Role of CAMKII in reinforcement learning: a computational model of glutamate and dopamine signaling pathways

Wanjerkhede, Shesharao M.; Bapi, Raju S.

doi:10.1007/s00422-011-0439-5

Cited by 5 publications

(3 citation statements)

References 89 publications

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“…One link may be via variational Bayesian formulations of reinforcement-learning update equations (see below), in which precision-weighted prediction errors play a key role [120]. On the other hand, there are computational simulations whose biological detail goes beyond the simulations in this paper [112], [121], [122], [123]. In this sense, the simulations reported here should be regarded as an illustration of how far one can get in modeling neuromodulation in the larger setting of Bayes optimal action and perception.…”

Section: Discussionmentioning

confidence: 99%

Dopamine, Affordance and Active Inference

et al. 2012

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The role of dopamine in behaviour and decision-making is often cast in terms of reinforcement learning and optimal decision theory. Here, we present an alternative view that frames the physiology of dopamine in terms of Bayes-optimal behaviour. In this account, dopamine controls the precision or salience of (external or internal) cues that engender action. In other words, dopamine balances bottom-up sensory information and top-down prior beliefs when making hierarchical inferences (predictions) about cues that have affordance. In this paper, we focus on the consequences of changing tonic levels of dopamine firing using simulations of cued sequential movements. Crucially, the predictions driving movements are based upon a hierarchical generative model that infers the context in which movements are made. This means that we can confuse agents by changing the context (order) in which cues are presented. These simulations provide a (Bayes-optimal) model of contextual uncertainty and set switching that can be quantified in terms of behavioural and electrophysiological responses. Furthermore, one can simulate dopaminergic lesions (by changing the precision of prediction errors) to produce pathological behaviours that are reminiscent of those seen in neurological disorders such as Parkinson's disease. We use these simulations to demonstrate how a single functional role for dopamine at the synaptic level can manifest in different ways at the behavioural level.

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Section: Discussionmentioning

confidence: 99%

Dopamine, Affordance and Active Inference

et al. 2012

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“…Our results extend these findings and demonstrate that the activity of CaMKII at its autophosphorylation site is reduced in HR rats compared with LR rats in the nucleus accumbens shell region. Given that CaMKII autophosphorylation contributes to a variety of neuroadaptations in the brain, and particularly in the striatum, including the remodeling of glutamatergic neurotransmission, activity-dependent trafficking of PSD-95, expression of neuronal-specific nitric oxide synthase and the generation of free radicals, and plays a significant role in learning and memory functions dependent on the striatum [54][55][56][57][58][59][60], we speculate that the possible mechanism of enhanced ethanol-seeking in HR rats involves altered glutamatergic signaling, oxidative stress and altered learning and memory functions induced by ethanol via reduced CaMKII autophosphorylation. Further studies are, however, needed to confirm this hypothesis.…”

Section: Discussionmentioning

confidence: 99%

Individual Differences in Ethanol Drinking and Seeking Behaviors in Rats Exposed to Chronic Intermittent Ethanol Vapor Exposure is Associated with Altered CaMKII Autophosphorylation in the Nucleus Accumbens Shell

Somkuwar

Mandyam

2019

Brain Sciences

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Chronic intermittent ethanol vapor exposure (CIE) in rodents produces reliable and high blood ethanol concentration and behavioral symptoms associated with moderate to severe alcohol use disorder (AUD)-for example, escalation of operant ethanol self-administration, a feature suggestive of transition from recreational to addictive use, is a widely replicated behavior in rats that experience CIE. Herein, we present evidence from a subset of rats that do not demonstrate escalation of ethanol self-administration following seven weeks of CIE. These low responders (LR) maintain low ethanol self-administration during CIE, demonstrate lower relapse to drinking during abstinence and reduced reinstatement of ethanol seeking triggered by ethanol cues when compared with high responders (HR). We examined the blood ethanol levels in LR and HR rats during CIE and show higher levels in LR compared with HR. We also examined peak corticosterone levels during CIE and show that LR rats have higher levels compared with HR rats. Lastly, we evaluated the levels of Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) in the nucleus accumbens shell and reveal that the activity of CaMKII, which is autophosphorylated at site Tyr-286, is significantly reduced in HR rats compared with LR rats. These findings demonstrate that dysregulation of the hypothalamic-pituitary-adrenal axis activity and plasticity-related proteins regulating molecular memory in the nucleus accumbens shell are associated with higher ethanol-drinking and -seeking in HR rats. Future mechanistic studies should evaluate CaMKII autophosphorylation-dependent remodeling of glutamatergic synapses in the ventral striatum as a plausible mechanism for the CIE-induced enhanced ethanol drinking and seeking behaviors.

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“…However, if the pathway map is small, and the values for the rate constants are available, it is possible to perform pathway map-based simulations. For example, mitogen-activated protein kinase (MAPK) mediated signal transduction [50,51], Fas-induced caspase activation [52], protein kinase A (PKA) activation [53], signal transduction via the mTOR pathway [54] and CAMKII activation [55] have all been successfully simulated.…”

Section: Pathway Map-based Simulationsmentioning

confidence: 99%

Systems‐based understanding of pharmacological responses with combinations of multidisciplinary methodologies

Kariya

Honma

Suzuki

2013

Biopharm & Drug Disp

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The importance of systems-based pharmacological approaches to drug discovery and development has increasingly been recognized. This reviews summarizes recent advances in the development of systems pharmacology and introduces the methods used for analysis. To understand the cellular response at the molecular level, pathway maps must be prepared to show how the function of the constituent molecules within cells are linked and integrated to form molecular networks. First, the methods used to prepare these pathway maps, such as databases, knowledge bases and software platforms, are introduced. Then the mathematical theories used to analyse the behavior of molecular networks are summarized. To quantitatively predict cellular responses, simulations are performed that are based on the rate equations for each reaction within the pathway map. If the number of reactions described in the pathway map is small, and if the parameter values for the rate constants are available, it is possible accurately to simulate the behavior of the molecular networks. However, to analyse complex maps, mathematical abstraction is required. Such abstraction methods are important to integrate cellular responses and to understand tissue/organ and in vivo pharmacological/toxicological responses. The scope and limitations of the methods are also discussed.

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Role of CAMKII in reinforcement learning: a computational model of glutamate and dopamine signaling pathways

Cited by 5 publications

References 89 publications

Dopamine, Affordance and Active Inference

Dopamine, Affordance and Active Inference

Individual Differences in Ethanol Drinking and Seeking Behaviors in Rats Exposed to Chronic Intermittent Ethanol Vapor Exposure is Associated with Altered CaMKII Autophosphorylation in the Nucleus Accumbens Shell

Systems‐based understanding of pharmacological responses with combinations of multidisciplinary methodologies

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