Salvino, P. | bioRxiv Science

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↗

bioRxiv2021

Decreased overall neuronal activity in a rodent model of impaired consciousness during absence seizures

Absence seizures are characterized by a brief behavioural impairment including apparent loss of consciousness. Neuronal mechanisms determining the behavioural impairment of absence seizures remain unknown, and their elucidation might highlight therapeutic options for reducing seizure severity. However, recent studies have questioned the similarity of animal spike-wave-discharges (SWD) to human absence seizures both behaviourally and neuronally. Here, we report that Genetic Absence Epilepsy Rats from Strasbourg recapitulate the decreased neuroimaging signals and loss of consciousness characteristic of human absence seizures. Overall neuronal firing is decreased but rhythmic in the somatosensory cortex and thalamus during these seizures. Interestingly, individual neurons in both regions tend to consistently express one of four distinct patterns of seizure-associated activity. These patterns differ in firing rate dynamics and in rhythmicity during seizure. One group of neurons showed a transient initial peak in firing at SWD onset, accounting for the brief initial increase in overall neuronal firing seen in cortex and thalamus. The largest group of neurons in both cortex and thalamus showed sustained decreases in firing during SWD. Other neurons showed either sustained increases or no change in firing. These findings suggest that certain classes of cortical and thalamic neurons may be particularly responsible for the paroxysmal oscillations and consequent loss of consciousness in absence epilepsy.

neuroscience↗