Testosterone and Adult Neurogenesis

Overview
  • Adult neurogenesis occurs in select regions: subgranular zone of the dentate gyrus (DG) in the hippocampus and the subventricular zone (SVZ).
  • Newly generated cells from the SVZ migrate to the olfactory bulbs; some become part of the main and accessory olfactory bulbs.
  • In the DG, new neurons migrate into the granule cell layer and extend axons to CA3; young neurons show enhanced excitability, higher Ca^{2+} conductance, and a lower LTP induction threshold.
Regions of Neurogenesis and Development
  • DG (hippocampus): ongoing generation and integration of new granule neurons.
  • SVZ: progenitors migrate via the rostral migratory stream to interneurons in the olfactory bulbs.
Testosterone Effects on Neurogenesis
  • Testosterone increases adult neurogenesis in the DG via an androgen-dependent pathway.
  • Primarily enhances survival of new neurons; little effect on proliferation.
  • Effects can be context-dependent and may involve indirect routes (e.g., via BDNF or glucocorticoids).
Mechanisms and Pathways
  • Likely androgen receptor (AR) involvement; direct AR signaling on dentate gyrus immature neurons is unclear.
  • MAPK pathway implicated in testosterone’s neuroprotective actions in vitro.
  • BDNF activation by androgens is suggested but not clearly demonstrated as a direct DG pathway.
Testosterone, Stress, and Neurogenesis
  • Acute and chronic stress reduce adult neurogenesis, largely via elevated glucocorticoids.
  • Physiological testosterone levels buffer stress-induced reductions in neurogenesis (e.g., in male rats).
  • Very high testosterone doses may fail to provide buffering effects.
  • Castration increases depressive-like behavior and reduces proliferation and 25-day survival of new cells; testosterone implants can mitigate stress-induced proliferation decreases in some contexts but not universally.
  • Testosterone’s antidepressant-like effects in some male models may not require changes in DG cell proliferation.
Behavioral and Functional Implications
  • In birds, testosterone boosts neurogenesis in HVC; in rodents, in olfactory bulbs and DG.
  • Testosterone-related cognitive advantages (e.g., in spatial tasks) may be partially due to neuroprotection against stress rather than solely changes in neurogenesis.
In Vitro Neuroprotection
  • Testosterone exhibits broad neuroprotective effects in vitro.
  • Activation of MAPK pathway is a key mediator.
Unresolved Questions and Future Directions
  • Whether testosterone acts directly on ARs on new neurons in the DG, or via indirect pathways.
  • Which stages of neural development are most affected by testosterone.
  • Whether testosterone’s effects are general neuroprotection or involve unique molecular pathways in adult neurons.
  • Determine how AR regulation in the DG changes with age, sex, and hormonal status.
Quick Key Terms
  • DG: dentate gyrus; SVZ: subventricular zone; DCX: doublecortin (marker for immature neurons)
  • MAPK: mitogen-activated protein kinase
  • BDNF: brain-derived neurotrophic factor
  • LTP: long-term potentiation
  • HVC: a song control nucleus in birds used as a comparison for testosterone effects