Assembly and diversity of long-range inhibitory circuits in the brain

The mammalian neocortex hosts some of the most complex neural circuits in the brain. These typically consist of two main types of nerve cells — excitatory projection neurons which deliver information to other cells over long distances using the neurotransmitter glutamate, and inhibitory interneurons that provide local inhibition by secreting the neurotransmitter GABA. How these cortical circuits compute information remains largely unknown, but most current models of cortical processing are predicated on the basic tenet that output neurons — the cells that relay processed information to other cortical or brain regions — are excitatory glutamatergic neurons, and their activity is fine-tuned locally by GAGAergic interneurons. While there is considerable support for this circuit architecture, it is likely to be incomplete, because not all cortical inhibitory neurons are locally-projecting cells. An estimated 10% of GABAergic cells are, indeed, long-range projecting neurons. The presence of this neglected cell type in the cortex is likely to have important consequences for its function in both health and disease states. The main objective of my PhD is to understand the functional diversity and development of these cell types. Specifically, I will link the projection patterns of long-range cortical GABAergic neurons to their transcriptional signatures. I plan to use novel approach that combines mouse genetics with retrograde labelling and scRNAseq. I will characterise the relative abundance of long-range GABAergic neurons in different cortical regions, and then we will determine the development of the GABAergic cortico-striatal projections in mouse model. Collectively, my PhD work will let us understand long-range GABAergic neuron arise during development of the neocortex, how they integrate into functional circuits and, ultimately, how they shape the network in the adult brain.