Table 6.

Effects of physiological and energetic extracellular stimuli on temperament-related Ras-ERK (MAPK) and PI3K-AKT-mTOR pathways

Extracellular stimulus	Effect on Ras-ERK	Effect on PI3K-AKT-mTOR	Cellular response	References
Temperature
Cold	Inhibition		Quiescence (cold slows growth and metabolism, promotes repair of injury, reduces pain and inflammation)	Hypothermic stress154 repair of injury155
Hot		Activation	Growth and proliferation (heat increases growth and switches cells from catabolic to anabolic processes)	Heat stress156,157 anabolic switch158
Luminosity (visible light)
Dark		Inhibition	Slows and dampens circadian rhythmicity via mTOR	Night 145
Bright	Activation	Activation	Accelerates and enhances circadian rhythmicity via mTOR, directs neurite outgrowth via Ras-ERK	Visible light pulses145,159,160
Electromagnetic fields
External high frequency (not protected)	Inhibition	Inhibition	Exposure to non-thermal high-frequency EMF impairs hippocampus function, emotional stability, passive-avoidance learning, and regulation of impulse-control via inhibited Ras-Erk, and inhibited AKT and voltage-gated calcium channel signaling of self-control	External non-thermal GHz EMF exposure161,162
External high frequency (protected)			Administration of melatonin and omega-3 fatty acids protects against the harmful effects of non-thermal high-frequency EMF	Neuroprotection from non-thermal EMF163
Low-intensity and low-frequency EMF	Inhibition or activation		Exposure to low-intensity, frequency-modulated EMF can inhibit or activate depending on frequency, site, and temperament. 24 HZ EMF inhibits cell proliferation by inhibiting Ras-ERK (MAPK) pathways. In contrast, 10 HZ transcranial magnetic stimulation of dorsolateral PFC reduces negative affect in ways related to temperament and ERK pathway (uncoupling subgenual ACC from default mode network is reduced by higher Harm Avoidance, and increased by higher Persistence). Anti-depressant effects involve activation of Ras-Erk with proliferation of hippocampal-derived neural stem cells)	Frequency-modulated 10–25 HZ EMF exposure164–168
Hydration
Dry	Inhibition		Dehydration inhibits components like AMPK and TSC around mTOR signaling, thereby reducing cellular energy from glucose intake, glycogen synthesis, lipogenesis, and ERK expression	Hyper-osmotic dehydration169,170
Wet	Activation		Hydration promotes Ras-ERK and mTOR signaling, increasing cellular energy availability	Hypo-osmotic hydration171,172
Nutrition
Fasting		Inhibition by nutrient and energy depletion	The mTOR complex depends on nutrient availability so its activity is reduced by diverse mechanisms of energy depletion	Nutrient sensing by mTOR172
Feeding		Activation by various nutrients, particularly amino-acids, insulin-and growth-factor signaling		Nutrient sensing by mTOR172
Exercise
Inactive	Low activity	Low activity
Active	Activation	Activation	Exercise activates both ERK and mTOR signaling via increased expression of AMPK, CAMK4, and p38 genes, leading to increased cellular growth, energy availability from mitochondrial biogenesis in multiple body tissues, including neurons and muscle, and increased morphological plasticity of muscle and increased insulin sensitivity in diabetes and obesity.	Endurance training173–175
Sleep
Deprived	Inhibition		Sleep deprivation reduces expression of Ras-ERK pathway, leading to impaired learning and memory, as observed in parasomnias associated with increased Novelty Seeking	Sleep deprivation176,177
Unlimited	Activation		Duration of sleep is regulated by ERK pathway by effects on expression of activity-dependent neuromodulators like norepinephrine during wakefulness	Modulation of sleep and wakefulness178