RESUMO
During prenatal life, exposure to synthetic glucocorticoids (SGCs) can alter normal foetal development, resulting in disease later in life. Previously, we have shown alterations in the dendritic cytoarchitecture of Purkinje cells in adolescent rat progeny prenatally exposed to glucocorticoids. However, the molecular mechanisms underlying these alterations remain unclear. A possible molecular candidate whose deregulation may underlie these changes is the glucocorticoid receptor (GR) and neurotrophin 3/ tropomyosin receptor kinase C, neurotrophic complex (NT-3/TrkC), which specifically modulates the development of the neuronal connections in the cerebellar vermis. To date, no evidence has shown that the cerebellar expression levels of this neurotrophic complex are affected by exposure to a synthetic glucocorticoid in utero. Therefore, the first objective of this investigation was to evaluate the expression of GR, NT-3 and TrkC in the cerebellar vermis using immunohistochemistry and western blot techniques by evaluating the progeny during the postnatal stage equivalent to adolescence (postnatal Day 52). Additionally, we evaluated anxiety-like behaviours in progeny using the elevated plus maze and the marble burying test. In addition, an environmental enrichment (EE) can increase the expression of some neurotrophins and has anxiolytic power. Therefore, we wanted to assess whether an EE reversed the long-term alterations induced by prenatal betamethasone exposure. The major findings of this study were as follows: i) prenatal betamethasone (BET) administration decreases GR, NT-3 and TrkC expression in the cerebellar vermis ii) prenatal BET administration decreases GR expression in the cerebellar hemispheres and iii) enhances the anxiety-like behaviours in the same progeny, and iv) exposure to an EE reverses the reduced expression of GR, NT-3 and TrkC in the cerebellar vermis and v) decreases anxiety-like behaviours. In conclusion, an enriched environment applied 18 days post-weaning was able to restabilize GR, NT-3 and TrkC expression levels and reverse anxious behaviours observed in adolescent rats prenatally exposed to betamethasone.
RESUMO
Previous animal studies have indicated that excessive prenatal circulating glucocorticoid (GC) levels induced by the antenatal administration of synthetic GC (sGC) significantly alter neuronal development in the cerebellar and hippocampal neurons of the offspring. However, it is unknown whether antenatal sGC administration results in long-term neocortical pyramidal cell impairment. In the current study, we examined whether an equivalent therapeutic dose of antenatal betamethasone phosphate (BET) in pregnant rats alters the Golgi-stained basilar dendritic length and histochemical expression of dendritic microtubule-associated protein 2 (MAP2) of neocortical pyramidal cells in infant, adolescent, and young adult offspring. The results obtained showed that in utero BET exposure resulted in a significant reduction in the basilar dendritic length per neuron and a transient reduction in histochemical MAP2 immunoreactivity. Consistent with previous hippocampal and cerebellar data, the present findings suggest that prenatal BET administration alters the dendritic growth of cerebrocortical pyramidal cells.
RESUMO
BACKGROUND: Prenatal stress (PS) in experimental animals causes long-lasting changes in Purkinje cell dendritic morphology. Furthermore, these structural changes are associated with an increase in anxiogenic behaviors in the elevated plus maze (EPM) and open-field (OF) test. OBJECTIVES: As environmental enrichment (EE) has significant restorative effects on brain neurons and behavior, the aim of this study was to evaluate if postweaning EE mitigates the decrease in Purkinje cell dendritic expansion and exploratory behavior induced by PS in mice. MATERIALS AND METHODS: Restraint stress was induced from gestational day 14 (G14) to G21. Approximately 50% of the PS animals were submitted to the EE paradigm between postnatal days 22 (P22) and P52. At P52 and P82, male animals were behaviorally evaluated, and then the morphology of the cerebellar vermal Purkinje cells was analyzed. RESULTS: We found that EE significantly ameliorates the Purkinje cell dendritic atrophy and anxiety-like behavior in the EPM. CONCLUSION: Our data show that long-lasting Purkinje cell dendritic impairments and anxiety-like behavior can be mitigated by postweaning EE.
Assuntos
Encéfalo/patologia , Dendritos/patologia , Meio Ambiente , Efeitos Tardios da Exposição Pré-Natal/psicologia , Células de Purkinje/patologia , Estresse Psicológico/enfermagem , Estresse Psicológico/patologia , Fatores Etários , Animais , Animais Recém-Nascidos , Atrofia/patologia , Dendritos/ultraestrutura , Comportamento Exploratório/fisiologia , Feminino , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Gravidez , Coloração pela Prata , Estatísticas não Paramétricas , Estresse Psicológico/fisiopatologiaRESUMO
BACKGROUND: Preterm babies treated with synthetic glucocorticoids (sGC) in utero exhibit behavioral alterations and disturbances in brain maturation during infancy. However, the effects on dentate granule cell morphology and spatial memory in rats that were given clinically equivalent doses of antenatal betamethasone remain unclear. METHODS: Pregnant rats were randomly divided into the following two experimental groups: control (CON) and betamethasone-treated (BET) groups. At gestational day 20 (G20), BET dams were subcutaneously injected with a 0.17 mg/kg betamethasone solution, and CON animals received a similar volume of saline. At postnatal days 22 (P22) and P52, BET and CON offsprings were behaviorally evaluated in the Y-Maze test, and the dentate gyrus granular neurons were histologically analyzed. RESULTS: Animals prenatally treated with a single course of betamethasone exhibit a significant decrement in the dendritic outgrowth of dentate granule cells along with impaired spatial memory when evaluated at P52. Moreover, the body and brain weight of the BET group was significantly lower than the CON group at P0, P22, and P52. CONCLUSION: The current results indicate that a single course of betamethasone in pregnant rats produces significant neuronal and behavioral impairments of the offspring at adolescence along with a decrement in somatic and brain weights at each of the three ages evaluated.
Assuntos
Betametasona/toxicidade , Dendritos/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Efeitos Tardios da Exposição Pré-Natal , Memória Espacial/efeitos dos fármacos , Animais , Betametasona/administração & dosagem , Giro Denteado/crescimento & desenvolvimento , Giro Denteado/patologia , Feminino , Neurônios/patologia , Gravidez , RatosRESUMO
Clinical and preclinical studies have demonstrated that prenatal stress (PS) induces neuronal and behavioral disturbances in the offspring. In the present study, we determined whether maternal voluntary wheel running (VWR) during pregnancy could reverse the putative deleterious effects of PS on the neurodevelopment and behavior of the offspring. Pregnant CF-1 mice were randomly assigned to control, restraint stressed or restraint stressed+VWR groups. Dams of the stressed group were subjected to restraint stress between gestational days 14 and delivery, while control pregnant dams remained undisturbed in their home cages. Dams of the restraint stressed+VWR group were subjected to exercise between gestational days 1 and 17. On postnatal day 23 (P23), male pups were assigned to one of the following experimental groups: mice born from control dams, stressed dams or stressed+VWR dams. Locomotor behavior and pyramidal neuronal morphology were evaluated at P23. Animals were then sacrificed, and Golgi-impregnated pyramidal neurons of the parietal cortex were morphometrically analyzed. Here, we present two major findings: first, PS produced significantly diminished dendritic growth of parietal neurons without altered locomotor behavior of the offspring; and second, maternal VWR significantly offset morphological impairments.
Assuntos
Comportamento Animal , Condicionamento Físico Animal/métodos , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Células Piramidais/patologia , Estresse Psicológico/prevenção & controle , Estresse Psicológico/fisiopatologia , Animais , Feminino , Masculino , Camundongos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologia , Restrição Física , Estresse Psicológico/patologiaRESUMO
Preclinical studies indicate that selegiline (deprenyl), frequently used in some neurodegenerative diseases, exert protective effects on central nervous system neurons of individuals exposed to social isolation (SI). Furthermore, it has been suggested that SI produces neuronal dysfunction due in part to an excessive intracellular Ca(2+) overload. Since the main intracellular Ca(2+) buffering mechanism involves changes in the calcium-binding protein calbindin-D28k (CB), and that CB neuronal expression can increase in response to Ca(2+) transients, we hypothesized that chronic selegiline administration in early socially isolated animals could minimize cell CB expression as an indirect indicator of protective mechanism against Ca(2+) overload. In the present study male rats were weaned at postnatal day 21 (P21) and randomly assigned to social deprivation (SI) or control (SC) environments for 30 days (P21-51). SI animals were further subdivided in two experimental groups: socially deprived-saline (SI-SAL) and socially isolated-selegiline (SI-SEL) for additional 30 days (P52-82). Medial frontal CB immunoreactivity (CB-ir) neurons were quantitatively and qualitatively analyzed. The results obtained indicate that neocortical cells of adult rats submitted to early SI show a significant increase in the number of CB-ir neurons per cortical field, while selegiline treatment significantly reduces this parameter.
Assuntos
Cálcio/metabolismo , Córtex Cerebral/metabolismo , Neurônios/metabolismo , Proteína G de Ligação ao Cálcio S100/metabolismo , Selegilina/farmacologia , Isolamento Social , Desmame , Animais , Calbindina 1 , Calbindinas , Córtex Cerebral/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Masculino , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Several clinical studies have shown that abusing volatile solvents, mainly toluene, produces neurological, neuropathological and neuropsychiatric disorders. Symptoms of these disorders include loss in impulse control, distractibility and memory deficits, which are associated with mild brain atrophy. The entorhinal cortex is critically involved in mnemonic processes, and memory disorders are the major symptom detected in chronic solvent abusers. Therefore, in the present study, we evaluated (1) whether the entorhinal neuronal morphology was impaired by subchronic toluene exposure and (2) if melatonin protected the neuronal cytoarchitecture, as has been demonstrated in neocortical neurons. Consistent with our previous findings, the present study indicates that the entorhinal cell dendritic arborization was significantly reduced in toluene exposed animals, and melatonin administration significantly rescued the reduced dendritic branching induced by toluene neurotoxicity.
Assuntos
Dendritos/efeitos dos fármacos , Córtex Entorrinal/efeitos dos fármacos , Melatonina/farmacologia , Tolueno/toxicidade , Administração por Inalação , Animais , Dendritos/patologia , Córtex Entorrinal/patologia , Feminino , Melatonina/uso terapêutico , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Neurônios/patologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Gravidez , Ratos , Ratos Sprague-Dawley , Tolueno/administração & dosagemRESUMO
The present study investigated the effects of toluene inhalation and the restorative effects of melatonin on branching and basal dendritic outgrowth of superficial pyramidal neurons in rat's frontal, parietal, and occipital cortices. At postnatal day 21 (P21), Sprague-Dawley male rats were randomly assigned to either an air-only group or a toluene group. From P22 to P32 the animals were exposed to either clean air or toluene vapors (5000-6000 ppm) for 10 min/day. This strategy simulated common toluene abuse in humans, which consists of 15-20 rapid inhalations of highly concentrated solvent. Once the inhalation period was over (P32), toluene exposed animals were randomly reassigned to one of following experimental groups: (i) air-control/saline; (ii) toluene/saline; (iii) toluene/melatonin 0.5mg/kg; (iv) toluene/melatonin 1.0mg/kg; (v) toluene/melatonin 5.0mg/kg; and (vi) toluene/melatonin 10mg/kg. Seven days after the last inhalation (P39), all the animals were sacrificed under deep anesthesia; brains were dissected out and stained according to the Golgi-Cox-Sholl procedure. Layer II/III pyramidal neurons were morphologically analyzed by measuring their basilar dendritic length and the number of branches. The results obtained revealed that (i) toluene inhalation significantly reduced dendritic outgrowth and branching in all cortical areas studied, and (ii) intraperitoneal administration of melatonin (0.5-10mg/kg) was able to restore the dendritic impairment induced by toluene exposure.
Assuntos
Dendritos/efeitos dos fármacos , Melatonina/farmacologia , Neocórtex/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Células Piramidais/efeitos dos fármacos , Tolueno/toxicidade , Animais , Dendritos/patologia , Feminino , Exposição por Inalação/efeitos adversos , Masculino , Melatonina/administração & dosagem , Melatonina/uso terapêutico , Neocórtex/patologia , Fármacos Neuroprotetores/administração & dosagem , Fármacos Neuroprotetores/uso terapêutico , Síndromes Neurotóxicas/etiologia , Síndromes Neurotóxicas/patologia , Síndromes Neurotóxicas/prevenção & controle , Células Piramidais/patologia , Ratos , Ratos Sprague-Dawley , DesmameRESUMO
We have previously shown that toluene inhalation produces significant impairments in the basilar dendritic outgrowth of pyramidal cortical cells. This neurotoxic effect was markedly inhibited by melatonin administration at a dose of 5mg kg(-1). The present study was designed to determine whether toluene and melatonin equally affect all basilar dendritic segments or if a differential response exists between the segments. Twenty-eight male mice were weaned at postnatal day 21 (P21) and randomly assigned to either the control (C; n=10,) or toluene (T; n=18) group. Between P22-P32, male rats were placed into a glass chamber and exposed to either toluene vapors (5-000-6000 ppm) or clean air for 10 min a day. When toluene exposure ended (P32), animals were further assigned to the following experimental groups: (a) control/saline (C/S; n=10), (b) toluene/saline (T/S; n=10), or (c) toluene/melatonin 5mg kg(-1) (T/M; n=8). Melatonin or vehicle solutions were administered daily between P32 and P38. Forty-eight hours after the final toluene exposure, the animals were sacrificed, and the pyramidal cortical cells were stained using the Golgi-Cox-Sholl procedure. The number of basilar dendritic branches/order was counted using the centrifugal ordering method. The results indicate that (i) toluene inhalation significantly impairs both proximal and distal basilar dendritic ramifications (in the parietal and frontal/occipital cortices, respectively) and (ii) melatonin both protects neurons from toluene neurotoxicity in all cortical areas studied and increases the complexity of the dendritic tree above control values.
Assuntos
Córtex Cerebral/efeitos dos fármacos , Dendritos/efeitos dos fármacos , Melatonina/farmacologia , Fármacos Neuroprotetores/farmacologia , Células Piramidais/efeitos dos fármacos , Tolueno/antagonistas & inibidores , Animais , Córtex Cerebral/patologia , Dendritos/patologia , Feminino , Masculino , Melatonina/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Neurotoxinas/antagonistas & inibidores , Neurotoxinas/toxicidade , Células Piramidais/patologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Solventes/toxicidade , Tolueno/toxicidade , VolatilizaçãoRESUMO
Solvent abuse during pregnancy may cause "fetal solvent syndrome", which is characterized by mild brain atrophy and associated with behavioral, cognitive, and emotional abnormalities. The present study investigated whether solvent inhalation during the preweaning period (P2-P21) alters the morphological maturation of frontal, parietal, and occipital cortical neurons. Twelve hours after delivery (postnatal day 0, P0), litters were cross-fostered, culled to 8 pups/dam and housed together with a dam in standard laboratory cages. Litters were randomly assigned to the "air-only" group (n=64, 8 litters) and to the "solvent-sniffer" group (n=72, 9 litters). During P2-P21, each animal was exposed daily to either organic solvent vapors (75% toluene and 18% n-hexane, a solvent mixture commonly found in glues and adhesives) or clean air. To determine the impact of early solvent inhalation on cortical neuronal differentiation, brains were stained using the Golgi-Cox-Sholl procedure to quantitatively assess neocortical pyramidal cell dendrogenesis. Preweaning, solvent-exposed animals displayed dramatic impairments in dendritic growth as well as significant reductions in brain weight and size.