CIRCUIT-HUBS · Functional connectivity of developing hippocampal networks: characterization of “circuit-hubs”

Functional connectivity of developing hippocampal networks: characterization of circuit-hubs

Hypothesis and objectives The hypothesis at the basis of our research proposal was that synchronous network events are dependent on precise connectivity patterns between neurons. In particular we tested the existence of 'circuit-hubs' that are 'super-connected' cells that provide developing networks with fast transmission of information. Therefore our proposal was organised along three main objectives: (1) understanding the functional topography of hippocampal circuits; (2) proposing a morphophysiological description of 'circuit-hubs'; (3) analysing the function of 'circuit hubs'. Our hypothesis was correct and in our project we were able to demonstrate for the first time the existence of neuronal hubs and we achieved all the three objectives. Objective 1: understanding the functional topography of hippocampal circuits. Neuronal networks share common features with very diverse networks such as internet and airline. All of them include hubs, super-connected nodes. Using fast two-photon calcium imaging, we first demonstrated that the functional organisation (topology) of the developing hippocampal networks follows a scale-free model. These complex topologies have been found in contexts as diverse as the Internet, social sciences, airline traffic or biology. Therefore analogously to hubs in internet or airline traffic, we proofed the existence of neuronal hubs. Objective 2: proposing a morphophysiological description of 'circuit-hubs'. Hub neurons are GABAergic cells with widespread axonal arborisations compared to non-hub neurons. Therefore hubs are able to contact many cells in the network and orchestrate their activity. By using transgenic GFP mice and morphological reconstruction of neurons, we demonstrated that hub neurons are GABAergic neurons (i.e. a sub class of neurons releasing the neurotransmitter GABA) with very spread arborisation. Objective 3: analysing the function of 'circuit hubs'. Perturbations of network activity induced by the stimulation of hub neurons. We demonstrated how stimulation of a single hub cell can affect the activity of the all neuronal network. In particular, we observed that stimulation of the hub can: 1) trigger activity in the all network 2) slowing down the rhythm of network events 3) abolish the of synchronous network events. By the end of the project we can reach the following results which are in agreement with what expected and described in the project.: (1) By reconstructing the temporal dynamics of the network we identified 'hub cells' capable to orchestrate its activity. (2) By performing targeted electrophysiological recordings of hub neurons we characterised their functional properties and confirmed that they orchestrate the oscillatory activity of the network. (3) Hub neurons, although still immature, display spread and wide morphological features. (4) Hub neurons are specific cell types (GABAergic cells). (5) We demonstrated that inter- and multidisciplinary strategies bridging mathematics and physics to neurobiology are strongly appropriate in brain research. Expected outcome beyond the scope of the proposal By reaching the above mentioned objectives, we can open a wide field of investigation that goes far beyond questions of developmental neurobiology. Indeed, the next logical step which followed the outcomes of this project was to perform experiments on genetically engineered mice where the specific neurochemical marker for these neurons would be tagged with GFP. Based on our results, we hypothesise that hub neurons are early developed neurons. Therefore we started to perform experiments on GFP mice where early developed neurons marked with GFP proteins. In this way, we'll be able to perform a full description of these cells.

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