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For decades, the mammalian hippocampus has been the focus of cellular, anatomical, behavioral, and computational studies aimed at understanding the fundamental mechanisms underlying cognition. Long recognized as the brain's seat for learning and memory, a wealth of knowledge has been accumulated on how the hippocampus processes sensory input, builds complex associations between objects, events, and space, and stores this information in the form of memories to be retrieved later in life. However, despite major efforts, our understanding of hippocampal cognitive function remains fragmentary, and models trying to explain it are continually revisited. Here, we review the literature across all above‐mentioned domains and offer a new perspective by bringing attention to the most distinctive, and generally neglected, feature of the mammalian hippocampal formation, namely, the structural separability of the two blades of the dentate gyrus into “supra‐pyramidal” and “infra‐pyramidal”. Next, we discuss recent reports supporting differential effects of adult neurogenesis in the regulation of mature granule cell activity in these two blades. We propose a model for how differences in connectivity and adult neurogenesis in the two blades can potentially provide a substrate for subtly different cognitive functions.

The fragile X mental retardation protein (FMRP) is an important regulator of protein translation, and a lack of FMRP expression leads to a cognitive disorder known as fragile X syndrome (FXS). Clinical symptoms characterizing FXS include learning impairments and heightened anxiety in response to stressful situations. The Fmr1-/y mouse has previously been shown to have deficits in context discrimination and novel object recognition tasks, which primarily rely on the dentate gyrus (DG) region of the hippocampal formation, but not in the Morris water maze (MWM) or the elevated plus-maze tasks, which primarily depend on the Cornu Ammonis (CA1) region. Furthermore, previous research has demonstrated N-methyl-D-aspartate receptor (NMDAR)-associated synaptic plasticity impairments in the DG but not in the CA1. However, the impact of acute stress on synaptic plasticity in the Fmr1-/y hippocampus has not been examined. The current study sought to extend previous behavioural investigations in the Fmr1-/y mouse, as well as examine the impact of stress on activation of the hypothalamic-pituitary-adrenal (HPA)-axis and on hippocampal synaptic plasticity. To further characterize hippocampus-dependent behaviour in this mouse model, the DG-dependent metric change spatial processing and CA1-dependent temporal order discrimination tasks were evaluated. The results reported here support previous findings and demonstrate that Fmr1-/y mice have performance deficits in the DG-dependent task but not in the CA1-dependent task, suggesting that previously reported subregional differences in NMDAR-associated synaptic plasticity deficits in the hippocampus of the Fmr1-/y mouse model may also manifest as selective behavioural deficits in hippocampus-dependent tasks. In addition, following acute stress, mice lacking FMRP showed a faster elevation of the glucocorticoid corticosterone and a more immediate impairment in long-term potentiation (LTP) in the DG. Stress-induced LTP impairments were rescued by administering the glucocorticoid receptor (GR) antagonist RU38486. Administration of RU38486 also enhanced LTP in Fmr1-/y mice in the absence of acute stress to wild-type levels, and this enhancement was blocked by application of the NMDAR antagonist 2-amino-5-phosphonopentanoic acid. These results suggest that a loss of FMRP results in enhanced GR signalling that may adversely affect NMDAR-dependent synaptic plasticity in the DG. Finally, synaptic plasticity alterations reported in this work were found to be specific to the DG and were unidirectional, i.e., restricted to LTP, as NMDAR- and metabotropic glutamate receptor (mGluR)-LTD were both unaffected by acute stress in the DG or the CA1 regions. This study offers new insights into synaptic plasticity impairments in the Fmr1-/y mouse model, and suggests stress and GRs as important contributors to learning and memory deficits in FXS. / Graduate

Cardiovascular disease (CVD) is the leading cause of death in the United States. Nearly half of the people diagnosed with heart failure (HF) die within 5 years of diagnosis. Brain abnormalities secondary to CVD have been observed in many discrete regions, including the hippocampus. Nearly 25% of patients with CVD also have major depressive disorder (MDD), and hippocampal dysfunction is a characteristic of both diseases. In this study, the hippocampus and an area of the hippocampal formation, the dentate gyrus (DG), were studied in a canine model of HF. Using this canine HF model previously, we have determined that myocardial infarction with mitral valve regurgitation (MI/MR) + spinal cord stimulation (SCS) can preserve cardiac function. The goal of this study was to determine if the SCS can also protect the brain in a similar fashion. Both the entire hippocampus and the DG tissues were dissected from canine brains and analyzed. These findings provide strong evidence that, in addition to the cardioprotective effects observed previously, SCS following MI/MR induces neuroprotective effects in the brain.

Lensemble du travail de recherche réalisé s'est concentré sur l'évaluation du rôle fonctionnel que peut exercer le gène circadien Per2 sur les capacités de prolifération et différenciation des cellules souches/progénitrices à l'origine de la neurogenèse hippocampique. Ce travail a comporté d'une part, une cartographie phénotypique exhaustive de l'identité des cellules exprimant la protéine PER2 au sein de la structure hippocampique, et d'autre part une étude approfondie des conséquences de la l'invalidation de ce gène sur la régulation de la neurogenèse dans l'hippocampe de souris adultes. Dans la première partie de notre travail, nous avons démontré par une analyse immunohistochimique détaillée, qu'au niveau du gyrus dentelé (DG) de souris adultes, les cellules proliférantes exprimaient la protéine PER2 et que cette expression persistait dans les cellules de la lignée neuronale à différents stades de maturation. Par ailleurs, à l'inverse du noyau suprachiasmatique (centre générateur des rythmes circadiens), nous avons également pu observer une expression constante de cette protéine durant une période de 24h (Borgs et al, soumis). Dans la seconde partie de notre travail, nous nous sommes interrrogés sur le rôle fonctionnel que pouvait exercer le facteur de transcription circadien Per2 dans le DG de souris adultes. Nous avons montré que linvalidation de ce gène entraine dans le DG des souris déficientes pour la protéine PER2, une augmentation significative de la prolifération des progéntieurs neuronaux, ainsi que du nombre de neurones immatures. Cependant, nous navons observé aucune différence dans la génération de neurones matures (neurogenèse) entre le DG de souris sauvages et de souris invalidées pour Per2. Nos données ont révélé que le surplus de cellules en prolifération et de neurones immatures observés dans le DG de souris délétées pour Per2 apparaît donc totalement compensé par une augmentation de la mort cellulaire (Borgs et al, soumis). Pour étudier limplication fonctionnel de la protéine PER2 sur le contrôl de la prolifération de progéniteurs/cellules souches à lorigine de la neurogenèse adulte, nous avons mis au point la culture en suspension de cellules souches/progénitrices issues du DG post-natale de souris sauvages et déficientes pour Per2. Après 5 jours de culture, nous avons observé la formation de neurosphères dont la taille et dont la croissance était plus importante chez les souris déficientes pour Per2 que chez leurs homologues sauvages. Ce modèle de culture de DG nous a permis détudier de façon plus présice le destin cellulaire emprunté par les cellules proliférantes/souches dans le modèle muté, comparé au modèle sauvage. En condition de culture favorisant la différenciation, nous avons observé un plus grand nombre de neurones générés à partir des neurosphères issues de cellules de DG de souris mutées pour PER2. Ce modèle de culture de cellules progénitrices/souches issues du DG, confirme les résultats précédemment obtenus concernant le rôle de Per2 dans le contrôle de la prolifération et de la génération de nouveaux neurones in vivo. Parallèlement, nous avons tenté de déterminer si lexpression de Per2 pouvait exercer un rôle similaire au DG au sein de la zone sous ventriculaire antérieure (SVZ), la seconde zone où persiste de la neurogenèse tout au long de la vie. La SVZ du cerveau adulte représente un réservoir de progéniteurs proliférant qui vont cheminer le long dun courant rostral de migration pour atteindre le bulbe olfactif dans lequel ils vont se différencier en neurones. La protéine Per2 se révèle être exprimée dans les progéniteurs en prolifération exprimant Ki67. Tout comme dans le DG de souris adultes déficientes pour Per2, nous avons dénombré in vivo et in vitro une augmentation importante du nombre de cellules en prolifération comparé aux souris sauvages. Per2 semble donc être un des protagonistes impliqué dans la régulation de la prolifération et de la différenciation des progéniteurs/cellules souches à lorigine de la neurogenèse hippocampique.

Previous research on the relationship between spatial memory and adult hippocampal neurogenesis has been controversial. In the present study, neurogenesis was compared between two natural populations of the same species that differ in their reliance on spatial memory to cache and retrieve stored food. Western red squirrels store food in a single site whereas eastern red squirrels store food in multiple sites. Neurogenesis was assessed using endogenous markers of the number of proliferating cells (Ki-67) and the number of immature neurons (DCX), and neuronal recruitment was determined by measuring the area of the dentate gyrus of the hippocampus. The number of proliferating cells, immature neurons and neuronal recruitment were enhanced in the eastern compared to the western red squirrels, reflecting the food storing strategies used by the squirrels. This suggests that there is a positive correlation between adult hippocampal neurogenesis and spatial learning and memory.

Previous research on the relationship between spatial memory and adult hippocampal neurogenesis has been controversial. In the present study, neurogenesis was compared between two natural populations of the same species that differ in their reliance on spatial memory to cache and retrieve stored food. Western red squirrels store food in a single site whereas eastern red squirrels store food in multiple sites. Neurogenesis was assessed using endogenous markers of the number of proliferating cells (Ki-67) and the number of immature neurons (DCX), and neuronal recruitment was determined by measuring the area of the dentate gyrus of the hippocampus. The number of proliferating cells, immature neurons and neuronal recruitment were enhanced in the eastern compared to the western red squirrels, reflecting the food storing strategies used by the squirrels. This suggests that there is a positive correlation between adult hippocampal neurogenesis and spatial learning and memory.

Long-term adrenalectomy (ADX) results in a specific loss of dentate gyrus granule cells in the hippocampus of adult rats, occurring over a period of weeks to months. This loss of granule cells results in cognitive deficits in a number of tasks that depend on intact hippocampal function. The gradual nature of ADX-induced cell death and the ensuing deficits in cognition are similar to those experienced by patient populations suffering from a variety of pathological conditions. Here we present an animal model by which we use ADX to produce a loss of granule cells within the hippocampus of rats. We also provide experimental evidence for a treatment strategy by which the lost granule cells may be replaced, with the goal of functional recovery in mind. / xii, 191 leaves : ill. (chiefly col.) ; 28 cm

Fetal Alcohol Spectrum Disorders (FASD) are the most common cause of cognitive impairment in the United States (Sokol et al., 2003). In young school children in North America and some Western European countries, recent reports have estimated the prevalence of FASD to be as high as 2-5% (May et al., 2009). Currently there are no widely accepted treatment options for FASD, mainly due to the fact that the underlying neurological deficits that occur with prenatal ethanol exposure (PNEE) are still largely unknown. This thesis examines the long-lasting changes that occur in the hippocampus following PNEE using biochemical and electrophysiological techniques. We find that PNEE produces a reduction of the endogenous antioxidant glutathione (GSH), resulting in an increase in oxidative stress that is accompanied by long-lasting reductions in long-term potentiation (LTP) of synaptic efficacy. Interestingly, males exhibited greater deficits in synaptic plasticity than females, despite similar reductions in GSH in both sexes. By depleting GSH in control animals we determined that LTP in the DG of female animals is more resistant to changes in GSH, which may explain the sexual dichotomy observed in these studies of PNEE. Based on these findings, ethanol-exposed animals received postnatal dietary supplementation with either a precursor of GSH, N-Acetylcysteine (NAC) or Omega-3 fatty acids. These supplements helped to counteract the effects of PNEE and improved hippocampal function. The findings in this thesis support the hypothesis that increasing antioxidant capacity can enhance hippocampal function, which in turn may improve learning and memory in FASD, providing a therapeutic avenue for children suffering with these disorders. / Graduate / 0570 Nutrition / 0317 Neuroscience / anna.r.patten@gmail.com