Biology subjects

Luo, J. K.

Publications and source records attributed to Luo, J. K..

3 recordsLinked to original sources

bioRxiv2025

A cholinergic mechanism orchestrating task-dependent computation across the cortex

In an ever-changing environment, animals often need to switch between performing different tasks involving distinct sets of cognitive processes. Many such tasks involve neural activity distributed across the cortex, with dynamics that depend on both task demands and behavioral strategy1-17. A fundamental but unanswered question is what circuit mechanisms orchestrate these task-dependent dynamics. Here, we hypothesized that acetylcholine release in the cortex plays a key role. The cortexs only long-range source of this neuromodulator is the basal forebrain cholinergic system, which targets the entire cortical sheet and can individually modulate single regions on sub-second timescales18-26. To test our hypothesis, we first imaged cholinergic axons innervating the cortex while mice switched frequently between two navigational decision-making tasks in virtual reality (VR), only one of which required gradual accumulation of sensory evidence. We found that cholinergic input to the cortex is spatiotemporally heterogeneous and multiplexes sensory, motor, arousal, and cognitive signals in a task- and strategy-dependent fashion, with overall higher activity during evidence accumulation. Crucially, beyond contextual variables, cholinergic activity directly tracked task computations themselves, encoding an evidence-dependent decision variable only in the accumulation task. To test if acetylcholine release is causal to the performance of each task, we optogenetically silenced cholinergic terminals in the cortex while simultaneously imaging excitatory cortical activity. We found that this input is selectively required for evidence accumulation, and for large-scale cortical coding of evidence and choice during the accumulation task. Thus, we have identified a new cholinergic mechanism that orchestrates cortex-wide activity in a task-dependent manner and serves as a key node in the distributed brain network underlying the accumulation of sensory evidence.

neuroscience↗

bioRxiv2025

Cognitive processes are disentangled at cortex-wide scales

Most decisions involve multiple cognitive processes. Recent findings suggest that these processes are distributed across the cortex1-21, but that single regions implement them via orthogonal population-activity patterns14,21-33. How are these local geometries combined across the cortex? Here, we designed a virtual-navigation task for mice that dissociates the accumulation and short-term memory of sensory evidence, and choice. Combining dimensionality reduction and decoding models with cortex-wide widefield Ca2+ imaging, we observed distributed but near-orthogonal coding subspaces for these different cognitive processes, and that this geometry breaks down during erroneous choices. Further, only the memory subspace corresponded to a spontaneous activity-timescale hierarchy, suggesting that it co-opts intrinsic circuit properties. Thus, we reconcile previous findings by showing that cortex-wide dynamics supporting distinct cognitive processes are disentangled.

neuroscience↗

bioRxiv2021

Postsynaptic neuroligin-1 mediates presynaptic endocytosis during neuronal activity

Fast, high-fidelity neurotransmission and synaptic efficacy requires tightly regulated coordination of pre- and postsynaptic compartments and alignment of presynaptic release sites with postsynaptic receptor nanodomains. Neuroligin-1 (Nlgn-1) is a postsynaptic cell-adhesion protein exclusively localised to excitatory synapses that is crucial for coordinating the transsynaptic alignment of presynaptic release sites with postsynaptic AMPA receptors as well as postsynaptic transmission and plasticity. However, little is understood about whether the postsynaptic machinery can mediate the molecular architecture and activity of the presynaptic nerve terminal, and thus it remains unclear whether there are presynaptic contributions to Nlgn1-dependent control of signalling and plasticity. Here, we employed a presynaptic reporter of neurotransmitter release and synaptic vesicle dynamics, synaptophysin-pHluorin (sypHy), to directly assess the presynaptic impact of loss of Nlgn1. We show that lack of Nlgn1 had no effect on the size of the readily releasable or entire recycling pool of synaptic vesicles, nor did it impact exocytosis. However, we observed significant changes in the retrieval of synaptic vesicles by compensatory endocytosis, specifically during activity. Our data extends growing evidence that synaptic adhesion molecules critical for forming transsynaptic scaffolds are also important for regulating activity-induced endocytosis at the presynapse.

neuroscience↗