Biology subjects

Wills, T.

Publications and source records attributed to Wills, T..

5 recordsLinked to original sources

bioRxiv2026

Targeting melanosome pH is an effective method for the treatment of oculocutaneous albinism

Oculocutaneous albinism (OCA) is a genetic condition associated with impaired visual acuity and increased skin cancer risk. When OCA is due to defects in melanosome ion transport, abnormally acidic conditions in the melanosome lumen inhibit tyrosinase, the critical pigment synthetic enzyme. Hence, a therapeutic approach that optimizes melanosome pH to increase pigment production presents a potential treatment for OCA and a method for decreasing skin cancer risk. Here, we report that reduction in sAC (ADCY10) activity via naturally occurring human variants in ADCY10 restores OCA pigmentation, and sAC inhibition increases melanin synthesis in both human and mouse OCA models. These findings demonstrate that targeting melanosome pH is an effective, previously untapped therapeutic strategy for OCA and elevated skin cancer risk.

physiology↗

bioRxiv2024

Unifying Subicular Function: A Predictive Map Approach

The successor representation has emerged as a powerful model for understanding mammalian navigation and memory; explaining the spatial coding properties of hippocampal place cells and entorhinal grid cells. However, the diverse spatial responses of subicular neurons, the primary output of the hippocampus, have eluded a unified account. Here, we demonstrate that incorporating rodent behavioural biases into the successor representation successfully reproduces the heterogeneous activity patterns of subicular neurons. This framework accounts for the emergence of boundary and corner cells - neuronal types absent in upstream hippocampal regions. We provide evidence that subicular firing patterns are more accurately described by the successor representation than a purely spatial or boundary vector cell model of subiculum. Our work reveals a temporal hierarchy in hippocampal-subicular processing, with subiculum encoding predictive representations over longer time horizons than CA1, capturing extended behavioural patterns and environmental affordances.

neuroscience↗

bioRxiv2024

Repix: reliable, reusable, versatile chronic Neuropixels implants using minimal components

Neuropixels probes represent the state-of-the-art for high-yield electrophysiology in neuroscience: the simultaneous recording of hundreds of neurons is now routinely carried out in head-restrained animals. In contrast, neural recording in unrestrained animals, as well as recording and tracking neurons over days, remains challenging, though it is possible using chronic implants. A major challenge is the availability of simple methods that can be implemented with limited or no prior experience with Neuropixels probes, while achieving reliable, reusable, versatile high-density electrophysiology. Here we developed, deployed, and evaluated the real-world performance of Repix, a chronic implantation system that permits the repeated re-use of Neuropixels probes. The lightweight system allows implanted animals to express a full range of natural behaviors, including social behaviors. We show that Repix allows the recording of hundreds of neurons across many months, up to a year, with implants across cortical and subcortical brain regions. Probes can be reused repeatedly with stable yield. Repix has been used by 16 researchers in 10 laboratories to date, and we evaluated the real-world performance of Repix in a variety of chronic recording paradigms in both mice and rats with a combined 209 implantations. We found that the key advantage of Repix is robustness and simplicity. Adopters of Repix became proficient at five procedures on average, regardless of prior experience with in vivo electrophysiology. With the companion protocol alongside this article, the performance and user-friendliness of Repix should facilitate a wide uptake of chronic Neuropixels recordings.

neuroscience↗

bioRxiv2023

Visual boundary cues, alone, can anchor place and grid cells in virtual reality

The hippocampal formation contains neurons responsive to an animals current location and orientation, which together provide the organism with a neural map of space1-3. Spatially tuned neurons rely on external landmark cues and internally generated movement information to estimate position4,5. An important class of landmark cue are the boundaries delimiting an environment, which can define place cell field position6,7 and stabilise grid cell firing8. However, the precise nature of the sensory information used by the hippocampus to detect boundaries remains unknown. Here we use 2-dimensional virtual reality (VR)9 to show that purely visual cues from the surrounding walls are both sufficient and necessary to stabilise place and grid cell responses. Unstable grid cells retain internally coherent, hexagonally arranged firing fields, but these fields drift with respect to the virtual environment over periods >5 sec. Optic flow from a virtual floor does not slow drift dynamics, emphasising the importance of boundary-related visual information. Surprisingly, place fields are more stable close to boundaries even when these are invisible. Invisible boundary locations can only be inferred from the relative movements of the animal and a reward beacon, specifically, from the mismatch between observed beacon movement and that predicted from motor output. This shows that boundary information can be detected through sensorimotor feedback. We find that subsets of place cells show allocentric directional tuning towards the beacon, with strength of tuning correlating with place field stability when boundaries are removed.

neuroscience↗

bioRxiv2019

Vector Trace cells in the Subiculum of the Hippocampal formation

Successfully navigating in physical or semantic space requires a neural representation of allocentric (map-based) vectors to boundaries, objects, and goals. Cognitive processes such as path-planning and imagination entail recall of vector representations, but evidence of neuron-level memory for allocentric vectors has been lacking. Here we describe a novel neuron type (Vector Trace cell, VTC) whose firing generates a new vector field when a cue is encountered, and also a trace version of that field for hours after cue removal. VTCs are concentrated in subiculum distal to CA1. Compared to non-trace cells, VTCs fire at further distances from cues, and exhibit earlier-going shifts in preferred theta phase in response to newly introduced cues, demonstrating a theta-linked neural substrate for memory encoding. VTCs suggest a vector-based model of computing spatial relationships between an agent and multiple spatial objects, or between different objects, freed from the constraints of direct perception of those objects.

neuroscience↗