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

“LTP is one model of synaptic plasticity that refers to the strengthening of synaptic connections between neurons (Bliss and Collingridge, 1993).”

“In animal models of stress/MDD, certain micro-scale changes have been recorded which demonstrate that AE can promote hippocampal neurogenesis, vascularization, BDNF expression (both brain-wide and within the hippocampus), IGF-1 expression, VEGF expression, and hippocampal synaptic plasticity (Adlard and Cotman, 2004;…”

“…et al., 1997; Smith et al., 2010; Chang et al., 2012; Roig et al., 2013; Verburgh et al., 2013) but mostly in older age groups (Etnier et al., 1997; Colcombe and Kramer, 2003; Angevaren et al., 2008; van Uffelen et al., 2008; Smith et al., 2010; Snowden et al., 2011; Chang et al., 2012), as well as…”

“Animal models have shown AE to be associated with a region-specific up-regulation of BDNF in the hippocampus (Neeper et al., 1995; Marlatt et al., 2012; Uysal et al., 2015).”

“SSRI medications have been shown to stimulate the rate of hippocampal neurogenesis (Malberg et al., 2000; Boldrini et al., 2009), but again this may not be representative of increased granule cells.”

“…inhibit other important neuroplastic mechanisms such as synaptic plasticity (Law and Deakin, 2001; Kolomeets et al., 2007; Kobayashi, 2009; McEwen et al., 2012; Sanderson et al., 2012) and BDNF expression (Krishnan and Nestler, 2008; Green et al., 2011; Favalli et al., 2012) within the hippocampus.”

“The human hippocampus plays a vital role in the formation of declarative memories, most prominently of which, in the formation of episodic and spatiotemporal memories (Burgess et al., 2002).”

“…are important to the development and maintenance of functioning neural cells in the brain (Barbacid, 1995) and are likely to play a crucial role in mediating the impact of AE on hippocampal neuroplasticity and functioning (Cotman et al., 2007; Voss et al., 2013a; Bolijn and Lucassen, 2015).”

“The hippocampus plays an important role in both learning and memory (Jarrard, 1993) and affective processing (Phillips et al., 2003).”

“Some studies have used diffusion tensor imaging (DTI) to demonstrate that the growth in hippocampal volume induced by AE is correlated with improvements in the microstructural integrity of hippocampal gray-matter, based on the assumption that a low mean diffusivity is indicative of an increased…”

“…task performance, such as in spatial and contextual memory or pattern separation tasks, but not in tasks that are less hippocampus dependent, such as delay conditioning (Gould et al., 1999; Shors et al., 2002; Snyder et al., 2005, 2011; Deng et al., 2009; Sahay et al., 2011; Lucassen et al., 2013).”

“However, some studies have found AE to be associated with greater white-matter volume in the temporal lobes that surround the hippocampus in older adults (Colcombe et al., 2003, 2006; Tseng et al., 2013; Burzynska et al., 2014).”

“Key mechanisms at both the cellular and molecular level will be discussed below in terms of their contribution to AE-induced enhancements in hippocampal functioning.”

“It has been demonstrated in animal models that AE stimulates the sprouting of new capillaries (angiogenesis) and improves vasculature within the hippocampus (Trejo et al., 2001; van Praag et al., 2005).”

“…thought to interact with energy metabolism to facilitate both pre-and post-synaptic mechanisms and the induction of LTP (Gomez-Pinilla and Hillman, 2013; Edelmann et al., 2014), as well as promoting the proliferation and survival of adult-born granule cells (Korol et al., 2013; Park and Poo, 2013).”

“Higher levels of aerobic fitness have been consistently associated with larger hippocampal or temporal lobe volumes in healthy adolescent (Chaddock et al., 2010) and older adults (Colcombe et al., 2003; Bugg and Head, 2011; Head et al., 2012; Niemann et al., 2014).”

“Hippocampal dysfunctioning may therefore contribute toward deficits in the regulation of emotional processing and stress responses that are often seen in patients with MDD (Sapolsky, 2000; Davidson et al., 2002).”

“…cortex and the amygdala, the hippocampus is also implicated in emotional regulation (O’Donnell and Grace, 1995; Seidenbecher et al., 2003; Lisman and Grace, 2005; Maren and Hobin, 2007) as well as playing an important role in regulating feedback inhibition from the…”

“…functioning, processing speed, motor functioning, and memory in healthy young and middle aged adults (Etnier et al., 1997; Smith et al., 2010; Chang et al., 2012; Roig et al., 2013; Verburgh et al., 2013) but mostly in older age groups (Etnier et al., 1997; Colcombe and Kramer, 2003;…”

“The subgranular zone of the hippocampal dentate gyrus (DG) is one of the just two primary locations where neurogenesis is known to occur in the adult rodent and human brain (Spalding et al., 2013; Kempermann et al., 2015).”

“Interestingly, a stimulus as peripheral as aerobic exercise (AE) has been demonstrated to have a strong influence on inducing neuroplasticity (Voss et al., 2013a) and promoting cognitive performance (Smith et al., 2010).”

“…deficits in schizophrenia may in fact, be through cognitive remediation which has produced some significant improvements in a number of cognitive domains and functional outcomes (McGurk et al., 2007; Reddy et al., 2014), however, effect sizes remain only small to moderate (Wykes et al., 2011).”

“…antidepressant treatment had a stronger impact on up-regulating BDNF than either intervention had individually (Russo-Neustadt et al., 2001; Baj et al., 2012) – this is particularly important as BDNF regulation is thought to be crucial to the antidepressant mechanism (Duman and Aghajanian, 2012).”

“As hippocampal functioning may be an important factor supporting working memory (Fell and Axmacher, 2011; Chaieb et al., 2015) promoting hippocampal integrity may indirectly contribute toward alleviating working memory deficits and improving executive functioning.”

“…task performance, such as in spatial and contextual memory or pattern separation tasks, but not in tasks that are less hippocampus dependent, such as delay conditioning (Gould et al., 1999; Shors et al., 2002; Snyder et al., 2005, 2011; Deng et al., 2009; Sahay et al., 2011; Lucassen et al., 2013).”

“Also, the hippocampus, and particularly the DG, is crucial in selecting and separating similar events in space and time, and hence pattern separation is a main function attributed to the hippocampus (Yassa and Stark, 2011; Oomen et al., 2013, 2014).”

“…task performance, such as in spatial and contextual memory or pattern separation tasks, but not in tasks that are less hippocampus dependent, such as delay conditioning (Gould et al., 1999; Shors et al., 2002; Snyder et al., 2005, 2011; Deng et al., 2009; Sahay et al., 2011; Lucassen et al., 2013).”

“…directly impacts upon performance in spatial and contextual memory tasks (Linnarsson et al., 1997; Alonso et al., 2002; Heldt et al., 2007; Peters et al., 2010), and also that the downregulation of BDNF inhibits AE induced improvements in spatial memory performance (Vaynman et al., 2004).”

“Spatial and episodic memory processes are inherently related given their specific reliance on the hippocampus (Bird and Burgess, 2008) and the fact that episodic memories are encoded in a spatio-temporal context (Tulving, 1993), making spatial information important in episodic memory formation.”

“Large-scale epidemiological studies have consistently correlated high levels of aerobic fitness with greater academic achievement and IQ scores (Sibley and Etnier, 2003; Tomporowski et al., 2008, 2014; Howie and Pate, 2012) as well as with a greater preservation of cognitive function in old age…”

“Indeed, immature granule cells are particularly suited to participate in the learning process as they have a lower threshold for LTP induction (Schmidt-Hieber et al., 2004) and demonstrate enhanced LTP compared to surrounding mature granule cells (Lee S.W. et al., 2012).”

“Secondly, psychiatric symptoms can be dichotomously described as being either affective or cognitive in nature, yet a disproportionate amount of the current literature has exclusively focussed on ameliorating affective symptoms (Millan et al., 2012).”

“…(Vancampfort et al., 2012; Firth et al., 2015; Rimes et al., 2015) and affective symptoms in MDD (Cooney et al., 2012), in some cases just as effectively as antidepressants (Blumenthal et al., 1999, 2007; Brosse et al., 2002), or in terms of neurogenesis, exceeding it (Marlatt et al., 2010).”

“…et al., 1997; Colcombe and Kramer, 2003; Angevaren et al., 2008; van Uffelen et al., 2008; Smith et al., 2010; Snowden et al., 2011; Chang et al., 2012), as well as in older individuals with mild cognitive impairments or dementia (Heyn et al., 2004; van Uffelen et al., 2008; Gates et al., 2013).”

“…deficits in schizophrenia may in fact, be through cognitive remediation which has produced some significant improvements in a number of cognitive domains and functional outcomes (McGurk et al., 2007; Reddy et al., 2014), however, effect sizes remain only small to moderate (Wykes et al., 2011).”

“For example, some studies argue that a high-intensity exercise is optimal for reducing symptoms in MDD (Singh et al., 2005), while others have suggested that that a mild (Dunn et al., 2005) or a moderate intensity exercise intervention would be optimal (Stanton and Reaburn, 2014).”

“…the process of neurogenesis forms a substrate for experience-dependent change (Opendak and Gould, 2015; Lucassen and Oomen, 2016), which has been implicated in fear and anxiety and depression like-behavior (Sahay and Hen, 2007; Besnard and Sahay, 2015; Lucassen et al., 2015; Hu et al., 2016).”

“For example, the development of a psychiatric disorder significantly increases the risk of psychiatric comorbidity (Fusar-Poli et al., 2014; Avenevoli et al., 2015).”

“Firstly, a number of psychiatric and neurological disorders seem to have a particularly potent influence on hippocampal structure (Bartsch and Wulff, 2015) and its deterioration may underlie certain aspects of their symptomatology.”

“Both antipsychotic (De Hert et al., 2012) and antidepressant (Anderson et al., 2012) medications are associated with numerous adverse side effects that range from more common and less severe symptoms like headaches or nausea, to less common but more severe symptoms like cardiovascular or metabolic…”

“Hippocampal dysfunctioning may therefore contribute toward deficits in the regulation of emotional processing and stress responses that are often seen in patients with MDD (Sapolsky, 2000; Davidson et al., 2002).”

“Schizophrenia is associated with deficits in cognitive domains of executive functioning, processing speed, memory and attention (Mesholam-Gately et al., 2009; Keefe and Harvey, 2012).”

“…2010; Chang et al., 2012; Roig et al., 2013; Verburgh et al., 2013) but mostly in older age groups (Etnier et al., 1997; Colcombe and Kramer, 2003; Angevaren et al., 2008; van Uffelen et al., 2008; Smith et al., 2010; Snowden et al., 2011; Chang et al., 2012), as well as in older individuals with…”

“AE is conversely associated with lowering the risk of various other conditions developing that range from age-and dementia-related cognitive decline to mood and anxiety disorders (Martinsen, 2008; Ahlskog et al., 2011; Mammen and Faulkner, 2013).”

“These stem cells undergo subsequent stages of proliferation, migration and neuronal differentiation, eventually producing adult-generated, fully functional, neurons that are well integrated into existing neural circuits (Kempermann et al., 2015).”

“The heterogeneity of schizophrenia makes the disorder extremely difficult to model in animals and most approaches have focussed on replicating certain groups of schizophrenia-like behaviors in animals (Nestler and Hyman, 2010).”

“One brain region with a high degree of endogenous neuroplasticity is the hippocampus (Bavelier and Neville, 2002).”

“As will be discussed below, it has been extensively demonstrated in animal models that AE stimulates a cascade of neuroplastic mechanisms within the hippocampus that are often paralleled by functional improvements (Voss et al., 2013a; Opendak and Gould, 2015).”

“…(Vancampfort et al., 2012; Firth et al., 2015; Rimes et al., 2015) and affective symptoms in MDD (Cooney et al., 2012), in some cases just as effectively as antidepressants (Blumenthal et al., 1999, 2007; Brosse et al., 2002), or in terms of neurogenesis, exceeding it (Marlatt et al., 2010).”

“Indeed, the inhibition of VEGF or IGF-1 has been demonstrated to impair the promotional impact of AE on the rate of neurogenesis (Trejo et al., 2001; Fabel et al., 2003; Ding et al., 2006) and spatial memory performance (Ding et al., 2006).”

“However, some studies have found AE to be associated with greater white-matter volume in the temporal lobes that surround the hippocampus in older adults (Colcombe et al., 2003, 2006; Tseng et al., 2013; Burzynska et al., 2014).”

“…is a growing cohort of evidence to suggest that AE is associated with increases in hippocampal gray-matter volume in both healthy and non-healthy individuals (Hötting and Röder, 2013; Hamilton and Rhodes, 2015), and with increases in hippocampal microstructural integrity (Kleemeyer et al., 2015).”

“…(Sibley and Etnier, 2003; Tomporowski et al., 2008, 2014; Howie and Pate, 2012) as well as with a greater preservation of cognitive function in old age (Yaffe et al., 2001; Barnes et al., 2003; Middleton et al., 2008; Wendell et al., 2014) and fewer incidences of dementia (Hamer and Chida, 2009).”

“Similarly, human patients with MDD have consistently demonstrated clinically relevant deficits in domains of executive functioning, psychomotor speed, attention, and memory (McDermott and Ebmeier, 2009; Lee R.S. et al., 2012; McIntyre et al., 2013; Rock et al., 2013).”

“…that long-term antipsychotic treatment in humans may be linked to a reduction in both global gray-and white-matter volumes (Navari and Dazzan, 2009; Ho et al., 2011; Vernon et al., 2011; Fusar-Poli et al., 2013) as well as region-specific reductions in hippocampal volume (Panenka et al., 2007).”

“Psychiatric disorders like schizophrenia and MDD have been primarily treated using pharmacotherapy such as with antipsychotic or antidepressant medications, both of which have been shown to reduce psychiatric symptoms (Leucht et al., 2012; Undurraga and Baldessarini, 2012).”

“The efficacy of AE is already being investigated as a therapeutic intervention to counteract cognitive decline and deteriorating hippocampal integrity associated with aging or neurological disorders like dementia (Ahlskog et al., 2011).”

“…studies have consistently correlated high levels of aerobic fitness with greater academic achievement and IQ scores (Sibley and Etnier, 2003; Tomporowski et al., 2008, 2014; Howie and Pate, 2012) as well as with a greater preservation of cognitive function in old age (Yaffe et al., 2001;…”

“…is likely to be an important factor contributing toward the cognitive deficits associated with MDD (Perera et al., 2008; Kaymak et al., 2010; Nagahara and Tuszynski, 2011; Turner et al., 2012) and schizophrenia (Ranganath et al., 2008; Schobel et al., 2009; Heckers and Konradi, 2010; Zhang…”

“Indeed, the inhibition of VEGF or IGF-1 has been demonstrated to impair the promotional impact of AE on the rate of neurogenesis (Trejo et al., 2001; Fabel et al., 2003; Ding et al., 2006) and spatial memory performance (Ding et al., 2006).”

“Pattern completion is a complimentary process to pattern separation whereby through the activation of associative networks in the CA3 region, partial information can act as a recall cue to return the full representation of a previously stored memory (Nakashiba et al., 2012).”

“…task performance, such as in spatial and contextual memory or pattern separation tasks, but not in tasks that are less hippocampus dependent, such as delay conditioning (Gould et al., 1999; Shors et al., 2002; Snyder et al., 2005, 2011; Deng et al., 2009; Sahay et al., 2011; Lucassen et al., 2013).”

“…task performance, such as in spatial and contextual memory or pattern separation tasks, but not in tasks that are less hippocampus dependent, such as delay conditioning (Gould et al., 1999; Shors et al., 2002; Snyder et al., 2005, 2011; Deng et al., 2009; Sahay et al., 2011; Lucassen et al., 2013).”

“Conversely, up-regulating either VEGF or IGF-1 can stimulate neurogenesis independently of AE (Aberg et al., 2000; Carro et al., 2000; Trejo et al., 2001; Cao et al., 2004).”

“Conversely, up-regulating either VEGF or IGF-1 can stimulate neurogenesis independently of AE (Aberg et al., 2000; Carro et al., 2000; Trejo et al., 2001; Cao et al., 2004).”

“AE also interacts with the glutamatergic system through increasing the expression of N -methyl- D -aspartic acid (NMDA) receptors in the hippocampus (specifically, both NR2A and NR2B subtypes), which contributes toward the synaptic plasticity of the region (Molteni et al., 2002; Farmer et al., 2004).”

“Contrastingly, AE is known to elicit comparatively few adverse side effects and is associated with improvements in the social, physical and affective well being of individuals with psychiatric disorders (Fiuza-Luces et al., 2013).”

“…aged adults (Etnier et al., 1997; Smith et al., 2010; Chang et al., 2012; Roig et al., 2013; Verburgh et al., 2013) but mostly in older age groups (Etnier et al., 1997; Colcombe and Kramer, 2003; Angevaren et al., 2008; van Uffelen et al., 2008; Smith et al., 2010; Snowden et al., 2011; Chang et…”

“…continue to experience these cognitive symptoms are more likely to relapse and display worse psychosocial functioning outcomes (Papakostas et al., 2008; Bortolato et al., 2016), which can impact their capacity to socialize or to function well at work (Jaeger et al., 2006; McIntyre et al., 2013).”

“Conversely, up-regulating either VEGF or IGF-1 can stimulate neurogenesis independently of AE (Aberg et al., 2000; Carro et al., 2000; Trejo et al., 2001; Cao et al., 2004).”

“Some RCTs have stipulated that AE influences divergent cognitive domains, whereas others have suggested AE had no significant impact on cognition at all (Etnier et al., 2006; van Uffelen et al., 2008; Snowden et al., 2011; Gates et al., 2013; Kelly et al., 2014; Young et al., 2015).”

“…connectivity with the prefrontal cortex and the amygdala, the hippocampus is also implicated in emotional regulation (O’Donnell and Grace, 1995; Seidenbecher et al., 2003; Lisman and Grace, 2005; Maren and Hobin, 2007) as well as playing an important role in regulating feedback inhibition from…”

“The capacity to promote cognitive performance in this way implies that AE may have an important clinical relevance in counteracting the cognitive decline associated with aging or dementia (Kramer et al., 2006) and has catalyzed its systematic investigation.”

“Forming an episodic memory involves the association of an event or feature with a particular location in space and occurs through this LTP mechanism in the hippocampus (Bannerman et al., 2014).”

“…induced by AE correlates with a greater performance on spatial memory tasks such as a virtual Morris Water Maze task (Erickson and Kramer, 2009; Szabo et al., 2011; Herting and Nagel, 2012) and on contextual memory tasks (Chaddock et al., 2010) with correlations ranging from r = 0.12 to r = 0.36.”

“SSRI medications have been shown to stimulate the rate of hippocampal neurogenesis (Malberg et al., 2000; Boldrini et al., 2009), but again this may not be representative of increased granule cells.”

“…of BDNF expression directly impacts upon performance in spatial and contextual memory tasks (Linnarsson et al., 1997; Alonso et al., 2002; Heldt et al., 2007; Peters et al., 2010), and also that the downregulation of BDNF inhibits AE induced improvements in spatial memory performance…”

“This primarily occurs through the role that neurogenesis plays in facilitating memory formation by dictating a computational mechanism known as pattern separation (Aimone et al., 2011; Sahay et al., 2011).”

“These morphological changes are associated with higher rates of LTP induction and facilitate changes in dendritic strength (van Praag, 2008).”

“…or ablation of neurogenesis impairs performance on spatial and contextual memory tasks while improved performances on these tasks are seen when neurogenesis is stimulated (Deng et al., 2010; Snyder and Cameron, 2012; Aimone et al., 2014; Vadodaria and Jessberger, 2014; Kent et al., 2015).”

“…(Sibley and Etnier, 2003; Tomporowski et al., 2008, 2014; Howie and Pate, 2012) as well as with a greater preservation of cognitive function in old age (Yaffe et al., 2001; Barnes et al., 2003; Middleton et al., 2008; Wendell et al., 2014) and fewer incidences of dementia (Hamer and Chida, 2009).”

“For example, a recent systematic review concluded that AE was effective at reducing the risk of patients with schizophrenia developing a comorbid disorder (Firth et al., 2015).”

“Using hippocampus dependent paradigms, AE has been reliably demonstrated to improve task performance in animal models (van Praag, 2009; Voss et al., 2013a), although this does also depend on others aspects of AE such as the duration and intensity of AE (Naylor et al., 2005; Ploughman et al., 2007;…”

“Patients with schizophrenia show a disproportionately low level of pattern separation relative to pattern completion (Tamminga et al., 2010).”

“…MDD also inhibit other important neuroplastic mechanisms such as synaptic plasticity (Law and Deakin, 2001; Kolomeets et al., 2007; Kobayashi, 2009; McEwen et al., 2012; Sanderson et al., 2012) and BDNF expression (Krishnan and Nestler, 2008; Green et al., 2011; Favalli et al., 2012) within the…”

“AE interventions have also been shown to increase hippocampal volume in patients with mild cognitive impairments (ten Brinke et al., 2015), schizophrenia (Pajonk et al., 2010), and multiple sclerosis (Leavitt et al., 2014).”

“For example, the development of a psychiatric disorder significantly increases the risk of psychiatric comorbidity (Fusar-Poli et al., 2014; Avenevoli et al., 2015).”

“A reduced hippocampal volume is one of the most consistently reported structural abnormalities in patients of MDD (Schmaal et al., 2016) and of schizophrenia (Ellison-Wright and Bullmore, 2010; Adriano et al., 2012).”

“Indeed, the inhibition of VEGF or IGF-1 has been demonstrated to impair the promotional impact of AE on the rate of neurogenesis (Trejo et al., 2001; Fabel et al., 2003; Ding et al., 2006) and spatial memory performance (Ding et al., 2006).”

“…(Deng et al., 2010) and block AE-induced improvements in spatial (Clark et al., 2009) and contextual (Wojtowicz et al., 2008) memory performance, but only in conditions in which the task required fine spatial discriminations (i.e., where pattern separation was necessary; Creer et al., 2010).”

“As will be discussed below, it has been extensively demonstrated in animal models that AE stimulates a cascade of neuroplastic mechanisms within the hippocampus that are often paralleled by functional improvements (Voss et al., 2013a; Opendak and Gould, 2015).”

“…after remission following successful antidepressant treatment, most patients continue to experience cognitive deficits, particularly within domains of executive function, memory, and attention (Hammar and Ardal, 2009; Bora et al., 2013; Rock et al., 2013; Popovic et al., 2015; Solé et al., 2015).”

“For example, deficits in working memory represent an aspect of executive functioning impaired in MDD (Lee R.S. et al., 2012; Rock et al., 2013) and schizophrenia (Forbes et al., 2009).”

“…change used an automated algorithm to segment the hippocampus (Scheewe et al., 2013; Rosenbaum et al., 2015), which is known to be less accurate than the manual method (Morey et al., 2009) employed in the former study (Pajonk et al., 2010) – although this was not always the case (Lin et al., 2015).”

“To illustrate this point, deficits in pattern separation could negatively influence one’s capacity to correctly discriminate between stimuli and lead to a tendency for overgeneralization (Kheirbek et al., 2012; Shelton and Kirwan, 2013).”

“…seem to have a particularly deleterious impact on DG volume (Tamminga et al., 2010; Huang et al., 2013; Travis et al., 2015), which is reminiscent of the reduced level of neurogenesis found in animal models of both disorders (Eisch and Petrik, 2012; Lucassen et al., 2015; Allen et al., 2016).”

“…that long-term antipsychotic treatment in humans may be linked to a reduction in both global gray-and white-matter volumes (Navari and Dazzan, 2009; Ho et al., 2011; Vernon et al., 2011; Fusar-Poli et al., 2013) as well as region-specific reductions in hippocampal volume (Panenka et al., 2007).”

“Some RCTs have stipulated that AE influences divergent cognitive domains, whereas others have suggested AE had no significant impact on cognition at all (Etnier et al., 2006; van Uffelen et al., 2008; Snowden et al., 2011; Gates et al., 2013; Kelly et al., 2014; Young et al., 2015).”

“…(Vancampfort et al., 2012; Firth et al., 2015; Rimes et al., 2015) and affective symptoms in MDD (Cooney et al., 2012), in some cases just as effectively as antidepressants (Blumenthal et al., 1999, 2007; Brosse et al., 2002), or in terms of neurogenesis, exceeding it (Marlatt et al., 2010).”

“Pertaining to its highly neuroplastic nature (Bavelier and Neville, 2002), the hippocampus is particularly vulnerable to structural and functional deterioration in a wide range of neurological and psychiatric disorders (Bartsch and Wulff, 2015).”

“Until recently, human studies had primarily focussed on examining the impact of AE on performance in frontal-executive or attentional tasks rather than on specific hippocampus dependent forms of cognition (Ruscheweyh et al., 2011).”

“…task performance, such as in spatial and contextual memory or pattern separation tasks, but not in tasks that are less hippocampus dependent, such as delay conditioning (Gould et al., 1999; Shors et al., 2002; Snyder et al., 2005, 2011; Deng et al., 2009; Sahay et al., 2011; Lucassen et al., 2013).”

“…after remission following successful antidepressant treatment, most patients continue to experience cognitive deficits, particularly within domains of executive function, memory, and attention (Hammar and Ardal, 2009; Bora et al., 2013; Rock et al., 2013; Popovic et al., 2015; Solé et al., 2015).”

“…have recently suggested that the effectiveness of antipsychotic and antidepressant medications is only marginally different from that of a placebo (Leucht et al., 2009; Rief et al., 2009), and neither have been able to successfully remediate cognitive dysfunction (Keefe et al., 2013, 2014; Solé…”

“…continue to experience these cognitive symptoms are more likely to relapse and display worse psychosocial functioning outcomes (Papakostas et al., 2008; Bortolato et al., 2016), which can impact their capacity to socialize or to function well at work (Jaeger et al., 2006; McIntyre et al., 2013).”

“…animal studies, which have found that the manipulation of BDNF expression directly impacts upon performance in spatial and contextual memory tasks (Linnarsson et al., 1997; Alonso et al., 2002; Heldt et al., 2007; Peters et al., 2010), and also that the downregulation of BDNF inhibits AE induced…”

“For example, some studies argue that a high-intensity exercise is optimal for reducing symptoms in MDD (Singh et al., 2005), while others have suggested that that a mild (Dunn et al., 2005) or a moderate intensity exercise intervention would be optimal (Stanton and Reaburn, 2014).”

“The dendrites of granule cells within the DG have been shown to increase in length, complexity, and spine density in response to AE (Eadie et al., 2005; Redila and Christie, 2006) as well as spine density in surrounding pyramidal cells of the entorhinal cortex and CA1 regions (Stranahan et al.,…”

“…directly impacts upon performance in spatial and contextual memory tasks (Linnarsson et al., 1997; Alonso et al., 2002; Heldt et al., 2007; Peters et al., 2010), and also that the downregulation of BDNF inhibits AE induced improvements in spatial memory performance (Vaynman et al., 2004).”

“One brain region with a high degree of endogenous neuroplasticity is the hippocampus (Bavelier and Neville, 2002).”

“…2010; Chang et al., 2012; Roig et al., 2013; Verburgh et al., 2013) but mostly in older age groups (Etnier et al., 1997; Colcombe and Kramer, 2003; Angevaren et al., 2008; van Uffelen et al., 2008; Smith et al., 2010; Snowden et al., 2011; Chang et al., 2012), as well as in older individuals with…”

“…i.e., both the rate of cell proliferation as well as the survival of newborn granule cells (Cotman et al., 2007; Kempermann et al., 2010; Lucassen et al., 2010; Vivar et al., 2013) and despite being difficult to study in humans (Manganas et al., 2007; Ho et al., 2013; Jessberger and Gage,…”

“AE also interacts with the glutamatergic system through increasing the expression of N -methyl- D -aspartic acid (NMDA) receptors in the hippocampus (specifically, both NR2A and NR2B subtypes), which contributes toward the synaptic plasticity of the region (Molteni et al., 2002; Farmer et al., 2004).”