Background: Cognitive control is defined as the ability to act flexibly in the environment by either behaving automatically or inhibiting said automatic behaviour and it can be measured using an interleaved pro/anti-saccade task. Decline in cognitive control has been attributed to normal aging and neurological illnesses such as Parkinson’s disease (PD) as well as decline in other cognitive abilities. This parallel might highlight the role played by cognitive control in information processing and working memory. However, little is known about the relationship between cognitive control and other cognitive processes such as visual memory, decision making, and visual search. We thus propose to correlate the incidence of impaired cognitive control with deficits in visual memory, decision making and visual search in three groups: younger adults, older adults and patients with idiopathic PD.

Methods: Seventy-one participants, namely 34 adults (M =22.75, SD =3.8), 22 older adults (M =67.4, SD =8.3), and 20 PD patients (M =65.59, SD =8.2) performed four tasks: interleaved pro/anti-saccade, visual memory, decision making, and serial and pop-out visual search.

Results: Results show that within each group, anti-saccade error rate (ER) were significantly and negatively correlated with visual memory ER (r_younger =?0.378, P=0.036; r_older =?0.440, P_older =0.046; r_PD =?0.609, P=0.016). On the other hand, correct decision-making reaction times (RT) were significantly correlated with anti-saccade ER, and RTs only in older adults (r_ER =0.529, P=0.014; r_RT =0.512, P=0.018) and PD patients (r_ER =0.727, P=0.012; r_RT =0.769, P=0.001). For visual search, PD patients showed a significant relationship between RTs for correct pro-saccades and pop-out (r=0.665, P=0.007), and serial (r=0.641, P=0.010) search RTs. Furthermore, there was a significant correlation between MoCA scores and anti-saccade RTs (r=?0.559, P=0.030) and ER (r=?0.562, P=0.029) in PD patients. Taken together, these results support the hypothesis of PD patients’ reliance on bottom-up processes as top-down processes decline. For younger adults, there was a significant correlation between serial search performance and both anti-saccade ER (r=0.488, P=0.005), and correct pro-saccade ER (r=0.413, P=0.021). In older adults, this relationship was absent, but anti-saccade ER significantly correlated with pop-out search times (r=0.473, P=0.030).

Conclusions: We found significant relationships between cognitive tasks and cognitive control as measured through the interleaved pro/anti-saccade task across and within participant groups, providing evidence of the appropriateness of the use of the interleaved pro/anti-saccade task as a measure of overall cognitive control.

Background: Cognitive control is defined as the ability to act flexibly in the environment by either behaving automatically or inhibiting said automatic behaviour and it can be measured using an interleaved pro/anti-saccade task. Decline in cognitive control has been attributed to normal aging and neurological illnesses such as Parkinson’s disease (PD) as well as decline in other cognitive abilities. This parallel might highlight the role played by cognitive control in information processing and working memory. However, little is known about the relationship between cognitive control and other cognitive processes such as visual memory, decision making, and visual search. We thus propose to correlate the incidence of impaired cognitive control with deficits in visual memory, decision making and visual search in three groups: younger adults, older adults and patients with idiopathic PD.

Methods: Seventy-one participants, namely 34 adults (M =22.75, SD =3.8), 22 older adults (M =67.4, SD =8.3), and 20 PD patients (M =65.59, SD =8.2) performed four tasks: interleaved pro/anti-saccade, visual memory, decision making, and serial and pop-out visual search.

Results: Results show that within each group, anti-saccade error rate (ER) were significantly and negatively correlated with visual memory ER (r_younger =?0.378, P=0.036; r_older =?0.440, P_older =0.046; r_PD =?0.609, P=0.016). On the other hand, correct decision-making reaction times (RT) were significantly correlated with anti-saccade ER, and RTs only in older adults (r_ER =0.529, P=0.014; r_RT =0.512, P=0.018) and PD patients (r_ER =0.727, P=0.012; r_RT =0.769, P=0.001). For visual search, PD patients showed a significant relationship between RTs for correct pro-saccades and pop-out (r=0.665, P=0.007), and serial (r=0.641, P=0.010) search RTs. Furthermore, there was a significant correlation between MoCA scores and anti-saccade RTs (r=?0.559, P=0.030) and ER (r=?0.562, P=0.029) in PD patients. Taken together, these results support the hypothesis of PD patients’ reliance on bottom-up processes as top-down processes decline. For younger adults, there was a significant correlation between serial search performance and both anti-saccade ER (r=0.488, P=0.005), and correct pro-saccade ER (r=0.413, P=0.021). In older adults, this relationship was absent, but anti-saccade ER significantly correlated with pop-out search times (r=0.473, P=0.030).

Conclusions: We found significant relationships between cognitive tasks and cognitive control as measured through the interleaved pro/anti-saccade task across and within participant groups, providing evidence of the appropriateness of the use of the interleaved pro/anti-saccade task as a measure of overall cognitive control.

Background: All neurons of the visual system exhibit response to differences in luminance. This neural response to visual contrast, also known as the contrast response function (CRF), follows a characteristic sigmoid shape that can be fitted with the Naka-Rushton equation. Four parameters define the CRF, and they are often used in different visual research disciplines, since they describe selective variations of neural responses. As novel technologies have grown, the capacity to record thousands of neurons simultaneously brings new challenges: processing and robustly analyzing larger amounts of data to maximize the outcomes of our experimental measurements. Nevertheless, current guidelines to fit neural activity based on the Naka-Rushton equation have been poorly discussed in depth. In this study, we explore several methods of boundary-setting and least-square curve-fitting for the CRF in order to avoid the pitfalls of blind curve-fitting. Furthermore, we intend to provide recommendations for experimenters to better prepare a solid quantification of CRF parameters that also minimize the time of the data acquisition. For this purpose, we have created a simplified theoretical model of spike-response dynamics, in which the firing rate of neurons is generated by a Poisson process. The spike trains generated by the theoretical model depending on visual contrast intensities were then fitted with the Naka-Rushton equation. This allowed us to identify combinations of parameters that were more important to adjust before performing experiments, to optimize the precision and efficiency of curve fitting (e.g., boundaries of CRF parameters, number of trials, number of contrast tested, metric of contrast used and the effect of including multi-unit spikes into a single CRF, among others). Several goodness-of-fit methods were also examined in order to achieve ideal fits. With this approach, it is possible to anticipate the minimal requirements to gather and analyze data in a more efficient way in order to build stronger functional models.

Methods: Spike-trains were randomly generated following a Poisson distribution in order to draw both an underlying theoretical curve and an empirical one. Random noise was added to the fit to simulate empirical conditions. The correlation function was recreated on the simulated data and re-fit using the Naka-Rushton equation. The two curves were compared: the idea being to determine the most advantageous boundaries and conditions for the curve-fit to be optimal. Statistical analysis was performed on the data to determine those conditions for experiments. Experiments were then conducted to acquire data from mice and cats to verify the model.

Results: Results were obtained successfully and a model was proposed to assess the goodness of the fit of the contrast response function. Various parametres and their influence of the model were tested. Other similar models were proposed and their performance was assessed and compared to the previous ones. The fit was optimized to give semi-strict guidelines for scientists to follow in order to maximize their efficiency while obtaining the contrast tuning of a neuron.

Conclusions: The aim of the study was to assess the optimal testing parametres of the neuronal response to visual gratings with various luminance, also called the CRF. As technology gets more powerful and potent, one must make choices when experimenting. With a strong model, robust boundaries, and strong experimental conditioning, the best fit to a function can lead to more efficient analysis and stronger cognitive models.

Background: All neurons of the visual system exhibit response to differences in luminance. This neural response to visual contrast, also known as the contrast response function (CRF), follows a characteristic sigmoid shape that can be fitted with the Naka-Rushton equation. Four parameters define the CRF, and they are often used in different visual research disciplines, since they describe selective variations of neural responses. As novel technologies have grown, the capacity to record thousands of neurons simultaneously brings new challenges: processing and robustly analyzing larger amounts of data to maximize the outcomes of our experimental measurements. Nevertheless, current guidelines to fit neural activity based on the Naka-Rushton equation have been poorly discussed in depth. In this study, we explore several methods of boundary-setting and least-square curve-fitting for the CRF in order to avoid the pitfalls of blind curve-fitting. Furthermore, we intend to provide recommendations for experimenters to better prepare a solid quantification of CRF parameters that also minimize the time of the data acquisition. For this purpose, we have created a simplified theoretical model of spike-response dynamics, in which the firing rate of neurons is generated by a Poisson process. The spike trains generated by the theoretical model depending on visual contrast intensities were then fitted with the Naka-Rushton equation. This allowed us to identify combinations of parameters that were more important to adjust before performing experiments, to optimize the precision and efficiency of curve fitting (e.g., boundaries of CRF parameters, number of trials, number of contrast tested, metric of contrast used and the effect of including multi-unit spikes into a single CRF, among others). Several goodness-of-fit methods were also examined in order to achieve ideal fits. With this approach, it is possible to anticipate the minimal requirements to gather and analyze data in a more efficient way in order to build stronger functional models.

Methods: Spike-trains were randomly generated following a Poisson distribution in order to draw both an underlying theoretical curve and an empirical one. Random noise was added to the fit to simulate empirical conditions. The correlation function was recreated on the simulated data and re-fit using the Naka-Rushton equation. The two curves were compared: the idea being to determine the most advantageous boundaries and conditions for the curve-fit to be optimal. Statistical analysis was performed on the data to determine those conditions for experiments. Experiments were then conducted to acquire data from mice and cats to verify the model.

Results: Results were obtained successfully and a model was proposed to assess the goodness of the fit of the contrast response function. Various parametres and their influence of the model were tested. Other similar models were proposed and their performance was assessed and compared to the previous ones. The fit was optimized to give semi-strict guidelines for scientists to follow in order to maximize their efficiency while obtaining the contrast tuning of a neuron.

Conclusions: The aim of the study was to assess the optimal testing parametres of the neuronal response to visual gratings with various luminance, also called the CRF. As technology gets more powerful and potent, one must make choices when experimenting. With a strong model, robust boundaries, and strong experimental conditioning, the best fit to a function can lead to more efficient analysis and stronger cognitive models.

Background: It is well known that the pulvinar establishes reciprocal connections with areas of the visual cortex, allowing the transfer of cortico-cortical signals through transthalamic pathways. However, the exact function of these signals in coordinating activity across the visual cortical hierarchy remains largely unknown. In anesthetized cats, we have explored whether pulvinar inactivation affects the dynamic of interactions between the primary visual cortex (a17) and area 21a, a higher visual cortical area, as well as between layers within each cortical area. We found that pulvinar inactivation modifies the local field potentials (LFPs) coherence between a17 and 21a during a visual stimulation. In addition, the Granger causality analysis showed that the functional connectivity changed across visual areas and between cortical layers during pulvinar inactivation, the effects being stronger in layers of the same area. We observed that the effects of pulvinar inactivation arise at two different epochs of the visual response, i.e., at the early and late components. The proportion of feedback and feedforward functional events was higher during the early and the late phases of the responses, respectively. We also found that pulvinar inactivation facilitates the feedback propagation of gamma oscillations from 21a to a17. This feedback transmission was predominant during the late response. At the temporal level, pulvinar inactivation also delayed the signals from a17 and 21a, depending on the source and the target of the cortical layer. Thus, the pulvinar can not only modify the functional connectivity between intra and inter cortical layers but may also control the temporal dynamics of neuronal activity across the visual cortical hierarchy.

Methods: In vivo electrophysiological recordings of visual cortical areas, area 17 and 21a, in anesthetized cats, were then explored with temporal serial analysis (i.e., Fourier analysis, Coherence, Cross-correlation and Granger causality) of the local field potential.

Results: Inactivation of the thalamic nucleus modifies the dynamics of areas 17 and 21a. The changes observed depends on the source and the target of the cortical layer. The pulvinar inactivation arise at two different epochs of visual response.

Conclusions: The pulvinar modifies the functional connectivity between intra and inter cortical layers and may also control the temporal dynamics of neuronal activity across the visual cortical hierarchy.

Background: It is well known that the pulvinar establishes reciprocal connections with areas of the visual cortex, allowing the transfer of cortico-cortical signals through transthalamic pathways. However, the exact function of these signals in coordinating activity across the visual cortical hierarchy remains largely unknown. In anesthetized cats, we have explored whether pulvinar inactivation affects the dynamic of interactions between the primary visual cortex (a17) and area 21a, a higher visual cortical area, as well as between layers within each cortical area. We found that pulvinar inactivation modifies the local field potentials (LFPs) coherence between a17 and 21a during a visual stimulation. In addition, the Granger causality analysis showed that the functional connectivity changed across visual areas and between cortical layers during pulvinar inactivation, the effects being stronger in layers of the same area. We observed that the effects of pulvinar inactivation arise at two different epochs of the visual response, i.e., at the early and late components. The proportion of feedback and feedforward functional events was higher during the early and the late phases of the responses, respectively. We also found that pulvinar inactivation facilitates the feedback propagation of gamma oscillations from 21a to a17. This feedback transmission was predominant during the late response. At the temporal level, pulvinar inactivation also delayed the signals from a17 and 21a, depending on the source and the target of the cortical layer. Thus, the pulvinar can not only modify the functional connectivity between intra and inter cortical layers but may also control the temporal dynamics of neuronal activity across the visual cortical hierarchy.

Methods: In vivo electrophysiological recordings of visual cortical areas, area 17 and 21a, in anesthetized cats, were then explored with temporal serial analysis (i.e., Fourier analysis, Coherence, Cross-correlation and Granger causality) of the local field potential.

Results: Inactivation of the thalamic nucleus modifies the dynamics of areas 17 and 21a. The changes observed depends on the source and the target of the cortical layer. The pulvinar inactivation arise at two different epochs of visual response.

Conclusions: The pulvinar modifies the functional connectivity between intra and inter cortical layers and may also control the temporal dynamics of neuronal activity across the visual cortical hierarchy.

Background: For years, studies using several animal models have highlighted the predominant role of the primary visual area in visual information processing. Its six cortical layers have morphological, hodological and physiological differences, although their roles regarding the integration of visual contrast and the messages sent by the layers to other brain regions have been poorly explored. Given that cortical layers have distinct properties, this study aims to understand these differences and how they are affected by a changing visual contrast.

Methods: A linear multi-channel electrode was placed in the primary visual cortex (V1) of the anesthetized mouse to record neuronal activity across the different cortical layers. The laminar position of the electrode was verified in real time by measuring the current source density (CSD) and the multi-unit activity (MUA), and confirmed post-mortem by histological analysis. Drifting gratings varying in contrast enabled the measurement of the firing rate of neurons throughout layers. We fitted this data to the Naka-Rushton equations, which generated the contrast response function (CRF) of neurons.

Results: The analysis revealed that the baseline activity as well as the rate of change of neural discharges (the slope of the CRF) had a positive correlation across the cortical layers. In addition, we found a trend between the cortical position and the contrast evoking the semi-saturation of the activity. A significant difference in the maximum discharge rate was also found between layers II/III and IV, as well as between layers II/III and V.

Conclusions: Since layers II/III and V process visual contrast differently, our results suggest that higher cortical visual areas, as well subcortical regions, receive different information regarding a change in visual contrast. Thus, a contrast may be processed differently throughout the different areas of the visual cortex.

Background: For years, studies using several animal models have highlighted the predominant role of the primary visual area in visual information processing. Its six cortical layers have morphological, hodological and physiological differences, although their roles regarding the integration of visual contrast and the messages sent by the layers to other brain regions have been poorly explored. Given that cortical layers have distinct properties, this study aims to understand these differences and how they are affected by a changing visual contrast.

Methods: A linear multi-channel electrode was placed in the primary visual cortex (V1) of the anesthetized mouse to record neuronal activity across the different cortical layers. The laminar position of the electrode was verified in real time by measuring the current source density (CSD) and the multi-unit activity (MUA), and confirmed post-mortem by histological analysis. Drifting gratings varying in contrast enabled the measurement of the firing rate of neurons throughout layers. We fitted this data to the Naka-Rushton equations, which generated the contrast response function (CRF) of neurons.

Results: The analysis revealed that the baseline activity as well as the rate of change of neural discharges (the slope of the CRF) had a positive correlation across the cortical layers. In addition, we found a trend between the cortical position and the contrast evoking the semi-saturation of the activity. A significant difference in the maximum discharge rate was also found between layers II/III and IV, as well as between layers II/III and V.

Conclusions: Since layers II/III and V process visual contrast differently, our results suggest that higher cortical visual areas, as well subcortical regions, receive different information regarding a change in visual contrast. Thus, a contrast may be processed differently throughout the different areas of the visual cortex.

Background: Decrease of ocular blood flow has been linked to the pathogenesis of ocular diseases such as glaucoma and age-related macular degeneration. Current methods that measure the pulsatile blood flow have major limitations, including the assumption that ocular rigidity is the same in all eyes. Our group has recently developed a new method to measure the pulsatile choroidal volume change by direct visualization of the choroid with OCT imaging and automated segmentation. Our goal in this study is to describe the distribution of PCBF in a healthy Caucasian population.

Methods: Fifty-one subjects were recruited from the Maisonneuve-Rosemont Hospital Ophthalmology Clinic and underwent PCBF measurement in one eye. The distribution of PCBF in healthy eyes was assessed.

Results: The distribution of PCBF among the healthy eyes was found to be 3.94±1.70 μL with this technique.

Conclusions: This study demonstrates the normal range of PCBF values obtained in a healthy Caucasian population. This technique could be used for further investigation of choroid pulsatility and to study glaucoma pathophysiology.

Background: Decrease of ocular blood flow has been linked to the pathogenesis of ocular diseases such as glaucoma and age-related macular degeneration. Current methods that measure the pulsatile blood flow have major limitations, including the assumption that ocular rigidity is the same in all eyes. Our group has recently developed a new method to measure the pulsatile choroidal volume change by direct visualization of the choroid with OCT imaging and automated segmentation. Our goal in this study is to describe the distribution of PCBF in a healthy Caucasian population.

Methods: Fifty-one subjects were recruited from the Maisonneuve-Rosemont Hospital Ophthalmology Clinic and underwent PCBF measurement in one eye. The distribution of PCBF in healthy eyes was assessed.

Results: The distribution of PCBF among the healthy eyes was found to be 3.94±1.70 μL with this technique.

Conclusions: This study demonstrates the normal range of PCBF values obtained in a healthy Caucasian population. This technique could be used for further investigation of choroid pulsatility and to study glaucoma pathophysiology.

Background: Zellweger spectrum disorder (ZSD) is an autosomal recessive disease caused by mutations in any one of 13 PEX genes whose protein products are required for peroxisome assembly. Retinopathy leading to blindness is one of the major handicaps faced by affected individuals, but treatment for this is supportive only. To test whether we could improve visual function in ZSD, we performed a proof-of-concept trial for PEX1 gene augmentation therapy using the Pex1-G844D mouse model, which bears the equivalent to a common human mutation. This model exhibits a gradual decline in scotopic ffERG response, an always residual photopic ffERG response, diminished visual acuity, and cone and bipolar cell anomalies.

Methods: We administered subretinal injections of a PEX1-containing viral vector (AAV8.CMV.hPEX1.HA) to 2 mouse cohorts of 5 or 9 weeks of age. A GFP-containing vector was used as a control in the contralateral eye of each animal. Efficient expression of the virus was confirmed by retinal histology/immunohistochemistry, and its ability to recover peroxisome import was confirmed in vitro. Preliminary ffERG and optokinetic (OKN) analyses were performed on a subset of animals at 8, 16, and 20 weeks after gene delivery. Final ffERG and OKN measures were performed when each cohort reached 32 weeks of age (23 or 27 weeks post injection).

Results: Preliminary ffERG and OKN analyses at 8 weeks post injection showed mildly better retinal response and visual acuity, respectively, in the PEX1-injected eyes, as did ffERG analysis when each cohort reached 25 weeks of age (16 or 20 weeks after gene delivery). This effect was more pronounced in the cohort treated at 5 weeks of age, when ffERG response is highest in Pex1-G844D mice. At 32 weeks of age, the ffERG response in the PEX1-injected eyes was double that of GFP-injected eyes, on average, though there was no change in OKN. Furthermore, in PEX1-injected eyes the photopic ffERG response improved over time, and the decline in scotopic b-wave amplitude was ameliorated compared to un-injected eyes.

Conclusions: AAV8.CMV.hPEX1.HA was subretinally delivered into the left eye of 5- and 9-week-old Pex1-G844D retina. Successful expression of the protein with no gross histologic side effect was observed. Neither the injection, nor exposure to the AAV8 capsid or the transgenic protein negatively altered the ERG or OKN response. At 5–6 months after gene delivery, therapeutic vector-treated eyes showed improved ERG compared to control eyes, on average, in both the “prevention” and “recovery” cohorts. This implies clinical potential of gene delivery to improve vision in patients with ZSD. Retinal immunohistochemistry (to visualize retinal cell types) and biochemical analyses will be performed on treated and untreated retinas, and may inform the mechanism of ERG improvement.

Background: Zellweger spectrum disorder (ZSD) is an autosomal recessive disease caused by mutations in any one of 13 PEX genes whose protein products are required for peroxisome assembly. Retinopathy leading to blindness is one of the major handicaps faced by affected individuals, but treatment for this is supportive only. To test whether we could improve visual function in ZSD, we performed a proof-of-concept trial for PEX1 gene augmentation therapy using the Pex1-G844D mouse model, which bears the equivalent to a common human mutation. This model exhibits a gradual decline in scotopic ffERG response, an always residual photopic ffERG response, diminished visual acuity, and cone and bipolar cell anomalies.

Methods: We administered subretinal injections of a PEX1-containing viral vector (AAV8.CMV.hPEX1.HA) to 2 mouse cohorts of 5 or 9 weeks of age. A GFP-containing vector was used as a control in the contralateral eye of each animal. Efficient expression of the virus was confirmed by retinal histology/immunohistochemistry, and its ability to recover peroxisome import was confirmed in vitro. Preliminary ffERG and optokinetic (OKN) analyses were performed on a subset of animals at 8, 16, and 20 weeks after gene delivery. Final ffERG and OKN measures were performed when each cohort reached 32 weeks of age (23 or 27 weeks post injection).

Results: Preliminary ffERG and OKN analyses at 8 weeks post injection showed mildly better retinal response and visual acuity, respectively, in the PEX1-injected eyes, as did ffERG analysis when each cohort reached 25 weeks of age (16 or 20 weeks after gene delivery). This effect was more pronounced in the cohort treated at 5 weeks of age, when ffERG response is highest in Pex1-G844D mice. At 32 weeks of age, the ffERG response in the PEX1-injected eyes was double that of GFP-injected eyes, on average, though there was no change in OKN. Furthermore, in PEX1-injected eyes the photopic ffERG response improved over time, and the decline in scotopic b-wave amplitude was ameliorated compared to un-injected eyes.

Conclusions: AAV8.CMV.hPEX1.HA was subretinally delivered into the left eye of 5- and 9-week-old Pex1-G844D retina. Successful expression of the protein with no gross histologic side effect was observed. Neither the injection, nor exposure to the AAV8 capsid or the transgenic protein negatively altered the ERG or OKN response. At 5–6 months after gene delivery, therapeutic vector-treated eyes showed improved ERG compared to control eyes, on average, in both the “prevention” and “recovery” cohorts. This implies clinical potential of gene delivery to improve vision in patients with ZSD. Retinal immunohistochemistry (to visualize retinal cell types) and biochemical analyses will be performed on treated and untreated retinas, and may inform the mechanism of ERG improvement.

Background: Retinal pigment epithelium (RPE) is vital for the homeostasis of the subretina including photoreceptors and choroid. Interestingly, our previous results suggested that the recently discovered lactate receptor GPR81 is abundantly expressed in RPE. To date, only one previous study has shown that activating GPR81 could enhance DNA repair by activating HDAC1. Consequently, we investigated whether GPR81 exhibits epigenetic modification in the subretina by using GPR81?/? mice.

Methods: GPR81?/? mice and wide type littermates were generated on a background of C57BL/6J mice. The thicknesses of their choroid were evaluated by immunohistochemistry. Meanwhile, Q-PCR, western blot and choroid sprout assay were performed. In vitro, primary retinal pigment epithelium (pRPE) cells were isolated from mice, and cultured for treatments.

Results: The thickness of choroid was reduced in GPR81?/? mice compared to GPR81+/+ mice, suggesting that GPR81 is important for the integrity of choroid. In the choroid sprout assay, lactate treated RPE/choroid complex showed a significant increase in angiogenesis compared to controls while lactate treated KO RPE/choroid complex showed no difference compared to their controls. For Q-PCR, most of the genes screened elevated their expression in GPR81?/? mice compared to WT mice, suggesting epigenetic modification may exist, which were confirmed by histone acetylation and HDACs activity assay.

Conclusions: Taking together, the lactate receptor GPR81 in RPE is very important for maintaining homeostasis of the subretina. This novel discovery sheds new light on the relationship between metabolism and epigenetic modification.

Background: Retinal pigment epithelium (RPE) is vital for the homeostasis of the subretina including photoreceptors and choroid. Interestingly, our previous results suggested that the recently discovered lactate receptor GPR81 is abundantly expressed in RPE. To date, only one previous study has shown that activating GPR81 could enhance DNA repair by activating HDAC1. Consequently, we investigated whether GPR81 exhibits epigenetic modification in the subretina by using GPR81?/? mice.

Methods: GPR81?/? mice and wide type littermates were generated on a background of C57BL/6J mice. The thicknesses of their choroid were evaluated by immunohistochemistry. Meanwhile, Q-PCR, western blot and choroid sprout assay were performed. In vitro, primary retinal pigment epithelium (pRPE) cells were isolated from mice, and cultured for treatments.

Results: The thickness of choroid was reduced in GPR81?/? mice compared to GPR81+/+ mice, suggesting that GPR81 is important for the integrity of choroid. In the choroid sprout assay, lactate treated RPE/choroid complex showed a significant increase in angiogenesis compared to controls while lactate treated KO RPE/choroid complex showed no difference compared to their controls. For Q-PCR, most of the genes screened elevated their expression in GPR81?/? mice compared to WT mice, suggesting epigenetic modification may exist, which were confirmed by histone acetylation and HDACs activity assay.

Conclusions: Taking together, the lactate receptor GPR81 in RPE is very important for maintaining homeostasis of the subretina. This novel discovery sheds new light on the relationship between metabolism and epigenetic modification.