Cholinergic neuromodulation of prefrontal attractor dynamics controls performance in spatial working memory.

The behavioral and neural effects of the endogenous release of acetylcholine following stimulation of the Nucleus Basalis of Meynert (NB) have been recently examined in two male monkeys (Qi et al. 2021). Counterintuitively, NB stimulation enhanced behavioral performance while broadening neural tuning in the prefrontal cortex (PFC). The mechanism by which a weaker mnemonic neural code could lead to better performance remains unclear. Here, we show that increased neural excitability in a simple continuous bump attractor model can induce broader neural tuning and decrease bump diffusion, provided neural rates are saturated. Increased memory precision in the model overrides memory accuracy, improving overall task performance. Moreover, we show that bump attractor dynamics can account for the nonuniform impact of neuromodulation on distractibility, depending on distractor distance from the target. Finally, we delve into the conditions under which bump attractor tuning and diffusion balance in biologically plausible heterogeneous network models. In these discrete bump attractor networks, we show that reducing spatial correlations or enhancing excitatory transmission can improve memory precision. Altogether, we provide a mechanistic understanding of how cholinergic neuromodulation controls spatial working memory through perturbed attractor dynamics in PFC. Significance statement Acetylcholine has been thought to improve cognitive performance by sharpening neuronal tuning in prefrontal cortex. Recent work has shown that electrical stimulation of the cholinergic forebrain in awake-behaving monkeys induces a reduction in prefrontal neural tuning under stimulation conditions that improve performance. To reconcile these divergent observations, we provide network simulations showing that these derive consistently from specific conditions in prefrontal attractor dynamics: firing rate saturation leads to increased storage precision and reduced neural tuning upon cholinergic activation via an increase in neural excitability, a reduction in neural correlations, and an increase in excitatory transmission. Our study integrates previously reported data into a consistent mechanistic view of how acetylcholine controls spatial working memory via attractor network dynamics in prefrontal cortex.