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Our New paper is online in NATURE COMMUNICATIONS: Short antisense oligonucleotides alleviate the pleiotropic toxicity of RNA harboring expanded CGG repeats. |

Magdalena Derbis, Emre Kul, Daria Niewiadomska , Michał Sekrecki, Agnieszka Piasecka, Katarzyna Taylor, Renate K. Hukema , Oliver Stork & Krzysztof Sobczak

HTTPS://DOI.ORG/10.1038/S41467-021-21021-W

Abstract

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an incurable neurodegenerative disorder caused by expansion of CGG repeats in the FMR1 5’UTR. The RNA containing expanded CGG repeats (rCGGexp) causes cell damage by interaction with complementary DNA, forming R-loop structures, sequestration of nuclear proteins involved in RNA metabolism and initiation of translation of polyglycine-containing protein (FMRpolyG), which forms nuclear insoluble inclusions. Here we show the therapeutic potential of short antisense oligonucleotide steric blockers (ASOs) targeting directly the rCGGexp. In nuclei of FXTAS cells ASOs affect R-loop formation and correct miRNA biogenesis and alternative splicing, indicating that nuclear proteins are released from toxic sequestration. In cytoplasm, ASOs significantly decrease the biosynthesis and accumulation of FMRpolyG. Delivery of ASO into a brain of FXTAS mouse model reduces formation of inclusions, improves motor behavior and corrects gene expression profile with marginal signs of toxicity after a few weeks from a treatment.


New Paper online: Allostatic Regulation of GAD65 by Juvenile Stress

Our newest paper is online: Allostatic gene regulation of inhibitory synaptic factors in the rat ventral hippocampus in a juvenile/adult stress model of psychopathology by Anne Albrecht, Menahem Segal and Oliver Stork

Here we show the region-specific long-term regulation of GABA-related molecular factors in the hippocampus after a juvenile stress experience. Our data highlight the role of ventral hippocampus and mechanisms that control local excitation/inhibition balance in development in adaptive and maladaptive stress responding.

https://onlinelibrary.wiley.com/doi/epdf/10.1111/ejn.15091

Abstract

Early life stress is an important vulnerability factor for the development of anxiety disorders, depression and late-onset cognitive decline. Recently we demonstrated that juvenile stress (JS) lastingly enhanced long-term potentiation via reduction of steady-state glutamine synthetase mRNA expression and the associated dysregulation of the astrocytic glutamate-glutamine cycle in the rat ventral CA1. We now investigated the regulation of steady-state mRNA expression of neuronal gene products that determine GABAergic and glutamatergic neurotransmission in layers of the ventral and dorsal CA1 after JS. We further studied their interaction with stress in young adult age (AS) to address their putative role in psychopathology development. Strikingly, mRNA levels of the glutamic acid decarboxylase (GAD) isoforms GAD65 and of the GABA-A receptor a2 (Gabra2) were increased after single JS or AS, but not after combined JS/AS stress experience. In fact, JS/AS resulted in layer-specific reduction of Gabra2 and also of Gabra1 mRNA levels in the ventral CA1. Furthermore, GAD65 and Gabra2 mRNAs were correlated with glutamatergic AMPA and NMDA receptor subunit mRNAs after single JS and AS, but not after combined JS/AS. Together, these data indicate a loss of allostatic regulation of steady-state mRNA levels of key GABAergic components that may result in a dysregulation of excitation/ inhibition balance in the ventral CA1 upon dual stress exposure. Finally, individual differences in local glucocorticoid receptor mRNA expression may contribute to this regulation.

Storklab contributes to three projects in the new Collaborative Research Center (CRC1436): “Neural Resources of Cognition”

The new CRC1436 “Neural Resources of Cognition”, which has been approved by the German Research Foundation on November 30th, will start its work on January 1st, 2021. Info at : https://www.ovgu.de/Universität/Im+Portrait/Profilierungsschwerpunkte/Forschung+_+Transfer/PM+63_2020-p-110490.html

Storklab participates in three projects of this CRC:

Project A07 (together with Prof. Dr. Dr. Anne Albrecht, Institute for Anatomy) –  Orexinergic modulation of neural resource

Project Z01 (together with Dr. Michael Kreutz, Leibniz Institute for Neurobiology and Prof. Dr. Frank Angenstein, German Center for Neurodegenertive Diseases) – Functional neural circuit analysis and small animal imaging in vivo

Project IRTG (together with Prof. Dr. Toemme Noesselt, Institute of Psychology) – Integrated Research Training Group

We are looking forward to these exciting collaborations!

 

Gürsel Caliskan established a Frontiers research topic on functional aspects of neural oscillations

Gürsel Caliskan, Sanja Mikulovic, Gabrielle Girardeau

Accumulating evidence supports the fundamental role of mesoscopic oscillatory network activities in sustaining numerous physiological functions. Indeed, mesoscopic scale recordings from rodents, primates, and humans have demonstrated the causal and/or correlative role of these brain rhythms in distinct behavioral domains including innate, emotional, and cognitive behavior. Depending on the behavioral state, these voltage deflections can range from slow (< 1 Hz) to fast oscillations (>200 Hz) and appear in distinct brain structures. They mediate local and brain-wide coordination of information processing via synchronization of neuronal activity. Thus, genetic or environmental factors that lead to alterations in oscillations can lead to disease states that are associated with aberrant innate, emotional, and cognitive behavior.

Despite the increasing attempts over the last decades, mesoscopic scale biomarkers of diverse neuropsychiatric, neurodevelopmental and neurodegenerative disorders are still sparsely identified. Studying mesoscopic brain rhythms in both healthy and diseased states provides an excellent approach in understanding healthy oscillations as well as distinguishing them from disease-associated “oscillopathies”. Thus, a collective effort on the identification of functional aspects of specific network oscillation patterns could accelerate the utilization of mesoscopic brain rhythms as biomarkers and as an entry point for therapy development in distinct disease states that are associated with aberrant innate, emotional, and cognitive behavior.

The goal of this Research Topic is to highlight the recent advances in the study of mesoscopic network activities with the aim of providing an overview of this wide-ranging topic. A particular emphasis will be on the functional aspects of network oscillations, their unique roles in innate, emotional, and cognitive behavior, and their involvement in distinct disease states. Studies using rodent models, primates, and/or human subjects are welcome. We seek Original Research, Review, Mini-Review, Hypothesis and Theory, Perspective, Clinical Trial, Case Report, and Opinion articles that cover, but are not limited to, the following topics:

• Oscillatory correlates of innate and emotional behavior

• Oscillatory correlates of emotional memory modulation

• Oscillatory correlates of cognition including studies focusing on spatial memory, working memory

• Role of sleep-associated oscillations in emotional vs. cognitive memory

In vitro / in vivo evidence for oscillatory changes from animal models of neuropsychiatric, neurodevelopmental and neurodegenerative disorders

In vitro / in vivo studies providing insights into molecular and cellular correlates of network oscillations

• Novel approaches to measure mesoscopic oscillatory activities in the brain, combination of different methods

Please se:

https://www.frontiersin.org/research-topics/17218/functional-aspects-of-mesoscopic-brain-oscillations-insights-from-in-vivo-and-in-vitro-studies

New paper together with the Kreutz Lab: Synaptic control of DNA methylation involves activity-dependent degradation of DNMT3A1 in the nucleus

Abstract

DNA methylation is a crucial epigenetic mark for activity-dependent gene expression in neurons. Very little is known about how synaptic signals impact promoter methylation in neuronal nuclei. In this study we show that protein levels of the principal de novo DNA-methyltransferase in neurons, DNMT3A1, are tightly controlled by activation of N-methyl-D-aspartate receptors (NMDAR) containing the GluN2A subunit. Interestingly, synaptic NMDARs drive degradation of the methyltransferase in a neddylation-dependent manner. Inhibition of neddylation, the conjugation of the small ubiquitin-like protein NEDD8 to lysine residues, interrupts degradation of DNMT3A1. This results in deficits in promoter methylation of activity-dependent genes, as well as synaptic plasticity and memory formation. In turn, the underlying molecular pathway is triggered by the induction of synaptic plasticity and in response to object location learning. Collectively, the data show that plasticity-relevant signals from GluN2A-containing NMDARs control activity-dependent DNA-methylation involved in memory formation.

Our new paper is online: Region-specific involvement of interneuron subpopulations in trauma-related pathology and resilience

Region-specific involvement of interneuron subpopulations in trauma-related pathology and resilience.  Tsur SR, Demiray YE, Tripathi K, Stork O, Richter-Levin G, Albrecht A.Neurobiol Dis. 2020 Jun 16:104974.

Abstract

Only a minority of trauma-exposed individuals develops Posttraumatic stress disorder (PTSD) and active processes may support trauma resilience. Individual behavioral profiling allows investigating neurobiological alterations related to resilience or pathology in animal models of PTSD and is utilized here to examine the activation of different interneuron subpopulations of the dentate gyrus-amygdala system associated with trauma resilience or pathology. To model PTSD, rats were exposed to juvenile stress combined with underwater trauma (UWT) in adulthood. Four weeks later, individual anxiety levels were assessed in the elevated plus maze test for classifying rats as highly anxious ‘affected’ vs. ‘non-affected’, i.e. behaving as control animals. Analyzing the activation of specific interneuron subpopulations in the dorsal and ventral dentate gyrus (DG), the basolateral (BLA) and central amygdala by immunohistochemical double-labeling for cFos and different interneuron markers, revealed an increased activation of cholecystokinin (CCK)-positive interneurons in the ventral DG, together with increased activation of parvalbumin- and CCK-positive interneurons in the BLA of affected trauma-exposed rats. By contrast, increased activation of neuropeptide Y (NPY)-positive interneurons was observed in the dorsal DG of trauma-exposed, but non-affected rats. To test for a direct contribution of NPY in the dorsal DG to trauma resilience, a local shRNA-mediated knock down was performed after UWT. Such a treatment significantly reduced the prevalence of resilient animals. Our results suggest that distinct interneuron populations are associated with resilience or pathology in PTSD with high regional specificity. NPY within the dorsal DG was found to significantly contribute to trauma resilience.

Keywords: Behavioral profiling; Cholecystokinin; Dentate gyrus; Interneurons; Neuropeptide Y; Neuropeptides; PTSD; Pathology; Rat; Resilience.

Our new publication is online:  Active resilience in response to traumatic stress.

Richter-Levin G, Müller I, Tripathi K, Stork O. Active resilience in response to traumatic stress. In: Chen A, (ed). Stress Resilience: Molecular and Behavioral Aspects. San Diego: Elsevier Inc./Academic Press, 2020: 95-106. Link

 

Abstract

The mechanisms behind individual variability which leads only some individuals to develop stress-related psychopathologies is one of the key questions in stress research today. Here we explore the contribution of one target molecule, the GABA synthetic enzyme glutamic acid decarboxylase (GAD)65, to mechanisms of vulnerability and resilience. GAD65 is critically involved in the activity-dependent regulation of GABAergic inhibition in the central nervous system. It is also required for the maturation of the GABAergic system during adolescence, a phase that is critical for the development of several neuropsychiatric diseases. Mice bearing null mutation of the GAD65 gene develop hyperexcitability of the amygdala and hippocampus, and a phenotype of increased anxiety and pathological fear memory reminiscent of post-traumatic stress disorder. However, GAD65 haplodeficiency, which results in delayed postnatal increase of GABA levels, provides resilience to juvenile-stress induced anxiety to GAD65(+/-) mice. 

Results obtained so far clearly indicate that GAD65 functioning is relevant to both stress vulnerability and stress resilience. The variable results regarding stress-related alterations in the expression of GAD65, together with the differences between effects of homozygous GAD65(-/-) knockout and GAD65 haplodeficiency, suggest that the role of GAD65 in stress vulnerability and resilience may differ in different brain regions and between different developmental stages.  More temporal- and spatial- specific manipulations of expression are required in order to more accurately describe the role played by this enzyme in coping with stress. 

Gad65 is brought here only as an example. Similar caution is required when examining the role of other target molecules in individual difference related to stress vulnerability and stress resilience.