RESUMEN
Autism spectrum disorders (ASDs) are neuropsychiatric diseases characterized by impaired social interaction, communication deficits, and repetitive and stereotyped behaviors. ASD etiology is unknown, and both genetic and environmental causes have been proposed. Different brain structures are believed to play a role in ASD-related behaviors, including medial prefrontal cortex (mPFC), hippocampus, piriform cortex (Pir), basolateral amygdala (BLA) and Cerebellum. Compelling evidence suggests a link between white matter modifications and ASD symptoms in patients. Besides, an hypomyelination of the mPFC has been associated in rodents to social behavior impairment, one of the main symptoms of ASD. However, a comparative analysis of myelination as well as oligodendroglial (OL)-lineage cells in brain regions associated to social behaviors in animal models of ASD has not been performed so far. Here, we investigated whether OL-lineage cells and myelination are altered in a murine model of ASD induced by the prenatal exposure to valproic acid (VPA). We showed an hypomyelination in the BLA and Pir of adult VPA-exposed mice. These results were accompanied by a decrease in the number of OL-lineage cells and of mature OLs in the Pir, in addition to the mPFC, where myelination presented no alterations. In these regions the number of oligodendrocyte progenitors (OPCs) remained unaltered. Likewise, activation of histone deacetylases (HDACs) on OL-lineage cells in adulthood showed no differences. Overall, our results reveal OL-lineage cell alterations and hypomyelination as neuropathological hallmarks of ASD that have been overlooked so far.
RESUMEN
Temporal processing in the seconds-to-minutes range, known as interval timing, is a crucial cognitive function that requires activation of cortico-striatal circuits via dopaminergic-glutamatergic pathways. In humans, both children and adults with autism spectrum disorders (ASD) present alterations in their estimation of time intervals. At present, there are no records of interval timing studies in animal models of ASD. Hence, the objective of the present work was to evaluate interval timing in a mouse model of prenatal exposure to valproic acid (VPA) - a treatment used to induce human-like autistic features in rodent models. Animals were assessed for their ability to acquire timing responses in 15-s and 45-s peak-interval (PI) procedures. Our results indicate that both female and male mice prenatally exposed to VPA present decreased timing accuracy and precision compared to control groups, as well as deviations from the scalar property. Moreover, the observed timing deficits in male VPA mice were reversed after early social enrichment. Furthermore, catecholamine determination by HPLC-ED indicated significant differences in striatal dopaminergic, but not serotonergic, content in female and male VPA mice, consistent with previously identified alterations in dopamine metabolism in ASD. These deficits in temporal processing in a mouse model of autism complement previous results in humans, and provide a useful tool for further behavioral and pharmacological studies.
Asunto(s)
Trastorno del Espectro Autista/fisiopatología , Dopamina/metabolismo , GABAérgicos/farmacología , Neostriado/metabolismo , Efectos Tardíos de la Exposición Prenatal/fisiopatología , Desempeño Psicomotor/fisiología , Percepción del Tiempo/fisiología , Ácido Valproico/farmacología , Animales , Trastorno del Espectro Autista/metabolismo , Conducta Animal/fisiología , Modelos Animales de Enfermedad , Femenino , Masculino , Ratones , Embarazo , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Efectos Tardíos de la Exposición Prenatal/metabolismo , Serotonina/metabolismo , Conducta SocialRESUMEN
During an infection, animals suffer several changes in their normal physiology and behavior which may include lethargy, appetite loss, and reduction in grooming and general movements. This set of alterations is known as sickness behavior and although it has been extensively believed to be orchestrated primarily by the immune system, a relevant role for the central nervous system has also been established. The aim of the present work is to develop a simple animal model to allow studying how the immune and the nervous systems interact coordinately during an infection. We administered a bacterial lipopolysaccharide (LPS) into the thorax of honey bees to mimic a bacterial infection, and then we evaluated a set of stereotyped behaviors of the animals that might be indicative of sickness behavior. First, we show that this immune challenge reduces the locomotor activity of the animals in a narrow time window after LPS injection. Furthermore, bees exhibit a loss of appetite 60 and 90 min after injection, but not 15 h later. We also demonstrate that LPS injection reduces spontaneous antennal movements in harnessed animals, which suggests a reduction in the motivational state of the bees. Finally, we show that the LPS injection diminishes the interaction between animals, a crucial behavior in social insects. To our knowledge these results represent the first systematic description of sickness behavior in honey bees and provide important groundwork for the study of the interaction between the immune and the neural systems in an insect model.
RESUMEN
Peripheral inflammation, both during the prenatal period and in adulthood, impairs adult neurogenesis. We hypothesized that, similar to other programming effects of prenatal treatments, only prenatal inflammation causes long-term consequences in adult neurogenesis and its neurogenic niche. To test this, pregnant Wistar rats were subcutaneously injected with lipopolysaccharide (LPS; 0.5 mg/kg) or saline solution every other day from gestational/embryonic day (GD) 14-20. In addition adult animals were injected with a single intraperitoneal saline or LPS injection (1 mg/kg) and the effects on neurogenesis were assessed 7 days later. Alternatively, to evaluate long-term consequences of adult LPS injections, LPS (1 mg/kg) was administered peripherally to adult rats four times every other day, and the effects on neurogenesis were assessed 60 days later. Prenatal and adult LPS treatments reduced adult neurogenesis and provoked specific microglial (but not astroglial) activation in the dentate gyrus (DG). However, only prenatal inflammation-mediated effects were long-lasting (at least 60 days). Moreover, these effects were specific to the DG since the Subventricular Zone (SVZ) and the Rostral Migratory Stream (RMS) were not affected. In addition, these stimuli caused differential effects on the molecular components of the neurogenic niche; only prenatal LPS treatment reduced the local levels of TGF-ß1 mRNA in the DG. Finally, TGF-ß1 exerted its pro-neurogenic effects via the Smad 2/3 pathway in a neural stem cell culture. Taken together, these data add evidence to the duration, regional specificity and dramatic consequences of prenatal immune programming on CNS physiology, compared with the limited response observed in the adult brain.
Asunto(s)
Giro Dentado/citología , Lipopolisacáridos/toxicidad , Neurogénesis/fisiología , Factor de Crecimiento Transformador beta1/metabolismo , Factores de Edad , Animales , Astrocitos/citología , Giro Dentado/efectos de los fármacos , Giro Dentado/embriología , Giro Dentado/metabolismo , Femenino , Inflamación/patología , Masculino , Microglía/citología , Neurogénesis/efectos de los fármacos , Embarazo , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
Prenatal exposure to inflammatory stimuli is known to influence adult brain function. In addition, adult hippocampal neurogenesis is impaired by a local pro-inflammatory microenvironment. On this basis, we hypothesized that a pro-inflammatory insult during gestation would have negative effects on adult neurogenesis in the offspring. Pregnant Wistar rats received subcutaneous injections of lipopolysaccharide (LPS; 0.5mg/kg) or saline every other day from gestational day 14 to 20. The adult offspring prenatally treated with LPS showed a decrease in the proliferating cells and the newborn neurons of the dentate gyrus. Furthermore, prenatal LPS treatment impaired performance in the neurogenesis-dependent novel object recognition test. Maternal care was impaired by prenatal LPS administration but did not contribute to the effects of prenatal LPS on adult neurogenesis. Persistent microglial activation and downregulated expression of transforming growth factor beta-1 (TGFß(1)) occurred specifically in the adult hippocampus of animals treated prenatally with LPS. Importantly, chronic hippocampal TGFß(1) overexpression restored neurogenesis as well as recognition memory performance to control levels. These findings demonstrate that prenatal inflammation triggered by LPS impairs adult neurogenesis and recognition memory. Furthermore, we provide a model of reduced adult neurogenesis with long-lasting defined alterations in the neurogenic niche. Finally, we show that the expression of a single cytokine (TGFß(1)) in the hippocampus can restore adult neurogenesis and its related behavior, highlighting the role of TGFß(1) in these processes.
Asunto(s)
Conducta Animal/fisiología , Hipocampo/fisiología , Memoria/fisiología , Neurogénesis/fisiología , Efectos Tardíos de la Exposición Prenatal/patología , Efectos Tardíos de la Exposición Prenatal/psicología , Factor de Crecimiento Transformador beta1/biosíntesis , Adenoviridae/genética , Animales , Antimetabolitos , Bromodesoxiuridina , Proliferación Celular , Citocinas/biosíntesis , Regulación hacia Abajo/fisiología , Femenino , Vectores Genéticos , Hipocampo/citología , Lipopolisacáridos/farmacología , Activación de Macrófagos/fisiología , Conducta Materna , Microglía/fisiología , Embarazo , ARN/biosíntesis , ARN/genética , ARN/aislamiento & purificación , Ratas , Ratas Wistar , Reconocimiento en Psicología/fisiología , Factor de Crecimiento Transformador beta1/genética , beta-Galactosidasa/biosíntesis , beta-Galactosidasa/genéticaRESUMEN
Interleukin-1beta (IL-1) expression is associated with a spectrum of neuroinflammatory processes related to chronic neurodegenerative diseases. The single-bolus microinjection of IL-1 into the central nervous system (CNS) parenchyma gives rise to delayed and localized neutrophil recruitment, transient blood-brain barrier (BBB) breakdown, but no overt damage to CNS integrity. However, acute microinjections of IL-1 do not mimic the chronic IL-1 expression, which is a feature of many CNS diseases. To investigate the response of the CNS to chronic IL-1 expression, we injected a recombinant adenovirus expressing IL-1 into the striatum. At the peak of IL-1 expression (days 8 and 14 post-injection), there was a marked recruitment of neutrophils, vasodilatation, and breakdown of the BBB. Microglia and astrocyte activation was evident during the first 14 days post-injection. At days 8 and 14, extensive demyelination was observed but the number of neurons was not affected by any treatment. Finally, at 30 days, signs of inflammation were no longer present, there was evidence of tissue reorganization, the BBB was intact, and the process of remyelination was noticeable. In summary, our data show that chronic expression of IL-1, in contrast to its acute delivery, can reversibly damage CNS integrity and implicates this cytokine or downstream components as major mediators of demyelination in chronic inflammatory and demyelinating diseases.
Asunto(s)
Barrera Hematoencefálica , Enfermedades Desmielinizantes/patología , Interleucina-1/metabolismo , Vaina de Mielina/patología , Neutrófilos/patología , Adenoviridae/genética , Animales , Astrocitos/metabolismo , Encéfalo/metabolismo , Encéfalo/patología , Sistema Nervioso Central/patología , Ensayo de Inmunoadsorción Enzimática , Vectores Genéticos , Inmunohistoquímica , Inflamación , Leucocitos/metabolismo , Masculino , Microscopía Electrónica , Vaina de Mielina/metabolismo , Neuronas/patología , Neutrófilos/metabolismo , Permeabilidad , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
The interleukin-1 (IL-1) cytokine family (IL-1alpha, IL-beta, and the IL-1 receptor antagonist) is involved in immune and inflammatory responses both in the brain and in the periphery. Recently, it has also been shown to influence behavior and memory consolidation. However, within the experimental systems studied, it has remained unclear whether the role of IL-1beta is associated solely with a pathophysiological process or whether it is a neuromodulator in normal adult brain. To evaluate the involvement of the nonpathological endogenous IL-1 system in learning, we studied the expression of IL-1alpha, IL-1beta, and IL-1ra during memory consolidation. We observed a learning-specific hippocampal IL-1alpha mRNA induction, but not that of IL-1beta or IL-1ra mRNAs, after inhibitory avoidance training. Moreover, when IL-1 receptor activity was inhibited using an adenoviral vector that expresses the IL-1 receptor antagonist (IL-1ra) in the hippocampus, both short-term and long-term memory retention scores were facilitated. In contrast, endogenous hippocampal IL-1 played no role in the habituation to a novel environment. These results demonstrate that endogenous hippocampal IL-1 specifically modulates a fear-motivated learning task, and suggest that IL-1alpha activity in the CNS is part of the hippocampal memory processing.
Asunto(s)
Hipocampo/inmunología , Interleucina-1/genética , Aprendizaje/fisiología , Memoria/fisiología , Animales , Reacción de Prevención/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Conducta Exploratoria/fisiología , Habituación Psicofisiológica , Proteína Antagonista del Receptor de Interleucina 1 , Interleucina-1/antagonistas & inhibidores , Masculino , Memoria/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Ratas , Ratas Wistar , Receptores de Interleucina-1/antagonistas & inhibidores , Receptores de Interleucina-1/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sialoglicoproteínas/genética , Vocalización AnimalRESUMEN
Microglial activation has been associated with the pathogenesis of Parkinson's disease (PD). Among the many components of this reaction, cytokines have been proposed as candidates to mediate neurodegenerative or neuroprotective effects. We investigated the interleukin-1 system and tumour necrosis factor-alpha mRNA and protein levels at different time intervals in the subacute intrastriatal 6-hydroxydopamine rat model of PD, in parallel with the inflammatory response. Immunohistochemistry showed that microglial cells were activated from days 6-30 postlesion in the substantia nigra pars compacta. This microglial activation was accompanied by an atypical proinflammatory cytokine production: Interleukin-1alpha and beta mRNAs were found to be elevated 30 days post-6-hydroxydopamine injection (2- and 16-fold, respectively), but no induction for interleukin-1alpha or beta at the protein level was detected by ELISA. As a control, a classical proinflammatory stimulus, namely endotoxin, was capable of inducing these cytokines at similar mRNA levels but also at the protein level. In addition, tumour necrosis factor-alpha mRNA was hardly or not detected in the substantia nigra at any time point studied. Our data point out a tight control of key proinflammatory cytokine production in our model of PD. This work supports the notion that chronic neuronal death per se does not induce secretion of these proinflammatory cytokines but that an additional stimulus is necessary to stimulate proinflammatory cytokine production. The production of proinflammatory cytokines from "primed" microglia may in turn modulate disease progression as has been recently proposed in a model of prion disease.
Asunto(s)
Glicoproteínas , Inflamación/metabolismo , Interleucina-1/metabolismo , Microglía/metabolismo , Enfermedad de Parkinson/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Adrenérgicos/toxicidad , Animales , Northern Blotting , Bromodesoxiuridina/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Ectodisplasinas , Endotoxinas/farmacología , Ensayo de Inmunoadsorción Enzimática , Lateralidad Funcional , Proteína Ácida Fibrilar de la Glía/metabolismo , Inmunohistoquímica/métodos , Inflamación/inducido químicamente , Lectinas/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Oxidopamina/toxicidad , Enfermedad de Parkinson/genética , Desempeño Psicomotor/efectos de los fármacos , ARN Mensajero/metabolismo , Ratas , Ratas Wistar , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Sustancia Negra/efectos de los fármacos , Sustancia Negra/metabolismo , Factores de Tiempo , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Information storage in the brain is a temporally graded process involving different memory types or phases. It has been assumed for over a century that one or more short-term memory (STM) processes are involved in processing new information while long-term memory (LTM) is being formed. Because brain-derived neutrophic factor (BDNF) modulates both short-term synaptic function and activity-dependent synaptic plasticity in the adult hippocampus, we examined the role of BDNF in STM and LTM formation of a hippocampal-dependent one-trial fear-motivated learning task in rats. Using a competitive RT-PCR quantitation method, we found that inhibitory avoidance training is associated with a rapid and transient increase in BDNF mRNA expression in the hippocampus. Bilateral infusions of function-blocking anti-BDNF antibody into the CA, region of the dorsal hippocampus decreased extracellular signal-regulated kinase 2 (ERK2) activation and impaired STM retention scores. Inhibition of ERK1/2 activation by PD098059 produced similar effects. In contrast, intrahippocampal administration of recombinant human BDNF increased ERK1/2 activation and facilitated STM. The infusion of anti-BDNF antibody impaired LTM when given 15 min before or 1 and 4 hr after training, but not at 0 or 6 hr posttraining, indicating that two hippocampal BDNF-sensitive time windows are critical for LTM formation. At the same time points, PD098059 produced no LTM deficits. Thus, our results indicate that endogenous BDNF is required for both STM and LTM formation of an inhibitory avoidance learning. Additionally, they suggest that this requirement involves ERK1/2-dependent and -independent mechanisms.