The Cellular and Systems Neurobiology Lab

There are two broad research programs in our lab. The first seeks to determine the organization and physiology of neural circuits in the brain involved with cognition and behavior and how they are perturbed in brain disorders. We integrate multi-faceted approaches from genetic engineering to quantitative neurobiology, integrating single-cell genomics, electrophysiology, imaging, neuroanatomy and quantitative behavioral analyses. Our second research program aims to link fundamental neuroscience to the understanding and treatment of neuropsychiatric and neurodegenerative disorders using multi-omic approached in human biofluids.

1. Cellular mechanisms underlying intellectual disability: engram pathology

Our aim is to understand how a stable memory trace is formed in the brain upon learning. We leverage on cutting-edge techniques like optogenetics and chemogenetics to achieve spatial and temporal resolution within specific sets of cells, so called engrams. Engrams are clusters of neurons that activate during the learning process and reactivate when memories are recalled. Our laboratory's research revealed impaired engram allocation in Down syndrome (DS) (Fernández-Blanco et al 2023). We have demonstrated that the overexpression of specific genes can result in an inherent interference with the establishment of stable memory traces (Ruiz-Mejias et al 2016; De Toma et al 2019; Ortega et al 2022). We also pioneered the discovery of new molecular players such as long non-coding RNAs or retrotransposons, a breakthrough that has revolutionized therapeutic approaches for cognitive disorders (Martinez de Lagran et al 2022; Sierra et al 2023). Distinct from other laboratories, we view astrocytes as an integral part of the synapse with roles in synapse function, and plasticity. We have discovered that activating astrocytes we rescue learning deficits in a mouse model of DS.

2. Translational Medicine and precision neuropsychiatry

We aim to identify potential candidate genes and regulatory elements that play pivotal roles in complex genetic conditions. Our genetic-dissection studies with DS mouse models pointed to the critical contribution of Dyrk1A overexpression to cognitive deficits in DS. This work led to the discovery of the first successful treatment for cognitive impairment in DS, which also increases functional brain connectivity (de la Torre et al 2017; 2020). This led to ten clinical trials in individuals with DS and Fragile X syndrome (Xicota et al, 2020; Cieuta-Walti et al, 2022). Furthermore, we have showed reduced functional connectivity on brain regions critical for learning and memory such as the prefrontal cortex and the hippocampus and, by harnessing the power of artificial intelligence, we are modelling the hippocampus to uncover mechanisms underlying its dysfunction in DS (Manubens-Gil et al 2023).

Our laboratory is embarking on an innovative trajectory, focusing on the fusion of pharmacogenomics and pharmaco-transcriptomics in neuropsychiatric disorders (Xicota et al, 2022; Pisanu et al 2022; Sathyanarayanan et al 2023). We focus on an urgent challenge in mental health: the emergence of drug resistance in a substantial number of patients. Through Horizon Europe and EraPerMed projects uniting genetic and genomic methodologies with AI-driven techniques, we aim to elucidate the biological mechanisms central to an individual's response to treatment and pave the way for therapies that are not only more effective but also more precisely aligned with the unique needs of each patient.