Investigating the role of NMDA receptor hypofunction in psychosis using neuroimaging across scales and species

Basic data for this project

Description

The N-methyl-D-aspartate receptor (NMDAR) is critically involved in the regulation of the balance between excitatory and inhibitory neural networks and has been in the focus of current pathophysiological accounts of psychosis, a syndrome characterized by delusions and hallucinations. The critical role of NMDAR in psychosis is suggested by two lines of evidence. First, NMDAR antagonists such as ketamine induce transient psychotic symptoms in healthy individuals. Second, psychosis is a characteristic feature of anti-NMDAR encephalitis, an autoimmune disorder leading to NMDAR hypofunction. However, the precise mechanism by which NMDAR hypofunction causes psychosis has remained elusive. We believe that the only way towards a comprehensive understanding of the role of NMDAR hypofunction in psychosis is to bring together researchers from all involved fields - neurology, psychiatry and neurophysiology. We are therefore teaming up for an interdisciplinary collaboration comprising leading research groups in the fields of psychosis research, autoimmune encephalitis, and microcircuit dysfunction. We propose a comprehensive approach that will use innovative, multimodal neuroimaging across scales and species to elucidate the functional consequences NMDAR hypofunction within the computational framework of predictive coding. We will conduct parallel experiments in mice and humans to study the effects of both acute and chronic NMDAR hypofunction on the neurocomputational mechanisms underlying perceptual decision-making. Firstly, to investigate network dysregulations at the microcircuit level, we will perform dual-color two-photon calcium imaging in the visual cortex of awake, behaving mice with either acute pharmacologically-induced or chronic autoimmune NMDAR hypofunction. We will differentiate between the contributions of excitatory and inhibitory neurons during perceptual decision-making. As mouse models are obviously limited in the assessment of the relationship between NMDAR function and actual psychotic symptoms, studies investigating this relationship in humans are required. We will thus, secondly, perform analogous experiments in a parallel human fMRI study, in which we will assess the neurocomputational mechanisms of perceptual decision-making in healthy participants under ketamine vs. placebo as well as in patients with anti-NMDAR encephalitis compared to healthy controls.