The ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve... Show moreThe ventral tegmental area dopamine (VTA-DA) mesolimbic circuit processes emotional, motivational, and social reward associations together with their more demanding cognitive aspects that involve the mesocortical circuitry. Coping with stress increases VTA-DA excitability, but when the stressor becomes chronic the VTA-DA circuit is less active, which may lead to degeneration and local microglial activation. This switch between activation and inhibition of VTA-DA neurons is modulated by e.g. corticotropin-releasing hormone (CRH), opioids, brain-derived neurotrophic factor (BDNF), and the adrenal glucocorticoids. These actions are coordinated with energy-demanding stress-coping styles to promote behavioral adaptation. The VTA circuits show sexual dimorphism that is programmed by sex hormones during perinatal life in a manner that can be affected by glucocorticoid exposure. We conclude that insight in the role of stress in VTA-DA plasticity and connectivity, during reward processing and stress-coping, will be helpful to better understand the mechanism of resilience to breakdown of adaptation. Show less
Confidence in a theory increases when it is confirmed by relevant data. Alongside some consistent findings, the data in the prevailing thesis largely detail a lack of confirmation of the... Show moreConfidence in a theory increases when it is confirmed by relevant data. Alongside some consistent findings, the data in the prevailing thesis largely detail a lack of confirmation of the neurotrophin hypothesis. And where expected associations were established (e.g., abnormally low serum BDNF concentrations in the depressed state), the meaning often was not that clear (e.g., reverse causation). I therefore conclude, whilst taking limitations into account and acknowledging that the results are contingent upon imperfect and peripheral measurement, that the most reliable evidence in humans does not corroborate the neurotrophin hypothesis. So, given the data, the final words of this thesis are that solid work over novelty shows that the neurotrophin hypothesis should no longer be credited in its original form. All that glitters is not gold - back to the drawing table Show less
