Assessing ketamine-dependent brain activity using pharmacological fMRI and electrophysiology

Abstract

Functional magnetic resonance imaging (fMRI) has revolutionized the study of functional organization in the human brain. However, there is wider potential for fMRI in translational research. A variation of this technique which promises to broaden the stimulation repertoire in small laboratory animals is pharmacological-fMRI (phMRI). This approach has been used to map the central effects of drugs on both excitatory and inhibitory neurotransmitters in the brain. However, a common issue affecting all these types of studies is the differentiation of changes that are due to the modulation of blood flow affects on the vasculature from the modulation of neural activity and secondary vascular responses. To ensure more selective stimulation of specific brain circuits and neurotransmitter systems, a strong rationale exists to integrate phMRI with more invasive techniques such as electrophysiology.NMDA receptor antagonists are frequently used as pharmacological models of schizophrenia, and offer a good translational approach to evaluate efficacy of new potential antipsychotic drugs. In this thesis, the psychotomimetic effects of ketamine have been investigated using pharmacological fMRI and electrophysiology. Firstly, we developed a phMRI assay to map the brain circuitry activated by subanaesthetic ketamine in the rat brain. These measurements were corroborated in a second study, which also assessed the novel antipsychotic mechanisms of the drug minocycline. While minocycline appeared to suppress ketamine-induced neuronal activity, it also demonstrated a pharmacological induced disruption of neurovascular coupling, with consequences for the interpretation of the data. To overcome this issue, a third study compared the phMRI data with electrophysiological findings to unambiguously show that minocycline can prevent ketamine-induced deficits in glutamate neurotransmission. Finally, to improve the translational capacity of phMRI, we examined the feasibility of using a 3T clinical scanner for small animal imaging studies.Altogether, these results highlight some encouraging correspondences in the circuits that are activated by ketamine both across species and imaging modality. Importantly, the combination of phMRI and electrophysiology proved instrumental in uncovering the functional basis of the antipsychotic-like behavior of minocycline.

Date of Award	1 Jan 1824
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Stephen Williams (Supervisor) & Geoff JM Parker (Supervisor)