RESUMEN
Toxoplasma gondii (TOXO) is a neuroinvasive protozoan parasite that induces the formation of persistent cysts in mammalian brains. It infects approximately 1.1million people in the United States annually. Latent TOXO infection is implicated in the etiology of psychiatric disorders, especially schizophrenia (SCZ), and has been correlated with modestly impaired cognition. The acoustic startle response (ASR) is a reflex seen in all mammals. It is mediated by a simple subcortical circuit, and provides an indicator of neural function. We previously reported the association of TOXO with slowed acoustic startle latency, an index of neural processing speed, in a sample of schizophrenia and healthy control subjects. The alterations in neurobiology with TOXO latent infection may not be specific to schizophrenia. Therefore we examined TOXO in relation to acoustic startle in an urban, predominately African American, population with mixed psychiatric diagnoses, and healthy controls. Physiological and diagnostic data along with blood samples were collected from 364 outpatients treated at an inner-city hospital. TOXO status was determined with an ELISA assay for TOXO-specific IgG. A discrete titer was calculated based on standard cut-points as an indicator of seropositivity, and the TOXO-specific IgG concentration served as serointensity. A series of linear regression models were used to assess the association of TOXO seropositivity and serointensity with ASR magnitude and latency in models adjusting for demographics and psychiatric diagnoses (PTSD, major depression, schizophrenia, psychosis, substance abuse). ASR magnitude was 11.5% higher in TOXO seropositive subjects compared to seronegative individuals (p=0.01). This effect was more pronounced in models with TOXO serointensity that adjusted for sociodemographic covariates (F=7.41, p=0.0068; F=10.05, p=0.0017), and remained significant when psychiatric diagnoses were stepped into the models. TOXO showed no association with startle latency (t=0.49, p=0.63) in an unadjusted model, nor was TOXO associated with latency in models that included demographic factors. After stepping in individual psychiatric disorders, we found a significant association of latency with a diagnosis of PTSD (F=5.15, p=0.024), but no other psychiatric diagnoses, such that subjects with PTSD had longer startle latency. The mechanism by which TOXO infection is associated with high startle magnitude is not known, but possible mechanisms include TOXO cyst burden in the brain, parasite recrudescence, or molecular mimicry of a host epitope by TOXO. Future studies will focus on the neurobiology underlying the effects of latent TOXO infection as a potential inroad to the development of novel treatment targets for psychiatric disease.
Asunto(s)
Reflejo de Sobresalto/inmunología , Medio Social , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Población Urbana , Estimulación Acústica , Adulto , Negro o Afroamericano , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Schizophrenia is a highly disabling psychiatric disorder with a proposed neurodevelopmental basis. One mechanism through which genetic and environmental risk factors might act is by triggering persistent brain inflammation, as evidenced by long-lasting neuro-immunological disturbances in patients. Our goal was to investigate whether microglia activation is a neurobiological correlate to the altered behaviour in the maternal immune activation (MIA) model, a well-validated animal model with relevance to schizophrenia. A recent observation in the MIA model is the differential maternal body weight response to the immune stimulus, correlated with a different behavioural outcome in the offspring. Although it is generally assumed that the differences in maternal weight response reflect differences in cytokine response, this has not been investigated so far. Our aim was to investigate whether (i) the maternal weight response to MIA reflects differences in the maternal cytokine response, (ii) the differential behavioural phenotype of the offspring extends to depressive symptoms such as anhedonia and (iii) there are changes in chronic microglia activation dependent on the behavioural phenotype. METHODS: Based on a dose-response study, MIA was induced in pregnant rats by injecting 4mg/kg Poly I:C at gestational day 15. Serum samples were collected to assess the amount of TNF-α in the maternal blood following MIA. MIA offspring were divided into weight loss (WL; n=14) and weight gain (WG; n=10) groups, depending on the maternal body weight response to Poly I:C. Adult offspring were behaviourally phenotyped for prepulse inhibition, locomotor activity with and without amphetamine and MK-801 challenge, and sucrose preference. Finally, microglia activation was scored on CD11b- and Iba1-immunohistochemically stained sections. RESULTS: Pregnant dams that lost weight following MIA showed increased levels of TNF-α compared to controls, unlike dams that gained weight following MIA. Poly I:C WL offspring showed the most severe behavioural outcome. Poly I:C WG offspring, on the other hand, did not show clear behavioural deficits. Most interestingly a reduced sucrose preference indicative of anhedonia was found in Poly I:C WL but not Poly I:C WG offspring compared to controls. Finally, there were no significant differences in microglia activation scores between any of the investigated groups. CONCLUSIONS: The individual maternal immune response to MIA is an important determinant of the behavioural outcome in offspring, including negative symptoms such as anhedonia. We failed to find any significant difference in the level of microglia activation between Poly I:C WL, Poly I:C WG and control offspring.
Asunto(s)
Conducta Animal/fisiología , Sistema Inmunológico/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Esquizofrenia/inmunología , Animales , Conducta Animal/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Sistema Inmunológico/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/inmunología , Poli I-C/farmacología , Embarazo , Ratas , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/inmunología , Aumento de Peso/efectos de los fármacos , Aumento de Peso/inmunología , Pérdida de Peso/efectos de los fármacos , Pérdida de Peso/inmunologíaRESUMEN
Over the past decade a neurodevelopmental animal model with high validity for schizophrenia has been developed based on the environmental risk factor known as maternal immune activation (MIA). The immunological basis of this model, together with extensive data from clinical and preclinical context, suggests the involvement of an aberrant neuro-immune system in the pathophysiology of schizophrenia. The goal of this study was to examine microglia activation in adult behaviourally phenotyped MIA offspring. MIA was induced in pregnant rats using viral mimetic Poly I:C at gestational day 15. Adult offspring were behaviourally phenotyped at postnatal days (PND) 56, 90 and 180 through the evaluation of prepulse inhibition (PPI) of the acoustic startle and spontaneous locomotion. Finally, the presence of activated microglia in brain regions associated with schizophrenia was evaluated using post-mortem immunohistochemistry against OX-42 (CD11b) and ED-1 (CD68). Although a deficit in PPI could not be replicated despite the high number of animals tested, we found an overall decrease in basal startle response and spontaneous locomotion in offspring born to Poly I:C- compared to saline-treated dams, accompanied by increased microglial density with characteristics of non-reactive activation in the chronic stage of the model. These findings provide additional evidence for a role played by microglial activation in schizophrenia-related pathology in general and psychomotor slowing in particular, and warrant extensive research on the underlying mechanism in order to establish new drug targets for the treatment of schizophrenia patients with an inflammatory component.
Asunto(s)
Microglía/inmunología , Actividad Motora/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Esquizofrenia/inmunología , Estimulación Acústica , Animales , Modelos Animales de Enfermedad , Femenino , Microglía/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Poli I-C/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Ratas , Reflejo de Sobresalto/inmunología , Esquizofrenia/fisiopatologíaRESUMEN
Maternal infection is a risk factor for autism spectrum disorder (ASD) and schizophrenia (SZ). Indeed, modeling this risk factor in mice through maternal immune activation (MIA) causes ASD- and SZ-like neuropathologies and behaviors in the offspring. Although MIA upregulates pro-inflammatory cytokines in the fetal brain, whether MIA leads to long-lasting changes in brain cytokines during postnatal development remains unknown. Here, we tested this possibility by measuring protein levels of 23 cytokines in the blood and three brain regions from offspring of poly(I:C)- and saline-injected mice at five postnatal ages using multiplex arrays. Most cytokines examined are present in sera and brains throughout development. MIA induces changes in the levels of many cytokines in the brains and sera of offspring in a region- and age-specific manner. These MIA-induced changes follow a few, unexpected and distinct patterns. In frontal and cingulate cortices, several, mostly pro-inflammatory, cytokines are elevated at birth, followed by decreases during periods of synaptogenesis and plasticity, and increases again in the adult. Cytokines are also altered in postnatal hippocampus, but in a pattern distinct from the other regions. The MIA-induced changes in brain cytokines do not correlate with changes in serum cytokines from the same animals. Finally, these MIA-induced cytokine changes are not accompanied by breaches in the blood-brain barrier, immune cell infiltration or increases in microglial density. Together, these data indicate that MIA leads to long-lasting, region-specific changes in brain cytokines in offspring-similar to those reported for ASD and SZ-that may alter CNS development and behavior.
Asunto(s)
Conducta Animal/fisiología , Encéfalo/inmunología , Citocinas/metabolismo , Efectos Tardíos de la Exposición Prenatal/inmunología , Factores de Edad , Animales , Conducta Animal/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Femenino , Ratones , Especificidad de Órganos , Poli I-C/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/inmunologíaRESUMEN
Inflammation-induced disruption of fetal neurodevelopmental processes has been linked to the precipitation of long-lasting behavioral abnormalities and associated neuropathology. Recent longitudinal investigations in prenatal immune activation models have revealed developmental correspondences between the ontogeny of specific dopaminergic neuropathology and the postnatal onset of distinct forms of dopamine-dependent functional abnormalities implicated in schizophrenia. Two examples of such developmental correspondences are increased expression of the orphan nuclear receptor Nurr1 (NR4A2) in ventral midbrain areas and disruption of prepulse inhibition of the acoustic startle reflex, with both the neuroanatomical and behavioral effects emerging only in adult but not pre-pubertal subjects exposed to prenatal maternal inflammation. In the present study, we tested the hypothesis that Nurr1 may be a critical molecular mediator of prepulse inhibition deficits induced by prenatal immune activation. To this end, we compared the effects of prenatal immune challenge on adult PPI in wild-type (wt) mice and mice with a heterozygous constitutive deletion of Nurr1 (Nurr1+/-) using a well established mouse model of maternal immune activation by exposure to the viral mimetic poly(I:C) (=polyriboinosinic-polyribocytidilic acid). We found that prenatal poly(I:C) treatment on gestation day 9 was similarly effective in disrupting prepulse inhibition in adult wt and Nurr1+/- mice. Prenatal poly(I:C) treatment also generally increased midbrain Nurr1-positive cells and counteracted the genetically driven Nurr1 deficit in the substantia nigra. Our data thus suggest that at least under the present experimental conditions, Nurr1 is not essential for the development of prepulse inhibition deficits induced by prenatal immune activation.
Asunto(s)
Encéfalo/inmunología , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Efectos Tardíos de la Exposición Prenatal/inmunología , Reflejo de Sobresalto/inmunología , Estimulación Acústica , Animales , Encéfalo/metabolismo , Femenino , Ratones , Ratones Noqueados , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Poli I-C/farmacología , Embarazo , Efectos Tardíos de la Exposición Prenatal/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
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
BACKGROUND: Among the diverse animal models proposed for schizophrenia, the neonatal ventral hippocampal lesion (NVHL) is one of the most widely used. However, its construct validity can be questioned because there is no evidence of a lesion present in schizophrenia. Other approaches that have tried to capture environmental influences on development include diverse models of maternal infection. METHODS: As the early postnatal days in rodents are equivalent to the third trimester of human pregnancy in terms of brain development, we decided to test whether a neonatal immune challenge with an injection of the bacterial endotoxin lipopolysaccharide (LPS) into the ventral hippocampus caused deficits in interneuron function similar to those reported for the NVHL. RESULTS: Neonatal LPS injection caused a persistent elevation in cytokines in several brain regions, deficits in prepulse inhibition of the acoustic startle response, and a loss of the periadolescent maturation in the response of prefrontal cortical fast-spiking interneurons to dopamine. CONCLUSIONS: The same phenotypes elicited by a NVHL can be obtained with an intrahippocampal immune challenge, suggesting that perinatal environmental factors can affect adult prefrontal interneuron maturation during adolescence.
Asunto(s)
Dopamina/farmacología , Hipocampo/inmunología , Interneuronas/efectos de los fármacos , Corteza Prefrontal/citología , Estimulación Acústica/efectos adversos , Potenciales de Acción/efectos de los fármacos , Animales , Animales Recién Nacidos , Citocinas/metabolismo , Agonistas de Dopamina/farmacología , Ensayo de Inmunoadsorción Enzimática/métodos , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Regulación del Desarrollo de la Expresión Génica/fisiología , Hipocampo/efectos de los fármacos , Interneuronas/fisiología , Lipopolisacáridos/farmacología , Inhibición Neural/efectos de los fármacos , Inhibición Neural/fisiología , Técnicas de Placa-Clamp , Corteza Prefrontal/efectos de los fármacos , Quinpirol/farmacología , Ratas , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/inmunologíaRESUMEN
Maternal infection during pregnancy increases the risk for neurodevelopmental disorders such as schizophrenia and autism in the offspring. This association appears to be critically dependent on the precise prenatal timing. However, the extent to which distinct adult psychopathological and neuropathological traits may be sensitive to the precise times of prenatal immune activation remains to be further characterized. Here, we evaluated in a mouse model of prenatal immune challenge by the viral mimic, polyriboinosinic-polyribocytidilic acid (PolyIC), whether prenatal immune activation in early/middle and late gestation may influence the susceptibility to some of the critical cognitive, pharmacological, and neuroanatomical dysfunctions implicated in schizophrenia and autism. We revealed that PolyIC-induced prenatal immune challenge on gestation day (GD) 9 but not GD17 significantly impaired sensorimotor gating and reduced prefrontal dopamine D1 receptors in adulthood, whereas prenatal immune activation specifically in late gestation impaired working memory, potentiated the locomotor reaction to the NMDA-receptor antagonist dizocilpine, and reduced hippocampal NMDA-receptor subunit 1 expression. On the other hand, potentiation of the locomotor reaction to the dopamine-receptor agonist amphetamine and reduction in Reelin- and Parvalbumin-expressing prefrontal neurons emerged independently of the precise times of prenatal immune challenge. Our findings thus highlight that prenatal immune challenge during early/middle and late fetal development in mice leads to distinct brain and behavioral pathological symptom clusters in adulthood. Further examination and evaluation of in utero immune challenge at different times of gestation may provide important new insight into the neuroimmunological and neuropathological mechanisms underlying the segregation of different symptom clusters in heterogeneous neuropsychiatric disorders such as schizophrenia and autism.
Asunto(s)
Trastorno Autístico/inmunología , Encéfalo/inmunología , Inductores de Interferón/farmacología , Poli I-C/farmacología , Efectos Tardíos de la Exposición Prenatal/inmunología , Esquizofrenia/inmunología , Estimulación Acústica , Factores de Edad , Anfetaminas/farmacología , Animales , Trastorno Autístico/patología , Encéfalo/metabolismo , Encéfalo/patología , Moléculas de Adhesión Celular Neuronal/metabolismo , Estimulantes del Sistema Nervioso Central/farmacología , Maleato de Dizocilpina/farmacología , Antagonistas de Aminoácidos Excitadores/farmacología , Proteínas de la Matriz Extracelular/metabolismo , Femenino , Inductores de Interferón/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteínas del Tejido Nervioso/metabolismo , Parvalbúminas/metabolismo , Poli I-C/inmunología , Embarazo , Efectos Tardíos de la Exposición Prenatal/patología , Receptores de Dopamina D1/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteína Reelina , Reflejo de Sobresalto/inmunología , Esquizofrenia/patología , Serina Endopeptidasas/metabolismo , Organismos Libres de Patógenos Específicos , Ácido gamma-Aminobutírico/metabolismoRESUMEN
Maternal infection during pregnancy is a risk factor for some psychiatric illnesses of neurodevelopmental origin such as schizophrenia and autism. In experimental animals, behavioral and neuropathological outcomes relevant to schizophrenia have been observed in offspring of infected dams. However, the type of infectious agent used and gestational age at time of administration have varied. The objective of the present study was to compare the effects of prenatal challenge with different immune agents given at different time windows during gestation on behavioral outcomes in offspring. For this, pregnant rats were administered bacterial endotoxin (lipopolysaccharide, LPS), the viral mimic polyinosinic: polycytidylic acid (poly I:C), or turpentine, an inducer of local inflammation, at doses known to produce fever, at three different stages in pregnancy: embryonic day (E)10-11, E15-16 and E18-19. Prepulse inhibition of acoustic startle (PPI) was later measured in male adult offspring. PPI was significantly decreased in offspring after prenatal LPS treatment at E15-16 and E18-19. Intramuscular injection of pregnant dams with turpentine at E15-16 also decreased PPI in adult offspring. Maternal poly I:C administration had no significant effect on PPI in offspring. In contrast to prenatal LPS exposure, acute LPS administration to naive adult males had no effect on PPI. Thus, prenatal exposure both to a systemic immunogen and to local inflammation at brief periods during later pregnancy produced lasting deficits in PPI in rat offspring. These findings support the idea that maternal infection during critical windows of pregnancy could contribute to sensorimotor gating deficits in schizophrenia.
Asunto(s)
Encéfalo/inmunología , Período Crítico Psicológico , Inhibición Neural/inmunología , Complicaciones Infecciosas del Embarazo/inmunología , Efectos Tardíos de la Exposición Prenatal/inmunología , Estimulación Acústica , Análisis de Varianza , Animales , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Cognición/fisiología , Femenino , Edad Gestacional , Inflamación/inducido químicamente , Inflamación/inmunología , Lipopolisacáridos/inmunología , Masculino , Poli I-C/inmunología , Embarazo , Ratas , Ratas Sprague-Dawley , Reflejo de Sobresalto/inmunología , TrementinaRESUMEN
Maternal stress, viral infection, and obstetric complications, which trigger cytokine signaling, are hypothesized to be involved in schizophrenia and its related disorders. The etiologic contribution of individual cytokines to such psychiatric disorders, however, remains to be evaluated. To estimate the impact of peripheral cytokine challenge on neurobehavioral development, we examined effects of four proinflammatory cytokines on rat neonates and their later behavioral performance. Sublethal doses of interleukin-1 alpha, interleukin-2, interleukin-6, or interferon-gamma were subcutaneously administered to rat pups for 9 days. These animals displayed alterations in physical development, including lower weight gain and/or accelerated eyelid opening. In addition, behavioral abnormalities related to fear/anxiety levels and sensorimotor gating emerged at different developmental stages, depending on the cytokine species administered. During juvenile stages, neonatal interleukin-2 treatment increased exploratory locomotor activity, whereas other cytokine treatments did not. At the post-puberty stage, however, the interleukin-2-induced abnormal motor activity became undetectable, whereas interleukin-1 alpha-treated rats developed abnormalities in startle response, prepulse inhibition (PPI), and social interaction. Subchronic treatment of an anti-psychotic drug, clozapine, ameliorated the impairment of prepulse inhibition without altering startle responses. These animal experiments illustrate that, during early postnatal development, inflammatory cytokine challenge in the periphery can induce future psycho-behavioral and/or cognitive impairments with various latencies, although the pathologic mechanisms underlying these abnormalities remain to be determined.