Fig. 1

Differentiating mechanisms underlying the neuromodulation effects of DBS and optogenetics. Left: A hypothesis posits that single pulses of electrical stimuli activate all converging presynaptic inputs to stimulate target neurons. Responses at the target location are determined by the distribution of excitatory/inhibitory (E/I) afferent inputs [48, 49]. Repetitive high-frequency stimulation (HFS) can lead to neuronal suppression due to short-term synaptic depression [48, 50]. This results from rapid decreases in synaptic strength after brief bursts of activity, depleting presynaptic neurotransmitters [53]. Local action potentials (APs) evoked by the stimulus can propagate orthodromically to facilitate neurotransmitter release at the distal end of the soma and antidromically to activate upstream neurons [88]. Occasionally, the AP reaches the base of the axonal arbor first and then bifurcates at various branch points, eventually invading the entire axonal arbor and reaching all terminal points (Invasion). This leads to neurotransmitter release at terminal locations beyond the stimulation site [81, 87]. Right: In contrast, optogenetics (right) relies on genetically-encoded proteins that change conformation in response to a light stimulation, regulating cell activity [34]. Opsin tools expressed on membranes of specific neurons enable selective activation or inhibition of those neurons with light, leaving other non-opsin-expressing cells unaffected by the illumination [28]