Abstract
Hippocampal CA3 is a region of the brain essential for memory processing. Neuromodulators, such as acetylcholine and noradrenaline, are released into the hippocampus during particular behavioural states and are suggested to modulate hippocampal circuitry to enable the encoding of memories during novel and salient experiences.In this thesis, I used a combination of biophysical neuron modelling, ex vivo whole-cell patch clamp and optogenetic techniques to assess the impact of acetylcholine on synaptic transmission and dendritic integration in CA3 pyramidal neurons.
NMDA-mediated nonlinear integration was investigated in a biophysical multi-compartment model of a CA3 pyramidal neuron. Increasing the number of stimulated synaptic inputs within individual dendritic branches generated nonlinear increases in the dendritic response amplitude, with lower thresholds for nonlinearity in the distal SLM dendrites, due to increased dendritic input resistance. Simulation of acetylcholine, via inhibition of specific potassium channels, reduced the threshold for NMDA-mediated nonlinear synaptic integration to a greater extent in the proximal SR dendrites compared to the SLM dendrites.
In ex vivo hippocampal slices, bath application of a cholinergic agonist reduced CA3-CA3 recurrent transmission, via a pre-synaptic mechanism, and increased CA3 neuron excitability. On the other hand, noradrenaline had no impact on CA3 recurrent transmission or on neuron excitability. In contrast, optogenetic stimulation of cholinergic fibres in the CA3 region did not affect this recurrent transmission or synaptic transmission from perforant path stimulation. Endogenous acetylcholine did however reduce inhibitory inputs to CA3 pyramidal neurons, suggesting a disinhibitory action, with the primary impact of increasing CA3 excitability.
Overall, the ability of acetylcholine to increase CA3 neuron excitability and reduce the threshold of dendritic nonlinearity indicates potential mechanisms for cholinergic facilitation of synaptic plasticity and memory encoding within the CA3 network.
Date of Award | 21 Mar 2023 |
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Original language | English |
Awarding Institution |
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Supervisor | Jack R Mellor (Supervisor), Cian O'Donnell (Supervisor) & Krasimira T Tsaneva-Atanasova (Supervisor) |