Modulation of synaptic plasticity by exercise

CHAPTER TWELVE

Modulation of synaptic plasticity by exercise Luis Bettioa,†, Jonathan S. Thackera,†, Craig Huttona, Brian R. Christiea,b,c,* a

Division of Medical Sciences, University of Victoria, Victoria, BC, Canada Island Medical Program, University of British Columbia, Victoria, BC, Canada c Department of Cellular and Physiological Sciences, University of British Columbia, Victoria, BC, Canada *Corresponding author: e-mail address: [email protected] b

Contents 1. Introduction 2. Synaptic plasticy and regular exercise in hippocampus 2.1 Dentate gyrus (DG) 2.2 Cornu ammonis (CA1) 3. Possible mediators of exercise-induced changes in the hippocampus 3.1 BDNF 3.2 IGF-1 3.3 VEGF 3.4 Glucocorticoids 4. Exercise as a promising therapeutic against impaired hippocampal synaptic plasticity 5. Concluding remarks References

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Abstract Synaptic plasticity is an experience-dependent process that results in long-lasting changes in synaptic communication. This phenomenon stimulates structural, molecular, and genetic changes in the brain and is the leading biological model for learning and memory processes. Synapses are able to show persistent increases in synaptic strength, or long-term potentiation (LTP), as well as persistent decreases in synaptic strength, known as long-term depression (LTD). Understanding the complex interactions that regulate these activity-dependent processes can provide insight for the development of strategies to improve cognitive function. Twenty years ago, we provided the first evidence indicating that aerobic exercise can reliably enhance LTP, and went on to show that it can also regulate some of the mechanisms

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These authors contributed equally to this work.

International Review of Neurobiology, Volume 147 ISSN 0074-7742 https://doi.org/10.1016/bs.irn.2019.07.002

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involved in LTD induction. Since then, several laboratories have confirmed and expanded these findings, helping to identify different molecular mechanisms involved in exercise-mediated changes in synaptic efficacy. This chapter reviews this material and shows how these experimental findings may prove valuable for alleviating the burden of neurodegenerative diseases in an aging population.

1. Introduction The brain can be conceptualized as a large neuronal network that has to learn how to respond appropriately to sensory input to enable its survival. The process of synaptic plasticity is widely believed to be the best biological model for understanding how experience-dependent processes affect synaptic communication (Lamprecht & LeDoux, 2004). The idea that learning requires structural changes in the brain was initially proposed by Ramo´n y Cajal (1909), when his neuroanatomical studies indicated that some degree of structural plasticity could occur after an injury (Stahnisch & Nitsch, 2002). In 1949, the Canadian physiologist Donald Hebb formally introduced the idea that neuronal activity could reorganize synapses. His fundamental idea (Hebbian plasticity) was that the repeated stimulation of specific receptors could lead to permanent changes in synaptic connectivity (Hebb, 1949). This concept is now commonly summarized with the adage “neurons that fire together, wire together” (Shatz, 1992). Hebb’s postulate was first shown experimentally in the hippocampal formation by Bliss and Lomo (1973). They showed that brief trains of high frequency stimulation (HFS) could produce a long-lasting increase in the amplitude of excitatory postsynaptic potentials (EPSPs) in the hippocampus (Bliss & Gardner-Medwin, 1973; Lomo, 1966). The hippocampus has since become one of the most studied structures in the brain due to both its propensity to exhibit synaptic plasticity and relevance for cognitive and emotional processing (Bird & Burgess, 2008). It also offers a simplified laminar structure with unidirectional connections, making it an ideal structure for both in vivo and in vitro experimentation (Andersen, Bliss, & Skrede, 1971; Bliss & Gardner-Medwin, 1973; Bliss & Lomo, 1973; Lomo, 1966). The term long-term potentiation (LTP) is commonly used to describe the strengthening of synapses, and LTP has since become the most widely accepted biological model for learning and memory mechanisms (Bliss & Collingridge, 1993). Many basic properties of LTP support the hypothesis that this phenomenon may be a biological substrate for learning and memory

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including cooperativity, associativity, durability and input specificity (Abraham, Logan, Greenwood, & Dragunow, 2002; Bliss & Collingridge, 1993). In addition to these discoveries, Stent (1973) postulated the inverse to Hebbian plasticity, after finding that some forms of activity lead to the weakening of the synapse. This study paved the way for the observation that a brief stimulation of an excitatory pathway can lead to a persistent decrease in its efficacy, a phenomenon that became known as long-term depression (LTD) (Dunwiddie & Lynch, 1978; Lynch, Dunwiddie, & Gribkoff, 1977). Despite having opposite effects, it seems that LTP and LTD have complementary roles in the regulation of cognitive processes, given that LTD has been proposed to prevent LTP saturation and even increase its effects, as well as limit the degree of excitation and eliminate unnecessary circuits (Christie, Kerr, & Abraham, 1994; Pinar et al., 2017). The years that followed the discovery of these processes were marked by the elucidation of several mechanisms that mediate bidirectional changes in synaptic efficacy. Of particular importance was the discovery of the contribution of N-methyl-D-aspartate receptors (NMDARs) (Collingridge, Kehl, & Mclennan, 1983), postsynaptic depolarization (Malinow & Miller, 1986; Wigstrom, Gustafsson, Huang, & Abraham, 1986) and calcium influx (Lynch, Larson, Kelso, Barrionuevo, & Schottler, 1983) for the induction of LTP. These findings were soon followed by the observation that NMDAR activation is also critical for LTD induction (Christie & Abraham, 1992; Dudek & Bear, 1992), although subsequent studies have provided evidence for NMDAR-independent forms of LTD (Pen˜asco et al., 2019; Robbe, Manzoni, Bockaert, Remaury, & Kopf, 2002; Snyder, Philpot, et al., 2001). NMDAR activation is dependent on two temporally sensitive events: (1) the ligand-binding of glutamate to its receptor site in the presence of glycine and (2) the voltage-dependent removal of a Mg2+ blockade of its channel pore. The requirement for synchronization (as would occur with high frequency synaptic activation) between these events is why NMDARs are generally considered as neuronal coincidence indicators of synaptic potentiation/depression (Tsien, 2000). Another overlapping mechanism implicated in both LTP and LTD induction is the increase in postsynaptic calcium concentration and activation of calcium/ calmodulin-dependent protein kinase II (CAMKII) (Coultrap et al., 2014; Mayford, Wang, Kandel, & O’Dell, 1995). The robust flux of Ca2+ into synapses following NMDAR activation is driven by the almost 20,000-fold gradient of [Ca2+] between intracellular and extracellular environments (Clapham, 2007). Under resting conditions the cytosol is actively deprived

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of intracellular [Ca2+], since Ca2+ triggers changes in both charge and conformational properties of countless proteins (Clapham, 2007; Mattson, 2007). However, while the application of a HFS or tetanic stimulation triggers a strong and brief increase in calcium influx, a low frequency stimulation leads to a weak and prolonged influx (Christie, Schexnayder, & Johnston, 1997; L€ uscher & Malenka, 2012; Nishiyama, Hong, Mikoshiba, Poo, & Kato, 2000; Yang, Tang, & Zucker, 1999). These events are crucial to determine whether a stimulus will lead to the induction of LTP or LTD, given that distinct protein kinases and/or phosphatases may be activated depending on their degree of calcium affinity and the parameters related to Ca2+ influx (e.g., rate and amount of Ca2+) ( Johnston et al., 2003; Malenka & Bear, 2004). One of the most relevant mechanisms implicated in the induction of LTP is the activation of protein kinases that regulate α-amino-3hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) function (Barria, Muller, Derkach, Griffith, & Soderling, 1997; Boehm et al., 2006). AMPARs are important mediators of fast synaptic transmission whose activity is potentiated during LTP through the phosphorylation of their GluA1 subunits and insertion of new receptors into the postsynaptic membrane (Barria et al., 1997; Benke, Luthl, Isaac, & Collingridge, 1998; Derkach, Barria, & Soderling, 1999; Lee, Kameyama, Huganir, & Bear, 1998; Lee et al., 2003; Makino & Malinow, 2009). These molecular events lead to a short-term increase in synaptic efficacy that can last for 1–2 h, which is commonly called early phase LTP (E-LTP) (Davis, Vanhoutte, Pages, Caboche, & Laroche, 2000; Nguyen, Abel, & Kandel, 2016). On the other hand, the consolidation of LTP is linked to the activity of protein kinase A (PKA) and extracellular signal-related protein kinase (ERK), which control transcriptional processes and the synthesis of proteins critical for the long-term maintenance of increased synaptic efficacy (a phenomenon called late-phase LTP, L-LTP) (Davis et al., 2000; Impey et al., 1998; Otani, Marshall, Tate, Goddard, & Abraham, 1989). This temporally distinct phase lasts from several hours to weeks and is characterized by a sustained secretion of brain derived neurotrophic factor (BDNF) (Figurov, Pozzo-Miller, Olafsson, Wang, & Lu, 1996; Kang & Schuman, 1995; Kovalchuk, Hanse, Kafitz, & Konnerth, 2002; Lu, Nagappan, Guan, Nathan, & Wren, 2013). In addition, L-LTP is associated with an increased activity of the mechanistic target of rapamycin (mTOR) signaling, a kinase required for the synthesis of proteins involved in LTP maintenance including postsynaptic density (PSD) proteins and synaptic proteins

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(Hoeffer & Klann, 2010). This step is crucial for supporting the structural changes accompanying long-term plasticity such as dendritic enlargement and formation of new dendritic spines (Bramham, 2008; Leal, Comprido, & Duarte, 2014). As a matter of fact, synaptic remodeling is the basis for LTP consolidation and has been proposed to be the biological correlate for memory storage (Abel et al., 1997), with evidence indicating that experience-dependent LTP can remain stable for at least 1 year (Abraham et al., 2002). Conversely, the molecular changes induced by LTD lead to opposite effects on synaptic function, namely, a reduction in synaptic efficacy and shrinkage or elimination of dendritic spines (Tada & Sheng, 2006; Zhou, Homma, & Poo, 2004). Possible explanations for the remarkably divergent effects induced by both processes include the activation of different subunits of NMDARs, and the fact that LTD induces a lower elevation in calcium concentration (Christie et al., 1997). These in turn may activate distinct protein kinases/phosphatases that have a higher affinity for calcium (Mulkey, Endo, Shenolikar, & Malenka, 1994). For instance, NMDAR-dependent LTD activates the low-affinity protein phosphatase calcineurin, which has been shown to trigger localized cycles of phosphorylation and dephosphorylation that culminate in AMPAR endocytosis (Beattie et al., 2000; Fox, Russell, Titterness, Yu, & Christie, 2007; Sanderson, Gorski, & Dell’Acqua, 2016). In the past years, it became clear that abnormalities in synaptic function (e.g., deficits in LTP and/or LTD) play a key role in several pathological conditions including neurodevelopmental and neurodegenerative diseases, as well as psychiatric disorders (Duman & Aghajanian, 2012; Van Spronsen & Hoogenraad, 2010; Zoghbi & Bear, 2012). In this scenario, a number of studies have focused on therapeutic interventions capable of inducing the molecular and structural changes that lead to an increased synaptic efficacy (Lu et al., 2013). One of the most promising approaches to stimulate this process is the practice of regular physical exercise. This non-pharmacological intervention is able to regulate distinct forms of neuroplasticity, while improving cognitive and affective processes and protecting against neurodegeneration (Erickson et al., 2011). The beneficial effects that exercise exerts on brain function result from a combination of multiple factors, and the precise mechanisms triggering these changes has been the focus of intense investigation. In this chapter, we are going to focus on the most relevant findings linking physical exercise with improvements in synaptic function.

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2. Synaptic plasticy and regular exercise in hippocampus Generally, there are two broad classes of physical exercise studied, resistance exercise and aerobic exercise. Whereas resistance exercises are those that favor the production of force under low repetition and predominately recruit anaerobic respiration; a combination that stimulates skeletal muscle growth and strength, aerobic exercise, is continuous, rhythmical muscle contractions under comparatively lower forces for a duration that exceeds the capacity of anaerobic respiration (>10 min). Aerobic exercise promotes a greater efficiency and capacity of the aerobic respiratory system. By virtue, adaptation following resistance exercise is myo-centric, whereas aerobic exercise promotes adaptation across various body tissues. Tissues with a high resting metabolic rate appear to be the most sensitive to adaptation following chronic aerobic exercise exposure (Fiuza-Luces, Garatachea, Berger, & Lucia, 2013; Gallagher et al., 1998), and the brain is one of the most metabolically active tissues; while it only constitutes about 2% of an adult human’s body weight, it accounts for roughly 20% of resting metabolism (Sokoloff, 1960). Although a number of investigations in humans suggest improvements in cognition following resistance exercise training, especially among the elderly, little to no evidence exists in rodents exploring possible mechanisms. Thus, this chapter will focus on the acute and chronic adaptations resulting from exposure to aerobic exercise. Over the past half century a number of animal models have been developed and widely accepted for the study of physiological responses to aerobic exercise (for a comprehensive review, refer to Kregel et al., 2006). As in humans, there are two classifications of experimental exercise in rodents, forced exercise and voluntary exercise. Forced exercise relies on the use of either a motorized treadmill or wheel (or in the case of forced swim, water), to “force” an animal into performing exercise. Forced treadmill exercise is an attractive exercise model as it allows greater experimental control of workload intensity, duration, and in many cases the measurement of metabolic rate. Forced-exercise models also provide experimenters the ability to assess both acute and chronic paradigms, while setting and measuring improvements in performance. However, animals do not natively take to forced-exercise, often necessitating a familiarization period, which may or may not contain brief exposures to aversive stimuli (e.g., electric grids, sweeping brush, burst of air) to incentivize the animals to perform;

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which has been shown to produce a greater than expected stress response during exercise (Contarteze, Manchado, Gobatto, & De Mello, 2008). However, once accustomed to the forced-exercise paradigms rodents display a high degree of compliance and become proficient in performing under a number of varying exercise procedures. In contrast, voluntary exercise in rodents involves the provision of ab libitum access to a running wheel. Voluntary exercise models are advantageous as they are cheaper, can be implemented en masse, and there is very little intervention required on the part of the researcher. Unlike forced-exercise, rodents have an inherent drive to run on running wheels and will spontaneous run if afforded the opportunity. The natural running behavior in rodents favors short, intermittent bouts of high intensity exercise lasting only a few minutes in duration (Rodnick, Reaven, Haskell, Sims, & Mondon, 1989). With 5–6 weeks of wheel access, animals have been reported to run up to as much as 18–20 km/day (Kregel et al., 2006). However, spontaneous wheel running also allows the animal complete control over intensity and duration which leads to large discrepancies in running wheel distances reported, with studies displaying animals readily redistribute into low-activity (2–5 km/day), intermediate-activity (6–9 km/day) and high-activity (12–14 km/day) runners (Mondon, Dolkas, Sims, & Reaven, 1985; Rodnick et al., 1989). Therefore, the selection of the exercise type (e.g., forced vs voluntary), exercise modality (e.g., treadmill vs wheel), and frequency (e.g., acute vs chronic) are important to consider, not only for study design, but also in the interpretation and generalizability of the results as they apply within the greater context of neuroplasticity.

2.1 Dentate gyrus (DG) The first studies investigating the impact of aerobic exercise on hippocampal plasticity were stimulated by the experimental observation that running wheel access is associated with an increased BDNF expression in several areas of the brain (Neeper, Go´auctemez-Pinilla, Choi, & Cotman, 1995; Neeper, Go´mez-Pinilla, Choi, & Cotman, 1996). Subsequently, we were able to show that mice with free access to a running wheel exhibited both enhanced neurogenesis and LTP in the DG, but that there was no significant increase in LTP in the CA1 subregion, an area that lacks significant neurogenic activity (van Praag, Christie, Sejnowski, & Gage, 1999). It is tempting to speculate that this result reflects, at least in part, synaptic plasticity that can be attributed solely to enhanced neurogenesis. However, we later showed

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that newborn neurons require 4–5 weeks to fully integrate into hippocampal circuitry (van Praag et al., 2002). Thus, while enhanced neurogenesis can lower the threshold for inducing LTP (Farmer et al., 2004; Snyder, Kee, & Wojtowicz, 2001) and contribute to MWM performance (GilMohapel et al., 2013; Kempermann & Gage, 2002; van Praag et al., 1999), there appears to be a temporal disjunction between how rapidly one can observe increases in synaptic plasticity with exercise and how rapidly exercise affects the process of neurogenesis. Indeed, other studies have found that as little as 5–10 days of voluntary running can significantly increase LTP in the male DG (Farmer et al., 2004; O’Callaghan, Ohle, & Kelly, 2007; Vasuta et al., 2007); although longer running periods seem to be required to generate equivalent effects in females (Titterness, Wiebe, Kwasnica, Keyes, & Christie, 2011). Additional evidence suggests in order to maintain the exercise-induced augmentation to LTP, the subject needs to regularly engage in exercise (Radahmadi, Hosseini, & Alaei, 2016). Despite these exciting findings, there is a paucity of evidence in the literature regarding the effects of exercise on bidirectional synaptic plasticity. A previous study from our group found that running enhances LTP in the DG of rats, but does not have a significant effect on LTD magnitude, although it might alter the receptor subunits that play a primary role in it (Vasuta et al., 2007). Specifically, we were able to demonstrate that voluntary exercise changes the mechanisms of LTD induction by increasing the participation of GluN2A subunit-containing NMDARs in this process (Vasuta et al., 2007). One possibility to explain these findings may be that LTD is a relevant component of cognitive processing in physiological conditions (Collingridge, Peineau, Howland, & Wang, 2010), and that the influence of exercise on this type of synaptic plasticity may be more evident in pathological situations.

2.2 Cornu ammonis (CA1) Despite the number of synaptic plasticity studies performed in the CA1 subfield, there is a surprising dearth of research investigating the influence exercise has on modulating bidirectional plasticity in CA1 region. The initial investigations by van Praag et al. (1999) exploring exercise effects in CA1 reported that LTP remained unchanged following chronic engagement in exercise intervention. The absence of exercise-induced facilitation in CA1 LTP was overshadowed by the opposing discovery in DG, likely contributing to the underrepresentation of CA1 and exercise investigations that

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followed. Notwithstanding, there has since been a selection of investigations confirming the lack of exercise-induced effects on CA1 LTP (Dahlin, Andersson, Thoren, Hanse, & Seth, 2019; Dao et al., 2013). Although healthy CA1 LTP is reported to be non-responsive to exercise, exercise does appear to rescue CA1 LTP deficits when used as a therapeutic in a number of aging, pathological, and stress models (Patten et al., 2016). Together these data suggest the interactions between exercise and CA1 plasticity are more complicated than initially proposed, and signify a potential avenue for further exploration.

3. Possible mediators of exercise-induced changes in the hippocampus 3.1 BDNF BDNF has been proposed to be a major mediator of the increased synaptic efficacy observed in the hippocampus of rodents that had free access to a running wheel (Cotman & Berchtold, 2002; Farmer et al., 2004; Go´mezPinilla, Ying, Roy, Molteni, & Edgerton, 2002; Vaynman, Ying, & Gomez-Pinilla, 2003) or forced-treadmill exercise (Alomari, Khabour, Alzoubi, & Alzubi, 2013). Interestingly, we were able to demonstrate that, similar to our LTP findings (van Praag et al., 1999), the increased BDNF expression induced by exercise occurs in a subregion-specific manner (elevated levels in the DG but not in the CA1 (Farmer et al., 2004). BDNF is initially synthesized from its precursor (proBDNF), and both molecules are known to exert opposing effects on synaptic function (Yang et al., 2014). In this context, while BDNF stimulates synaptic potentiation in the hippocampus by activating tropomyosin receptor kinase B (TrkB) signaling, proBDNF facilitates LTD by activating its p75NTR receptors (Woo et al., 2005). Voluntary wheel running appears to impact BDNF processing by stimulating the cleavage of proBDNF, and therefore increasing BDNF levels in the hippocampus (Ding, Ying, & Go´mez-Pinilla, 2011; Sartori et al., 2011). Furthermore, it is also known that many metabolic pathways associated with free running wheel exercise play a relevant role in BDNF expression (Carro, Nun˜ez, Busiguina, & Torres-Aleman, 2000; Gomez-Pinilla, Vaynman, & Ying, 2008; Kim & Leem, 2016; Sleiman et al., 2016; Wrann et al., 2013). Of particular importance is the induction of fibronectin type III domain-containing protein 5 (FNDC5)/irisin, a peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-dependent protein released from muscle cells during endurance

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exercise (Bostr€ om et al., 2012). The activation of PGC1α/FNDC5/BDNF signaling has been demonstrated in the hippocampus of mice exposed to regular wheel running, and it seems to be an important mediator of the beneficial effects of exercise for brain function (Islam, Young, & Wrann, 2017; Wrann, 2015; Wrann et al., 2013). Regular exercise is also associated with elevated levels and/or activity of several proteins downstream to BDNF that are critical for induction and maintenance of LTP. These include CAMKII (Vaynman et al., 2003; Vaynman, Ying, & GomezPinilla, 2004), ERK (Shen, Tong, Balazs, & Cotman, 2001), PSD-95 (Hu, Ying, Gomez-Pinilla, & Frautschy, 2009) and mTOR (Elfving, Christensen, Ratner, Wienecke, & Klein, 2013; Fang et al., 2013), as well as synaptic proteins such as synapsin I and synaptophysin (Vaynman, Ying, Yin, & Gomez-Pinilla, 2006). Considering the importance of these molecular events for structural changes in synaptic contacts, it is likely that they are also mediating alterations observed in the cytoarchitecture of the DG after regular exercise (i.e., increased dendritic length and complexity, spine density, and proliferation of neural progenitors) (Eadie, Redila, & Christie, 2005; Redila & Christie, 2006). It is important to point out that BDNF probably plays a role in both neurogenesis-dependent andindependent mechanisms that lead to synaptic strengthening after exercise. This hypothesis is supported by the observation that BDNF is acutely elevated in the hippocampus following running (Soya et al., 2007), and this upregulation can last up to 2 weeks after exercise ended (Berchtold, Castello, & Cotman, 2010). Furthermore, there is experimental evidence indicating that newborn neurons contribute to LTP in the DG through BDNF-dependent mechanisms (Bergami et al., 2008; Saxe et al., 2006). Although BDNF is the most heavily studied molecule with regards to exercise-induced plasticity in brain, there remains a lot to be determined, including its interactions with a number of other hormone systems.

3.2 IGF-1 Insulin-like growth factor 1 (IGF-1) is a small polypeptide hormone (7.5 kDa) with a similar structure to insulin. Like BDNF, IGF-1 has also garnered attention in the ongoing debate for underlying mechanisms between exercise and neuroplasticity. IGF-1 has traditionally been associated with energy and metabolism maintenance across a wide array of tissues (FiuzaLuces et al., 2013). In the central nervous system (CNS), IGF-1 signaling appears to be coupled to development, protection and overall maintenance

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of neurons and their synapses (Cheng et al., 2003). During development the brain highly expresses IGF-1, which contributes to neuronal survival and synapse migration, however, as the brain matures the production of IGF-1 greatly diminishes and the system becomes more reliant on peripherally derived IGF-1. This relationship is dissimilar to that of the IGF-1 receptor (IGF-1R) which remains actively expressed in the CNS across the lifespan. However, in a similar fashion as BDNF, IGF-1 gene expression in brain is stimulated by chronic voluntary wheel running (Ding, Vaynman, Akhavan, Ying, & Gomez-Pinilla, 2006). In fact, there is strong interplay between IGF-1 and BDNF expression: exogenous administration of IGF-1 stimulates hippocampal BDNF expression (likely via PGC1-α), and blocking IGF-1 receptor (IGF-1R) activity selectively interferes with the increase in neurogenesis after exercise (Carro, Trejo, Busiguina, & Torres-Aleman, 2001; Vaynman et al., 2003). Moreover, there is a surprising level of conservation between downstream signaling partners of both TrkB and IGF-1R, which likely contributes to their complimentary roles in synaptic plasticity (Ding et al., 2006). Specifically, both receptors retain tyrosine kinase domains that activate CaMKII and MAPKII signaling cascades, as well as, regulating synapsin I expression, which are all known contributors to exercise-induced hippocampal plasticity. All in all, IGF-1 interactions resulting from exercise are quite complex, both exercise-induced peripheral and central release of IGF-1 have a number of mediatory impacts on hippocampal function and cross talk between IGF-1 and other protein hormones, notably BDNF, appears to be strongly associated with hippocampal synaptic plasticity.

3.3 VEGF In addition to BDNF and IGF-1, other trophic factors are likely to support enhancements to plasticity induced by exercise, particularly vascular endothelial growth factor (VEGF), a major regulator of angiogenesis (Morland et al., 2017; Uysal et al., 2015). VEGF’s expression and release are primarily stimulated by hypoxic events, which causes the nuclear translocation of hypoxia-inducible factor 1α (HIF-1α) where it acts on HIF-responsive elements within the promoter region of the VEGF gene. However, HIF-1α expression remains unchanged in response to exercise, even after several weeks of treadmill exercise training, making it less likely that exerciseinduced VEGF exercise is related to hypoxic events. Instead, others have proposed increased VEGF expression may be in response to brain lactate

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levels which increases the activity of hydroxycarboxylic acid receptor 1 (HCAR1) and stimulates VEGF expression. Morland et al. (2017) provide convincing evidence for the lactate hypothesis: (1) exogenous lactate and 7 weeks of interval treadmill exercise stimulates VEGF expression, (2) both lactate and exercise increased angiogenesis in wild-type, and (3) knockoutmodels of HCAR1 lack increases in VEGF expression and do not undergo angiogenesis in response to either treatment (lactate or exercise) (Morland et al., 2017). Interestingly, the authors found the DG to be more sensitive than other regions of brain to these responses which is likely related to VEGF secondary involvement in neurogenesis. Previous work display VEGF administration can stimulate in vitro and in vivo neurogenesis (Cao et al., 2004; Fabel et al., 2003), and VEGF expression is critical for exerciseinduced neurogenesis (Fabel et al., 2003); although, VEGF’s ability to enhance LTP does not appear to depend on neurogenesis (Licht et al., 2011). In addition to neurogenesis, VEGF is able to induce rapid and profound changes in synaptic plasticity (specifically, LTP) within the DG when bath applied over acutely prepared slices. VEGF’s influence on LTP occurs either directly or indirectly by stimulating calcium-dependent mechanisms including CAMKII, PKC, ERK and mTOR signaling (Kim et al., 2008). More recently, VEGF has been shown to potentiate postsynaptic NMDAreceptor responses, increasing GluN2B synaptic surface content, and promote the incorporation of GluA1-containing AMPA-receptors (De Rossi et al., 2016). The overall effect of these changes is a VEGF-dependent increase in synaptogenesis. Overall, these studies highlight the importance VEGF has on regulating synaptic function and provides clues to the possible overlapping mechanisms of this hormone system with those aforementioned.

3.4 Glucocorticoids Circulating levels of glucocorticoids, such as cortisol or corticosterone (CORT), are heavily regulated by diurnal rhythm in both humans and rats, respectively (Harrington & Hooton, 1985; Joels, Sarabdjitsingh, & Karst, 2012; Selmaoui & Touitou, 2003; Van Cauter & Turek, 1995; Windle, Wood, Shanks, Lightman, & Ingram, 1998). Under basal conditions, roughly 80% of CORT is transported through circulation bound to corticosteroid-binding globulin (high affinity, low capacity), and 15% by albumin (low affinity, high capacity), while the remainder is free or unbound CORT (Perogamvros, Ray, & Trainer, 2012). As a steroid derived hormone, unbound CORT is the only bioactive form, and freely

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bypasses capillary vasculature, where it enters cells via simple diffusion (Mendel, 1992; Pardridge, 1981). Once CORT gains access to the cytosol it binds to one of two subclasses of receptors, either low affinity glucocorticoid (GC) or high affinity mineralocorticoids (MC) (Funder, 1997; Kim & Yoon, 1998). The activation of either GC or MCs by CORT promotes migration of the receptor to the nucleus causing upregulation, or suppression of gene transcription, a process known as transactivation or transrepression (Hanawalt & Hanawalt, 1993). Acute exposure to stressful stimuli results in the dramatic upregulation of hypothalamic-pituitaryadrenal axis (HPA) activity and spikes in circulating glucocorticoids which are necessary to facilitate adaptation to meet the homeostatic challenge. These transient spikes in peripheral CORT enhance NMDAR Ca2+ currents and promote AMPAR surface trafficking, which has been linked to improvements in CA1 LTP and hippocampal dependent learning (Tse, Bagot, Hutter, Wong, & Wong, 2011; Whitehead et al., 2013). Moreover, providing exogenous dosages of CORT to adrenalectomized aged animals (whereby neurogenesis is diminished) completely recovers the lack of neurogenesis, indicating a role of CORT in this process (Cameron & McKay, 1999). To the contrary, prolonged or repeated exposure to environmentally adverse events leads to chronic elevations in CORT, which can oppose these acute positive effects. Exercise is a form of stress, acutely it can produce similar spikes in CORT release, and chronic exercise has been shown to promote consistent elevations in circulating CORT in the initial 4 weeks following the start of training (see review, Stranahan, Lee, & Mattson, 2008). However, others have noted prolonged exercise paradigms (>5 weeks) can have a positive influence on HPA axis activity, in particular exercise can attenuate CORT release in response to a bout of voluntary or forced exercise (Girard & Garland, 2002; Radahmadi, Alaei, Sharifi, & Hosseini, 2015; Tharp & Buuck, 2017), as well as other acute stressors (Gerecke, Kolobova, Allen, & Fawer, 2013; Greenwood, Loughridge, Sadaoui, Christianson, & Fleshner, 2013); but, how prolonged exercise-induced elevations in CORT contribute to exercise-induced neurogenesis and/or plasticity remains unclear. Nonetheless, there is general consensus that exercise protects against negative effects of chronic stress including detriments in learning and memory. First, in complete opposition to other forms of stress prolonged exercise exposure promotes increases glucocorticoid receptor expression, while decreasing mineralocorticoid receptor sensitivity (Droste et al., 2003), a pattern associated with a reduction in anxiogenic behaviors (Droste, Chandramohan, Hill, Linthorst, & Reul, 2007). Others have

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hypothesized exercise benefits may be related to interactions between CORT and BDNF. A number of investigations support the notion that both acute stress and exogenous CORT administration can inhibit BDNF expression and reduce BDNF’s bioavailability within hippocampus (Cotman & Berchtold, 2002). Surprisingly, unlike stress, exercised animals display increases in both BDNF and CORT making exercise unique among other types of physical stress (Adlard & Cotman, 2004). However, the interaction between exercise-induced CORT and BDNF has yet to be systemically investigated. Overall, glucocorticoids have not garnered as much attention as other neurotrophic factors in response to exercise effects on plasticity, however, it is clear they are integral part of the physiological response to exercise and there is a need to better characterize the HPA axis response and its interactions to exercise.

4. Exercise as a promising therapeutic against impaired hippocampal synaptic plasticity It is well established that the hippocampus is particularly vulnerable to neurodegenerative (Bettio, Rajendran, & Gil-Mohapel, 2017) and psychiatric disorders (Sapolsky, 2000), and that the dysfunction in this brain region observed in neuropathological conditions is mediated by deficits in synaptic plasticity and BDNF signaling (Duman, Aghajanian, Sanacora, & Krystal, 2016; Lu et al., 2013; Nagahara & Tuszynski, 2011). These features make physical exercise an attractive strategy to improve cognitive and emotional responses in patients. One such example stems from animal and human studies indicating the beneficial effects physical exercise exerts on hippocampal function may reduce the risk and postpone the development of Alzheimer’s disease (AD) (Intlekofer & Cotman, 2013). Deficits in LTP and synaptic loss are a common feature of AD and directly contribute to the cognitive impairments seen in this neurodegenerative disease ( Jacobsen et al., 2006; Rowan, Klyubin, Cullen, & Anwyl, 2003; Trinchese et al., 2004). AD is characterized by the accumulated formation of fibrous deposits known as amyloid plaques (consisting of oligomeric Aβ peptides) and the aggregation of hyperphosphorylated tau protein that produces neurofibrillary tangles (NFT) (Masters et al., 2015). A defined physiological role of Aβ and other amyloid precursor protein derivatives in AD is subject of ongoing debate, however, the neurotoxicity of Aβ appears to be

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dose-dependent: at picomolar concentrations (typical for the healthy brain) it promotes and is necessary for activity-dependent synaptic plasticity (Puzzo et al., 2011), but in the high nanomolar range (or greater; as observed in AD) it impairs LTP (Puzzo et al., 2008) and causes synaptic degeneration (Shankar et al., 2008). Moreover, intracerebroventricular (ICV) injections of human extracted Aβ from AD tissue have shown to potently impair LTP, enhance LTD, and reduce dendritic spine density in the rodent hippocampus (Selkoe et al., 2016; Walsh et al., 2002). With regards to tauopathy, transgenic mice prone to developing hippocampal tauopathy display a blunted ability to learn and recall, which is undoubtedly related to the attenuation of LTP in these animals ( Jeugd et al., 2011; Oddo et al., 2003). Despite the many gaps which remain in our understanding of AD, there is overwhelming evidence from human and animal studies suggesting the disease effects hippocampal synaptic morphology and plasticity (Scheff, Price, Schmitt, Dekosky, & Mufson, 2007; Scheff, Price, Schmitt, & Mufson, 2006; Terry et al., 1991), providing a potential target through which AD could benefit from exercise. Exercise has emerged as a promising therapeutic to combat the progressive decline in synaptic function associated with AD (Patten et al., 2016; Radak et al., 2010). A number of transgenic models of AD appear to benefit from voluntary exercise exposure. In particular, transgenic mouse models of AD display noticeable behavioral improvements in novel recognition (Tg2576 model—Yuede et al., 2009) and radial-arm maze performance (ε4 allele APOE gene—Nichol, Deeny, Seif, Camaclang, & Cotman, 2013) when given free access to running wheels for 16- and 6-weeks, respectively. Forced-treadmill exercise (30 min/day, 5 days/week, for 5 months) also appears to prevent a decay in water maze performance repeatedly observed in APP/PS1 transgenic mice, an effect that is mirrored by improvements in DG LTP, but not LTD (Liu, Zhao, Cai, Zhao, & Shi, 2011). A follow-up investigation using the same exercise paradigm administered during an advanced stage of AD (Aβ deposits already present) in APP/PS1 mice, observed similar improvements in both water maze performance and LTP, suggesting exercise prevents cognitive decline at any stage of AD progression (Zhao, Liu, Zhang, & Tong, 2015). Chronic (4 weeks of 10–15 m/min 2  15 min/day for 5 days) treadmill exercise has also been shown to drastically reduce errors on radial arm maze and conserve both CA1 and DG synaptic plasticity (e-LTP and l-LTP) from ICV injections of human Aβ in Wistar rats, effects which may be related to an elevation

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in BDNF observed in both CA1 and DG (Dao, Zagaar, Levine, & Alkadhi, 2016; Dao et al., 2013). BDNF has been a focus of exercise-induced effects for the past few decades; however, there have been more recent developments in upstream pro-hormones such as Irisin/FNDC5. FNDC5 has recently been discovered to be reduced in both animal models of AD and human brain tissues of AD patients (Lourenco et al., 2019). Lourenco et al. (2019) reveal convincing evidence that exercise-induced increases in brain levels of FNDC5 can rescue memory impairment and synaptic plasticity in a number of transgenic models of AD (Lourenco et al., 2019). Consequentially, blocking peripheral FNDC5 ablates the positive influence exercise has on rescuing deficits in LTP of AD mice (Lourenco et al., 2019). Experiments like these expose the potential of exercise not only as a prevention/treatment, but as a model to identify novel treatment vectors for staving off age-associated and neurodegenerative impairments in synaptic function.

5. Concluding remarks The current excitement regarding the therapeutic potential of exercise is palpable, and no doubt it will continue to be a key area of research in the decades to come. Exercise is one of the most demanding voluntary activities mammals can participate in. It requires extensive coordination across various brain areas, the synergistic activation of muscles, and altered homeostatic regulation of almost every organ in the body to maintain an energy balance. There is growing interest in exploiting the benefits of exercise for synaptic plasticity in patient populations, as a number of neuropathologies involve altered synaptic function/plasticity. This makes it crucial to understand the mechanisms that underlie how exercise impacts some of the fundamental mechanisms involved in synaptic plasticity. As research advances, we are likely to further unveil the intricacies and interplay between a number of hormone systems (i.e., BDNF, IGF-1, VEGF and CORT; Fig. 1). Moreover, fundamental research in exercise is already uncovering novel therapeutic vectors, such as FNDC5/irisin, that have potential to treat a number of currently untreatable conditions (e.g., AD). This work is becoming increasingly important as the global population shifts to one that is predominantly an aging population. As neurodegenerative disease become more prevalent, the potential for exercise to help alleviate this burden becomes more germane as a therapeutic vector.

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Fig. 1 Schematic representation of the effects of chronic aerobic exercise on brain function and hippocampal synaptic plasticity. Regular exercise is associated with an increase in several molecular mediators that regulate synaptic function such as brain derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and insulin-like growth factor 1 (IGF-1). In addition, exercised rodents present alterations in brain structure including the formation of new dendritic spines and enhanced hippocampal neurogenesis. These changes strongly contribute to the beneficial effects that exercise exerts on synaptic plasticity and cognitive function, namely, improvements in hippocampal long-term potentiation (LTP) and better performance in learning and memory tasks.

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