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Spatial-temporal characteristics of Cortical Reorganization after Spinal Cord Injury and the role of interneurons and astrocytes

Periodic Reporting for period 1 - CRASCI (Spatial-temporal characteristics of Cortical Reorganization after Spinal Cord Injury and the role of interneurons and astrocytes)

Reporting period: 2018-08-01 to 2020-07-31

Problem
Spinal cord injury (SCI) is a damage to the spinal cord that causes temporary or permanent changes in strength, sensation and other autonomic functions in body parts below the injury level. In addition, SCI also affects brain activity as it interrupts the sensory information flow from the periphery to the somatosensory cortex (S1, brain region responsible to receive and interpret the information from the world to generate an output behaviour). The loss of incoming signals to the brain initiates a process of plasticity (reconnection between neurons) called cortical reorganization (CoRe), in which neuronal activity from adjacent, intact brain regions increases and expands towards the affected area. CoRe is crucial for the functional recovery of SCI patients, but when exacerbated can trigger pathologies such as neurophatic pain, phantom sensation and spasticity that drastically decrease the quality life of the patients. Therefore, knowing the mechanisms by which CoRe occurs in time is key to generate new therapeutic strategies to promote and/or limit the extension of the reorganization following SCI and other traumatic brain injuries.

Societal Impact
The SCI is one of the most important worldwide causes of death and disability affecting patients, relatives, caretakers and the society. In 2016, ~0.93 million of new SCI cases were addressed, with ~27.04 millions of prevalent cases. The estimated average annual burden is very high with an annual cost for the 1st year between EUR 92k and 212k in Spain. Nowadays there is no cure or treatment for SCI. Therefore, the number of patients is always increasing becoming a public health problem worldwide. In the last decade, new neuromodulation techniques applied to the brain have revolutionized the SCI field, showing that directly modulation of brain activity can trigger new spontaneous neuronal connections in the spinal cord to promote locomotion and can be used to treat secondary pathologies associated with the lesion. Therefore, a deep spatial-temporal characterization of the changes in brain activity and the cellular components underlying such alterations is utterly important to improve and/or generate new therapeutic protocols. By interconnecting two prominent fields in physiology research, system neuroscience and neuronal network, the findings emerging from this MSCA project offer promising outcomes for brain injuries with direct impact on both the society and the scientific community.

CRASCI overall objectives
CRASCI focused on the study of the mechanisms controlling/limiting the extension of the cortical reorganization after SCI. To do that, the multidisciplinary project had three main objectives: (i) an in-depth S1 layering characterization of the CoRe at distinct time points after SCI, (ii) to investigate how reorganisation following SCI changes the activity of inhibitory interneurons and (iii) to study the role of astrocytes in modulating somatosensory CoRe.

Conclusions of the Action
CRASCI was completed according to the proposed plan in Annex I, without major deviations. The achievements within the Project were:
1.The characterization of the overall physiological phenomena of CoRe across layers and the role of astrocytes in controlling the strength of the corticocortical connections responsible to such process.
2.The development and the implementation of new techniques to study in vivo the role of neuron-astrocyte interaction in triggering neuronal plasticity.
3.Successful integration of the MSCA fellow at the Host, fulfilment of the training objectives (i.e. new scientific, communication and teaching skills, scientific leadership, management and increased scientific network) and accomplishment of the two way transfer of knowledge between the researcher and the Host lab/institution.
4.The MSCA fellow successfully achieved a Career Development Plan that ultimately led to a Tenured-Track position as an independent researcher (Ramon y Cajal Program Researcher) at the Host Institution.
CRASCI was performed in 5 WPs. WP1 studied how SCI changes neuronal activity within cortical areas receiving information from body regions below injury level. Our data indicates a layering-dependent mechanism of CoRe, with L2/3 underlying the most significant increase in activity. This result is of importance as L2/3 undergoes most of the connectivity between distinct brain areas and could be key to control reorganization. WP2 studied if changes in neuronal activity were mediated by simultaneous alterations of inhibitory neurons. Using anatomical techniques we found that inhibitory synapses onto excitatory L5 neurons are increased after SCI, leading to a decreased excitability. In WP3 we genetically manipulated astrocytes and found that these glial cells modulate neuronal expansion and therefore could be used as a therapeutical target to enhance/limit CoRe. Following our data in SCI, we also studied the astrocyte role in traumatic brain injury and showed that the interplay between astrocytes and microglia leads to synaptic remodeling with beneficial impact on motor behavior.

Exploitation and dissemination:
CRASCI was disseminated through articles, meetings and local media. I have already published some of the data in one of the top journals in the field (9/275, IF: 8.78) as first and corresponding author and have another one as 1st author under revision. Two more manuscripts, as last and corresponding author, are in preparation and will be submitted by the end of the year. I was invited speaker in 2 International and 2 National Meetings, 1 Regional Symposium, and organized an International Symposium. I also presented our findings as 6 posters in 3 European Meetings as leading researcher. Mentoring included 1 PhD student, 2 Master Students, 2 Final Undergrad student projects and 3 undergrads. I am a current professor at the Neuroscience Master. As part of dissemination, at the beginning, local radio interviews and press dissemination were given to notify society that a MSCA project would start at the Host Institution. During the whole time, I also participated to disseminate the joy of science at local schools by going to their classrooms or preparing online videos about science. With the support of MSCA, my grad student created a video to broadcast the MSCA project to the society. I actively engaged in activities to disseminate the role for WOMEN in SCIENCE and I am the current president of the Dissemination Committee of our Institution.
CRASCI development went beyond its initial objectives, with the demonstration of two major scientific advances. First, the spatial-temporal characterization of CoRe enabled the understanding of not only the mechanisms of somatosensory reorganization but also helped us dwell on the principles of brain plasticity that may underlie memory, cognitive processes, phantom sensations, chronic pain, and the study of human diseases. The in-depth longitudinal characterization of the CoRe strength can be used as biomarkers to determine the progression of the brain plasticity and to create new therapeutic protocols to modulate with precision neuronal activity. Second, the evidence pointing astrocytes are key elements in the mechanism of reorganization following injuries may be used in the future to the development of pharmacological treatments to promote behaviour recovery after central nervous system injuries.
Layering-cortical reorganization: role for astrocytes in L2/3 and inhibition in L5