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Juan Pablo Lopez1
1Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
Abstract: Dr. Juan Pablo Lopez is an Assistant Professor in the Department of Neuroscience at Karolinska Institutet. He is interested in understanding the behavioral language, molecular mechanisms, and cellular circuits associated with stress-related psychiatric disorders and their treatments. His research program tackles psychiatrically relevant questions such as: Why, if exposed to the same trauma, does one individual develop psychiatric symptoms, whereas another does not? What are the critical periods of development where adversity becomes neurobiologically embedded? What are the molecular mechanisms underlying clinical improvement? What are the biological correlates of treatment response? To achieve these objectives, his laboratory implements a combination of state-of-the-art molecular, cellular, and computational neuroscience tools, which ultimately aims to bridge pre-clinical research and human psychiatry. During this talk, he will discuss new findings describing cell-type specific molecular mechanisms underlying the response to chronic stress, the sustained antidepressant effects of ketamine, as well as the implementation of automated behavioral tracking and analysis systems of complex behaviors for groups of mice.
Charlotta Henningson, Jakub Mlost, Iskra Pollak Dorocic
Pollak Dorocic Lab, Department of Biophysics and Biochemistry, Stockholm University, Stockholm, Sweden
Abstract: The serotonergic system has been implicated in the pathophysiology of both depression and anxiety and is the target of the most prescribed class of medications for these disorders, the selective serotonin reuptake inhibitors (SSRIs). Serotonergic neurons have historically been defined as a single population, but more recent work uncovered molecular diversity within the system. This opens new questions about the function and organization of these subgroups of serotonergic neurons and how they may be differently modulated by SSRIs. Using spatial transcriptomics, a novel RNA sequencing method that connects the gene expression to a position in the tissue based on location specific barcodes, we investigated the molecular organization of the mouse serotonin system in the major forebrain projecting serotonergic nuclei, the Dorsal Raphe (DR). We uncovered six molecularly distinct and anatomically segregated serotonergic subpopulations within the DR. Next, we explored gene expression changes within the nucleus after acute and chronic SSRI treatment. We found a large number of differentially expressed genes between the treatment categories, and identified specific and opposite changes in expression of two neuropeptides that are co-expressed in serotonergic neurons, thyrotropin-releasing hormone (Trh) and prodynorphin (Pdyn). Both have previously been shown to play a role in the depressive state. Our data expands the knowledge on the serotonergic organization within the DR and identifies multiple differentially expressed genes and expression dynamics over the course of SSRI treatment, ultimately providing new insights into the molecular effects of SSRIs.
Magdalena Ziemiańska1, Mateusz Zięba2, Sławomir Gołda2,
Anna Radlicka-Borysewska1, Łukasz Szumiec1, Marcin Piechota2, Michał Korostyński2,
Jan Rodriguez Parkitna1
1Department of Molecular Neuropharmacology, Maj Institute of Pharmacology,
Polish Academy of Sciences, Krakow, Poland
2Department of Molecular Neuropharmacology, Laboratory of Pharmacogenomics, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
Abstract: Despite the well-established use of psychotropic medications in psychiatry, the neurobiological basis underlying their therapeutic effects remains elusive. Drug-induced spatial gene expression profiling in the brain offers insight into the mechanisms of drug action. The transcriptional response patterns may expose the molecular mechanisms of long-term neuronal plasticity affected by the treatment. Here, we examined a spatially resolved transcriptomic profile of risperidone, an antipsychotic medication. This approach sheds new light on the drug-action therapeutic mechanism responsible for alleviating the symptoms of schizophrenia. The spatial transcriptomics signature recapitulates the patterns of gene expression consistent with neuroanatomy of the mouse brain. Subsequently, drug-induced transcriptional alterations were mapped on the brain sections. Region-specific changes in gene expression regulation were found in 95 genes (p < 0.01, log2ratio = 0.8, minimum expression threshold = 0.2). Further enrichment analysis of the risperidone-induced genes identified 18 genes enriched in schizophrenia, 8 of which were previously identified in Genome-Wide Associated Studies (GWAS) in humans e.g. Cacna1i, Cldn5. Further investigation is needed to understand how the antipsychotic drug action mechanism is linked to gene expression changes occurring in the course of schizophrenia.
Funding: This work was supported by National Science Centre, Poland NCN OPUS UMO-2020/39/B/NZ7/01494
Anna Guguła1, Patryk Sambak1, Aleksandra Trenk1, Sylwia Drabik1, Aleksandra Nogaj1, Zbigniew Sołtys1, Andrew L. Gundlach2, Anna Błasiak1
1Department of Neurophysiology and Chronobiology Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland
2The Florey Institute of Neuroscience and Mental Health, and Florey Department of Neuroscience
and Mental Health, The University of Melbourne, Parkville, Victoria, Australia
Abstract: Early-life stress (ELS) disrupts brain development, increasing susceptibility to stress-related disorders and compulsive behaviour in adulthood. Expanding evidence links these disorders with the activity of the stress-sensitive brainstem nucleus incertus (NI), synthesising the neuropeptides relaxin-3 (RLN3) and cholecystokinin (CCK). Despite the known involvement of NI RLN3 neurons in stress responses and drug-seeking behaviour, their vulnerability to developmental stress remains unexplored, and the knowledge about NI CCK neurons is sparse. Thus, this study investigated the impact of an established ELS model, maternal separation (MS), on NI neuronal populations.
Control and MS-subjected adult male Sprague-Dawley rats underwent acute restraint stress and subsequent immunostaining of NI neurons, in situ hybridisation, or whole-cell patch-clamp recordings combined with dendritic tracing and morphological assessment of NI neurons.
MS triggered multi-level, cell-type specific changes in NI neurons, altering their activation in response to acute stress, active and passive membrane properties, and action potential characteristics. Additionally, MS caused dendritic tree remodelling of NI CCK neurons and altered expression of stress-related CRHR1 and TrkA receptor mRNA in the NI.
These MS-induced changes within NI neurons may contribute to the development of ELS-related disorders, including compulsive behaviours, emphasising the need for further exploration, particularly regarding MS stress-sensitive NI CCK neurons
Funding: National Science Centre, Poland, UMO-2018/30/E/NZ4/00687, UMO-2023/49/B/NZ4/01885, UMO-2017/27/N/NZ4/01545
