Optogenetic versus electrical stimulation of dopamine terminals in the nucleus accumbens reveals local modulation of presynaptic release

Abstract

The nucleus accumbens is highly heterogeneous, integrating regionally distinct afferent projections and accumbal interneurons, resulting in diverse local microenvironments. Dopamine (DA) neuron terminals similarly express a heterogeneous collection of terminal receptors that modulate DA signaling. Cyclic voltammetry is often used to probe DA terminal dynamics in brain slice preparations; however, this method traditionally requires electrical stimulation to induce DA release. Electrical stimulation excites all of the neuronal processes in the stimulation field, potentially introducing simultaneous, multi-synaptic modulation of DA terminal release. We used optogenetics to selectively stimulate DA terminals and used voltammetry to compare DA responses from electrical and optical stimulation of the same area of tissue around a recording electrode. We found that with multiple pulse stimulation trains, optically stimulated DA release increasingly exceeded that of electrical stimulation. Furthermore, electrical stimulation produced inhibition of DA release across longer duration stimulations. The GABAB antagonist, CGP 55845, increased electrically stimulated DA release significantly more than light stimulated release. The nicotinic acetylcholine receptor antagonist, dihydro-β-erythroidine hydrobromide, inhibited single pulse electrically stimulated DA release while having no effect on optically stimulated DA release. Our results demonstrate that electrical stimulation introduces local multi-synaptic modulation of DA release that is absent with optogenetically targeted stimulation.

Chronic ethanol exposure increases inhibition of optically targeted phasic dopamine release in the nucleus accumbens core and medial shell ex vivo

“…Immunohistochemistry was used to verify ChR2 expression in dopamine axons in the nucleus accumbens as previously described (Melchior et al 2015a). Mice were anesthetized with ketamine (100mg/kg) and xylazine (8 mg/kg) and transcardially perfused with phosphate-buffered saline (PBS) followed by 10% buffered formalin phosphate (Fischer Scientific, Waltham, MA, USA).…”

“…That is, a single pulse-stimulated DA signal is low in amplitude compared to neighboring regions such as the NAc core and dorsal striatum (Jones et al 1996a). This can be overcome by applying multiple pulses in a stimulation train; however, electrical stimulation trains recruit modulation of DA terminals from concurrent excitation of the surrounding non-dopaminergic neuronal types within the tissue (Melchior et al 2015a). This recruitment often distorts the stimulated DA signal and makes assessments of whether heteroreceptor modulation is occurring through direct (terminal receptors) or indirect (multi-synaptic) mechanisms difficult to determine.…”

What do phasic cholinergic signals do?

“…1A). However, optogenetically-evoked transients differ from endogenous transients by rising and decaying faster, primarily reflecting that optogenetically-evoked transients essentially are artifacts of stimulating one particular population of neurons in isolation, whereas endogenous transients reflect the cholinergic component of the activation of distributed and heterogeneous neuronal networks (see also Melchior, Ferris, Stuber, Riddle, & Jones, 2015; Millard, Whitmire, Gollnick, Rozell, & Stanley, 2015). With the rising popularity of optogenetic methods, it is important to note this limitation which optogenetic methods share with many, if not all, more traditional methods used to evoke brain function, such as electrical stimulation or pharmacological receptor stimulation.…”

Optogenetic Approaches to Target Specific Neural Circuits in Post-stroke Recovery

“…Given the complex network and numerous distinct subtypes of excitatory and inhibitory neurons, cells during electrical stimulation may cause cancellation effects between circuits, making it difficult to characterize detailed local circuits and long-range projections. A recent study compared optogenetic and electrical stimulation of dopamine release in the terminals [112], and demonstrated that selective optogenetic stimulation produced higher dopamine release than electrical stimulation. The same study found that local electrical stimulation produced multisynaptic modulation on dopamine release and this effect was absent in selective optogenetic stimulation [112].…”

“…A recent study compared optogenetic and electrical stimulation of dopamine release in the terminals [112], and demonstrated that selective optogenetic stimulation produced higher dopamine release than electrical stimulation. The same study found that local electrical stimulation produced multisynaptic modulation on dopamine release and this effect was absent in selective optogenetic stimulation [112]. Furthermore, Dai et al [113] directly compared optogenetics and electrical stimulation in rhesus monkeys and demonstrated that both stimulation approaches produced a similar response in a lateral visuospatial discrimination task while stimulating the intraparietal area.…”