A Dopamine–Acetylcholine Cascade: Simulating Learned and Lesion-Induced Behavior of Striatal Cholinergic Interneurons

Abstract

Tan CO, Bullock D. A dopamine-acetylcholine cascade: simulating learned and lesion-induced behavior of striatal cholinergic interneurons. J Neurophysiol 100: 2409 -2421, 2008. First published August 20, 2008 doi:10.1152/jn.90486.2008. The giant cholinergic interneurons of the striatum are tonically active neurons (TANs) that respond with pauses to appetitive and aversive cues and to novel events. Whereas tonic activity emerges from intrinsic properties of these neurons, glutamatergic inputs from intralaminar thalamic nuclei and dopaminergic inputs from midbrain are required for genesis of pause responses. No prior computational models encompass both intrinsic and synaptically gated dynamics. We present a mathematical model that robustly accounts for behavior-related electrophysiological properties of TANs in terms of their intrinsic physiological properties and known afferents. In the model, balanced intrinsic hyperpolarizing and depolarizing currents engender tonic firing and glutamatergic inputs from thalamus (and cortex) both directly excite and indirectly inhibit TANs. If this inhibition, probably mediated by GABAergic nitric oxide synthase interneurons, exceeds a threshold, a persistent K ϩ conductance current amplifies its effect to generate a prolonged pause. Dopamine (DA) signals modulate both the intrinsic mechanisms and the external inputs of TANs. Simulations revealed that many learningdependent behaviors of TANs, including acquired pauses to taskrelevant cues, are explicable without recourse to learning-dependent changes in synapses onto TANs, due to a tight coupling between DA bursts and TAN pauses. These interactions imply that reward-predicting cues often cause striatal projection neurons to receive a cascade of signals: an adaptively scaled DA burst, a brief acetylcholine (ACh) burst, and an ACh pause. A sensitivity analysis revealed a unique TAN response surface, which shows that DA inputs robustly cooperate with thalamic inputs to control cue-dependent pauses of ACh release, which strongly affects performance-and learning-related dynamics in the striatum. I N T R O D U C T I O NThe striatum is a key component of forebrain circuits and understanding forebrain functions requires integrative models of how afferent signals to striatum interact with striatal microcircuits to shape performance and learning. In the striatum, dopamine (DA) and acetylcholine (ACh) have opposing effects on voluntary behavior and on the activation/inhibition of the striatum's principal neurons, the medium spiny projection neurons (MSPNs) (Bernardi et al. 1993;DiChiara et al. 1994;Gabel and Nisenbaum 1999). Striatal DA and ACh signals each have spontaneous and learned components and both DA and ACh have been implicated as modulators of cortico-striatal learning (Centonze et al. 1999;Morris et al. 2004;Pisani et al. 2001;Wang et al. 2006;Zhou et al. 2001Zhou et al. , 2003. Although DA is released by afferents from the midbrain, the striatum's source of ACh is intrinsic. Only giant aspiny interneurons, which are tonically a...

A Local Circuit Model of Learned Striatal and Dopamine Cell Responses under Probabilistic Schedules of Reward

“…ACh release by model striatal TANs modulates the matricial MSPNs via a dual control of FS-INs by ACh (de Rover et al, 2002;Koó s and Tepper, 2002), and via a direct inhibitory influence of ACh on SP-MSPNs (Bernard et al, 1993;DiChiara et al, 1994). Interestingly, simulations (Tan and Bullock, 2008b) show that many data accord with the hypothesis that TANs' conditioned pause responses largely reflect learned phasic DA inputs. Cholinergic modulation of SP-MSPNs may shed light on the individual differences in uncertainty responses observed (Fig.…”

“…The equations governing model striatal FS-INs and TANs, whose inclusion improves but was not critical for emergence of the basic DA responses (as shown below), are derived and discussed in detail by Tan and Bullock (2008b), and provided as supplemental Equations S1-S8 (available at www.jneurosci.org as supplemental material) for completeness. Operation of the model in real time is explained in more detail next.…”

“…Similarly, the choice of parameters for, and associated sensitivity analyses of, striatal TANs was delineated by Tan and Bullock (2008b). An additional key component in the current model is the overall effect of the striatal microcircuit.…”

“…The last term, T, reflects the direct inhibitory action of ACh on MSPNs (DiChiara et al, 1994). The model used to generate the ACh signal T is treated by Tan and Bullock (2008b) and summarized in Striatal Microcircuit in the supplemental material (Eq. S7, available at www.jneurosci.org as supplemental material).…”

Dopamine mediated dynamical changes in the striatum: a numerical study

“…We analyzed the robustness of the TAN subthreshold oscillations and demonstrated how they are affected by dopaminergic modulation [1]. The TAN-DAN interaction is reciprocal and precisely timed [2]. TAN pause responses co-occur with the DAN bursts and both influence the activities of the MSN neurons and the feed-forward FSN neurons.…”