Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway

Abstract

Mechanisms controlling release of brain-derived neurotrophic factor (BDNF) in the mesolimbic dopamine reward pathway remain unknown. We report that phasic optogenetic activation of this pathway increases BDNF amounts in the nucleus accumbens (NAc) of socially stressed mice but not of stress-naive mice. This stress gating of BDNF signaling is mediated by corticotrophin-releasing factor (CRF) acting in the NAc. These results unravel a stress context-detecting function of the brain's mesolimbic circuit.

Figure 1

Phasic activation of the VTA-NAc pathway increases BDNF in NAc of socially stressed mice, but not of stress-naïve mice. (a) Schematic of PRV-Cre infused into NAc, AAV-DIO-ChR2-eYFP infused into VTA, and ferrule implantation into VTA. Below, experimental timeline detailing subthreshold social defeat stress. (b) Phasic stimulation with AAV-DIO-ChR2-eYFP of VTA-NAc cells decreases social interaction (F_2,20=4.56, *P<0.05, n=7–9). No Target denotes the absence, and Target the presence, of a social target (CD1 mouse) during behavior. Blue bars represent blue light activation during social interaction test. (c) Phasic but not tonic stimulation of VTA-NAc cells increases BDNF levels in NAc 24 hr post-stimulation (F_2,19=14.55, **P<0.01, n=7–8). (d) Schematic of AAV2/5-DIO-ChR2-EYFP into NAc and ferrule implantation into VTA of TH-Cre mice. Below, experimental timeline. (e) Phasic stimulation with AAV2/5-DIO-ChR2-EYFP of VTA DA neurons that project to NAc induces social avoidance (F_2,15=19.35, ***P<0.001, n=6). (f) Phasic but not tonic stimulation of VTA DA neurons projecting to NAc increases BDNF levels in NAc 24 hr post-stimulation (F_2,15=3.69, *P<0.05, n=6). (g) Experimental timeline of naïve animals. (h) Phasic stimulation of VTA-NAc cells does not induce social avoidance in stress-naïve animals (F_2,18=1.12, P=0.35, n=6–8). (i) Phasic stimulation does not increase BDNF levels in the absence of subthreshold social defeat stress (F_2,18=0.03, P=0.97, n=6–8). (j) Experimental timeline of naïve animals with repeated optical stimulation. (k) Five days of repeated stimulation for 20 min of VTA-NAc cells does not induce social avoidance in stress-naïve mice (F_2,24=0.30, P=0.74, n=8–10). (l) Five days of repeated stimulation for 20 min of VTA-NAc cells does not change BDNF levels in the absence of subthreshold defeat stress (F_2,21=0.38, P=0.69, n=8). All data presented as mean ± s.e.m.

Figure 2

BDNF is necessary for the optogenetically induced susceptible phenotype. (a) Schematic and timeline of VTA-NAc neurons with cannula implantation into NAc for infusion of the TrkB inhibitor, ANA-12, 1 hr prior to behavior test with optical stimulation. (b) Intra-NAc ANA-12 infusions eliminates social avoidance with phasic stimulation (F_2,23=5.59, **P<0.01, n=6–10), but (c) does not prevent the increase in BDNF levels in NAc (F_2,22=16.18, **P<0.01, n=8–9). (d) Schematic and timeline showing targeting of VTA-NAc cells in fl/fl BDNF and control animals. (e) Phasic stimulation of VTA-NAc cells does not induce social avoidance in fl/fl BDNF mice (unpaired t-test, t₁₁=2.9, P<0.01; n=6–7) and (f) does not increase BDNF in NAc (unpaired t-test, t₉=4.78, **P<0.01; n=5–6).

Figure 3

CRF is required for the phasic firing induced increase in BDNF in NAc in the context of stress. (a) Timeline of animals that received intra-NAc CRF antagonist infusions. (b) Intra-NAc CRF antagonist (alpha-helical CRF) infusion eliminates social avoidance seen with subthreshold stress plus phasic stimulation of VTA-NAc neurons (F_2,21=3.99, *P<0.05, n=6–9) and (c) blocks the expected BDNF increase in NAc (F_2,18=4.66, *P<0.05, n=6–8). (d) Timeline of stress-naïve animals that received intra-NAc CRF infusions. (e) Intra-NAc CRF infusions in stress-naïve animals does not alter social interaction behavior (F_2,23=0.58, P=0.57, n=8–9). (f) Phasic stimulation alone induces an increase in NAc BDNF levels in intra-NAc CRF infused, stress-naïve mice (F_2,19=5.88, *P<0.01, n=6–8). (g) Timeline of stress and stimulation-naïve animals that received intra-NAc CRF infusions. (h) Intra-NAc CRF infusions in stress and stimulation-naïve animals does not alter social interaction behavior (F_5,12=0.082, P=0.922, n=5). (i) Intra-NAc CRF infusions of 1 or 5 μg does not alter NAc BDNF levels (F_2,12=0.186, P=0.833, n=5).