Neurobiology of Physical Exercise: Perspectives on Psychophysiological Effects and Opioidergic Neurotransmission

Abstract: Regular physical exercise promotes health and prevents and treats multiple chronic diseases. Despite the well-acknowledged health benefits, many people remain physically inactive. Affective responses induced by exercise are believed to influence future exercise behaviour. Previous studies suggest that pleasurable sensations experienced in response to exercise are regulated by the endogenous opioid system. The opioid system is also involved in the reward processing, and may modulate food reward responses after exercise, possibly contributing to subsequent caloric intake and weight loss outcomes. In this thesis, affective responses to high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT) were investigated over a two-week training intervention in untrained healthy subjects and subjects with type 2 diabetes or prediabetes. Positron emission tomography (PET) was used to explore endogenous opioid release after HIIT and MICT in young healthy subjects. The interaction between exercise-induced opioid activation and changes in food reward processing were assessed using functional magnetic resonance imaging (fMRI). HIIT generated a more negative overall affective experience in comparison with MICT; however, this lessened over the training period. Thus, HIIT appears as a tolerable exercise method for sedentary adults with and without diabetes. Furthermore, HIIT induced opioid release in key brain regions implicated in emotion and pain processing and the opioid release correlated with measures of negative emotionality. In contrast, MICT did not result in significant opioid release, although increased opioid activation correlated with increased euphoria after MICT as well as with increased neural responses to palatable foods. These results indicate that the intensity of the exercise regulates endogenous opioid release and concomitant changes in affect and reward processing. Taken together, these findings may have practical implications in developing more tolerable and likeable exercise programs to enhance physical activity participation in different population groups, as well as in optimising the efficient use of exercise in health care, for example in weight loss interventions and in the treatment of various affective disorders.Tiivistelmä: Säännöllinen liikunta ylläpitää terveyttä sekä ennaltaehkäisee ja hoitaa lukuisia sairauksia. Terveyshyödyistä huolimatta moni jää kuitenkin sohvaperunaksi. Liikunnan harrastaminen riippuu osin siitä, miltä liikunta tuntuu. Aikaisempien tutkimusten perusteella aivojen opioidijärjestelmän ajatellaan olevan liikunnasta saatavan mielihyvän taustalla. Opioidijärjestelmä säätelee myös ruuan ja syömisen aiheuttamaa mielihyvää, ja se voi siten muovata liikunnan aikaansaamia muutoksia ruuan palkitsevuudessa vaikuttaen näin syömiskäyttäytymiseen ja painonhallintaan. Tässä väitöskirjatyössä tutkittiin, miltä kovatehoinen intervalliharjoittelu (highintensity interval training, HIIT) ja keskitehoinen kestävyysharjoittelu (moderate- intensity continuous training) tuntuvat kahden viikon liikuntajakson aikana liikunnallisesti passiivisilla terveillä koehenkilöillä, sekä tyypin 2 diabeetikoilla ja esidiabeetikoilla. Lisäksi positroniemissiotomografia (PET) -kuvantamisella selvitettiin aivojen opioidijärjestelmän toimintaa HIIT ja MICT harjoitusten jälkeen terveillä nuorilla miehillä. Toiminnallisen magneettikuvantamisen (fMRI) avulla tutkittiin liikunnan vaikutuksia herkullisten ruokakuvien aikaansaamiin hermostollisiin vasteisiin aivoissa. Lyhytkestoinen HIIT aiheutti huomattavasti negatiivisemman tunnekokemuksen kuin pitkäkestoinen MICT, mikä kuitenkin helpottui jo kahden viikon harjoittelujakson aikana niin terveillä kuin tyypin 2 diabeetikoilla ja esidiabeetikoilla. Näin ollen rankka HIIT voi soveltua liikuntavaihtoehdoksi myös aikaisemmin liikuntaa harrastamattomille. Lisäksi havaittiin, että liikunnan intensiteetti säätelee opioidijärjestelmän toimintaa. HIIT vapautti endogeenisiä opioideja tunteiden ja kivun säätelyyn liittyvillä aivoalueilla. Opioidien vapautuminen oli yhteydessä negatiivisiin tuntemuksiin. Vastaavaa opioidien vapautumista ei havaittu MICT:n jälkeen, joskin suurempi opioidiaktivaatio oli yhteydessä lisääntyneeseen euforisuuden tuntemukseen ja suurempiin hermostollisiin vasteisiin herkullisille ruokakuville pitkäkestoisen liikunnan jälkeen. Tutkimuksista saatuja tuloksia voidaan hyödyntää kehitettäessä uudenlaisia lähestymistapoja paitsi ihmisten liikunnalliseen aktivoimiseen, myös liikunnan tehokkaampaan hyödyntämiseen painonpudotuksessa ja esimerkiksi masennuksen ja riippuvuuksien hoidossa

Opioid Release after High-Intensity Interval Training in Healthy Human Subjects

Central opioidergic mechanisms may modulate the positive effects of physical exercise such as mood elevation and stress reduction. How exercise intensity and concomitant effective changes affect central opioidergic responses is unknown. We studied the effects of acute physical exercise on the cerebral μ-opioid receptors (MOR) of 22 healthy recreationally active males using positron emission tomography (PET) and the MOR-selective radioligand [11C]carfentanil. MOR binding was measured in three conditions on separate days: after a 60-min aerobic moderate-intensity exercise session, after a high-intensity interval training (HIIT) session, and after rest. Mood was measured repeatedly throughout the experiment. HIIT significantly decreased MOR binding selectively in the frontolimbic regions involved in pain, reward, and emotional processing (thalamus, insula, orbitofrontal cortex, hippocampus, and anterior cingulate cortex). Decreased binding correlated with increased negative emotionality. Moderate-intensity exercise did not change MOR binding, although increased euphoria correlated with decreased receptor binding. These observations, consistent with endogenous opioid release, highlight the role of the μ-opioid system in mediating affective responses to high-intensity training as opposed to recreational moderate physical exercise

Noninvasive and Quantitative Monitoring of the Distributions and Kinetics of MicroRNA-Targeting Molecules in Vivo by Positron Emission Tomography

MicroRNAs (miRNAs) are endogenous, small, noncoding ribonucleic acids (RNAs) that bind to the 3' untranslated regions of messenger RNAs (mRNAs) and induce translational repression or mRNA degradation. Although numerous studies have reported that miRNAs are of potential use for disease diagnostics and gene therapy, little is known about their fates in vivo. This study elucidated the whole-body distributions and kinetics of intravenously administered miRNA-targeting molecules in vivo by positron emission tomography (PET) imaging. A 22-mer sequence targeting miR-1513 was conjugated with three different chelators and labeled with gallium-68 (Ga-68). These tracers were compared with a scrambled 22-mer sequence; 22-mer with two single base substitutions; anti-miR-34 22-mer; hexathymidylate (T-6), a 6-mer sequence; and an unconjugated chelator. miR-15b was chosen as a target because it is important for bone remodeling. All three Ga-68-labeled anti-miR-15b molecules had similar biodistributions and kinetics, and they all accumulated in the bones, kidneys, and liver. The bone accumulation of these tracers was the highest in the epiphyses of long tubular bones, maxilla, and mandible. By contrast, the scrambled 22-mer sequence, the 6-mer, and the unconjugated chelator did not accumulate in bones. PET imaging successfully elucidated the distributions and kinetics of Ga-68-labeled chelated miRNA-targeting molecules in vivo. This approach is potentially useful to evaluate new miRNA-based drugs

Aerobic exercise modulates anticipatory reward processing via the mu-opioid receptor system

Physical exercise modulates food reward and helps control body weight. The endogenous mu-opioid receptor (MOR) system is involved in rewarding aspects of both food and physical exercise, yet interaction between endogenous opioid release following exercise and anticipatory food reward remains unresolved. Here we tested whether exercise-induced opioid release correlates with increased anticipatory reward processing in humans. We scanned 24 healthy lean men after rest and after a 1 h session of aerobic exercise with positron emission tomography (PET) using MOR-selective radioligand [C-11]carfentanil. After both PET scans, the subjects underwent a functional magnetic resonance imaging (fMRI) experiment where they viewed pictures of palatable versus nonpalatable foods to trigger anticipatory food reward responses. Exercise-induced changes in MOR binding in key regions of reward circuit (amygdala, thalamus, ventral and dorsal striatum, and orbitofrontal and cingulate cortices) were used to predict the changes in anticipatory reward responses in fMRI. Exercise-induced changes in MOR binding correlated negatively with the exercise-induced changes in neural anticipatory food reward responses in orbitofrontal and cingulate cortices, insula, ventral striatum, amygdala, and thalamus: higher exercise-induced opioid release predicted higher brain responses to palatable versus nonpalatable foods. We conclude that MOR activation following exercise may contribute to the considerable interindividual variation in food craving and consumption after exercise, which might promote compensatory eating and compromise weight control

68Ga-DOTA-E[c(RGDfK)]2 Positron Emission Tomography Imaging of SHARPIN-Regulated Integrin Activity in Mice

Sharpincpdm mice demonstrated increased integrin activity and vascularization in B16-F10-luc melanoma tumors, as demonstrated by RGD-based in vivo PET imaging. These data indicate that SHARPIN, a protein previously associated with increased cancer growth and metastasis, may also have important regulatory roles in controlling the tumor microenvironment

Bodily maps of exercise-induced sensations

Physical exercise is a strong physiological and mechanical stimulus that elicits various bodily sensations. They shape the affective experience and in turn contribute to the psychological benefits of exercise. Despite the centrality of interoception and somatosensation in generating subjective sensations and the capacity for physical exercise in altering the bodily states, there is a paucity of data on bodily experiences and sensations evoked by physical exercise. Here we mapped bodily sensations evoked by exercise in two studies. In the first proof-of-concept study we asked participants (n=305; 143 females) to imagine undergoing aerobic or strength training and report the expected bodily sensations. In the second field study we mapped participants' (n=133; 105 females) emotions and bodily sensations before and after actual exercise sessions. Both studies utilised visual analogue scales for sensation rating and a topographical self-report tool for mapping bodily sensations: participants were asked to colour on a human body silhouette all the bodily regions where each specified sensation (e.g. “Energized”) was felt. The findings revealed a wide array of mostly positive exercise-induced bodily sensations with distinct topographies, consistent across individuals. The field experiment confirmed that bodily sensations of activity and exhaustion intensified following exercise in topographically specific manner, and that experience of exhaustion in the body mapping was linearly associated with physiological and subjective indices of exertion. Altogether these results show that different exercise-induced sensations have distinct bodily topographies, suggesting that the exercise-induced emotions may arise from the interoceptive and somatosensory pathways

mu-opioid receptor system mediates reward processing in humans

The endogenous mu-opioid receptor (MOR) system regulates motivational and hedonic processing. We tested directly whether individual differences in MOR are associated with neural reward responses to food pictures in humans. We scanned 33 non-obese individuals with positron emission tomography (PET) using the MOR-specific radioligand [C-11] carfentanil. During a functional magnetic resonance imaging (fMRI) scan, the subjects viewed pictures of appetizing versus bland foods to elicit reward responses. MOR availability was measured in key components of the reward and emotion circuits and used to predict BOLD-fMRI responses to foods. Viewing palatable versus bland foods activates regions involved in homeostatic and reward processing, such as amygdala, ventral striatum, and hypothalamus. MOR availability in the reward and emotion circuit is negatively associated with the fMRI reward responses. Variation in MOR availability may explain why some people feel an urge to eat when encountering food cues, increasing risk for weight gain and obesity

Evaluation of [⁶⁸Ga]Ga-DOTA-TCTP-1 for the Detection of Metalloproteinase 2/9 Expression in Mouse Atherosclerotic Plaques

Background: The expression of matrix metalloproteinases 2/9 (MMP-2/9) has been implicated in arterial remodeling and inflammation in atherosclerosis. We evaluated a gallium-68 labeled peptide for the detection of MMP-2/9 in atherosclerotic mouse aorta. Methods: We studied sixteen low-density lipoprotein receptor deficient mice (LDLR-/-ApoB100/100) kept on a Western-type diet. Distribution of intravenously-injected MMP-2/9-targeting peptide, [68Ga]Ga-DOTA-TCTP-1, was studied by combined positron emission tomography (PET) and contrast-enhanced computed tomography (CT). At 60 min post-injection, aortas were cut into cryosections for autoradiography analysis of tracer uptake, histology, and immunohistochemistry. Zymography was used to assess MMP-2/9 activation and pre-treatment with MMP-2/9 inhibitor to assess the specificity of tracer uptake. Results: Tracer uptake was not visible by in vivo PET/CT in the atherosclerotic aorta, but ex vivo autoradiography revealed 1.8 ± 0.34 times higher tracer uptake in atherosclerotic plaques than in normal vessel wall (p = 0.0029). Tracer uptake in plaques correlated strongly with the quantity of Mac-3-positive macrophages (R = 0.91, p < 0.001), but weakly with MMP-9 staining (R = 0.40, p = 0.099). Zymography showed MMP-2 activation in the aorta, and pre-treatment with MMP-2/9 inhibitor decreased tracer uptake by 55% (p = 0.0020). Conclusions: The MMP-2/9-targeting [68Ga]Ga-DOTA-TCTP-1 shows specific uptake in inflamed atherosclerotic lesions; however, a low target-to-background ratio precluded in vivo vascular imaging. Our results suggest, that the affinity of gelatinase imaging probes should be steered towards activated MMP-2, to reduce the interference of circulating enzymes on the target visualization in vivo

Aerobic Fitness is Associated with Cerebral mu-Opioid Receptor Activation in Healthy Humans

Introduction: Central μ-opioid receptors (MORs) modulate affective responses to physical exercise. Individuals with higher aerobic fitness report greater exercise-induced mood improvements than those with lower fitness, but the link between cardiorespiratory fitness and the MOR system remains unresolved. Here we tested whether maximal oxygen uptake (VO2peak) and physical activity level are associated with cerebral MOR availability and whether these phenotypes predict endogenous opioid release following a session of exercise.Methods: We studied 64 healthy lean men who performed a maximal incremental cycling test for VO2peak determination, completed a questionnaire assessing moderate-to-vigorous physical activity (MVPA, min/week), and underwent positron emission tomography (PET) with [11C]carfentanil, a specific radioligand for MOR. A subset of 24 subjects underwent additional PET scan also after a one-hour session of moderate-intensity exercise and 12 of them also after a bout of high-intensity interval training (HIIT).Results: Higher self-reported MVPA level predicted greater opioid release after HIIT, and both VO2peak and MVPA level were associated with a larger decrease in cerebral MOR binding after aerobic exercise in the ventral striatum, orbitofrontal cortex, and insula. That is, more trained individuals showed greater opioid release acutely following exercise in brain regions especially relevant for reward and cognitive processing. Fitness was not associated with MOR availability.Conclusions: We conclude that regular exercise training and higher aerobic fitness may induce neuroadaptation within the MOR system, which might contribute to improved emotional and behavioural responses associated with long-term exercise.</p