Modeling micro-anatomical and dynamic properties of cognition-related brain systems

Funded by EU (JPND), MINECO, CRG, Jerôme Lejeune Foundation

The main focus of the project is to understand how genetic perturbation in mental disorders modifies the way the brain integrates information. Alterations in the architectural properties of the neurons are observed in most mental disorders and are assumed to be the cause of the cognitive disturbances. Thus, the main question in the field remains how these disturbances of neuronal architecture constrain the network and influence the flow and storage of information in neuronal circuits. We integrate experimental data from cleared brains with physiological and cellular quantitative measurements with computer modeling. To this aim we have developed a suite of unified tools specially designed for analyzing data from brain clearing methods including workflows for network connectivity instantiation and network dynamics simulation. Our first analysis in intellectual disability mouse models revealed that the dendritic tree architecture and the distribution of synaptic contacts have significant implications on information processing efficiency and storage capacity, and suggests that those single-neuron features permeate to the network level, determining the computational capacities of neural ensembles (Manubens et al in preparation). Using a conductance-based computational model, we demonstrated that selective disinhibition of fast-spiking interneurons could explain overinhibition and decreased gamma power and firing rate in cortical circuit, that might be central to the pathophysiology of Down syndrome (Ruiz-Mejías et al 2016). We also have described how subtle alterations in the activation pattern of amygdala-hippocampus-medial prefrontal cortex fear circuit produced increased fear memories in a panic disorder mouse model (Santos et al 2013, Damico et al 2017). This innovative and powerful analytical platform combined with in vivo systems (genetically modified mouse models) and human pathologies will help us understand the neurobiology of mental disorders and the effects on network topology of pro-cognitive treatments.

Ruiz-Mejias M, … Dierssen M. Overexpression of Dyrk1A, a Down Syndrome Candidate, Decreases Excitability and Impairs Gamma Oscillations in the Prefrontal Cortex. J Neurosci. (2016) 36(13):3648-59.

Pons-Espinal M, Martinez de Lagrán M, Dierssen M. Environmental enrichment rescues DYRK1A activity and hippocampal adult neurogenesis in TgDyrk1A.Neurobiol Dis. (2013) 60:18-31.

Santos M, … Dierssen M. Hippocampal hyperexcitability underlies enhanced fear memories in TgNTRK3, a panic disorder mouse model. J Neurosci. (2013) 18;33(38):15259-71.

D'Amico D, Gener T, de Lagrán MM, Sanchez-Vives MV, Santos M, Dierssen M. Infralimbic Neurotrophin-3 Infusion Rescues Fear Extinction Impairment in a Mouse Model of Pathological Fear. Neuropsychopharmacology (2017) 42(2): 462-472.

Exploring molecular mechanisms of pro-cognitive therapies

Funded by MINECO, CRG, Jerôme Lejeune Foundation

Down syndrome (DS) is the most frequent genetic cause of intellectual disability. It is a multifaceted condition characterized by impairments in cognition, communication, behavior and/or motor skills resulting from abnormal brain development and function. Although DS is caused by the trisomy with more than 300 triplicated genes located on chromosome 21, there are a reduced number of dosage-sensitive candidate genes that play a critical role in the pathogenesis of the disorder. Our group has made important contributions demonstrating that overexpression of DYRK1A, a DS candidate gene, is sufficient and necessary to recapitulate some of the DS phenotypes (Martinez de Lagrán et al, 2012, Dierssen et al 2012). Importantly, it is a druggable molecular target we could also demonstrate that the genetic, pharmacological or environmental normalization of its overdosage rescues behavioral, cognitive and neuronal phenotypes in preclinical studies with DS mouse models and in clinical trials in humans (de la Torre et al 2016). Specifically, it is involved in complex remodeling of neural circuitry in the hippocampus (Martinez de Lagran et al, 2012; Pons-Espinal et al, 2013). Importantly, we could also demonstrate that the genetic, pharmacological or environmental normalization of its overdosage, possibly along with effects at other levels (epigenetic, transcriptomic), rescues behavioral, cognitive and neuronal phenotypes in preclinical studies with DS mouse models and in clinical trials in humans (Dierssen, 2012). The triplication of DYRK1A, can lead to an epigenetic imbalance. DYRK1A interacts with the REST/NRSF-SWI/SNF chromatin-remodeling complex and regulates histone acetylation, therefore influencing gene expression. We are exploring proteomic alterations, transcriptome regulation and epigenomic modifications (De Toma et al., 2016) to decipher the most relevant mechanisms. The first proteomic studies have shown that the consequences of DYRK1A overexpression spread along plasticity-related molecular pathways (Ortega et al in preparation). This may explain why DYRK1A kinase normalization is a good molecular target in Down syndrome. Finally, we are interested in the common mechanisms underlying different intellectual disabilities. In fact, EGCG, the main polyphenol extracted from green tea, is able to restore the cognitive impairment in both Fragile X syndrome and Down syndrome (De la Torre et al, 2016, and De la Torre et al in preparation), despite the opposite defects at the neuronal level. We are studying the common transcriptomic pathways, which are altered in these two diseases. Interestingly, many genes involved in Down syndrome are also affected due to the lack of the FMRP protein in Fragile X syndrome (De Toma et al., 2016, De Toma et al in press).

de la Torre R, … Dierssen M. Safety and efficacy of cognitive training plus epigallocatechin-3-gallate in young adults with Down's syndrome (TESDAD): a double-blind, randomized, placebo-controlled, phase 2 trial. Lancet Neurol. (2016) 15(8):801-810

Martinez de Lagran M, … Dierssen M. Dyrk1A influences neuronal morphogenesis through regulation of cytoskeletal dynamics in mammalian cortical neurons. Cereb Cortex. (2012) 22: 2867-77

Toma ID, Gil LM, Ossowski S, Dierssen M. Where Environment Meets Cognition: A Focus on Two Developmental Intellectual Disability Disorders. Neural Plast. (2016) 2016:4235898

Dierssen M. Down syndrome: the brain in trisomic mode. Nat Rev Neurosci. (2012) 13: 844-58.

High-throughput phenotypic cluster

Funded by EU (Era-Net), MINECO

Intellectual disabilities are frequently accompanied by behavioral disturbance. We have developed an experimental framework, including high-throughput longitudinal behavioral recording (Espinosa et al., 2018), and an open access software to visualize, integrate and analyze longitudinal big behavioral data (Pergola, Espinosa et al., in preparation). This allows the detection of subtle signs of behavioral disturbances that appear at an early stage of morbidity development. Among others, we have explored learning (Catuara et el, 2015) and obesity (Fructuoso et al, in preparation) phenotypes in intellectual disability disorders, focusing on Down syndrome. We found hat trisomy 21 leads to abnormal feeding behaviors and differential endocrine and neurochemical adaptations to an obesogenic environment (Fructuoso et al, 2018).

Espinosa-Carrasco J, … Dierssen M. Time-course and dynamics of obesity-related behavioral changes induced by energy-dense foods in mice. Addict Biol. (2018) Epub ahead of print

Fructuoso M, … Dierssen M. Increased levels of inflammatory plasma markers and obesity risk in a mouse model of Down syndrome. Free Radic Biol Med. (2018) 114:122-130

Catuara-Solarz S, Espinosa-Carrasco J, Erb I, Langohr K, Notredame C, Gonzalez JR, Dierssen M Principal Component Analysis of the Effects of Environmental Enrichment and (-)-epigallocatechin-3-gallate on Age-Associated Learning Deficits in a Mouse Model of Down Syndrome. Front Behav Neurosci. (2015) 9: 330.