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Songbirds, Steroids, and Adult Neurogenesis Brad Walters Biological Sciences Lehigh University September, 2008 Songbirds, steroids, and neurogenesis… Some tissues regenerate well… http://flickr.com/photos/museumoflondon/2392340925/ 1 2 3 4 http://www.anat.ucl.ac.uk/business/becker1.shtml Others, not so good… http://commons.wikimedia.org/wiki/Image:MCAO-sheep.jpg The absence of evidence is not evidence of absence!!! Visualizing Neurogenesis: nucleotides (e.g. thymidine) get incorporated into DNA strands during replication Altman, 1962 [3H] Thymidine incorporates into dividing cells! http://www.bcscience.com/bc9/pgs/quiz_section5.1.htm Some songbird brains change dramatically across seasons Brenowitz et al, 1991 Margoliash, 2005 Nottebohm, 1981 Do the changes in volume result from Neurogenesis? Nucleus Axon Hillock Dendrites A neuron stained with [3H]thymidine, counterstained with methylene blue. Bar = 50µm Goldman and Nottebohm, 1983 Axon Electron micrograph of a new neuron in HVC. N = nucleus, A = axonal hillock, D = dendrite, Voltage (mV) But are they really neurons? Time (msec) Paton and Nottebohm, 1984 No… But seriously… Are they really neurons? The retrograde tracer, Fluorogold was injected into RA, a nucleus known to be innervated by axons projecting from HVC. Kirn and Nottebohm, 1991 Seasonal neurogenesis in songbirds suggests the involvement of steroid hormones. Spring Fall Kirn and Nottebohm, 1993 Smith et al. 1997 Testosterone increases neurogenesis Bottjer and Dignan, 1988 However, Testosterone can be metabolized in the brain… 5-α Reductase Aromatase Testosterone Dihydrotestosterone (DHT) 17β-Estradiol (Estrogen) So which steroid is it? C T DHT E2 DHT+E2 C T DHT E2 DHT+E2 Tramontin et al. 2003 Estrogen increases neurogenesis in adult songbirds… Average # of HVC Neurons/Section 18 200 HVC Neurons 150 100 N=7 N=8 [3H] Positive HVC Neurons 16 * 50 Average # of New HVC Neurons/Section 14 * 12 10 8 6 4 N=7 N=8 2 0 0 No1 E 2 E Replaced No1 E 2 E Replaced adapted from Hidalgo et al. 1995 Estrogens enhance mammalian neurogenesis. Tanapat et al. 1999 Proliferation Migration Integration Perpetuation Differentiation Adapted from Gage, 2003 Which process or processes are being affected by Estrogen provision? • Functional Neurogenesis is comprised of… 1. 2. 3. 4. Proliferation Migration Differentiation Perpetuation (Survival) 5. Integration Does E affect neural stem cell proliferation? Two main questions: – Do estrogens increase the number of cells entering the cell cycle at any given point in time? – Do estrogens increase the rate at which cells proceed through the cell cycle? Does E affect neuronal migration? • E acts on cells involved in the migration process. • E influences migration away from VZ. Williams et al., 1999 Does E affect Differentiation? 200 Fold Change of mRNA expression • Does E affect cell fate directly? • Does E affect factors that affect cell fate? 150 100 50 0 Brànnvall et al. 2002 BMP-2 Fadrozole Saline Modified from Walters and Saldanha, 2008 Perpetuation (Survival) * * FAD FAD+E2 Saldanha et al. 2005 With regard to adult neurogenesis, estrogen affects… • Proliferation: tentative yes • Migration: tentative yes • Differentiation: maybe • Survival: yes • Integration: ??? This is the next big question!!! OTHER FACTORS KNOWN TO INFLUENCE NEUROGENESIS INCLUDE: Glucocorticoids (-) Testosterone (+) Progesterone (+) BEHAVIOR Exercise (+) Enriched Environment (+) NEUROTRANSMITTERS Serotonin (+) Norepinephrine (+) Glutamate (-) Gage, 2003 HORMONES Summary • Brain Injury and Neurodegenerative diseases can be devastating to the adult brain. • However, neurogenesis in the CNS does occur throughout life. • Thymidine analogs are a powerful, but limited, tool for measuring this process. • Songbirds are an indispensable model organism in this field. • Steroid hormones affect neurogenesis. • Estrogen increases neurogenesis most likely by increasing survival as well as via proliferation (probably), and possibly by affecting cell fate and/or migration. • There are many factors, often working together, that affect neurogenesis. • Clinical applications will depend heavily on the site specific migration and integration of new neurons. Acknowledgements PI Colin Saldanha Collaborators Ryan Wynne Work funded by: NIH (NINDS) 047267