Abstract
Theta and gamma rhythms and their cross-frequency coupling play critical roles in perception, attention, learning, and memory. Available data suggest that forebrain acetylcholine (ACh) signaling promotes theta-gamma coupling, although the mechanism has not been identified. Recent evidence suggests that cholinergic signaling is both temporally and spatially constrained, in contrast to the traditional notion of slow, spatially homogeneous, and diffuse neuromodulation. Here, we find that spatially constrained cholinergic stimulation can generate theta-modulated gamma rhythms. Using biophysically-based excitatory-inhibitory (E-I) neural network models, we simulate the effects of ACh on neural excitability by varying the conductance of a muscarinic receptor-regulated K+ current. In E-I networks with local excitatory connectivity and global inhibitory connectivity, we demonstrate that theta-gamma-coupled firing patterns emerge in ACh modulated network regions. Stable gamma-modulated firing arises within regions with high ACh signaling, while theta or mixed theta-gamma activity occurs at the peripheries of these regions. High gamma activity also alternates between different high-ACh regions, at theta frequency. Our results are the first to indicate a causal role for spatially heterogenous ACh signaling in the emergence of localized theta-gamma rhythmicity. Our findings also provide novel insights into mechanisms by which ACh signaling supports the brain region-specific attentional processing of sensory information.
Highlights
Acetylcholine (ACh) signaling in neocortex emanates from the basal forebrain (BF)
An example of such evidence is presented on Fig 1. In this experiment four platinum recording sites were fabricated onto a ceramic backbone electrode where the upper and lower pairs of recording sites were separated by 100 μm (Fig 1A)
We postulate that relevant network dynamics occur on two separate temporal scales: 1) fast dynamics on a timescale of milliseconds associated with neuronal firing, and 2) slow timescales on the order of 5–10 s associated with localized ACh release and subsequent degradation or uptake
Summary
Acetylcholine (ACh) signaling in neocortex emanates from the basal forebrain (BF). Recent anatomical studies indicate that in contrast to more traditional views of the BF projection system as “diffusely” organized, afferent and efferent projections of the BF ACh system are highly topographically organized [1,2,3,4]. Our simulation results indicate that localized theta (* 5 − 10Hz) and gamma (* 30 − 100Hz) band activity rhythms emerge in response to spatially segregated ACh modulation of neural excitability. The modeled spatial cholinergic distributions are meant to represent a short snapshot from the evidence of spatially circumscribed ACh signaling in recording studies in rodents (Fig 1D), where discrete locations of high levels of cholinergic signaling were observed adjacent to locations with low levels of cholinergic activity. We analyzed the emerging neuronal activity patterns in the presence of stationary high levels of cholinergic signaling in a single versus in multiple locations of the network. For multiple high-ACh ‘hotspots’, these gamma oscillations appeared only within the currently active network regions, resulting in their modulation at theta frequency
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