Cortical microcircuiltry after traumatic brain injury: molecules to networks

Traffic accidents, accidental falls and violent attacks may result in the damage to a person’s brain: the ability to move, feel, speak, form memories and judgments can be lost at once. Repairing this damage is often beyond our current therapeutic abilities. Nerve cells become disconnected following the impact and parts of the brain become unable to communicate with each other. Yet some cells manage to establish new contacts and some level of recovery can arise although it is never complete. Which nerve cells are important for recovery? What happens to those disconnected cells, and why some do some succeed and others fail at making new connections? Are memories, movements, and feelings lost beyond repair, or can we restore lost functions? We have to answer these questions to improve the condition of those patients for whom there are few treatment options.
In this project, we will use the most advanced technologies available for visualizing how and when nerve cells lose connections after trauma and regain the ability to communicate with each other. We will develop new methods, bringing together scientists from computer science, medicine and biology to understand which nerve cells need to be stimulated for recovery to happen. Then, we will look for ways to promote such recovery. We will screen for drugs that have a positive regenerative effect on damaged neural cells and can therefore be used in the treatment of traumatic brain injuries. We will also study new ways to predict how successful the recovery will be. Our long-term goal is to funnel all this information into a coherent rehabilitation program aimed at severely impaired patients and help them to regain integrity of brain and mind.

Traumatic brain and spinal cord injury lead to severe motor, sensory and cognitive dysfunctions, which are then followed by a variable recovery in performance. The acute functional deficits depend on the injury severity and extent of neuronal and connectivity loss (deLanerolle et al., 2015). Direct severing of neuronal processes by the mechanical forces set forth detrimental consequences of pathogenic cascades, such as signaling cascades and inflammation. On the other hand, the recovery phase depends on the compensatory and repair responses attributed to the spontaneous circuit connectivity rearrangements that take place after neurotrauma. In a partial spinal cord injury model, sprouting of existing supraspinal and propriospinal connectivity, as well as the formation of new detour connections to input-deprived neurons are fundamental in triggering the recovery of effective locomotor function. Notably, this remodeling of local and long-range connectivity is critically dependent on a specific somatosensory input, namely, from muscle spindle afferents. Moreover, synaptic input and activity properties also shape vulnerability and neuronal survival, suggesting that the connectivity of a neuronal network also affects the activation of signaling cascades at the level of a single neuron.

As functional and structural connectivity are key targets of acute pathogenic cascades and are significant modulators of recovery, it is essential to understand both acute and chronic effects of TBI in the context of neural circuitry.

The proposed collaborative project, therefore, aims to understand changes within the cortical microcircuitry in the acute and recovery phases and to identify factors, both in intracellular and extracellular context, which shape this restructuring. The ultimate aim of the project is to derive new targets for translational applications.