A Role Beyond Learning for NMDA Receptors in Reward-Based Decision-Making—a Pharmacological Study Using d-Cycloserine

Scholl, Jacqueline; Günthner, Jan; Kolling, Nils; Favaron, Elisa; Rushworth, Matthew F. S.; Harmer, Catherine J.; Reinecke, Andrea

doi:10.1038/npp.2014.144

Cited by 32 publications

(43 citation statements)

References 36 publications

(36 reference statements)

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“…Lower values indicate better fit. On both measures, models using linear integration of magnitude and probability (M1-M3) provided an overwhelmingly better fit, as found previously (Scholl et al, 2014). While the model fit measures do not agree on whether modeling learning with a shared or separate learning rates (α) is best (M1 vs. M2), we note that for the key parameter of interest here, the use of learnt information (γ), we obtain the same value using either model (r = 1.0, p<10 −36 ).…”

Section: Resultssupporting

confidence: 83%

Excitation and inhibition in anterior cingulate predict use of past experiences

Scholl

Kolling

Nelissen

et al. 2017

eLife

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Dorsal anterior cingulate cortex (dACC) mediates updating and maintenance of cognitive models of the world used to drive adaptive reward-guided behavior. We investigated the neurochemical underpinnings of this process. We used magnetic resonance spectroscopy in humans, to measure levels of glutamate and GABA in dACC. We examined their relationship to neural signals in dACC, measured with fMRI, and cognitive task performance. Both inhibitory and excitatory neurotransmitters in dACC were predictive of the strength of neural signals in dACC and behavioral adaptation. Glutamate levels were correlated, first, with stronger neural activity representing information to be learnt about the tasks’ costs and benefits and, second, greater use of this information in the guidance of behavior. GABA levels were negatively correlated with the same neural signals and the same indices of behavioral influence. Our results suggest that glutamate and GABA in dACC affect the encoding and use of past experiences to guide behavior.DOI: http://dx.doi.org/10.7554/eLife.20365.001

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Section: Resultssupporting

confidence: 83%

Excitation and inhibition in anterior cingulate predict use of past experiences

Scholl

Kolling

Nelissen

et al. 2017

eLife

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“…In humans, results have so far been mixed, with some studies reporting that DCS could enhance motor learning ( Kuriyama et al, 2011 ), fear conditioning ( Kalisch et al, 2009 ) or incremental learning ( Forsyth et al, 2015 ), but others failing to find an effect on motor learning ( Cherry et al, 2014 ; Feld et al, 2013 ; Kuo et al, 2008 ), fear extinction ( Guastella et al, 2007 ; Klumpers et al, 2012 ) or reward learning ( Scholl et al, 2014 ).…”

Section: Introductionmentioning

confidence: 99%

“…DCS might exert its clinical effects via learning-independent cognitive mechanisms in which NMDA receptors play a role, such as evidence integration or decision-making ( Floresco et al, 2008 ; Scholl et al, 2014 ; Shen et al, 2010 ; Standage and Pare, 2011 ; Standage et al, 2013 ). In an exploratory analysis of non-learning dependent effects we found that DCS led participants to shift their balance in how quickly and accurately they responded towards more careful responding compared with placebo.…”

Section: Introductionmentioning

confidence: 99%

The NMDA receptor partial agonist d-cycloserine does not enhance motor learning

et al. 2016

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Rationale:There has recently been increasing interest in pharmacological manipulations that could potentially enhance exposure-based cognitive behaviour therapy for anxiety disorders. One such medication is the partial NMDA agonist d-cycloserine. It has been suggested that d-cycloserine enhances cognitive behaviour therapy by making learning faster. While animal studies have supported this view of the drug accelerating learning, evidence in human studies has been mixed. We therefore designed an experiment to measure the effects of d-cycloserine on human motor learning.Methods:Fifty-four healthy human volunteers were randomly assigned to a single dose of 250mg d-cycloserine versus placebo in a double-blind design. They then performed a motor sequence learning task.Results:D-cycloserine did not increase the speed of motor learning or the overall amount learnt. However, we noted that participants on d-cycloserine tended to respond more carefully (shifting towards slower, but more correct responses).Conclusion:The results suggest that d-cycloserine does not exert beneficial effects on psychological treatments via mechanisms involved in motor learning. Further studies are needed to clarify the influence on other cognitive mechanisms.

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“…No drug or placebo was administered on the second day. Although the idea of using NMDAR agonists to enhance cognition is not new, past studies examining diverse cognitive domains have yielded mixed results (24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36). Difficulty reconciling divergent effects has limited our ability to harness NMDAR agonists as cognitive enhancers.…”

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confidence: 99%

Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain

Forsyth

Bachman

Mathalon

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Experience-dependent plasticity is a fundamental property of the brain. It is critical for everyday function, is impaired in a range of neurological and psychiatric disorders, and frequently depends on long-term potentiation (LTP). Preclinical studies suggest that augmenting N-methyl-D-aspartate receptor (NMDAR) signaling may promote experience-dependent plasticity; however, a lack of noninvasive methods has limited our ability to test this idea in humans until recently. We examined the effects of enhancing NMDAR signaling using D-cycloserine (DCS) on a recently developed LTP EEG paradigm that uses high-frequency visual stimulation (HFvS) to induce neural potentiation in visual cortex neurons, as well as on three cognitive tasks: a weather prediction task (WPT), an information integration task (IIT), and a n-back task. The WPT and IIT are learning tasks that require practice with feedback to reach optimal performance. The n-back assesses working memory. Healthy adults were randomized to receive DCS (100 mg; n = 32) or placebo (n = 33); groups were similar in IQ and demographic characteristics. Participants who received DCS showed enhanced potentiation of neural responses following repetitive HFvS, as well as enhanced performance on the WPT and IIT. Groups did not differ on the n-back. Augmenting NMDAR signaling using DCS therefore enhanced activitydependent plasticity in human adults, as demonstrated by lasting enhancement of neural potentiation following repetitive HFvS and accelerated acquisition of two learning tasks. Results highlight the utility of considering cellular mechanisms underlying distinct cognitive functions when investigating potential cognitive enhancers.D-cycloserine | NMDA receptor | neuroplasticity | long-term potentiation | learning E xperience-dependent neuroplasticity is the capacity of the brain to change in response to environmental input, learning, and use. It is a fundamental property of the brain and is critical for everyday functioning. It allows us to learn and remember patterns, predict and obtain reward, and refine and accelerate response selection for adaptive behavior (1). During development, experience-dependent plasticity interacts with genetic programming to organize neurons into the structurally and functionally connected circuits that characterize a mature brain. Although this basic circuitry is established by early adulthood, experience-dependent plasticity continues to shape connectivity within these circuits such that important inputs and action outputs are represented by larger and more coordinated populations of neurons. Given that these changes are the primary means through which the adult brain enables new behavior and that such plasticity is impaired in a range of neurological and psychiatric disorders (2), identifying manipulations that can harness experiencedependent plasticity offers exciting possibilities. Here, we tested whether augmenting N-methyl-D-aspartate receptor (NMDAR) activity could enhance experience-dependent plasticity in the adult human brain.The ...

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A Role Beyond Learning for NMDA Receptors in Reward-Based Decision-Making—a Pharmacological Study Using d-Cycloserine

Cited by 32 publications

References 36 publications

Excitation and inhibition in anterior cingulate predict use of past experiences

Excitation and inhibition in anterior cingulate predict use of past experiences

The NMDA receptor partial agonist d-cycloserine does not enhance motor learning

Augmenting NMDA receptor signaling boosts experience-dependent neuroplasticity in the adult human brain

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