Medial forebrain bundle DBS differentially modulates dopamine release in the nucleus accumbens in a rodent model of depression

Neuromodulation in Psychiatric disorders: Experimental and Clinical evidence for reward and motivation network Deep Brain Stimulation: Focus on the medial forebrain bundle

“…Different functional implications of dopamine firing and release has been reported as VTA dopamine firing was found to be involved in learning, whereas NAC dopamine release has been implicated in motivational drive and in encoding value of work (Mohebi et al., 2019). With our preliminary results reporting the prolonged dopamine release in response to mfb DBS in depressed rats compared to control rats (Ashouri Vajari et al., 2020), evidences point towards the involvement of dopamine release as a potential substrate of mfb DBS; however, further studies are required to delineate the underlying neural circuitry: mfb DBS at short pulse widths are unlikely to recruit dopamine fibres directly; hence, an indirect mechanism involving glutamatergic or GABAergic circuits may play a vital role as well (Ikemoto, 2010; Schlaepfer et al., 2013, 2014).…”

“…In a recent study from our laboratory, we explored the effects of varying mfb stimulation parameters on dopamine release in the NAC, and compared the dopamine release profiles—measured using FSCV—across the experimental depression model, FSL and healthy control animals. We, for the first time, have shown that clinically relevant mfb DBS stimulation (130 Hz frequency and 100 μs pulse duration) evoked a dopamine release in the NAC in both groups of animals, albeit, the induced dopamine response was larger and longer lasting in the FSL animals compared to the healthy controls (Ashouri Vajari et al., 2020). We have also investigated the dopamine release profiles with varying pulse widths of the stimulation.…”

“…Studies targeting the ventromedial part of the prefrontal cortex have concentrated on serotonin‐dependent mechanisms (Hamani et al., 2010; Rummel et al., 2016); similarly, the antidepressant effects described following mfb DBS focus on modulation of the mesolimbic dopaminergic midbrain reward system (Dandekar et al., 2017; Edemann‐Callesen et al., 2015; Thiele et al., 2018). Targeting this network is justified as dopaminergic neurons in the VTA in the FSL model have reduced burst activity which is “corrected” by electrical stimulation (Friedman et al., 2007, 2008; Friedman et al., 2009, 2012), and dopamine release has been measured in the nucleus accumbens by voltammetry following mfb or VTA DBS by us and others (Ashouri Vajari et al., 2020; Klanker et al., 2017; Settell et al., 2017).…”

“…There is evidence that healthy control animals respond differently to mfb DBS, in terms of behavioural response or inducing dopamine release, suggestive of physiological and anatomical differences in the mfb in the depression model and the healthy controls. For example, in our voltammetry study, the FSL animals showed longer and larger mfb‐DBS‐mediated dopamine responses which could be related to a combination of reasons (that needs to be tested experimentally), such as differences in the number of descending glutamatergic fibres recruited by the stimulation; the number or distribution of ionotropic glutamate receptors on VTA dopaminergic neurons; the proportion of myelinated/unmyelinated ascending dopaminergic axons, or the excitability of the dopaminergic neurons in the FSL/healthy control animals (Ashouri Vajari et al., 2020). Dopamine transmission from the VTA is tightly modulated by the inhibitory inputs from the tail of the VTA, which is regulated by the lateral habenula (Bourdy & Barrot, 2012).…”

“…NAC, nucleus accumbens; Hipp, hippocampus; VTA, ventral tegmental area; DRN, dorsal raphae nucleus; SNC, substantia nigra pars compacta; CPu, caudate putamen (=dorsal striatum); PFC, prefrontal cortex; Tu, olfactory tubercle. The references used in the figure: 1 (Ewing et al., 1983); 2 (Kuhr et al., 1984); 3 (Stamford et al., 1986); 4 (Stamford et al., 1987); 5 (Kuhr et al., 1987); 6 (Gonon, 1988); 7 (Howard et al., 2013); 8 (Furlanetti, et al., 2015); 9 (Furlanetti et al., 2015); 10 (Bregman et al., 2015); 11 (Klanker et al., 2017); 12 (Dandekar et al., 2017); 13 (Dandekar et al., 2019); 14 (Thiele et al., 2020); 15 (Ashouri Vajari et al., 2020); 16 (Settell et al., 2017); 17 (Friedman et al., 2012)…”