Our brain processes information through electrical signaling by its neurons. Because of difficult access to living human neurons, their function in supporting cognition remains largely unexplored. If we want to understand the biological basis of human cognition, we need to focus on human neurons and mechanisms underlying their computation. A critical requirement of fast neuronal computation is the ability of neurons to generate fast and stable output - action potentials. Indeed, I recently showed that fast action potential signaling directly links to cognitive ability in the same individuals. In addition, we recently demonstrated that human neocortex contains neuron types not found in other mammals and these types are selectively vulnerable in brain disorders with cognitive decline. According to my preliminary data, exactly these neuron types have surprisingly fast signaling. How do these human-specific neurons achieve fast cellular computation supporting human cognition? Here, I aim to study which cellular and molecular mechanisms drive fast and stable signaling in human neuron types. I will link these data to human cognition by investigating how and which genes of intelligence associate with fast signaling in specific neuron types. These questions can only now be addressed with our recent transcriptomic, morpho-electric Patch-RNA-sequencing technique applied to human neurons. Combined with molecular interventions and computational modeling, I will provide a novel mechanistic understanding of fast cellular computation mechanisms in human cortex. This will help explain how selective loss of neuron types in human brain disorders gives rise to cognitive decline. My strong publication record in applying novel, original approach to study human neuron function in relation to cognition puts me in a unique position to address this. Finally, my work is the first to take a cellular perspective on human cognition and establishes a unique research line: Human Cellular Cognitive Neurosciences.

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Urgency: An estimated 179 million individuals in Europe are currently suffering from a brain disorder. These disorders are often persistent, leading to significant emotional and financial burdens to patients, their family, and society at large. For many brain disorders, including depression, substance abuse, autism, schizophrenia, insomnia, and dementia, there is no cure. Available treatments address symptom relief and are only effective in subsets of patients. The World Economic Forum, the World Health Organization and the European Brain Council all urge for improved understanding of brain disorders. Problem definition: Most brain disorders have in common a so-called ‘complex’ aetiology: i.e., they are influenced by multiple genetic and environmental risk factors. Each factor contributes only a small proportion to the total disease risk, and each individual potentially carries a different combination of genetic risk factors. Recent genetic discovery studies provided unprecedented insight into the genetic architecture of brain disorders by revealing many of the genes involved. Despite this enormous success, these results have not translated into mechanistic insight. That is because the detected genetic effects are small and numerous, and their combined biological implications are unclear. This complex nature of brain disorders has so far seriously hampered mechanistic disease insight, a prerequisite for successfully developing treatments. Opportunity: Two major recent advancements are of high relevance: First, novel genomics’ technologies have led to large-scale initiatives that provide genetic and transcriptomic signature maps of the human brain, down to cellular resolution. These maps are radically changing our understanding of the brain, and contain enormous potential for the interpretation of the functional role of the hundreds of genes implicated in brain disorders, as they allow mapping of risk genes to cells via their cellular expression. Aligning results from genetic discovery studies with these novel cellular signature maps of the brain will translate genetic discoveries into actionable starting points for functional follow-up studies. Second, a recent revolution in tools and technologies in experimental neuroscience enables studying cells and circuitry with unprecedented resolution. These new precision tools facilitate rapid genome editing, targeted intervention of the activity of neurons in the brain and the study of human neurons derived from patient cells. They provide promising new avenues to functionally investigate the role of cells in circuitry and in causal relationships with disease-relevant behaviour. Taken together these recent advances provide unparalleled opportunities to gain mechanistic insight into specific brain (dys)function and lay a new foundation for designing innovative treatment options for brain disorders. Goal & Approach: Our primary goal is to gain insight into the molecular and cellular basis of complex brain disorders, by closely connecting genetics to neurobiology, facilitating new experimental approaches, and enabling the design of novel treatment strategies. First, we will develop algorithms to align results from genetic discovery studies with cellular signature maps of the brain and generate actionable hypotheses on the involvement of specific cell types (neurons and glia) in multiple brain disorders. Second, we will verify the involvement of these cell types in human and animal models relevant to selected brain disorders. Third, we will identify the neural circuitry in which identified cell types are involved. Fourth, we will determine the role of identified cell types and neural circuitry in behaviour relevant for the brain disorders. Fifth, at multiple stages of our project we will generate results that can potentially serve as starting points for novel treatment regimens – we will actively monitor this and push translation of our results. The project will build a computational and technological platform to translate genetic findings into mechanistic insights into brain disorders, so urgently needed. The consortium consists of 21 excellent researchers selected for their expertise representing the scientific fields that are crucial to meet the project’s goal. The project capitalizes on recent exciting advances in genetics and neurobiology and is highly timely; never before were the odds so much in favour of mechanistically understanding brain disorders. The BRAINSCAPE consortium is exceptionally well-positioned to successfully realize this unique opportunity.

During CNS drug development the pharmaceutical industry relies heavily on having objective evidence for intervention effects. EEG is increasingly included to provide this evidence. Traditionally, EEG analysis has focused on the spectral features of the EEG, thereby missing information in the temporal and spatial domain. Using only spectral features means that drug-induced effects on brain activity may be overlooked. Consequently, the insights can be inconclusive or even wrong, leading to incorrect decision making during drug development. In contrast, the Neurophysiological Biomarker Toolbox (NBT) provides comprehensive mapping and integration of biomarkers based on the EEG, resulting in accurate indices of drug effects on the brain, which are urgently needed in the pharmaceutical industry.