Search

The visual cliff assay (VCA) has been used in multiple animal models including humans to assess stereopsis, the pinnacle percept of binocular function that is markedly disrupted in amblyopia. Amblyopia is a neurodevelopmental disorder of the visual system caused by refractive error, strabismus, or obscuration of the visual axis during infancy and early childhood. While the current standard of care can improve visual acuity in the amblyopic eye, gains are infrequently associated with improvements in stereoscopic depth perception and typically only achieved when treatment is initiated in early childhood. The mouse model of amblyopia induced by monocular deprivation (MD) is a powerful tool to study the mechanistic pathophysiology of this disorder and test novel therapeutics. However, to date, only one study has used the VCA to assess the effects of MD in mice in a limited capacity. Advantages of the VCA include no need for operant conditioning or training, completion in minutes, and minimal equipment. We comprehensively characterize and validate fundamental aspects of the VCA including test-retest reliability and contributions of binocularity using multiple monocular and binocular manipulations with clinically relevant paradigms. After long-term (3 weeks) MD, mice exhibit reduced predilection for the safe side, decreased latency to cross to the cliff side, and more crosses to the cliff side compared to sham littermate controls. Our data demonstrate that the VCA can detect binocular deficits in amblyopia but with important limitations that guide how the VCA should be applied to read out binocular function in both mechanistic and therapeutic studies in mice.

PurposeThe effectiveness of traditional amblyopia therapies is largely restricted to childhood. However, recovery in adulthood is possible following removal or vision-limiting disease of the fellow eye. Study of this phenomenon is currently limited to isolated case reports and a few case series, with reported incidence ranging from 19-77%1–5. We set out to accomplish two distinct goals: (1) define the incidence of clinically meaningful recovery and (2) elucidate the clinical features associated with greater amblyopic eye gains.MethodsA systematic review of 3 literature databases yielded 23 reports containing 109 cases of patients ≥18 years old with unilateral amblyopia and vision-limiting fellow eye pathology.ResultsStudy 1 revealed 25/42 (59.5%) of adult patients gained ≥2 logMAR lines in the amblyopia eye after FE vision loss. The overall degree of improvement is clinically meaningful (median 2.6 logMAR lines). Study 2 showed that for cases with amblyopic eye visual acuity improvement, recovery occurs within 12 months of initial loss of fellow eye vision. Regression analysis revealed that younger age, worse baseline acuity in the amblyopic eye, and worse vision in the fellow eye independently conferred greater gains in amblyopic eye visual acuity. Recovery occurs across amblyopia types and fellow eye pathologies, although disease entities affecting fellow eye retinal ganglion cells demonstrate shorter latencies to recovery.ConclusionsAmblyopia recovery after fellow eye injury demonstrates that the adult brain harbors the neuroplastic capacity for clinically meaningful recovery, which could potentially be harnessed by novel approaches to treat adults with amblyopia.

In mouse primary visual cortex (V1), familiar stimuli evoke significantly altered responses when compared to novel stimuli. This stimulus-selective response plasticity (SRP) was described originally as an increase in the magnitude of visual evoked potentials (VEPs) elicited in layer (L) 4 by familiar phase-reversing grating stimuli. SRP is dependent on NMDA receptors (NMDAR) and has been hypothesized to reflect potentiation of thalamocortical synapses in L4. However, recent evidence indicates that the synaptic modifications that manifest as SRP do not occur on L4 principal cells. To shed light on where and how SRP is induced and expressed, the present study had three related aims: (1) to confirm that NMDAR are required specifically in glutamatergic principal neurons of V1, (2) to investigate the consequences of deleting NMDAR specifically in L6, and (3) to use translaminar electrophysiological recordings to characterize SRP expression in different layers of V1. We find that knockout of NMDAR in L6 principal neurons disrupts SRP. Current-source density analysis of the VEP depth profile shows augmentation of short latency current sinks in layers 3, 4 and 6 in response to phase reversals of familiar stimuli. Multiunit recordings demonstrate that increased peak firing occurs to in response to phase reversals of familiar stimuli across all layers, but that activity between phase reversals is suppressed. Together, these data reveal important aspects of the underlying phenomenology of SRP and generate new hypotheses for the expression of experience-dependent plasticity in V1.Significance StatementRepeated exposure to stimuli that portend neither reward nor punishment leads to behavioral habituation, enabling organisms to dedicate attention to novel or otherwise significant features of the environment. The neural basis of this process, which is so often dysregulated in neurological and psychiatric disorders, remains poorly understood. Learning and memory of stimulus familiarity can be studied in mouse visual cortex by measuring electrophysiological responses to simple phase-reversing grating stimuli. The current study advances knowledge of this process by documenting changes in visual evoked potentials, neuronal spiking activity, and oscillations in the local field potentials across all layers of mouse visual cortex. In addition, we identify a key contribution of a specific population of neurons in layer 6 of visual cortex.

During a critical period of postnatal life, monocular deprivation (MD) of kittens by eyelid closure reduces the size of neurons in layers of the dorsal lateral geniculate nucleus (dLGN) connected to the deprived eye, and shifts cortical ocular dominance in favor of the non-deprived eye, modeling deprivation amblyopia in humans. Following long-term MD, temporary retinal inactivation of the non-deprived eye with microinjection of tetrodotoxin can promote superior recovery from MD, and at older ages, in comparison to conventional occlusion therapy. This suggests that monocular inactivation (MI) is a more potent approach to producing neural plasticity than occlusion. In the current study we assessed the modification of neuron size in the dLGN as a means of measuring the impact of a brief period of MI imposed at different ages during postnatal development. The biggest impact of inactivation was observed when it occurred at the peak of the critical period for ocular dominance plasticity. The effect of MI was evident in both the binocular and monocular segments of the dLGN, distinguishing it from MD that produces changes only within the binocular segment. With increasing age, the capacity for inactivation to alter postsynaptic cell size diminished but was still significant beyond the classic critical period. In comparison to MD, inactivation consistently produced effects that were about double in magnitude, and inactivation exhibited efficacy to produce neural modifications at older ages than MD. Notwithstanding the large neural alterations precipitated by inactivation, its anatomical effects were remediated with a short period of binocular visual experience, and vision through the previously inactivated eye fully recovered after washout of TTX. Our results demonstrate that MI is a potent means of modifying the visual pathway, and does so beyond the age at which occlusion is effective. The magnitude and longevity of inactivation to evoke neural modification highlights its potential to ameliorate disorders of the visual system such as amblyopia.

BackgroundRecovery from amblyopia in adulthood following fellow eye (FE) vision loss is a well-known phenomenon. Incidence of recovery varies widely following different FE pathologies and rate of recovery following FE ischemic optic neuropathy (ION) has not been examined. We aimed to determine frequency and degree of improvement in amblyopic eye (AE) visual function following ION in the FE.MethodsWe performed a retrospective chart review of patients between 2007-2021 confirmed to have amblyopia and ischemic optic neuropathy in different eyes. Patients with unstable ocular pathology potentially limiting vision were excluded. We compared best-corrected visual acuity (VA) in each eye before and after FE ION over time. For patients with available data, we examined change in perimetric performance over time.ResultsAmong the 12 patients who met inclusion criteria (mean age 67±8 years), 9 (75%) improved ≥1 line and 2 (17%) improved ≥3 lines. Median time from ION symptom onset to maximal improvement was 6 months (range: 2-101 months). Reliable perimetric data were available for 6 patients. Mean sensitivity improved in the amblyopic eye for all patients, with a mean improvement of 1.9±1.1 dB. There was no correspondence between foci of ION-related field loss and gains in field sensitivity in the AE.ConclusionA high proportion of patients with amblyopia and contralateral ION experience improvement in their amblyopic eye. Modest gains in perimetric sensitivity in the AE may accompany FE ION. These findings support the view that residual plasticity in the adult visual cortex can be tapped to support functional improvement in amblyopia.

Fragile X syndrome (FXS) is caused by silencing of the human FMR1 gene and is the leading monogenic cause of intellectual disability and autism. Abundant preclinical data indicated that negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5) might be efficacious in treating FXS in humans. Initial attempts to translate these findings in clinical trials have failed, but these failures provide the opportunity for new discoveries that will improve future trials. The emergence of acquired treatment resistance (“tolerance”) after chronic administration of mGluR5 NAMs is a potential factor in the lack of success. Here we confirm that FXS model mice display acquired treatment resistance after chronic treatment with the mGluR5 NAM CTEP in three assays commonly examined in the mouse model of FXS: (1) audiogenic seizure susceptibility, (2) sensory cortex hyperexcitability, and (3) hippocampal protein synthesis. Cross-tolerance experiments suggest that the mechanism of treatment resistance likely occurs at signaling nodes downstream of glycogen synthase kinase 3α (GSK3α), but upstream of protein synthesis. The rapid emergence of tolerance to CTEP begs the question of how previous studies showed an improvement in inhibitory avoidance (IA) cognitive performance after chronic treatment. We show here that this observation was likely explained by timely inhibition of mGluR5 during a critical period, as brief CTEP treatment in juvenile mice is sufficient to provide a persistent improvement of IA behavior measured many weeks later. These data will be important to consider when designing future fragile X clinical trials using compounds that target the mGluR5-to-protein synthesis signaling cascade.

The immediate early geneArcis critical for maintenance of long-term memory. How Arc mediates this process remains unclear, but it has been proposed to sustain Hebbian synaptic potentiation, which is a key component of memory encoding. This form of plasticity is modelled experimentally by induction of long-term potentiation (LTP), which increases Arc mRNA and protein expression. However, mechanistic data implicates Arc in the endocytosis of AMPA-type glutamate receptors and the weakening of synapses. Here, we took a comprehensive approach to determine if Arc is necessary for hippocampal LTP. We find that Arc is not required for LTP maintenance and must regulate memory storage through alternative mechanisms.

The molecular basis for the decline in experience-dependent neural plasticity over age remains poorly understood. In visual cortex, the robust plasticity induced in juvenile mice by brief monocular deprivation (MD) during the critical period is abrogated by genetic deletion of Arc, an activity-dependent regulator of excitatory synaptic modification. Here we report that augmenting Arc expression in adult mice prolongs juvenile-like plasticity in visual cortex, as assessed by recordings of ocular dominance (OD) plasticity in vivo. A distinguishing characteristic of juvenile OD plasticity is the weakening of deprived-eye responses, believed to be accounted for by the mechanisms of homosynaptic long-term depression (LTD). Accordingly, we also found increased LTD in visual cortex of adult mice with augmented Arc expression, and impaired LTD in visual cortex of juvenile mice that lack Arc or have been treated in vivo with a protein synthesis inhibitor. Further, we found that although activity-dependent expression of Arc mRNA does not change with age, expression of Arc protein is maximal during the critical period and declines in adulthood. Finally, we show that acute augmentation of Arc expression in wild type adult mouse visual cortex is sufficient to restore juvenile-like plasticity. Together, our findings suggest a unifying molecular explanation for the age- and activity-dependent modulation of synaptic sensitivity to deprivation.Significance StatementNeuronal plasticity peaks early in life during critical periods and normally declines with age, but the molecular changes that underlie this decline are not fully understood. Using the mouse visual cortex as a model, we found that activity-dependent expression of the neuronal protein Arc peaks early in life, and that loss of activity-dependent Arc expression parallels loss of synaptic plasticity in the visual cortex. Genetic overexpression of Arc prolongs the critical period of visual cortex plasticity and acute viral expression of Arc in adult mice can restore juvenile-like plasticity. These findings provide a mechanism for the loss of excitatory plasticity with age, and suggest that Arc may be an exciting therapeutic target for modulation of the malleability of neuronal circuits.

It has been more than 50 years since the first description of ocular dominance plasticity-the profound modification of primary visual cortex (V1) following temporary monocular deprivation. This discovery immediately attracted the intense interest of neurobiologists focused on the general question of how experience and deprivation modify the brain as a potential substrate for learning and memory. The pace of discovery has quickened considerably in recent years as mice have become the preferred species to study visual cortical plasticity, and new studies have overturned the dogma that primary sensory cortex is immutable after a developmental critical period. Recent work has shown that, in addition to ocular dominance plasticity, adult visual cortex exhibits several forms of response modification previously considered the exclusive province of higher cortical areas. These "higher brain functions" include neural reports of stimulus familiarity, reward-timing prediction, and spatiotemporal sequence learning. Primary visual cortex can no longer be viewed as a simple visual feature detector with static properties determined during early development. Rodent V1 is a rich and dynamic cortical area in which functions normally associated only with "higher" brain regions can be studied at the mechanistic level., National Eye Institute (Grant RO1 EY023037), National Institute of Mental Health (U.S.) (Grant K99 MH09965)

The involvement of the perirhinal cortex and the fornix in retrograde and anterograde amnesia in the rat was investigated in this experiment. Male Sprague-Dawley rats were trained on a series of five visual discrimination problems at distinct time intervals prior to receiving bilateral, electrolytic lesions of the perirhinal cortex or the fornix, combined lesions of both these structures, or sham operations. Following recovery from surgery, rats were retested on the preoperatively learned discrimination problems, as well as learning a new discrimination and discrimination reversal. Results indicated that all animals with lesions exhibited temporally graded retrograde amnesia, whereby memories acquired in the recent past (1-3 weeks) were impaired, and memories acquired in the remote past (6-8 weeks) were spared. There was no difference in the magnitude of retrograde amnesia between the three lesion groups. Animals in the perirhinal, fornix, and combined lesion groups were able to learn a new discrimination problem at a rate comparable to control rats; however, the animals with lesions were impaired at learning the discrimination reversal. The perirhinal, fornix, and combined lesion animals also exhibited a significantly faster forgetting rate over a 2-week retention interval than control rats. These results suggest that medial temporal structures including the perirhinal cortex and the fornix are involved in the consolidation of mnemonic information and that their involvement in this process occurs over a discrete period of time.