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This is one of four prestigious prizes for advances in neuroscience supported by the British Neuroscience Associations (BNA) and the Israel Society for Neuroscience (ISFN).
Early-Onset Cone Photoreceptor Degeneration Is Associated With High Myopia in RPGR-Related Retinal Dystrophy.
Purpose: High myopia is a feature of several inherited retinal diseases, including X-linked retinitis pigmentosa (XLRP) which is characterized by childhood onset, centripetal photoreceptor degeneration, and rapid progression to blindness by the fourth decade. Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene cause over 90% of XLRP cases. It presents with a varied clinical phenotype, categorized into the predominant rod-cone, cone-rod, and cone dystrophy. This case-series study examines the clinical characteristics of patients with RPGR-related retinal dystrophy to identify associations with refractive error. Methods: Data collected between October 2023 and April 2024 from retinal imaging, clinical ophthalmic examination, and genetic analysis were retrospectively analyzed. Results: Twenty-four male patients were identified, with a mean age of 30 years (range 7-57). The median (IQR) best-corrected visual acuity was 60 (55-66) letters in the cone-rod/cone phenotype and 65 (49-73) letters in the rod-cone phenotype. High axial myopia showed preponderance in cone-dominated degenerations. Estimated mean refractive error was -7.92DS (95% CI: [-11.39, -4.44]) in the cone-rod phenotype and -3.52DS (95% CI: [-5.87, -1.17]) in the rod-cone phenotype, adjusting for age and genetic mutation. This difference between phenotype was significant (p=0.041). In a subanalysis, no significant association was found between refractive error and nucleotide position. Evaluation of disease progression found that all patients with a fast-progressing, rod-cone phenotype had high myopia. Conversely, one patient who presented with a slow-progressing, cone-rod phenotype did not have high myopia. Conclusions: Refractive trends in this cohort suggest that cone photoreceptor degeneration occurring during early childhood is associated with high myopia. Image degradation primarily due to cone photoreceptor dysfunction may act as a stimulus to drive myopia development in early childhood. These observations advocate for the earlier treatment of myopia in cone-dominated RPGR-related retinal dystrophy to preserve retinal function and minimize the risks of retinal gene therapy surgery for patients enrolling in clinical trials. Trial Registration: ClinicalTrials.gov identifier: NCT03116113.
A cognitive map for value-guided choice in the ventromedial prefrontal cortex.
The prefrontal cortex (PFC) is crucial for economic decision-making. However, how PFC value representations facilitate flexible decisions remains unknown. We reframe economic decision-making as a navigation process through a cognitive map of choice values. We found rhesus macaques represented choices as navigation trajectories in a value space using a grid-like code. This occurred in ventromedial PFC (vmPFC) local field potential theta frequency across two datasets. vmPFC neurons deployed the same grid-like code and encoded chosen value. However, both signals depended on theta phase: occurring on theta troughs but on separate theta cycles. Finally, we found sharp-wave ripples-a key signature of planning and flexible behavior-in vmPFC. Thus, vmPFC utilizes cognitive map-based computations to organize and compare values, suggesting an alternative architecture for economic choice in PFC.
Neural mechanisms of credit assignment for delayed outcomes during contingent learning.
Adaptive behavior in complex environments critically relies on the ability to appropriately link specific choices or actions to their outcomes. However, the neural mechanisms that support the ability to credit only those past choices believed to have caused the observed outcomes remain unclear. Here, we leverage multivariate pattern analyses of functional magnetic resonance imaging (fMRI) data and an adaptive learning task to shed light on the underlying neural mechanisms of such specific credit assignment. We find that the lateral orbitofrontal cortex (lOFC) and hippocampus (HC) code for the causal choice identity when credit needs to be assigned for choices that are separated from outcomes by a long delay, even when this delayed transition is punctuated by interim decisions. Further, we show when interim decisions must be made, learning is additionally supported by lateral frontopolar cortex (lFPC). Our results indicate that lFPC holds previous causal choices in a 'pending' state until a relevant outcome is observed, and the fidelity of these representations predicts the fidelity of subsequent causal choice representations in lOFC and HC during credit assignment. Together, these results highlight the importance of the timely reinstatement of specific causes in lOFC and HC in learning choice-outcome relationships when delays and choices intervene, a critical component of real-world learning and decision making.
A tale of two algorithms: Structured slots explain prefrontal sequence memory and are unified with hippocampal cognitive maps.
Remembering events is crucial to intelligent behavior. Flexible memory retrieval requires a cognitive map and is supported by two key brain systems: hippocampal episodic memory (EM) and prefrontal working memory (WM). Although an understanding of EM is emerging, little is understood of WM beyond simple memory retrieval. We develop a mathematical theory relating the algorithms and representations of EM and WM by unveiling a duality between storing memories in synapses versus neural activity. This results in a formalism of prefrontal WM as structured, controllable neural subspaces (activity slots) representing dynamic cognitive maps without synaptic plasticity. Using neural networks, we elucidate differences, similarities, and trade-offs between the hippocampal and prefrontal algorithms. Lastly, we show that prefrontal representations in tasks from list learning to cue-dependent recall are unified as controllable activity slots. Our results unify frontal and temporal representations of memory and offer a new understanding for dynamic prefrontal representations of WM.
An Analysis of Scotopic Microperimetry in Healthy Adults.
PurposeScotopic microperimetry measures retinal sensitivity under very low light and may be useful in conditions characterized by nyctalopia, such as retinitis pigmentosa and age-related macular degeneration. The Scotopic Macular Integrity Assessment device enables two-color perimetry to isolate rod and cone responses. This study assesses the reliability, test-retest repeatability, and sensitivity in healthy participants aiming to establish normative values.MethodsScotopic microperimetry was performed using cyan and red stimuli on a 37-point radial grid after dark adaptation on control participants with no history of eye disease and visual acuity of 0.1 logarithm of the minimum angle of resolution or better. Fixation stability, fixation losses, and identification of the rod-free zone were used as reliability metrics. A subset underwent repeat testing within 4 weeks.ResultsThirty-nine participants (19 male and 20 female), median age 24 years (interquartile range, 9.5 years) and 23 years (interquartile range, 9 years) for the right and left eyes, respectively, completed testing. Overall 77 eyes underwent scotopic testing, with 82% meeting reliability criteria. Mean cyan and red sensitivities were 19.9 ± 1.1 dB and 20.9 ± 1.2 dB in right eyes, and 20.1 ± 1.4 dB and 21.3 ± 1.4 dB in left eyes, respectively. Volumetric cyan and red sensitivities were 2868 ± 157 dB.deg2 and 3077 ± 176 dB.deg2 in the right eyes, respectively, and 2892 ± 205 dB.deg2 and 3126 ± 207 dB.deg2 in the left eyes, respectively. Mean sensitivity coefficients of repeatability (CoR) were ± 1.4 dB (cyan) and ± 2.1 dB (red) while pointwise coefficients of repeatability were ± 7.2 dB (95% confidence interval, 6.5-7.6 dB) for cyan and ± 7.9 dB (95% confidence interval, 7.3-8.4 dB) for red, with no significant differences between eyes or genders. Fixation stability assessed using the 95% bivariate contour ellipse area for cyan was 2.9 ± 5.9 deg2 and 2.3 ± 2.2 deg2 for the right and left eyes, respectively, and for red were 0.7 ± 0.6 deg2 and 0.9 ± 0.8 deg2 for the right and left eyes, respectively. Again, there were no significant differences between cyan and red tests (Friedman test, bivariate contour ellipse area 63%, P = 0.455; bivariate contour ellipse area 95%, P = 0.432).ConclusionsScotopic microperimetry using the Scotopic Macular Integrity Assessment device was feasible and well-tolerated. Repeatability metrics demonstrated limitations in fine spatial mapping of scotopic retinal sensitivity.Translational relevanceThis study highlights potential areas for future improvements in scotopic microperimetry before its use as an outcome measure in clinical trials for retinal disease.
Constructing future behavior in the hippocampal formation through composition and replay.
The hippocampus is critical for memory, imagination and constructive reasoning. Recent models have suggested that its neuronal responses can be well explained by state spaces that model the transitions between experiences. Here we use simulations and hippocampal recordings to reconcile these views. We show that if state spaces are constructed compositionally from existing building blocks, or primitives, hippocampal responses can be interpreted as compositional memories, binding these primitives together. Critically, this enables agents to behave optimally in new environments with no new learning, inferring behavior directly from the composition. We predict a role for hippocampal replay in building and consolidating these compositional memories. We test these predictions in two datasets by showing that replay events from newly discovered landmarks induce and strengthen new remote firing fields. When the landmark is moved, replay builds a new firing field at the same vector to the new location. Together, these findings provide a framework for reasoning about compositional memories and demonstrate that such memories are formed in hippocampal replay.
Exploring standard and low luminance visual acuity and the Moorfields Acuity Chart as outcome measures in inherited retinal disease
AbstractIntroductionStandard visual acuity (VA) is often insensitive to subtle changes in vision that result from inherited retinal disease. Low luminance VA (LLVA) has grown in popularity as an alternative acuity measure. A new test, the Moorfields Acuity Chart (MAC) has been designed as a more sensitive and repeatable test for use in patients with age‐related macular degeneration. The study explores the utility and repeatability of standard VA, LLVA and the MAC in a mixed cohort of patients with inherited retinal disease.MethodsParticipants were recruited as part of the visual function in retinal degeneration study (Ethics Reference 20/WM/0283). Standard VA was obtained using the Early Treatment of Diabetic Retinopathy study (ETDRS) chart placed at 4 m. LLVA was obtained using the same ETDRS chart with the addition of a 2.0‐log unit neutral density filter. MAC VA was obtained using standard clinic room lighting. All participants completed repeated testing.ResultsThirty‐five patient participants and 36 healthy controls, with logMAR 1.00 (6/60) or better, completed testing. Both LLVA and MAC VA were reduced compared to standard VA in patient participants and healthy controls (linear mixed model: p < 0.001). All three acuity tests show comparable sensitivity, specificity and repeatability. A subset of participants (patient participants n = 34, healthy controls n = 35) completed microperimetry. Post hoc analysis of microperimetry volume sensitivity correlated significantly with all of the acuity tests and showed no significant difference in the gradient of the slopes. This suggests that VA, LLVA and MAC VA decline at a consistent rate with disease progression.ConclusionAll three acuity tests could be considered viable outcome measures for clinical trials. For patients with early to moderate inherited retinal disease (logMAR 1.00 (6/60) or better), no single acuity chart appeared significantly beneficial.
Permissive central tolerance plus defective peripheral checkpoints license pathogenic memory B cells in CASPR2-antibody encephalitis
Autoantibody-mediated diseases targeting one autoantigen provide a unique opportunity to comprehensively understand the development of disease-causing B cells and autoantibodies. Convention suggests that such autoreactivities are generated during germinal center reactions. Here, we explore earlier immune checkpoints, focusing on patients with contactin-associated protein-like 2 (CASPR2)–autoantibody encephalitis. In both disease and health, high (~0.5%) frequencies of unmutated CASPR2-reactive naïve B cells were identified. By contrast, CASPR2-reactive memory B cells were exclusive to patients, and their B cell receptors demonstrated affinity-enhancing somatic mutations with pathogenic effects in neuronal cultures and mice. The unmutated, precursor memory B cell receptors showed a distinctive balance between strong CASPR2 reactivity and very limited binding across the remaining human proteome. Our results identify permissive central tolerance, defective peripheral tolerance, and autoantigen-specific tolerance thresholds in humans as sequential steps that license CASPR2-directed pathology. By leveraging the basic immunobiology, we rationally direct tolerance-restoring approaches, with an experimental paradigm applicable across autoimmunity.
Neuronal pSTAT1 hallmarks synaptic pathology in autoimmune encephalitis against intracellular antigens.
Autoimmune encephalitis (AE) is an inflammatory syndrome of the central nervous system (CNS) triggered by aberrant immune responses against neuronal intracellular (IC-AE) or surface (NS-AE) autoantigens. The resulting neuronal alterations and clinical trajectories differ, with IC-AE often leading to fatal outcomes. Unfortunately, the scarce availability of tissue from AE cases has hampered systematic analyses that would allow an understanding of the pathogenesis underlying neuronal alterations in T cell-mediated AE syndromes. Here, we assembled a cohort comprising both NS-AE (n = 8) and IC-AE (n = 12) from multiple institutions to delineate key histopathological features that distinguish neuronal pathology between IC-AE and NS-AE. In contrast to NS-AE, IC-AE lesions present a prominent neuronal pSTAT1 signature, accompanied by a high proportion of brain-resident memory CD8 + T cells and neurodegenerative GPNMB + phagocytes which show synaptic engulfment with little C3-complement deposition. Our findings highlight distinct histopathological features of IC-AE compared to NS-AE, providing actionable biomarkers for diagnostics and treatment strategies.