Visual cortex plasticity: a complex interplay of genetic and environmental influences

Abstract

The central nervous system architecture is highly dynamic and continuously modified by sensory experience through processes of neuronal plasticity. Plasticity is achieved by a complex interplay of environmental influences and physiological mechanisms that ultimately activate intracellular signal transduction pathways regulating gene expression. In addition to the remarkable variety of transcription factors and their combinatorial interaction at specific gene promoters, epigenetic mechanisms that regulate transcription have emerged as conserved processes by which the nervous system accomplishes the induction of plasticity. Experience-dependent changes of DNA methylation patterns and histone posttranslational modifications are, in fact, recruited as targets of plasticity-associated signal transduction mechanisms. Here, we shall concentrate on structural and functional consequences of early sensory deprivation in the visual system and discuss how intracellular signal transduction pathways associated with experience regulate changes of chromatin structure and gene expression patterns that underlie these plastic phenomena. Recent experimental evidence for mechanisms of cross-modal plasticity following congenital or acquired sensory deprivation both in human and animal models will be considered as well. We shall also review different experimental strategies that can be used to achieve the recovery of sensory functions after long-term deprivation in humans.

Figure 1

Experimental paradigms that restore neuronal plasticity in adult life. Environmental enrichment [17, 81, 82], long-term fluoxetine administration [15, 16], visual deprivation by dark exposure [79, 80], food restriction [36], and IGF-1 treatment [83] are noninvasive experimental approaches that promote adult visual cortical plasticity by altering the balance of inhibition and excitation in the visual system. The potential for the reactivation of plasticity caused by some of these paradigms to promote the recovery of sensory functions after long-term sensory deprivation has been reported using amblyopia as a paradigmatic model [15, 36, 80, 81, 83].

Figure 2

The reinstatement of ocular dominance plasticity in adulthood is associated with signal transduction pathways that involve the enhanced action of either neuromodulatory projection systems (e.g., serotonin and acetylcholine) or IGF-1 signaling, which all set in motion physiological processes that modulate the inhibitory/excitatory ratio in favour of excitation [–17, 72, 73, 83]. A shift of the inhibitory/excitatory balance may directly activate intracellular mechanisms that eventually promote epigenetic modifications of chromatin structure (e.g., changes of DNA methylation patterns and/or posttranslational modifications of histones), which in turn allow for the expression of genes that act as downstream effectors of plastic phenomena in adult life. A pharmacological reduction of intracortical inhibition enhances plasticity while promoting the activity-dependent BDNF expression (unpublished data) and degradation of extracellular matrix (ECM) components that are inhibitory for plasticity [23]. BDNF-trkB signaling might upregulate the expression of additional genes associated with functional modifications in the visual cortex. Degradation of ECM components (e.g., CSPGs) may modify the inhibition/excitation ratio in the visual system. The interaction between BDNF-trkB signaling and ECM reorganization has yet to be explored. Continuous arrows represent established interactions between the molecular and cellular processes mentioned (boxes). Dashed lines represent interactions that remain to be ascertained.

Figure 3

Potential strategies for the treatment of human amblyopia in adult life. The recent findings that environmental enrichment [17, 81, 82, 137, 138], long-term administration of fluoxetine [15, 16], dark exposure [79, 80], food restriction [36], and IGF-1 signaling [83] all promote full recovery of visual acuity and binocularity in adult amblyopic animals, emphasize the potential of different pharmacological and/or behavioral interventions as complementary strategies for current therapies of human amblyopia in adult life. In particular, an enhanced sensory-motor activity together with a healthy diet planning, brief periods of visual deprivation by dark exposure, and pharmacological treatments (long-term antidepressant treatment or exogenous IGF-1 administration) may enhance plasticity by shifting the I/E ratio while increasing BDNF expression and epigenetic factors. These therapeutic interventions could be coupled to video game playing or computer-program-based training of the amblyopic eye in order to rescue normal visual functions after long-term sensory deprivation in humans.