Phasic cholinergic signaling promotes emergence of local gamma rhythms in excitatory–inhibitory networks

Abstract

Recent experimental results have shown that the detection of cues in behavioral attention tasks relies on transient increases of acetylcholine (ACh) release in frontal cortex and cholinergically driven oscillatory activity in the gamma frequency band (Howe et al. Journal of Neuroscience, 2017, 37, 3215). The cue-induced gamma rhythmic activity requires stimulation of M1 muscarinic receptors. Using biophysical computational modeling, we show that a network of excitatory (E) and inhibitory (I) neurons that initially displays asynchronous firing can generate transient gamma oscillatory activity in response to simulated brief pulses of ACh. ACh effects are simulated as transient modulation of the conductance of an M-type K + current which is blocked by activation of muscarinic receptors and has significant effects on neuronal excitability. The ACh-induced effects on the M current conductance, g Ks , change network dynamics to promote the emergence of network gamma rhythmicity through a Pyramidal-Interneuronal Network Gamma mechanism. Depending on connectivity strengths between and among E and I cells, gamma activity decays with the simulated g Ks transient modulation or is sustained in the network after the g Ks transient has completely dissipated. We investigated the sensitivity of the emergent gamma activity to synaptic strengths, external noise and simulated levels of g Ks modulation. To address recent experimental findings that cholinergic signaling is likely spatially focused and dynamic, we show that localized g Ks modulation can induce transient changes of cellular excitability in local subnetworks, subsequently causing population-specific gamma oscillations. These results highlight dynamical mechanisms underlying localization of ACh-driven responses and suggest that spatially localized, cholinergically induced gamma may contribute to selectivity in the processing of competing external stimuli, as occurs in attentional tasks.

Make a Left Turn: Cortico‐Striatal Circuitry Mediating the Attentional Control of Complex Movements

“…1). Consistent with the view that M1 stimulation is necessary for the generation of high-frequency oscillations and cross-frequency coupling, and thus for cues to control behavior, 34,49,[52][53][54] the administration of an M1 positive allosteric modulator (PAM) partly rescued the detection rates of rats with partial removal of cholinergic inputs to the cortex 55 and, in a rodent model of parkinsonian falls (see later), reduced the rates of falls. 56…”

“…The timescale of such supra‐trial‐based cholinergic control of attention may suggest the presence of a relatively slow mode of cholinergic signaling when compared with fast cholinergic transients described earlier. However, cholinergic transients produce relatively lasting postsynaptic neurophysiological effects, mentioned earlier, and such modulation of intrinsic and efferent cortical networks can serve to maintain the rules of stimulus–response mappings relevant to the current context and goal (“task sets”) over longer periods 54 . Thus, the postsynaptic effects of cholinergic transients may sufficiently explain the cholinergic mediation of attentional control 33 .…”

“…However, cholinergic transients produce relatively lasting postsynaptic neurophysiological effects, mentioned earlier, and such modulation of intrinsic and efferent cortical networks can serve to maintain the rules of stimulus-response mappings relevant to the current context and goal ("task sets") over longer periods. 54 Thus, the postsynaptic effects of cholinergic transients may sufficiently explain the cholinergic mediation of attentional control. 33 As we will see next, given the complementary roles of cortical cholinergic activity in maintaining high levels of attentional control and high cue detection rates, the impact of losses of ACh for gait control, postural stability, and fall rates can be conceptualized.…”

Reduction of falls in a rat model of PD falls by the M1 PAM TAK-071

“…Loss of cholinergic projections, which arise from the basal forebrain (BF) and innervate virtually all cortex as well as several thalamic nuclei, has been associated with increased falls in PD (Bohnen et al 2019;Muller et al 2013;Bohnen and Albin 2011;Bohnen et al 2009;Rochester et al 2012;Albin et al 2018b). Cortical cholinergic signaling is necessary for the integration of exteroceptive and interoceptive cues into ongoing behavior, thereby permitting these cues to influence and, if previously associated with defined responses, control behavior (Sarter and Lustig 2020;Lu et al 2020;Howe et al 2017;Gritton et al 2016;Berry et al 2014;Howe et al 2013;Parikh et al 2007;Venkatesan et al 2020;Picciotto et al 2012). Therefore, PD falls have been extensively demonstrated to be closely associated with a decline in such attentional capacities (Stuart et al 2017;Yarnall et al 2011;Lord et al 2010;Cools et al 2010;Allcock et al 2009;Yogev-Seligmann et al 2008;Shumway-Cook and Woollacott 2000;Chen et al 1996;Stam et al 1993; Kim et al 2017Kim et al , 2019Berry et al 2017).…”

“…The present experiment was designed to test the hypothesis that treating DL rats with a muscarinic M1 acetylcholine receptor (mAChR)-positive allosteric modulator (PAM) reduces their fall rate. The focus on M1 receptors as a key node in the attention-mediating functions of the BF cholinergic system in part arises from evidence showing that the cholinergic mediation of attention requires the M1-mediated generation of high-frequency oscillations in the cortex and of neuronal synchrony across multiple frequency bands (Howe et al 2017; see also Moran et al 2019;Gould et al 2015;Herrero et al 2008;Disney and Aoki 2008;Lu et al 2020). Such M1mediated effects are thought to orchestrate multiple neuronal populations for integrating the cognitive, sensory, and motor components of a cue-evoked behavioral response.…”