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1.
Neuroimage ; 225: 117463, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33075559

RESUMO

The brain undergoes a protracted, metabolically expensive maturation process from childhood to adulthood. Therefore, it is crucial to understand how network cost is distributed among different brain systems as the brain matures. To address this issue, here we examined developmental changes in wiring cost and brain network topology using resting-state functional magnetic resonance imaging (rsfMRI) data longitudinally collected in awake rats from the juvenile age to adulthood. We found that the wiring cost increased in the vast majority of cortical connections but decreased in most subcortico-subcortical connections. Importantly, the developmental increase in wiring cost was dominantly driven by long-range cortical, but not subcortical connections, which was consistent with more pronounced increase in network integration in the cortical network. These results collectively indicate that there is a non-uniform distribution of network cost as the brain matures, and network resource is dominantly consumed for the development of the cortex, but not subcortex from the juvenile age to adulthood.


Assuntos
Encéfalo/crescimento & desenvolvimento , Vias Neurais/crescimento & desenvolvimento , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/crescimento & desenvolvimento , Animais , Encéfalo/diagnóstico por imagem , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/crescimento & desenvolvimento , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/crescimento & desenvolvimento , Neuroimagem Funcional , Globo Pálido/diagnóstico por imagem , Globo Pálido/crescimento & desenvolvimento , Hipocampo/diagnóstico por imagem , Hipocampo/crescimento & desenvolvimento , Hipotálamo/diagnóstico por imagem , Hipotálamo/crescimento & desenvolvimento , Estudos Longitudinais , Imageamento por Ressonância Magnética , Vias Neurais/diagnóstico por imagem , Ratos , Descanso , Córtex Sensório-Motor/diagnóstico por imagem , Córtex Sensório-Motor/crescimento & desenvolvimento , Tálamo/diagnóstico por imagem , Tálamo/crescimento & desenvolvimento
2.
Neuroreport ; 30(16): 1062-1067, 2019 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-31464839

RESUMO

Many studies have reported abnormalities in the volume of subcortical structures in individuals with autism spectrum disorder (ASD), and many of these change with age. However, most studies that have investigated subcortical structures were cross-sectional and did not accurately segment the subcortical structures. In this study, we used volBrain, an automatic and reliable quantitative analysis tool, and a longitudinal design to examine developmental changes in the volume of subcortical structures in ASD, and quantified the relation between subcortical volume development and clinical correlates. Nineteen individuals with ASD (16 males; age: 12.53 ± 2.34 years at baseline; interval: 2.33 years) and 14 typically developing controls (TDC; 12 males; age: 13.50 ± 1.77 years at baseline; interval: 2.31 years) underwent T1-weighted MRI at two time points. Bilaterally, hippocampus volume increased from baseline to follow-up in both ASD and TDC, with no difference between groups. Left caudate and right thalamus volume decreased in ASD, but did not change in TDC. The decreases in left caudate and right thalamus volume were related to ASD social score. Right amygdala volume was larger in ASD than in TDC at baseline but not at follow-up. These results confirm previous cross-sectional findings regarding the development of subcortical structures in ASD. The association between developmental changes in left caudate and right thalamus volume and ASD social score offers an explanation for the social deficits in ASD. Results also captured the different abnormality of amygdala volume between childhood and late adolescence.


Assuntos
Tonsila do Cerebelo/patologia , Transtorno do Espectro Autista/patologia , Hipocampo/patologia , Tálamo/patologia , Adolescente , Adulto , Tonsila do Cerebelo/crescimento & desenvolvimento , Transtorno do Espectro Autista/etiologia , Criança , Estudos Transversais , Feminino , Hipocampo/crescimento & desenvolvimento , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Lobo Temporal/crescimento & desenvolvimento , Lobo Temporal/patologia , Tálamo/crescimento & desenvolvimento
3.
Brain Res ; 1642: 461-466, 2016 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-27086974

RESUMO

Precise spatiotemporal epigenetic regulation of the genome facilitates species-typical development; sexual differentiation of the brain by gonadal hormones and sex chromosomes causes extensive epigenetic reprogramming of many cells in the body, including the brain, and may indirectly predispose males and females to different psychiatric conditions. We and others have demonstrated sex differences in DNA methylation, as well as in the enzymes that form, or 'write', this epigenetic modification. However, while a growing body of evidence suggests that DNA methylation undergoes rapid turnover and is dynamically regulated in vivo, to our knowledge no studies have been done investigating whether sex differences exist in the epigenetic 'erasers' during postnatal development. Here we report sex differences in the expression of growth arrest and DNA damage inducible factor ß (Gadd45b), but not family members α (a) or γ (g), in the neonatal and juvenile rodent amygdala.


Assuntos
Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/metabolismo , Antígenos de Diferenciação/metabolismo , Caracteres Sexuais , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Antígenos de Diferenciação/genética , Proteínas de Ciclo Celular/metabolismo , Metilação de DNA/fisiologia , Di-Hidrotestosterona/administração & dosagem , Di-Hidrotestosterona/metabolismo , Estrogênios/administração & dosagem , Estrogênios/metabolismo , Feminino , Hormônios/administração & dosagem , Hormônios/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Modelos Animais , Proteínas Nucleares/metabolismo , Regiões Promotoras Genéticas/fisiologia , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Testosterona/administração & dosagem , Testosterona/metabolismo , Proteínas GADD45
4.
JAMA Neurol ; 71(10): 1266-74, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25111045

RESUMO

IMPORTANCE: The very early postnatal period witnesses extraordinary rates of growth, but structural brain development in this period has largely not been explored longitudinally. Such assessment may be key in detecting and treating the earliest signs of neurodevelopmental disorders. OBJECTIVE: To assess structural growth trajectories and rates of change in the whole brain and regions of interest in infants during the first 3 months after birth. DESIGN, SETTING, AND PARTICIPANTS: Serial structural T1-weighted and/or T2-weighted magnetic resonance images were obtained for 211 time points from 87 healthy term-born or term-equivalent preterm-born infants, aged 2 to 90 days, between October 5, 2007, and June 12, 2013. MAIN OUTCOMES AND MEASURES: We segmented whole-brain and multiple subcortical regions of interest using a novel application of Bayesian-based methods. We modeled growth and rate of growth trajectories nonparametrically and assessed left-right asymmetries and sexual dimorphisms. RESULTS: Whole-brain volume at birth was approximately one-third of healthy elderly brain volume, and did not differ significantly between male and female infants (347 388 mm3 and 335 509 mm3, respectively, P = .12). The growth rate was approximately 1%/d, slowing to 0.4%/d by the end of the first 3 months, when the brain reached just more than half of elderly adult brain volume. Overall growth in the first 90 days was 64%. There was a significant age-by-sex effect leading to widening separation in brain sizes with age between male and female infants (with male infants growing faster than females by 200.4 mm3/d, SE = 67.2, P = .003). Longer gestation was associated with larger brain size (2215 mm3/d, SE = 284, P = 4×10-13). The expected brain size of an infant born one week earlier than average was 5% smaller than average; at 90 days it will not have caught up, being 2% smaller than average. The cerebellum grew at the highest rate, more than doubling in 90 days, and the hippocampus grew at the slowest rate, increasing by 47% in 90 days. There was left-right asymmetry in multiple regions of interest, particularly the lateral ventricles where the left was larger than the right by 462 mm3 on average (approximately 5% of lateral ventricular volume at 2 months). We calculated volume-by-age percentile plots for assessing individual development. CONCLUSIONS AND RELEVANCE: Normative trajectories for early postnatal brain structural development can be determined from magnetic resonance imaging and could be used to improve the detection of deviant maturational patterns indicative of neurodevelopmental disorders.


Assuntos
Encéfalo/crescimento & desenvolvimento , Desenvolvimento Infantil , Idade Gestacional , Tonsila do Cerebelo/crescimento & desenvolvimento , Tronco Encefálico/crescimento & desenvolvimento , Núcleo Caudado/crescimento & desenvolvimento , Cerebelo/crescimento & desenvolvimento , Estudos de Coortes , Feminino , Globo Pálido/crescimento & desenvolvimento , Hipocampo/crescimento & desenvolvimento , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Recém-Nascido , Ventrículos Laterais/crescimento & desenvolvimento , Estudos Longitudinais , Imageamento por Ressonância Magnética , Masculino , Tamanho do Órgão , Putamen/crescimento & desenvolvimento , Tálamo/crescimento & desenvolvimento
5.
Neuroimage ; 97: 236-44, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-24736182

RESUMO

The amygdala is vulnerable to stress-dependent disruptions in neural development. Animal models have shown that stress increases dendritic arborization leading to larger amygdala volumes. Human studies of early stress and amygdala volume, however, remain inconclusive. This study compared amygdala volume in adults with childhood maltreatment to that in healthy controls. Eighteen participants from a longitudinal cohort and 33 cross-sectional controls (17 M/34 F, 25.5±3.1 years) completed a structural magnetic resonance imagining scan and the Maltreatment and Abuse Chronology of Exposure scale. Random forest regression with conditional trees was used to assess relative importance of exposure to adversity at each age on amygdala, thalamic or caudate volume. Severity of exposure to adversity across age accounted for 27% of the variance in right amygdala volume. Peak sensitivity occurred at 10-11 years of age, and importance of exposure at this time was highly significant based on permutation tests (p=0.003). The regression model showed that exposure during this sensitive period resulted in steep dose-response function with maximal response to even modest levels of exposure. Subjects in the highest exposure quartile (MACE-11, range=11-54) had a 9.1% greater right amygdala volume than subjects in the lowest exposure quartile (MACE-11, ≤3.5). No associations emerged between age of exposure and volume of the left amygdala or bilateral caudate or thalamus. Severity of adversity experienced at age 10-11 contributed to larger right but not left amygdala volume in adulthood. Results provide preliminary evidence that the amygdala may have a developmental sensitive period in preadolescence.


Assuntos
Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/patologia , Maus-Tratos Infantis , Adolescente , Adulto , Fatores Etários , Núcleo Caudado/crescimento & desenvolvimento , Núcleo Caudado/patologia , Criança , Pré-Escolar , Estudos de Coortes , Estudos Transversais , Feminino , Hipocampo/crescimento & desenvolvimento , Hipocampo/patologia , Humanos , Lactente , Estudos Longitudinais , Masculino , Fatores Sexuais , Estresse Psicológico/patologia , Tálamo/crescimento & desenvolvimento , Tálamo/patologia
6.
Reproduction ; 147(4): 537-54, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24352099

RESUMO

Perinatal life is a critical window for sexually dimorphic brain organization, and profoundly influenced by steroid hormones. Exposure to endocrine-disrupting compounds may disrupt this process, resulting in compromised reproductive physiology and behavior. To test the hypothesis that neonatal bisphenol A (BPA) exposure can alter sex-specific postnatal Esr2 (Erß) expression in brain regions fundamental to sociosexual behavior, we mapped Esr2 mRNA levels in the principal nucleus of the bed nucleus of the stria terminalis (BNSTp), paraventricular nucleus (PVN), anterior portion of the medial amygdaloid nucleus (MeA), super optic nucleus, suprachiasmatic nucleus, and lateral habenula across postnatal days (PNDs) 0-19. Next, rat pups of both sexes were subcutaneously injected with 10 µg estradiol benzoate (EB), 50 µg/kg BPA (LBPA), or 50 mg/kg BPA (HBPA) over the first 3 days of life and Esr2 levels were quantified in each region of interest (ROI) on PNDs 4 and 10. EB exposure decreased Esr2 signal in most female ROIs and in the male PVN. In the BNSTp, Esr2 expression decreased in LBPA males and HBPA females on PND 10, thereby reversing the sex difference in expression. In the PVN, Esr2 mRNA levels were elevated in LBPA females, also resulting in a reversal of sexually dimorphic expression. In the MeA, BPA decreased Esr2 expression on PND 4. Collectively, these data demonstrate that region- and sex-specific Esr2 expression is vulnerable to neonatal BPA exposure in regions of the developing brain critical to sociosexual behavior in rat.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Receptor beta de Estrogênio/genética , Hipotálamo/efeitos dos fármacos , Fenóis/toxicidade , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/metabolismo , Animais , Animais Recém-Nascidos , Comportamento Animal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Estradiol/análogos & derivados , Estradiol/farmacologia , Receptor beta de Estrogênio/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Masculino , Ratos , Ratos Long-Evans , Fatores Sexuais , Comportamento Sexual Animal/efeitos dos fármacos , Comportamento Social
7.
Eur Neuropsychopharmacol ; 24(2): 290-301, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23669059

RESUMO

Peer-interactions are particularly important during adolescence and teenagers display enhanced sensitivity toward rejection by peers. Social rejection has been shown to induce alterations in pain perception in humans. However, the neurobiological consequences of adolescent social rejection have yet to be extensively characterized, and no appropriate animal model is available. Here, we propose inadequate playful interactions in adolescent rats as a novel animal model for social peer-rejection and examine potential long-term consequences into adulthood. Acute social pairing of female adolescent Wistar rats with an age-matched rat from the less playful Fischer344 strain was found to alter social play and decrease pain reactivity, indicating Fischer rats as inadequate social partners for Wistar animals. Therefore, in a second experiment, adolescent female Wistar rats were either reared with another Wistar rat (adequate social rearing; control) or with a Fischer rat (inadequate social rearing; play-deprived). Beginning on day 50, all Wistar rats were group housed with same-strain partners and tested for behavioral, neurobiological and endocrine differences in adulthood. Playful peer-interactions were decreased during adolescence in play-deprived animals, without affecting social contact behavior. Consequently, adult play-deprived rats showed decreased pain sensitivity and increased startle reactivity compared to controls, but did not differ in activity, anxiety-related behavior or social interaction. Both groups also differed in their endocrine stress-response, and expression levels of the cannabinoid CB1 receptor were increased in the thalamus, whereas FAAH levels were decreased in the amygdala. The present animal model therefore represents a novel approach to assess the long-term consequences of peer-rejection during adolescence.


Assuntos
Encéfalo/crescimento & desenvolvimento , Encéfalo/fisiologia , Percepção da Dor/fisiologia , Jogos e Brinquedos , Receptor CB1 de Canabinoide/metabolismo , Comportamento Social , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/fisiologia , Animais , Ansiedade/fisiopatologia , Corticosterona/sangue , Feminino , Temperatura Alta , Atividade Motora/fisiologia , Ratos , Ratos Endogâmicos F344 , Ratos Wistar , Reflexo de Sobressalto/fisiologia , Especificidade da Espécie , Tálamo/crescimento & desenvolvimento , Tálamo/fisiologia
8.
Neuroscience ; 258: 174-83, 2014 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-24231734

RESUMO

Social isolation during the vulnerable period of adolescence produces emotional dysregulation manifested by abnormalities in adult behaviors that require emotional processing. The affected brain regions may include the basolateral amygdala (BLA), where plasticity of glutamatergic synapses in principal neurons plays a role in conditioned emotional responses. This plasticity is dependent on NMDA receptor trafficking denoted by intracellular mobilization of the obligatory NR1 NMDA subunit. We tested the hypothesis that the psychosocial stress of adolescent social isolation (ASI) produces a lasting change in NMDA receptor distribution in principal neurons in the BLA of adults that express maladaptive emotional responses to sensory cues. For this, we used behavioral testing and dual electron microscopic immunolabeling of NR1 and calcium calmodulin-dependent protein kinase II (CaMKII), a protein predominantly expressed in principal neurons of the BLA in adult C57Bl/6 mice housed in isolation or in social groups from post-weaning day 22 until adulthood (∼3 months of age). The isolates showed persistent deficits in sensorimotor gating evidenced by altered prepulse inhibition (PPI) of acoustic startle and hyperlocomotor activity in a novel environment. Immunogold-silver labeling for NR1 alone or together with CaMKII was seen in many somatodendritic profiles in the BLA of all mice irrespective of rearing conditions. However, isolates compared with group-reared mice had a significantly lower cytoplasmic (4.72 ± 0.517 vs 6.31 ± 0.517) and higher plasmalemmal (0.397 ± 0.0779 vs 0.216 ± 0.026) density of NR1 immunogold particles in CaMKII-containing dendritic spines. There was no rearing-dependent difference in the size or number of these spines or those of other dendritic profiles within the neuropil, which also failed to show an impact of ASI on NR1 immunogold labeling. These results provide the first evidence that ASI enhances the surface trafficking of NMDA receptors in dendritic spines of principal neurons in the BLA of adult mice showing maladaptive behaviors that are consistent with emotional dysregulation.


Assuntos
Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/fisiologia , Espinhas Dendríticas/metabolismo , Neurônios/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Isolamento Social , Estimulação Acústica , Tonsila do Cerebelo/ultraestrutura , Animais , Ansiedade , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Citoplasma/metabolismo , Citoplasma/ultraestrutura , Dendritos/metabolismo , Dendritos/ultraestrutura , Espinhas Dendríticas/ultraestrutura , Abrigo para Animais , Técnicas Imunoenzimáticas , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Microscopia Eletrônica , Atividade Motora , Neurônios/ultraestrutura , Filtro Sensorial
9.
J Neurosci ; 33(34): 13600-11, 2013 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-23966683

RESUMO

Animal and clinical studies show that gestational exposure to nicotine increases the propensity of offspring to consume nicotine, but the precise mechanism mediating this behavioral phenomenon is unclear. The present study in Sprague Dawley rats examined the possibility that the orexigenic peptide systems, enkephalin (ENK) and orexin (OX), which are stimulated by nicotine in adult animals and promote consummatory behavior, may be similarly responsive to nicotine's stimulatory effect in utero while having long-term behavioral consequences. The results demonstrated that nicotine exposure during gestation at low doses (0.75 or 1.5 mg/kg/d) significantly increased mRNA levels and density of neurons that express ENK in the hypothalamic paraventricular nucleus and central nucleus of the amygdala, OX, and another orexigenic peptide, melanin-concentrating hormone, in the perifornical lateral hypothalamus in preweanling offspring. These effects persisted in the absence of nicotine, at least until puberty. Colabeling of the cell proliferation marker BrdU with the neuronal marker NeuN and peptides revealed a marked stimulatory effect of prenatal nicotine on neurogenesis, but not gliogenesis, and also on the number of newly generated neurons expressing ENK, OX, or melanin-concentrating hormone. During adolescence, offspring also exhibited significant behavioral changes, increased consumption of nicotine and other substances of abuse, ethanol and a fat-rich diet, with no changes in chow and water intake or body weight. These findings reveal a marked sensitivity during gestation of the orexigenic peptide neurons to low nicotine doses that may increase the offspring's propensity to overconsume substances of abuse during adolescence.


Assuntos
Tonsila do Cerebelo/citologia , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hipotálamo/citologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Neurogênese/efeitos dos fármacos , Neuropeptídeos/metabolismo , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Fatores Etários , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/metabolismo , Animais , Animais Recém-Nascidos , Bromodesoxiuridina/metabolismo , Encefalinas/genética , Encefalinas/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Hormônios Hipotalâmicos/genética , Hormônios Hipotalâmicos/metabolismo , Hipotálamo/efeitos dos fármacos , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Marcação In Situ das Extremidades Cortadas , Peptídeos e Proteínas de Sinalização Intracelular/genética , Melaninas/genética , Melaninas/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuropeptídeos/genética , Orexinas , Fosfopiruvato Hidratase , Hormônios Hipofisários/genética , Hormônios Hipofisários/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley
10.
Toxicol Sci ; 133(1): 157-73, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23457122

RESUMO

Bisphenol A (BPA) exposure is ubiquitous, and in laboratory animals, early-life BPA exposure has been shown to alter sex-specific neural organization, neuroendocrine physiology, and behavior. The specific mechanisms underlying these brain-related outcomes, however, remain largely unknown, constraining the capacity to ascertain the potential human relevance of neural effects observed in animal models. In the perinatal rat brain, estrogen is masculinizing, suggesting that BPA-induced perturbation of estrogen receptor (ESR) expression may underpin later in-life neuroendocrine effects. We hypothesized that prenatal BPA exposure alters sex-specific ESR1 (ERα) and ESR2 (ERß) expression in postnatal limbic nuclei. Sprague Dawley rats were mated and gavaged on gestational days (GDs) 6-21 with vehicle, 2.5 or 25 µg/kg bw/day BPA, or 5 or 10 µg/kg bw/day ethinyl estradiol. An additional group was restrained but not gavaged (naïve control). Offspring were sacrificed the day after birth to quantify ESR gene expression throughout the hypothalamus and amygdala by in situ hybridization. Relative to the vehicle group, significant effects of BPA were observed on ESR1 and ESR2 expression throughout the mediobasal hypothalamus and amygdala in both sexes. Significant differences in ESR expression were also observed in the mediobasal hypothalamus and amygdala of the naïve control group compared with the vehicle group, highlighting the potential for gavage to influence gene expression in the developing brain. These results indicate that ESR expression in the neonatal brain of both sexes can be altered by low-dose prenatal BPA exposure.


Assuntos
Tonsila do Cerebelo/efeitos dos fármacos , Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Receptores de Estrogênio/genética , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/metabolismo , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Receptor alfa de Estrogênio/genética , Receptor beta de Estrogênio/genética , Feminino , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores Sexuais
11.
Behav Brain Res ; 235(2): 166-75, 2012 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-22867871

RESUMO

While variations in neonatal distress vocalizations have long been shown to reflect the integrity of nervous system development following a wide range of prenatal and perinatal insults, a paucity of research has explored the neurobiological basis of these variations. To address this, virgin Sprague-Dawley rats were bred and divided into three groups: [1] untreated, [2] chronic-cocaine treated (30 mg/kg/day, gestation days (GDs) 1-20); or [3] chronic saline treated (2 mg/kg/day, GDs 1-20). Pregnant dams were injected with Bromodeoxyuridine (10 mg/kg) on GDs 13-15 to label proliferating cells in limbic regions of interest. Ultrasonic vocalizations (USVs) were recorded on postnatal days (PNDs) 1, 14, and 21, from one male and female pup per litter. Variations in acoustic properties of USVs following cocaine-exposure were age and sex-dependent including measures of total number, total duration and amplitude of USVs, and percent of USVs with at least one harmonic. Following USV testing brains were stained with standard fluorescent immunohistochemistry protocols and examined for variations in neuronal development and if variations were associated with acoustic characteristics. Limbic region developmental differences following cocaine-exposure were sex- and age-dependent with variations in the ventral medial hypothalamus and central amygdala correlating with variations in vocalizations on PND 14 and 21. Results suggest maturation of the ventral medial hypothalamus and central amygdala may provide the basis for variations in the sound and production of USVs. As vocalizations may serve as a neurobehavioral marker for nervous system integrity, understanding the neurobiological basis of neonatal vocalizations may provide the basis for early intervention strategies in high-risk infant populations.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Cocaína/efeitos adversos , Deficiências do Desenvolvimento/patologia , Inibidores da Captação de Dopamina/efeitos adversos , Hipotálamo Médio/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Vocalização Animal/fisiologia , Estimulação Acústica , Fatores Etários , Tonsila do Cerebelo/crescimento & desenvolvimento , Análise de Variância , Animais , Animais Recém-Nascidos , Bromodesoxiuridina/metabolismo , Contagem de Células , Proliferação de Células , Deficiências do Desenvolvimento/etiologia , Modelos Animais de Doenças , Feminino , Análise de Fourier , Idade Gestacional , Hipotálamo Médio/crescimento & desenvolvimento , Masculino , Fosfopiruvato Hidratase/metabolismo , Gravidez , Ratos , Ratos Sprague-Dawley , Fatores Sexuais , Fatores de Tempo
12.
Brain Lang ; 114(2): 53-65, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19864015

RESUMO

Understanding how language emerged in our species calls for a detailed investigation of the initial specialization of the human brain for speech processing. Our earlier research demonstrated that an adult-like left-lateralized network of perisylvian areas is already active when infants listen to sentences in their native language, but did not address the issue of the specialization of this network for speech processing. Here we used fMRI to study the organization of brain activity in two-month-old infants when listening to speech or to music. We also explored how infants react to their mother's voice relative to an unknown voice. The results indicate that the well-known structural asymmetry already present in the infants' posterior temporal areas has a functional counterpart: there is a left-hemisphere advantage for speech relative to music at the level of the planum temporale. The posterior temporal regions are thus differently sensitive to the auditory environment very early on, channelling speech inputs preferentially to the left side. Furthermore, when listening to the mother's voice, activation was modulated in several areas, including areas involved in emotional processing (amygdala, orbito-frontal cortex), but also, crucially, a large extent of the left posterior temporal lobe, suggesting that the mother's voice plays a special role in the early shaping of posterior language areas. Both results underscore the joint contributions of genetic constraints and environmental inputs in the fast emergence of an efficient cortical network for language processing in humans.


Assuntos
Córtex Auditivo/fisiologia , Desenvolvimento da Linguagem , Música , Percepção da Fala/fisiologia , Lobo Temporal/fisiologia , Estimulação Acústica/métodos , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/fisiologia , Córtex Auditivo/crescimento & desenvolvimento , Vias Auditivas/crescimento & desenvolvimento , Vias Auditivas/fisiologia , Feminino , Lobo Frontal/crescimento & desenvolvimento , Lobo Frontal/fisiologia , Humanos , Lactente , Imageamento por Ressonância Magnética , Masculino , Mães , Fonética , Lobo Temporal/crescimento & desenvolvimento , Voz
13.
Neuron ; 63(5): 657-72, 2009 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-19755108

RESUMO

Electroclinical uncoupling of neonatal seizures refers to electrographic seizure activity that is not clinically manifest. Uncoupling increases after treatment with Phenobarbital, which enhances the GABA(A) receptor (GABA(A)R) conductance. The effects of GABA(A)R activation depend on the intracellular Cl(-) concentration ([Cl(-)](i)) that is determined by the inward Cl(-) transporter NKCC1 and the outward Cl(-) transporter KCC2. Differential maturation of Cl(-) transport observed in cortical versus subcortical regions should alter the efficacy of GABA-mediated inhibition. In perinatal rat pups, most thalamic neurons maintained low [Cl(-)](i) and were inhibited by GABA. Phenobarbital suppressed thalamic seizure activity. Most neocortical neurons maintained higher [Cl(-)](i), and were excited by GABA(A)R activation. Phenobarbital had insignificant anticonvulsant responses in the neocortex until NKCC1 was blocked. Regional differences in the ontogeny of Cl(-) transport may thus explain why seizure activity in the cortex is not suppressed by anticonvulsants that block the transmission of seizure activity through subcortical networks.


Assuntos
Tonsila do Cerebelo/fisiopatologia , Neocórtex/fisiopatologia , Neurônios/fisiologia , Convulsões/fisiopatologia , Tálamo/fisiopatologia , Ácido gama-Aminobutírico/metabolismo , Tonsila do Cerebelo/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Anticonvulsivantes/farmacologia , Bumetanida/farmacologia , Cloretos/metabolismo , Feminino , Técnicas In Vitro , Masculino , Neocórtex/efeitos dos fármacos , Neocórtex/crescimento & desenvolvimento , Fenobarbital/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/metabolismo , Convulsões/tratamento farmacológico , Caracteres Sexuais , Inibidores de Simportadores de Cloreto de Sódio e Potássio/farmacologia , Membro 2 da Família 12 de Carreador de Soluto , Transmissão Sináptica , Tálamo/efeitos dos fármacos , Tálamo/crescimento & desenvolvimento
14.
J Comp Neurol ; 513(5): 511-31, 2009 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-19226509

RESUMO

The establishment of appropriate neural circuitry depends on the coordination of multiple developmental events across space and time. These events include proliferation, migration, differentiation, and survival-all of which can be mediated by hepatocyte growth factor (HGF) signaling through the Met receptor tyrosine kinase. We previously found a functional promoter variant of the MET gene to be associated with autism spectrum disorder, suggesting that forebrain circuits governing social and emotional function may be especially vulnerable to developmental disruptions in HGF/Met signaling. However, little is known about the spatiotemporal distribution of Met expression in the forebrain during the development of such circuits. To advance our understanding of the neurodevelopmental influences of Met activation, we employed complementary Western blotting, in situ hybridization, and immunohistochemistry to comprehensively map Met transcript and protein expression throughout perinatal and postnatal development of the mouse forebrain. Our studies reveal complex and dynamic spatiotemporal patterns of expression during this period. Spatially, Met transcript is localized primarily to specific populations of projection neurons within the neocortex and in structures of the limbic system, including the amygdala, hippocampus, and septum. Met protein appears to be principally located in axon tracts. Temporally, peak expression of transcript and protein occurs during the second postnatal week. This period is characterized by extensive neurite outgrowth and synaptogenesis, supporting a role for the receptor in these processes. Collectively, these data suggest that Met signaling may be necessary for the appropriate wiring of forebrain circuits, with particular relevance to the social and emotional dimensions of behavior.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Neurônios/metabolismo , Prosencéfalo/crescimento & desenvolvimento , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Fatores Etários , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/metabolismo , Animais , Animais Recém-Nascidos , Transtorno Autístico/genética , Western Blotting , Diferenciação Celular , Embrião de Mamíferos , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Proteínas de Homeodomínio/fisiologia , Imuno-Histoquímica , Hibridização In Situ , Sistema Límbico/crescimento & desenvolvimento , Sistema Límbico/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/fisiologia , Reação em Cadeia da Polimerase , Prosencéfalo/embriologia , Prosencéfalo/metabolismo , Proteínas Proto-Oncogênicas c-met/genética , Proteínas Proto-Oncogênicas c-met/fisiologia , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/fisiologia , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/fisiologia
15.
Neurosci Res ; 60(4): 364-71, 2008 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18243386

RESUMO

Prenatal stress has been reported to alter the development of the central nervous system functions. This alteration is thought to be partly caused by increased fetal exposure to glucocorticoid. To clarify how prenatal stress affects neuroendocrine systems and behaviour in an age-dependent manner, we administered a synthetic glucocorticoid, dexamethasone, as a stressor to pregnant rats at gestational days 16-21 and examined the developmental changes in behaviour, hypothalamic corticotropin-releasing factor mRNA expression, corticosterone response and glucocorticoid receptor expression in male offspring. Prenatal dexamethasone exposure decreased corticotropin-releasing factor mRNA in the hypothalamus and disturbed the plasma corticosterone response to restraint stress in the offspring at postnatal week 4 (PW4). In contrast, it was not until PW10 that increased anxiety-like behaviour emerged in the dexamethasone-exposed offspring. In association with the acquisition of increased anxiety-like behaviour at PW10, glucocorticoid receptor expression was decreased in the amygdala in dexamethasone-exposed offspring at PW7 and PW10. Thus, our longitudinal analysis suggests that prenatal exposure to glucocorticoid hampers neuroendocrinological development in the offspring during early life, and that this disturbance results in the induction of increased anxiety-like behaviour in adulthood.


Assuntos
Ansiedade/etiologia , Ansiedade/metabolismo , Dexametasona , Sistemas Neurossecretores/crescimento & desenvolvimento , Sistemas Neurossecretores/metabolismo , Efeitos Tardios da Exposição Pré-Natal , Fatores Etários , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/metabolismo , Análise de Variância , Animais , Animais Recém-Nascidos , Ansiedade/patologia , Comportamento Animal/efeitos dos fármacos , Corticosterona/genética , Corticosterona/metabolismo , Hormônio Liberador da Corticotropina/genética , Hormônio Liberador da Corticotropina/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Feminino , Hipotálamo/efeitos dos fármacos , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Masculino , Gravidez , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Ratos , Ratos Sprague-Dawley , Restrição Física/métodos
16.
Epigenetics ; 2(3): 173-8, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17965589

RESUMO

Pervasive developmental disorder is a classification covering five related conditions including the neurodevelopmental disorder Rett syndrome (RTT) and autism. Of these five conditions, only RTT has a known genetic cause with mutations in Methyl-CpG-binding protein 2 (MeCP2), a global repressor of gene expression, responsible for the majority of RTT cases. However, recent evidence indicates that reduced MeCP2 expression or activity is also found in autism and other disorders with overlapping phenotypes. Considering the sex difference in autism diagnosis, with males diagnosed four times more often than females, we questioned if a sex difference existed in the expression of MeCP2, in particular within the amygdala, a region that develops atypically in autism. We found that male rats express significantly less mecp2 mRNA and protein than females within the amygdala, as well as the ventromedial hypothalamus (VMH), but not within the preoptic area (POA) on post-natal day 1 (PN1). At PN10 these differences were gone; however, on this day males had more mecp2 mRNA than females within the POA. The transient sex difference of mecp2 expression during the steroid-sensitive period of brain development suggests that mecp2 may participate in normal sexual differentiation of the rat brain. Considering the strong link between MeCP2 and neurodevelopmental disorders, the lower levels of mecp2 expression in males may also underlie a biological risk for mecp2-related neural disorders.


Assuntos
Tonsila do Cerebelo/crescimento & desenvolvimento , Transtorno Autístico/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/biossíntese , Hipotálamo/crescimento & desenvolvimento , Proteína 2 de Ligação a Metil-CpG/biossíntese , Proteínas Repressoras/biossíntese , Síndrome de Rett/metabolismo , Caracteres Sexuais , Tonsila do Cerebelo/metabolismo , Animais , Animais Recém-Nascidos , Transtorno Autístico/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Feminino , Humanos , Hipotálamo/metabolismo , Masculino , Proteína 2 de Ligação a Metil-CpG/genética , Área Pré-Óptica/crescimento & desenvolvimento , Área Pré-Óptica/metabolismo , Ratos , Ratos Sprague-Dawley , Proteínas Repressoras/genética , Síndrome de Rett/genética
17.
Neuroscience ; 115(1): 213-27, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12401335

RESUMO

Classic cadherins are multifunctional adhesion proteins that play roles in tissue histogenesis, neural differentiation, neurite outgrowth and synapse formation. Several lines of evidence suggest that classic cadherins may establish regional or laminar recognition cues by virtue of their differential expression and tight, and principally homophilic, cell adhesion. As a first step toward investigating the role this family plays in generating limbic system connectivity, we used RT-PCR to amplify type I and type II classic cadherins present in rat hippocampus during the principal period of synaptogenesis. We identified nine different cadherins, one of which, cadherin-9, is novel in hippocampus. Using in situ hybridization, we compared the cellular and regional distribution of five of the cadherins (N, 6, 8, 9 and 10) during the first two postnatal weeks in hippocampus, subiculum, entorhinal cortex, cingulate cortex, anterior thalamus, hypothalamus and amygdala. We find that each cadherin is differentially distributed in distinct, but highly overlapping fields that largely correspond to known anatomical boundaries and are often coordinately expressed in interconnected regions. For example, cadherin-6 expression defines CA1 and its principal target, the subiculum; cadherin-10 is differentially expressed in CA1 and CA3 in a manner correlating with the organization of interconnecting Schaffer collateral axons; and cadherin-9 shows a striking concentration in CA3. Some cadherin mRNAs are highly restricted to particular anatomical fields over the entire time course, while others are more broadly expressed and become concentrated within particular domains coincident with the timing of afferent ingrowth. Our data indicate that classic cadherins are sufficiently diverse and differentially distributed to support a role in cell surface recognition and adhesion during the formation of limbic system connectivity.


Assuntos
Caderinas/análise , Caderinas/metabolismo , Sistema Límbico/crescimento & desenvolvimento , Sistema Límbico/metabolismo , Tonsila do Cerebelo/química , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/metabolismo , Animais , Animais Recém-Nascidos , Núcleos Anteriores do Tálamo/química , Núcleos Anteriores do Tálamo/crescimento & desenvolvimento , Núcleos Anteriores do Tálamo/metabolismo , Caderinas/biossíntese , Córtex Entorrinal/química , Córtex Entorrinal/crescimento & desenvolvimento , Córtex Entorrinal/metabolismo , Biblioteca Gênica , Giro do Cíngulo/química , Giro do Cíngulo/crescimento & desenvolvimento , Giro do Cíngulo/metabolismo , Hipocampo/química , Hipocampo/crescimento & desenvolvimento , Hipocampo/metabolismo , Hipotálamo/química , Hipotálamo/crescimento & desenvolvimento , Hipotálamo/metabolismo , Hibridização In Situ , Sistema Límbico/química , Camundongos , Vias Neurais/química , Vias Neurais/crescimento & desenvolvimento , Vias Neurais/metabolismo , Isoformas de Proteínas/análise , Isoformas de Proteínas/biossíntese , Isoformas de Proteínas/metabolismo , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase Via Transcriptase Reversa
18.
J Comp Neurol ; 450(3): 241-55, 2002 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-12209853

RESUMO

Recently an animal model for neurodevelopmental disorders has been developed. In this model the effects of an early neonatal [postnatal day 7 (Pd7)] basolateral amygdala lesion are compared with the effects of a lesion later in life (Pd21). Early amygdala damage results in enduring behavioral disturbances that become more manifest after puberty. These disturbances were not present in animals lesioned at Pd21. Accordingly it was postulated that the early damage may affect the neuroanatomical and neurochemical organization and functioning of other brain structures. To obtain information on the innervation of the amygdala during normal development, we used the retrograde tracer fluoro-gold. From neonatal day 7 onward (studied until Pd19), retrogradely labeled cells were present in the caudal and rostral thalamus, the substantia innominata, and the prefrontal but not the caudal cortex. Development of the topography of the projecting cells differed substantially for the thalamic regions and substantia innominata vs. the cortical regions. In thalamic regions and substantia innominata, no changes were observed during the studied period (Pd7-Pd9). In the prefrontal cortex, the number of labeled cells increased (from Pd7 to Pd13), the topography of the location of the cells changed from unilateral to bilaminar (from Pd9 to Pd13), and the number of subareas in which the cells were present increased (from Pd7 to Pd13). In the caudal cortex, relatively few cells were present up to Pd15. From Pd17 onward, a bilaminar topography of the location of the cells was observed. These data provide information on the circuitry that may be involved in the aberrant neurodevelopment of neonatally amygdala-lesioned rats, which has been proposed as an animal model for neurodevelopmental psychopathological disorders.


Assuntos
Envelhecimento/fisiologia , Tonsila do Cerebelo/crescimento & desenvolvimento , Vias Neurais/crescimento & desenvolvimento , Córtex Pré-Frontal/crescimento & desenvolvimento , Ratos Wistar/crescimento & desenvolvimento , Estilbamidinas , Tálamo/crescimento & desenvolvimento , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/fisiologia , Modelos Animais de Doenças , Feminino , Corantes Fluorescentes , Imuno-Histoquímica , Masculino , Transtornos Mentais/patologia , Transtornos Mentais/fisiopatologia , Vias Neurais/citologia , Vias Neurais/fisiologia , Neurônios/citologia , Neurônios/fisiologia , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Ratos , Ratos Wistar/anatomia & histologia , Ratos Wistar/fisiologia , Tálamo/citologia , Tálamo/fisiologia
19.
J Comp Neurol ; 442(3): 239-49, 2002 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-11774339

RESUMO

Recently, an animal model for neurodevelopmental disorders has been developed. In this model, the effects of an early neonatal (postnatal day 7 [Pd 7]) basolateral amygdala lesion are compared with the effects of a lesion later in life (Pd 21). The reported data indicate that amygdala damage at a specific point early in life results in enduring behavioral disturbances that become more manifest after puberty, for example, only an early lesion resulted in a disruption of the prepulse inhibition, which is also observed in people suffering from schizophrenia. Accordingly, it was postulated that the early damage may affect the neuroanatomic and neurochemical organization and functioning of other brain structures. This was studied by use of the anterograde tracers biotinylated dextran amine and Phaseolus vulgaris-leucoagglutinin. At neonatal days 7, 9, 11, 13, and 26, amygdaloid fibers were in particular present in the mediodorsal thalamus (MDT), nucleus accumbens (Acb), and prefrontal cortex (PFC). The development of the topography of the amygdaloid innervation, however, differed markedly for the MDT and Acb compared with the PFC. For the MDT and Acb, no major changes in innervation were observed between Pd 7 and Pd 26, whereas the innervation of the PFC reorganized from a neonatal diffuse (Pd 7 and 9) to a restricted pattern (Pd 11, 13, and 26). In addition, the innervation changed to an adult-like bilaminar pattern. These data provide information on the circuitry that may be involved in the aberrant neurodevelopment of neonatally amygdala-lesioned rats, which have been proposed as an animal model for neurodevelopmental psychopathological disorders.


Assuntos
Tonsila do Cerebelo/crescimento & desenvolvimento , Biotina/análogos & derivados , Neostriado/crescimento & desenvolvimento , Vias Neurais/crescimento & desenvolvimento , Córtex Pré-Frontal/crescimento & desenvolvimento , Terminações Pré-Sinápticas/ultraestrutura , Ratos Wistar/crescimento & desenvolvimento , Tálamo/crescimento & desenvolvimento , Envelhecimento/fisiologia , Tonsila do Cerebelo/citologia , Tonsila do Cerebelo/fisiologia , Animais , Animais Recém-Nascidos , Diferenciação Celular/fisiologia , Dextranos , Feminino , Corantes Fluorescentes , Masculino , Neostriado/citologia , Neostriado/fisiologia , Vias Neurais/citologia , Vias Neurais/fisiologia , Fito-Hemaglutininas , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/fisiologia , Terminações Pré-Sinápticas/fisiologia , Ratos , Ratos Wistar/anatomia & histologia , Ratos Wistar/fisiologia , Tálamo/citologia , Tálamo/fisiologia
20.
Brain Dev ; 23 Suppl 1: S16-23, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11738836

RESUMO

Memory formation involves dynamic interactions among many brain structures and their linking pathways. The noradrenaline (NA) system in the CNS plays an important role in a wide variety of neurological and psychological functions. Alteration in the NA system is implicated in the pathological states of some neuropsychiatric disorders. Tyrosine hydroxylase (TH) is the initial and rate-limiting enzyme for the biosynthesis of catecholamines. The regulatory mechanism of the TH reaction is generally considered to play a key role in controlling the catecholaminergic actions. Mice heterozygous for the mutation of the gene encoding TH exhibit the reduced TH activity in tissues. These mice have a moderate reduction in NA accumulation and release in brain regions. The mutant mice exhibit deficits in the water-finding task associated with latent learning performance, suggesting the impairment in memory formation. Spatial learning performance measured by the water maze task is normal in the mutants. However, they display deficits in long-term memory formation of conditioned learning evaluated with three distinct behavioral paradigms, including active avoidance, cued fear conditioning, and conditioned taste aversion, without affecting short-term memory. These memory deficits are restored by the drug-induced stimulation of NA activity at the postconditioning phase. Analysis of the mutant mice indicates that the central NA system is essential for the consolidation process in long-term memory of conditioned learning. The process appears to be implicated in the NA activity in the cerebral cortex and/or amygdaloid complex.


Assuntos
Sistema Nervoso Central/crescimento & desenvolvimento , Transtornos da Memória/metabolismo , Vias Neurais/crescimento & desenvolvimento , Neurônios/metabolismo , Norepinefrina/biossíntese , Tirosina 3-Mono-Oxigenase/deficiência , Tonsila do Cerebelo/crescimento & desenvolvimento , Tonsila do Cerebelo/metabolismo , Tonsila do Cerebelo/fisiopatologia , Animais , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Condicionamento Psicológico/fisiologia , Regulação da Expressão Gênica no Desenvolvimento/fisiologia , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Transtornos da Memória/genética , Transtornos da Memória/fisiopatologia , Camundongos , Camundongos Knockout , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Tálamo/crescimento & desenvolvimento , Tálamo/metabolismo , Tálamo/fisiopatologia , Tirosina 3-Mono-Oxigenase/genética
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