Physical Activity Modulates Common Neuroplasticity Substrates in Major Depressive and Bipolar Disorder

Table 2

Preclinical studies of physical activity in rodent models of mood disorder. To determine the effects of PA on the brain of rodents, a computer search of MEDLINE using the terms “voluntary wheel running,” “rodents,” “depression,” and “mania” was used to produce a list of studies. Then, manual searches of key references were performed to identify additional studies. Articles met inclusion criteria if they were peer-reviewed and performed in rodent models of depression or bipolar disorder. Articles were excluded if they were reviews, conference abstracts, or expert opinions. Duplicate articles and those not available in English language were excluded also. Based on this search and subsequent screening, a total of 28 articles that spanned from 2001 to 2016 were identified. Of those studies, 20 examined the effects of PA on behavioral outcomes. Strikingly, PA mitigated adverse outcomes in 95% (19 out of 20) of the studies that utilized behavioral measures, including those that examined depressive [493–508], anxiety [493, 496], and social-[495] and fear-avoidant behaviors [131, 509]. Another study reported that exercise mitigated manic-like behavior [250]. The remaining studies generally reported that exercise mitigated cognitive impairments [131, 499, 509], optimized the glucocorticoid response [500, 501, 509, 510] and neurotransmitter levels [497, 498, 511], optimized BDNF in the hippocampus [251, 493, 499, 500, 504, 505, 512, 513], increased neurogenesis [251, 502, 505, 506, 513], enhanced sleep [250, 514], and increased synaptic markers [508].

References	MD model	Age (wks)	Treatment modality	Duration (wks)	Measure	Outcome
[496]	Wistar rats exposed to chronic unpredictable stress	8	Voluntary wheel running	4	Sucrose preference,; elevated plus-maze,; elevated T-maze, and forced-swim test	Reduced depressive-like; symptoms and ↓ anxiety; symptoms in stressed rats
[499]	C57BL/6 mice exposed to; chronic uncontrollable stress	8-9	Voluntary wheel running	4	Forced swim, tail; suspension, water maze, and BDNF	Reduced depressive-like; symptoms, ↑ spatial memory,; ↑ mature BDNF
[493]	C57BL/6 mice exposed to; chronic uncontrollable stress	“Adult” status, but actual age not specified	Voluntary wheel running	3-4	Learned helplessness, forced swim, tail; suspension,; elevated plus maze, and BDNF	Reduced depressive-like; symptoms and ↓ anxiety; symptoms in wheel runners,; ↑ hippocampal BDNF mRNA
[500]	Sprague-Dawley rats exposed to chronic uncontrollable stress	Not specified	Voluntary wheel running	4 wks	Sucrose preference test,; open field test, Morris; water maze, corticoste; rone, BDNF RNA, and; glucocorticoid receptor; RNA	Reduced depressive-like; symptoms, ↑ hippocampal; BDNF RNA following stress, ↓ corticosterone following stress, ↑ glucocorticoid RNA receptor following stress
[501]	Sprague-Dawley rats exposed to chronic uncontrollable stress	“Adult” status, but actual age not specified	Voluntary wheel running	4 wks voluntary wheel running prior to stress followed by 4 wks voluntary wheel running after stress	IgM antibodies, IgG2a; antibodies, and distance ran	Voluntary wheel running; reduced stress-induced; depressive-like symptoms and; ↓ stress- induced alterations in; immune function
[503]	Fischer F344 rats exposed to chronic uncontrollable stress	“Adult” status, but actual age not specified	Voluntary wheel running	2 and 6	Freezing behavior and shuttle-box escape learning	6 wks running after exposure to uncontrollable stress reduced depressive-like symptoms and; anxiety symptoms in runners
[515]	Fischer F344 rats exposed to chronic uncontrollable stress	8	Voluntary wheel running	5	Social exploration, shock-elicited freezing, escape behavior,; corticosterone, and body weight	Runners exhibited ↓ body weight, ↓ anxiety and reduced; depressive-like symptoms, and ↓ corticosterone response to stress
[505]	C57BL/6 mice exposed to chronic uncontrollable stress	8	Stressed animals with; no treatment, a dietary supplement (antioxidants),; voluntary wheel running, or both dietary supplement & free access to running wheel	4	Neurogenesis, hippocampal BDNF mRNA, VGF serum, and; saccharin preference	Combination of diet and exercise; (but neither alone) reduced depressive-like symptoms, ↑; neurogenesis in dentate gyrus in; diet + exercise group, ↑ BDNF; mRNA in hippocampus of exercise + diet group, and trend towards ↑ VGF in exercise + dietary supplement group only
[506]	ICR mice exposed to chronic uncontrollable stress	8	Treadmill running; 60 min, treadmill; running + SU1498; [a VGF receptor (Flk-1); inhibitor], and control	2	Open-field test, forced swim test, open-field test, BrdU, Ki67, and CD31 immunohistochemistry	Treadmill group exhibited ↑; hippocampal neurogenesis in; dentate gyrus and ↓ anxiety and; reduced depressive-like symptoms in a manner that is dependent on VEGF-Flk-1 signaling
[498]	Swiss mice	Age not specified	Voluntary wheel running	3	Forced swim, tail; suspension, and open-field test	Reduced depressive-like symptoms, an effect that appeared related to availability of bioamines
[507]	Diurnal sand rats housed in either short photoperiod (SP) (5 hr light/19 hr dark) or neutral light (12 light/12 dark)	24	Voluntary wheel running	3	Elevated plus-maze, forced-swim test, and social interaction	↓ disruptions in activity rhythms; of SP/exercise animals, ↓ anxiety; and reduced depressive- like; symptoms for SP/running wheel; group, ↑ number and duration of; social interaction for SP/running; wheel group
[504]	C57BL/6J mice	6-7	Voluntary wheel running	4	VGF protein, BDNF protein, plasticity genes (Egr2, Grb2, ornithine decarboxylase-1,; synapsin-1, and synCAM), forced-swim, and tail-suspension tests	Reduced depressive- like; symptoms, ↑ in VGF protein and ↑ in BDNF protein in hippocampus, altered synaptic plasticity gene profile activity
[502]	Flinders Sensitive Line (FSL) rat	22	Administered escitalopram,; escitalopram + voluntary; wheel running, vehicle diet, or vehicle diet + voluntary wheel running	4	BrdU immunohistochemistry and forced-swim test	↑ in hippocampal neurogenesis in escitalopram, escitalopram + wheel running, and wheel running only, reduced depressive-like symptoms in wheel runners and escitalopram + wheel running groups
[497]	SwHi rats and SwLo rats	6–14	Voluntary wheel running	3	Forced-swim test	Reduced depressive-like symptoms in SwLo wheel runners with concomitant ↑ galanin mRNA in locus coeruleus
[508]	Sprague-Dawley rats	“Adult” status, but actual age not specified	Voluntary wheel running; wheel during CORT; administration; voluntary wheel running; wheel prior to CORT administration; voluntary wheel running prior to and concurrent with CORT administration	2	Forced-swim test,; sucrose- preference test, BrdU immunohistochemistry, synaptophysin, and BDNF	Reduced depressive-like symptoms in animals that ran prior to and concurrent with CORT administration, ↑ neurogenesis and cell survival in animals that ran prior to and concurrent with CORT administration, ↔ BDNF or IGF-1 in animals running prior to and concurrent to CORT administration, ↑ synaptophysin proteins in animals running prior to and concurrent to CORT administration
[131]	Fischer 344 rats exposed to chronic uncontrollable stress	“Adult” status, but actual age not specified	Treadmills, motorized running wheels, or voluntary wheel running	6	Shock-elicited freezing; and shuttle-box escape	Both forced and voluntary wheel running reduced fear conditioning and ↓ cognitive impairments
[515]	Fischer 344 rats exposed to chronic uncontrollable stress	“Adult” status, but actual age not specified	Voluntary wheel running	6	Shuttle-box escape	Running reduced fear conditioning and cognitive learning, ↓ 5-HT2CR mRNA in basolateral amygdala and dorsal striatum
[495]	C57BL/6 mice exposed to chronic social defeat stress	10	Voluntary wheel running	<1	Social-interaction test,; open-field test,; monoamines	Reduced social avoidance in those that ran 2 hours after stress, ↔ anxiety levels, ↔ in depressive symptoms
[250]	Myshkin mice (Myk/+)	6–12	Administered melatonin; or voluntary wheel running	6	Open-field test, elevated plus-maze, light–dark box, accelerating rotarod, EEG and EMG recordings; during sleep, and BDNF protein	Both melatonin and PA reduced manic behaviors, melatonin ↑ sleep duration, ↔ in hippocampal BDNF mRNA following exercise
[516]	C57BL/6 mice exposed to lipopolysacharide	16 and 88	Voluntary wheel running	4 for young mice and 10 for aged mice	Tail-suspension, sucrose; preference, TNF-a,; IL-1B, IL-6, and IFN-γ	↔ in depressive- like behavior in presence of ↑ TNF-a, IL-1B, IL-6, and IFN-γ
[511]	Fischer 344 rats exposed to acute uncontrollable stress	“Adult” status, but actual age not specified	Voluntary wheel running	6-7	Serotonin and dopamine in striatum	Running prevented stress-induced elevation of extracellular serotonin and potentiated dopamine concentration in the dorsal striatum
[494]	Outbred Hsd:ICR mice stressed by wheel removal	7–9 wks	Voluntary wheel running	6 days	Forced swim, tail-; suspension, and; behavioral despair	High CORT males deprived access to running wheel showed ↑ depressive symptoms
[510]	C57BL/6 mice exposed to chronic uncontrollable stress	6	Voluntary wheel running	4	Corticosterone and adrenal weight	More rapid corticosterone response but returned to baseline more quickly in wheel runners, ↑ adrenal weight
[513]	C57BL/6 mice exposed to chronic uncontrollable stress	8	Voluntary wheel running	3–6	Corticosterone, BDNF,; neurogenesis, open-field, elevated O-maze, dark- light box, forced swim, and learned helplessness	↑ hippocampal BDNF, ↑ neurogenesis, ↑ cortico-sterone metabolites, ↑ anxiety-like behavior in novel and aversive environments
[512]	Fischer F344 rats exposed to chronic uncontrollable stress	“Adult” status, but actual age not specified	Voluntary wheel running	3 and 6	Shuttle-box escape and conditioned fear	6 wks of running ↑ hippocampal BDNF mRNA and protein; following stress
[251]	C57Bl/10 mice	8	Voluntary wheel; running, fluoxetine,; or combination of; fluoxetine and voluntary wheel running	3	BDNF, IGF-1, and BrdU; immunohistochemistry	↑ in hippocampal BDNF in fluoxetine group only, and ↑ in neurogenesis with fluoxetine group only
[517]	TrkB^hGFAP and TrkB Nestin mice that were conditionally ablated for the gene encoding TrkB, the high affinity receptor for BDNF, in a regional and cell-type-specific manner	Postnatal day 15 and “adult” status specified, but not actual age	Voluntary wheel running	6	Dark light test; open-field test; forced swim test, BrdU incorporating cells	neural Progenitor cell deletion of trkB, both in embryos and in the adult, causes ↓ hippocampal; neurogenesis and ↓ behavioral; improvements following chronic antidepressant administration or wheel running
[514]	F344 rats exposed to chronic uncontrollable stress	8	Voluntary wheel running prior to stress exposure	6	Sleep and temperature; rhythms	↑ entrainment of sleep/wake behavior and ↓ disruption of; diurnal rhythms of sleep and; temperature following stress

PA and MDs in preclinical studies. BDNF: brain-derived neurotrophic factor; CORT: corticosterone; CUS: chronic unpredictable stress; SP: short photoperiod; STAT3: signal transducer and activator of transcription pathway 3; tx: treatment; VEGF: vascular endothelial growth factor.