Investigating the role of hippocampal-cortical circuits in memory, and their dysfunction in a rat model of Fragile X syndrome
Item statusRestricted Access
Embargo end date17/08/2023
Moore, Joe W.
Place cells in the hippocampus form an internal spatial representation of an animal’s environment, which is thought to provide a basis for spatial and episodic memory. In order to form this representation, inputs from other areas of the brain, via the entorhinal cortex, must carry sensory information about the surroundings. The medial prefrontal cortex may also play a role, in organising information flexibly, and consolidating memories during sleep. The overall aim of this thesis is to study these brain networks and their function in spatial and episodic memory formation and consolidation, including assessing the role of specific connections and studying how network activity is affected in a model of intellectual disability. A key property of hippocampal place cells is anchoring of their firing to distal and proximal landmarks. The first experiment aimed to test the hypothesis that the medial entorhinal cortex (MEC) is required for anchoring of hippocampal place cells to distal landmarks. Tetrodes were implanted into dorsal CA1 of the hippocampus and place cells were recorded from mice in which the MEC had been lesioned, and control mice that had undergone a sham surgery. The mice explored a platform surrounded by visual landmark cues which were rotated by 90° around the platform between sessions. The place cells in the control mice were shown to anchor to the visual landmarks, as has been demonstrated previously, whereas the place cells from the lesioned mice did not rotate with the visual landmarks. A rotation protocol using objects within the environment as cues showed that place cells in MEC-lesioned mice did rotate their fields to follow objects. These findings suggest that information about distal visual landmarks, but not proximal objects, may be integrated into the hippocampal spatial representation via the MEC. The second experiment was designed to test the hypothesis that layer 2 stellate cells (L2SCs) in the MEC are required for episodic-like memory in mice. The MEC L2SCs form a major projection to the hippocampus, and are among the first neurons to be affected in Alzheimer’s disease. Mice with inactivated L2SCs were compared with control mice injected with a GFP virus on performance in a series of spontaneous object exploration tasks. No significant differences between the groups were found in object recognition, or object association memory, but low virus expression as well as low subject numbers meant that it was difficult to make reliable conclusions from these results. Fragile X Syndrome (FXS) is one of the most common inherited forms of intellectual disability. In the final experiment, a model of FXS, the Fmr1 knockout (Fmr1-/y) rat was used to test functional connectivity between the hippocampus and medial prefrontal cortex (mPFC) as a potential mechanism that may cause spatial memory deficits. Tetrodes were implanted into both regions in wild-type (WT) and Fmr1-/y rats, and the local field potentials in each region were recorded as the rats explored a familiar environment, followed by a novel environment. Fmr1-/y rats showed increased mPFC gamma power, as well as increased coherence between the mPFC and hippocampus, across all of the sessions. During a period of sleep following each day of environment exploration, cortical spindles, delta waves, and hippocampal ripples were detected and interactions between them analysed. Fmr1-/y rats had fewer ripples during slow wave sleep than WTs, and they were timed to a different phase of the cortical delta oscillation. Ripples were also less strongly modulated with the phase of mPFC spindle oscillations in Fmr1-/y rats. This evidence suggests discoordination of mPFC and hippocampal networks in Fmr1-/y rats that may underlie memory encoding and consolidation deficits. The results presented in this thesis contribute to understanding how sensory information is integrated into spatial and episodic memories, as well as how organisation and consolidation of memories may be affected in a model of intellectual disability.