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. 2014 Aug;39(9):2161-9.
doi: 10.1038/npp.2014.64. Epub 2014 Mar 14.

Hippocampal--prefrontal BDNF and memory for fear extinction

Luis E Rosas-Vidal  1 , Fabricio H Do-Monte  1 , Francisco Sotres-Bayon  1 , Gregory J Quirk  1
Affiliations

Hippocampal--prefrontal BDNF and memory for fear extinction

Luis E Rosas-Vidal et al. Neuropsychopharmacology. 2014 Aug.

Abstract

Infusing brain-derived neurotrophic factor (BDNF) into the infralimbic (IL) prefrontal cortex is capable of inducing extinction. Little is known, however, about the circuits mediating BDNF effects on extinction or the extent to which extinction requires BDNF in IL. Using local pharmacological infusion of BDNF protein, or an antibody against BDNF, we found that BDNF in the IL, but not prelimbic (PL) prefrontal cortex, is both necessary and sufficient for fear extinction. Furthermore, we report that BDNF in IL can induce extinction of older fear memories (14 days) as well as recent fear memories (1 day). Using immunocytochemistry, we show that BDNF is increased in the ventral hippocampus (vHPC), but not IL or PL, following extinction training. Finally, we observed that infusing BDNF into the vHPC increased the firing rate of IL, but not PL neurons in fear conditioned rats. These findings indicate that an extinction-induced increase in BDNF within the vHPC enhances excitability in IL targets, thereby supporting extinction memories.

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Figures

Figure 1
Figure 1
Brain-derived neurotrophic factor (BDNF) in infralimbic (IL), but not prelimbic (PL), prefrontal cortex induces extinction. (a, upper) Coronal drawings showing the angled cannulation approach and location of the injector tips in IL. (Lower) Infusion of BDNF in IL on day 2 (arrow) significantly decreased freezing on day 3 (Sal: n=11; BDNF: n=10). (b, upper) Coronal drawings showing the angled cannulation approach and location of the injector tips in IL. (Lower) Infusion of BDNF in IL 2 weeks after conditioning on day 14 (arrow) significantly decreased freezing on day 15 (Sal: n=9; BDNF: n=8). (c, upper) Coronal drawings showing the location of the injector tips in PL. (Lower) Infusion of BDNF in PL on day 2 (arrow) did not alter freezing levels on day 3 (Sal: n=9; BDNF: n=8). Unpaired Student's t-test. Data are shown as mean±SEM in blocks of two trials. *P<0.05, **P<0.01.
Figure 2
Figure 2
Brain-derived neurotrophic factor (BDNF) in infralimbic (IL), but not prelimbic (PL), is necessary for extinction. (a, upper) Coronal drawings showing the angled cannulation approach and location of the injector tips in IL. (Lower) Infusion of BDNF binding antibody (anti-BDNF) in IL (arrow) before extinction training impaired the acquisition of extinction and the retrieval of extinction the following day (day 3; Sal: n=15; anti-BDNF: n=13). (b, upper) Coronal drawings showing the location of the injector tips in PL. (Lower) Infusion of anti-BDNF in PL (arrow) before extinction training did not alter acquisition or retrieval of extinction (Sal: n=9; anti-BDNF: n=9). Repeated-measures analysis of variance (ANOVA) followed by Tukey's post hoc test. Data are shown as mean±SEM in blocks of two trials. *P<0.05, **P<0.01.
Figure 3
Figure 3
Extinction training increases neuronal brain-derived neurotrophic factor (BDNF) expression in the ventral hippocampus (vHPC) and basal amygdala (BA). (a) Freezing to tones during conditioning (Cond.) and extinction session (in blocks of two trials). (b) Representative micrographs showing labeling of NeuN (green), BDNF (red), and BDNF-NeuN overlap (white arrows). (c) Representative images showing labeling of NeuN and BDNF in infralimbic cortex (IL) and vHPC. (d and e) Neuronal BDNF expression in the medial prefrontal cortex (mPFC), vHPC, and amygdala following exposure to 2 tones (No Extinction) or 20 tones (Extinction), as measured by percent of overlapping area between BDNF- and NeuN-labeled images. Increased neuronal BDNF was observed in the CA1 subregion of the vHPC at both 1 h (d) and 2 h (e) after extinction training, compared with the No Extinction control. Increased neuronal BDNF was observed in the BA at 2 h after extinction training, when compared with the No Extinction group. PL, prelimbic cortex; IL, infralimbic cortex; CeM, medial portion of the central amygdala; CeL, lateral portion of the central amygdala. Two-way analysis of variance (ANOVA) between Extinction and No Extinction groups (1 h: n=8 per group; 2 h: n=4 per group). *P<0.05.
Figure 4
Figure 4
Brain-derived neurotrophic factor (BDNF) infused into ventral hippocampus (vHPC) reduces freezing to conditioned tones and increases the activity of infralimbic cortex (IL) neurons. (a, left) Coronal drawings showing the location of the injector tips within the vHPC. (right) Infusion of BDNF in the vHPC on day 2 (arrow) significantly decreased freezing (Sal: n=9; BDNF: n=11; repeated-measures analysis of variance (ANOVA) followed by Tukey's post hoc test; **P<0.01). (b, upper) Coronal drawings showing the location of the injector tips within the vHPC (BDNF) and the recording sites within IL (recording). (middle) Spontaneous firing in IL before and 30 min after BDNF infusion in the vHPC. BDNF infusion significantly increased the firing rate of eight cells (red) and decreased the rate of two cells (blue). An additional IL neuron significantly increased its firing rate from 9.33 to 17.3 Hz (data not shown); n=16. (lower) Raster plot (30 s) of representative IL neuron before and after BDNF infusion in the vHPC. (c, upper) Coronal drawings showing the location of the injector tips within the vHPC (BDNF), and the recording sites within prelimbic cortex (PL) (recording). (middle) Spontaneous firing in PL before and 30 min after BDNF infusion in the vHPC. BDNF infusion significantly increased the firing rate of one PL cell (red) and decreased the rate of six cells (blue); n=21. (lower) Raster plot (30 s) of representative PL neuron before and after BDNF infusion in the vHPC. Paired Student's t-test; **P<0.01.
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