Visual function in human and experimental glaucoma

Injury to optic nerve (ON) axons plays a major role in glaucoma progression. ON crush is an established model of axonal injury which results in retrograde degeneration and death of retinal ganglion cells (RGCs). However, it is unknown how signal transmission to higher visual structures such as primary visual cortex (V1) is affected after ON crush. In human glaucoma, visual function is assessed using visual field (VF) tests, but it is also not clear how the test results relate to the disease progression in the retina. Unilateral ON crush was performed on the left eyes of adult C57BL/6 mice. V1 function of the right hemisphere was assessed longitudinally by optical imaging (OI) and in vivo calcium two-photon imaging under anaesthesia before and at 7 days, 14 days and 30 days after ON crush. Human retinas from glaucoma patients were investigated for changes in RGC density and compared to the score from the VF data obtained prior to the patients’ death. ISI and 2P experiments demonstrate a significant shift in OD towards the ipsilateral eye and significant reduction of signal magnitude in V1 in response to contralateral eye stimulation in all ON crush animals. Additionally, response magnitude to ipsilateral eye stimulation was significantly increased after ON crush. While there was significant RGC loss in human glaucoma compared to age matched controls that was correlated to mean VF loss, the scores from the individual VF test points were uncorrelated to RGC density in anatomically equivalent areas. This work demonstrates that unilateral ON crush results in immediate loss of signal transmission from the retina to V1 via a crushed ON. A significant increase of responsiveness in V1 to non-crushed eye stimulation was observed, which indicates that injury of the ON in adulthood may evoke compensatory plasticity in V1

Enhancement of visual cortex plasticity by dark exposure

Dark rearing is known to delay the time course of the critical period for ocular dominance plasticity in the visual cortex. Recent evidence suggests that a period of dark exposure (DE) may enhance or reinstate plasticity even after closure of the critical period, mediated through modification of the excitatory–inhibitory balance and/or removal of structural brakes on plasticity. Here, we investigated the effects of a week of DE on the recovery from a month of monocular deprivation (MD) in the primary visual cortex (V1) of juvenile mice. Optical imaging of intrinsic signals revealed that ocular dominance in V1 of mice that had received DE recovered slightly more quickly than of mice that had not, but the level of recovery after three weeks was similar in both groups. Two-photon calcium imaging showed no significant difference in the recovery of orientation selectivity of excitatory neurons between the two groups. Parvalbumin-positive (PV+) interneurons exhibited a smaller ocular dominance shift during MD but again no differences in subsequent recovery. The percentage of PV+ cells surrounded by perineuronal nets, a structural brake on plasticity, was lower in mice with than those without DE. Overall, DE causes a modest enhancement of mouse visual cortex plasticity

Plasticity in adult mouse visual cortex following optic nerve injury

Optic nerve (ON) injury is an established model of axonal injury which results in retrograde degeneration and death of retinal ganglion cells as well anterograde loss of transmission and Wallerian degeneration of the injured axons. While the local impact of ON crush has been extensively documented we know comparatively little about the functional changes that occur in higher visual structures such as primary visual cortex (V1). We explored the extent of adult cortical plasticity using ON crush in aged mice. V1 function of the contralateral hemisphere was assessed longitudinally by intrinsic signal imaging and 2-photon calcium imaging before and after ON crush. Functional imaging demonstrated an immediate shift in V1 ocular dominance towards the ipsilateral, intact eye, due to the expected almost complete loss of responses to contralateral eye stimulation. Surprisingly, within 2 weeks we observed a delayed increase in ipsilateral eye responses. Additionally, spontaneous activity in V1 was reduced, similar to the lesion projection zone after retinal lesions. The observed changes in V1 activity indicate that severe ON injury in adulthood evokes cortical plasticity not only cross-modally but also within the visual cortex; this plasticity may be best compared with that seen after retinal lesions

Experience dependent plasticity of higher visual cortical areas in the mouse

Experience dependent plasticity in the visual cortex is a key paradigm for the study of mechanisms underpinning learning and memory. Despite this, studies involving manipulating visual experience have largely been limited to the primary visual cortex, V1, across various species. Here we investigated the effects of monocular deprivation (MD) on the ocular dominance (OD) and orientation selectivity of neurons in four visual cortical areas in the mouse: the binocular zone of V1 (V1b), the putative “ventral stream” area LM and the putative “dorsal stream” areas AL and PM. We employed two-photon calcium imaging to record neuronal responses in young adult mice before MD, immediately after MD, and following binocular recovery. OD shifts following MD were greatest in LM and smallest in AL and PM; in LM and AL, these shifts were mediated primarily through a reduction of deprived-eye responses, in V1b and LM through an increase in response through the non-deprived eye. The OD index recovered to pre-MD levels within 2 weeks in V1 only. MD caused a reduction in orientation selectivity of deprived-eye responses in V1b and LM only. Our results suggest that changes in OD in higher visual areas are not uniformly inherited from V1

Stable encoding of visual cues in the mouse retrosplenial cortex

The rodent retrosplenial cortex (RSC) functions as an integrative hub for sensory and motor signals, serving roles in both navigation and memory. While RSC is reciprocally connected with the sensory cortex, the form in which sensory information is represented in the RSC and how it interacts with motor feedback is unclear and likely to be critical to computations involved in navigation such as path integration. Here, we used 2-photon cellular imaging of neural activity of putative excitatory (CaMKII expressing) and inhibitory (parvalbumin expressing) neurons to measure visual and locomotion evoked activity in RSC and compare it to primary visual cortex (V1). We observed stimulus position and orientation tuning, and a retinotopic organization. Locomotion modulation of activity of single neurons, both in darkness and light, was more pronounced in RSC than V1, and while locomotion modulation was strongest in RSC parvalbumin-positive neurons, visual-locomotion integration was found to be more supralinear in CaMKII neurons. Longitudinal measurements showed that response properties were stably maintained over many weeks. These data provide evidence for stable representations of visual cues in RSC that are spatially selective. These may provide sensory data to contribute to the formation of memories of spatial information

Midget retinal ganglion cell dendritic and mitochondrial degeneration is an early feature of human glaucoma

Glaucoma is characterized by the progressive dysfunction and loss of retinal ganglion cells. However, the earliest degenerative events that occur in human glaucoma are relatively unknown. Work in animal models has demonstrated that retinal ganglion cell dendrites remodel and atrophy prior to the loss of the cell soma. Whether this occurs in human glaucoma has yet to be elucidated. Serial block face scanning electron microscopy is well established as a method to determine neuronal connectivity at high resolution but so far has only been performed in normal retina from model animals. To assess the structure-function relationship of early human glaucomatous neurodegeneration, regions of inner retina assessed to have none-to-moderate loss of retinal ganglion cell number were processed using serial block face scanning electron microscopy (n = 4 normal retinas, n = 4 glaucoma retinas). This allowed detailed 3D reconstruction of retinal ganglion cells and their intracellular components at a nanometer scale. In our datasets retinal ganglion cell dendrites degenerate early in human glaucoma, with remodeling and redistribution of the mitochondria. We assessed the relationship between visual sensitivity and retinal ganglion cell density and discovered that this only partially conformed to predicted models of structure-function relationships, which may be affected by these early neurodegenerative changes. In this study, human glaucomatous retinal ganglion cells demonstrate compartmentalized degenerative changes as observed in animal models. Importantly, in these models, many of these changes have been demonstrated to be reversible, increasing the likelihood of translation to viable therapies for human glaucoma

Identification of individual PV+ cells across imaging sessions and visual responses to oriented gratings in mouse V1. from Enhancement of visual cortex plasticity by dark exposure

Supplementary Figure 2: Identification of individual PV+ cells across imaging sessions and visual responses to oriented gratings in mouse V1. (A) Imaged area (270 m x 270 m) at the end of 30 d MD period, showing red fluorescent PV+ cells (at 1030 nm) and calcium signals (right); polar plot of orientation tuning (distance from centre corresponds to dF/F, %) and averaged calcium signal traces for contralateral (red lines) and ipsilateral eye responses (blue lines). (B) Same area imaged after one week of DE followed by one week of binocular recovery; conventions as in (A)

Stable Encoding of Visual Cues in the Mouse Retrosplenial Cortex

Altres ajuts: This work was supported by a Biotechnology and Biological Sciences Research Council research grant awarded to JA, AN, SV and FS (BB/L021005/1), a Sêr Cymru fellowship (80762-CU-080) to AR, a Wellcome Trust Strategic Award (100202/z/12/z) to Michael J. Owen, J.H., Lawrence Wilkinson, Adrian Harwood, Meng Li, David Linden, John Aggleton, Vincenzo Crunelli, and Derek Jones, and a Wellcome Trust ISSF Seedcorn Award (105613/Z/14/Z) to A.R. S.V. is funded by a Wellcome Trust Senior Research Fellowship (212273/Z/18/Z).The rodent retrosplenial cortex (RSC) functions as an integrative hub for sensory and motor signals, serving roles in both navigation and memory. While RSC is reciprocally connected with the sensory cortex, the form in which sensory information is represented in the RSC and how it interacts with motor feedback is unclear and likely to be critical to computations involved in navigation such as path integration. Here, we used 2-photon cellular imaging of neural activity of putative excitatory (CaMKII expressing) and inhibitory (parvalbumin expressing) neurons to measure visual and locomotion evoked activity in RSC and compare it to primary visual cortex (V1). We observed stimulus position and orientation tuning, and a retinotopic organization. Locomotion modulation of activity of single neurons, both in darkness and light, was more pronounced in RSC than V1, and while locomotion modulation was strongest in RSC parvalbumin-positive neurons, visual-locomotion integration was found to be more supralinear in CaMKII neurons. Longitudinal measurements showed that response properties were stably maintained over many weeks. These data provide evidence for stable representations of visual cues in RSC that are spatially selective. These may provide sensory data to contribute to the formation of memories of spatial information