Molecular correlates of cortical network modulation by long-term sensory experience in the adult rat barrel cortex

Abstract

Modulation of cortical network connectivity is crucial for an adaptive response to experience. In the rat barrel cortex, long-term sensory stimulation induces cortical network modifications and neuronal response changes of which the molecular basis is unknown. Here, we show that long-term somatosensory stimulation by enriched environment up-regulates cortical expression of neuropeptide mRNAs and down-regulates immediate-early gene (IEG) mRNAs specifically in the barrel cortex, and not in other brain regions. The present data suggest a central role of neuropeptides in the fine-tuning of sensory cortical circuits by long-term experience.

Figure 1.

Long-term sensory enrichment induces significant changes in gene expression. Microarray analysis revealed differentially expressed genes in the rat barrel cortex following 28 d of enriched environment (EE) rearing (large cage with enrichment, n = 8 animals/cage), in comparison to home-caged controls (HCC) (standard cage, n = 2 animals/cage). Gene names, abbreviations, fold changes, and color-coded gene ontologies for up-regulated (top panel) and down-regulated (bottom panel) genes are indicated, together with the accession number of each gene.

Figure 2.

qPCR analysis of gene expression in different cortical regions after 28 d of enriched environment (EE). Normalized expression values of selected up-regulated (A) and down-regulated (B) genes in the barrel cortex after 28 d of EE (enrichment in large cage, n = 8 animals/cage), in comparison to home-caged controls (HCC) (housed in standard cages, n = 2 animals/cage) (experiment 1). (C) In experiment 2, expression of the top three up-regulated and down-regulated genes was measured in the barrel cortex (S1) and primary motor (M1) and visual (V1) cortices after 28 d of EE in comparison to control animals housed (n = 8/cage) in large cages (LCC group). For normalization, β-actin or Ywhaz was selected as the housekeeping gene (most stable gene chosen). Bars represent average normalized expression values ± SEM (n = 8 animals/group). Asterisks represent significant differences between home-caged control (HCC) and EE groups or large cage control (LCC) and EE groups (Student's t-test; [*] P < 0.05, [**] P < 0.01, [***] P < 0.001). A graphical view of Pearson correlations after multiple testing correction between all measured mRNA levels in the barrel cortex in the HCC vs. EE comparison (D) and LCC vs. EE comparison (E) is shown. The correlations are color-coded as indicated in the bar at the bottom left (from −1 to +1), and statistically significant correlations are tagged with asterisks (Pearson correlation, [*] corrected P < 0.05, [**] corrected P < 0.01).

Figure 3.

Scheme summarizing the laminar distribution and the main molecular, anatomical, and electrophysiological properties of the various neuronal types in which the EE-up-regulated neuropeptides are expressed. On top are the differentially regulated neuropeptides. The lines indicate in which cell type the peptides can be found: (thick line) common, (thin line) rare. Next, calcium-binding proteins ([PV] parvalbumin, [CB] calbindin, [CR] calretinin) and other neuropeptides which can be co-expressed with the EE-regulated neuropeptides are indicated, followed by the main electrophysiological classes corresponding to the putative cell type ([AC] accommodating, [NAC] nonaccommodating, [BST] bursting [STUT] stuttering, [IS] irregular spiking, [RS] regular spiking, [IB] intrinsic burst spiking). Finally, the colored circles indicate in which cortical layer the corresponding neuropeptide is expressed (laminar distribution), the size of the circles being proportional to the amount of expression; a blue rectangle defines the layers where the putative cell type can be found. There is insufficient information on putative cell type, electrophysiological classes, and additional molecular markers for the neuropeptides/neuropeptide-binding protein Cart, Pnoc and Crhbp. The information has been summarized on the basis of several studies; each study where the specific information has been derived from is indicated by a number, and the list of numbers with corresponding references, details of the study, and hyperlinks can be found in Supplemental Table 2.