Bridging cells to cognition: evolutionary adaptations in cortical microcircuits and their genetic correlates

In Chapter 2, we investigated evolutionary adaptations in the human cortical microcircuits. The main research question of this chapter is, Can FSINs preserve their inhibitory function in the expanded human neocortex, and what are the underlying adaptations? Fast signalling of these interneurons has been intensively studied in both rodents and humans, and in this thesis, we sought to study how is this function preserved in three-fold thicker and more expanded human cortex. Using experimental recordings and computational modelling, we found the key adaptations which allowed the human fast spiking interneurons to preserve their fast input-to-output function and fast signal processing: 1) the elongated but structurally less complex dendrites of human FSINs, 2) faster action potential output generation as a result of the changes in neuronal morphology, and 3) larger synaptic inputs from surrounding pyramidal cells. While human circuits have undergone adaptations in the course of human brain evolution to support higher cognitive ability, individuals within human population also differ greatly in their intellectual abilities. These differences might be supported by structural and functional cellular mechanisms similar to evolutionary adaptations. We address the question of cellular basis of these interindividual differences in Chapter 3. Does individual variation in cytoarchitecture of the cortical columns and specifically L2/3 explain the difference in patients? Previous research in the lab showed, that cells within L2/3 of the human cortex are related to intelligence: individuals with higher IQ in our cohort showed a thicker cortex in the MTG. The thicker cortex contained larger cells with more complex dendritic trees, which fired fast action potentials and were able to follow fast synaptic inputs of higher frequencies. In chapter 3 we investigate these relationships further. We show that this cortical expansion is driven by the expansion of L2/3 specifically, and takes place in the left, but not right hemisphere. This is accompanied with changes in the microstructure of L2/3: we show that higher IQ is associated with thicker yet less densely populated cortical organisation, with larger cell bodies. In search of genetic origin of intelligence and brain evolution, hundreds of genes were identified that associate with cognitive abilities of show accelerated evolution in the human lineage. However, it is still unknown, how and if these genes influence the function of single cells in the cortex. In Chapter 4 we investigate the expression of genes previously implicated in human brain evolution and intelligence, and their relation to the structure and function of single neurons. We ask the questions, Are genes previously related to human brain evolution and intelligence expressed in the adult human brain cortex, in which cell types, what is their role, and do they influence the structure and function of single neurons? In our research we observed that on the cellular level some evolutionary adaptations in humans are similar to those underlying interindividual differences in cognition. Thus, thicker cortex, larger and faster cells and higher computational ability distinguish humans from mice but also shows a gradient in subjects with lower to higher IQ. In this chapter we investigate the potential link behind this overlap: genes. We study the expression of intelligence-and evolution-associated genes across brain areas and cell types and found that higher-order brain areas show higher expression of these genes. Moreover, within L2/3 of the MTG, larger and deeper human-specific cell types showed higher expression of these genes. When we correlated the expression of each gene separately to the single-cell features we found a subset of genes which showed significant correlation, and majority of these genes are mapped to synapses, indicating their potential role in life-long learning.