The Role of Medial Prefrontal Cortex Interneurons in Associative Recognition Memory

Abstract

Associative recognition memory, such as recognising an old friend or finding your car in a carpark, requires the quick integration of familiarity, spatial location and temporal information that is vital for everyday learning and episodic experience. The medial prefrontal cortex (mPFC) is proposed to be a key integration hub within the associative recognition memory circuit as it receives excitatory inputs from the nucleus reuniens (NRe) and intermediate hippocampus (iCA1 HPC), both pathways being critical for associative learning. Cortical inhibitory interneurons play essential roles in different forms of memory by gating signal flow and sculpting microcircuit dynamics. However, the role mPFC interneurons have in associative recognition memory and its networks is unknown.

Combining intersectional transsynaptic viral tracing, slice electrophysiology and in vivo wireless optogenetics in PV, NDNF and SST Cre mouse lines, the results in this thesis demonstrate that iCA1 HPC and NRe projections have distinct laminar distribution within the prelimbic cortex, NRe predominately targets layer 1 (L1) whereas iCA1 inputs are more uniformly distributed across prelimbic layers but primarily target layer 5. Optogenetic activation of iCA1 and NRe inputs to prelimbic cortex in vitro showed divergent short-term plasticity at L1 NDNF interneurons, while both pathways showed uniform synaptic depression at PV interneurons and low connectivity to SST interneurons. Wireless, in vivo optogenetic inhibition of NDNF and PV interneurons during an object-in-place associative recognition task demonstrated that both subtypes are required for memory retrieval after short and long delays but are not necessary for encoding or consolidation. Together, this work suggests that mPFC interneurons not only receive iCA1 and NRe inputs, but also differentially integrate these signals into mPFC microcircuits that may ultimately modulate the retrieval of associative recognition memory.

Date of Award	30 Sept 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Zafar I Bashir (Supervisor) & Elizabeth Warburton (Supervisor)