Abstract
The ventral tegmental area (VTA) is a midbrain structure at the heart of the dopaminergic system underlying adaptive behavior. Endogenous firing rates of dopamine cells in the VTA vary from fast phasic bursts to slow tonic activity. Artificial perturbations of the VTA, through electrical or optogenetic stimulation methods, generate different and sometimes even contrasting behavioral outcomes depending on stimulation parameters such as frequency, amplitude, and pulse width. Here, we investigate the global functional effects of electrical stimulation frequency (10, 20, 50, and 100 Hz) of the VTA in rhesus monkeys. We stimulated 2 animals with chronic electrodes, either awake or anesthetized, while concurrently acquiring whole-brain functional magnetic resonance imaging (fMRI) signals. In the awake state, activity as a function of stimulation frequency followed an inverted U-shape in many cortical and subcortical structures, with highest activity observed at 20 and 50 Hz and lower activity at 10 and 100 Hz. Under anesthesia, the hemodynamic responses in connected brain areas were slightly positive at 10 Hz stimulation, but decreased linearly as a function of higher stimulation frequencies. A speculative explanation for the remarkable frequency dependence of stimulation-induced fMRI activity is that the VTA makes use of different frequency channels to communicate with different postsynaptic sites.
Highlights
The ventral tegmental area (VTA) is a midbrain structure at the heart of the dopaminergic (DA) system which sends projections throughout most of the brain (Berger et al 1988; Mark Williams and Goldman-Rakic 1998)
To investigate how stimulation frequency affects the pattern of elicited brain activity, we electrically stimulated the VTA via chronic electrodes using different frequencies (10, 20, 50, and 100 Hz), while measuring the corresponding neural responses in a block-design functional magnetic resonance imaging (fMRI) experiment
During the fMRI experiments, VTA stimulation blocks lasted for 40 s with brief stimulation trains within a stimulation block starting every 4 s
Summary
The ventral tegmental area (VTA) is a midbrain structure at the heart of the dopaminergic (DA) system which sends projections throughout most of the brain (Berger et al 1988; Mark Williams and Goldman-Rakic 1998). Little is known, about the relationship between firing frequency and activity modulation at projection sites This temporal component of the VTA responses is key to understanding the wide range and sometimes contradictory behavioral effects related to dopamine signaling (Schultz 2007). Modulations of opposite polarities were found when stimulating the ventral thalamus in pigs (Paek et al 2015), with low (10 Hz) frequencies causing positive hemodynamic signals in M1, while high (130 Hz) frequencies generated negative modulations Such inconsistent results indicate that the effect of EM on distal structures may depend on several factors including the frequency of stimulation, the region stimulated, and the downstream structure being monitored. The diversity observed indicates that it is difficult to predict brain-wide effects of electrically stimulating any particular region and that these relationships must be tested empirically
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