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Hallucinating mice, dopamine and immunity; towards mechanistic treatment targets for psychosis
Hallucinations are a core symptom of psychotic disorders and have traditionally been difficult to study biologically. We developed a new behavioral computational approach to measure hallucinations-like perception in humans and mice alike. Using targeted neural circuit manipulations, we identified a causal role for striatal dopamine in mediating hallucination-like perception. Building on this, we currently investigate the neural and immunological upstream regulators of these dopaminergic circuits with the goal to identify new biological treatment targets for psychosis
Integration of 3D human stem cell models derived from post-mortem tissue and statistical genomics to guide schizophrenia therapeutic development
Schizophrenia is a neuropsychiatric disorder characterized by positive symptoms (such as hallucinations and delusions), negative symptoms (such as avolition and withdrawal) and cognitive dysfunction1. Schizophrenia is highly heritable, and genetic studies are playing a pivotal role in identifying potential biomarkers and causal disease mechanisms with the hope of informing new treatments. Genome-wide association studies (GWAS) identified nearly 270 loci with a high statistical association with schizophrenia risk; however each locus confers only a small increase in risk therefore it is difficult to translate these findings into understanding disease biology that can lead to treatments. Induced pluripotent stem cell (iPSC) models are a tractable system to translate genetic findings and interrogate mechanisms of pathogenesis. Mounting research with patient-derived iPSCs has proposed several neurodevelopmental pathways altered in SCZ, such as neural progenitor cell (NPC) proliferation, imbalanced differentiation of excitatory and inhibitory cortical neurons. However, it is unclear what exactly these iPS models recapitulate, how potential perturbations of early brain development translates into illness in adults and how iPS models that represent fetal stages can be utilized to further drug development efforts to treat adult illness. I will present the largest transcriptome analysis of post-mortem caudate nucleus in schizophrenia where we discovered that decreased presynaptic DRD2 autoregulation is the causal dopamine risk factor for schizophrenia (Benjamin et al, Nature Neuroscience 2022 https://doi.org/10.1038/s41593-022-01182-7). We developed stem cell models from a subset of the postmortem cohort to better understand the molecular underpinnings of human psychiatric disorders (Sawada et al, Stem Cell Research 2020). We established a method for the differentiation of iPS cells into ventral forebrain organoids and performed single cell RNAseq and cellular phenotyping. To our knowledge, this is the first study to evaluate iPSC models of SZ from the same individuals with postmortem tissue. Our study establishes that striatal neurons in the patients with SCZ carry abnormalities that originated during early brain development. Differentiation of inhibitory neurons is accelerated whereas excitatory neuronal development is delayed, implicating an excitation and inhibition (E-I) imbalance during early brain development in SCZ. We found a significant overlap of genes upregulated in the inhibitory neurons in SCZ organoids with upregulated genes in postmortem caudate tissues from patients with SCZ compared with control individuals, including the donors of our iPS cell cohort. Altogether, we demonstrate that ventral forebrain organoids derived from postmortem tissue of individuals with schizophrenia recapitulate perturbed striatal gene expression dynamics of the donors’ brains (Sawada et al, biorxiv 2022 https://doi.org/10.1101/2022.05.26.493589).
Chemistry of the adaptive mind: lessons from dopamine
The human brain faces a variety of computational dilemmas, including the flexibility/stability, the speed/accuracy and the labor/leisure tradeoff. I will argue that striatal dopamine is particularly well suited to dynamically regulate these computational tradeoffs depending on constantly changing task demands. This working hypothesis is grounded in evidence from recent studies on learning, motivation and cognitive control in human volunteers, using chemical PET, psychopharmacology, and/or fMRI. These studies also begin to elucidate the mechanisms underlying the huge variability in catecholaminergic drug effects across different individuals and across different task contexts. For example, I will demonstrate how effects of the most commonly used psychostimulant methylphenidate on learning, Pavlovian and effortful instrumental control depend on fluctuations in current environmental volatility, on individual differences in working memory capacity and on opportunity cost respectively.
Hallucinating mice and dopamine – towards mechanistic treatment targets for psychosis
Psychotic disorders are devastating conditions without any mechanistic treatment available. One major hurdle in the biological study of psychosis is the challenge of rigorously probing this condition in pre-clinical animal models. The goal of our research is to develop and exploit innovative frameworks for the study of psychosis in mice. In our present work, where we developed a cross-species computational psychiatry approach to probe hallucination-like perception. This enabled us to directly relate human and mouse behavior, and to demonstrate and dissect the causal role of striatal dopamine in hallucination-like perception. Our results suggest a neural circuit mechanism for the long-standing dopamine hypothesis of psychosis, and provide a new translational framework for the biological study of psychosis. This opens up exciting possibilities for advancing the biological understanding of psychosis and to identify mechanistic treatment targets.
The role of spatiotemporal waves in coordinating regional dopamine decision signals
The neurotransmitter dopamine is essential for normal reward learning and motivational arousal processes. Indeed these core functions are implicated in the major neurological and psychiatric dopamine disorders such as schizophrenia, substance abuse disorders/addiction and Parkinson's disease. Over the years, we have made significant strides in understanding the dopamine system across multiple levels of description, and I will focus on our recent advances in the computational description, and brain circuit mechanisms that facilitate the dual role of dopamine in learning and performance. I will specifically describe our recent work with imaging the activity of dopamine axons and measurements of dopamine release in mice performing various behavioural tasks. We discovered wave-like spatiotemporal activity of dopamine in the striatal region, and I will argue that this pattern of activation supports a critical computational operation; spatiotemporal credit assignment to regional striatal subexperts. Our findings provide a mechanistic description for vectorizing reward prediction error signals relayed by dopamine.
Cortical dopamine enables deep reinforcement learning and leverages dopaminergic heterogeneity
COSYNE 2023
Striatal dopamine encodes movement and value at distinct time points
COSYNE 2023
Achyrocline satureioides protects against neuronal dopaminergic damage in the Caenorhabditis elegans model of Parkinson’s disease
FENS Forum 2024
Astroglial control of prefrontal dopamine tone shapes behavior
FENS Forum 2024
Characterization of the cerebral dopamine neurotrophic factor (CDNF) in nucleus accumbens of rodents
FENS Forum 2024
Characterizing the role of movement in ventromedial striatal dopamine signals related to reward
FENS Forum 2024
Convergent regulation of dopamine release by striatal dopamine transporters and GABA receptors
FENS Forum 2024
Age effect on the willingness to work for sucrose in male rats: Involvement of the cerebral dopamine neurotrophic factor
FENS Forum 2024
ErbB inhibition rescues nigral dopamine neuron hyperactivity and repetitive behaviors in a mouse model of fragile X syndrome
FENS Forum 2024
Extrasynaptic NMDARs activation by co-agonist glycine controls the occurrence of bursts in nigral dopamine neurons
FENS Forum 2024
Facilitating memory consolidation through light exercise: The role of the coeruleo-hippocampal dopaminergic pathway
FENS Forum 2024
Extrastriatal dopamine differentially modulates erroneous perceptual confidence
FENS Forum 2024
The influence of lateralized retinal stimulation on dopaminergic neuron activity and striatal dopamine release
FENS Forum 2024
Prefrontal-tDCS rescues hippocampal dopamine signalling, resulting in cellular, functional and behavioural improvements and amyloid-β reduction in a mouse model of Alzheimer’s disease
FENS Forum 2024
Reciprocal regulation of striatal dopamine and serotonin release in healthy and parkinsonian mice
FENS Forum 2024
Relational dopamine/metabolic correlates of psychopathology in schizophrenia
FENS Forum 2024
Striatal dopamine and acetylcholine signal distinct variables during perceptual decision-making
FENS Forum 2024
Wave-like striatal dopamine peaks and troughs bracket spontaneous movement
FENS Forum 2024
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