My aim for this literature review is to present and discuss a possible relationship between physical exercise and different kinds of cognitive functions. With the increasing interest on the topic, more studies have been conducted and the results from the studies have been a little ambiguous. The most part of the studies has been showing that exercise has a positive effect on cognitive functions. The evidence from the studies also says that exercise can help the brain to regulate the production of new neurons and to increase brain volume in the prefrontal and temporal areas. That can be very beneficial for elderly people with dementia, Alzheimer's disease or other cognitive declines. Evidence of exercise combined with the right nutrition can enhance cognitive performance even more but to establish this more research is needed.

O conhecimento atual sugere que a neurogênese adulta é um mecanismo de plasticidade importante para a manutenção da homeostasia cerebral e conservado no cérebro de mamíferos. A neurogênese adulta pode ser modulada negativamente por exposição prolongada ao estresse e positivamente por fármacos antidepressivos. Nesse sentido, utilizamos o modelo de estresse crônico imprevisível (CUS) para mimetizar em animais o impacto da exposição crônica ao estresse sobre o comportamento e sobre a neurogênese adulta. A administração crônica de antidepressivos pode atenuar o aparecimento de respostas comportamentais em animais submetidos ao CUS, embora exista uma considerável latência para o surgimento desses efeitos. Recentemente, o canabidiol (CBD) emergiu como um novo fármaco com potencial terapêutico para tratamento de transtornos psiquiátricos, como a ansiedade e capaz de reduzir a latência para início dos efeitos em relação aos antidepressivos clássicos, sendo os mecanismos até então pouco compreendidos. Portanto, o objetivo deste trabalho foi investigar se o tratamento com CBD ou escitalopram (ESC) durante 7 ou 14 dias é capaz de atenuar respostas comportamentais do tipo ansiogênica em animais submetidos ao CUS e observar se esse efeito poderia correlacionar-se a diferentes mecanismos relacionados à neurogênese adulta. Para isso, camundongos C57BL/6 machos foram divididos em 6 grupos. Os animais de cada grupo receberam somente um tratamento: CBD (30mg/Kg), ESC (20mg/Kg) ou veículo diariamente durante 7 (n=9-10=grupo) ou 14 dias (n=6-10/grupo) de maneira independente e foram submetidos ou não ao CUS durante o mesmo período. Um dia após o último tratamento, os animais foram submetidos ao teste do Novelty Supressed Feeding (NSF). Além disso, foram realizadas análises de proliferação celular (Ki67), da sobrevivência celular (BrdU) e de marcadores associados a distintos tipos celulares (Sox2 e DCX). Os resultados obtidos no presente trabalho sugerem que o CBD é capaz de prevenir os efeitos do estresse crônico em protocolos de 7 e 14 dias de tratamento, enquanto que o antidepressivo escitalopram previne os efeitos do estresse apenas no protocolo de 14 dias. Além disso, o estresse não alterou significativamente a taxa de sobrevivência celular em ambos protocolos, mas promoveu redução da proliferação celular em 7 dias. Além disso, observou-se uma redução do número de células DCX+ no grupo dos animais estressados/veículo em relação ao grupo de animais controle/veículo no protocolo de 7 dias, diferença esta não encontrada no protocolo de 14 dias. Com relação ao efeito dos tratamentos, encontramos que o CBD ou ESC não previnem a redução da proliferação celular mediada pelo estresse, mas previnem a redução de células DCX+ no protocolo de 7 dias. Os resultados encontrados no presente trabalho sugerem que o CBD pode prevenir os efeitos do estresse em um menor período de tempo quando comparado ao ESC. Porém, o presente trabalho não demonstrou alteração significativa nos parâmetros relacionados à neurogênese, tampouco modulação diferencial entre os fármacos / Current knowledge suggests that adult neurogenesis is an important plasticity mechanism for the maintenance of cerebral homeostasis and conserved in the mammalian brain. Adult neurogenesis can be modulated negatively by prolonged exposure to stress and positively by antidepressant drugs. In the present study, we expose mice to the unpredictable chronic stress paradigm (CUS) and evaluated the impact of chronic exposure to stress on behavior. Chronic administration of antidepressants attenuate CUS-induced behavioral abnormalities in animals, although there is a considerable latency for the appearance of the effects of these drugs. Recently, cannabidiol (CBD) has emerged as a putative new drug with for the treatment of psychiatric disorders, such as anxiety. Therefore, the objective of this study was to investigate whether the treatment with CBD or escitalopram (ESC) for 7 or 14 days is able to attenuate CUS-induced anxiogenic response in mice and, if its effects are correlated with mechanism involving adul type in animals submitted to the CUS and to observe if this effect could correlate to different related mechanisms to adult neurogenesis. Male C57BL6 mice were divided in 6 groups. Each animal of every experimental group received: CBD (30mg / kg), ESC (20mg / kg) or vehicle daily for 7 (n = 9-10 = group) or 14 days (n = 6-10 / group) and were submitted or not to the CUS during the same period. One day after the last treatment, animals were submitted to the Novelty Supressed Feeding (NSF) test. In addition, analyzes of cell proliferation (Ki67), cell survival (BrdU) and markers associated with different cell types (Sox2 and DCX) were performed. The results obtained in the present work suggest that CBD is able to prevent the effects of chronic stress in protocols of 7 and 14 days of treatment, whereas the antidepressant escitalopram prevents the effects of stress only in the protocol of 14 days. In addition, stress did not significantly alter the rate of cell survival in both protocols, but promoted reduction of cell proliferation in 7 days. In addition, a reduction in the number of DCX + cells in the group of stressed animals / vehicle was observed in relation to the group of control / vehicle animals in the 7-day protocol, a difference not found in the 14-day protocol. Regarding the effect of treatments, we found that CBD or ESC did not prevent the reduction of cell proliferation mediated by stress, but prevented the reduction of DCX + cells in the 7-day protocol. The results found in the present study suggest that CBD can prevent the effects of stress in a shorter window when compared to ESC. These effects however seem not to be related to adult hippocampal neurogenesis

L'olfaction est un sens clé dans l'adaptation du comportement. Pour permettre des actions appropriées le système olfactif doit effectuer des discriminations fines entre stimuli. Les performances de discrimination peuvent être améliorées via l'apprentissage perceptif et une structure cérébrale clé : le bulbe olfactif. Cette structure est cible d'une forme de plasticité particulière qui est la neurogenèse adulte. C'est là que des nouveaux neurones, majoritairement des cellules granulaires, régulent l'activité des cellules relais. Il a été montré que ces neurones sont requis pour un apprentissage perceptif.La question centrale de cette thèse est d'élucider le rôle et la spécificité des nouveaux neurones dans l'apprentissage olfactif complexe et changeant.Nous avons d'abord étudié l'effet d'un apprentissage perceptif complexe sur la neurogenèse adulte. Cette étude à démontré la nécessité et suffisance des nouveaux neurones dans l'apprentissage perceptif simple. Elle a aussi montré que lorsque l'apprentissage devient complexe, un réseau plus large est recruté, requérant les neurones préexistant.L'environnement olfactif est aussi changeant. Dans une seconde étude nous avons investigué comment la mémoire olfactive est altérée par nouvelle mémoire et le rôle de la neurogenèse adulte dans ce processus. Elle a montré le rôle des nouveaux neurones à sous tendre la mémoire olfactive et l'importance du délai entre apprentissages dans la stabilisation mnésique.Finalement, le recours aux neurosciences computationnelles a eu pour but de définir le rôle des nouveaux neurones granulaire au niveau du premier niveau de transformation de l'information et comment le raffinement des représentations sensorielles émerge par décorrelation.Pour conclure, la perception olfactive est changeante en fonction des modifications environnementales et cette plasticité est sous tendu par une plasticité du circuit du bulbe olfactif, due en grande partie à la neurogenèse adulte / Olfaction is a key player in behavioral adaptation. To perform tasks accurately, the olfactory system has to perform fine discrimination between very close stimuli. The discrimination performances can be enhanced through perceptual learning and a key cerebral structure in this is the olfactory bulb. This structure is the target of a specific form of plasticity that is adult neurogenesis. In this structure, adult-born neurons differentiate mostly in granule cells that regulate the activity of the relay cells. It has previously been shown that these neurons are required to perform perceptual learning. The central question of this thesis work is to elucidate both the role and the specificity of adult born neurons during complex or changing olfactory learning.We first studied the effect of complex perceptual learning on adult neurogenesis. This study demonstrated the necessity and sufficiency of adult-born neurons for simple olfactory learning. It also showed that when learning becomes complex, a larger neural network is involved requiring preexisting neurons.The olfactory environment is also changing. In a second study we investigated how the memory of an olfactory information is altered by the acquisition of a new one and what is the role of adult neurogenesis in this process. This second study highlighted the role of adult-born neurons in underlying olfactory memory and the importance of delay between learning for memory stabilization.Lastly, an approach relying on computational neurosciences aimed at outlining a computational framework explaining the role of adult-born granule cells in early olfactory transformations and how sharpened sensory representations emerge from decorrelation.To conclude, olfactory perception is changing according to environmental modifications and this plasticity is underlain by an important plasticity of the olfactory bulb circuitry due in large part to adult neurogenesis

The Notch signalling pathway plays an essential role in cell-fate decisions and morphogenesis, and is frequently ectopically activated in human cancers. The signal is initiated through DSL ligand-dependent Notch proteolysis, which releases its intracellular domain. However, over-expression of the E3 ubiquitin ligase Deltex can bypass the requirement for Notch ligands and ectopically activate Notch by directing it into the endocytic pathway. It has been shown that Deltex induced endocytic-Notch signalling, but not DSL-induced signalling, requires both HOPS and AP-3 complex components that mediate trafficking to lysosomes and related organelles. I showed through a combination of the analysis of the dxsm mutant allele and by expression of mutant forms of Deltex in cell culture, that the C-terminal region of Deltex is important for Notch signalling, but is not required for Notch endocytosis. This suggests that the C-terminal region contains an interaction site that may direct endocytosed Notch to the correct endocytic compartment. A key question however was whether this endocytic pathway is utilised for full Notch signaling in normal development alongside the canonical activation mechanism. I therefore investigated the expression of Drosophila midline single-minded (sim), which is a Notch signal reporter gene, and embryonic neurogenesis which is repressed by Notch signalling. I found that deltex, HOPS and AP-3 mutants displayed gaps in sim expression and also a neurogenic phenotype similar to Notch loss-of-function, and consistent with a role for ligand-independent Notch activation in normal development. I found that the penetrance of these phenotypes increased when flies were cultured at higher temperature. These results suggest that Dx/HOPS/AP-3-dependent Notch activation provides a developmental robustness to the Notch signalling network. It was also found that AP-3 and HOPS components have an additional role in regulating cell survival, which is partially separable in time using a temperature shift assay. I also revealed a requirement of maternal Notch for cell survival in early embryonic development, which may be related to the HOPS-dependent function. Comparison of deltex, AP-3 and HOPS mutant phenotypes suggested that there may be functional redundancy of deltex with components that regulate Notch endocytosis, and of AP-3 with proteins that mediate subsequent trafficking to the late endosome/lysosome. Finally I characterised the molecular lesions of an allele of the HOPS component light and the AP-3 component ruby and identified lesions which were consistent with the loss-of-function of these genes.

O maior nicho neurogênico no encéfalo adulto está ao redor dos ventrículos laterais, mas a identificação das células que iniciam tal formação é controversa. Há uma inervação do peptídeo CART que pode abrir perspectivas para o entendimento de seu papel na modulação da neurogênese. Propormos estudar a citoarquitetura ultra-estrutural das células proliferativas na região periventricular e descrever a organização dessa região e sua inervação por axonios imunorreativos ao CART. Utilizamos ratos e camundongos adultos, preparados para análise ultraestrutural e neuroquímica em microscópios eletrônicos de transmissão e varredura de alta-resolução, de luz e laser confocal. O estudo da proliferação e inervação ocorreu com a administração do marcador de fase S BrdU e anticorpos anti-BrdU, anti-CART, anti-DCX, anti-GFAP e anti-GFP. Cada tipo celular do nicho neurogênico apresentou uma densidade própria de ir-BrdU. Identificamos células de revestimento ventricular inervadas por axônios. A maior densidade de inervação ir-CART ocorre ao longo do trajeto dos neurônios em formação. / The major neurogenic niche in adult brains surrounds the lateral ventricles, but the identity of the cell that initiates this process in controversial. There is an innervation made by the CART peptide that may lead to perspectives for understanding its role in modulation of neurogenesis. We propose to study the ultrastructural cytoarchitecture of proliferative cells in this region and its innervation by CART immunoreactive axons. We used adult rats and mice, prepared for ultrastructural and neurochemical analysis by transmission and high-resolution scanning electron, light and laser confocal microscopes. The proliferation and innervation studies occured with the S-phase marker BrdU and anti-Brdu, anti-CART, anti-DCX, anti-GFAP, anti-GFP antibodies. Each sort of cells in neurogenic niche presented a proper density of BrdU staining. We identified the cells lining the ventricle being innervated by axons. The major density of CART innervation occurs along the pathway of neurons in maturation process.

The Wnt signaling network has critical roles in embryonic development and is implicated in human disease. One of the outputs of the Wnt network, called the planar cell polarity (PCP) pathway, regulates tissue polarity and directs cell migration. Core PCP components (Frizzled, Dishevelled, Prickle, Vangl, Celsr) localize asymmetrically in polarized cells and establish polarity across the tissue through protein interactions between adjacent cells. The core PCP component activate tissue-specific "effectors" which translate the signal into morphological changes. PCP is related to several disease conditions, including neural tube defects, cystic kidney disease, and cance metastasis. However, mechanisms of the PCP underlying physiological and disease-related conditions are not well understood. Here, I explore functions of the core PCP component Pk, and its relationship to disease, in the zebrafish model system. Mutations in Pk1 and Pk2 have been identified in human progressive myoclonic epilepsy patients. Pk coodinate cell movement, neuronal migration and axonal outgrowth during embryonic development. Yet, how dysfunctions of pk relates to epilepsy is unknown. Here, I show that knockdown of pk1a sensitizes the zebrafish larva to convulsant drug. To model the defects in central nervous system, I examine neurogenesis in the retina and find that both pk1a and pk2 are required for proper dendritic outgrowth in the retinal inner plexiform layer. Furthermore, I characterize the epilepsy-related mutant forms of Pk1a and Pk2. The mutant Pk1a forms show reduced ability to suppress the retinal neurogenesis defects compared to the wild-type, as well as differential ubiquitination levels. Pk2 mutant forms also show differential activities in overexpression assays and seemingly more stable proteins relative to the wild-type. Taken together, pk1a and pk2 may contribute to epilepsy by affecting neuronal patterning and thus signal processing. Another aspect of PCP function has been implicated in cilia and cilia-related disorders, also called ciliopathy. PCP effectors have been shown to modulate ciliogenesis and core PCP proteins (Vang and Dvl) regulate cilia orientation. On the other hand, cilia are not required for PCP signaling, especially asymmetric core PCP protein localization. These findings leave open the question what is the precise relationship between PCP and cilia. The Bardet Biedl Syndrome (BBS) is a type of ciliopathy that leads to obesity, retinitis pigmentosa, polydactyly, mental retardation and other symptons. A subset of BBS genes share similar knockdown phenotype in cell migration as seen in PCP knockdown embryos. Shared pehnotypes have led some to proposethat PCP and bbs genes may interact. Yet a direct relationship has yet to be established. I examine the interaction between pk2 and a central Bbs gene, bbs7. By analyzing shared phenotypes in double knockdown embryos, I find no synergistic interaction between the two, suggesting they act in distinct pathways. Bbs regulate ciliary trafficking and in zebrafish, knockdown of bbs genes leads to delayed retrograde melanosome transport. Interestingly, I find knockdown of pk2 suppresses this retrograde transport delay. Additionally, pk2 knockdown embryos show a delay in anterograde melanosome transport. These findings highlight a new role for pk2 in intracellular transport and clarifies the relationship between PCP and BBS. In summary, my work here strengthens the link between pk mutations and human epilepsy and identifies functions of pk in retinal neurogenesis and in intracellular transport. To what extent the role of neurogenesis and intracellular transport are related is worth future study. Yet, this new information provides insights into potential mechanisms of epilepsy and the relationship between PCP and BBS.

La maladie de Huntington (MH) est un trouble neurologique transmis selon un mode autosomique dominant qui conduit à l’apparition de symptômes moteurs, psychiatriques et cognitifs chez l’adulte. La MH est caractérisée par une neurodégénérescence massive des neurones striataux et corticaux. La MH est causée par une mutation de la séquence codante de la protéine Huntingtine (HTT) conduisant à la production d’une protéine mutée (mHTT). La mHTT gagne de nouvelles fonctions toxiques mais perd aussi certaines fonctions normales. L’étude de ces deux aspects (à la fois gain et perte de fonction) est donc indispensable à la compréhension du processus pathologique de la MH.La HTT et mHTT participent au développement des structures cérébrales. Notre hypothèse est donc que les défauts développementaux induits par la mHTT contribuent à la progression physiopathologique de la MH. Notre équipe s’intéresse tout particulièrement au développement du cortex cérébral, largement atteint dans la MH. Nos précédentes études ont démontré le rôle de la HTT et l’effet de sa mutation dans la prolifération des précurseurs neuronaux du cortex cérébral. Cependant, les fonctions de la HTT et de la mHTT lors des étapes plus avancées du développement cortical, restent à ce jour inconnues.Mon projet de thèse se décompose en deux axes principaux : (i) l’étude des fonctions de la HTT dans les neurones nouvellement produits dans le cortex en développement, notamment au cours de leur migration et de leur maturation dendritique et (ii), la caractérisation de la neurogenèse corticale dans un modèle génétique de la MH : zQ175. / Huntington disease (HD) is an autosomal dominant inherited neurological disorder conducting to the appearance of motors, psychiatrics and cognitives symptoms during mid-adulthood. HD is characterised by a massive neurodegenerescence of both striatal and cortical neurons. HD is caused by a mutation in coding region of the protein Huntingtin (HTT) leading to the production of a mutated form (mHTT). mHTT gain new toxic function but also loss some of normal function of HTT. Therefore, studying both gain and loss of function is mandatory to better understand the physiopathological progression of HD.HTT and mHTT both contribute to development of cerebral structures. Our hypothesis is that developmental defects induced by mHTT could contribute at least in part to the physiological progression of HD. Our work focuses on cerebral cortex development a structure which is largely impacted in HD. Our previous studies demonstrated roles of HTT and the effect of mHTT in neuronal precursor proliferation during neurogenesis. However, roles and functions of HTT and mHTT during later step of cortical neurogenesis remain elusive.My PhD project has focused on two main aspects: (i) study the function of HTT in newborn post-mitotic neurons in cerebral cortex, notably during their migration and maturation, and (ii), characterising cortical neurogenesis in genetically integrated mouse model of HD: zQ175.

Stroke is a leading cause of death and disability worldwide. Although rapid recognition and prompt treatment have dropped mortality rates, most stroke survivors are left with permanent disability. Approximately 87% of all strokes result from the thromboembolic occlusion of the cerebrovasculature (ischemic strokes). Potential stroke therapeutics have included anti-inflammatory drugs, as well as many other targets with the goal of mitigating the acute and chronic inflammatory responses typically seen in an ischemic stroke. While these approaches have had great success in preclinical studies, their clinical translation has been less successful. Master inflammatory cytokines, such as IL-1, are of particular interest. IL-1’s isoforms, IL-1α and IL-1β, were long thought to have similar function. While IL-1β has been extensively studied in stroke, the role of IL-1α during post stroke inflammation has been overlooked. Because IL-1 inhibitors have been unsuccessful in clinical application, we reasoned that IL-1α may provide previously unknown benefits to the brain after injury. We hypothesized that IL-1α could be protective or even accelerate reparative processes in the brain such as producing new blood vessels (angiogenesis) or neurons (neurogenesis). To test that IL-1α is protective after stroke, we tested IL-1α’s protective effects on primary cortical neurons in in vitro models of stroke. We showed that IL-1α was directly protective on primary cortical neurons in a dose-dependent fashion. We then performed mouse middle cerebral artery occlusion stroke studies to determine the safety of giving IL-1α in vivo. These studies showed that administering IL-1α acutely was neuroprotective. However, intravenous (IV) administration of IL-1α resulted in transient, hemodynamic changes following drug delivery. To minimize these systemic effects, we administered IL-1α intra-arterially (IA) directly into the stroke affected brain tissue, allowing us to significantly lower the concentration of administered IL-1α. In comparison to IV, IA IL-1α showed greater histological protection from ischemic injury as well as improved functional recovery following stroke, all without systemic side effects. To test that IL-1α could aid in neurorepair following stroke, we tested IL-1α’s ability to help damaged blood vessels repair in vitro. We found that IL-1α significantly increased brain endothelial cell activation, proliferation, migration, and capillary formation. We tested IL-1α’s proangiogenic properties in vivo by administering IL-1α three days following stroke. Delayed administration allowed us to separate IL-1α’s acute neuroprotective effects from potential subacute angiogenic effects. We found that mice receiving IL-1α performed significantly better on behavioral tests and also showed greater vascularization within the penumbra two weeks following stroke. We also found that IL-1α treated animals showed more endothelial activation than vehicle treated animals. Finally, our studies showed that IL-1α treated animals showed increased early-phase neurogenesis with evidence of increased proliferation at the subventricular zone suggesting that IL-1α’s beneficial effects are even more far-reaching than previously thought. In conclusion, our experiments suggest that the inflammatory cytokine IL-1α is neuroprotective and neuroreparative in experimental ischemic stroke and worthy of further study as a novel stroke therapy.

The causes of autism spectrum disorder (ASD) are not all known, but it is suspected that the serotonin transporter (SERT) plays an important role for some subjects with ASD. Mutations in the SLC6A4 gene, that encodes SERT, including the Ala56 mutation (Gly56Ala), have been found in some autism patients. This mutation makes the transporter more active and reduces the probability of serotonergic neurotransmission in the brain, which is linked to behavioral changes that are associated with core domain deficits of ASD 1. Depression also has been linked to decreases in the availability of serotonin (5-hydroxytryptamine; 5-HT) in the central nervous system (CNS), and is associated with reduced hippocampal neurogenesis. Selective serotonin reuptake inhibitors (SSRIs), drugs used to block SERTs, are used to treat depression and/or anxiety by inhibiting SERT to increase synaptic 5-HT levels. / Includes bibliography. / Thesis (M.S.)--Florida Atlantic University, 2019. / FAU Electronic Theses and Dissertations Collection

Aberrations in brain serotonin (5-HT) neurotransmission have been implicated in psychiatric disorders including anxiety, depression and deficits in learning and memory. Many of these disorders are treated with drugs which promote the availability of 5-HT in the synapse. Selective serotonin uptake inhibitors (SSRIs) are known to stimulate the production of new neurons in the hippocampus (HPC) by increasing synaptic concentration of serotonin (5-HT). However, it is not clear which of the 5-HT receptors are involved in behavioral improvements and enhanced neurogenesis. The current study aimed to investigate the effects of 5HT2A agonists psilocybin and 251-NBMeO and the 5HT2A/C antagonist ketanserin on neurogenesis and hippocampal-dependent learning. Agonists and an antagonist to the 5-HT2A receptor produced alterations in hippocampal neurogenesis and trace fear conditioning. Future studies should examine the temporal effects of acute and chronic psilocybin administration on hippocampal-dependent learning and neurogenesis.