How the Body Talks to the Brain; Peripheral Mediators of Physical Activity-Induced Proliferation in the Adult Hippocampus

Abstract

In the hippocampal dentate gyrus, stem cells maintain the capacity to produce new neurons into adulthood. These adult-generated neurons become fully functional and are incorporated into the existing hippocampal circuit. The process of adult neurogenesis contributes to hippocampal functioning and is influenced by various environmental, hormonal and disease-related factors.One of the most potent stimuli of neurogenesis is physical activity (PA). While the bodily and peripheral changes of PA are well known, e.g. in relation to diet or cardiovascular conditions, little is known about which of these also exert central effects on the brain. Here, we discuss PA-induced changes in peripheral mediators that can modify hippocampal proliferation, and address changes with age, sex or PA duration/intensity. Of the many peripheral factors known to be triggered by PA, serotonin, FGF-2, IGF-1, VEGF, β-endorphin and adiponectin are best known for their stimulatory effects on hippocampal proliferation. Interestingly, while age negatively affects hippocampal proliferation per se, also the PA-induced response to most of these peripheral mediators is reduced and particularly the response to IGF-1 and NPY strongly declines with age. Sex differences per se have generally little effects on PA-induced neurogenesis. Compared to short term exercise, long term PA may negatively affect proliferation, due to a parallel decline in FGF-2 and the β-endorphin receptor, and an activation of the stress system particularly during conditions of prolonged exercise but this depends on other variables as well and remains a matter of discussion. Taken together, of many possible mediators, serotonin, FGF-2, IGF-1, VEGF, β-endorphin and adiponectin are the ones that most strongly contribute to the central effects of PA on the hippocampus. For a subgroup of these factors, brain sensitivity and responsivity is reduced with age.

Early‐life stress diminishes the increase in neurogenesis after exercise in adult female mice

“…Various (growth) factors have been implicated in the pro‐neurogenic effects of exercise, including catepsin B (Moon et al, ), BDNF (Marlatt, Potter, Lucassen, & van Praag, ), cytokines and various neurotransmitters, a.o. (Bolijn & Lucassen, ). Hence, to explain the current results, it will be interesting to study in the future whether ES differentially affects the induction of these factors by exercise.…”

Aerobic Exercise as a Tool to Improve Hippocampal Plasticity and Function in Humans: Practical Implications for Mental Health Treatment

“…Aerobic exercise has been linked to changes in a range of independent and interdependent mechanisms of neuroplasticity within the hippocampus (for comprehensive reviews, see: van Praag, 2009 ; Gomez-Pinilla and Hillman, 2013 ; Voss et al, 2013a ; Bolijn and Lucassen, 2015 ; Opendak and Gould, 2015 ). Key mechanisms at both the cellular and molecular level will be discussed below in terms of their contribution to AE-induced enhancements in hippocampal functioning.…”

“…This coincides with studies that have demonstrated a greater cerebral blood flow in the human hippocampus ( Pereira et al, 2007 ; Burdette et al, 2010 ; Maass et al, 2015 ), some of which have correlated this increase with improved performance on episodic memory tasks ( Pereira et al, 2007 ; Maass et al, 2015 ). The positive influence of improving vascularization may extend beyond a greater supply of oxygen and glucose through prompting the release of neurotrophic factors (the influence of which will be discussed below; Maass et al, 2015 ) or through facilitating other neuroplastic mechanisms like synaptic plasticity ( Christie et al, 2008 ) or neurogenesis ( Palmer et al, 2000 ; Pereira et al, 2007 ; Boecker et al, 2012 ; Bolijn and Lucassen, 2015 ; Biedermann et al, 2016 ). In fact, one recent human RCT found that the improvements in hippocampus dependent task performance and growth in hippocampal volume, which occurred following a 3-month AE intervention were predominantly attributable to a greater cerebral blood flow in the hippocampus ( Maass et al, 2015 ).…”

“…Neurotrophins are important to the development and maintenance of functioning neural cells in the brain ( Barbacid, 1995 ) and are likely to play a crucial role in mediating the impact of AE on hippocampal neuroplasticity and functioning ( Cotman et al, 2007 ; Voss et al, 2013a ; Bolijn and Lucassen, 2015 ). Brain-derived neurotrophic factor (BDNF) is a centrally produced neurotrophin of particular interest due to its high concentration within the hippocampus and its integral role in supporting neuronal survival and growth, and synaptic plasticity ( Cotman et al, 2007 ; Cowansage et al, 2010 ).…”

Beneficial contribution of health behaviors to learning and related brain mechanisms in older adults

“…week intervention. We predicted that hippocampal volume would benefit from the intervention specifically for individuals in the moderate intensity condition due to the accumulating effects of exercise-induced molecular cascades, such as neurogenesis (van Praag, Kempermann, et al, 1999;van Praag et al, 2005), synaptogenesis, changes in blood flow, and angiogenesis, among many others (Bolijn & Lucassen, 2015;Gage, 2002;May, 2011). Thus we were surprised to see that both groups experienced decreases in hippocampal volume, and that the decrease was not mitigated for individuals in the moderate exercise condition.…”