Neurogenesis in the Hippocampus and Learning

Andreas Gustafsson

http://www.bris.ac.uk/Depts/Synaptic/info/pathway/figs/hippocampus.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 SUB – Subicular areas DG –Dentate Gyrus 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(Bruel-

Jungerman)

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.