Frontiers in Systems Neuroscience (Apr 2015)
Neuromorphological and wiring pattern alterations effects on brain function: a mixed experimental and computational approach.
Abstract
Fundamental laws governing the wiring of neuronal networks in the brain are still largely unknown. Understanding both the role and importance of the connectivity patterns that can be observed at different scales in the central nervous system are of crucial interest for advancing our knowledge on neuroscience in health and disease. Intellectual disability pathologies provide an excellent opportunity to address these questions due to their characteristic alterations in neuronal structure and connectivity that induce relative changes of the neuronal network dynamics and, eventually, in their function. Our aim is to identify what are the essential properties of brain connectivity and how they constrain cognitive functions such as information processing, learning and memory. Our approach is based on a mixed experimental and computational approach, addressing different scales of interest ranging from the local connectivity in neuronal modules to the long-range connectomes of mammal brains. Specifically we use Down syndrome mouse models (Ts65Dn and TgDyrk1A) that recapitulate both cognitive impairments and neuromorphological alterations observed in the human chromosome 21 trisomy. Homogeneous neuronal cultures provide a simple enough framework to study spontaneous electrical activity and its dependence on specific structural parameters (dendritic arborisation, axonal path length, connectivity density and excitatory-inhibitory balance). This allows to link concepts such as information processing efficiency or percept storage capacity with the observed connectivity patterns detected in well-controlled in vitro experiments where the biological constraints are minimal. In addition, the study of fixed intact brains (by means of the state of the art CLARITY technique) brings us closer to biologically and medically relevant situations, allowing not only to confirm whether the functional links in neuronal cultures are also present in vivo, but also enabling the introduction of functional information (like behavioral studies and functional imaging) and another layer of structural alterations such as brain region morphology, neuronal density, and long-range connectivity. Taking together the experimental information from these systems we want to feed self-developed computational models that allow us to understand what are the fundamental characteristics of the observed connectivity patterns and the impact of each of the alterations on neuronal network function. These models will also provide a framework able to account for the emergent properties that bridge the gap between spontaneous electrical activity arousal/transmission and higher order information processing and memory storage capacities in the brain. As an additional part of the project we are now working on the application of the clearing, labeling and imaging protocols to human biopsy samples. Our aim is to obtain neuronal architecture and connectivity information from focal cortical dysplasia microcircuits using samples from intractable temporal lobe epilepsy patients that undergo deep-brain electrode recording diagnosis and posterior surgical extraction of the tissue. Our computational models can allow us to discern the contributions of the observed abnormalities to neuronal hyperactivity and epileptic seizure generation.
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