Ocular dominance (OD) plasticity in mouse primary visual cortex (V1) declines during postnatal development and is absent beyond postnatal day 110 if mice are raised in standard cages (SCs). An enriched environment (EE) promotes OD plasticity in adult rats. Here, we explored cellular mechanisms of EE in mouse V1 and the therapeutic potential of EE to prevent impairments of plasticity after a cortical stroke. Using in vivo optical imaging, we observed that monocular deprivation in adult EE mice (i) caused a very strong OD plasticity previously only observed in 4-wk-old animals, (ii) restored already lost OD plasticity in adult SC-raised mice, and (iii) preserved OD plasticity after a stroke in the primary somatosensory cortex. Using patch-clamp electrophysiology in vitro, we also show that (iv) local inhibition was significantly reduced in V1 slices of adult EE mice and (v) the GABA/AMPA ratio was like that in 4-wk-old SC-raised animals. These observations were corroborated by in vivo analyses showing that diazepam treatment significantly reduced the OD shift of EE mice after monocular deprivation. Taken together, EE extended the sensitive phase for OD plasticity into late adulthood, rejuvenated V1 after 4 mo of SCrearing, and protected adult mice from stroke-induced impairments of cortical plasticity. The EE effect was mediated most likely by preserving low juvenile levels of inhibition into adulthood, which potentially promoted adaptive changes in cortical circuits. O cular dominance (OD) plasticity induced by monocular deprivation (MD) is one of the best studied models of experience-dependent plasticity in the mammalian cortex (1, 2). OD plasticity in primary visual cortex (V1) of C57BL/6J mice is maximal at 4 wk of age, declines after 2-3 mo, and is absent beyond postnatal day 110 (PD110) if animals are raised in standard cages (SCs) (3-6). In 4-wk-old mice, 4 d of MD are sufficient to induce an OD shift to the open eye; therefore, neurons in the binocular V1, which are usually dominated by the contralateral eye in rodents (3, 7), become activated more equally by both eyes (5,8). This juvenile OD shift is predominantly mediated by a decrease in the visual cortical responses to the deprived eye (1, 9-11), whereas significant OD shifts in older animals up to PD110 need 7 d of MD and are mediated primarily by increased openeye responses in V1. Raising animals in an enriched environment (EE) gives them the opportunity of enhanced physical, social, and cognitive stimulation and influences brain physiology and behavior in many ways (12, 13). It has been shown previously that EE enhances visual system development in rats (14) and mice (15-17), increases levels of the brain-derived neurotrophic factor and serotonin (18), reduces both extracellular GABA levels (18, 19) and the density of ECM perineuronal nets (PNNs) (19), and promotes OD plasticity in adult and aging rats (18-21). Here, we explored cellular mechanisms of EE in V1 of mice and the therapeutic potential of EE to prevent impairments of plasticity after a c...

Ocular dominance (OD) plasticity in the mouse primary visual cortex (V1) declines during aging and is absent beyond postnatal day (P) 110 when mice are raised in standard cages (SCs; Lehmann and Löwel, 2008). In contrast, raising mice in an enriched environment (EE) preserved a juvenile-like OD plasticity into late adulthood (Greifzu et al., 2014). EE raising provides the mice with more social interactions, voluntary physical exercise, and cognitive stimulation compared with SC, raising the question whether all components are needed or whether one of them is already sufficient to prolong plasticity. To test whether voluntary physical exercise alone already prolongs the sensitive phase for OD plasticity, we raised mice from 7 d before birth to adulthood in slightly larger than normal SCs with or without a running wheel (RW). When the mice were older than P135, we visualized V1 activity before and after monocular deprivation (MD) using intrinsic signal optical imaging. Adult RW-raised mice continued to show an OD shift toward the open eye after 7 d of MD, while age-matched SC mice without a RW did not show OD plasticity. Notably, running just during the 7 d MD period restored OD plasticity in adult SC-raised mice. In addition, the OD shift of the RW mice was mediated by a decrease of deprived-eye responses in V1, a signature of "juvenile-like" plasticity. We conclude that voluntary physical exercise alone is sufficient to promote plasticity in adult mouse V1.

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The ability of the adult brain to undergo plastic changes is of particular interest in medicine, especially regarding recovery from injuries or improving learning and cognition. Matrix metalloproteinases (MMPs) have been associated with juvenile experience-dependent primary visual cortex (V1) plasticity, yet little is known about their role in this process in the adult V1. Activation of MMPs is a crucial step facilitating structural changes in a healthy brain; however, upon brain injury, upregulated MMPs promote the spread of a lesion and impair recovery. To clarify these seemingly opposing outcomes of MMP-activation, we examined the effects of MMP-inhibition on experience-induced plasticity in healthy and stoke-affected adult mice. In healthy animals, 7-day application of MMP-inhibitor prevented visual plasticity. Additionally, treatment with MMP-inhibitor once but not twice following stroke rescued plasticity, normally lost under these conditions. Our data imply that an optimal level of MMP-activity is crucial for adult visual plasticity to occur.DOI: http://dx.doi.org/10.7554/eLife.11290.001

In standard cage (SC) raised mice, experience-dependent ocular dominance (OD) plasticity in the primary visual cortex (V1) rapidly declines with age: in postnatal day 25–35 (critical period) mice, 4 days of monocular deprivation (MD) are sufficient to induce OD-shifts towards the open eye; thereafter, 7 days of MD are needed. Beyond postnatal day 110, even 14 days of MD failed to induce OD-plasticity in mouse V1. In contrast, mice raised in a so-called “enriched environment” (EE), exhibit lifelong OD-plasticity. EE-mice have more voluntary physical exercise (running wheels), and experience more social interactions (bigger housing groups) and more cognitive stimulation (regularly changed labyrinths or toys). Whether experience-dependent shifts of V1-activation happen faster in EE-mice and how long the plasticity promoting effect would persist after transferring EE-mice back to SCs has not yet been investigated. To this end, we used intrinsic signal optical imaging to visualize V1-activation i) before and after MD in EE-mice of different age groups (from 1–9 months), and ii) after transferring mice back to SCs after postnatal day 130. Already after 2 days of MD, and thus much faster than in SC-mice, EE-mice of all tested age groups displayed a significant OD-shift towards the open eye. Transfer of EE-mice to SCs immediately abolished OD-plasticity: already after 1 week of SC-housing and MD, OD-shifts could no longer be visualized. In an attempt to rescue abolished OD-plasticity of these mice, we either administered the anti-depressant fluoxetine (in drinking water) or supplied a running wheel in the SCs. OD-plasticity was only rescued for the running wheel- mice. Altogether our results show that raising mice in less deprived environments like large EE-cages strongly accelerates experience-dependent changes in V1-activation compared to the impoverished SC-raising. Furthermore, preventing voluntary physical exercise of EE-mice in adulthood immediately precludes OD-shifts in V1.