Biology subjects

McKinnon, C.

Publications and source records attributed to McKinnon, C..

4 recordsLinked to original sources

bioRxiv2025

Disruption of transthalamic circuitry from primary visual cortex impairs visual discrimination in mice

Layer 5 (L5) of the cortex provides strong driving input to higher-order thalamic nuclei, such as the pulvinar in the visual system, forming the basis of cortico-thalamo-cortical (transthalamic) circuits. These circuits provide a communication route between cortical areas in parallel to direct corticocortical connections, but their specific role in perception and behavior remains unclear. Using targeted optogenetic inhibition in mice performing a visual discrimination task, we selectively suppressed the corticothalamic input from L5 cells in primary visual cortex (V1) at their terminals in pulvinar. This suppresses transthalamic circuits from V1; furthermore, any effect on direct corticocortical projections and local V1 circuitry would thus result from transthalamic inputs (e.g., V1 to pulvinar back to V1 (Miller-Hansen and Sherman, 2022). Such suppression of transthalamic processing during visual stimulus presentation of drifting gratings significantly impaired discrimination performance across different orientations. The impact on behavior was specific to the portion of visual space that retinotopically coincided with the V1 L5 corticothalamic inhibition. These results highlight the importance of incorporating L5-initiated transthalamic circuits into cortical processing frameworks, particularly those addressing how the hierarchical propagation of sensory signals supports perceptual decision-making. SIGNIFICANCE STATEMENTAppreciation of pathways for transthalamic communication between cortical areas, organized in parallel with direct connections, has transformed our thinking about cortical functioning writ large. Studies of transthalamic pathways initially concentrated on their anatomy and physiology, but there has been a shift towards understanding their importance to cognitive behavior. Here, we have used an optogenetic approach in mice to selectively inhibit the transthalamic pathway from primary visual cortex to other cortical areas and back to itself. We find that such inhibition degrades the animals ability to discriminate, showing for the first time that specific inhibition of visual transthalamic circuitry reduces visual discrimination. This causal data adds to the growing evidence for the importance of transthalamic signaling in perceptual processing.

neuroscience↗

bioRxiv2023

A framework for decolonising and diversifying biomedical sciences curricula: rediscovery, representation and readiness

To date, most efforts to decolonise curricula have focussed on the arts and humanities, with many believing that science subjects are objective, unbiased, and unaffected by colonial legacies. However, research is shaped by cultural and historical context, and inequities exist in funding, publishing and acknowledging scientific achievements. Our curricula reflect these inequities, perpetuating bias to future generations of scientists. We examined attitudes and understanding towards decolonising and diversifying the curriculum among students and teaching staff in the biomedical sciences at the University of Bristol, to discover whether our current teaching practice is perceived as inclusive. We used a mixed methods study including surveys of staff (N=71) and students (N=121) and focus groups. Quantitative data showed that staff and students think decolonising the curriculum is important, but this is more important to female respondents (p<0.001). Students are less aware than staff of current efforts to decolonise the curriculum, while students from minority ethnic groups feel less represented by the curriculum than white students. Thematic analysis of qualitative data revealed three themes that are important for a decolonised curriculum: rediscovery, representation and readiness. We propose that this 3Rs framework could guide future efforts to decolonise and diversify the curriculum in the biomedical sciences and beyond.

scientific communication and education↗

bioRxiv2023

A transthalamic pathway is crucial for stimulus feature selectivity in higher order cortex

Perception arises from activity between cortical areas, first primary cortex and then higher order cortices. This communication is served in part by transthalamic (cortico-thalamo-cortical) pathways, which ubiquitously parallel direct corticocortical pathways, but their role in sensory processing has largely remained unexplored. Here, we show that the transthalamic pathway linking somatosensory cortices propagates task-relevant information required for correct sensory decisions. Using optogenetics, we specifically inhibited the pathway at its synapse in higher order somatosensory thalamus of mice performing a texture-based discrimination task. We concurrently monitored the cellular effects of inhibition in primary or secondary cortex using two-photon calcium imaging. Inhibition severely impaired performance despite intact direct corticocortical projections, thus challenging the purely corticocentric map of perception. Interestingly, the inhibition did not reduce overall cell responsiveness to texture stimulation in somatosensory cortex, but rather disrupted the texture selectivity of cells, a discriminability that develops over task learning. This discriminability was more disrupted in the secondary than primary somatosensory cortex, emphasizing the feedforward influence of the transthalamic route. Transthalamic pathways thus appear critical in delivering performance-relevant information to higher order cortex and are critical hierarchical pathways in perceptual decision-making.

neuroscience↗

bioRxiv2020

The deubiquitylase USP9X controls ribosomal stalling

When a ribosome stalls during translation, it runs the risk of collision with a trailing ribosome. Such an encounter leads to the formation of a stable di-ribosome complex, which needs to be resolved by a dedicated machinery. The initial stalling and the subsequent resolution of di-ribosomal complexes requires activity of Makorin and ZNF598 ubiquitin E3 ligases respectively, through ubiquitylation of the eS10 and uS10 sub-units of the ribosome. It is common for the stability of RING E3 ligases to be regulated by an interacting deubiquitylase (DUB), which often opposes auto-ubiquitylation of the E3. Here, we show that the DUB USP9X directly interacts with ZNF598 and regulates its abundance through the control of protein stability in human cells. We have developed a highly specific small molecule inhibitor of USP9X. Proteomics analysis, following inhibitor treatment of HCT116 cells, confirms previous reports linking USP9X with centrosome associated protein stability and reveals loss of ZNF598 and Makorin 2. In the absence of USP9X or following chemical inhibition of its catalytic activity, steady state levels of Makorins and ZNF598 are diminished and the ribosomal quality control pathway is impaired.

cell biology↗