Deep brain stimulation of the ventral striatum increases BDNF in the fear extinction circuit

Abstract

Deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) reduces the symptoms of treatment-resistant obsessive compulsive disorder (OCD), and improves response to extinction-based therapies. We recently reported that DBS-like stimulation of a rat homologue of VC/VS, the dorsal-VS, reduced conditioned fear and enhanced extinction memory (Rodriguez-Romaguera et al., 2012). In contrast, DBS of the ventral-VS had the opposite effects. To examine possible mechanisms of these effects, we assessed the effects of VS DBS on the expression of the neural activity marker Fos and brain-derived neurotrophic factor (BDNF), a key mediator of extinction plasticity in prefrontal-amygdala circuits. Consistent with decreased fear expression, DBS of dorsal-VS increased Fos expression in prelimbic and infralimbic prefrontal cortices and in the lateral division of the central nucleus of amygdala, an area that inhibits amygdala output. Consistent with improved extinction memory, we found that DBS of dorsal-VS, but not ventral-VS, increased neuronal BDNF expression in prelimbic and infralimbic prefrontal cortices. These rodent findings are consistent with the idea that clinical DBS of VC/VS may augment fear extinction through an increase in BDNF expression.

Keywords: Fos; amygdala; anxiety disorders; fear expression; high-frequency stimulation; obsessive compulsive disorder; prefrontal cortex.

Figure 1

DBS of the ventral striatum can either enhance or impair fear extinction, depending on the site of stimulation (modified from Rodriguez-Romaguera et al., 2012). (A) Placement of DBS electrode tips within the dorsal-VS (orange circles) and ventral-VS (green circles). (B) Individual data showing that DBS of dorsal-VS (n = 6) decreased fear expression on Day 2 (DBS ON) compared to Day 1 (DBS OFF), and enhanced extinction memory, as shown by the maintenance of low levels of freezing on Day 3 with DBS OFF. In contrast, DBS of ventral-VS (n = 6) increased fear expression on Day 2 (DBS ON) as compared to Day 1 (DBS OFF) and impaired extinction memory, as shown by the maintenance of high levels of freezing on Day 3 with DBS OFF. Data shown in blocks of two trials.

Figure 2

DBS of dorsal-VS increases neuronal activity within extinction circuits. (A) Placement of DBS electrode tips within the dorsal-VS (orange circles) and ventral-VS (green circles). (B) Representative micrographs showing Fos labeled neurons in prelimbic (PL) and infralimbic (IL) regions of medial prefrontal cortex (mPFC, 10x magnification, left), and the lateral portion of the central nucleus of the amygdala, including the intercalated cells (CeL/ITC), in rats administered DBS in the dorsal-VS (Amygdala, 4x magnification, right). (C) DBS of dorsal-VS increased Fos expression in PL, IL and CeL/ITC, but not in BA or CeM (Sham, n = 5; DBS of dorsal-VS, n = 4). In contrast, DBS of ventral-VS increased Fos in the basal nucleus of the amygdala (BA) and CeL/ITC, but not in PL, IL or CeM (Sham, n = 8; DBS of ventral-VS, n = 8). Legend: CeM = medial portion of the central nucleus of the amygdala, cc = corpus callosum, opt = optic tract. Data shown as mean and SEM. *p < 0.05 **p < 0.01.

Figure 3

DBS of dorsal-VS increases neuronal BDNF in PL and IL. (A) Placement of DBS electrode tips within the dorsal-VS (orange circles) and ventral-VS (green circles). (B) Representative micrographs showing IL labeling of neuronal marker NeuN (left), BDNF (middle), and BDNF-NeuN overlap (right, white arrows). (C) DBS of dorsal-VS increased BDNF-NeuN overlap in PL and IL subregions of the mPFC, but not in the amygdala (Sham, n = 4; DBS of dorsal-VS, n = 6). In contrast, DBS of ventral-VS increased BDNF-NeuN overlap in BA, but not in PL, IL, CeM or CeL/ITC (Sham, n = 5; DBS of ventral-VS, n = 5). Legend: CeM = medial portion of the central nucleus of the amygdala, CeL = lateral portion of the central nucleus of the amygdala, ITC = intercalated cells. Data shown as mean and SEM. **p < 0.01.

Figure 4

Suggested models of how DBS of dorsal-VS and ventral-VS affect fear. (A) Middle: DBS of dorsal-VS (ON) increases neuronal activity (Fos) in the IL-CeL_off circuit, decreasing freezing to a conditioned tone. Right: DBS of dorsal-VS also increases BDNF in IL and induces plasticity (pERK) in IL and CeL_off (Rodriguez-Romaguera et al., 2012), thereby enhancing extinction memory in the absence of DBS. (B) Middle: DBS of ventral-VS increases neuronal activity (Fos) in the BA-CeL_on circuit, increasing freezing to a conditioned tone. Right: DBS of ventral-VS also increases BDNF in BA, thereby impairing extinction memory in the absence of DBS.