Optimization of visual training for full recovery from severe amblyopia in adults

Eaton, Nicolette C.; Sheehan, Hanna Marie; Quinlan, Elizabeth

doi:10.1101/lm.040295.115

Cited by 28 publications

(30 citation statements)

References 53 publications

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“…It is important to note that dark exposure alone does not impact visual acuity or neuronal stimulus selectivity, which is regained only after repetitive visual experience (Montey et al, 2013; Eaton et al, 2016). Likewise, enrichment or locomotion alone does not strengthen visual performance (Kaneko & Stryker, 2014; Greifzu et al, 2016).…”

Section: Environmental Reactivation Of Critical Period In Adulthoodmentioning

confidence: 99%

“…There is also evidence that some manipulations may globally reinstate V1 plasticity across these distinct visual functions. For example, dark exposure in adulthood, which reactivates plasticity for the recovery of normal OD in amblyopic rats, mice, and kittens (He et al, 2007; Montey & Quinlan, 2011; Duffy & Mitchell, 2013; Stodieck et al, 2014; Eaton et al, 2016; Mitchell et al, 2016) promotes the recovery of stimulus selectivity and visual response strength (Montey et al, 2013). As critical periods for different visual functions may depend on separate underlying mechanisms, some manipulations may restore only selective features of V1 responses.…”

Section: Expanding the Focus Beyond Ocular Dominancementioning

confidence: 99%

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Critical periods in amblyopia

2018

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The shift in ocular dominance (OD) of binocular neurons induced by monocular deprivation is the canonical model of synaptic plasticity confined to a postnatal critical period. Developmental constraints on this plasticity not only lend stability to the mature visual cortical circuitry but also impede the ability to recover from amblyopia beyond an early window. Advances with mouse models utilizing the power of molecular, genetic, and imaging tools are beginning to unravel the circuit, cellular, and molecular mechanisms controlling the onset and closure of the critical periods of plasticity in the primary visual cortex (V1). Emerging evidence suggests that mechanisms enabling plasticity in juveniles are not simply lost with age but rather that plasticity is actively constrained by the developmental up-regulation of molecular ‘brakes’. Lifting these brakes enhances plasticity in the adult visual cortex, and can be harnessed to promote recovery from amblyopia. The reactivation of plasticity by experimental manipulations has revised the idea that robust OD plasticity is limited to early postnatal development. Here, we discuss recent insights into the neurobiology of the initiation and termination of critical periods and how our increasingly mechanistic understanding of these processes can be leveraged toward improved clinical treatment of adult amblyopia.

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Section: Environmental Reactivation Of Critical Period In Adulthoodmentioning

confidence: 99%

Section: Expanding the Focus Beyond Ocular Dominancementioning

confidence: 99%

Critical periods in amblyopia

2018

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“…For instance, enhancement of endogenous acetylcholine signaling by inhibition of acetylcholinesterase restored normal vision in adult mice after a period of amblyogenic rearing (Morishita, Miwa, Heintz, & Hensch, 2010). Physiological recovery from MD has been achieved in adult mice through the pairing of visual stimulation and locomotion (Kaneko & Stryker, 2014), and elimination of visually-driven activity through immersion in complete darkness for 10 days reduced the effects of an earlier period of MD in adult rats and juvenile mice (He, Ray, Dennis, & Quinlan, 2007;Montey & Quinlan, 2011;Eaton, Sheehan, & Quinlan, 2016;Erchova, Vasalauskaite, Longo, & Sengpiel, 2017). To our knowledge, no intervention employed in cats has demonstrated significant recovery from long-term MD when applied late into the critical period.…”

Section: Freemanmentioning

confidence: 99%

Recovery from the anatomical effects of long‐term monocular deprivation in cat lateral geniculate nucleus

Duffy

Fong

Mitchell

et al. 2017

J of Comparative Neurology

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Monocular deprivation (MD) imposed early in postnatal life elicits profound structural and functional abnormalities throughout the primary visual pathway. The ability of MD to modify neurons within the visual system is restricted to a so-called critical period that, for cats, peaks at about one postnatal month and declines thereafter so that by about 3 months of age MD has little effect. Recovery from the consequences of MD likewise adheres to a critical period that ends by about 3 months of age, after which the effects of deprivation are thought to be permanent and without capacity for reversal. The attenuation of plasticity beyond early development is a formidable obstacle for conventional therapies to stimulate recovery from protracted visual deprivation. In the current study we examined the efficacy of dark exposure and retinal inactivation with tetrodotoxin to promote anatomical recovery in the dorsal lateral geniculate nuclues (dLGN) from long-term MD started at the peak of the critical period. Whereas 10 days of dark exposure or binocular retinal inactivation were not better at promoting recovery than conventional treatment with reverse occlusion, inactivation of only the non-deprived (fellow) eye for 10 days produced a complete restoration of neuron soma size, and also reversed the significant loss of neurofilament protein within originally deprived dLGN layers. These results reveal a capacity for neural plasticity and recovery that is larger than anything previously observed following protracted MD in cat, and they highlight a possibility for alternative therapies applied at ages thought to be recalcitrant to recovery.

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“…In animal models, prolonged monocular deprivation 20 induces severe amblyopia, characterized by a significant decrease in the strength and 21 selectivity of neuronal responses in the deprived visual cortex (Harwerth et al, 1983) 22 (Montey et al, 2013) (Fong et al, 2016) and a significant loss of spatial acuity through 23 the deprived eye (Wiesel and Hubel, 1963) (Harwerth et al, 1983) (Liao et al,24 2011) (Montey et al, 2013). In rats, spatial acuity in the deprived eye is undetectable 25 following cMD initiated at eye opening (Eaton et al, 2016). Additionally, following 26 prolonged monocular deprivation, neurons in the dorsal lateral geniculate nucleus 27 (dLGN) that project to deprived binocular visual cortex have lower metabolism (Kennedy 28 et al, 1981) and smaller somata (Duffy et al, 2018).…”

Section: Introduction 16 17mentioning

confidence: 99%

Homeostatic regulation of perisynaptic MMP9 activity in the amblyopic visual cortex

Murase

Winkowski

Liu

et al. 2019

Preprint

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1 2 Dark exposure (DE) followed by light reintroduction (LRx) reactivates robust synaptic 3 plasticity in adult mouse V1, which allows recovery from amblyopia. Previously we 4 showed that LRx-induced perisynaptic proteolysis of extracellular substrates by MMP9 5 mediates the enhanced plasticity in binocular adult mice (Murase et al., 2017). 6However, it is unknown if a visual system compromised by amblyopia could engage this 7 pathway. Here we show that LRx to adult amblyopic mice induces perisynaptic MMP2/9 8 activity and degradation of ECM in the deprived and non-deprived V1. LRx restricted to 9 the amblyopic eye induces equally robust MMP2/9 activity at thalamo-cortical synapses 10 and ECM degradation in deprived V1. Two-photon live imaging demonstrates that the 11 history of visual experience regulates MMP2/9 activity in V1, and that DE lowers the 12 threshold for the proteinase activation. This homeostatic reduction of MMP2/9 activation 13 threshold by DE enables the visual input from the amblyopic pathway to trigger robust 14 perisynaptic proteolysis. 15 regions (Gogolla et al., 2009)(Romberg et al., 2013)(Kochlamazashvili et al., 62 2010)(Zhao et al., 2007)(Carstens et al., 2016)(Carstens and Dudek, 2019). Genetic 63 ablation of cartilage link protein (Crtl1/Halpn1), which prevents the condensation of 64 ECM molecules into PNNs, prevents the closure of the critical period for ocular 65 dominance plasticity (Carulli et al., 2010). Dark rearing from birth also results in similar 66 delays in the maturation of ECM/PNNs and the closure of the critical period (Pizzorusso 67 et al., 2002)(Mower, 1991)(Lander et al., 1997). 68 69 However, robust juvenile-like ocular dominance plasticity can be restored in adults by 70 complete visual deprivation through dark exposure (DE) followed by light reintroduction 71 (LRx) (He, H.-Y., Hodos, W., Quinlan, 2006). Our previous work demonstrated DE/LRx 72 induces an increase in perisynaptic activity of matrix-metalloproteinase 9 (MMP9) and 73 subsequent proteolysis of extracellular targets in binocular adult mice (Murase et al., 74 2017). Importantly, the reactivation of structural and functional plasticity by DE/LRx is 75 inhibited by pharmacological blockade and genetic ablation of MMP9. Although MMP9 -/-76 mice are resistant to DE/LRx induced plasticity, treatment with hyaluronidase recovers 77 structural and functional plasticity in adults. Importantly, the proteinase activity induced 78 by LRx is perisynaptic and enriched at thalamo-cortical synapses. 79 80 In adult rats rendered severely amblyopic by cMD from eye opening to adulthood, DE 81 followed by reverse occlusion enables recovery of the VEP amplitude and dendritic 82 spine density in deprived V1b (He et al., 2007)(Montey and Quinlan, 2011). Subsequent 83 visual training promotes a full recovery of visual acuity in the deprived eye (Eaton et al., 84 * * * *

show abstract

Optimization of visual training for full recovery from severe amblyopia in adults

Cited by 28 publications

References 53 publications

Critical periods in amblyopia

Critical periods in amblyopia

Recovery from the anatomical effects of long‐term monocular deprivation in cat lateral geniculate nucleus

Homeostatic regulation of perisynaptic MMP9 activity in the amblyopic visual cortex

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