Early-life adversity and depression: nature versus nurture.

Adverse early life experiences, in the form of poor maternal care, are recognized to program an abnormal stress response, which increases the risk of psychiatric disorders e.g. depression in adulthood. Moreover, the impact of adverse early-life experiences has the potential to extend to future generations, suggesting a contribution by genetic and possibly, epigenetic factors. The mechanisms of stress dysfunction are complex, but may involve inhibitory GABAA receptors (GABAARs), as these receptors crucially curtail stress-induced activation of the HPA axis. The levels of the endogenously occurring neurosteroid 5α-pregnan-3α-ol-20-one (5α3α-THPROG), a selective GABAAR enhancer, rise rapidly during acute stress, therefore suggesting that this neurosteroid may be an important regulator of the stress response. We have found a stressful event early in life results dramatic alterations how neurons in the stress circuitry communicate resulting in the adult developing an anxious/depressive-like phenotype. These alterations include both abnormal excitatory transmission and loss of the actions of 5α3α-THPROG.

You will be trained to utilize electrophysiological, behavioural and molecular biology techniques to explore how these changes may influence in adulthood the development of depressive-like behaviours and may be transmitted to subsequent generations. Such research should allow a better understanding of how early-life experience and genetics may cause vulnerability to psychiatric disorders, including addiction and influence the design of new pharmacological approaches to treat or prevent the development of depression.

References

  1. Gunn, B.G., Cunningham, L., Cooper, M.A., Corteen, N.L., Seifi, M., Swinny, J.D., Lambert, J.J., Belelli, D. (2013). Dysfunctional astrocytic and synaptic regulation of hypothalamic glutamatergic transmission in a mouse model of early-life adversity: relevance to neurosteroids and programming of the stress response. J. Neurosci. 33(50) 19534-19554.
  1. Gunn BG, Brown AR, Lambert JJ, Belelli D. (2011) Neurosteroids and GABA(A) receptor Interactions: A Focus on Stress. Front Neurosci. 5:131.
  1. Belelli D and Lambert JJ (2005) Neurosteroids: endogenous regulators of the GABA(A) receptor. Nat. Rev. Neurosci. 6, 565-575.


Supervisor: 
Professor Jerry Lambert
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