Fig. 4: Plasticity of prefrontal representation of fear memory, nociception and touch and their connectivity in inflammatory and neuropathic pain.
From: Prefrontal engrams of long-term fear memory perpetuate pain perception
a, Experimental scheme (top) and impact of fear conditioning on withdrawal responses of the contralateral paw to heat or to graded intensities of mechanical stimulation in naive mice (baseline) and mice with unilateral paw inflammation (CFA; n = 6 mice per group) or nerve injury (SNI; n = 8 mice per group). Data were analyzed by two-way ANOVA with a Tukey’s multiple comparisons test; *P < 0.05; FC, fear conditioning. b, Quantitative summary of overlapping prefrontal neurons commonly activated by a heat ramp (Fos) and long-term fear memory (ArchT–Venus) under baseline conditions (average Fos+ cells = 5,935 cells per mm3; average Venus+ cells = 3,028 cells per mm3) and after paw inflammation (average Fos+ cells = 7,306 cells per mm3; average Venus+ cells = 2,612 cells per mm3). Data were analyzed by unpaired t-test; *P < 0.05; n = 5 mice per group. c, Quantitative summary of overlapping prefrontal neuronal populations commonly activated by tactile stimulation (Fos) and long-term fear memory (ArchT–Venus) under sham (average Fos+ cells = 5,400 cells per mm3; average Venus+ cells = 4,656 cells per mm3) and neuropathic conditions (average Fos+ cells = 5,011 cells per mm3; average Venus+ cells = 5,319 per mm3). Data were analyzed by unpaired t-test; *P < 0.05; n = 4 mice per group. d–f, Scheme for labeling projections (d) and analysis of projection intensity (e) from prefrontal neurons tagged during tactile stimulation under baseline conditions (sham) and following SNI in mice subjected to fear conditioning or not. Projection density is shown in the form of heat maps of tactile-responsive prefrontal neurons (groups 2–5) that were either not exposed to fear conditioning (groups 2 and 4) or following fear conditioning (groups 3 and 5) under sham conditions (groups 2 and 3) and after SNI (groups 4 and 5); SNI FR, projection maps from prefrontal fear engram neurons labeled during long-term fear recall (group 1); n = 3 mice per group. PAG, periaqueductal gray. Data in f show average values of projection intensity in the rostral anterior cingulate cortex and mediodorsal thalamic nucleus. Data were analyzed by two-way ANOVA with a Šidák test for multiple comparisons; *P < 0.05. All data are shown as mean ± s.e.m. All P and F values are shown in Supplementary Table 1.
