The somatotropic axis: Effects on brain and cognitive functions

Abstract

Both hormones of the somatotropic axis, insulin-like growth factor-1 (IGF-1) and growth hormone (GH) can cross the blood-brain barrier and bind to their receptors in neurons and glia throughout the brain. Features of aging resemble those of GHD and aging is also associated with a decline in the activity of the GH–IGF-1 axis. Like GH, dopamine also decreases with age and both may influence cognitive decline associated with aging. Activity in the hippocampus- anterior cingulate cortex (ACC) circuit is sensitive to dopamine, suggesting a route through which GH may affect cognitive processes, since it is known that dopamine stimulates pituitary GH release in humans and GH stimulates β-endorphins, which in turn stimulates dopamine neurons. Brain function that has typically been associated with dopamine includes the ERN, but also the NoGo N2, and perhaps even the N2b. Previous studies have indicated that the effects of GH on cognition might pharmacologically involve the neurotransmitter dopamine and from an anatomical stance the VTA-hippocampus-ACC axis. We combined these notions in an integrative hypothesis stating that the effects of GH might for a significant part be due to GH stimulated projections from the hippocampus that modulate dopamine activity in the ACC. Therefore the thesis also includes more basic cognitive neuroscience research concerning the interrelations between electrophysiological correlates of ACC activity, and their relationship to interindividual differences in dopamine dependent learning from (probabilistic) feedback. The main topic of this thesis is to specify the influence of GH on cognition and brain function. In the studies that are presented, cognition is assessed by neuropsychological tests, which are covering multiple domains of cognition, experimental psychological tasks, which mainly concern selective attention and electrophysiological recordings. The effects of GH are studied both observationally and experimentally. The observational studies concerned the correlations between GH levels, including GH deficiency or GHD, in healthy older men and patients that underwent radiation therapy for brain tumors. In observational studies we addressed relations between on the one hand GH and IGF-1 levels and on the other (1) cognition in general (neuropsychology); (2) performance indices of selective attention (target detections, false-positive responses); and (3) attention-related brain function, the so-called selection potentials The experimental study involved a pharmacological trial of acute GH releasing Hormone (GHRH) with cognitive assessments as outcome measures. In sum, relations between somatotropic-axis function, and cognition and brain function were found: ● There is an acute effect on ACC-based brain function which is probably dependent on dopaminergic signaling; ● Pathologically low levels of GH result in reductions in basic processing speed, as well as impairments in (brain function related to) ‘higher’ forms of cognition such as the integrated processing of various sources of information; ● Even in healthy aging, there is a relation between IGF-1 levels and motor processing.