Synaptic circuit mechanisms of rhythmic oscillatory dynamics in the cerebral cortex

Rhythmic brain activity governs behaviour through the coordination of large numbers of nerve cells within and amongst specialised brain regions. Of particular importance is the formation or recall of everyday memories, which requires the synchronised action of millions of nerve cells of the temporal lobe within about a tenth of a second. In mammals, including humans, such synchronisation is observed as a 'slow' oscillating electrical rhythm measured by electroencephalography (EEG). Embedded within each cycle of the slow EEG signal, higher frequency oscillations emerge in relation to cognitive processes. Brain disorders including dementia and age-related memory impairments are accompanied by perturbation of these brain rhythms, thus highlighting their biological importance. The mechanisms for establishing and maintaining such rhythmic brain activity at various time scales, and the specific roles of the hundreds of nerve cell varieties that cooperate to deliver such a feat of function, remain to be defined. Brain rhythmicity creates sequential "windows" of increased and decreased activity levels of large groups of nerve cells, which enables the cerebral cortex to encode and link actual sequences of real-life events that are represented on distinct oscillatory cycles. In the proposed project, we will exploit our discovery of three novel varieties of nerve cells for establishing their roles in rhythmic oscillatory neuronal activity and memory processing. The novel types of nerve cell are found in a subcortical area deep within the brain called the medial septum, and each type sends parallel projections to a select area or areas of the cerebral cortex that each plays a distinct role in the formation and recall of memories. These cooperative brain areas, including the hippocampus and entorhinal cortex, are the ones first affected by neurodegeneration in Alzheimer's disease. Using a novel technology for the molecular dissection of gene expression profiles of these and other nerve cells in the medial septum, we will provide a comprehensive definition of cell types in both the mouse and the human brain. Building on our recent discoveries, we will establish how the function of these types of nerve cells changes in a mouse model of Alzheimer's disease. We will then use external modulation of the activity of some of these specific pathways to test how to improve memory processing. This project will thus advance our understanding of the functional organisation of the mammalian brain in relation to memory processing.

Neuronal rhythmic synchronous activity in the theta frequency range (4-10 Hz) modulates the frequency and amplitude of gamma frequency (30-120 Hz) synchronisation, reflecting cognitive processes in the cerebral cortex. Theta oscillations are generated in a network of brain stem and midbrain structures and are transmitted to the cortex by the medial septum and diagonal band nuclei (MS/DB), but the principles of organisation of this pathway remain undefined. To identify the cell types in the MS/DB, I propose to provide a comprehensive gene expression profile of neurons using a pioneering technique, in situ RNA sequencing, and compare cell types in the murine and human MS/DB. In the ongoing MRC programme, we discovered that individual neurons in the MS/DB are highly specialised in time and space. We have defined four groups of strongly rhythmic GABAergic neuronal types in vivo. Three of these novel cell types are characterised: the Orchid cells, the Teevra cells and the dentate gyrus-targeting cells. They differ in their cortical target regions and brain state dependent firing in awake mice. We propose to establish their functional roles and contributions to behavioural states in normal and in the THY-Tau22 mouse model of Alzheimer's disease, by analysing their activity and synaptic connections. Using pharmaco- and opto-genetic modulation of their activity, first we focus on Teevra cells that selectively innervate specific GABAergic neurons via GABAergic synapses in hippocampal CA3 area, which provides context-dependent drive to the CA1 area during memory representation. We will test the hypothesis that the disinhibitory temporal windows assisted by Teevra cells increase hippocampal pyramidal cell excitability, providing temporal windows of context dependent read-out of hippocampus-dependent memory traces to the cerebral cortex and subcortical systems. This project will advance understanding of the functional organisation of the brain in relation to memory processing.

The results of the project and the training provided in it will have benefits to a wide range of stakeholders:
(1) Researchers: neuroscientists engaging in basic brain research, both experimentalists and theoretical, clinicians working with patients suffering from dementia, neuroimaging specialists researching the human brain (e.g. functional MRI, connectomics), engineers and technologists (e.g. those working on brain-machine interfaces), molecular biologists, biochemists.
(2) Private sector: pharmaceutical companies undertaking drug discovery and clinical trials relating to Alzheimer's disease.
(3) Organisations, Institutes and government: national policy makers assessing the medium and long-term impact of basic neuroscience on society, European brain science initiatives such as the Human Brain Project, international Institutes (e.g. Allen Institute, Peter Somogyi serves on the Advisory Council of the theme "Human cortical cell types").
(4) Public sector: Alzheimer's Research UK charity, schools and other educational establishments, care homes.
Each group will benefit from the research in different ways:
The short-term benefits will be the impact on the research carried out by other neuroscientists and clinicians within the same field. Once our data are disseminated (e.g. through peer-review publication), other laboratories will immediately be able to use the results to design, modify or further support their experiments or re-evaluate their previous findings. For example, for researchers using Alzheimer's disease mouse models, they will directly be able to determine whether our findings on cell types within the basal forebrain projecting to cortical areas that degenerate in Alzheimer's disease may explain their results. Since our research output includes both neuroanatomical (e.g. projections from subcortical regions to the cortex) and neurophysiological data (e.g. role of network oscillations), studies on the human brain (e.g. neuroimaging) will gain a deeper understanding of the link between neuronal communication across cortical areas and 'functional' connectivity. Within the first 6 months of the project, as it is a continuation of current research, we expect to have published significant progress explaining cellular and synaptic mechanisms of setting up and maintaining rhythmic synchronised brain activity in the cerebral cortex.
In the medium to long-term, our research will benefit human health, as our results will be incorporated into understanding and explaining information processing in the brain.