Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear - PubMed (original) (raw)

Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear

Jose Rodriguez-Romaguera et al. Proc Natl Acad Sci U S A. 2012.

Abstract

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces symptoms of intractable obsessive-compulsive disorder (OCD), but the mechanism of action is unknown. OCD is characterized by avoidance behaviors that fail to extinguish, and DBS could act, in part, by facilitating extinction of fear. We investigated this possibility by using auditory fear conditioning in rats, for which the circuits of fear extinction are well characterized. We found that DBS of the VS (the VC/VS homolog in rats) during extinction training reduced fear expression and strengthened extinction memory. Facilitation of extinction was observed for a specific zone of dorsomedial VS, just above the anterior commissure; stimulation of more ventrolateral sites in VS impaired extinction. DBS effects could not be obtained with pharmacological inactivation of either dorsomedial VS or ventrolateral VS, suggesting an extrastriatal mechanism. Accordingly, DBS of dorsomedial VS (but not ventrolateral VS) increased expression of a plasticity marker in the prelimbic and infralimbic prefrontal cortices, the orbitofrontal cortex, the amygdala central nucleus (lateral division), and intercalated cells, areas known to learn and express extinction. Facilitation of fear extinction suggests that, in accord with clinical observations, DBS could augment the effectiveness of cognitive behavioral therapies for OCD.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Fig. 1.

DBS in the VS can either facilitate or impair extinction depending on the site of stimulation. (A) Schematic of the behavioral protocol used to assess the effects of DBS, which was delivered for 3 h on the extinction training day (1 h preextinction, 1 h during, 1 h postextinction). (B Left) Coronal view. Electrode placements color-coded for extinction memory. Circle diameter indicates the estimated spread of current from electrode tip. (Right) Sagittal view. Dorsal DBS was dorsal to anterior commissure (black structure in B) and Ventral DBS was ventrolateral to anterior commissure. Placements lateral to Dorsal DBS were excluded from subsequent analyses. (C) Freezing plots for Sham (n = 16), Dorsal DBS (n = 6), and Ventral DBS (n = 8) groups. Dorsal DBS reduced freezing on day 2 and facilitated extinction recall on day 3. Ventral DBS had the opposite effects. Data are shown in blocks of two trials. (D) Dorsal DBS did not affect locomotion (line crosses) or anxiety (time in center) in the open-field task (Sham, n = 6; Dorsal DBS, n = 9) or the rate of pressing for food (Sham, n = 7; Dorsal DBS, n = 9). Ventral DBS did not affect locomotion or anxiety in the open-field task (Sham, n = 10; Ventral DBS, n = 8) or the rate of pressing for food (Sham, n = 7; Dorsal DBS, n = 7). Data are shown as mean and SEM. *P < 0.05.

Fig. 2.

Fig. 2.

DBS interacts with extinction training. (A Left) Placement of DBS electrode tips within the Dorsal DBS site. (Right) Percentage freezing during extinction retrieval on Day 3. DBS (3 h) in the absence of extinction training (0 trials) did not facilitate extinction memory (Sham, n = 8; Dorsal DBS, n = 5). DBS administered during (pre-during-post) an 8-trial extinction session facilitated extinction memory (Sham, n = 12; Dorsal DBS, n = 11); the same stimulation with a 15-trial extinction session facilitated extinction memory more robustly (data are from Fig. 1). (B Left) Placement of DBS electrode tips within the Dorsal DBS site. (Right) Dorsal DBS (3 h) confined to preextinction (pre only; Sham, n = 9; Dorsal DBS, n = 10) or postextinction (post only; Sham, n = 8; Dorsal DBS, n = 7) periods did not facilitate extinction memory on day 3. Data are shown in blocks of two trials with mean and SEM. *P < 0.05.

Fig. 3.

Fig. 3.

The effects of DBS cannot be obtained with pharmacological inactivation of VS. (A Upper) Placement of cannula tips within the Dorsal (orange circles) and Ventral (green circles) DBS sites. (Lower) Micrograph showing the spread of fluorescently labeled MUS (4× magnification), similar to the current spread of DBS (Fig. 1_B_). (B) MUS infused into the Dorsal DBS site, but not into the Ventral DBS site, significantly reduced the rate of pressing for food (compared with preinfusion baseline). (C) MUS in either Dorsal or Ventral sites did not, however, reduce fear expression or facilitate extinction memory [saline (SAL), n = 11; Dorsal MUS, n = 9; Ventral MUS, n = 9]. Data are shown in blocks of two trials with mean and SEM. *P < 0.05.

Fig. 4.

Fig. 4.

Dorsal DBS induces plasticity within extinction circuits. (A) Dorsal DBS increased pERK in PL, IL, OFC, and CeL/ITC, but not in BA or CeM. (B) Ventral DBS did not increase pERK in PL, IL, OFC, CeL/ITC, BA, or CeM. (C) Representative micrographs showing pERK-labeled neurons in IL and PL regions of mPFC (10× magnification; Left) and OFC (10× magnification; Right) in rats administered Dorsal DBS. (D) Representative micrograph showing pERK-labeled neurons in the CeL/ITC in rats administered Dorsal DBS (4× magnification). LO, lateral OFC; wm, white matter; opt, optic tract; VO, ventral OFC. Data are shown as mean and SEM. **P < 0.01.

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