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. 2013 Jan 29;110(5):1923-8.
doi: 10.1073/pnas.1221742110. Epub 2013 Jan 14.

∆FosB differentially modulates nucleus accumbens direct and indirect pathway function

Brad A Grueter  1 , Alfred J Robison, Rachael L Neve, Eric J Nestler, Robert C Malenka
Affiliations

∆FosB differentially modulates nucleus accumbens direct and indirect pathway function

Brad A Grueter et al. Proc Natl Acad Sci U S A. .

Abstract

Synaptic modifications in nucleus accumbens (NAc) medium spiny neurons (MSNs) play a key role in adaptive and pathological reward-dependent learning, including maladaptive responses involved in drug addiction. NAc MSNs participate in two parallel circuits, direct and indirect pathways that subserve distinct behavioral functions. Modification of NAc MSN synapses may occur in part via changes in the transcriptional potential of certain genes in a cell type–specific manner. The transcription factor ∆FosB is one of the key proteins implicated in the gene expression changes in NAc caused by drugs of abuse, yet its effects on synaptic function in NAc MSNs are unknown. Here, we demonstrate that overexpression of ∆FosB decreased excitatory synaptic strength and likely increased silent synapses onto D1 dopamine receptor–expressing direct pathway MSNs in both the NAc shell and core. In contrast, ∆FosB likely decreased silent synapses onto NAc shell, but not core, D2 dopamine receptor–expressing indirect pathway MSNs. Analysis of NAc MSN dendritic spine morphology revealed that ∆FosB increased the density of immature spines in D1 direct but not D2 indirect pathway MSNs. To determine the behavioral consequences of cell type-specific actions of ∆FosB, we selectively overexpressed ∆FosB in D1 direct or D2 indirect MSNs in NAc in vivo and found that direct (but not indirect) pathway MSN expression enhances behavioral responses to cocaine. These results reveal that ∆FosB in NAc differentially modulates synaptic properties and reward-related behaviors in a cell type- and subregion-specific fashion.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Overexpression of ∆FosB in NAc modifies D1 MSN synaptic strength in shell and core. (A) Representative EPSCs (A1) recorded at –70 and +40 mV from a NAc shell D1 control (black) and ∆FosB(+) (red) MSN and summary graph (A2) of the ratio of the AMPAR EPSC over the NMDAR EPSC for each control (n = 7) and ∆FosB(+) (n = 7) D1 MSN. Bar graphs in this and all subsequent figures show mean ± SEM (calibration bars for evoked EPSCs in this panel and all subsequent figures are 50 pA/25 ms). (B) Same as A for D1 MSNs in NAc core (n = 7 cells in each group). (C and D) Sample mEPSCs from NAc shell (C1) and core (D1) control (black) and ∆FosB(+) (red) D1 MSNs (calibration bars for mEPSCs in this panel and all subsequent figures are 20 pA/1 s). Cumulative probability plots comparing mEPSC amplitudes recorded from control and ∆FosB(+) D1 MSNs in NAc shell (C2) and core (D2). Bar graphs show average mEPSC amplitudes in these cell populations (C3 and D3) (n = 5 cells in each group). (E and F) Summary of normalized AMPAR EPSC amplitudes as a function of membrane potential recorded from control and ∆FosB(+) D1 MSNs in NAc shell (E1, n = 5 cells in each group) and core (F1,n = 4 cells in each group). Bar graphs show average rectification indices for these cells (E2 and F2). (G and H) Representative EPSCs at +40 mV for control (black) and ∆FosB(+) (red) D1 MSNs in NAc shell (G1) and core (H1). Bar graphs showing time to half-peak amplitude of EPSCs at +40 mV recorded from these cells (G2 and H2, n = 7 cells in each group). *P < 0.05 in this and all subsequent figures.
Fig. 2.
Fig. 2.
Overexpression of ∆FosB in NAc modifies D2 MSN synaptic strength in the shell but not the core. (A) Representative EPSCs (A1) recorded at –70 and +40 mV from a NAc shell D2 control (black) and ∆FosB(+) (green) MSN and summary graph (A2) of the ratio of the AMPAR EPSC over the NMDAR EPSC for each control (n = 6) and ∆FosB(+) (n = 6) D2 MSNs. (B) Same as A for D2 MSNs in NAc core (n = 6 control cells, 7 ∆FosB(+) cells). (C and D) Sample mEPSCs from NAc shell (C1) and core (D1) control (black) and ∆FosB(+) (green) D2 MSNs. Cumulative probability plots comparing mEPSC amplitudes recorded from control and ∆FosB(+) D2 MSNs in the NAc shell (C2) and core (D2). Bar graphs show average mEPSC amplitudes in these cell populations (C3 and D3) (n = 5–7 cells in each group). (E and F) Summary of normalized AMPAR EPSC amplitudes as a function of membrane potential recorded from control and ∆FosB(+) D2 MSNs in NAc shell [E1, n = 4 control, 5 ∆FosB(+) cells] and core (F1, n = 4 cells in each group). Bar graphs show average rectification indices for these cells (E2 and F2). (G and H) Representative EPSCs at +40 mV for control (black) and ∆FosB(+) (green) D2 MSNs in the NAc shell (G1) and core (H1). Bar graphs showing time to half-peak amplitude of EPSCs at +40 mV recorded from these cells (G2 and H2, n = 6–7 cells in each group).
Fig. 3.
Fig. 3.
ΔFosB expression has opposite effects on silent synapse analysis in D1 and D2 NAc MSNs. (A) Plots of AMPAR EPSCs (−70 mV) and NMDAR EPSC (+40 mV) amplitudes from a control (A1) and ∆FosB(+) (A2) D1 MSN in NAc shell. (B) Summary of ratio of 1/CV2 of NMDAR EPSCs to 1/CV2 of AMPAR EPSCs from control and ∆FosB(+) D1 MSNs in the shell (B1) and the core (B2) (n = 6–8 cells in each group). (C) Summary of 1/CV2 analysis for control and ∆FosB(+) D2 MSNs in the NAc shell (C1) and core (C2) (n = 6–7 cells in each group).
Fig. 4.
Fig. 4.
ΔFosB expression increases immature spines in D1 but not D2 NAc MSNs. (A) Sample pictures of spines from control (GFP) and ∆FosB(+) D1 and D2 NAc MSNs. (B–E) Quantification of effects of ΔFosB expression on each dendritic spine subtype in both D1 and D2 NAc MSNs (n = 11–14 neurons in each group; *P < 0.05, two-tailed t test).
Fig. 5.
Fig. 5.
Expression of ΔFosB in D1 but not D2 NAc MSNs promotes behavioral responses to cocaine. (A–D) Locomotor response to saline (triangles) or cocaine (squares) was measured daily in animals expressing GFP alone (open) or GFP and ∆FosB (filled) in D1 (red) or D2 (green) NAc MSNs. Cocaine doses of 3.75 (A and B) and 7.5 mg/kg (C and D) are shown. (n = 6–10 mice in each group; *different from GFP, P < 0.05, one-way ANOVA). (E and F) Cocaine place preference at the indicated dose for animals expressing GFP alone (open) or GFP and ∆FosB (filled) in D1 (red) or D2 (green) NAc MSNs. (n = 6–10 mice in each group; *different from GFP, P < 0.05, two-tailed t test).
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