Title: Co-operative interactions of identified neurons in hippocampal network activity
Funder: Medical Research Council

Abstract: Neurons of the cerebral cortex generate temporally patterned neuronal activity, which assists and constrains interactions with other neuronal centres and the environment. Synchronous rhythmic cortical activity correlates with behaviour and performance, and also indicates malfunctions in diseases. Understanding how the co-operation of diverse cell types leads to synchronous rhythmic activity and how this activity supports performance will help to explain cortical function and disorders. This programme defines how synchronous activity and embedded information processing emerges in the CA3 area of the hippocampus, a brain area involved in learning, memory encoding and retrieval, where more than twenty distinct cell types may exist in the rat. The cell types are identified by synaptic connections, in vivo firing patterns and cell type specific sets of signalling molecules. Building on our insights into the CA1 hippocampal region, we focus on how high-frequency gamma and sharp wave associated ripple oscillations are initiated and generated in the CA3 area. Gamma oscillations organise pyramidal cells into assemblies forming representation, whereas ripple oscillations may be involved in memory consolidation. We dissect the oscillations in time and space elucidating the contributions of different cell types. A central hypothesis is that sharp wave events in the CA1 area, a highly synchronous network state, are generated by phasic disinhibition of CA3 pyramidal cells, due to the inhibition of specific types of GABAergic neuron. We will establish the source of inhibitory inputs to these interneurons and monitor the contribution of each cell class to network and behavioural performance. The results will give a systems level explanation of how temporally defined and highly accurate neuronal activity emerges through the co-operation of identified neurons in a well-defined cortical network. Aims: To define how specific cell types contribute to the timing of neuronal population activity in the hippocampus. To establish the identity of GABAergic neurons in the CA3 area and determine their in vivo firing patterns relative to network oscillations and pyramidal cell activity. To test the hypothesis that disinhibition (i.e. the phasic inhibition, or deactivation of key GABAergic neurons in the CA3 area) is a condition of the synchronous pyramidal cell discharge in CA3 assembly activity that generates sharp waves in the CA1 area. To discover what inputs might inhibit GABAergic neurons. To test how sharp wave ripple events influence downstream targets of hippocampal output. To explain how behaviour specific changes in interneuron firing contribute to pyramidal assembly activity. To test if the cell types recognised on the basis of synaptic target specificity and molecular expression profiles in rodents can be identified in the human cortex. The realisation of these aims will explain the role of identified neurons in well-defined and behaviourally significant cortical network events.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL