RESUMEN
Human immunodeficiency virus (HIV) infection is associated with mood disorders and behavioral disinhibition. Impairments in sensorimotor gating and associated neurocognitive disorders are reported, but the HIV-proteins and mechanisms involved are not known. The regulatory HIV-1 protein, Tat, is neurotoxic and its expression in animal models increases anxiety-like behavior concurrent with neuroinflammation and structural changes in limbic and extra-limbic brain regions. We hypothesized that conditional expression of HIV-1 Tat1-86 in the GT-tg bigenic mouse model would impair sensorimotor gating and increase microglial reactivity in limbic and extralimbic brain regions. Conditional Tat induction via doxycycline (Dox) treatment (0-125 mg/kg, i.p., for 1-14 days) significantly potentiated the acoustic startle reflex (ASR) of GT-tg mice and impaired prepulse inhibition (PPI) of this response in a dose-dependent manner when Dox (100mg/kg) was administered for brief (1 day) or prolonged (daily for 7 days) intervals. A greater proportion of active/reactive Iba1-labeled microglia was seen in the anterior cingulate cortex (ACC), dentate gyrus, and nucleus accumbens core when Tat protein was induced under either brief or prolonged expression conditions. Other subregions of the medial prefrontal cortex, amygdala, hippocampal formation, ventral tegmental area, and ventral pallidum also displayed Tat-induced microglial activation, but only the activation observed in the ACC recapitulated the pattern of ASR and PPI behaviors. Tat exposure also increased frontal cortex GFAP. Pretreatment with indomethacin attenuated the behavioral effects of brief (but not prolonged) Tat-exposure. Overall, exposure to HIV-1 Tat protein induced sensorimotor deficits associated with acute and persistent neuroinflammation in limbic/extralimbic brain regions.
Asunto(s)
Encéfalo/inmunología , Microglía/fisiología , Filtrado Sensorial/inmunología , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/metabolismo , Animales , Encéfalo/patología , Proteínas de Unión al Calcio/metabolismo , Modelos Animales de Enfermedad , Doxiciclina , Proteína Ácida Fibrilar de la Glía , VIH-1 , Masculino , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Microfilamentos/metabolismo , Microglía/patología , Proteínas del Tejido Nervioso/metabolismo , Productos del Gen tat del Virus de la Inmunodeficiencia Humana/genéticaRESUMEN
Schizophrenia is associated with deficits in the hippocampus, a brain area important for learning and memory. The dentate gyrus (DG) of the hippocampus develops both before and after birth. To study the relative contribution of mature and adult-born DG granule cells to disease etiology, we compared both cell populations in a mouse model of psychiatric illness resulting from maternal immune activation. Polyriboinosinic-polyribocytidilic acid (PolyIC, 5mg/kg) or saline was given on gestation day 15 to pregnant female C57Bl/6 mice. Male offspring (n=105), was administered systemic bromodeoxyuridine (BrdU, 50mg/kg) (n=52) or intracerebral retroviral injection into the DG (n=53), to label dividing cells at one month of age. Two months later behavioral tests were performed to evaluate disease phenotype. Immunohistochemistry and whole-cell patch clamping were used to assess morphological and physiological characteristics of DG cells. Three-month-old PolyIC exposed male offspring exhibited deficient pre-pulse inhibition, spatial maze performance and motor coordination, as well as increased depression-like behavior. Histological analysis showed reduced DG volume and parvalbumin positive interneuron number. Both mature and new hippocampal neurons showed modifications in intrinsic properties such as increased input resistance and lower current threshold, and decreased action potential number. Reduced GABAergic inhibitory transmission was observed only in mature DG neurons. Differential impairments in mature DG cells and adult-born new neurons may have implications for behavioral deficits associated with maternal immune activation.
Asunto(s)
Cognición/fisiología , Giro Dentado/inmunología , Inductores de Interferón/farmacología , Actividad Motora/inmunología , Neuronas/inmunología , Poli I-C/farmacología , Complicaciones Infecciosas del Embarazo/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Inhibición Prepulso/inmunología , Animales , Cognición/efectos de los fármacos , Giro Dentado/citología , Giro Dentado/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Actividad Motora/efectos de los fármacos , Inhibición Neural/efectos de los fármacos , Inhibición Neural/inmunología , Neurogénesis/efectos de los fármacos , Neurogénesis/inmunología , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Embarazo , Complicaciones Infecciosas del Embarazo/fisiopatología , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Inhibición Prepulso/efectos de los fármacos , Esquizofrenia/inmunología , Esquizofrenia/fisiopatología , Filtrado Sensorial/efectos de los fármacos , Filtrado Sensorial/inmunologíaRESUMEN
The synchrony of neural firing is believed to underlie the integration of information between and within neural networks in the brain. Abnormal synchronization of neural activity between distal brain regions has been proposed to underlie the core symptomatology in schizophrenia. This study investigated whether abnormal synchronization occurs between the medial prefrontal cortex (mPFC) and the hippocampus (HPC), two brain regions implicated in schizophrenia pathophysiology, using the maternal immune activation (MIA) animal model in rats. This neurodevelopmental model of schizophrenia is induced through a single injection of the synthetic immune system activator polyriboinosinic-polyribocytidylic acid, a synthetic analog of double-stranded RNA, a molecular pattern associated with viral infection, in pregnant rat dams. It is based on epidemiological evidence of increased risk of schizophrenia in adulthood after prenatal exposure to infection. In the present study, EEG coherence and neuronal phase-locking to underlying EEG were measured in freely moving MIA and control offspring. The MIA intervention produced significant reductions in mPFC-HPC EEG coherence that correlated with decreased prepulse inhibition of startle, a measure of sensory gating and a hallmark schizotypal behavioral measure. Furthermore, changes in the synchronization of neuronal firing to the underlying EEG were evident in the theta and low-gamma frequencies. Firing within a putative population of theta-modulated, gamma-entrained mPFC neurons was also reduced in MIA animals. Thus, MIA in rats produces a fundamental disruption in long-range neuronal synchrony in the brains of the adult offspring that models the disruption of synchrony observed in schizophrenia.
Asunto(s)
Enfermedades Virales del Sistema Nervioso Central/inmunología , Sincronización Cortical , Modelos Animales de Enfermedad , Intercambio Materno-Fetal/inmunología , Neuronas/patología , Efectos Tardíos de la Exposición Prenatal/inmunología , Esquizofrenia/inmunología , Animales , Animales Recién Nacidos , Enfermedades Virales del Sistema Nervioso Central/embriología , Enfermedades Virales del Sistema Nervioso Central/patología , Electroencefalografía , Femenino , Hipocampo/embriología , Hipocampo/inmunología , Hipocampo/virología , Masculino , Poli I-C/toxicidad , Corteza Prefrontal/embriología , Corteza Prefrontal/inmunología , Corteza Prefrontal/virología , Embarazo , Ratas , Ratas Sprague-Dawley , Esquizofrenia/patología , Esquizofrenia/virología , Filtrado Sensorial/inmunologíaRESUMEN
Gene-environment interaction may play a role in the etiology of schizophrenia. Transgenic mice expressing dominant-negative DISC1 (DN-DISC1 mice) show some histological and behavioral endophenotypes relevant to schizophrenia. Viral infection during neurodevelopment provides a major environmental risk for schizophrenia. Neonatal injection of polyriboinosinic-polyribocytidylic acid (polyI:C), which mimics innate immune responses elicited by viral infection, leads to schizophrenia-like behavioral alteration in mice after puberty. To study how gene-environmental interaction during neurodevelopment results in phenotypic changes in adulthood, we treated DN-DISC1 mice or wild-type littermates with injection of polyI:C during the neonatal stage, according to the published method, respectively, and the behavioral and histological phenotypes were examined in adulthood. We demonstrated that neonatal polyI:C treatment in DN-DISC1 mice resulted in the deficits of short-term, object recognition, and hippocampus-dependent fear memories after puberty, although polyI:C treatment by itself had smaller influences on wild-type mice. Furthermore, polyI:C-treated DN-DISC1 mice exhibited signs of impairment of social recognition and interaction, and augmented susceptibility to MK-801-induced hyperactivity as compared with vehicle-treated wild-type mice. Of most importance, additive effects of polyI:C and DN-DISC1 were observed by a marked decrease in parvalbumin-positive interneurons in the medial prefrontal cortex. These results suggest that combined effect of neonatal polyI:C treatment and DN-DISC1 affects some behavioral and histological phenotypes in adulthood.
Asunto(s)
Conducta Animal/fisiología , Hipocampo/inmunología , Proteínas del Tejido Nervioso/genética , Fenotipo , Análisis de Varianza , Animales , Animales Recién Nacidos , Proliferación Celular , Condicionamiento Clásico/fisiología , Maleato de Dizocilpina/toxicidad , Miedo/fisiología , Femenino , Reacción Cataléptica de Congelación/fisiología , Hipocampo/metabolismo , Hipercinesia/inducido químicamente , Hipercinesia/genética , Hipercinesia/inmunología , Inmunohistoquímica , Inductores de Interferón/administración & dosificación , Antígeno Ki-67/metabolismo , Masculino , Memoria a Corto Plazo/fisiología , Ratones , Ratones Transgénicos , Parvalbúminas/metabolismo , Poli I-C/administración & dosificación , Reconocimiento en Psicología/fisiología , Reflejo de Sobresalto/genética , Reflejo de Sobresalto/inmunología , Filtrado Sensorial/genética , Filtrado Sensorial/inmunología , Conducta Social , Coloración y EtiquetadoRESUMEN
It has been reported that viral infection in the first and second trimesters of pregnancy in humans increases the risk of subsequently developing schizophrenia. To develop a mouse model of immune activation during the early postnatal period, neonatal ICR mice were repeatedly injected with polyriboinosinic-polyribocytidilic acid (polyI:C; an inducer of strong innate immune responses) for 5 days (postnatal day 2-6) which may correspond, in terms of brain development, to the early second trimester in human. Cognitive and emotional behavior as well as the extracellular level of glutamate in the hippocampus were analyzed at the age of 10-12 weeks old. PolyI:C-treated mice showed anxiety-like behavior, impairment of object recognition memory and social behavior, and sensorimotor gating deficits, as compared to the saline-treated control group. Depolarization-evoked glutamate release in the hippocampus was impaired in polyI:C-treated mice compared to saline-treated control mice. Furthermore, to investigate the effect of neonatal immune activation on the expression levels of schizophrenia-related genes, we analyzed mRNA levels in the hippocampus 2 and 24h after polyI:C treatment. No significant differences or only transient and marginal changes were observed between polyI:C-treated and saline-treated control mice in the expression levels of schizophrenia-related genes in the hippocampus.