Dopaminergic and glutamatergic contribution to the formation of decision variables in fronto-parietal brain circuits

We make innumerable decisions every day. Decision making requires accumulation of evidence for or against a proposition and ultimately for a specific action. However, it is not sufficient to simply accumulate evidence, the evidence must be evaluated. How useful it is? When is enough enough? Many of these aspects of decision making have been studied at the psychological and, to some extent, the neuronal level. Accumulation of evidence has been studied in the context of value based decisions, social decisions, economic decisions, gambling decisions, memory-based decisions, and, importantly, perceptual decisions. These studies have provided a rich theoretical background within which decision making can be explained, and they have generated tools to delineate the different cognitive components that are involved in decision making.
At the neuronal level, signatures of decision making have been found in various cortical and subcortical areas. Neurons in these areas gradually alter their activity as evidence in favor or against a proposition is gathered, and they retain the representation of accumulated evidence even when the evidence is removed, i.e. a memory trace of evidence exists. Finally, many of these neurons convert the evidence into a categorical decision, when sufficient evidence has been gathered, or when urgency so dictates.
Despite these insights, we currently do not understand how brain areas involved in decision making exchange information, or how the process of evidence accumulation, evidence evaluation, and categorization is made possible. Specifically we do not understand which brain chemicals (transmitters and their related receptors) are critical in enabling these processes. An understanding thereof is essential to understand decision making at a mechanistic level, and to understand how deficits in decision making come about in mental disorders such as Schizophrenia, Impulsive compulsive disorders, or Parkinson (for example).
We aim to study these questions in macaque monkeys, the most appropriate animal model to relate neuronal data to human conditions. Neuronal signatures of decision making are best understood in the domain of perceptual decisions. In the laboratory, this is studied by confronting subjects with noisy sensory stimuli, who have to discriminate what stimulus has been presented. We will exploit well established paradigms which have helped understand the neural computations involved in perceptual decision making, namely a reaction time version of a coherent motion discrimination task, and a task where sequential information about the likely choice location has to be integrated over time. In the coherent motion task the subject is confronted with noisy motion stimuli and has to decide what direction of motion is present. In the sequential sampling task, monkeys are presented with different symbols which indicate a likelihood that a given choice location will yield a reward. We will record neuronal activity in the parietal and the frontal cortex, which have been studied in the context of these tasks. We intentionally copy existing paradigms and record in areas where the basic response properties are well delineated, as this allows to test specific predictions how different brain chemicals support different components of the decision making process. We focus on the dopaminergic and the glutamatergic system, as these have been implicated with different cognitive dysfunctions that affect decision making (e.g. working memory, evidence accumulation, evidence evaluation), but their contribution at the neuronal level remains poorly understood. We will determine how these systems contribute to evidence accumulation, evidence evaluation, and threshold setting to form a categorical decision.
The study will generate a better understanding of the neuronal mechanisms of decision making in health and disease, aiming to help improve therapeutic approaches in the future.

Decision making requires accumulation of evidence, evaluation of its quality, and setting a bound to terminate the accumulation once sufficient evidence is available.
Neural correlates of perceptual decision making have been delineated in different cortical and subcortical areas, in particular in areas LIP (and less so) FEF/DLPFC. Specifically, neuronal activity in LIP follows predictions from bounded drift diffusion models, where momentary noisy evidence is integrated loss less until it reaches a threshold, thereby triggering the decision. To date we do not understand the mechanisms involved. Theoretical work suggests that the process of evidence accumulation is achieved through slow recurrent excitation, signalled by NMDA receptors, in conjunction with feedback inhibition in local networks. At the same time, Parkinson patient data suggest that evidence accumulation depends on dopaminergic signalling. Given the close interaction of dopaminergic and NMDA receptors, it is likely that both systems are critical for adequate decision making and normal cognitive operations.
We will determine which aspect of decision making are supported by D1, D2 and different NMDA (NR2A, NR2B) receptors, by recording single unit activity in area LIP, FEF and DLPFC under control conditions and when D1, D2, and NMDAR agonists and antagonists are applied in the vicinity of the recorded neurons while animals perform a reaction time stochastic motion task or a sequential symbol sampling task. The rich theoretical and analytical framework, generated by previous studies, will help determine which aspects of decision making are affected by our drug manipulations. We predict that the quality of the integrator will depend on NMDAR availability, the speed of accumulation will be controlled by D1 receptors, and the conversion to a categorical decision by D2 receptors. These hypotheses will be tested by systematically varying specific stimulus parameters and speed-accuracy trade-offs.

The research will have its major impact on the academic neuroscience/cognitive neuroscience community (see academic beneficiaries). It will inform cognitive neuroscience, computational neuroscience, and systems neuroscience in general.
Although the research falls under the category of 'basic science', it may still inform clinicians, as we will investigate the neuronal mechanisms of decision making in higher cortical areas. These will reveal how well defined cognitive operations depend and are shaped by NMDA and dopamine receptor activation. Understanding how these operations are influenced by specific receptor agonists and antagonists is important for diagnosis. Ideally, it has an impact on Psychopharmacology, by revealing the effects of NMDAR antagonists and dopaminergic antagonists on neuronal integration and communication properties. In theory, it could lead to altered drug treatment strategies, as it may aid our understanding why specific drugs (designed to treat specific cognitive dysfunctions/symptoms) have undesired side effect. Whether this requires the development of more specific drugs in the future, will have to be assessed based on the result obtained. These potential clinical impacts are, however, speculative and currently only a possibility, not an immediately anticipated outcome, as the research is basic research in principle.