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FRIMED2-FRIPRO forskerprosjekt, medisin og helse

Neural processing and plasticity in cortical circuits of behaving animals

Awarded: NOK 8.7 mill.

How can the brain be stable enough for memories to be stored and intact for decades but at the same time be plastic enough for us to learn throughout life? This seemingly paradox is one of the unresolved long-standing questions in neuroscience. One of the most well established models for studying brain plasticity has bee activity-dependent plasticity in the visual cortex. Here, brief changes in the sensory inputs lead to profound and long-lasting changes in the cellular responses and wiring of neurons in the visual cortex. In humans, one takes advantage of these findings in the treatment of strabismus where the brain stops to use the recessive eye if left untreated. Therefore, children with strabismus wear a patch on the dominant eye to force the brain to use the recessive eye. If left untreated, the patient may become functional blind, amblyopia, on the recessive eye despite a healthy eye. The cell-specific and molecular mechanisms underlying this plasticity still remains fairly unknown. In the present project we use advanced microscopy, electrophysiology and genetic tools to identify the underlying mechanisms on activity-dependent plasticity in the visual cortex. The outcome of these investigations bring insights into the operating principles of activity-dependent plasticity in the visual cortex as well as other plasticity processes in the brain. Traditionally, measurements of neural activity in the visual cortex have been conducted in anesthetised animals. However, anesthesia has profound effects on brain activity and function and in order to understand cognitive processes such as learning we need to investigate awake and behaving animals. We started out investigating how neural responses from the same neurons compares between the anaesthetic and awake states. This work was published in eNeuro in 2017. During this work we have discovered a novel functional characteristic of a subpopulation of neurons in the visual cortex. These neurons have features that seem important for processing of visual information and could only be discovered by our quite unique recordings from awake and freely moving animals. This unique finding has been presented at international scientific conferences and the work will soon be submitted for publication. We went on to investigate how activity-dependent plasticity is reflected in neural activity on the single neuron level. We therefore, for the first time, followed neuron activity from the very same neuron across the course of plasticity processes. This work was published in Journal of Neuroscience in 2017. Furthermore, we investigated molecular mechanisms for brain plasticity first by developing a mouse model which allowed us to locally delete the gene for a core protein in the extracellular matrix surrounding specific neuron sub-types. By local deletion of this gene in the visual cortex of adult mice we could show that this protein was essential to the condensation of the extracellular matrix and by this manipulation, the plasticity was restored to juvenile levels. This work was was published in Journal of Neuroscience. Finally, we tested a transgenic mouse line where transporters for neurotransmitters in the synapse have been manipulated. We found that these transporters are necessary for brain plasticity. This work was published in Cerebral Cortex. Altogether, the investigations in this project have provided novel insights into visual information processing and the molecular and neural mechanisms directing visual cortex plasticity. The findings and methods established are followed up in other projects and have laid the foundation for new plans for research proposals.

Prosjektet har avdekket nye mekanismer for behandling av synsiformasjon i hjernen og bidratt til å utvikle nye metoder i vår forskningsgruppe. Prosjektet har bidratt til nye tverrfaglige samarbeid og har dannet grunnlaget for andre prosjektsøknader. Prosjektet dannet grunnlaget for 3 PhD prosjekter (Lensjø (2017), Aasebø (2018) og Mogbarhan (2018)).

What are the mechanisms underlying the remarkable ability of the brain to learn from experience? It is well known that closing one eye for only a few days in early postnatal life leads to rapid and long-lasting changes in visual cortex, but how does such plasticity relate to the lifelong ability of the brain to learn? Most of our knowledge of the physiology of visual cortex comes from in vitro preparations and acute recordings in anesthetized animals. However, in order to understand neural processes of the awake brain, studies of animals that interact with its environment are needed. Furthermore, in previous studies of spine dynamics a causal relation between spine turnover (structure) and function remains elusive because the functional and structural changes of the same neurons have not yet been assessed. We propose to identify network dynamics and plasticity changes in visual cortex of behaving mice and rats that experience one of two forms of activity-dependent plasticity: perceptual learning or sensory deprivation. A multilevel approach will be taken to identify the cell-specific morphological and functional changes to single neurons and network processing that operate during these two forms of activity-dependent plasticity. To achieve this, we will combine genetic tools with transcranial two photon microscopy and large-scale electrophysiological recordings with single cell resolution. This research will pioneer the combined functional and structural analysis of cortical circuits in animals interacting with its environment to provide a mechanistic understanding of neural plasticity and computations in the awake brain. This line of experiments in behaving animals opens an avenue of possibilities on which I will base my future research to untangle how experience modifies cortical circuits to provide a substrate for long-lasting memories.

Funding scheme:

FRIMED2-FRIPRO forskerprosjekt, medisin og helse

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