How does the neural circuitry of the hippocampal dentate gyrus shape our memories?

  • Yingxin Li

Student thesis: Doctoral ThesisDoctor of Philosophy (PhD)

Abstract

Episodic memory (EM) is the ability to recall a specific episode, such as the temporal sequence (when), the spatial setting (where) and the people or the objects involved (“what”) in a spatiotemporal context. However, encoding highly similar episodes and places in EM needs to be optimised by a memory discrimination process called pattern separation performed by the hippocampal dentate gyrus (hDG) circuitry.

Excitatory hilar mossy cells (MCs) are involved in pattern separation through their connections with different inhibitory interneuron populations, providing net feedback inhibition to granule cells (GCs) in the hDG circuitry. In this study, I investigated how MCs and their synaptic connections with parvalbumin-expressing interneurons (PVIs) influence the dynamics of hDG circuitry by using pharmacological agents to reduce neurotransmission from MCs, genetically modified (GM) mice to selectively remove MCs from hDG circuitry and optogenetics to manipulate the activity of PVIs during GC whole cell/field recordings. Additionally, I used GM animals that lack MCs to distinguish between the long-range projections of MCs and cholecystokinin-expressing interneurons (CCKIs) in hDG circuitry.

My results showed that 1) Genetic deletion of MCs from hDG circuitry disinhibited GC responses to medial perforant pathway (MPP) stimulation at 10 Hz, 20 Hz and 50 Hz, but not 5 Hz. 2) Pharmacological inhibition of MCs disinhibited GC responses to MPP stimulation at 10 Hz, 20 Hz and 50 Hz, but not 5 Hz. 3) Optogenetic activation of PVIs partially normalized GC responses to MPP stimulation at 10 Hz in GM animals. 4) MCs that express CCK neuropeptides, but not CCKIs, form long-range axonal projections to ipsilateral distal and contralateral hDG.

These findings suggest that the MCs regulate GC responses to MPP stimulation by recruiting interneurons at frequencies associated with pattern separation processing in the hDG.
Date of Award18 Jun 2024
Original languageEnglish
Awarding Institution
  • University of Bristol
SupervisorDenize Atan (Supervisor) & Zafar I Bashir (Supervisor)

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