Exercise and Dietary Factors Mediate Neural Plasticity Through Modulation of BDNF Signaling
Abstract
The term “neural plasticity” was first used to describe non-pathological changes in neuronal structure. Today, it is generally accepted that the brain is a dynamic system whose morphology and function is influenced by a variety of factors including stress, diet, and exercise. Neural plasticity involves learning and memory, the synthesis of new neurons, the repair of damaged connections, and several other compensatory mechanisms. It is altered in neurodegenerative disorders and following damage to the central or peripheral nervous system. Understanding the mechanisms that regulate neural plasticity in both healthy and diseased states is of significant importance to promote cognition and develop rehabilitation techniques for functional recovery after injury. In this minireview, we will discuss the mechanisms by which environmental factors promote neural plasticity with a focus on exercise- and diet-induced factors. We will highlight the known circulatory factors that are released in response to exercise and discuss how all factors activate pathways that converge in part on the activation of BDNF signaling. We propose to harness the therapeutic potential of exercise by using BDNF as a biomarker to identify novel endogenous factors that promote neural plasticity. We also discuss the importance of combining exercise factors with dietary factors to develop a lifestyle pill for patients afflicted by CNS disorders.
1Introduction
Neural plasticity is defined as the ability of the nervous system to perform adaptive structural and functional changes [1]. Impaired neural plasticity is observed in central nervous system (CNS) disorders [2] including psychiatric diseases such as depression [3]. Neural plasticity is influenced by environmental factors such as exercise, diet and stress [4]. Exercise promotes neural plasticity primarily by inducing the release of metabolites and proteins from the muscle, liver and bones that converge on the activation of hippocampal brain derived neurotrophic factor (BDNF) [5–12] signaling. The activation of BDNF signaling increases synaptogenesis, neurogenesis, angiogenesis and gliogenesis [13]. It also enhances cerebral blood flow [14], increases grey and white matter volume [15–17], and mediates neuronal activity [18–21]. As a result, exercise has been linked to improved cognitive and motor function. The composition of the human diet is also linked to changes in neural plasticity. Indeed, different dietary factors either promote or inhibit neural plasticity.
In this minireview, we will highlight the common pathways that are modulated by the liver-brain, muscle-brain, and bone-brain axes to induce neuronal plasticity. We will specifically focus on the convergence of the different circulatory factors that regulate neural plasticity on Bdnf expression and signaling in the brain. Our discussions will highlight the importance of using Bdnf expression and signaling as a biomarker to identify novel exercise and dietary factors that can be of therapeutic value. These discussions will also pave the way to completing the puzzle of how the different organ systems interact with the brain to modulate its responses.
2Environmental factors involved in neural plasticity
Two important environmental factors that modulate neural plasticity are exercise and diet. Exercise activates the liver-brain, muscle-brain and bone-brain axes to modulate neural plasticity. We will next focus on how exercise and dietary signals are integrated in the brain to promote neural plasticity.
3Exercise-induced factors and neural plasticity
Exercise promotes healthy brain function and improves the symptoms of a wide range of neurodegenerative diseases [22–24]. These effects are achieved by promoting neural plasticity [25, 26]. For example, mice with access to a running wheel exhibit a significant increase in hippocampal neurogenesis and enhanced spatial and temporal memory [27]. Magnetic resonance imaging (MRI) studies revealed that extended voluntary exercise increases hippocampal volume in mice [28]. Similar findings were also reported in human studies. MRI was used to show that adults who practiced moderate-intensity exercise for 12 weeks have significant increases in the volume of several brain regions, especially the hippocampus [29]. Altogether, these findings suggest that physical activity improves cognitive functions by inducing structural changes in different brain regions.
Exercise mediates its positive effects on the brain by activating several distinct pathways including neurotrophic and angiogenic pathways. One important pathway that is induced by exercise is BDNF signaling. In animal models, exercise induces BDNF expression in the hippocampus [30]. For example, middle-age rats that undergo daily treadmill exercise have increased hippocampal BDNF protein and mRNA levels as well as enhanced spatial memory and object recognition [31, 32]. BDNF production provides trophic support and increases synaptogenesis and dendritic and axonal branching and spine turnover. Blocking BDNF signaling inhibits the exercise-mediated improvement of spatial learning tasks [33] as well as the exercise-induced expression of synaptic proteins [34]. Moreover, mice with a single nucleotide polymorphism in the BDNF gene Val66Met (BDNFMet/Met) have impaired exercise-induced neural plasticity [35]. BDNF promotes neural plasticity by activating tropomyosin receptor kinase B (TrkB) [36]. Exercise fails to promote neurogenesis and to enhance neural plasticity in TrkB deficient mice [37]. In humans, aerobic exercise training induces an increase in serum BDNF levels. This is associated with an increase in the volume of the hippocampus, suggesting that exercise-induced BDNF expression could reverse hippocampal volume loss and expand spatial memory [38]. Indeed, exercise induces hippocampal BDNF signaling through an elaborate coordinated response that involves several tissues and organs.
Exercise activates cross-talk between different tissues and the brain. It promotes the liver, muscles and bones to release factors into the circulation that reach the brain and promote learning, memory formation and neural plasticity [10, 11]. Not all the potential exercise factors have been identified or carefully studied. However, careful examination of what is currently known about exercise factors reveals that they activate converging and redundant pathways in the brain with BDNF signaling playing a pivotal role in the integrated response. Indeed, the integrated and beneficial effect of circulating exercise factors on cognitive function and neural plasticity is mediated in large part through the induction or activation of hippocampal BDNF signaling [5, 9–12, 39]. From here, hippocampal BDNF expression can be used as a biomarker to identify novel exercise factors that can become part of a comprehensive treatment for CNS disorders such as depression. Currently a limited number of exercise factors have been identified and have been shown to regulate the communication between the liver, muscle, bones and the brain. We will discuss what is known about these exercise factors below, while highlighting how they all regulate BDNF signaling supporting the usefulness of using this pathway as a biomarker to identify novel exercise factors that may have therapeutic relevance.
3.1Liver-brain axis
Upon exercise, the liver secretes the ketone body beta-hydroxybutyrate (BHB) [9], as well as the protein, glycosylphosphatidylinositol-specific phospholipase D1 (Gpld1) [6]. BHB is a specific inhibitor of the class I histone deacetylases [40] that increases BDNF levels in the hippocampi of mice [9, 41] and rescues neurogenesis in the dentate gyrus of adult mice [42]. Similar to BHB, Gpld1 promotes BDNF protein expression and in turn rescues impaired neurogenesis and several age-related cognitive deficits [6].
3.2Muscle-brain axis
The muscle also secretes several factors during exercise that regulate neural plasticity by inducing BDNF expression [5, 8, 12, 43]. Such factors include the myokine FNDC5 and its cleavage product irisin [7, 12], lactate [5], cathepsin B [44] and α-ketoglutaric acid (AKG) [45].
Increases in FNDC5 levels in cortical neuronal cultures enhance BDNF levels, thereby promoting neural plasticity [12]. This increase in FNDC5 is mediated through the exercise-dependent activation of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1a) [12]. Moreover, peripheral delivery of FNDC5 also induces hippocampal BDNF expression [12]. Indeed, exercise-induced FNDC5 and its cleavage product irisin are effective in rescuing neural plasticity deficits in AD mouse models [46] and depression models [47–49].
Lactate is also an exercise factor released by the muscle and delivered by the blood to the hippocampus where it promotes spatial learning, memory formation and rescues depression-like symptoms [5, 50]. Lactate promotes neural plasticity by inducing the expression of plasticity-related genes such as BDNF, activity-regulated cytoskeleton-associated gene (Arc), c-Fos, and the zinc finger-containing transcription factor 268 (Zif268) gene [5, 43, 51]. This induction is downstream of Sirt-1 dependent activation of the PGC1a/FNDC5 pathway [5] and can also be mediated through stimulation of N-methyl D-aspartate (NMDA) receptor activity [43, 51]. Interestingly, blocking the monocarboxylate transporter that is responsible for both lactate as well as BHB uptake into neurons abolishes exercise’s ability to promote learning and memory formation [5]. This is consistent with both lactate and BHB being necessary for voluntary exercise’s positive effects on learning and memory formation.
During exercise, the muscle releases Cathepsin B, which in turn induces the expression of doublecortin and BDNF in adult hippocampal progenitor cell cultures [44]. Blocking cathepsin B prevents neurite outgrowth, indicating that this exercise factor is involved in neural plasticity [8]. It is important to block BDNF signaling in order to determine whether it is indeed responsible for cathepsin B’s effects.
Finally, the muscle releases multiple Kreb’s cycle intermediates during exercise. For example, the muscle releases AKG during resistance exercise [45]. This metabolite extends the life span of aging mice by regulating inflammatory processes [52]. Whether this endogenous metabolite is another exercise factor that regulates neuronal plasticity and rescues cognitive deficits associated with neurodegeneration or social avoidance associated with depression and the involvement of BDNF signaling needs to be further investigated.
3.3Bone-brain axis
The bones have emerged as an endocrine organ that releases osteocalcin during exercise. A single session of a high-intensity interval exercise in sedentary males increases osteocalcin levels. Increases in osteocalcin levels are tightly associated with increases in BDNF expression and neural plasticity [53]. Osteocalcin is released by the bones into the circulation, crosses the blood brain barrier (BBB) and activates the G Protein-Coupled Receptor 158 (GPR158) receptors in the hippocampus [54]. This signaling pathway promotes hippocampal-dependent memory through the activation of the inositol 1,4,5-trisphosphate and BDNF pathways [54]. Interestingly, osteocalcin is necessary for the ability of plasma from young animals to rescue cognitive deficits in aging animals [54]. Indeed, even though osteocalcin is not expressed in the brain of mice, its genetic deletion leads to impaired cognitive behavior and increased depression and anxiety-like behavior [55]. Taken together, current evidence emphasizes the importance of this bone-derived protein for the proper function of the brain. However, it is important to determine whether osteocalcin is both necessary and sufficient to mediate the effects of exercise.
4Diet and neural plasticity
Another lifestyle factor that is tightly linked to exercise and that regulates neural plasticity is diet [56]. Diets rich in factors such as BHB and lactate that are released in response to exercise also mediate neural plasticity. Interestingly, like exercise, multiple diets and dietary factors that enhance neural plasticity also converge in part on their ability to activate BDNF signaling in the brain.
Multiple studies have highlighted the importance of different dietary factors and their ability to modulate neural plasticity [57]. For example, omega-3 fatty acids have long-lasting effects that persist in adulthood. These fatty acids are structural components of the brain and are crucial for neuronal membrane synthesis [58]. Adolescents with increased levels of omega-3 fatty acids have reduced risks of developing psychotic disorders [59]. Both enhanced emotional function and memory improvement are observed in rats fed with omega-3 fatty acids [60, 61]. Three omega-3 fatty acids –α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)- increase neurogenesis, promote long-term potentiation, induce the expression of synaptic proteins and enhance cognitive function and mood [62]. Liu and colleagues (2015) demonstrated that injection of DHA in two different rodent models of spinal cord injury promotes neural plasticity by inducing anatomical sprouting [63]. DHA also normalizes BDNF levels, reduces oxidative damage, and counteracts learning disability after traumatic brain injury in rats [64]. Combined supplementation of vitamin B12 and omega-3 fatty acids increases NGF levels in the hippocampus, and BDNF in both hippocampus and cortex and decreases reference and working memory error in rats [65].
Other dietary factors that regulate the expression of genes involved in neural plasticity are ketone bodies [66]. Like exercise, intermittent metabolic switching is linked to the production of ketones such as BHB and acetoacetate (ACA) [67]. Low carbohydrate and protein diets that are enriched in fat, such as the ketogenic diet, promote the synthesis of ACA and BHB in the liver [68]. BHB in turn upregulates the expression of BDNF, promoting synaptic plasticity through the activation of tyrosine kinase receptors that stimulate synaptogenesis, neuroplasticity, and neuronal survival [9, 39]. In an uncontrolled intervention study in which sedentary obese adults followed a 12-week ketogenic diet, serum BDNF levels were significantly increased within the first 2 weeks. This increase was associated with enhanced working memory and processing speed [69].
High protein diets rich in branched chain amino acids (BCAA) rescue social deficits induced by chronic stress and increase BDNF expression in the hippocampus [48]. Inhibition of TRKB signaling abolishes the ability of BCAA to promote resilience to stress and to rescue social avoidance [48]. Interestingly, BCAA activate the exercise-regulated PGC1a/FNDC5 pathway known to induce hippocampal BDNF signaling. Although both voluntary exercise and BCAA promoted resilience to stress, combining them did not yield synergistic effects confirming that they affect similar pathways [48].
Finally, the Mediterranean diet has neuroprotective effects [70]. This diet depends on the extensive use of olive oil, as well as the consumption of fish, and meat along with the moderate intake of wine [71]. This diet is rich in olive oil constituents, omega-3 fatty acids, and polyphenols that exert antioxidant and anti-inflammatory effects, and promote the expression of BDNF, leading to increased neural plasticity and cell survival [72]. The Mediterranean diet also increases serum levels of osteocalcin which is known to increase BDNF levels in the hippocampus [73, 74].
It is worthwhile to mention that not all dietary factors are beneficial; some may be detrimental to neural plasticity, cognitive functions and stress responses. For example, prolonged consumption of a high-fat diet exacerbates depressive-like behaviors in male adult rats, as well as decreases synaptic markers within the hippocampus. This suggests that chronic intake of this diet has detrimental effects on neural plasticity and behavioral function [75]. Interestingly, BDNF levels oscillate during the consumption of a high-fat diet; initially, levels increase, but progressively they fall below baseline levels after long-term consumption [76]. In addition, Fusco and colleagues (2019) suggested that a maternal high-fat diet could have multigenerational negative effects on synaptic plasticity through epigenetic mechanisms that inhibit BDNF expression in the hippocampus of the progeny. Epigenetic modifications that are related to gene activation, such as H3K9ac and H3K4me3, were found to be decreased in the germline and hippocampus of male descendants of mothers consuming this diet [77].
Altogether, the aforementioned studies provide strong evidence for the important roles played by dietary factors in regulating neural plasticity. Regulation of BDNF expression in response to metabolic changes and diet serves as a pivot linking peripheral factors to neural plasticity. Interestingly, diet is a key modifiable factor that regulates neural plasticity by influencing the composition of the gut microbiota and in turn the bidirectional interplay between the gut and the brain. The role of BDNF in this interplay needs further investigation. In addition, different combinations of dietary factors and exercise factors need to be tested to identify combinations that may yield synergistic effects on neural plasticity.
5Clinical implications
The exercise and dietary factors discussed converge on regulation of BDNF signaling. Defects in BDNF signaling are observed in a number of diseases. Post-mortem studies in AD patients show significantly decreased BDNF expression in the hippocampus, and cortex [78, 79]. In addition, decreased levels of BDNF are observed in the cortex of AD mouse models [80, 81]. Conversely, BDNF gene delivery to the brain of transgenic AD mice prevents neuronal loss and synaptic degeneration and enhances neurogenesis [82]. In rats, exogenous BDNF treatment decreases the Aβ peptide in brains [83]. Neuroprotective effects were also observed in non-human primate models of AD [84]. Reduced BDNF mRNA is measured in dopaminergic neurons in Parkinson’s disease (PD) [85]. In Huntington’s disease (HD), the presence of mutant Huntingtin results in aberrant BDNF transport and in decreased BDNF expression [86, 87]. Indeed, symptomatic HD patients who exhibit impaired motor function have significantly lower BDNF levels [88].
Since BDNF signaling is disrupted in a wide array of CNS disorders, there have been considerable efforts to develop BDNF as a therapeutic (reviewed in [89]). Despite the encouraging preclinical data, the ability to deliver BDNF to the brain remains a challenge. This is because it is a polar protein that doesn’t easily cross the BBB. This necessitates its direct delivery into the brain. Indeed, several clinical trials were conducted to assess the neuroprotective effect of exogenous BDNF administration. Clinical trials did not show any significant effects on survival following either subcutaneous/intrathecal recombinant BDNF administration. However, further analysis of these studies suggests that the trials failed because BDNF could not cross the BBB to reach the degenerating neurons [89]. Indeed, the use of the recombinant BDNF protein is hampered by protein degradation, and an inability to cross the BBB in significant quantities. The use of viral vectors may also activate the immune response, induce mutations and overload the neurons with excess BDNF, which is associated with epilepsy. As a result, harnessing the therapeutic potential of endogenous pathways that can promote BDNF signaling in the brain may serve as a strategy to overcome the difficulties associated with BDNF delivery. From here, focusing on identifying endogenous exercise factors and dietary factors that can easily cross the BBB to induce BDNF signaling at physiological levels and not pathological levels can allows us to assemble an exercise/diet pill that can be tested as a therapeutic for CNS disorders. As mentioned previously, it is important to control for age and sex differences while assembling this pill.
6Conclusions
During physical activity, the liver, muscles and bones release a host of factors that include proteins and metabolites into the circulation. These circulatory exercise factors cross the BBB, and increase BDNF expression resulting in enhanced neural plasticity, spatial learning and memory formation [5, 12, 44]. It is clear that the composition of the circulatory factors following exercise dramatically changes [6]. Indeed, blood transfusion experiments revealed that these factors mediate the effects of exercise on neurogenesis and cognition [6]. It is important to systematically assess the available proteomic and metabolomic data to identify novel exercise factors that promote neural plasticity. Considering that a vast majority of the currently established exercise factors mediate their function through activation of hippocampal BDNF signaling and considering the disruptions in BDNF signaling observed in CNS diseases, rapid screens of the top identified metabolites and proteins to determine their ability to induce BDNF can help in narrowing down the search for novel components of an exercise pill. An important consideration is the need to assess the effectiveness of the exercise factors across different sexes and age groups. Most of the beneficial effects of the currently known exercise factors have been primarily identified in young males. Thus, it is important to compare the composition of the circulatory factors in males versus females as well as in younger versus older animals. Such studies will help in developing personalized exercise pills that could vary according to the age or sex of the individual requiring treatment.
ACKNOWLEDGMENT
None.
FUNDING
Authors have no funding to report.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
REFERENCES
[1] | Puderbaugh M , Emmady PD , Neuroplasticity. StatPearls. Treasure Island (FL). 2021. |
[2] | Winner B , Winkler J , Adult neurogenesis in neurodegenerative diseases, Cold Spring Harb Perspect Biol (2015) ;7: (4):a021287. |
[3] | Price RB , Duman R , Neuroplasticity in cognitive and psychological mechanisms of depression: an integrative model, Mol Psychiatry (2020) ;25: (3):530–43. |
[4] | Li X , Hu L , The Role of Stress Regulation on Neural Plasticity in Pain Chronification, Neural Plast (2016) ;2016: 6402942. |
[5] | El Hayek L , Khalifeh M , Zibara V , Abi Assaad R , Emmanuel N , Karnib N , et al., Lactate Mediates the Effects of Exercise on Learning and Memory through SIRT1-Dependent Activation of Hippocampal Brain-Derived Neurotrophic Factor (BDNF), J Neurosci (2019) ;39: (13):2369–82. |
[6] | Horowitz AM , Fan X , Bieri G , Smith LK , Sanchez-Diaz CI , Schroer AB ,et al., Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain, Science (2020) ;369: (6500)167–73. |
[7] | Islam MR , Valaris S , Young MF , Haley EB , Luo R , Bond SF , et al., Exercise hormone irisin is a critical regulator of cognitive function, Nat Metab (2021) ;3: (8):1058–70. |
[8] | Jiang M , Meng J , Zeng F , Qing H , Hook G , Hook V , et al. Cathepsin B inhibition blocks neurite outgrowth in cultured neurons by regulating lysosomal trafficking and remodeling, J Neurochem (2020) ;155: (3):300–12. |
[9] | Sleiman SF , Henry J , Al-Haddad R , El Hayek L , Abou Haidar E , Stringer T , et al. Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body beta-hydroxybutyrate, Elife (2016) )5. |
[10] | Stephan JS , Sleiman SF , Exercise factors as potential mediators of cognitive rehabilitation following traumatic brain injury, Curr Opin Neurol (2019) ;32: (6):808–14. |
[11] | Stephan JS , Sleiman SF , Exercise Factors Released by the Liver, Muscle, and Bones Have Promising Therapeutic Potential for Stroke, Front Neurol (2021) ;12: :600365. |
[12] | Wrann CD , White JP , Salogiannnis J , Laznik-Bogoslavski D , Wu J , Ma D , et al. Exercise induces hippocampal BDNF through a PGC-1alpha/FNDC5 pathway, Cell Metab (2013) ;18: (5):649–59. |
[13] | El-Sayes J , Harasym D , Turco CV , Locke MB , Nelson AJ , Exercise-Induced Neuroplasticity: A Mechanistic Model and Prospects for Promoting Plasticity, Neuroscientist (2019) ;25: (1):65–85. |
[14] | Smith JC , Paulson ES , Cook DB , Verber MD , Tian Q , Detecting changes in human cerebral blood flow after acute exercise using arterial spin labeling: implications for fMRI, J Neurosci Methods (2010) ;191: (2):258–62. |
[15] | Colcombe SJ , Erickson KI , Scalf PE , Kim JS , Prakash R , McAuley E , et al. Aerobic exercise training increases brain volume in aging humans, J Gerontol A Biol Sci Med Sci (2006) ;61: (11):1166–70. |
[16] | Erickson KI , Leckie RL , Weinstein AM , Physical activity, fitness, and gray matter volume, Neurobiol Aging. 35 SupplS (2014) ;2: :20–8. |
[17] | Fletcher MA , Low KA , Boyd R , Zimmerman B , Gordon BA , Tan CH , et al. Comparing Aging and Fitness Effects on Brain Anatomy, Front Hum Neurosci (2016) ;10: :286. |
[18] | Bailey SP , Hall EE , Folger SE , Miller PC , Changes in EEG during graded exercise on a recumbent cycle ergometer, J Sports Sci Med (2008) ;7: (4):505–11. |
[19] | Gutmann B , Mierau A , Hulsdunker T , Hildebrand C , Przyklenk A , Hollmann W , et al. Effects of physical exercise on individual resting state EEG alpha peak frequency, Neural Plast (2015) ;2015: :717312. |
[20] | Moraes H , Ferreira C , Deslandes A , Cagy M , Pompeu F , Ribeiro P , et al. Beta and alpha electroencephalographic activity changes after acute exercise, Arq Neuropsiquiatr (2007) ;65: (3A):637–41. |
[21] | Rajab AS , Crane DE , Middleton LE , Robertson AD , Hampson M , MacIntosh BJ , A single session of exercise increases connectivity in sensorimotor-related brain networks: a resting-state fMRI study in young healthy adults, Front Hum Neurosci (2014) ;8: :625. |
[22] | Gubert C , Hannan AJ , Exercise mimetics: harnessing the therapeutic effects of physical activity, Nat Rev Drug Discov (2021) ;20: (11):862–79. |
[23] | Liu Y , Yan T , Chu JM , Chen Y , Dunnett S , Ho YS , et al. The beneficial effects of physical exercise in the brain and related pathophysiological mechanisms in neurodegenerative diseases, Lab Invest (2019) ;99: (7):943–57. |
[24] | Bliss ES , Wong RH , Howe PR , Mills DE , Benefits of exercise training on cerebrovascular and cognitive function in ageing, J Cereb Blood Flow Metab (2021) ;41: (3):447–70. |
[25] | Mandolesi L , Gelfo F , Serra L , Montuori S , Polverino A , Curcio G , et al. Environmental Factors Promoting Neural Plasticity: Insights from Animal and Human Studies, Neural Plast (2017) ;2017: :7219461. |
[26] | Moon HY , Praag HV , Physical Activity and Brain Plasticity, J Exerc Nutrition Biochem (2019) ;23: (4):23–5. |
[27] | Vivar C , Peterson BD , van Praag H , Running rewires the neuronal network of adult-born dentate granule cells, Neuroimage (2016) ;131: :29–41. |
[28] | Islam MR , Luo R , Valaris S , Haley EB , Takase H , Chen YI , et al. Diffusion tensor-MRI detects exercise-induced neuroplasticity in the hippocampal microstructure in mice, Brain Plast (2020) ;5: (2):147–59. |
[29] | Nauer RK , Dunne MF , Stern CE , Storer TW , Schon K , Improving fitness increases dentate gyrus/CA3 volume in the hippocampal head and enhances memory in young adults, Hippocampus (2020) ;30: (5):488–504. |
[30] | Cotman CW , Berchtold NC , Christie LA , Exercise builds brain health: key roles of growth factor cascades and inflammation, Trends Neurosci (2007) ;30: (9):464–72. |
[31] | Gomes da Silva S , Unsain N , Masco DH , Toscano-Silva M , de Amorim HA , Silva Araujo BH , et al. Early exercise promotes positive hippocampal plasticity and improves spatial memory in the adult life of rats, Hippocampus (2012) ;22: (2):347–58. |
[32] | Pietrelli A , Matkovic L , Vacotto M , Lopez-Costa JJ , Basso N , Brusco A , Aerobic exercise upregulates the BDNF-Serotonin systems and improves the cognitive function in rats, Neurobiol Learn Mem (2018) ;155: :528–42. |
[33] | Vaynman S , Ying Z , Gomez-Pinilla F , Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition, Eur J Neurosci (2004) ;20: (10):2580–90. |
[34] | Vaynman SS , Ying Z , Yin D , Gomez-Pinilla F , Exercise differentiallyregulates synaptic proteins associated to the function of BDNF, Brain Res (1070) )1 124–30. |
[35] | Ieraci A , Madaio AI , Mallei A , Lee FS , Popoli M , Brain-Derived Neurotrophic Factor Val66Met Human Polymorphism Impairs the Beneficial Exercise-Induced Neurobiological Changes in Mice, Neuropsychopharmacology (2016) ;41: (13):3070–9. |
[36] | Guo W , Nagappan G , Lu B , Differential effects of transient and sustained activation of BDNF-TrkB signaling, Dev Neurobiol (2018) ;78: (7):647–59. |
[37] | Li Y , Luikart BW , Birnbaum S , Chen J , Kwon CH , Kernie SG , et al. TrkB regulates hippocampal neurogenesis and governs sensitivity to antidepressive treatment, Neuron (2008) ;59: (3):399–412. |
[38] | Erickson KI , Voss MW , Prakash RS , Basak C , Szabo A , Chaddock L , et al. Exercise training increases size of hippocampus and improves memory, Proc Natl Acad Sci U S A (2011) ;108: (7):3017–22. |
[39] | Sleiman SF , Chao MV , Downstream Consequences of Exercise Through the Action of BDNF, Brain Plast (2015) ;1: (1):143–8. |
[40] | Shimazu T , Hirschey MD , Newman J , He W , Shirakawa K , Le Moan N , et al. Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor, Science (2019) ;339: (6116):211–4. |
[41] | Sada N , Fujita Y , Mizuta N , Ueno M , Furukawa T , Yamashita T , Inhibition of HDAC increases BDNF expression and promotes neuronalrewiring and functional recovery after brain injury, Cell Death Dis (2020) ;11: (8):655. |
[42] | Benjamin JS , Pilarowski GO , Carosso GA , Zhang L , Huso DL , Goff LA , et al. A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome, Proc Natl Acad Sci U S A (2017) ;114: (1):125–30. |
[43] | Muller P , Duderstadt Y , Lessmann V , Muller NG , Lactate and BDNF: Key Mediators of Exercise Induced Neuroplasticity? J Clin Med (2020) ;9: (4). |
[44] | Moon HY , Becke A , Berron D , Becker B , Sah N , Benoni G , et al. Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function, Cell Metab (2016) ;24: (2):332–40. |
[45] | Yuan Y , Xu P , Jiang Q , Cai X , Wang T , Peng W , et al. Exercise-induced alpha-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation, EMBO J (2020) ;39: (7):e103304. |
[46] | Lourenco MV , Frozza RL , de Freitas GB , Zhang H , Kincheski GC , Ribeiro FC , et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer’s models, Nat Med (2019) ;25: (1):165–75. |
[47] | Gruhn K , Siteneski A , Camargo A , Freitas AE , Olescowicz G , Brocardo PS , et al. Physical exercise stimulates hippocampal mTORC1 and FNDC5/irisin signaling pathway in mice: Possible implication for its antidepressant effect, Behav Brain Res (2021) ;400: :113040. |
[48] | Nasrallah P , Haidar EA , Stephan JS , El Hayek L , Karnib N , Khalifeh M , et al. Branched-chain amino acids mediate resilience to chronic social defeat stress by activating BDNF/TRKB signaling, Neurobiol Stress (2019) ;11: :100170. |
[49] | Siteneski A , Cunha MP , Lieberknecht V , Pazini FL , Gruhn K , Brocardo PS , et al. Central irisin administration affords antidepressant-like effect and modulates neuroplasticity-related genes in the hippocampus and prefrontal cortex of mice, Prog Neuropsychopharmacol Biol Psychiatry (2018) ;84: (Pt A):294–303. |
[50] | Karnib N , El-Ghandour R , El Hayek L , Nasrallah P , Khalifeh M , Barmo N , et al. Lactate is an antidepressant that mediates resilience to stress by modulating the hippocampal levels and activity of histone deacetylases, Neuropsychopharmacology (2019) ;44: (6):1152–62. |
[51] | Yang J , Ruchti E , Petit JM , Jourdain P , Grenningloh G , Allaman I , et al. Lactate promotes plasticity gene expression by potentiating NMDA signaling in neurons, Proc Natl Acad Sci U S A (2014) ;111: (33):12228–33. |
[52] | Asadi Shahmirzadi A , Edgar D , Liao CY , Hsu YM , Lucanic M , Asadi Shahmirzadi A , et al. Alpha-Ketoglutarate, an Endogenous Metabolite, Extends Lifespan and Compresses Morbidity in Aging Mice, Cell Metab.447-56 e (2020) ;32: (3):6. |
[53] | Nicolini C , Michalski B , Toepp SL , Turco CV , D’Hoine T , Harasym D , et al. A Single Bout of High-intensity Interval Exercise IncreasesCorticospinal Excitability, Brain-derived Neurotrophic Factor, andUncarboxylated Osteolcalcin in Sedentary, Healthy Males, Neuroscience (2020) ;437: :242–55. |
[54] | Khrimian L , Obri A , Ramos-Brossier M , Rousseaud A , Moriceau S , Nicot AS , et al. Gpr158 mediates osteocalcin’s regulation of cognition, J Exp Med (2017) ;214: (10):2859–73. |
[55] | Oury F , Khrimian L , Denny CA , Gardin A , Chamouni A , Goeden N , et al. Maternal and offspring pools of osteocalcin influence brain development and functions, Cell (2013) ;155: (1):228–41. |
[56] | Murphy T , Dias GP , Thuret S , Effects of diet on brain plasticity in animal and human studies: mind the gaNeural Plast (2014) ;2014: :563160. |
[57] | Phillips C , Lifestyle Modulators of Neuroplasticity: How Physical Activity, Mental Engagement, and Diet Promote Cognitive Health during Aging, Neural Plast (2017) ;2017: :3589271. |
[58] | Cutuli D , Functional and Structural Benefits Induced by Omega-3 Polyunsaturated Fatty Acids During Aging, Curr Neuropharmacol (2017) ;15: (4):534–42. |
[59] | Mongan D , Healy C , Jones HJ , Zammit S , Cannon M , Cotter DR , Plasma polyunsaturated fatty acids and mental disorders in adolescence and early adulthood: cross-sectional and longitudinal associations in a general population cohort, Transl Psychiatry (2021) ;11: (1):321. |
[60] | McCall N , Mahadevia D , Corriveau JA , Glenn MJ , Adult emotionality and neural plasticity as a function of adolescent nutrient supplementation in male rats, Pharmacol Biochem Behav (2015) ;132: :125–35. |
[61] | Tareke AA , Dama Adi WRDBB , Bariso M , The Role of Omega 3 Fatty Acids in Memory Improvement: Possible Mechanisms and Therapeutic Potential, Journal of Medicine (2019) ;54: (1):1–12. |
[62] | Crupi R , Marino A , Cuzzocrea S , n-3 fatty acids: role in neurogenesis and neuroplasticity, Curr Med Chem (2013) ;20: (24):2953–63. |
[63] | Liu ZH , Yip PK , Adams L , Davies M , Lee JW , Michael GJ , et al. A Single Bolus of Docosahexaenoic Acid Promotes Neuroplastic Changes in the Innervation of Spinal Cord Interneurons and Motor Neurons and Improves Functional Recovery after Spinal Cord Injury, J Neurosci (2015) ;35: (37):12733–52. |
[64] | Wu A , Ying Z , Gomez-Pinilla F , Dietary omega-3 fatty acids normalize BDNF levels, reduce oxidative damage, and counteract learning disability after traumatic brain injury in rats, J Neurotrauma (2004) ;21: (10):1457–67. |
[65] | Rathod RS , Khaire AA , Kale AA , Joshi SR , Effect of vitamin B12 and omega-3 fatty acid supplementation on brain neurotrophins and cognition in rats: A multigeneration study, Biochimie (2016) ;128-129: :201–8. |
[66] | Maalouf M , Rho JM , Mattson MP , The neuroprotective properties of calorie restriction, the ketogenic diet, and ketone bodies, Brain Res Rev (2009) ;59: (2):293–315. |
[67] | Mattson MP , Moehl K , Ghena N , Schmaedick M , Cheng A , Intermittent metabolic switching, neuroplasticity and brain health, Nat Rev Neurosci (2018) ;19: (2):63–80. |
[68] | Longo R , Peri C , Cricri D , Coppi L , Caruso D , Mitro N , et al. Ketogenic Diet: A New Light Shining on Old but Gold Biochemistry, Nutrients. (2019) ;11: (10). |
[69] | Mohorko N , Cernelic-Bizjak M , Poklar-Vatovec T , Grom G , Kenig S , Petelin A , et al. Weight loss, improved physical performance, cognitive function, eating behavior, and metabolic profile in a 12-week ketogenic diet in obese adults, Nutr Res (2019) ;62: :64–77. |
[70] | Lacatusu CM , Grigorescu ED , Floria M , Onofriescu A , Mihai BM , The Mediterranean Diet: From an Environment-Driven Food Culture to an Emerging Medical Prescription, Int J Environ Res Public Health (2019) ;16: (6). |
[71] | Hidalgo-Mora JJ , Garcia-Vigara A , Sanchez-Sanchez ML , Garcia-Perez MA , Tarin J , Cano A , The Mediterranean diet: A historical perspective on food for health, Maturitas (2020) ;132: :65–9. |
[72] | Farooqui AA , Farooqui T , Antiaging and neuroprotective properties of mediterranean diet components in humans. In: Syed Ibrahim R, Ufuk C, editors. Molecular basis and emerging strategies for anti-aging interventions. Singapore: Springer; 2018. |
[73] | Fernandez-Real JM , Bullo M , Moreno-Navarrete JM , Ricart W , Ros E , Estruch R , et al. A Mediterranean diet enriched with olive oil is associated with higher serum total osteocalcin levels in elderly men at high cardiovascular risk, J Clin Endocrinol Metab (2012) ;97: (10):3792–8. |
[74] | Filip R , Possemiers S , Heyerick A , Pinheiro I , Raszewski G , Davicco MJ , et al. Twelve-month consumption of a polyphenol extract from olive (Olea europaea) in a double blind, randomized trial increases serum total osteocalcin levels and improves serum lipid profiles in postmenopausal women with osteopenia, J Nutr Health Aging (2015) ;19: (1):77–86. |
[75] | Arcego DM , Toniazzo AP , Krolow R , Lampert C , Berlitz C , Dos Santos Garcia E , et al. Impact of High-Fat Diet and Early Stress on Depressive-Like Behavior and Hippocampal Plasticity in Adult Male Rats, Mol Neurobiol (2018) ;55: (4):2740–53. |
[76] | Ramalho AF , Bombassaro B , Dragano NR , Solon C , Morari J , Fioravante M , et al. Dietary fats promote functional and structural changes in the median eminence blood/spinal fluid interface-the protective role for BDNF, J Neuroinflammation (2018) ;15: (1):10. |
[77] | Fusco S , Spinelli M , Cocco S , Ripoli C , Mastrodonato A , Natale F , et al. Maternal insulin resistance multigenerationally impairs synaptic plasticity and memory via gametic mechanisms, Nat Commun (2019) ;10: (1):4799. |
[78] | Garzon D , Yu G , Fahnestock M , A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophic factor transcripts 1, 2 and 3 in Alzheimer’s disease parietal cortex, J Neurochem (2002) ;82: (5):1058–64. |
[79] | Phillips HS , Hains JM , Armanini M , Laramee GR , Johnson SA , Winslow JW , BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease, Neuron (1991) ;7: (5):695–702. |
[80] | Peng S , Garzon DJ , Marchese M , Klein W , Ginsberg SD , Francis BM , et al. Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer’s disease, J Neurosci (2009) ;29: (29):9321–9. |
[81] | Ng TKS , Ho CSH , Tam WWS , Kua EH , Ho RC , Decreased Serum Brain-Derived Neurotrophic Factor (BDNF) Levels in Patients with Alzheimer’s Disease (AD): A Systematic Review and Meta-Analysis, Int J Mol Sci (2019) ;20: (2). |
[82] | Jiao SS , Shen LL , Zhu C , Bu XL , Liu YH , Liu CH , et al. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer’s disease, Transl Psychiatry.e (2016) ;6: (10):907. |
[83] | Arancibia S , Silhol M , Mouliere F , Meffre J , Hollinger I , Maurice T , et al. Protective effect of BDNF against beta-amyloid induced neurotoxicity in vitro and in vivo in rats, Neurobiol Dis (2008) ;31: (3):316–26. |
[84] | Nagahara AH , Merrill DA , Coppola G , Tsukada S , Schroeder BE , Shaked GM , et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease, Nat Med (2009) ;15: (3):331–7. |
[85] | Howells DW , Porritt MJ , Wong JY , Batchelor PE , Kalnins R , Hughes AJ , et al. Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra, Exp Neurol (2000) ;166: (1):127–35. |
[86] | Zuccato C , Belyaev N , Conforti P , Ooi L , Tartari M , Papadimou E , et al. Widespread disruption of repressor element-1 silencing transcription factor/neuron-restrictive silencer factor occupancy at its target genes in Huntington’s disease, J Neurosci (2007) ;27: (26):6972–83. |
[87] | Zuccato C , Tartari M , Crotti A , Goffredo D , Valenza M , Conti L , et al. Huntingtin interacts with REST/NRSF to modulate the transcription of NRSE-controlled neuronal genes, Nat Genet (2003) ;35: (1):76–83. |
[88] | Campbell RR , Wood MA , How the epigenome integrates information and reshapes the synapse, Nat Rev Neurosci (2019) ;20: (3):133–47. |
[89] | Deng P , Anderson JD , Yu AS , Annett G , Fink KD , Nolta JA , Engineered BDNF producing cells as a potential treatment for neurologic disease, Expert Opin Biol Ther (2016) ;16: (8):1025–33. |
