RESUMO
Animal models of psychiatric disorders are a challenging but highly relevant issue. Most psychiatric disorders are very heterogeneous syndromes, resulting from multiple and varied causal factors and characterized by symptoms that can only be inferred with significant limitations in non-human models. As constructing a model that reproduces a whole psychiatric syndrome seems virtually impossible, researchers have tried to focus on endophenotypes, i.e., discrete traits that are more proximal to predisposing genes than the whole syndrome. These can be explored in a wide range of approaches, such as in pharmacological, lesion, and environmental models. Another challenge is to understand how genes interact with environmental factors over time to result in the syndromic phenotype. A better understanding of the subcellular mechanisms that enhance or allow brain resistance to environmental influences is required, as is a global thesis compatible with the diversity of diseases sharing similar behavioral and biological traits. With an experimental inventory of the possible causes of minor developmental failures, we may systematically explore their consequences in the adult animal and be able to decide if this will enlighten the understanding of one or another psychiatric disease.
Assuntos
Modelos Animais de Doenças , Endofenótipos , Transtornos Mentais/genética , Animais , Humanos , Fenótipo , RatosRESUMO
Animal models of psychiatric disorders are a challenging but highly relevant issue. Most psychiatric disorders are very heterogeneous syndromes, resulting from multiple and varied causal factors and characterized by symptoms that can only be inferred with significant limitations in non-human models. As constructing a model that reproduces a whole psychiatric syndrome seems virtually impossible, researchers have tried to focus on endophenotypes, i.e., discrete traits that are more proximal to predisposing genes than the whole syndrome. These can be explored in a wide range of approaches, such as in pharmacological, lesion, and environmental models. Another challenge is to understand how genes interact with environmental factors over time to result in the syndromic phenotype. A better understanding of the subcellular mechanisms that enhance or allow brain resistance to environmental influences is required, as is a global thesis compatible with the diversity of diseases sharing similar behavioral and biological traits. With an experimental inventory of the possible causes of minor developmental failures, we may systematically explore their consequences in the adult animal and be able to decide if this will enlighten the understanding of one or another psychiatric disease.
Assuntos
Animais , Humanos , Ratos , Modelos Animais de Doenças , Endofenótipos , Transtornos Mentais/genética , FenótipoRESUMO
Rats with a neonatal ventral hippocampal lesion (NVHL) have been used to model certain features of schizophrenia because they display dopaminergic activity and behavioral alterations consistent with a dysfunctional prefrontal cortex after puberty. Microdialysis studies in normal rats demonstrated increased prefrontal dopamine release during the incentive phase of behavior in an experimental situation specifically designed to evidence this behavioral aspect: the so called "sensory-specific satiety" procedure. Our hypothesis is that if dopaminergic activity in the prefrontal cortex of NVHL rats differs from sham lesioned rats, the responsiveness to the aforementioned experimental situation should also be different. Extracellular medial prefrontal dopamine outflow increased in hungry control rats when they had access to food and decreased across satiety. It increased again when a new food was presented, even when the rats were satiated. NVHL rats also had increased dopamine prefrontal outflow in these conditions, but it remained high after the end of the consumption period. The food consumption behavior declined less rapidly and the reinstatement of food consumption, usually produced by new food, did not occur in NVHL rats, provided the lesions were large. These data were discussed in relation to several theoretical backgrounds developed about the incentive aspect of behavior and for understanding the pathophysiology of schizophrenia.
Assuntos
Dopamina/metabolismo , Hipocampo/fisiopatologia , Córtex Pré-Frontal/metabolismo , Resposta de Saciedade/fisiologia , Animais , Animais Recém-Nascidos , Ingestão de Alimentos/fisiologia , Hipocampo/efeitos dos fármacos , Ácido Ibotênico/toxicidade , Microdiálise , Córtex Pré-Frontal/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
Rats with a bilateral neonatal ventral hippocampus lesion (NVHL) are used as models of neurobiological aspects of schizophrenia. In view of their decreased number of GABAergic interneurons, we hypothesized that they would show increased reactivity to acoustic stimuli. We systematically characterized the acoustic reactivity of NVHL rats and sham operated controls. They were behaviourally observed during a loud white noise. A first cohort of 7 months' old rats was studied. Then the observations were reproduced in a second cohort of the same age after characterizing the reactivity of the same rats to dopaminergic drugs. A third cohort of rats was studied at 2, 3, 4, 5 and 6 months. In subsets of lesioned and control rats, inferior colliculus auditory evoked potentials were recorded. A significant proportion of rats (50-62%) showed aberrant audiogenic responses with explosive wild running resembling the initial phase of audiogenic seizures. This was not correlated with their well-known enhanced reactivity to dopaminergic drugs. The proportion of rats showing this strong reaction increased with rats' age. After the cessation of the noise, NVHL rats showed a long freezing period that did neither depend on the size of the lesion nor on the rats' age. The initial negative deflection of the auditory evoked potential was enhanced in the inferior colliculus of only NVHL rats that displayed wild running. Complementary anatomical investigations using X-ray scans in the living animal, and alizarin red staining of brain slices, revealed a thin layer of calcium deposit close to the medial geniculate nuclei in post-NVHL rats, raising the possibility that this may contribute to the hyper-reactivity to sounds seen in these animals. The findings of this study provide complementary information with potential relevance for the hyper-reactivity noted in patients with schizophrenia, and therefore a tool to investigate the underlying biology of this endophenotype.
Assuntos
Vias Auditivas/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Hipocampo/fisiopatologia , Atividade Motora/efeitos dos fármacos , Reflexo de Sobressalto/efeitos dos fármacos , Estimulação Acústica , Fatores Etários , Anfetamina/toxicidade , Análise de Variância , Animais , Vias Auditivas/fisiopatologia , Cocaína/toxicidade , Eletrodos Implantados , Eletroencefalografia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Hipocampo/efeitos dos fármacos , Hipercinese/induzido quimicamente , Ácido Ibotênico/toxicidade , Imageamento por Ressonância Magnética , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Coloração e RotulagemRESUMO
The neonatal hippocampus lesion thought to model schizophrenia should show the same modifications in behavioural tests as other models, especially pharmacological models, namely decreased latent inhibition, blocking and overshadowing. The present study is set out to evaluate overshadowing in order to complement our previous studies, which had tested latent inhibition. "Overshadowing" refers to the decreased conditioning that occurs when the to-be-conditioned stimulus is combined with another stimulus at the conditioning stage. We used the same two Pavlovian conditioning paradigms as in our previous works, namely conditioned taste aversion (CTA) and conditioned emotional response (CER). A sweet taste overshadowed a salty conditioned stimulus, and a tone overshadowed a flashing light. Totally different stimuli were used to counter possible sensory biases. The protocols were validated with two groups of Sprague Dawley rats. The same two protocols were then applied to a cohort of rats whose ventral hippocampus had been destroyed when they were 7days old. Only rats with extended ventral hippocampus lesions were included. The overall effect of Pavlovian conditioning was attenuated, significantly so in the conditioned emotional response paradigm, but overshadowing appeared not to be modified in either the conditioned emotional response or the conditioned taste aversion paradigm.
Assuntos
Aprendizagem da Esquiva/fisiologia , Lesões Encefálicas/patologia , Condicionamento Psicológico/fisiologia , Emoções , Hipocampo/patologia , Paladar/fisiologia , Estimulação Acústica/métodos , Animais , Animais Recém-Nascidos , Comportamento Animal , Comportamento de Ingestão de Líquido/fisiologia , Imageamento por Ressonância Magnética , Masculino , Ratos , Ratos Sprague-Dawley , Tempo de Reação/fisiologiaRESUMO
OBJECTIVE: Diagnostic and therapy of somatic diseases like diabetes and hypertension have improved notably with the use of experimental models. For schizophrenia the proposal of a model has made little impact and even scepticism. Nevertheless the most recent studies indicate that "Cognitive Sciences" applied to specific models may help us to find out mechanisms of the disease. This article reviews the models presently under investigation for schizophrenia. RESULTS AND DISCUSSION: The difficulty to model schizophrenia results from the subjectivity of its symptoms, the difficult to reproduce them in animals and the disease complexity. Research on such a complex phenotype can only proceed by separating its components (endophenotypes) from each other and by the respective manipulation of its experimental counterparts, made by specific interventions (e.g. pharmacological, surgical, genetic), in the search of a common mechanism leading to these endophenotypes. For integrating these findings with symptoms a global explanatory theory is required. So far, the disease seems to result from a diffuse neuronal disconnection as a consequence of minor brain abnormalities with a genetic and/or environmental cause. CONCLUSIONS: An integrative approach of the diversity of models presently used may improve our understanding of schizophrenia.
Assuntos
Modelos Animais de Doenças , Fenótipo , Esquizofrenia , Psicologia do Esquizofrênico , Animais , Estudos de Viabilidade , Humanos , Ratos , Reprodutibilidade dos Testes , Esquizofrenia/genética , Esquizofrenia/fisiopatologiaRESUMO
OBJETIVO: O uso de modelos experimentais tem permitido importantes avanços no diagnóstico e na terapêutica de doenças somáticas, tais como diabetes e hipertensão. No caso da esquizofrenia, entretanto, as tentativas de modelos experimentais causaram, historicamente, pouco impacto e algum ceticismo. Estudos mais recentes, contudo, indicam que a Ciência Cognitiva aplicada ao uso de modelos pode nos ajudar na compreensão da fisiopatologia da esquizofrenia. O estudo objetivou realizar uma revisão crítica dos modelos experimentais propostos para a esquizofrenia. RESULTADOS E DISCUSSÃO: As dificuldades próprias dos modelos de esquizofrenia são a subjetividade dos sintomas, a dificuldade em reproduzi-los em animais e a complexidade clínica a ser totalizada. Fenótipo tão complexo só pode ser abordado pela separação de seus componentes (endofenótipos) e pela respectiva manipulação de seus correlatos experimentais, feita por intervenções específicas (e.g. farmacológicas, cirúrgicas, genéticas) na busca de um mecanismo comum para estes endofenótipos. A correlação entre resultados e sintomas deve apoiar-se em hipótese explanatória abrangente. Até o presente, a doença parece envolver desconexão neuronal difusa decorrente de anormalidades cerebrais sutis, de causa genética e/ou ambiental. CONCLUSÕES: A integração da informação dos modelos atualmente em uso pode contribuir de modo significativo para a compreensão da esquizofrenia.
Assuntos
Animais , Humanos , Ratos , Modelos Animais de Doenças , Fenótipo , Esquizofrenia , Psicologia do Esquizofrênico , Estudos de Viabilidade , Reprodutibilidade dos Testes , Esquizofrenia/genética , Esquizofrenia/fisiopatologiaRESUMO
The neural network of the inferior colliculus (IC), implicated in the generation of defensive behavior to aversive acoustic stimuli, is under tonic GABAergic control. Dopamine also seems to have a modulatory role in these neural circuits. It is still unclear how such changes in transmission of acoustic information influence the motor expression of the defensive behavior. Startle reaction to a sudden noise has been used as an effective way to measure the motor reactivity of rats to fearful acoustic stimuli. In this work we examined the processing of sensorial information--assessed by the recording of auditory evoked potentials (AEP)--and the behavioral effects--evaluated by the freezing and startle responses--during the reduction of GABA levels caused by microinjections of semicarbazide (SMC, 6 microg/0.2 microl), a glutamic acid decarboxylase inhibitor, into the IC. These data were compared to the effects of the overall arousal elicited by apomorphine (APO, 0.5 mg/kg, i.p.). The results obtained show that IC microinjections of SMC induced freezing behavior, enhanced the AEP and impaired the startle reaction to a loud sound. On the other hand, APO changed neither the AEP nor the startle in the same experimental conditions. These results suggest that the release of GABAergic control of the neural substrates of aversion in the IC results in an increased processing of auditory information along with an inhibitory influence on the motor pathways responsible for the startle response.
Assuntos
Aprendizagem da Esquiva/fisiologia , Potenciais Evocados Auditivos , Colículos Inferiores/fisiologia , Reflexo de Sobressalto/fisiologia , Ácido gama-Aminobutírico/fisiologia , Estimulação Acústica/métodos , Animais , Apomorfina/farmacologia , Nível de Alerta , Comportamento Animal/efeitos dos fármacos , Mapeamento Encefálico , Agonistas de Dopamina/farmacologia , Inibidores Enzimáticos/administração & dosagem , Potenciais Evocados Auditivos/efeitos dos fármacos , Glutamato Descarboxilase/farmacologia , Masculino , Microinjeções , Ratos , Ratos Wistar , Reflexo de Sobressalto/efeitos dos fármacos , Semicarbazidas/administração & dosagemRESUMO
This work evaluated the influence of chronic mild stress on latent inhibition (LI) in rats, using a conditioned emotional response (CER) procedure. Rats were assigned to four groups: a non pre-exposed control group (NPC), a non pre-exposed stressed group (NPS), a pre-exposed control group (PC), and a pre-exposed stressed group (PS). Stressed animals were submitted to a chronic mild stress (CMS) regimen for three weeks. The off-baseline conditioned emotional response procedure had four phases: licking response training, tone-shock conditioning, retraining, and testing. Conditioning consisted of 2 tone (30 s) and shock (0.5 s) associations. Tone-shock conditioning evidenced by NPS and NPC groups suggests that stress did not interfere with the expression of a conditioned emotional response. Pre-exposure was carried out using 6 tones (30 s) during 2 sessions before conditioning. Prior exposure to the tone resulted in a decrease in learning that was greater in stressed animals. The results indicate an increase in latent inhibition induced by chronic mild stress. Such LI potentiation after CMS may be related to dopamine (DA) neurotransmission reduction in the central nervous system.