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Weronika Tomaszewska1, Magdalena Gomółka1, Patrycja Chudzicka-Ormaniec1, Adria Jaume-Cararda2, Bożena Kamińska-Kaczmarek2, Anna Ziomkiewicz3, Ali Jawaid1
1Laboratory of TREND (Translational Research in Neuropsychiatric Disorders), Centre of Excellence for Neural Plasticity and Brain Disorders (Braincity), Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
2Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw, Poland
3Laboratory of Anthropology, Institute of Zoology and Biomedical Research, Jagiellonian University, 30-387 Krakow, Poland
Abstract: The main goal of this project is to systematically examine miRNA changes in human body fluids, that are relevant to long-term sequelae of childhood trauma including its intergenerational transmission.
Small RNA sequencing followed by RT-qPCR assays were performed to identify and validate differentially regulated miRNAs in the serum of children with recent trauma in the form of paternal loss and maternal separation (PLMS), sperm of adult men with history of complex trauma, and milk from lactating mothers with history of childhood trauma. Pathway analysis for altered miRNAs was performed based on the Tarbase database.
Small RNA sequencing analysis revealed 48 miRNAs to be differentially expressed in the serum of PLMS children vs. control; whereas 29 miRNAs were differentially expressed in the sperm of adult men with a history of trauma. Several differentially regulated miRNAs over-lapped between analyses. Furthermore, the pathway analysis and functional relevance of the altered miRNAs suggest potential implication of lipids-associated miRNA carriers in the observed changes.
Funding: This study found overlapping miRNA changes in a range of body fluids after childhood trauma that seem to be conserved across diverse cohorts and age-groups. The close relevance of these miRNAs to lipid-derived carriers is the premise of our current investigations.
Kinga Farkas1,2, Ágota Vass1, Eszter Komoróczy1, Gabriella Vizin3,4
1Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary
2Brain, Memory and Language Research Group, Institute of Cognitive Neuroscience and Psychology, Research Centre for Natural Sciences, Budapest, Hungary
3Institute of Psychology, ELTE Eötvös Loránd University, Budapest, Hungary
4Department of Clinical Psychology, Semmelweis University, Budapest, Hungary
Abstract: Individuals with autism spectrum disorder (ASD) are four times more likely to experience depression in their lifetime than neurotypical individuals, according to a recent meta-analysis. However, the nature of this relationship remains unclear. We hypothesized that attachment style, mentalization, social support and psychological flexibility might affect depressive symptoms, but due to difficulties in theory of mind and social communication in ASD, the extent of their effects differs between individuals with and without an autism spectrum disorder diagnosis. 1783 participants (ASD N=133, non-ASD N=1650) completed an online questionnaire, comprising Autism Spectrum Quotient (AQ), Beck Depression Inventory (BDI), Mentalization Questionnaire (MZQ), Adult Attachment Scale (AAS, anxious and avoidant), Multidimensional Scale of Perceived Social Support (MSPSS) and Acceptance and Action Questionnaire-II (AAQ-II). We performed a moderated mediation analysis. The significant association between AQ and BDI was partially mediated by MZQ, AAS, MSPSS and AAQ, but ASD diagnosis moderates this effect. In the non-ASD group MZQ and AAQ-II, while in ASD group Avoidant Attachment and AAQ-II have significant indirect effects. In summary, in ASD avoidant attachment style, while in non-ASD mentalization has a larger indirect effect on depressive symptoms. This difference is of great importance for the design of therapeutic interventions.
Funding: Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the Neurology thematic program of Semmelweis University.
Hryniewiecka, K.1,Lipiec, M.1,2, Baggio, S.1, Kublik, E.2, Wiśniewska, M.1
1Laboratory of Molecular Neurobiology, Centre of New Technologies, University of Warsaw, Poland
2Laboratory of Emotions Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
Abstract: Tcf7l2 is a high confidence risk gene for autism spectrum disorder, but its role in ASD development is not known. To address this question we investigate functional consequences of TCF7L2 deficiency in the brain. Evidence from our laboratory shows that Tcf7l2 is highly expressed in thalamus where it regulates the expression of excitability genes. The thalamus is a candidate structure for ASD pathogenesis, as it relays both sensory signals from periphery as well as signals between associative, motivational, executive and motor cortical regions.
We hypothesize that TCF7L2 deficiency in thalamic neurons impairs the activity of thalamo-cortical circuits, whose dysfunctions are common in psychiatric disorders such as ASD.
In our laboratory, a mouse strain was created with postanal knockout of TCF7L2 in thalamus. To determine electrophysiological characteristics of thalamic neurons and thalamo-cortical connections in these mice, a series of tests will be performed, including recording of respose to sensory stimulation in vivo from thalamus and cortex with Neuropixel probes and patch-clamp. Our preliminary patch-clamp results show decreased excitability of neurons and disfunction of burst mode firing in the knockout strain. Moreover, pilot study of prepulse inhibition in vivo showed a lower decrease of inhibited reponse in knockout compared to wild type.
Funding: NCN OPUS 19 2020/37/B/NZ4/03261.
Suelen Baggio1, Kamil Koziński1, Andrzej Nagalski1, Marcin A Lipiec1, Łukasz M Szewczyk1, Katarzyna Hryniewiecka1, Alicja Puścian2, Ewelina Kanapska2, Marta Wiśniewska1
1Laboratory of Molecular Neurobiology, Centre of New Technologies, University of Warsaw, Warsaw, Poland
2Laboratory of Emotions Neurobiology, Nencki Institute of Experimental Biology, Warsaw, Poland
Abstract: Autism spectrum disorder (ASD) embraces several behavioral and sensorimotor alterations. ASD is associated with neurodevelopmental impairments. Considering the important role of thalamocortical connections in processing sensory information and producing behavioral responses, impaired thalamic development can contribute to ASD symptoms. However, this assumption is poorly supported experimentally. Therefore, this study aims to understand the role of the thalamus in the pathogenesis of ASD using a new mouse model, a strain developed in our laboratory in which the regulator of thalamic maturation TCF7L2 is knocked out postnatally. To validate ASD-associated phenotypes, we analyzed the mice's behavioral profile through the following behavioral tests: Open field, Marble-burying test, Buried food test, and Eco-HAB. TCF7L2 KO mice present a decrease in social performance, not interacting with other mice during the exploration of a cage and spending less time in the compartment containing social scent. They show a decrease in grooming behavior and no difference in repetitive behavior. In addition, they do not show impairments in locomotor activity or olfactory function, according to the Open field and Buried Food tests. These results corroborate a hypothesis that thalamic dysfunctions originating from perinatal development can be a primary cause of social deficits and behavioral inflexibility in ASD.
Funding: 501-D313-66-0006518 (Wiśniewska OPUS19).
Sabina Podlewska,RyszardBugno,Grzegorz Satała, Andrzej J. Bojarski
Maj Institute of Pharmacology Polish Academy of Sciences, Kraków, Poland
Abstract: Serotonin receptor 5-HT7, a representative of aminergic family of G protein-coupled receptors (GPCRs), is proved to play important role in a number of pathophysiological process occurring in the central nervous system (CNS), such as depression, anxiety, cognitive disorders, disturbances of the sleep-wake cycle, and schizophrenia. Therefore, it is extensively examined as a drug target in the treatment of various CNS disorders.
The number of already known 5-HT7R ligands is relatively high (there are over 4800 records of compounds with experimentally verified activity towards 5-HT7R deposited in the ChEMBL database); however, due to the relatively high similarity of the 5-HT7R binding site with the binding pocket of the hERG potassium channel, high fraction of 5-HT7R ligands are subject to the risk of displaying cardiotoxicity. The responsibility for the interaction with hERG is mostly put to the basic nitrogen of a compound (which is the main feature of most 5-HT7R ligands).
In the study, we performed virtual screening procedure towards the search of non-standard ligands of 5-HT7R, which do not contain the basic nitrogen atom in their structure. The protocol consisted of application of machine learning methods and docking. Experimental validation of the results indicated several compounds with micromolar affinity to the 5-HT7R.
Funding: The study was supported by the grant OPUS 2018/31/B/NZ2/00165 financed by the National Science Centre, Poland (www.ncn.gov.pl).
