Neurogenesis in the Hippocampus and Learning Andreas Gustafsson http://www.bris.ac.uk/Depts/Synaptic/info/pathway/figs/hippoca mpus.gif Hippocampus Shows Spatial Learning Place specific behavior is observed in CA3 and CA1, as well as the Entorhinal cortex (Fyhn) Cartoon Wiring of the Hippocampus EC- Entorhinal Cortex DG –Dentate Gyrus SUB – Subicular areas SI – Sensory Information Dentate Gyrus • A portion of the hippocampus • Three layers- molecular, granule, hilus • Granule Cells have axons that synapse on CA3 pyramidal cells • Recent Studies have shown that the dentate gyrus undergoes adult neurogenesis, on the order of thousands of cells (Cameron) What are these new cells doing? • What are the thousands of new cells generated each day doing? • What are they responsible for? • Is it important for memory? General Approach 1) Block cell division 2) Measure behavioral effect 3) Show anatomical difference between treated and control animals Methods • BrdU – labeled thymidine analog, indicates mitosis • Irradiation- kills proliferating cells (Snyder) • MAM – methylates DNA, preventing mitosis (Bruel-Jungerman) Methods • Water Maze (Snyder) • Behavior in a novel environment(BruelJungerman) Cell Staining is Pretty Behavioral Change From Bruel-Jungerman Effect of Environmental Enrichment and MAM treatment- Cell Count Water Maze Training (Snyder) Conclusions • Neurogenesis of granule cells is necessary for long term learning, seemingly on a two week time course. • Neurogenesis is promoted by an enriched environment. Pathologies Associated with Aberrant Granule Cell Behavior • Epileptic patients and model systems show different granule cell behavior and morphology. This observation begs the question “Why?” Normal Granule Cell Proliferation Shapiro Epileptic Phenotype • A seizer seems to generate to two new cell types: hilar ectopic granule cells (HEGC) and and cells with hilar basal dendrites (HBD) Epileptic Granule Cell Proliferation Shapiro Hypothesis • The event of a seizure causes massive cell death in the hilar layer. • Granule cells, which are always dividing, fill in the gaps in the hilar layer. • Abberant placement of granule cells leads to recurrent excitatory loops. References • • • • • • Spatial Representation in the Entorhinal Cortex, Marianne Fyhn, Sturla Molden, Menno P.Witter, Edvard I.Moser, May-Britt Moser. Brown, T.H. and Zador, A.M. (1990). Hippocampus. In The synaptic Organization of the Brain, 3rd ed. (G.M. Shepherd). Oxford University Press. Cameron,H.A.&McKay,R.D.G.(2001)Adult neurogenesis produces a large pool of new granule cells in the dentate gyrus.J.Comp.Neurol.,435 ,406 .417. Bruel-Jungerman, Elodie, Laroche, Serge & Rampon, Claire (2005) New neurons in the dentate gyrus are involved in the expression of enhanced long-term memory following environmental enrichment. European Journal of Neuroscience 21 (2), 513-521. A role for adult neurogenesis in spatial long-term memory J.S. Snyder, N.S. Hong, R.J. McDonald and J.M. Wojtowicza Neuroscience Volume 130, Issue 4, 2005, Pages 843-852 Integration of newly born dentate granule cells into adult brains: hypotheses based on normal and epileptic rodents. Shapiro LA, Ribak CE. Brain Res Brain Res Rev. 2005 Feb;48(1):43-56.