Table 1.

Physical activity effects on the brain, across animal and human studies^a

	Neurotrophins				Cognition and behavior	Synaptic plasticity hippocampus (DG)	Neurogenesis and brain structure			Others	References
	Species	Factor	Brain area	Periphery					Factor
Adults	Animal	↑BDNF ↑proBDNF ↑TrkB receptor	Hippocampus, DG, perirhinal cortex, amygdala	Lumbar spinal cord, soleus muscle	↑Learning and memory ↑Pattern separation ↑Discrimination ↑Adaptation ↓Anxiety	↑LTP ↑Proteins associated (CREB, synapsin I, syntaxin, synaptotagmin, NMDAR2A, NMDAR2B, CaMKII, MAPK, GAP-43)	↑Proliferation ↑Survival ↑Neurogenesis		↑Early gene expression (Arc, c-Fos, Zif268) Notch1 modulation	↑Angiogenesis	[27,30,32,34,48, 66–75,78–80,87, 106,110,116,136, 151,161,163,174, 175,201,207–209]
		↑VEGF	Hippocampus	Lung, skeletal muscle
		↑IGF-1	Hippocampus, striatum, septum, cerebellum, cortex, thalamus, red nucleus, hypothalamus, brain stem nuclei	Cerebrospinal fluid
	Human	↑BDNF (transient)		Blood plasma and serum, skeletal muscle	↑Executive function ↑Visuospatial memory ↑Relational memory (children only) ↑Pattern separation ↑Academic achievement (children)		↑Hippocampal volume	↑Hippocampal blood volume (DG only)			[39,40,55,57,98, 254,255,259]
Aging	Animal	↑BDNF ↑TrkB receptor ↑IGF-1	Hippocampus, DG, perirhinal cortex		↑Learning and memory ↔Pattern separation ↑Adaptation ↑Motor ability ↓Anxiety	↑LTP	↑Neurogenesis		↑Immune factors (GRO-KC, IL-18, leptin, IL-1β, MCP-1, VEGF)	↑Angiogenesis	[34,76,80,81,116,165]
	Human	↑BDNF (transient)		Blood plasma and serum, skeletal muscle	↑Executive function ↑Attention and processing speed ↑Memory ↑ADAS-Cog (with subjective memory impairment)		↑Hippocampal volume ↑Gray matter density in prefrontal cortex (voxel wise) ↑Gray matter density in lateral temporal cortex ↑Distributed frontal and temporal white matter integrity associated with increased fitness from walking	↑Hippocampal blood flow	↑Transient BDNF (peripheral) ↔Basal BDNF, IGF-1, VEGF (peripheral)	↑Functional synchrony of frontal and temporal aspects of the DMN	[28,57,61–63,98,122, 124,187,189,256–258]
Alzheimer’s disease	Animal	↑BDNF ↑TrkB receptor	Hippocampus		↑Learning and memory ↓Anxiety ↑Sensorimotor function ↑Exploratory behavior	↑LTP ↑Proteins associated (synaptophysin)	↑Neurogenesis		↓IL-1β ↓TNF-α ↑CD40 ↑MHCII ↓Aβ40 ↓Aβ	↓Aβ load ↓Tau AT100 epitope ↑NPC1 ↑NPC2 ↓APP ↓MAP2ab ↑SOD1	[183,184,225,241–249]
	Human				↑Global cognition						[186–188]

Abbreviations: GAP-43, growth-associated protein 43; IL, interleukin; MCP-1, monocyte chemoattractant protein 1; ADAS-Cog, AD Assessment Scale – Cognitive Subscale; TNF-α, tumor necrosis factor alpha; MHCII, major histocompatibility complex class II; APP, amyloid precursor protein; MAP2ab, microtubule-associated protein 2ab; NPC1 and NPC2, Niemann–Pick type C1 and C2; SOD1, superoxide dismutase 1.

^aOnly evidence from randomized controlled trials (RCTs) or intervention trials are shown for human studies, because this most closely parallels experimental control in animal studies. ↑, Increase; ↓, decrease; ↔, no change.