-containing neurons in the prelimbic region of the medial prefrontal cortex, the agranular insular cortex, and the dorsomedial striatum. Increased activation of D1R-containing neurons in the prelimbic cortex (but not the agranular insular cortex or dorsomedial striatum) was observed in animals of high GCA relative to those of low GCA (quantified by c-Fos activation in response to the D1 agonist). However, a Western blot analysis revealed no differences in the density of D1Rs in the prelimbic cortex between animals of high and low GCA. Last, it was observed that working memory training promoted an increase in animals' GCA and enhanced D1R-mediated neuronal activation in the prelimbic cortex. These results suggest that the sensitivity (but not density) of D1Rs in the prelimbic cortex may both regulate GCA and be a target for working memory training.
Assuntos
Cognição/fisiologia , Aprendizagem/fisiologia , Memória de Curto Prazo/fisiologia , Neurônios/metabolismo , Córtex Pré-Frontal/fisiologia , Receptores de Dopamina D1/metabolismo , Animais , Benzazepinas/farmacologia , Cognição/efeitos dos fármacos , Corpo Estriado/fisiologia , Agonistas de Dopamina/farmacologia , Aprendizagem/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Camundongos , Córtex Pré-Frontal/efeitos dos fármacosRESUMO
Mounting evidence suggests that long-lasting, protein synthesis-dependent changes in synaptic strength accompany both the initial acquisition and subsequent recall of specific memories. Within brain areas thought to be important for learning and memory, including the hippocampus, learning-related plasticity is likely mediated in part by NMDA receptor activation and experience-dependent changes in gene expression. In the present study, we examined the role of activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) expression in the acquisition, recall, and reconsolidation of memory in a trace fear conditioning paradigm. First, we show that the expression of Arc protein in ventral hippocampus (VH) is dramatically enhanced by memory recall 24h after the acquisition of trace fear conditioning, and that both memory recall and the associated recall-induced enhancement of Arc expression are blocked by pre-training administration of 2-amino-5-phosphonovaleric acid (APV). Next, we show that while infusion of Arc antisense oligodeoxynucleotides (ODNs) into VH prior to testing had little effect on memory recall, it significantly reduced both Arc protein expression and freezing behavior during subsequent testing sessions. Collectively, these results suggest that Arc/Arg3.1 protein plays an important functional role in both the initial acquisition of hippocampal-dependent memory and the reconsolidation of these memories after recall.
Assuntos
Condicionamento Psicológico/fisiologia , Proteínas do Citoesqueleto/metabolismo , Medo/fisiologia , Hipocampo/metabolismo , Memória/fisiologia , Proteínas do Tecido Nervoso/metabolismo , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Condicionamento Psicológico/efeitos dos fármacos , Proteínas do Citoesqueleto/genética , Hipocampo/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Rememoração Mental/efeitos dos fármacos , Rememoração Mental/fisiologia , Proteínas do Tecido Nervoso/genética , Ratos , Ratos Sprague-DawleyRESUMO
While a number of early studies demonstrated that hippocampal damage attenuates the expression of recent, but not remotely trained tasks, an emerging body of evidence has shown that damage to, or inactivation of, the hippocampus often impairs recall across a wide range of training-testing intervals. Collectively, these data suggest that the time course of hippocampal involvement in the storage or recall of previously-acquired memories may differ according to hippocampal subregion and the particular learning task under consideration. The present study examined the contributions of dorsal (DH) and ventral (VH) hippocampus to the expression of previously-acquired trace fear conditioning, a form of Pavlovian conditioning in which the offset of an initially neutral cue or cues and the onset of an aversive stimulus is separated by a temporal (trace) interval. Specifically, either saline or the GABA-A agonist muscimol was infused into DH or VH prior to testing either 1, 7, 28, or 42 days after trace fear conditioning. The results revealed a marked dissociation: pre-testing inactivation of DH failed to impair performance at any time-point, while pre-testing inactivation of VH impaired performance at all time-points. Importantly, pre-testing inactivation of VH had no effect on the performance of previously-acquired delay conditioning, suggesting that the deficits observed in trace conditioning cannot be attributed to a deficit in performance of the freezing response. Collectively, these data suggest that VH, but not DH, remains a neuroanatomical locus critical to the recall or expression of trace fear conditioning over an extended period of time.
Assuntos
Condicionamento Clássico/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Estimulação Acústica , Animais , Condicionamento Clássico/efeitos dos fármacos , Sinais (Psicologia) , Medo/efeitos dos fármacos , Agonistas de Receptores de GABA-A/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Memória/fisiologia , Muscimol/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
The dorsal and ventral subregions of the hippocampus likely play dissociable roles in some forms of learning. For example, we have previously demonstrated that temporary inactivation of ventral, but not dorsal, hippocampus dramatically impaired the acquisition of trace fear conditioning, while temporary inactivation of dorsal, but not ventral, hippocampus impaired spatially guided reinforced alternation (Czerniawski et al. (2009) Hippocampus 19:20-32). Importantly, emerging data suggest that lesions, temporary inactivation, and NMDA receptor antagonism within these subregions can produce quite different patterns of behavioral effects when administered into the same region. Specifically, while neither lesions nor temporary inactivation of dorsal hippocampus impair the acquisition of trace fear conditioning, learning in this paradigm is severely impaired by pre-training administration of the NMDA receptor antagonist dl-2-phosphonovaleric acid (APV) in dorsal hippocampus; the effect of NMDA receptor antagonism within ventral hippocampus on the acquisition and expression of trace conditioning, or on learning in general, has not yet been systematically explored. The present study extends our previous work examining the differential effect of lesions or inactivation of the dorsal and ventral hippocampal subregions by systematically examining the effect of regionally selective pre-training or pre-testing administration of APV on the acquisition and expression of trace and contextual fear conditioning. The results of these studies demonstrate that while pre-training NMDA receptor antagonism within either the dorsal or ventral subregion of the hippocampus impaired the acquisition of both trace and contextual conditioning, pre-testing NMDA receptor antagonism within ventral, but not dorsal, hippocampus impaired the expression of previously-acquired trace and contextual fear conditioning. These data suggest that selectively manipulating the integrity of individual subregions may result in compensatory mechanisms that can support learning, and that NMDA-dependent plasticity within both dorsal and ventral hippocampus is normally required for the acquisition and maintenance of memory in trace and contextual fear conditioning.
Assuntos
Condicionamento Clássico/efeitos dos fármacos , Condicionamento Psicológico/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipocampo/efeitos dos fármacos , Valina/análogos & derivados , Estimulação Acústica/efeitos adversos , Análise de Variância , Animais , Condicionamento Clássico/fisiologia , Condicionamento Psicológico/fisiologia , Comportamento Exploratório/fisiologia , Medo/fisiologia , Reação de Congelamento Cataléptica/efeitos dos fármacos , Reação de Congelamento Cataléptica/fisiologia , Hipocampo/anatomia & histologia , Hipocampo/fisiologia , Masculino , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Ratos , Ratos Sprague-Dawley , Valina/farmacologiaRESUMO
Converging evidence examining the effects of post-training manipulations of the hippocampus suggests that the hippocampus may play a time-limited role in the maintenance of a variety of forms of memory. In particular, either lesions or inactivation of the dorsal hippocampus results in many cases in a time-limited retrograde impairment in nondiscriminative contextual conditioning paradigms. However, the extent to which hippocampal manipulations result in a time-limited retrograde amnesia for a variety of forms of learning has recently been called into question (reviewed in Sutherland, Sparks, & Lehmann (2010)). The present study examined the effect of inactivation of the dorsal hippocampus either 7, 28, or 42 days following training in an explicitly nonspatial, discriminative contextual conditioning paradigm (Otto & Poon, 2006; Parsons & Otto, 2008). Inactivation of the dorsal hippocampus resulted in a significant deficit in the expression of contextual conditioning at 7 and 28 days, but not 42 days, following training. Importantly, inactivation of the hippocampus did not affect either baseline freezing levels or conditioning to an explicit CS. Together with previous data exploring hippocampal contributions to discriminative unimodal contextual conditioning, these data suggest that the hippocampus may play a particularly prominent role in the temporary maintenance of memory in discriminative contextual paradigms.
Assuntos
Amnésia Retrógrada/fisiopatologia , Aprendizagem por Associação/fisiologia , Aprendizagem por Discriminação/fisiologia , Hipocampo/fisiologia , Memória/fisiologia , Análise de Variância , Animais , Condicionamento Clássico/fisiologia , Modelos Animais de Doenças , Reação de Congelamento Cataléptica/fisiologia , Estudos Longitudinais , Masculino , Ratos , Ratos Sprague-Dawley , Olfato , Estatísticas não Paramétricas , Fatores de TempoRESUMO
Emerging evidence suggests that the hippocampus can be anatomically and functionally dissociated along its septotemporal axis into dorsal and ventral subregions. With respect to function, we have recently demonstrated that pre-training excitotoxic lesions of ventral, but not dorsal, hippocampus impair the acquisition of trace fear conditioning, whereas post-training lesions of either dorsal or ventral hippocampus impair the subsequent expression of trace fear conditioning (Yoon and Otto (2007) Neurobiol Learn Mem 87:464-475). In addition to trace fear conditioning, dorsal and ventral hippocampus appear to be differentially involved in a number of spatial memory tasks. The present study examined the effects of temporary inactivation of dorsal or ventral hippocampus on the acquisition and expression of trace fear conditioning and on performance of a spatial delayed reinforced alternation task. The findings demonstrate a double dissociation of dorsal and ventral hippocampal function: inactivation of ventral, but not dorsal, hippocampus attenuated the acquisition and expression of trace fear conditioning, whereas inactivation of dorsal, but not ventral, hippocampus dramatically impaired performance in the delayed reinforced alternation task. These data further support the notion that dorsal and ventral hippocampus contribute differentially to performance in a variety of paradigms.
Assuntos
Aprendizagem da Esquiva/fisiologia , Condicionamento Psicológico/fisiologia , Medo/fisiologia , Hipocampo/anatomia & histologia , Hipocampo/fisiologia , Memória/fisiologia , Animais , Mapeamento Encefálico , Denervação , Masculino , Transtornos da Memória/patologia , Transtornos da Memória/fisiopatologia , Testes Neuropsicológicos , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Percepção Espacial/fisiologia , Fatores de TempoRESUMO
The current study examined the effects of temporary inactivation of the DH on freezing, rearing, ambulating, grooming, and whisking behavior in an explicitly nonspatial contextual fear conditioning paradigm in which olfactory stimuli served as temporally and spatially diffuse contexts. Prior either to training, testing, or both, male Sprague-Dawley rats received bilateral microinfusions of saline or the GABA(A) agonist muscimol into the DH. Results indicate that temporary inactivation of DH produced both anterograde and retrograde deficits in contextually conditioned freezing, while sparing the acquisition and expression of freezing to a discrete auditory or olfactory CS. These data suggest that there is a decidedly nonspatial component to the role of DH in contextual conditioning, and that olfactory contextual conditioning is a fruitful means of further exploring this function.
Assuntos
Condicionamento Clássico/fisiologia , Medo/fisiologia , Reação de Congelamento Cataléptica/fisiologia , Hipocampo/fisiologia , Estimulação Acústica , Animais , Condicionamento Clássico/efeitos dos fármacos , Reação de Congelamento Cataléptica/efeitos dos fármacos , Agonistas GABAérgicos/farmacologia , Hipocampo/efeitos dos fármacos , Masculino , Muscimol/farmacologia , Odorantes , Ratos , Ratos Sprague-Dawley , Olfato/fisiologia , Percepção Espacial/efeitos dos fármacos , Percepção Espacial/fisiologiaRESUMO
Although there is general consensus that the hippocampus is not critically involved in the acquisition of fear conditioned to an explicit conditioned stimulus (CS), the extent to which the hippocampus participates in contextual fear conditioning remains unclear. To further characterize the potential role of the hippocampus in contextual fear conditioning, the present experiments examined the effect of excitotoxic lesions of dorsal hippocampus on the acquisition of a novel contextual fear conditioning paradigm in which a unimodal (olfactory) cue served to disambiguate discrete "contexts" within a single behavioral training chamber. Selective lesions of dorsal hippocampus severely attenuated olfactory contextual conditioning without affecting conditioning to an explicit auditory or olfactory CS. Additional experiments indicate that these contextual conditioning deficits cannot be attributed to a lesion-induced decrement in olfactory perception, a preferential impairment of "weak" forms of conditioning, or hyperactivity. Thus, the hippocampus appears to contribute importantly to the acquisition of fear conditioned to explicitly nonspatial, unimodal, temporally, and spatially diffuse contextual stimuli.
Assuntos
Condicionamento Psicológico/fisiologia , Medo , Hipocampo/fisiologia , Estimulação Acústica/métodos , Análise de Variância , Animais , Aprendizagem por Associação/fisiologia , Comportamento Animal , Reação de Congelamento Cataléptica/fisiologia , Masculino , Atividade Motora/fisiologia , Condutos Olfatórios/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
The basolateral amygdaloid complex (BLA) and orbitofrontal cortex (OFC) share extensive reciprocal connections, and interactions between these regions likely contribute to both mnemonic and affective processes. The present study examined the potential differential contributions of the BLA and OFC to performance of an olfactory discrimination task that incorporates auditory conditioned reinforcement and to expression of immediate post-shock freezing behavior. Damage to the BLA had little effect on performance of the conditioned reinforcement task but abolished immediate post-shock freezing behavior. In contrast, damage to OFC resulted in both a mild but significant performance decrement in the conditioned reinforcement task and a significant attenuation of immediate post-shock freezing behavior. These findings suggest that immediate post-shock freezing behavior is likely critically dependent upon interactions between the BLA and OFC. However, although mnemonic processes underlying accurate performance of the conditioned reinforcement task might be supported by OFC in part, such processes are independent of either the BLA or interactions between these two regions.
Assuntos
Tonsila do Cerebelo/fisiologia , Condicionamento Clássico/fisiologia , Aprendizagem por Discriminação/fisiologia , Lobo Frontal/fisiologia , Olfato/fisiologia , Estimulação Acústica , Tonsila do Cerebelo/efeitos dos fármacos , Análise de Variância , Animais , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Condicionamento Clássico/efeitos dos fármacos , Sinais (Psicologia) , Aprendizagem por Discriminação/efeitos dos fármacos , Extinção Psicológica/fisiologia , Lobo Frontal/efeitos dos fármacos , Masculino , N-Metilaspartato/farmacologia , Neurotoxinas/farmacologia , Odorantes , Ratos , Ratos Sprague-Dawley , Reforço PsicológicoRESUMO
The rapid encoding of contextual memory requires the CA3 region of the hippocampus, but the necessary genetic pathways remain unclear. We found that the activity-dependent transcription factor Npas4 regulates a transcriptional program in CA3 that is required for contextual memory formation. Npas4 was specifically expressed in CA3 after contextual learning. Global knockout or selective deletion of Npas4 in CA3 both resulted in impaired contextual memory, and restoration of Npas4 in CA3 was sufficient to reverse the deficit in global knockout mice. By recruiting RNA polymerase II to promoters and enhancers of target genes, Npas4 regulates a learning-specific transcriptional program in CA3 that includes many well-known activity-regulated genes, which suggests that Npas4 is a master regulator of activity-regulated gene programs and is central to memory formation.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Região CA3 Hipocampal/fisiologia , Regulação da Expressão Gênica , Memória , Transcrição Gênica , Animais , Região CA3 Hipocampal/citologia , Condicionamento Psicológico , Elementos Facilitadores Genéticos , Medo , Deleção de Genes , Genes Precoces , Aprendizagem , Camundongos , Camundongos Knockout , Neurônios/fisiologia , Regiões Promotoras Genéticas , RNA Polimerase II/metabolismo , Ativação TranscricionalRESUMO
The effect of excitotoxic lesions of dorsal vs. ventral hippocampus on the acquisition and expression of auditory trace fear conditioning was examined in two studies. In Experiment 1, animals received excitotoxic lesions of either the dorsal or ventral hippocampus or sham surgeries one week prior to conditioning, and were tested 24 h later. In Experiment 2, animals received excitotoxic lesions of either the dorsal or ventral hippocampus or sham surgeries 24 h after training, and were tested one week after surgery. Both pre- and post-training lesions of ventral hippocampus impaired the acquisition and expression, respectively, of auditory trace fear conditioning. Pre-training lesions of dorsal hippocampus had no effect on the acquisition of trace fear conditioning, while post-training lesions of dorsal hippocampus dramatically impaired expression during subsequent testing. Although in some cases animals with lesions of ventral hippocampus exhibited locomotor hyperactivity, it is unlikely that the pattern of observed deficits can be attributed to this effect. Collectively these data suggest that the dorsal and ventral hippocampus may contribute differentially to the mnemonic processes underlying fear trace conditioning.