Investigating the connections of medial prefrontal cortex interneurons across adolescence

Abstract

The medial prefrontal cortex (mPFC) is a highly interconnected region, allowing it to orchestrate a diverse range of behaviours including decision making, working memory, attentional processes, and visceromotor activity. Layer 1 (L1) of the mPFC contains neuron-derived neurotrophic factor (NDNF) and vasoactive intestinal peptide (VIP) interneurons and is theorised to integrate bottom-up and top-down signals within the cortex, receiving a wide range of local circuit interactions, long range inputs, and thalamocortical connections. Synaptic refinement and pruning continues throughout adolescence in the mPFC, and is described as neurobiological critical period, whereby aberrant connectivity is associated with higher incidences of neurodevelopmental disorders. To understand how this synaptic refinement influences the connectivity of different mPFC interneurons (INs), we used monosynaptic rabies tracing to study how inputs to NDNF and VIP mPFC interneurons change across development. We show that the role of NDNF INs in the integration of higher-order feedback signals is stable across development, and that whole-brain inputs become sparser with age, consistent with a reduction in the proportion of connected presynaptic neurons due to synaptic pruning and refinement. In contrast, whole-brain inputs to VIP mPFC INs remain relatively constant across development. Thalamic inputs to both IN subtypes became more cell-type specific across development, with the ventromedial thalamus (VM) preferentially inputting onto NDNF INs, and the mediodorsal thalamus (MD) preferentially inputting onto VIP INs. Overall, our data suggests that NDNF INs may play a more pronounced role in the developing connectivity of the mPFC, whereas VIP INs are less impacted. These results provide novel insights into how the whole-brain connectivity of the mPFC changes across development and may provide further insights into the pathology of neurodevelopmental disorders.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Paul G Anastasiades (Supervisor) & Gabriella C Margetts-Smith (Supervisor)