Modeling Effects of Spatially Heterogeneous Acetylcholine on Neural Oscillations and Synaptic Plasticity
Creators: name: Yang, Yihao
Publisher: name: My University
Year: 2023
Subjects: subject: Acetylcholine
subject: spatially heterogeneous ACh
subject: cross-frequency coupling
subject: theta-gamma coupling
subject: synaptic plasticity
subject: Physics
subject: Science

description: Acetylcholine (ACh) is one of the brain’s most powerful neuromodulators and has been shown to influence numerous cognitive functions such as arousal, attention, learning and memory. Recent evidence suggests that cholinergic signaling is both temporally and spatially constrained, in contrast to the traditional notion of slow, spatially homogeneous, and diffuse modulation of brain networks by acetylcholine (ACh). This raises the question of how this feature impacts neural processing of information, particularly in cortical networks. Using biophysically-based excitatory-inhibitory (E-I) neural network models, we analyze the effects of spatially heterogeneous ACh modulation on properties of information processing in the brain, including the generation of rhythmic oscillatory activity and the evolution of synaptic connectivity by synaptic plasticity. In the model networks, we specifically simulate muscarinic receptor-mediated effects of ACh on neural excitability by varying the conductance of a muscarinic receptor-regulated K+ current. We first consider how spatially heterogeneous ACh modulation can contribute to theta and gamma band rhythmic firing and their cross-frequency coupling, a hallmark of attention and information processing. While forebrain ACh signaling has been linked to theta-gamma coupling, the underlying mechanism has not been identified. In E-I networks with local excitatory connectivity and global inhibitory connectivity, we demonstrate that theta-gamma-coupled firing patterns naturally emerge in spatially constrained ACh modulated network regions. Specifically, our modeling results show that 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. Theta-gamma coupled firing also occurs when high gamma activity alternates at theta frequency between spatially distinct high ACh regions. These 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. Next, we study how external stimuli and spatially heterogeneous ACh signaling can influence the directionality and spatial patterning of synaptic plasticity in multi-module neuronal networks. We construct two-dimensional E-I network modules interconnected with plastic excitatory synaptic connections that change via a spike-timing-dependent plasticity (STDP) rule. We analyze how differences in the external stimuli and ACh modulation in each module affect the pattern of inter-module synaptic connectivity. We identify that activity in high ACh regions within a module is prone to induce feedback firing bursts and thus strengthens synapses incoming to the high ACh region while weakening outgoing synapses. Besides unidirectional strengthening, similar ACh modulation patterns in both the modules, leads to synchronized network bursts across different modules and thus reciprocal strengthening of connections. These multi-module E-I networks with inter-module topographical connectivity and spatially constrained ACh signaling also demonstrate spatial localization of synaptic plasticity. Taken together, by understanding brain rhythm generation and plasticity pattern evolution of synapses under the influence of spatially heterogeneous ACh, this dissertation lays a foundation to understanding how spatially heterogeneous ACh neuromodulation influences neural dynamics associated with cognitive function.