HumanCircuits · Understanding the specialized function of human neurons and circuits

Human cognition stands out from other species, but how neurons and circuits in the human brain support cognition is poorly understood. Our recent work showed that human brain holds specialized neuron types – pyramidal neurons in cortical layer 3 (L3 PNs) – with distinct properties that associate with IQ scores. In the human brain, L3 PNs form circuits with each other and another human-specialized interneuron type, double bouquet cell (DBC). These circuits might be critical for human cognition as they are selectively lost in cognitive disorders, but their function in the human brain is unknown. In addition, our data show that human L3 PNs are modulated in a distinct manner by a metabotropic glutamate receptor 3 (mGluR3), a receptor that is important in human and primate cognition. Here, I will test my prediction that cortical computation in the human brain relies on the hyperconnected network of human-specialized neuron types with strong and fast synaptic connections, that can be regulated by mGluR3 to increase computational power. This can only be achieved by novel techniques we recently applied to neurosurgery brain tissue: to study the neuronal function and synaptic properties, I will use multi-cell patch-clamp recordings of genetically-labelled L3 and DBC circuits in organotypic cultures of human brain tissue. To study the molecular mechanism of mGluR3 action, I will combine single cell RNA sequencing (patch-seq technique), and mechanistic interventions by manipulating mGluR3 pathway with viral CRISPRi/a tools. Finally, to link these results to cognition, I will collect cognitive scores and in vivo network function from the same subjects. My proposal will not only deliver valuable data on human neurons but will also provide mechanistic understanding of how human brain operates on neuronal level in circuits important for cognition. Ultimately, mGluR3 might prove to be a promising therapeutic target for diseases marked by cognitive decline.