Synaptic circuit mechanisms of rhythmic slow oscillatory dynamics in the rodent and human cerebral cortex

Co-ordinated neuronal activity in the brain is intrinsically linked with behaviour. Malfunction of neuronal coordination results in psychiatric and neurological disorders. Much of the brain activity is rhythmic, as rhythmicity facilitates local and global interactions and enables the representation of temporal sequences. Rhythmicity resets the parameters of neuronal population activity for encoding and delivering information in support of behavioural needs. Importantly, the action of single nerve cells as well as groups of neurons can change systematically relative to the population rhythm and is used by the brain for coding of information.
We explore a widespread rhythmicity in the cerebral cortex in the so-called theta frequency range (4-12 cycles per second) in rodents and the homologous brain areas in humans. Theta oscillations are linked to higher frequency oscillations associated with cognitive processes. Such linking of rhythmicity with different frequencies is a basic principle of the brain, as changes in the strength of links indicate behavioural performance, cognitive states such as navigation, decision-making and memory and are impaired by pathology such as dementia. We identify the nerve cells, the links between them, and sites where influencing the memory system with drugs, or changing the activity of selected pathways restores normal rhythmic activity and improves co-ordination by attenuating pathological activity.

Co-ordinated neuronal activity is intrinsically linked with behaviour and malfunction of neuronal coordination results in psychiatric and neurological disorders. Timing is crucial for neuronal integration including events lasting from milliseconds up to several seconds. Much of the neuronal activity is rhythmic in the brain. Rhythmicity facilitates local and global interactions and enables the representation of temporal sequences. Rhythmicity provides flexibility by resetting the frequency, amplitude and phase of population activity for encoding and delivering information in support of behavioural needs. Importantly, firing of single neurons and that of groups of neurons can change systematically relative to the population rhythm and reflect temporal coding of information.
We study the mechanism of a widespread cortical oscillation, rhythmic slow activity in the theta frequency range, typically 4-12 Hz in the temporal cortex of rodents and humans. Theta oscillations modulate higher frequency gamma (30-120 Hz) oscillations associated with cognitive processes in humans. Such cross-frequency coupling is a basic principle of brain function as changes in coupling strength indicate dynamic changes in neuronal network activity underlying behaviour, cognitive states such as navigation, decision-making and memory performance.
Programme objectives
• To define how specific cell types contribute to the timing of neuronal population activity in the hippocampus and temporal cortex.
• To establish the identity of GABAergic neurons in the cerebral cortex and subcortical areas innervating it, and to determine their in vivo firing patterns relative to theta, gamma and high frequency 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 cortical network is a condition of the synchronous pyramidal cell discharge.
• To explain how behaviour specific changes emerge in interneuron firing and how these changes contribute to pyramidal cell activity.
• To define the cellular and synaptic mechanisms of subcortical influence on cortical network oscillations.
• To determine the identity and distribution of specific neuronal types in the medial septum and cortex of the human brain.
• To identify specific sites and links in the temporal lobe memory system for modulation by drugs and electrical activity in order to improve pathological memory processes.
We explore how distinct neuronal types contribute to behaviour, and how the network mechanisms governing neuronal activity relate to both normal and abnormal brain function in rodent disease models. We hypothesise that temporal coordination of neuronal assemblies is regulated by a temporal redistribution of inhibition over principal cell subcellular domains. We reveal how the firing patterns of different GABAergic, cholinergic and glutamatergic neurons relate to network oscillations during different behavioural states such as movement and sleep and how their connectivity to other cells explains the underlying network oscillations. By extracellular recording and single cell labelling, we can capture the temporal properties during different network and behavioural states and also determine the synaptic sites of interaction through cell type identification and axon target distribution. The rigorous definition of circuits, cells and molecules helps to define the chronocircuitry of the brain.