Potential therapeutic mechanism of deep brain stimulation of the nucleus accumbens in obsessive-compulsive disorder

Abstract

Deep brain stimulation (DBS) of the nucleus accumbens (NAc) (NAc-DBS) is an effective solution to refractory obsessive-compulsive disorder (OCD). However, evidence for the neurobiological mechanisms of OCD and the effect of NAc-DBS is still lacking. One hypothesis is that the electrophysiological activities in the NAc are modulated by DBS, and another hypothesis is that the activities of neurotransmitters in the NAc are influenced by DBS. To investigate these potential alterations, rats with quinpirole (QNP)- induced OCD were treated with DBS of the core part of NAc. Then, extracellular spikes (SPK) and local field potentials (LFP) in the NAc were recorded, and the levels of relevant neurotransmitters and related proteins were measured. Analysis of SPK revealed that the firing rate was decreased and the firing pattern was changed after NAc-DBS, and analysis of LFP showed that overall power spectral density (PSD) levels were reduced after NAc-DBS. Additionally, we found that the relative powers of the theta band, alpha band and beta band were increased in OCD status, while the relative powers of the delta band and gamma band were decreased. This pathological pattern of power distribution was reformed by NAc-DBS. Furthermore, we found that the local levels of monoamines [dopamine (DA) and serotonin (5-HT)] and amino acids [glutamate (Glu) and gamma-aminobutyric acid (GABA)] in the NAc were increased in OCD status, and that the expression of the two types of DA receptors in the NAc exhibited an opposite change. These abnormalities could be reversed by NAc-DBS. These findings provide a more comprehensive understanding about the function of the NAc in the pathophysiology of OCD and provide more detailed evidence for the potential effect of NAc-DBS.

Keywords: deep brain stimulation; electrophysiology in vivo; neurotransmitters; nucleus accumbens; obsessive-compulsive disorder; therapy.

FIGURE 1

Changes in the levels of neurotransmitters of interest in the NAc in the control, sham stimulation and NAc-DBS groups. (A) Illustration of dopaminergic projections to the NAc. (B) The bar graph represents the mean level of the response intensity indicating the concentration of DA in the NAc. (C) Illustration of serotonergic projections to the NAc. (D) The bar graph represents the mean level of the intensity of 5-HT in the NAc. (E) Illustration of histaminergic projections to the NAc. (F) The bar graph represents the mean level of the intensity of histamine in the NAc. (G) Illustration of cholinergic projections to the NAc. (H) The bar graph represents the mean level of the intensity of ACh in the NAc. (I) Illustration of glutamatergic projections to the NAc. (J) The bar graph represents the mean level of the intensity of Glu in the NAc. (K) Illustration of the GABAergic pathway in the NAc. (L) The bar graph represents the mean level of the intensity of GABA in the NAc. All illustrations are modified from the stereotaxic atlas of Paxinos and Watson (6th edition). DA, dopamine; VTA, ventral tegmental area; 5-HT, serotonin; RN, raphe nuclei; TMN, tuberomammillary nucleus; ACh, acetylcholine; BF, basal forebrain; PTC, pontomesencephalo-tegmental complex; Glu, glutamate; BLA, basolateral amygdala; CA, hippocampus; GABA, gamma-aminobutyric acid; VP, ventral pallidum; SN, substantia nigra; EP, entopeduncular nucleus. The data are presented as the mean ± SEM; n = 11 vs. n = 23 vs. n = 21; ****P < 0.0001, **P < 0.01, *P < 0.05; ns, no significance.

FIGURE 2

Graphical presentation of the timeline of the whole experiment design.

FIGURE 3

Location instruction and behavioral assessments. (A) Schematic diagram indicating the location of the micro-electrode in the NAc, modified from the stereotaxic atlas of Paxinos and Watson (6th edition). (B) Traces and 2D heatmaps of rats injected with QNP (OCD) and saline (control) in the OFT. (C) The bar graphs represent the level of number of home base visits and total moving distance in the OFT, by the control and OCD groups. (D) 2D heatmaps of rats in the EPM. The horizontal direction represents the closed arms, and the vertical direction represents the open arms. (E) The bar graphs represent the level of percentage of visit times to closed arms and percentage of total spent time in closed arms. OCD, obsessive-compulsive disorder; QNP, quinpirole; OFT, open field test; EPM, elevated plus maze; DBS, deep brain stimulation; HPLC, high-performance liquid chromatography; MS, mass spectrometry; NAc, nucleus accumbens. The data are presented as the mean ± SEM; n = 8 vs. n = 92; ****P < 0.0001; ns: no significance.

FIGURE 4

Alterations in the firing rate and firing patterns of neurons in the NAc. (A) Representative distribution curves of interspike intervals of control, sham stimulation and NAc-DBS groups. (B) The bar graph represents the mean level of firing rates. (C) The bar graphs represent the mean and the mode of ISI. (D) The bar graphs represent the level of CV and AI of ISI. ISI, interspike interval; CV, coefficient of variance; AI, asymmetry index. The data are presented as the mean ± SEM; n = 24 vs. n = 47 vs. n = 48; ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05; ns, no significance.

FIGURE 5

Illustrations of the difference in LFP activity in the NAc. (A) Representative time-frequency spectrograms in 10 s showing the power level of LFP from 1 to 80 Hz in the NAc of the control, sham stimulation and NAc-DBS groups. (B) The mean PSD curve with 95% confidence interval from 1 to 80 Hz. (C) The bar graphs represent the mean level of relative LFP powers of the delta band, theta band, alpha band, beta band and gamma band in the NAc in the different group. PSD, power spectral density. The data are presented as the mean ± SEM; n = 8 vs. n = 34 vs. n = 28; ****P < 0.0001, ***P < 0.001, **P < 0.01, *P < 0.05; ns, no significance.

FIGURE 6

Differences in pathological sections among the control, sham stimulation and NAc-DBS groups. (A) Immunofluorescence staining for TH was performed to label all dopaminergic neurons in the VTA. (B) Immunofluorescence staining for TPH2 was performed to label all serotonergic neurons in the RN. (C,D) Immunohistochemical staining for DRD1 and DRD2 in the NAc. The top image is the NAc core, and the bottom image is the NAc shell. (E) The bar graph represents the mean level of the immunofluorescence intensity of TH in the VTA. (F) The bar graph represents the mean level of the immunofluorescence intensity of TPH2 in the RN. (G) The bar graphs represent the mean level of IOD of DRD1 in the core and shell of the NAc. (H) The bar graphs represent the mean level of IOD of DRD2 in the core and shell of the NAc. VTA, ventral tegmental area; TH, tyrosine hydroxylase; RN, raphe nuclei; TPH2, tryptophan hydroxylase-2; NAc, nucleus accumbens; DRD1, dopamine receptor-1; DRD2, dopamine receptor-2; IOD, integrated optical density. The data are presented as the mean ± SEM; n = 10 vs. n = 19 vs. n = 19 (immunofluorescence); n = 8 vs. n = 17 vs. n = 15 (immunohistochemistry); ***P < 0.001, **P < 0.01, *P < 0.05; ns, no significance.