NEUROGENESIS:

1. NEUROGENESIS: Mediating the therapeutic effects of antidepressant treatment

2. Ramon y Cajal Hippocampal Formation “In adult centers the nerve paths are something fixed, ended, immutable. Everything may die, nothing may be regenerated”.

3. Where?

4. How?

5. Ambiguities

6. NEUROGENESIS: Mediating the therapeutic effects of antidepressant treatment

7. Antidepressant drugs

8. Santarelli et al. (2009) • Mice were treated with Fluoxetine • Injection with BrdUon the last day of treatment • 60% increase in BrdU-positive cells after 11 or 28 days (but not 5). • Chronic fluoxetine treatment caused an increase in progenitor cells (70 ±2% will differentiate in neurons). Effects of fluoxetine

9. Santarelli et al. (2009) • WT and 5-HT1A-KO mice were treated with fluoxetine or vehicle • Fluoxetine increased BrdU-labeled cells in WT but not KO mice • Same experiment w/ 8-OH-DPAT • Activation of 5-HT1A is necessary and sufficient for effects of fluoxetine on neurogenesis. Effects of fluoxetine on neurogenesis

10. Santarelli et al. (2009) • Tested with NSF paradigm • KO mice =  latency • KO mice = insensitive to fluoxetine • Same experiment with 8-OH-DPAT •  Latency in WT mice only • Activation of 5-HT1A is necessary and sufficient for effects of fluoxetine on behavior • Thus there is correspondence between neurogenesis and behavior. Effects of fluoxetine on behavior

11. Santarelli et al. (2009) • Irradiation of the SGZ (=selective ablation of precursors by apoptosis). • ~85% reduction in BrdU-labeled cells • Increase in apoptotic nuclei Effects of irradiation

12. Santarelli et al. (2009) Effects of irradiation on NSF • Fluoxetine = • Latency to feed in sham but not SGZ irradiated mice • Latency to feed in sham and SVZ / Caudate irradiated mice Effects of irradiation on CUS • F = better state of the fur &  grooming latency in sham but not irradiated mice • Disrupting hippocampal neurogenesis with x-irradiation blocked the effects of chronic AD treatment.

13. Electroconvulsive shock

14. Perera et al. (2007) • 3 groups of bonnet macaques: ECS, sham, untreated • ECS 3 times a week, for 4 weeks • BrdUinjections: immediate group + delayed group (4 weeks later) • BrdU-positive cells were increased by 10 for both immediate &delayed groups treated with ECS. • The cells that proliferated after the intervention survived for at least 1 month. • ECS didn’t affect the maturational fates (60% matured into neurons) • Thus the increase in cell proliferation resulted in an overall increase in neurogenesis. • 1st study to show ECS-induced up-regulation of neurogenesis in NHPs

15. Exercise

16. Bjørnebekk, Mathé & Brené (2005) • Flinders Sensitive Line (FSL) &Flinders Resistant Line (FRL) rats. • Free access or no access running wheels. • Forced Swim Task (FST) after 30 d of running: swimming vs. floating (immobility). • BrdU Injection 4 d after the FST. • Depressed rats had lower cell proliferation in DG compared to control; • Running normalized the cell proliferation levels in depressed rats + decreased immobility in the FST • Running has an antidepressant effect • Correspondence between neurogenesis &behavior

17. Erikson et al. (2011) • Older adults without dementia • 2 groups: aerobic exercise group &stretching control group. • MRI scans before the intervention, after 6 months &after 1 year. • Stretching group = ~1.5% decline in anterior hippocampal volume (1 year). • Exercise group= ~2% increase in volume. • This is equivalent to adding 1-2 y worth of volume to the hippocampus. • Effect was minimal on the posterior hippocampus, and nonsignificant on the thalamus and caudate nucleus (control regions). • Exercise is effective at reversing age-related volume loss. This effect is specific to the anterior hippocampus.

18. Erikson et al. (2011) • The intervention was effective at increasing fitness levels, as shown by an improvement in the VO2 max (maximal oxygen consumption). • Larger changes in fitness were associated with larger changes in volume. • Higher fitness levels at baseline were associated with less hippocampal volume loss over the 1-y interval. • Only the right anterior hippocampus was protected by higher fitness levels.

19. Erikson et al. (2011) • Greater changes in serum BDNF were associated with greater increases in volume for the anterior hippocampus only. • BDNF mediates cell proliferation in the dentate. Thus exercise-induced increases in hippocampal volume may be mediated by increases in BDNF.

20. The time needed for treatments to affect behavior corresponds to that needed for neurons to mature in the SGZ. • For antidepressant drugs this time corresponds to 4 weeks. • For ECT, both increased neurogenesis and the behavioral effects can be observed within 1 week. • Suppressing neurogenesis by irradiation blocks the behavioral effects of treatment. • While MRI scans have shown depressed populations to have a reduced volume of the hippocampus, exercise, which can alleviate depression, increases neurogenesis, BDNF levels and hippocampal volume. • These all support the neurogenic hypothesis of depression, which maintains that adult hippocampal neurogenesis is an underlying mechanism of action shared by antidepressant treatments. Indeed, the hippocampus plays a critical role in many cognitive functions affected by depression. CONCLUSION

21. However, the functional role of new neurons remains to be determined. It is indeed possible that antidepressant-induced neurogenesis is an epiphenomenon unrelated to therapeutic effects. There are other potentially therapeutic mechanisms of antidepressants independent of neurogenesis, which are being investigated. • Another limitation concerns the fact that although major depressive disorder is a human condition, it has been mostly studied in rodents, due to the difficulty of analyzing cellular mechanisms in the human brain premortem. LIMITATIONS