Neurobiological Processes Induced by Aerobic Exercise through the Endocannabinoidome

Fabiola Forteza, Giada Giorgini, Frédéric Raymond, Fabiola Forteza, Giada Giorgini, Frédéric Raymond

Abstract

Evidence suggesting the triangulation of the endocannabinoid system, exercise, and neurological health is emerging. In addition to the endocannabinoids N-arachidonoylethanolamine (anandamide; AEA) and 2-arachidonoylglycerol (2-AG), the expanded endocannabinoid system, known as the endocannabinoidome (eCBome), appears to be an important player in this relationship. The eCBome includes several endocannabinoid-like mediators such as N-acylethanolamines and 2-monoacylglycerols, the enzymes involved in their biosynthesis and degradation, and the receptors they affect. This review aims to relate the functional interactions between aerobic exercise, and the molecular and cellular pathways related to endocannabinoids, in the hypothalamus, hippocampus, and the periphery, with special attention given to associations with emotional state, cognition, and mental health. Given the well-documented roles of many eCBome members in regulating stress and neurological processes, we posit that the eCBome is an important effector of exercise-induced central and peripheral adaptive mechanisms that benefit mental health. Gut microbiota imbalance, affecting the gut-brain axis and metabolism, also influences certain eCBome-modulated inflammation pathways. The integrity of the gut microbiota could thus be crucial in the onset of neuroinflammation and mental conditions. Further studies on how the modulation by exercise of the peripheral eCBome affects brain functions could reveal to be key elements in the prevention and treatment of neuropsychological disorders.

Keywords: brain; central nervous system; depression; endocannabinoids; mental health; microbiome; peripheral nervous system; physical activity; stress.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Interaction between endocannabinoids, glutamate, and the HPA axis under stressful conditions. This figure summarizes the theory presented by Hill et al. (2010) about the intervention of eCBs, the glutamatergic (Glu) system, glucocorticoids (GC) and the corticotropin-releasing hormone (CRH) in response to different stressful stimuli, the stress response being dependent on glutamatergic neurons and CB1 signaling in murine models. The synapses illustrated occur in the amygdala, hypothalamus (HYP), hippocampus or prefrontal cortex (PC). Symbols show the nature of the effect on the HPA axis, either neutral (−), excitatory (+) or inhibitory (x). (A) The non-stressed condition enables to maintain normal levels of AEA and to stabilize Glu activity onto the basolateral amygdala (BLA) neurons, which does not affect the HPA axis. Under acute stressful situations (B), the HPA is activated to ensure the survival of the organism. In response to stress, fatty acid amide hydrolase (FAAH) activation promotes the hydrolysis of AEA in all brain regions considered, whereas there are unchanged or lower 2-AG levels in the amygdala and in the HYP, respectively. The impaired AEA/CB1 signaling onto Glu synapses in turn induces a higher Glu input onto BLA neurons. A negative fast feedback occurs when there is a hypersecretion of cortisol (C). Biosynthesis of eCBs is then engaged to activate CB1 receptors in Glu terminals, thus diminishing or even suppressing Glu release and further CRH production in a retrograde manner. BLA-GABAergic outflow through eCB signaling can also generate a negative fast feedback in the amygdala. During chronic stress (D), the insufficient increases of 2-AG/CB1 signaling induced by many stressful circumstances downregulates CB1 signaling in the medial PC and the HYP that results in a “hypocannabinoid state”.
Figure 2
Figure 2
The possible ECS-related neurological outcomes of aerobic exercise and metabolic processes in hippocampal, hypothalamic, and peripheral tissues. The eCBs are involved in brain and exercise interactions. (A) Cross-sectional and prospective studies have been selected and used to summarize the implication of eCBs in mood, temper, cognition, and motor skills in relation to acute and chronic aerobic exercise. Looking at the hippocampus, aerobic exercise was associated with the increase of CB1 signaling and hippocampal BDNF expression (Ferreira-Vieira et al., 2014), exerting a neutral to positive impact into neuroplasticity and mental factors in animals. In the hypothalamus, the HPA axis and CB1 signaling reduce stress and fear. In the periphery, aerobic exercise seems to have positive impacts on the phenotype of human brain factors through the rise of OEA, AEA and a cortisol-AEA-GABA cascade. (B) The eCBs also impact on metabolism, thus playing a secondary neurological role. In the hippocampus, some animal studies suggested that CB1 overactivity would lead to inflammation and obesity-related consequences such as hyperphagia and glucose intolerance. The hypothalamic AMPK, eCBs, dopaminergic and ghrelin systems might interact to activate feeding, as well as CRH release. In the skeletal muscle, liver and adipose tissues of humans and animals, eCB/CB1 signaling would play the same role with possible inhibitory effects by OEA. CB1 signaling would also increase lipopolysaccharide (LPS) levels, low-grade inflammation, and insulin resistance. Physical activity and diet could be putative triggers of energy seeking molecular mechanisms and be implicated in inflammatory processes.
Figure 3
Figure 3
Gut-brain axis routes in mental health. The gut microbiota and the CNS are connected through immune, vagus nerve, metabolic and neuroendocrine-mediated pathways. These processes can all contribute to mental health or illness where eCBs and other molecules interfere depending on the cell or tissue. SCFAs are primary products of the fermentation of complex fibers by gut microbes in an intestinal balanced environment i.e., eubiosis. SCFAs induce GABA and serotonin (5-HT) production, attenuating depressive-like behavior. These neurotransmitters can also exert their roles in the brain where, with BDNF and CB1, they can bring positive mood changes. On the other hand, LPS-mediated low-grade inflammation in the gut caused by disruption of microbiota composition (dysbiosis) and intestinal barrier perturbation, would induce tryptophan degradation, raising kynurenine (KYN) levels and reducing 5-HT release, two events associated with depressive mood. The action of pro-inflammatory interleukins (pro-IL) and LPS would evolve in an inflammatory state in the brain. Inflammatory stimuli and stressor exposure would engage HPA overstimulation. HPA function through GC and ACTH circuitry release in gut microbiota-mediated anxiety-like behaviors is notable (Kang et al., 2014). Strong bidirectional correlations are found between major depressive disorder (MDD), psychosis, Alzheimer’s disease, autism spectrum disorder and intestinal dysbiosis, which correlates with the dietary and exercise patterns.

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