Indiana University-Purdue University Indianapolis (IUPUI) / After spinal cord injury (SCI), poor axonal regeneration of the central nervous system, which mainly attributed to glial scar and low intrinsic regenerating capacity of severely injured neurons, causes limited functional recovery. Combinatory strategy has been applied to target multiple mechanisms. Schwann cells (SCs) have been explored as promising donors for transplantation to promote axonal regeneration. Among the central neurons, descending propriospinal neurons (DPSN) displayed the impressive regeneration response to SCs graft. Glial cell line-derived neurotrophic factor (GDNF), which receptor is widely expressed in nervous system, possesses the ability to promote neuronal survival, axonal regeneration/sprouting, remyelination, synaptic formation and modulate the glial response. We constructed a novel axonal permissive pathway in rat model of thoracic complete transection injury by grafting SCs over-expressing GDNF (SCs-GDNF) both inside and caudal to the lesion gap. Behavior evaluation and histological analyses have been applied to this study. Our results indicated that tremendous DPSN axons as well as brain stem axons regenerated across the lesion gap back to the caudal spinal cord. In addition to direct promotion on axonal regeneration, GDNF also significantly improved the astroglial environment around the lesion. These regenerations caused motor functional recovery. The dendritic plasticity of axotomized DPSN also contributed to the functional recovery. We applied a G-mutated rabies virus (G-Rabies) co-expressing green fluorescence protein (GFP) to reveal Golgi-like dendritic morphology of DPSNs and its response to axotomy injury and GDNF treatment. We also investigated the neurotransmitters phenotype of FluoroGold (FG) labeled DPSNs. Our results indicated that over 90 percent of FG-labeled DPSNs were glutamatergic neurons. DPSNs in sham animals had a predominantly dorsal-ventral distribution of dendrites. Transection injury resulted in alterations in the dendritic distribution, with dorsal-ventral retraction and lateral-medial extension of dendrites. Treatment with GDNF significantly increased the terminal dendritic length of DPSNs. The density of spine-like structures was increased after injury and treatment with GDNF enhanced this effect.

Thesis (PhD (Biomedical Sciences. Medical Physiology.))--University of Stellenbosch, 2010. / ENGLISH ABSTRACT: Adverse experiences during early life causes alterations in the development of the central nervous system structures that may result in abnormal functioning of the brain. It is well known that, in humans, adverse early-life experiences such as social separation, deprivation, maternal neglect and abuse increase the risk of developing psychiatric disorders, such as depression, later in life. We used maternal separation in the rat as a model for early life stress to firstly determine how different brain systems are dysregulated by this stressful experience and additional chronic or acute stress during adulthood. Rat pups were separated from their mothers on postnatal day 2-14 for 3 hours per day while control rats were normally reared. The behavior, stress response, neurotrophin, apoptotic marker and serotonin levels in the ventral hippocampus, striatum and frontal cortex were measured during adulthood. A different group of maternally separated rats were allowed chronic voluntary exercise and similar measurements were done to determine whether exercise was able to normalize the deficits caused by early life stress. Differentially expressed cytosolic proteins of the ventral hippocampus of maternally separated rats versus normally reared rats were also identified. Protein expression levels of maternally separated rats that received chronic voluntary exercise or escitalopram treatment were subsequently determined to unravel the mechanism of therapeutic action for these two interventions. We found that maternal separation increased the baseline corticosterone response of rats and induced a blunted adrenocorticotropin hormone after acute restraint stress. Baseline neurotrophin levels were significantly decreased in the ventral hippocampus. Maternal separation followed by chronic restraint stress during adulthood resulted in increased depressive-like behavior compared to control rats. Maternal separation alone or followed by acute restraint stress during adulthood induced changes in apoptotic marker expression in the striatum and frontal cortex. In rats subjected to maternal separation and chronic restraint stress during adulthood, we found that chronic voluntary exercise decreased their depressive-like behavior and increased brain derived neurotrophin levels in the striatum. Serotonin levels were not affected by maternal separation, but chronic voluntary exercise increased serotonin in the ventral hippocampus of normally reared rats. Maternal separation induced a number of changes in the expression of cytosolic proteins and these stress-induced changes were identified in proteins relating to cytoskeletal structure, neuroplasticity, oxidative stress, energy metabolism, protein metabolism, and cell signaling. Chronic voluntary exercise was able to restore the expression levels of a number of proteins affected by maternal separation that increased the risk for neuronal death. When comparing the efficacy of exercise to that of escitalopram treatment it was evident that, in contrast to exercise, escitalopram targets a different subset of proteins affected by maternal separation, except for a few involved in energy metabolism pathways and neuroprotection. In this study we have shown that chronic voluntary exercise has therapeutic effects in maternally separated rats, decreasing depressive-like behavior, increasing neurotrophin expression and restoring cytosolic protein expression that were dysregulated by early life stress. / AFRIKAANSE OPSOMMING: Negatiewe stresvolle ervarings gedurende die vroeë stadium van ‘n mens se lewe veroorsaak veranderinge in die ontwikkeling van breinstrukture en het ‘n nadelige uitwerking op die funksionering van die brein. Dit is bekend dat stresvolle ervarings in kinders, byvoorbeeld sosiale afsondering, verwaarlosing en mishandeling, die risiko vir die ontwikkeling van psigiatriese steurings soos depressie gedurende volwassenheid kan verhoog. In hierdie studie gebruik ons moederlike skeiding van neonatale rotte as ‘n model vir vroeë lewensstres om te bepaal hoe dit verskillende sisteme in die brein negatief beinvloed, en dan ook die effek van addisionele kroniese of akute stres gedurende volwassenheid. Die neonatale rotte is weggeneem van hulle moeders af vanaf dag 2 tot 14 vir 3 ure elke dag terwyl kontrole rotte by hulle moeders gebly het. Die gedrag, stres respons, neurotrofiene, apoptotiese merkers en serotonien vlakke is gemeet in die ventrale hippokampus, frontale korteks en striatum gedurende volwassenheid. Rotte wat van hulle moeders geskei is, is dan toegelaat om vir ses weke in wiele te hardloop om te bepaal of kroniese vrywillige oefening die negatiewe effekte wat veroorsaak is deur stres kan ophef. ‘n Bepaling van sitosoliese proteien uitdrukking in die ventrale hippokampus is ook gedoen om die uitwerking van moederlike skeiding op proteienvlak vas te stel. Hierdie protein data is dan vergelyk met die van gestresde rotte wat kroniese oefening of escitalopram behandeling ontvang het om die meganisme van werking van beide behandelings te bepaal. Ons het gevind dat moederlike skeiding die rustende kortikosteroon vlakke van rotte verhoog terwyl dit adrenokortikotropien vlakke na akute stres inhibeer. Moederlike skeiding het ook die neurotrofien vlakke in die ventrale hippokampus verlaag en addisionele kroniese stres gedurende volwassenheid het ‘n verhoging in depressie-agtige gedrag veroorsaak. Moederlike skeiding alleen, sowel as gevolg deur akute stress gedurende volwassenheid het ook veranderinge in die uitdrukking van apoptotiese merkers in die striatum en frontale korteks veroorsaak. Kroniese vrywillige oefening na moederlike skeiding en addisionele stres gedurende volwassenheid kon depressie-agtige gedrag verlaag en neurotrofienvlakke in die striatum verhoog. Serotonien vlakke was nie beinvloed deur moederlike skeiding nie, maar oefening in kontrole rotte het serotonien verhoog in die ventrale hippokampus. Moederlike skeiding het heelwat veranderinge in die uitdrukking van sitosoliese proteiene van die ventrale hippokampus veroorsaak wat ingedeel kan word in die volgende funksionele kategorieë: sitoskelet, neuroplastisiteit, oksidatiewe stres, energiemetabolisme, proteinmetabolisme en seintransduksie. Oefening kon die uitdrukking van verskeie stres-geïnduseerde veranderinge in proteiene weer herstel terwyl dit wou bleik asof escitalopram se meganisme van werking op ‘n ander vlak geskied. Ons bevindinge bewys dat kroniese vrywillige oefening ‘n goeie behandeling is na vroeë lewenstres en dat dit depressiewe gedrag verminder, neurotrofien vlakke verhoog en sitosoliese proteien skeiding alleen, sowel as gevolg deur akute stress gedurende volwassenheid het ook veranderinge in die uitdrukking van apoptotiese merkers in die striatum en frontale korteks veroorsaak. Kroniese vrywillige oefening na moederlike skeiding en addisionele stres gedurende volwassenheid kon depressie-agtige gedrag verlaag en neurotrofienvlakke in die striatum verhoog. Serotonien vlakke was nie beinvloed deur moederlike skeiding nie, maar oefening in kontrole rotte het serotonien verhoog in die ventrale hippokampus. Moederlike skeiding het heelwat veranderinge in die uitdrukking van sitosoliese proteiene van die ventrale hippokampus veroorsaak wat ingedeel kan word in die volgende funksionele kategorieë: sitoskelet, neuroplastisiteit, oksidatiewe stres, energiemetabolisme, proteinmetabolisme en seintransduksie. Oefening kon die uitdrukking van verskeie stres-geïnduseerde veranderinge in proteiene weer herstel terwyl dit wou bleik asof escitalopram se meganisme van werking op ‘n ander vlak geskied. Ons bevindinge bewys dat kroniese vrywillige oefening ‘n goeie behandeling is na vroeë lewenstres en dat dit depressiewe gedrag verminder, neurotrofien vlakke verhoog en sitosoliese proteien vlakke kan herstel.

published_or_final_version / Anatomy / Master / Master of Philosophy

La compréhension et l'étude du système nerveux est un des grands enjeux du XXIème siècle à la fois pour la recherche fondamentale, mais également pour la mise au point de neuroprothèses implantables pour la réhabilitation fonctionnelle (exemple : implants rétiniens, implants cochléaires). Depuis quelques années, des systèmes basés sur l'utilisation de multi-électrodes (MEA : Multi-Electrode-Array) offrent la possibilité d'enregistrer des milliers de cellules interconnectées entre-elles sur plusieurs jours sur des tranches de tissu nerveux ou des systèmes nerveux complets. Mais une des limites de cette technique est le faible nombre de voies de ces systèmes (64 voies). Les travaux de cette thèse ont consisté à développer une technologie de fabrication permettant la réalisation d'un système multiélectrode s « haute densité 3D ». Cela passe par le développement d'une nouvelle technologie dans la réalisation de micro pointes basée sur la gravure profonde du silicium (DRIE), qui permet d'obtenir des pointes en silicium de 80 µm de haut espacées de 50 µm. Des matrices 60, 256 et 1024 voies ont été fabriquées par cette technique. L'utilisation de la stimulation est aussi un point important dans l'étude de ces grands réseaux, mais il n'est pas possible actuellement de disposer de système permettant une stimulation focale. Pour résoudre ce problème, nous avons développé des matrices spécifiques permettant d'obtenir des stimulations focales du tissu. Nous avons également dans ces travaux de thèse étudié le comportement de l'interface métal/liquide, qui est cruciale pour la réalisation de MEA, en utilisant des techniques d'électrochimie / One challenge of the XXIème century will be to understand dynamics of large neural networks for research and to develop neuroprothesis implant (ex retinal implant, cochlear implant). Today microelectrodes arrays (MEAs) positioned in contact with the neural tissue offer the opportunity to record and simulate neuronal tissue. But the main drawback of his technique is low number of recording sites (typically 64). During this thesis, we have developed a specific process using deep reactive ions etching (DRIE), to achieve high density 3D MEAs containing several hundreds of microelectrodes. We have fabricated microneedles 80 µm of height with spacing of 50 µm and MEAs with 60 – 256 and 1024 microelectrodes have been built with this process. Microstimulation, which makes use of electrodes on the micron scale, is gaining increasing interest in both fundamental and clinical research, opening the possibility to stimulate small groups of neurons instead of large regions. However, controlling the spatial extent of microstimulation to achieve focal activation of neuron networks is a challenge. We have proposed a new configuration of MEA specifically designed to achieve a local stimulation. We have also characterised the interface metal/liquid, that was very important for MEA and we have used electrochemistry techniques

There are approximately 6000 to 8000 rare diseases, each with a prevalence of less than 1 / 10 000, but in aggregate affecting 6 to 8% of the population. It is important to evaluate disease development and progression to know the natural course of any disease. This information can be utilized in diagnostics and in assessing effects of therapeutic interventions as they become available. This thesis describes the natural clinical history and evolution of imaging findings of two rare diseases over approximately two decades. Papers I, II and III present clinical, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) findings in LMNB1-related autosomal dominant leukodystrophy (ADLD). MRI was found to be very sensitive in finding pathology in patients with LMNB1-related ADLD, even before the onset of clinical symptoms. However, even patients with widespread MRI changes can have a relatively mild symptomatology and present only slight disturbances in metabolic examinations such as MRS and FDG-PET. This is compatible with relatively intact axons, even as myelin impairment is widespread. Paper IV presents clinical and MRI findings in the brain and musculature in SIL1-positive Marinesco-Sjögren syndrome (MSS), and describes a new, mild phenotype of the disease with no intellectual disabilities and only slight motor disabilities. With a 19-year-long radiological follow-up, a slow progressive atrophic process in the cerebellum and brainstem could be demonstrated. MRI of the musculature shows early involvement of the quadriceps and gastrocnemii but not the tibialis anterior, progressing to widespread atrophy in the back and upper and lower limbs at the age of 20 years. In the mildest phenotype, the most severely affected muscles were the m gluteus maximus, m sartorius, m peroneus longus, and the lateral head of the m gastrocnemius.

Recent studies examining cell-cell interactions during CNS development and following disease or trauma have highlighted our limited understanding of the in vivo functions of the myelinating cell of the CNS, the oligodendrocyte. With this in mind, our laboratory has developed techniques by which a profile of proteins derived from or regulated by oligodendrocytes can be elucidated. Specifically, we have demonstrated that oligodendrocytes can be selectively eliminated from one optic nerve of a rat by treating the animal with a unilateral exposure of X-irradiation at the time of birth. Consequently, this approach allowed us to experimentally create, within the same animal, one optic nerve devoid of oligodendrocytes and their progenitors (the X- irradiated side) and one optic nerve containing the normal oligodendrocyte population (the untreated side). Using this experimental animal model we hypothesized that uncharacterized proteins, derived from and regulated by oligodendrocytes, which are crucial for CNS development can be identified. Specifically, by comparing protein profiles found within the normal myelinating optic nerve versus the X-irradiated optic nerve, where oligodendrocytes are absent, potential oligodendrocyte-derived proteins can be quickly identified. Further verification that these proteins are indeed related to oligodendrocytes and/or the processes of myelination can be obtained by their reappearance in the 2-D gel protein profile of P28 X-irradiated nerves that, as we have shown previously, undergo a delayed myelination. We then employed mass spectrometric analysis to determine the identities of oligodendrocyte derivedregulated proteins. In this thesis, I will begin by describing our current knowledge of the proteins expressed by oligodendrocytes and their role(s) in oligodendrocyte function. This will be followed by a detailed description of the experimental model system we utilized in an attempt to elucidate the complete repertoire of oligodendrocyte-regulated proteins. We will then describe the results generated fiom our methodology and discuss the implications of our findings in relation to the functional cooperation between oligodendrocytes and other cells of the developing central nervous system. The results generated fiom this project should lead to a clearer understanding of the role of oligodendrocytes and'of the array of proteins whose expression patterns are associated with these cells during CNS development.

While the classical function of myelin is to facilitate saltatory conduction, this membrane and the myelin-making oligodendrocytes (OLGs) are now recognized as regulators of plasticity and remodeling in the central nervous system (CNS). Thus, OLG maturation and myelination are highly vulnerable processes along CNS development. We previously showed that rat brain myelination is altered by perinatal exposure to buprenorphine, an opioid analogue in clinical trials for the treatment of pregnant opioid addicts. We now found that the in vivo effects on myelination could result from direct alteration in the balance between μ-opioid receptor (MOR) and nociceptin/orphanin FQ receptor (NOPR) activities in the OLGs. Furthermore, we found that myelination could also be affected by the FDA-approved methadone. A delicate balance between MOR and NOPR signaling may play a crucial role timing OLG maturation and myelin formation and exogenous opioids may disrupt this interplay, altering the developmental pattern of brain myelination.

A família de Siluriformes Neotropicais Cetopsidae possui cinco gêneros e 43 espécies válidas, com ampla distribuição nas regiões norte e central da América do Sul, tanto cis- como trans-andina. Cetopsidae é proposta como um grupo monofilético, suportado pela maioria dos estudos morfológicos e moleculares. Os estudos evolutivos sobre o sistema nervoso de bagres neotropicais são bastante escassos, apesar desse complexo apresentarimportantes modificações potencialmente informativas para estudos de inferência filogenética. Para testar a significância dos caracteres neuroanatômicos em filogenias, a morfologia externa das principais subdivisões encefálicas de Cetopsidae foi descrita, ilustrada e interpretada. Além disso, análises comparativas do desenvolvimento desse complexo foram realizadas em Helogenes marmoratus e Cetopsis gobioides com o intuito de estabelecer homologias e compreender suas modificações ontogenéticas. Os caracteres foram delimitados e testados separadamente em análises filogenéticas e posteriormente combinados com caracteres morfológicos e moleculares com diferentes métodos de análise. Para determinar o volume de cada região analisada, um modelo elipsoide foi utilizado. Amplas comparações baseadas no formato, posição relativa e volume das principais regiões encefálicas são apresentadas para a maioria das espécies representativas de todos os gêneros de Cetopsidae. As mesmas comparações também foram realizadas ao longo do desenvolvimento de Helogenes marmoratus e Cetopsis gobioides. Além disso, comparações com integrantes de outras famílias filogeneticamente relacionadas em Siluriformes forneceram um amplo contexto para um maior entendimento das principais modificações evolutivas que moldaram o encéfalo doscetopsídeos. Análises filogenéticas de todos os caracteres morfológicos foram primeiramente conduzidas em separado, e posteriormente em matrizes concatenadas sob o critério da Parcimônia. Análises Bayesianas com sequências alinhadas e concatenadas de três genes mitocondriais (COI, 16S e Cytb) foram implementadas. Por fim, análises filogenéticas com todos os dados combinados foram conduzidas sob os critérios da Parcimônia e Bayesiano. Padrões morfológicos distintos foram definidos para cada uma das duas principais subdivisões de Cetopsidae, as subfamílias Helogeninae e Cetopsinae. Poucas variações intraespecíficas na morfologia externa do encéfalo xii existem entre todas as espécies examinadas aqui. As modificações observadas ao longo do desenvolvimento do encéfalo de Helogenes marmoratus e Cetopsis gobioides foram utilizadas para a formulação correta de caracteres e seus estados. Todos os gêneros foram recuperados como grupos monofiléticos pelos caracteres neuroanatômicos.Mapeamentos filogenéticos revelaram alguns padrões morfológicos sugestivos com especializações alimentares e outras características de história de vida correlacionadas ao sistema nervoso central. Os caracteres morfológicos e moleculares se mostraram bastante congruentes nas hipóteses filogenéticas, comas incongruências restritas à tribo Cetopsini. Todas as análises recuperaram Helogeninae como grupo-irmão dos demais cetopsídeos, seguido por Cetopsidiini, Denticetopsini e Cetopsini como grupos-irmãos sucessivos.Os resultados obtidos no presente estudo suportam a ideia de que análises amplas e concatenadas de dados morfológicos e moleculares resultam em hipóteses de relacionamentos robustas e bem suportadas. Os caracteres neuroanatômicos são altamente informativos para inferências filogenéticas, que podem ser exploradospara uma maior compreensão da evolução de Otophysi. / The Neotropical South American catfish Cetopsidae is a family of Siluriformes that includes five genera and 43valid species distributed over a large portion of northern and central regions of South America, on both sides of the Andean cordilleras. The monophyly of the family is supported by several previous studies, based on both morphological and molecular characters. Despite the scarcity of evolutionary studies on the nervous system of neotropical catfishes, that complex shows great variation potentially informative for phylogenetic inference. In order to test the significance of neurological traits in a phylogenetic framework, the gross morphology of brain subdivisions in the catfish family Cetopsidae is described, illustrated and interpreted. In addition, comparative analyzes of the development of this complex were carried out in Helogenes marmoratus and Cetopsis gobioidesin order to establish homologies and ontogenetic transformations. Characters were delimited and tested separately in phylogenetic analyzes and later combined with other morphological and molecular characters with different methods of analysis. The volume of major brain subdivision was calculated by an ellipsoid model. A comprehensive comparison based on shape, relative position, and volume of the main brain subdivisions is presented for representative species of all genera and most available species in the family. The same comparisons were also made throughout the development of Helogenes marmoratus and Cetopsis gobioides. Comparisons with other phylogenetically related siluriform families provide a broader context for the understanding of the main evolutionary transformations which shaped the cetopsid brain. Phylogenetic analyzes of all morphological characters were first conducted separately, and later in matrices concatenated under the Parsimony criterion. Bayesian analyzes of three aligned and concatenated mitochondrial gene sequences (COI, 16S and Cytb) were implemented. Analyzes of all the data combined were conducted under both Parsimony and Bayesian criteria. Profoundly distinct morphological patterns are identified for each of the two main cetopsid subdivisions, subfamilies Helogeninae and Cetopsinae. Little intraspecific variation on major subdivisions of the brain exists in species examined herein. The modifications observed throughout the development of the brain inHelogenes marmoratus and Cetopsis gobioides were used for the correct delimitation xiv of characters and their states. The monophyly of all genera is supported by putative neuroanatomic characters. Phylogenetic mapping reveals recurrent morphological patterns suggestive of an association with specific feeding specializations and other life-history traits. Morphological and molecular characters were highly congruent in phylogenetic hypotheses, with inconsistencies restricted to the tribe Cetopsini. All analyzes recovered Helogeninae as thesister group toall remaining cetopsids, followed by Cetopsidiini, Denticetopsini and Cetopsini as successive sister groups. Results of the present study support the idea that large and concatenated analyzes of morphological and molecular characters result in robust well-supported hypotheses of relationships. Neuroanatomical characters are highly informative for phylogenetic inferenceand area promising field to be explored in understanding the evolution of Otophysi.

O estudo dos efeitos do estresse em modelos animais contribui para investigar os mecanismos de sinalização envolvidos nas enfermidades humanas. O projeto foi dividido em duas partes. Primeiramente investigou-se o efeito do estresse crônico imprevisível (ECI) na evolução clínica da encefalomielite autoimune experimental (EAE) e as concentrações circulantes de corticosterona (CORT). O ECI agravou os sinais clínicos da EAE em ratos, mas as concentrações plasmáticas de CORT durante o desenvolvimento da doença pareceram depender unicamente do desafio imunológico. Posteriormente investigaram-se os mediadores inflamatórios e o estresse oxidativo em diversas áreas do SNC de ratos submetidos à isquemia e reperfusão mesentérica. Foram observadas alterações distintas, conforme o tecido analisado, na expressão gênica de NOS e COX, atividade da NOS Ca2+-dep e da arginase e no conteúdo de TBARS. Conclui-se que, nas primeiras horas de reperfusão intestinal, as estruturas analisadas reagem diferentemente ao estresse oxidativo. / The study of stress effects in different animal models help to clarify signalization mechanisms involved in human diseases. The present project was divided in two parts. Firstly, we investigated the effects of chronic unpredictable stress (CUS) on the course of experimental autoimmune encephalomyelitis (EAE) and circulating corticosterone (CORT) concentrations. CUS aggravated the clinical signs of the disease in Lewis rats. However, plasma CORT during the development of clinical signs seemed to be solely dependent on the immunological challenge. Secondly, we investigated the oxidative and defense mechanisms in several CNS regions of rats submitted to an intestinal ischemia-reperfusion model. There were distinct results, as tissue analysis, in genic expression of NOS and COX, calcium-dependent nitric oxide synthase and arginase activities and TBARs content. Based on these results, we concluded that, at least during the first two hours of intestinal reperfusion, CNS lesions may be efficiently prevented by defense mechanisms able to modulate the oxidative injury.

O enriquecimento ambiental (EA) é um modelo experimental capaz de promover a melhora no aprendizado e na formação de memórias hipocampo-dependentes, bem como a redução de manifestações comportamentais relacionadas ao estresse, incluindo a ansiedade. Embora a relação causal entre estresse e ansiedade ainda não está esclarecida, algumas evidências apontem para a importância da sinalização de hormônios glicocorticoides (via receptores GR e MR) no sistema nervoso central, principalmente na amígdala e no hipocampo, além do fator neurotrófico BDNF e de algumas vias de sinalização intracelular, como proteínas quinases MAPK e o fator de transcrição CREB. No presente trabalho verificamos que o EA previne o surgimento de sintomas do tipo ansioso desencadeado por estresse agudo em ratos, efeito verificado imediatamente após o estresse, e que tal efeito pode estar relacionado à modulação, no complexo amigdalóide basolateral, da sinalização nuclear de GR, da atividade de ERK (pertencente à família das MAPK) e de CREB, bem como à alteração na expressão do receptor de BDNF. / Environmental enrichment (EE) is an experimental model that promotes improvements in learning and memory, as well as reduction in stress-induced behaviors, including anxiety. Although the casual relationship between stress and anxiety remains unclear, some studies show the importance of glucocorticoids hormones signaling (via GR and MR receptors) in the central nervous system, primarily in the amygdala and the hippocampus. In addition, the significance of the neurotrophic factor BDNF and some intracellular signaling pathways, such as protein kinases MAPK and the transcription factor CREB, has been described. In this study we found that EE prevents the emergence of anxiety-related behavior triggered by acute stress in rats, an effect observed just after the stress stimulus. This effect may be related to the modulation, in the basolateral amygdala, of nuclear GR signaling, ERK (a MAPK protein) and CREB activity, as well as to changes in the expression of BDNF receptor.