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Thalamic control of Neuroplasticity

Periodic Reporting for period 4 - SENSORTHALAMUS (Thalamic control of Neuroplasticity)

Reporting period: 2020-01-01 to 2021-02-28

The cerebral cortex is organized into highly specialized sensory areas. Thus, it is fundamental to understand how these areas acquire and maintain their identity and functional organization. Challenging normal brain development and forcing the brain to the limits of plasticity, has offered us the possibility to shed light on these issues. In this project, we have used prenatal sensory deprivation as a model to understand the mechanisms underlying early neuroplasticity, events that are expected to influence the organization of sensory cortical areas. Adopting a multidisciplinary and innovative approach, we have demonstrated that reorganization of both the deprived and the spared cortical territories occurs in an experience independent manner in a mechanism that involves thalamus. The thalamus shows waves of spontaneous activity that serve to communicate distinct sensory systems during development. In mice bilaterally enucleated before birth (mimicking congenitally blind conditions), there is a modification in the pattern of thalamic waves that leads to cross-modal changes in gene expression and the expansion of the somatosensory territory in postnatal blind pups. Within the consecution of this project, we also reveal the role of this embryonic thalamic waves during the natural development and found that these waves play a central role in the development of sensory maps. First, we found that the map of the somatosensory system is already functional before birth. If this prenatal map its modified by removing thalamic waves in vivo, there is a permanent and irreversible lack of the somatosensory map in the adult leading to deficit in sensory behavior in these mice. Finally, with the final goal of recovering sensory circuits in sensory deprived mice, within the consecution of this project we successfully reprogrammed thalamic astrocytes in vitro and in vivo into fully functional thalamocortical neurons. Remarkably, we found that the origin of brain astrocytes determines the identity of the induced neurons they give rise opening new avenues for future brain repair. The novel information obtained in this project has opened new research lines in our lab and in the field and has provided central knowledge on how sensory inputs and thalamocortical connections govern cortical activity and architecture, ultimately sculpting perceptual behaviour.
This report corresponds to the final reporting period of the project (6 + 8 months extension). During this period the project has developed without major scientific deviations from the last reported plan and followed the original goals.

Aim 1 (100% completion). This aim was finished in year 2, as planned. We have successfully generated embryonically visually deprived mice by in utero bilateral enucleation in embryos (embBE). We exploited this animal model to check for neuroplastic compensatory mechanisms in the cortex and found that after embBE, the barrel field area in the primary somatosensory cortex (S1) is significantly expanded before sensory processing. Our work has demonstrated the existence of a novel mechanism that takes place in the perinatal thalamus and allows neuroplasticity of cortical territories to unfold upon input sensory loss (Moreno-Juan et al., 2017).

Aim 2 (100% completion). We defined the thalamic mechanisms derived from peripheral input loss that are involved in the plasticity of sensory cortical areas. Those mechanisms involved spontaneous activity patterns in the thalamus and an intra-thalamic communication among sensory-nuclei (Moreno-Juan et al., 2017). We have also determined the role of embryonic thalamic waves in the formation of sensory cortical maps (Anton-Bolaños et al., 2019) and cortico-thalamic circuits formation (Moreno-Juan et al., under second review eLife). During this period, we characterized the mechanisms involved in the integration of thalamic interneurons and the impact of their number modification in the sensory-deprived conditions. We found that blocking thalamic waves lead to an increase sensory of GABAergic interneurons in the visual (dLGN) thalamus, and thus perturbs the integration of interneurons in the visual system. This part of the project and results are being prepared for publication (Huerga et al.). We have also successfully overcome the difficulties mentioned in our last reporting period on the recordings of spontaneous activity in thalamus and cortex of non-anaesthetized new-born mice by combining meso-scale calcium imaging with extracellular recordings. These experiments yield promising results that we have already presented at international meetings (Society for Neuroscience Meeting, Chicago 2019; FENS 2020) and are going to be submitted for publication shortly (Guillamon-Vivancos et al.).

Aim 3 (100% completion). During the consecution of the project, and as written in the proposal, we successfully reprogrammed thalamic astrocytes in vitro and found that the origin of brain astrocytes determines the identity of the induced neurons they give rise. In this period, we have performed RNAseq analysis and single-cell sequencing analysis and found the signalling cascade by which this fate determination is achieved. This aim has been recently published in the journal Science Advances (Herrero-Navarro et al., 2021).

During the consecution the project, we have yielded a significant number of scientific peer reviewed papers (13 in total), some of them published in very high impact journals such as Science, Science Advances and Nature Communications, among others. We envisage at least 3 more high impact papers derived from this grant that are expected to be submitted shortly (Guillamón-Vivancos et al., in preparation, Moreno-Juan et al., in preparation and Huerga et al., in preparation). The successful competition of this project can be also measured by the number of invited talks to world-wide recognised meetings, awards received and mentoring derived.

Most significant achievements derived from the ERC-CoG grant:

1) Direct publications from the laboratory (in peer-reviewed journals, see in project publications)

2) Co-author publications from collaborations related to the project (in peer-reviewed journals, see in project publications)

3) Prizes and Awards
Alberto Sols award to the best publication in 2019
“Constantes y Vitales” Award to the best publication in Biomedicine in Spain 2019
Award to the Scientific Merit from the “Generalitat Valenciana” 2018
Joseph Altman prize in Developmental Neurobiology 2018
The IBRO-Kemali International Prize winner 2017

4) Invited Speaker to International Meetings, importantly: Janelia Conference in Neural Circuit Assembly (2020), Thalamocortical Gordon Research (2020), Cortical development Meeting (2020), FENS2020, EMBO Workshop Molecular Neurobiology (2020), EMBO Neural Guidance Cues Workshop (2019), EMBO conference on Cell Biology of the Neuron (2019), EMBL Symposium: Probing Neural Dynamics with Behavioural Genetics (2019), SPONT2018 (Co-organizer), ABCAM 'Programming and Reprogramming the Brain' (Munich, 2017); Brain Conference (Copenhagen, 2017); CSHL Meeting (New York, 2016); ISDN (Antibes, 2016), AXON2015 (Viena, 2015).
As a consequence of the productivity and visibility derived from the ERC CoG, I am a member of the program committee for the Spanish Society for Neuroscience (SENC) and I was in 2018 for the Federation of European Neuroscience Societies (FENS).
The results obtained in this Project have provided important insight into the extent to which sensory inputs and thalamocortical connections control the functional modulation of cortical areas, and ultimately sculpt perceptual behavior. Furthermore, this cutting-edge research has provided a detailed understanding on the role of the thalamus in the development of sensory maps crucial for normal sensory perception and its role as an inducer of neuroplastic changes during development. We believe that our findings of the reprogramming capacity of brain astrocytes it is not only important to establish the brain’s true adaptive potential but also, to elucidate the intervening developmental constraints and to guide future rehabilitation strategies.