The role of neural progenitor diversity in striatal neural circuit formation and function

Thesis

The striatum transforms excitatory inputs from across the cortex and thalamus into inhibitory outputs that shape basal ganglia activity and control motor and cognitive behaviours. GABAergic spiny projection neurons (SPNs) are the major neuronal cell type within the striatum and are typically classified into broad populations according to their output targets and location within spatial and neurochemical domains. However, how the cellular and circuit diversity within these populations is established developmentally is largely unknown. As SPNs are born from heterogeneous pools of embryonic neural progenitors, this thesis investigates whether distinct developmental origins can manifest as differences between adult SPNs.

In utero labelling was used to distinguish a molecularly and morphologically distinct apical intermediate progenitor (aIP) pool from other progenitors (OPs) and aIP and OP-derived SPNs were compared with a range of techniques in the postnatal striatum. Firstly, aIP-derived SPNs are shown to have greater dendritic complexity than OP-derived SPNs while sharing similar intrinsic electrical properties. Next, using “patch-seq”, aIP-derived SPNs are found to be enriched for a specific SPN subtype, providing a new link between progenitor diversity and the reported transcriptional heterogeneity of the striatum. Neural circuit mapping approaches then uncover that aIP-derived SPNs receive a weaker excitatory drive from the parafascicular nucleus of the thalamus, showing that progenitor origin can bias the fine-scale synaptic connectivity of striatal SPNs. Finally, single-cell RNA-seq during striatal neural circuit assembly identifies gene regulatory network activity in developing SPNs that reflects their progenitor origin and likely drives their functional maturation. Taken together, these results demonstrate that cellular and circuit complexity in the postnatal striatum can arise from distinct progenitor pools and establish progenitor origin as a novel functional division of SPNs.

Authors: Gordon, J

• DOI: 10.5287/ora-pmxx801yx
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Striatum; neural circuits; transcriptomics
• Subjects: Developmental neurobiology