RESUMEN
In recent years schizophrenia has been recognized as a neurodevelopmental disorder likely involving a perinatal insult progressively affecting brain development. The poly I:C maternal immune activation (MIA) rodent model is considered as a neurodevelopmental model of schizophrenia. Using this model we and others demonstrated the association between neuroinflammation in the form of altered microglia and a schizophrenia-like endophenotype. Therapeutic intervention using the anti-inflammatory drug minocycline affected altered microglia activation and was successful in the adult offspring. However, less is known about the effect of preventive therapeutic strategies on microglia properties. Previously we found that deep brain stimulation of the medial prefrontal cortex applied pre-symptomatically to adolescence MIA rats prevented the manifestation of behavioral and structural deficits in adult rats. We here studied the effects of deep brain stimulation during adolescence on microglia properties in adulthood. We found that in the hippocampus and nucleus accumbens, but not in the medial prefrontal cortex, microglial density and soma size were increased in MIA rats. Pro-inflammatory cytokine mRNA was unchanged in all brain areas before and after implantation and stimulation. Stimulation of either the medial prefrontal cortex or the nucleus accumbens normalized microglia density and soma size in main projection areas including the hippocampus and in the area around the electrode implantation. We conclude that in parallel to an alleviation of the symptoms in the rat MIA model, deep brain stimulation has the potential to prevent the neuroinflammatory component in this disease.
Asunto(s)
Estimulación Encefálica Profunda/métodos , Microglía/efectos de los fármacos , Animales , Conducta Animal/fisiología , Encéfalo/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Minociclina/farmacología , Núcleo Accumbens/efectos de los fármacos , Núcleo Accumbens/metabolismo , Poli I-C/farmacología , Corteza Prefrontal/efectos de los fármacos , Embarazo , Complicaciones Infecciosas del Embarazo , Efectos Tardíos de la Exposición Prenatal/inmunología , Ratas , Ratas Wistar , Esquizofrenia/inmunología , Esquizofrenia/terapiaRESUMEN
Adult neurogenesis in the hippocampus is impaired in schizophrenic patients and in an animal model of schizophrenia. Amongst a plethora of regulators, the immune system has been shown repeatedly to strongly modulate neurogenesis under physiological and pathological conditions. It is well accepted, that schizophrenic patients have an aberrant peripheral immune status, which is also reflected in the animal model. The microglia as the intrinsic immune competent cells of the brain have recently come into focus as possible therapeutic targets in schizophrenia. We here used a maternal immune stimulation rodent model of schizophrenia in which polyinosinic-polycytidilic acid (Poly I:C) was injected into pregnant rats to mimic an anti-viral immune response. We identified microglia IL-1ß and TNF-α increase constituting the factors correlating best with decreases in net-neurogenesis and impairment in pre-pulse inhibition of a startle response in the Poly I:C model. Treatment with the antibiotic minocycline (3mg/kg/day) normalized microglial cytokine production in the hippocampus and rescued neurogenesis and behavior. We could also show that enhanced microglial TNF-α and IL-1ß production in the hippocampus was accompanied by a decrease in the pro-proliferative TNFR2 receptor expression on neuronal progenitor cells, which could be attenuated by minocycline. These findings strongly support the idea to use anti-inflammatory drugs to target microglia activation as an adjunctive therapy in schizophrenic patients.
Asunto(s)
Antibacterianos/farmacología , Microglía/efectos de los fármacos , Minociclina/farmacología , Neurogénesis/efectos de los fármacos , Esquizofrenia/fisiopatología , Filtrado Sensorial/efectos de los fármacos , Animales , Encéfalo/efectos de los fármacos , Citocinas/biosíntesis , Modelos Animales de Enfermedad , Masculino , Microglía/inmunología , Poli I-C/farmacología , Ratas , Ratas Wistar , Esquizofrenia/inmunología , Esquizofrenia/metabolismoRESUMEN
Deep brain stimulation at high frequencies (HFS) is currently studied in the treatment of therapy-refractory obsessive-compulsive disorder (OCD). The diversity of targeted brain areas and the discrepancy in demonstrating beneficial effects, highlight the need for better mapping of brain regions in which HFS may yield anti-compulsive effects. This goal may be achieved by investigating the effects of HFS in appropriate animal models of OCD. The present study tested the effect of bilateral HFS or pharmacological inactivation (as induced by intracerebral administration of the GABA-agonist muscimol) of both the Globus pallidus (GP; rodent equivalent to human GP externus) and the Nucleus entopeduncularis (EP; rodent equivalent to human GP internus) on checking behaviour in the quinpirole rat model of OCD. We demonstrate that HFS of the GP does not and HFS of the EP only partially reduces OCD-like behaviour in rats. In contrast, pharmacological inactivation of both GP and EP significantly reduces OCD-like behaviour in the model. These data contrast previously derived data on the effectiveness of HFS of the subthalamic nucleus, nucleus accumbens, GP and EP in the same and other rat models of OCD. We conclude that (i) although GP and EP play an important role in the pathophysiology of OCD, these areas may not represent first choice target structures for HFS, (ii) the effectiveness of HFS may depend on different subtypes of OCD, represented in different animal models, and (iii) differential net mechanisms may subserve the effectiveness of HFS and pharmacological inactivation.
Asunto(s)
Conducta Compulsiva/fisiopatología , Conducta Compulsiva/psicología , Estimulación Encefálica Profunda , Núcleo Entopeduncular/fisiopatología , Globo Pálido/fisiopatología , Animales , Agonistas de Dopamina/farmacología , Estimulación Eléctrica , Electrodos Implantados , Núcleo Entopeduncular/efectos de los fármacos , Agonistas del GABA/administración & dosificación , Agonistas del GABA/farmacología , Globo Pálido/efectos de los fármacos , Masculino , Microinyecciones , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Muscimol/administración & dosificación , Muscimol/farmacología , Quinpirol/farmacología , Ratas , Ratas WistarRESUMEN
Electrical deep brain stimulation (DBS) is currently studied in the treatment of therapy-refractory obsessive compulsive disorders (OCDs). The variety of targeted brain areas and the inconsistency in demonstrating anti-compulsive effects, however, highlight the need for better mapping of brain regions in which stimulation may produce beneficial effects in OCD. Such a goal may be advanced by the assessment of DBS in appropriate animal models of OCD. Currently available data on DBS of the nucleus accumbens (NAc) on OCD-like behavior in rat models of OCD are contradictory and partly in contrast to clinical data and theoretical hypotheses about how the NAc might be pathophysiologically involved in the manifestation of OCD. Consequently, the present study investigates the effects of DBS of the NAc core and shell in a quinpirole rat model of OCD. The study demonstrates that electrical modulation of NAc core and shell activity via DBS reduces quinpirole-induced compulsive checking behavior in rats. We therefore conclude that both, the NAc core and shell constitute potential target structures in the treatment of OCD.
Asunto(s)
Dopamina/metabolismo , Terapia por Estimulación Eléctrica/métodos , Núcleo Accumbens/fisiopatología , Trastorno Obsesivo Compulsivo/fisiopatología , Trastorno Obsesivo Compulsivo/terapia , Animales , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Agonistas de Dopamina/farmacología , Masculino , Vías Nerviosas/anatomía & histología , Vías Nerviosas/fisiopatología , Núcleo Accumbens/anatomía & histología , Núcleo Accumbens/efectos de los fármacos , Trastorno Obsesivo Compulsivo/inducido químicamente , Quinpirol/farmacología , Ratas , Ratas Wistar , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/fisiologíaRESUMEN
Maternal infection during pregnancy enhances the offspring's risk for severe neuropsychiatric disorders in later life, including schizophrenia. Recent attempts to model this association in animals provided further experimental evidence for a causal relationship between in-utero immune challenge and the postnatal emergence of a wide spectrum of behavioural, pharmacological and neuroanatomical dysfunctions implicated in schizophrenia. However, it still remains unknown whether the prenatal infection-induced changes in brain and behavioural functions may be associated with multiple changes at the neurochemical level. Here, we tested this hypothesis in a recently established mouse model of viral-like infection. Pregnant dams on gestation day 9 were exposed to viral mimetic polyriboinosinic-polyribocytidilic acid (PolyI:C, 5 mg/kg i.v.) or vehicle treatment, and basal neurotransmitter levels were then compared in the adult brains of animals born to PolyI:C- or vehicle-treated mothers by high-performance liquid chromatography on post-mortem tissue. We found that prenatal immune activation significantly increased the levels of dopamine and its major metabolites in the lateral globus pallidus and prefrontal cortex, whilst at the same time it decreased serotonin and its metabolite in the hippocampus, nucleus accumbens and lateral globus pallidus. In addition, a specific reduction of the inhibitory amino acid taurine in the hippocampus was noted in prenatally PolyI:C-exposed offspring relative to controls, whereas central glutamate and gamma-aminobutyric acid (GABA) content was largely unaffected by prenatal immune activation. Our results thus confirm that maternal immunological stimulation during early/middle pregnancy is sufficient to induce long-term changes in multiple neurotransmitter levels in the brains of adult offspring. This further supports the possibility that infection-mediated interference with early fetal brain development may predispose the developing organism to the emergence of neurochemical imbalances in adulthood, which may be critically involved in the precipitation of adult behavioural and pharmacological abnormalities after prenatal immune challenge.