Frequency- and State-Dependent Network Effects of Electrical Stimulation Targeting the Ventral Tegmental Area in Macaques

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.

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Faculty Opinions recommendation of Electrical stimulation of the ventral tegmental area induces reanimation from general anesthesia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718230967.793498856 ◽

2014 ◽

Author(s):

Stan Leung ◽

Tao Luo

Keyword(s):

Electrical Stimulation ◽

General Anesthesia ◽

Ventral Tegmental Area ◽

Ventral Tegmental ◽

Stimulation Of

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A probabilistic atlas of the human ventral tegmental area (VTA) based on 7 Tesla MRI data

Brain Structure and Function ◽

10.1007/s00429-021-02231-w ◽

2021 ◽

Vol 226 (4) ◽

pp. 1155-1167 ◽

Cited By ~ 1

Author(s):

Anne C. Trutti ◽

Laura Fontanesi ◽

Martijn J. Mulder ◽

Pierre-Louis Bazin ◽

Bernhard Hommel ◽

...

Keyword(s):

Ventral Tegmental Area ◽

Region Of Interest ◽

Reward Processing ◽

7 Tesla ◽

Subcortical Structures ◽

7 Tesla Mri ◽

Subcortical Nuclei ◽

Ventral Tegmental ◽

The Brain

AbstractFunctional magnetic resonance imaging (fMRI) BOLD signal is commonly localized by using neuroanatomical atlases, which can also serve for region of interest analyses. Yet, the available MRI atlases have serious limitations when it comes to imaging subcortical structures: only 7% of the 455 subcortical nuclei are captured by current atlases. This highlights the general difficulty in mapping smaller nuclei deep in the brain, which can be addressed using ultra-high field 7 Tesla (T) MRI. The ventral tegmental area (VTA) is a subcortical structure that plays a pivotal role in reward processing, learning and memory. Despite the significant interest in this nucleus in cognitive neuroscience, there are currently no available, anatomically precise VTA atlases derived from 7 T MRI data that cover the full region of the VTA. Here, we first provide a protocol for multimodal VTA imaging and delineation. We then provide a data description of a probabilistic VTA atlas based on in vivo 7 T MRI data.

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Characteristics of Electrically Evoked Somatodendritic Dopamine Release in Substantia Nigra and Ventral Tegmental Area In Vitro

Journal of Neurophysiology ◽

10.1152/jn.1997.77.2.853 ◽

1997 ◽

Vol 77 (2) ◽

pp. 853-862 ◽

Cited By ~ 100

Author(s):

M. E. Rice ◽

S. J. Cragg ◽

S. A. Greenfield

Keyword(s):

Electrical Stimulation ◽

Substantia Nigra ◽

Ventral Tegmental Area ◽

Dopamine Release ◽

Substantia Nigra Pars Compacta ◽

Frequency Dependent ◽

Body Regions ◽

Ventral Tegmental ◽

Da Release

Rice, M. E., S. J. Cragg, and S. A. Greenfield. Characteristics of electrically evoked somatodendritic dopamine release in substantia nigra and ventral tegmental area in vitro. J. Neurophysiol. 77: 853–862, 1997. Somatodendritic dopamine (DA) release from neurons of the midbrain represents a nonclassical form of neuronal signaling. We assessed characteristics of DA release during electrical stimulation of the substantia nigra pars compacta (SNc) in guinea pig midbrain slices. With the use of parameters optimized for this region, we compared stimulus-induced increases in extracellular DA concentration ([DA]o) in medial and lateral SNc, ventral tegmental area (VTA), and dorsal striatum in vitro. DA release was monitored directly with carbon-fiber microelectrodes and fast-scan cyclic voltammetry. Detection of DA in SNc was confirmed by electrochemical, pharmacological, and anatomic criteria. Voltammograms of the released substance had the same peak potentials as those of DA obtained during in vitro calibration, but different from those of the indoleamine 5-hydroxytryptamine. Similar voltammograms were also obtained in the DA-rich striatum during local electrical stimulation. Contribution from the DA metabolite 3,4-dihydroxyphenylacetic acid to somatodendritic release was negligible, as indicated by the lack of effect of the monoamine oxidase inhibitor pargyline (20 μM) on the signal. Lastly, DA voltammograms could only be elicited in regions that were subsequently determined to be positive for tyrosine hydroxylase immunoreactivity (TH-ir). The frequency dependence of stimulated DA release in SNc was determined over a range of 1–50 Hz, with a constant duration of 10 s. Release was frequency dependent up to 10 Hz, with no further increase at higher frequencies. Stimulation at 10 Hz was used in all subsequent experiments. With this paradigm, DA release in SNc was tetrodotoxin insensitive, but strongly Ca2+ dependent. Stimulated [DA]o in the midbrain was also site specific. At the midcaudal level examined, DA efflux was significantly greater in VTA (1.04 ± 0.05 μM, mean ± SE) than in medial SNc (0.52 ± 0.05 μM), which in turn was higher than in lateral SNc (0.35 ± 0.03 μM). This pattern followed the apparent density of TH-ir, which was also VTA > medial SNc > lateral SNc. This report has introduced a new paradigm for the study of somatodendritic DA release. Voltammetric recording with electrodes of 2–4 μm tip diameter permitted highly localized, direct detection of endogenous DA. The Ca2+ dependence of stimulated release indicated that the process was physiologically relevant. Moreover, the findings that somatodendritic release was frequency dependent across a range characteristic of DA cell firing rates and that stimulated [DA]o varied markedly among DA cell body regions have important implications for how dendritically released DA may function in the physiology and pathophysiology of substantia nigra and VTA.

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