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The Neurobiology of the Addicted Brain
Currents of Hope: how noninvasive brain stimulation is reshaping modern psychiatric care; Adapting to diversity: Integrating variability in brain structure and function into personalized / closed-loop non-invasive brain stimulation for substance use disorders
In March we will focus on TMS and host Ghazaleh Soleimani and Colleen Hanlon. The talks will talk place on Thursday, March 28th at noon ET – please be aware that this means 5PM CET since Boston already switched to summer time! Ghazaleh Soleimani, PhD, is a postdoctoral fellow in Dr Hamed Ekhtiari’s lab at the University of Minnesota. She is also the executive director of the International Network of tES/TMS for Addiction Medicine (INTAM). She will discuss “Adapting to diversity: Integrating variability in brain structure and function into personalized / closed-loop non-invasive brain stimulation for substance use disorders”. Colleen Hanlon, PhD, currently serves as a Vice President of Medical Affairs for BrainsWay, a company specializing in medical devices for mental health, including TMS. Colleen previously worked at the Medical University of South Carolina and Wake Forest School of Medicine. She received the International Brain Stimulation Early Career Award in 2023. She will discuss “Currents of Hope: how noninvasive brain stimulation is reshaping modern psychiatric care”. As always, we will also get a glimpse at the “Person behind the science”. Please register va talks.stimulatingbrains.org to receive the (free) Zoom link, subscribe to our newsletter, or follow us on Twitter/X for further updates!
Epigenetic rewiring in Schinzel-Giedion syndrome
During life, a variety of specialized cells arise to grant the right and timely corrected functions of tissues and organs. Regulation of chromatin in defining specialized genomic regions (e.g. enhancers) plays a key role in developmental transitions from progenitors into cell lineages. These enhancers, properly topologically positioned in 3D space, ultimately guide the transcriptional programs. It is becoming clear that several pathologies converge in differential enhancer usage with respect to physiological situations. However, why some regulatory regions are physiologically preferred, while some others can emerge in certain conditions, including other fate decisions or diseases, remains obscure. Schinzel-Giedion syndrome (SGS) is a rare disease with symptoms such as severe developmental delay, congenital malformations, progressive brain atrophy, intractable seizures, and infantile death. SGS is caused by mutations in the SETBP1 gene that results in its accumulation further leading to the downstream accumulation of SET. The oncoprotein SET has been found as part of the histone chaperone complex INHAT that blocks the activity of histone acetyltransferases suggesting that SGS may (i) represent a natural model of alternative chromatin regulation and (ii) offer chances to study downstream (mal)adaptive mechanisms. I will present our work on the characterization of SGS in appropriate experimental models including iPSC-derived cultures and mouse.
NeurotechEU Summit
Our first NeurotechEU Summit will be fully digital and will take place on November 22th from 09:00 to 17:00 (CET). The final programme can be downloaded here. Hosted by the Karolinska Institutet, the summit will provide you an overview of our actions and achievements from the last year and introduce the priorities for the next year. You will also have the opportunity to attend the finals of the 3 minute thesis competition (3MT) organized by the Synapses Student Society, the student charter of NeurotechEU. Good luck to all the finalists: Lynn Le, Robin Noordhof, Adriana Gea González, Juan Carranza Valencia, Lea van Husen, Guoming (Tony) Man, Lilly Pitshaporn Leelaarporn, Cemre Su, Kaya Keleş, Ramazan Tarık Türksoy, Cristiana Tisca, Sara Bandiera, Irina Maria Vlad, Iulia Vadan, Borbála László, and David Papp! Don’t miss our keynote lecture, success stories and interactive discussions with Ms Vanessa Debiais Sainton (Head of Higher Education Unit, European Commission), Prof. Staffan Holmin (Karolinska Institutet), Dr Mohsen Kaboli (BMW Group, member of the NeurotechEU Associates Advisory Committee), and Prof. Peter Hagoort (Max Planck Institute for Psycholinguistics, Donders Institute). Would you like to use this opportunity to network? Please join our informal breakout sessions on Wonder.me at 11:40 CET. You will be able to move from one discussion group to another within 3 sessions: NeurotechEU ecosystem - The Associates Advisory Committee: Synergies in cross-sectoral initiatives Education next: Trans-European education and the European Universities Initiatives - Lessons learned thus far. Equality, diversity and inclusion at NeurotechEU: removing access barriers to education and developing a working, learning, and social environment where everyone is respected and valued. You can register for this free event at www.crowdcast.io/e/neurotecheu-summit
Towards targeted therapies for the treatment of Dravet Syndrome
Dravet syndrome is a severe epileptic encephalopathy that begins during the first year of life and leads to severe cognitive and social interaction deficits. It is mostly caused by heterozygous loss-of-function mutations in the SCN1A gene, which encodes for the alpha-subunit of the voltage-gated sodium channel (Nav1.1) and is responsible mainly of GABAergic interneuron excitability. While different therapies based on the upregulation of the healthy allele of the gene are being developed, the dynamics of reversibility of the pathology are still unclear. In fact, whether and to which extent the pathology is reversible after symptom onset and if it is sufficient to ensure physiological levels of Scn1a during a specific critical period of time are open questions in the field and their answers are required for proper development of effective therapies. We generated a novel Scn1a conditional knock-in mouse model (Scn1aSTOP) in which the endogenous Scn1a gene is silenced by the insertion of a floxed STOP cassette in an intron of Scn1a gene; upon Cre recombinase expression, the STOP cassette is removed, and the mutant allele can be reconstituted as a functional Scn1a allele. In this model we can reactivate the expression of Scn1a exactly in the neuronal subtypes in which it is expressed and at its physiological level. Those aspects are crucial to obtain a final answer on the reversibility of DS after symptom onset. We exploited this model to demonstrate that global brain re-expression of the Scn1a gene when symptoms are already developed (P30) led to a complete rescue of both spontaneous and thermic inducible seizures and amelioration of behavioral abnormalities characteristic of this model. We also highlighted dramatic gene expression alterations associated with astrogliosis and inflammation that, accordingly, were rescued by Scn1a gene expression normalization at P30. Moreover, employing a conditional knock-out mouse model of DS we reported that ensuring physiological levels of Scn1a during the critical period of symptom appearance (until P30) is not sufficient to prevent the DS, conversely, mice start to die of SUDEP and develop spontaneous seizures. These results offer promising insights in the reversibility of DS and can help to accelerate therapeutic translation, providing important information on the timing for gene therapy delivery to Dravet patients.
Ex vivo gene therapy for epilepsy. Seizure-suppressant and neuroprotective effects of encapsulated GDNF-producing cells
A variety of pharmacological treatments exist for patients suffering from focal seizures, but systemically administered drugs offer only symptomatic relief and frequently cause unwanted side effects. Moreover, available drugs are ineffective in one third of the patients. Thus, developing more targeted and effective treatment strategies is highly warranted. Neurotrophic factors are candidates for treating epilepsy, but their development has been hampered by difficulties in achieving stable and targeted delivery of efficacious concentrations within the brain. We have developed an implantable cell encapsulation system that delivers high and consistent levels of neurotrophic molecules directly to a specific brain region. The potential of this approach has been tested by delivering glial cell line-derived neurotrophic factor (GDNF) to the hippocampus of epileptic rats. In vivo studies demonstrated that these intrahippocampal implants continue to secrete GDNF and produce high hippocampal GDNF tissue levels in a long-lasting manner. Identical implants rapidly and greatly reduced seizure frequency in the pilocarpine model. This effect increased in magnitude over 3 months, ultimately leading to a reduction of spontaneous seizures by more than 90%. Importantly, these effects were accompanied by improvements in cognition and anxiety, and by the normalization of many histological alterations that are associated with chronic epilepsy. In addition, the antiseizure effect persisted even after device removal. Finally, by establishing a unilateral epileptic focus using the intrahippocampal kainate model, we found that delivery of GDNF exclusively within the focus suppressed already established spontaneous recurrent seizures. Together, these results support the concept that the implantation of encapsulated GDNF-secreting cells can deliver GDNF in a sustained, targeted, and efficacious manner. These findings may form the basis for clinical translation of this approach.
Domain Specificity in the Human Brain: What, Whether, and Why?
The last quarter century has provided extensive evidence that some regions of the human cortex are selectively engaged in processing a single specific domain of information, from faces, places, and bodies to language, music, and other people’s thoughts. This work dovetails with earlier theories in cognitive science highlighting domain specificity in human cognition, development, and evolution. But many questions remain unanswered about even the clearest cases of domain specificity in the brain, the selective engagement of the FFA, PPA, and EBA in the perception of faces, places, and bodies, respectively. First, these claims lack precision, saying little about what is computed and how, and relying on human judgements to decide what counts as a face, place, or body. Second, they provide no account of the reliably varying responses of these regions across different “preferred” images, or across different “nonpreferred” images for each category. Third, the category selectivity of each region is vulnerable to refutation if any of the vast set of as-yet-untested nonpreferred images turns out to produce a stronger response than preferred images for that region. Fourth, and most fundamentally, they provide no account of why, from a computational point of view, brains should exhibit this striking degree of functional specificity in the first place, and why we should have the particular visual specializations we do, for faces, places, and bodies, but not (apparently) for food or snakes. The advent of convolutional neural networks (CNNs) to model visual processing in the ventral pathway has opened up many opportunities to address these long-standing questions in new ways. I will describe ongoing efforts in our lab to harness CNNs to do just that.
Functional characterization of human iPSC-derived neurons at single-cell resolution
Recent developments in induced pluripotent stem cell (iPSC) technology have enabled easier access to human cells in vitro. With increasing availability of human iPSC-derived neurons, both healthy and disease cell lines, screening compounds for neurodegenerative diseases on human cells can potentially be performed in the earlier stages of drug discovery. To accelerate the functional characterization of iPSC-derived neurons and the effect of compounds, reproducible and relevant results are necessary. In this webinar, the speakers will: Introduce high-resolution functional imaging of human iPSC-derived neurons Showcase how to extract functional features of hundreds of cells in a cell culture sample label-free Discuss electrophysiological parameters for characterizing the differences among several human neuronal cell lines