RESUMEN
Perinatal infection is a well-identified risk factor for a number of neurodevelopmental disorders, including brain white matter injury (WMI) and Autism Spectrum Disorders (ASD). The underlying mechanisms by which early life inflammatory events cause aberrant neural, cytoarchitectural, and network organization, remain elusive. This study is aimed to investigate how systemic lipopolysaccharide (LPS)-induced neuroinflammation affects microglia phenotypes and early neural developmental events in rats. We show here that LPS exposure at early postnatal day 3 leads to a robust microglia activation which is characterized with mixed microglial proinflammatory (M1) and anti-inflammatory (M2) phenotypes. More specifically, we found that microglial M1 markers iNOS and MHC-II were induced at relatively low levels in a regionally restricted manner, whereas M2 markers CD206 and TGFß were strongly upregulated in a sub-set of activated microglia in multiple white and gray matter structures. This unique microglial response was associated with a marked decrease in naturally occurring apoptosis, but an increase in cell proliferation in the subventricular zone (SVZ) and the dentate gyrus (DG) of hippocampus. LPS exposure also leads to a significant increase in oligodendrocyte lineage population without causing discernible hypermyelination. Moreover, LPS-exposed rats exhibited significant impairments in communicative and cognitive functions. These findings suggest a possible role of M2-like microglial activation in abnormal neural development that may underlie ASD-like behavioral impairments.
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Comunicación Animal , Cognición/efectos de los fármacos , Sustancia Gris , Lipopolisacáridos/toxicidad , Microglía , Neurogénesis/efectos de los fármacos , Sustancia Blanca , Animales , Animales Recién Nacidos , Trastorno del Espectro Autista/inducido químicamente , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/patología , Trastorno del Espectro Autista/fisiopatología , Giro Dentado/metabolismo , Giro Dentado/patología , Giro Dentado/fisiopatología , Sustancia Gris/metabolismo , Sustancia Gris/patología , Sustancia Gris/fisiopatología , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Inflamación/fisiopatología , Ventrículos Laterales/metabolismo , Ventrículos Laterales/patología , Ventrículos Laterales/fisiopatología , Lectinas Tipo C/metabolismo , Receptor de Manosa , Lectinas de Unión a Manosa/metabolismo , Microglía/metabolismo , Microglía/patología , Oligodendroglía/metabolismo , Oligodendroglía/patología , Ratas , Ratas Sprague-Dawley , Receptores de Superficie Celular/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Sustancia Blanca/metabolismo , Sustancia Blanca/patología , Sustancia Blanca/fisiopatologíaRESUMEN
Abnormal cortical circuitry and function as well as distortions in the modulatory neurological processes controlling cortical plasticity have been argued to underlie the origin of autism. Here, we chemically distorted those processes using an antidepressant drug-exposure model to generate developmental neurological distortions like those characteristics expressed in autism, and then intensively trained altered young rodents to evaluate the potential for neuroplasticity-driven renormalization. We found that young rats that were injected s.c. with the antidepressant citalopram from postnatal d 1-10 displayed impaired neuronal repetition-rate following capacity in the primary auditory cortex (A1). With a focus on recovering grossly degraded auditory system processing in this model, we showed that targeted temporal processing deficits induced by early-life antidepressant exposure within the A1 were almost completely reversed through implementation of a simple behavioral training strategy (i.e., a modified go/no-go repetition-rate discrimination task). Degraded parvalbumin inhibitory GABAergic neurons and the fast inhibitory actions that they control were also renormalized by training. Importantly, antidepressant-induced degradation of serotonergic and dopaminergic neuromodulatory systems regulating cortical neuroplasticity was sharply reversed. These findings bear important implications for neuroplasticity-based therapeutics in autistic patients.
Asunto(s)
Antidepresivos de Segunda Generación/administración & dosificación , Conducta Animal , Corteza Cerebral/fisiopatología , Efectos Tardíos de la Exposición Prenatal , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificación , Animales , Femenino , Masculino , Embarazo , Ratas , Ratas Sprague-DawleyRESUMEN
Serotonin (5-hydroxytryptamine, 5-HT) has been implicated to play critical roles in early neural development. Recent reports have suggested that perinatal exposure to selective serotonin reuptake inhibitors (SSRIs) resulted in cortical network miswiring, abnormal social behavior, callosal myelin malformation, as well as oligodendrocyte (OL) pathology in rats. To gain further insight into the cellular and molecular mechanisms underlying SSRIs-induced OL and myelin abnormalities, we investigated the effect of 5-HT exposure on OL development, cell death, and myelination in cell culture models. First, we showed that 5-HT receptor 1A and 2A subtypes were expressed in OL lineages, using immunocytochemistry, Western blot, as well as intracellular Ca(2+) measurement. We then assessed the effect of serotonin exposure on the lineage development, expression of myelin proteins, cell death, and myelination, in purified OL and neuron-OL myelination cultures. For pure OL cultures, our results showed that 5-HT exposure led to disturbance of OL development, as indicated by aberrant process outgrowth and reduced myelin proteins expression. At higher doses, such exposure triggered a development-dependent cell death, as immature OLs exhibited increasing susceptibility to 5-HT treatment compared to OL progenitor cells (OPC). We showed further that 5-HT-induced immature OL death was mediated at least partially via 5-HT2A receptor, since cell death could be mimicked by 5-HT2A receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane hydrochloride, (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride, but atten-uated by pre-treatment with 5-HT2A receptor antagonist ritanserin. Utilizing a neuron-OL myelination co-culture model, our data showed that 5-HT exposure significantly reduced the number of myelinated internodes. In contrast to cell injury observed in pure OL cultures, 5-HT exposure did not lead to OL death or reduced OL density in neuron-OL co-cultures. However, abnormal patterns of contactin-associated protein (Caspr) clustering were observed at the sites of Node of Ranvier, suggesting that 5-HT exposure may affect other axon-derived factors for myelination. In summary, this is the first study to demonstrate that manipulation of serotonin levels affects OL development and myelination, which may contribute to altered neural connectivity noted in SSRIs-treated animals. The current in vitro study demonstrated that exposure to high level of serotonin (5-HT) led to aberrant oligodendrocyte (OL) development, cell injury, and myelination deficit. We propose that elevated extracellular serotonin levels in the fetal brain, such as upon the use of selective serotonin reuptake inhibitors (SSRIs) during pregnancy, may adversely affect OL development and/or myelination, thus contributing to altered neural connectivity seen in Autism Spectrum Disorders. OPC = oligodendrocyte progenitor cell.
Asunto(s)
Linaje de la Célula/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Oligodendroglía/efectos de los fármacos , Serotonina/efectos adversos , Animales , Muerte Celular/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos , Células Madre Embrionarias/efectos de los fármacos , Femenino , Proteínas de la Mielina/genética , Proteínas de la Mielina/metabolismo , Vaina de Mielina/metabolismo , Neuronas/efectos de los fármacos , Neuronas/fisiología , Oligodendroglía/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT2A/metabolismoRESUMEN
RATIONALE: Perinatal exposure of rats to selective serotonin reuptake inhibitors (SSRIs) produces sensory and social abnormalities paralleling those seen in autistic spectrum disorders (ASDs). However, the possible mechanism(s) by which this exposure produces behavioral abnormalities is unclear. OBJECTIVE: We hypothesized that the lasting effects of neonatal SSRI exposure are a consequence of abnormal stimulation of 5-HT1A and/or 5-HT1B receptors during brain development. We examined whether such stimulation would result in lasting sensory and social deficits in rats in a manner similar to SSRIs using both direct agonist stimulation of receptors as well as selective antagonism of these receptors during SSRI exposure. METHODS: Male and female rat pups were treated from postnatal days 8 to 21. In Experiment 1, pups received citalopram (20 mg/kg/day), saline, (±)-8-hydroxy-dipropylaminotetralin hydrobromide (8-OH-DPAT; 0.5 mg/kg/day) or 7-trifluoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]-quinoxaline dimaleate (CGS-12066B; 10 mg/kg/day). In Experiment 2, a separate cohort of pups received citalopram (20 mg/kg/day), or saline which was combined with either N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-2-pyridinylcyclo-hexanecarboxamide maleate (WAY-100635; 0.6 mg/kg/day) or N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-1-1'-biphenyl-4-carboxamide (GR-127935; 6 mg/kg/day) or vehicle. Rats were then tested in paradigms designed to assess sensory and social response behaviors at different time points during development. RESULTS: Direct and indirect neonatal stimulation of 5-HT1A or 5-HT1B receptors disrupts sensory processing, produces neophobia, increases stereotypic activity, and impairs social interactions in manner analogous to that observed in ASD. CONCLUSION: Increased stimulation of 5-HT1A and 5-HT1B receptors plays a significant role in the production of lasting social and sensory deficits in adult animals exposed as neonates to SSRIs.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/crecimiento & desarrollo , Receptor de Serotonina 5-HT1A/metabolismo , Receptor de Serotonina 5-HT1B/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , 8-Hidroxi-2-(di-n-propilamino)tetralin/farmacología , Animales , Animales Recién Nacidos , Encéfalo/metabolismo , Citalopram/farmacología , Conducta Exploratoria/efectos de los fármacos , Femenino , Reacción Cataléptica de Congelación/efectos de los fármacos , Locomoción/efectos de los fármacos , Masculino , Oxadiazoles/farmacología , Piperazinas/farmacología , Piridinas/farmacología , Quinoxalinas/farmacología , Ratas , Ratas Long-Evans , Antagonistas de la Serotonina/farmacología , Agonistas de Receptores de Serotonina/farmacología , Conducta SocialRESUMEN
Manipulation of serotonin (5HT) during early development has been shown to induce long-lasting morphological changes within the raphe nuclear complex and serotonergic circuitry throughout the brain. Recent studies have demonstrated altered raphe-derived 5HT transporter (SERT) immunoreactive axonal expression in several cortical target sites after brief perinatal exposure to selective 5HT reuptake inhibitors such as citalopram (CTM). Since the serotonergic raphe nuclear complex projects to the olfactory bulb (OB) and perinatal 5HT disruption has been shown to disrupt olfactory behaviors, the goal of this study was to further investigate such developmental effects in the OB of CTM exposed animals. Male and female rat pups were exposed to CTM from postnatal day 8-21. After animals reach adulthood (>90 days), OB tissue sections were processed immunohistochemically for SERT antiserum. Our data revealed that the density of the SERT immunoreactive fibers decreased ~40% in the OB of CTM exposed male rats, but not female rats. Our findings support a broad and long-lasting change throughout most of the 5HT system, including the OB, after early manipulation of 5HT. Because dysfunction of the early 5HT system has been implicated in the etiology of neurodevelopmental disorders such as autism spectrum disorders (ASDs), these new findings may offer insight into the abnormal olfactory perception often noted in patients with ASD.
RESUMEN
The contribution of the zona incerta (ZI) of the thalamus on spike-wave discharges (SWDs) was investigated. Chronic recordings of bilateral cortices, bilateral vibrissa muscle, and unilateral ZI were performed in Long-Evans rats to examine the functional role of SWDs. Rhythmic ZI activity appeared at the beginning of SWD and was accompanied by higher-oscillation frequencies and larger spike magnitudes. Bilateral lidocaine injections into the mystacial pads led to a decreased oscillation frequency of SWDs, but the phenomenon of ZI-related spike magnitude enhancement was preserved. Moreover, 800-Hz ZI microstimulation terminates most of the SWDs and whisker twitching (WT; >80%). In contrast, 200-Hz ZI microstimulation selectively stops WTs but not SWDs. Stimulation of the thalamic ventroposteriomedial nucleus showed no obvious effect on terminating SWDs. A unilateral ZI lesion resulted in a significant reduction of 7- to 12-Hz power of both the ipsilateral cortical and contralateral vibrissae muscle activities during SWDs. Intraincertal microinfusion of muscimol showed a significant inhibition on SWDs. Our present data suggest that the ZI actively modulates the SWD magnitude and WT behavior.
Asunto(s)
Potenciales de Acción , Músculo Esquelético/fisiología , Subtálamo/fisiología , Anestésicos Locales/farmacología , Animales , Corteza Cerebral/fisiología , Estimulación Eléctrica , Agonistas de Receptores de GABA-A/farmacología , Lidocaína/farmacología , Muscimol/farmacología , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Músculo Esquelético/inervación , Ratas , Ratas Long-Evans , Vibrisas/inervación , Vibrisas/fisiologíaRESUMEN
Brain inflammation via intracerebral injection with lipopolysaccharide (LPS) in early life has been shown to increase risks for the development of neurodegenerative disorders in adult rats. To determine if neonatal systemic LPS exposure has the same effects on enhancement of adult dopaminergic neuron susceptibility to rotenone neurotoxicity as centrally injected LPS does, LPS (2 µg/g body weight) was administered intraperitoneally into postnatal day 5 (P5) rats and when grown to P70, rats were challenged with rotenone, a commonly used pesticide, through subcutaneous minipump infusion at a dose of 1.25 mg/kg/day for 14 days. Systemically administered LPS can penetrate into the neonatal rat brain and cause acute and chronic brain inflammation, as evidenced by persistent increases in IL-1ß levels, cyclooxygenase-2 expression and microglial activation in the substantia nigra (SN) of P70 rats. Neonatal LPS exposure resulted in suppression of tyrosine hydroxylase (TH) expression, but not actual death of dopaminergic neurons in the SN, as indicated by the reduced number of TH+ cells and unchanged total number of neurons (NeuN+) in the SN. Neonatal LPS exposure also caused motor function deficits, which were spontaneously recoverable by P70. A small dose of rotenone at P70 induced loss of dopaminergic neurons, as indicated by reduced numbers of both TH+ and NeuN+ cells in the SN, and Parkinson's disease (PD)-like motor impairment in P98 rats that had experienced neonatal LPS exposure, but not in those without the LPS exposure. These results indicate that although neonatal systemic LPS exposure may not necessarily lead to death of dopaminergic neurons in the SN, such an exposure could cause persistent functional alterations in the dopaminergic system and indirectly predispose the nigrostriatal system in the adult brain to be damaged by environmental toxins at an ordinarily nontoxic or subtoxic dose and develop PD-like pathological features and motor dysfunction.
Asunto(s)
Encéfalo/patología , Neuronas Dopaminérgicas/patología , Inflamación/complicaciones , Lipopolisacáridos/toxicidad , Rotenona/toxicidad , Animales , Animales Recién Nacidos , Conducta Animal/efectos de los fármacos , Western Blotting , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Recuento de Células , Neuronas Dopaminérgicas/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Inmunohistoquímica , Inflamación/inducido químicamente , Inflamación/metabolismo , Masculino , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/patología , Síndromes de Neurotoxicidad/fisiopatología , Ratas , Ratas Sprague-Dawley , Desacopladores/toxicidadRESUMEN
Oligodendrocyte (OL) development relies on many extracellular cues, most of which are secreted cytokines from neighboring neural cells. Although it is generally accepted that both astrocytes and microglia are beneficial for OL development, there is a lack of understanding regarding whether astrocytes and microglia play similar or distinct roles. The current study examined the effects of astrocytes and microglia on OL developmental phenotypes including cell survival, proliferation, differentiation, and myelination in vitro. Our data reveal that, although both astrocytes- and microglia-conditioned medium (ACDM and MCDM, respectively) protect OL progenitor cells (OPCs) against growth factor withdrawal-induced apoptosis, ACDM is significantly more effective than MCDM in supporting long-term OL survival. In contrast, MCDM preferentially promotes OL differentiation and myelination. These differential effects of ACDM and MCDM on OL development are highlighted by distinct pattern of cytokine/growth factors in the conditioned medium, which correlates with differentially activated intracellular signaling pathways in OPCs upon exposure to the conditioned medium.
RESUMEN
Converging lines of evidence show that a sizable subset of autism-spectrum disorders (ASDs) is characterized by increased blood levels of serotonin (5-hydroxytryptamine, 5-HT), yet the mechanistic link between these two phenomena remains unclear. The enzymatic degradation of brain 5-HT is mainly mediated by monoamine oxidase (MAO)A and, in the absence of this enzyme, by its cognate isoenzyme MAOB. MAOA and A/B knockout (KO) mice display high 5-HT levels, particularly during early developmental stages. Here we show that both mutant lines exhibit numerous behavioural hallmarks of ASDs, such as social and communication impairments, perseverative and stereotypical responses, behavioural inflexibility, as well as subtle tactile and motor deficits. Furthermore, both MAOA and A/B KO mice displayed neuropathological alterations reminiscent of typical ASD features, including reduced thickness of the corpus callosum, increased dendritic arborization of pyramidal neurons in the prefrontal cortex and disrupted microarchitecture of the cerebellum. The severity of repetitive responses and neuropathological aberrances was generally greater in MAOA/B KO animals. These findings suggest that the neurochemical imbalances induced by MAOA deficiency (either by itself or in conjunction with lack of MAOB) may result in an array of abnormalities similar to those observed in ASDs. Thus, MAOA and A/B KO mice may afford valuable models to help elucidate the neurobiological bases of these disorders and related neurodevelopmental problems.
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Trastorno Autístico/enzimología , Relaciones Interpersonales , Aprendizaje por Laberinto/fisiología , Monoaminooxidasa/deficiencia , Actividad Motora/fisiología , Animales , Trastorno Autístico/genética , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Noqueados , Monoaminooxidasa/genética , Actividad Motora/genética , Vocalización Animal/fisiologíaRESUMEN
Monoamine oxidase A (MAO-A) is the key enzyme for the degradation of brain serotonin (5-hydroxytryptamine, 5-HT), norepinephrine (NE) and dopamine (DA). We recently generated and characterized a novel line of MAO-A hypormorphic mice (MAO-A(Neo)), featuring elevated monoamine levels, social deficits and perseverative behaviors as well as morphological changes in the basolateral amygdala and orbitofrontal cortex. Here we showed that MAO-A(Neo) mice displayed deficits in motor control, manifested as subtle disturbances in gait, motor coordination, and balance. Furthermore, magnetic resonance imaging of the cerebellum revealed morphological changes and a moderate reduction in the cerebellar size of MAO-A(Neo) mice compared to wild type (WT) mice. Histological and immunohistochemical analyses using calbindin-D-28k (CB) expression of Purkinje cells revealed abnormal cerebellar foliation with vermal hypoplasia and decreased in Purkinje cell count and their dendritic density in MAO-A(Neo) mice compared to WT. Our current findings suggest that congenitally low MAO-A activity leads to abnormal development of the cerebellum.
Asunto(s)
Cerebelo/fisiología , Marcha/fisiología , Monoaminooxidasa/genética , Actividad Motora/fisiología , Animales , Calbindinas , Recuento de Células , Cerebelo/metabolismo , Dendritas/metabolismo , Dendritas/fisiología , Ratones , Ratones Transgénicos , Monoaminooxidasa/metabolismo , Células de Purkinje/metabolismo , Células de Purkinje/fisiología , Prueba de Desempeño de Rotación con Aceleración Constante , Proteína G de Unión al Calcio S100/metabolismoRESUMEN
Locus coeruleus (LC) consists of a densely packed nuclear core and a surrounding plexus of dendritic zone, which is further divided into several subregions. Whereas many limbic-related structures topographically target specific subregions of the LC, the precise projections from two limbic areas, that is, medial prefrontal cortex (mPFC) and dorsal raphe (DR), have not been investigated. The goal of the present study is to identify and compare the distribution patterns of mPFC and DR afferent terminals to the LC nuclear core as opposed to specific pericoerulear dendritic regions (Peri-LC). To address these issues, anterograde tracer injections were combined with dopamine-ß-hydroxylase (DBH) immunofluorescent staining to reveal the distribution patterns around the LC nuclear complex. Our data suggest that both mPFC-LC and DR-LC projections exhibit selective afferent terminal patterns. More specifically, mPFC-LC projecting fibers mainly target the rostromedial Peri-LC, whereas DR-LC projecting fibers demonstrate a preference to the caudal juxtaependymal Peri-LC. Thus, our present findings provide further evidences that afferents to the LC are topographically organized. Understanding the relationship among different inputs to the LC may help to elucidate the organizing principle which likely governs the interactions between the broad afferent sources of the LC and its global efferent targets.
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Vías Aferentes/fisiología , Locus Coeruleus/fisiología , Vías Nerviosas/fisiología , Neuronas/fisiología , Corteza Prefrontal/fisiología , Núcleos del Rafe/fisiología , Vías Aferentes/anatomía & histología , Animales , Dopamina beta-Hidroxilasa/metabolismo , Técnica del Anticuerpo Fluorescente , Locus Coeruleus/anatomía & histología , Masculino , Vías Nerviosas/anatomía & histología , Neuronas/citología , Corteza Prefrontal/anatomía & histología , Núcleos del Rafe/anatomía & histología , Ratas , Ratas Long-EvansRESUMEN
An in vitro myelination model derived from rat central nervous system (CNS) remains to be established. Here, we describe a simple and reproducible myelination culture method using dissociated neuron-oligodendrocyte (OL) co-cultures from either the embryonic day 16 (E16) rat spinal cord or cerebral cortex. The dissociated cells are plated directly on poly-L-lysine-coated cover slips and maintained in a modified myelination medium that supports both OL and neuron differentiation. The spinal cord derived OL progenitor cells develop quickly into myelin basic protein (MBP)+ mature OLs and start to myelinate axons around 17 days in vitro (DIV17). Myelination reaches its peak around six weeks (DIV40) and the typical nodes of Ranvier are revealed by paranodal proteins Caspr and juxaparanodal protein Kv1.2 immunoreactivity. Electron microscopy (EM) shows typical myelination cytoarchitecture and synaptic organization. In contrast, the cortical-derived co-culture requires triiodothyronine (T3) in the culture medium for myelination. Finally, either hypomyelination and/or demyelination can be induced by exposing proinflammatory cytokines or demyelinating agents to the co-culture, suggesting the feasibility of this modified in vitro myelination model for myelin-deficit investigation.
RESUMEN
Neonatal exposure to antidepressants produces lasting impairments in male sexual behavior. Although perturbation of the serotonin system during neonatal life has been implicated in the long-term behavioral effects of neonatal antidepressant exposure, dose-response studies were necessary to confirm that inhibition of the serotonin transporter during the neonatal period is sufficient to produce impairments in sexual behavior. Therefore, the present study examined the dose-response effects of neonatal citalopram exposure on sexual behavior. In addition, the effects of exposure on anxiety-related behavior were examined since alterations in this behavioral measure could affect sexual behavior. Male Long-Evans rats were injected subcutaneously with citalopram (CTM) in one of three doses (5, 10 or 20mg/kg/d), or saline (SAL) in a volume of 0.1 ml twice daily (07:00 and 14:00 h) from PD8 to PD21. The rats were tested as adults (>PD90) for anxiety-like behavior and exploration in the elevated plus maze test and sexual behavior. Neonatal citalopram exposure produced persistent reductions in male sexual behavior characterized by significant dose-dependent reductions in the percentage of male rats displaying mounting as well as dose-dependent reductions in the number of mounts and mount latency. Neonatal citalopram exposure also produced significant dose-dependent linear trends for reductions in intromission and ejaculation behavior. However, neonatal SSRI exposure was not found to produce any effects on exploration or anxiety-like behavior in the elevated plus maze test. The present findings support the hypothesis that inhibition of the serotonin transporter during neonatal life by an SSRI is directly responsible for the long-term effects on male sexual behavior.
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Citalopram/toxicidad , Inhibidores Selectivos de la Recaptación de Serotonina/toxicidad , Conducta Sexual Animal/efectos de los fármacos , Animales , Animales Recién Nacidos , Citalopram/administración & dosificación , Relación Dosis-Respuesta a Droga , Aprendizaje por Laberinto/efectos de los fármacos , Ratas , Ratas Long-Evans , Inhibidores Selectivos de la Recaptación de Serotonina/administración & dosificaciónRESUMEN
Selective serotonin reuptake inhibitors (SSRIs), such as citalopram (CTM), have been widely prescribed for major depressive disorder, not only for adult populations, but also for children and pregnant mothers. Recent evidence suggests that chronic SSRI exposure in adults increases serotonin (5-HT) levels in the raphe system and decreases norepinephrine (NE) locus ceruleus (LC) neural activity, suggesting a robust opposing interaction between these two monoamines. In contrast, perinatal SSRI exposure induces a long-lasting downregulation of the 5-HT-raphe system, which is opposite to that seen with chronic adult treatment. Therefore, the goal of the present investigation was to test the hypothesis that perinatal CTM exposure (20 mg/kg/d) from postnatal day 1 (PN1) to PN10 leads to hyperexcited NE-LC circuit function in adult rats (>PN90). Our single-neuron LC electrophysiological data demonstrated an increase in spontaneous and stimulus-driven neural activity, including an increase in phasic bursts in CTM-exposed animals. In addition, we demonstrated a corresponding immunoreactive increase in the rate-limiting catalyzing catecholamine enzyme (tyrosine hydroxylase) within the LC and their neocortical target sites compared to saline controls. Moreover, these effects were only evident in male exposed rats, suggesting a sexual dimorphism in neural development after SSRI exposure. Together, these results indicate that administration of SSRIs during a sensitive period of brain development results in long-lasting alterations in NE-LC circuit function in adults and may be useful in understanding the etiology of pervasive developmental disorders such as autism spectrum disorder.
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Citalopram/farmacología , Locus Coeruleus , Neuronas/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Animales Recién Nacidos , Dopamina beta-Hidroxilasa/metabolismo , Femenino , Locus Coeruleus/citología , Locus Coeruleus/embriología , Locus Coeruleus/crecimiento & desarrollo , Masculino , Fibras Nerviosas/metabolismo , Red Nerviosa/efectos de los fármacos , Red Nerviosa/metabolismo , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Estimulación Física/efectos adversos , Embarazo , Ratas , Ratas Long-Evans , Cola (estructura animal)/inervación , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Serotonin (5-HT) plays a key role in early brain development, and manipulation of 5-HT levels during this period can have lasting neurobiological and behavioral consequences. It is unclear how perinatal exposure to drugs, such as selective serotonin reuptake inhibitors (SSRIs), impacts cortical neural network function and what mechanism(s) may elicit the disruption of normal neuronal connections/interactions. In this article, we report on cortical wiring organization after pre- and postnatal exposure to the SSRI citalopram. We show that manipulation of 5-HT during early development in both in vitro and in vivo models disturbs characteristic chemoarchitectural and electrophysiological brain features, including changes in raphe and callosal connections, sensory processing, and myelin sheath formation. Also, drug-exposed rat pups exhibit neophobia and disrupted juvenile play behavior. These findings indicate that 5-HT homeostasis is required for proper brain maturation and that fetal/infant exposure to SSRIs should be examined in humans, particularly those with developmental dysfunction, such as autism.
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Antidepresivos de Segunda Generación/farmacología , Corteza Cerebral/efectos de los fármacos , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Animales , Trastorno Autístico/fisiopatología , Conducta Animal , Corteza Cerebral/metabolismo , Corteza Cerebral/fisiología , Femenino , Homeostasis , Inmunohistoquímica , Masculino , Ratas , Serotonina/metabolismoRESUMEN
In rodents, noradrenergic (NE) locus coeruleus (LC) neurons are well known to express tyrosine hydroxylase (TH) immunoreactivity. However, due to its very low enzyme activity, NE cortical fibers do not typically express TH immunoreactivity, thus dopamine-ß-hydroxylase (DBH) immunoreactivity is commonly utilized as a marker for NE cortical fibers. In this study, we performed double and/or triple immunofluorescent staining using antibodies against TH, DBH, and/or norepinephrine transporter (NET) to investigate the altered NE TH expression of cortical fibers in citalopram (CTM)-exposed rats and monoamine oxidase (MAO) A knock out (KO) mice. We have noted the following novel findings: (1) neonatal exposure to the selective serotonin reuptake inhibitor (SSRI) CTM enhanced NE TH immunoreactive fibers throughout the entire neocortex, and a few of them appeared to be hypertrophic; (2) slightly enhanced NE cortical TH immunoreactive fibers were also noted in MAO A KO mice, and many of them revealed varicosities compared with the rather smooth NE cortical TH immunoreactive fibers in wild-type (WT) mice; (3) LC dendrites of MAO A KO mice exhibited beaded morphology compared with the smooth LC dendrites in WT mice. Our findings suggest that both genetic and environmental factors during early development may play a critical role in the regulation and proper function of NE TH expression in the neocortex.
Asunto(s)
Citalopram/farmacología , Locus Coeruleus/metabolismo , Monoaminooxidasa/fisiología , Neuronas/metabolismo , Norepinefrina/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Animales , Animales Recién Nacidos , Dopamina beta-Hidroxilasa/metabolismo , Femenino , Técnicas para Inmunoenzimas , Locus Coeruleus/efectos de los fármacos , Locus Coeruleus/patología , Ratones , Ratones Noqueados , Neuronas/efectos de los fármacos , Neuronas/patología , Proteínas de Transporte de Noradrenalina a través de la Membrana Plasmática/metabolismo , Ratas , Ratas Long-Evans , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
We have demonstrated that neonatal exposure to selective serotonin reuptake inhibitors has lasting effects on behavior and serotonergic neurons in Long Evans rats. Hyperserotoninemia and altered sensory processing are reported in autistic spectrum disorders (ASD). We hypothesized that early life exposure to SSRIs alters sensory processing, disrupts responses to novelty, and impairs social interactions in a manner similar to that observed in ASD. Male and female Long-Evans rat pups were administered citalopram, buproprion, fluoxetine, or saline from postnatal day (P) 8-21. Rats were tested for response to a novel tone before weaning (P25). Later, rats were tested 2× for response to a novel object (P39), and to a novel conspecific (P78, P101). In addition, rats were assessed for juvenile play behaviors (P32-P34) and later, we assessed sexual response to an estrus female in male rats (P153-184). Antidepressant exposure increased freezing after tone, diminished novel object exploration, and reduced conspecific interaction up to 3× compared to saline exposed rats. Juvenile play was profoundly reduced in antidepressant-exposed males when compared to saline exposed groups. Exposure to the SSRIs, but not bupropion disrupted male sexual behaviors. Moreover, specific male responses to female proceptive behaviors were disrupted in SSRI, but not bupropion exposed rats. We conclude that neonatal exposure to antidepressants in rats results in sensory and social abnormalities that parallel many of those reported in ASD.
Asunto(s)
Antidepresivos/farmacología , Conducta Animal/efectos de los fármacos , Trastornos Generalizados del Desarrollo Infantil/fisiopatología , Conducta Social , Animales , Animales Recién Nacidos , Niño , Femenino , Humanos , Locomoción/efectos de los fármacos , Masculino , Embarazo , Ratas , Ratas Long-Evans , Serotonina/metabolismo , Inhibidores Selectivos de la Recaptación de Serotonina/farmacologíaRESUMEN
Brain inflammation in early life has been proposed to play important roles in the development of neurodegenerative disorders in adult life. To test this hypothesis, we used a neonatal rat model of lipopolysaccharide (LPS) exposure (1000 EU/g body weight, intracerebral injection on P5) to produce brain inflammation. By P70, when LPS-induced behavioral deficits were spontaneously recovered, animals were challenged with rotenone, a commonly used pesticide, through subcutaneous mini-pump infusion at a dose of 1.25 mg/kg per day for 14 days. This rotenone treatment regimen ordinarily does not produce toxic effects on behaviors in normal adult rats. Our results show that neonatal LPS exposure enhanced the vulnerability of nigrostriatal dopaminergic neurons to rotenone neurotoxicity in later life. Rotenone treatment resulted in motor neurobehavioral impairments in rats with the neonatal LPS exposure, but not in those without the neonatal LPS exposure. Rotenone induced losses of tyrosine hydroxylase immunoreactive neurons in the substantia nigra and decreased mitochondrial complex I activity in the striatum of rats with neonatal LPS exposure, but not in those without this exposure. Neonatal LPS exposure with later exposure to rotenone decreased retrogradely labeled nigrostriatal dopaminergic projecting neurons. The current study suggests that perinatal brain inflammation may enhance adult susceptibility to the development of neurodegenerative disorders triggered later on by environmental toxins at an ordinarily non-toxic or sub-toxic dose. Our model may be useful for studying mechanisms involved in the pathogenesis of nonfamilial Parkinson's disease and the development of potential therapeutic treatments.
Asunto(s)
Neuronas Dopaminérgicas/efectos de los fármacos , Insecticidas/toxicidad , Lipopolisacáridos/farmacología , Rotenona/toxicidad , Sustancia Negra/citología , Factores de Edad , Animales , Animales Recién Nacidos , Peso Corporal/efectos de los fármacos , Antígeno CD11b/metabolismo , Proteínas de Unión al Calcio/metabolismo , Neuronas Dopaminérgicas/ultraestructura , Sinergismo Farmacológico , Complejo I de Transporte de Electrón/metabolismo , Femenino , Infusiones Subcutáneas/métodos , Masculino , Proteínas de Microfilamentos/metabolismo , Microscopía Electrónica de Transmisión , Actividad Motora/efectos de los fármacos , Movimiento/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Embarazo , Desempeño Psicomotor/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Conducta Estereotipada/efectos de los fármacos , Vibrisas/inervaciónRESUMEN
The serotonin (5HT) system of the brain is involved in many CNS functions including sensory perception, stress responses and psychological disorders such as anxiety and depression. Of the nine 5HT nuclei located in the mammalian brain, the dorsal raphe nucleus (DRN) has the most extensive forebrain connectivity and is implicated in the manifestation of stress-related psychological disturbances. Initial investigations of DRN efferent connections failed to acknowledge the rostrocaudal and mediolateral organization of the nucleus or its neurochemical heterogeneity. More recent studies have focused on the non-5HT contingent of DRN cells and have revealed an intrinsic intranuclear organization of the DRN which has specific implications for sensory signal processing and stress responses. Of particular interest are spatially segregated subsets of nitric oxide producing neurons that are activated by stressors and that have unique efferent projection fields. In this regard, both the midline and lateral wing subregions of the DRN have emerged as prominent loci for future investigation of nitric oxide function and modulation of sensory- and stressor-related signals in the DRN and coinciding terminal fields.