When is adult hippocampal neurogenesis necessary for learning? evidence from animal research.
ABSTRACT The hippocampus is a key brain structure involved in the short- and long-term processing of declarative memory. Since adult hippocampal neurogenesis was first found, numerous studies have tried to establish the contribution of newborn neurons to hippocampus-dependent cognitive functions. However, this large amount of research has generated contradictory results. In this paper, we review the body of evidence investigating the relationship between hippocampal neurogenesis and learning to conclude the functional role of adult-born hippocampal neurons. First, factors that could explain discrepancies among experiments are taken into account. Then, in addition to methodological differences, we emphasize the importance of the age of the newborn neurons studied, as to how their maturation influences both their properties and potential functionality. Next, we discuss which declarative memory components could require involvement of adult hippocampal neurogenesis, taking into consideration the representational demands of the task, its difficulty and the level of performance reached by the subject. Finally, other factors that could modulate neurogenesis and memory, such as stress levels or previous experience of the animal, should also be taken into consideration in interpreting experiments focused on neurogenesis. In conclusion, our analysis of published studies suggests that new adult-born neurons, under certain circumstances, have a crucial and irreplaceable role in hippocampal learning.
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ABSTRACT: Although adolescence is a common age to initiate alcohol consumption, the long-term consequences of exposure to alcohol at this time of considerable brain maturation are largely unknown. In studies utilizing rodents, behavioral evidence is beginning to emerge suggesting that the hippocampus may be persistently affected by repeated ethanol exposure during adolescence, but not by comparable alcohol exposure in adulthood. The purpose of this series of experiments was to explore a potential mechanism of hippocampal dysfunction in adults exposed to ethanol during adolescence. Given that disruption in adult neurogenesis has been reported to impair performance on tasks thought to be hippocampally related, we used immunohistochemistry to assess levels of doublecortin (DCX), an endogenous marker of immature neurons, in the dentate gyrus (DG) of the hippocampus 3-4 weeks after adolescent (postnatal day, PD28-48) or adult (PD70-90) intermittent ethanol exposure to 4 g/kg ethanol administered intragastrically. We also investigated another neurogenic niche, the subventricular zone (SVZ), to determine if the effects of ethanol exposure were region specific. Levels of cell proliferation and cell death were also examined in the DG via assessing Ki67 and cleaved caspase-3 immunoreactivity, respectively. Significantly less DCX was observed in the DG of adolescent (but not adult) ethanol-exposed animals about 4 weeks after exposure when these animals were compared to control age-mates. The effects of adolescent ethanol on DCX immunoreactivity were specific to the hippocampus, with no significant exposure effects emerging in the SVZ. In both the DG and the SVZ there was a significant age-related decline in neurogenesis as indexed by DCX. The persistent effect of adolescent ethanol exposure on reduced DCX in the DG appears to be related to significant increases in cell death, with significantly more cleaved caspase-3-positive immunoreactivity observed in the adolescent ethanol group compared to controls, but no alterations in cell proliferation when indexed by Ki67. These results suggest that a history of adolescent ethanol exposure results in lowered levels of differentiating neurons, probably due at least in part to increased cell death of immature neurons. These effects were evident in adulthood, weeks following termination of the chronic exposure, and may contribute to previously reported behavioral deficits on hippocampal-related tasks after chronic ethanol exposure in adolescence. © 2014 S. Karger AG, Basel.Developmental Neuroscience 06/2014; · 3.41 Impact Factor
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ABSTRACT: Se reconoce que el ejercicio puede aumentar la neurogénesis adulta y este fenómeno podría evidenciarse en diferentes niveles (comportamental, celular, electrofisiológico). El objetivo del estudio fue evaluar el efecto de la estimulación de la neurogénesis hipocampal mediante el ejercicio, sobre la memoria de trabajo evaluada mediante una tarea de laberinto en T en ratas macho adultas de la sepa Wistar. Se utilizó un diseño experimental de dos grupos en el cual un grupo experimental GE (n = 12) fue sometido a un programa de ejercicio forzado durante 5 días, al mismo tiempo que se administró un marcador de síntesis de ADN (Bromo-deoxi-uridina [BrdU](50 mg/kg IP.), los animales control GC (n = 9) no fueron expuestos al ejercicio pero se les administró igual dosis de BrdU. Tres (3) animales (GE = 2; GC = 1) se sometieron a cirugía de implantación de electrodos en la corteza frontal medial (+3,0 mm AP; ± 0.5 mm ML; -3.0mm DV) e hipocampo (-3.0mm AP; ± 1.8mm ML; -3.5mm DV) para registro electroencefalográfico durante la ejecución en el laberinto en T. 6-8 semanas después de la aplicación del ejercicio se evaluó la memoria de trabajo en laberinto en T y se analizaron cuatro (4) días de elección evaluando la alternancia de las opciones como indicador de memoria de trabajo. No se encontró diferencia comportamental entre los grupos experimental y control en variables comportamentales (alternancia, índice de preferencia, tiempo de respuesta, tiempo de ensayo, consumo de comida). El registro electroencefalográfico de los animales no mostró una tendencia a la coherencia entre las áreas registradas, siendo éste un indicador fisiológico del proceso de elección. En cuanto a la cantidad de nuevas neuronas no se encontraron diferencias por grupos.12/2014, Degree: Master, Supervisor: Fernando Cardenas; Manuel Rojas
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ABSTRACT: Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been identified in a neurodevelopmental disorder characterized by early-onset intractable seizures, severe developmental delay, intellectual disability, and Rett's syndrome-like features. Since the physiological functions of CDKL5 still need to be elucidated, in the current study we took advantage of a new Cdkl5 knockout (KO) mouse model in order to shed light on the role of this gene in brain development. We mainly focused on the hippocampal dentate gyrus, a region that largely develops postnatally and plays a key role in learning and memory. Looking at the process of neurogenesis, we found a higher proliferation rate of neural precursors in Cdkl5 KO mice in comparison with wild type mice. However, there was an increase in apoptotic cell death of postmitotic granule neuron precursors, with a reduction in total number of granule cells. Looking at dendritic development, we found that in Cdkl5 KO mice the newly-generated granule cells exhibited a severe dendritic hypotrophy. In parallel, these neurodevelopmental defects were associated with impairment of hippocampus-dependent memory. Looking at the mechanisms whereby CDKL5 exerts its functions, we identified a central role of the AKT/GSK-3β signaling pathway. Overall our findings highlight a critical role of CDKL5 in the fundamental processes of brain development, namely neuronal precursor proliferation, survival and maturation. This evidence lays the basis for a better understanding of the neurological phenotype in patients carrying mutations in the CDKL5 gene.Neurobiology of Disease 06/2014; · 5.20 Impact Factor