פעילויות מרכז המחקר

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Animal fitness largely depends on its ability to perform certain behaviors and physiological processes at particular times of the daily cycle. Such temporal regulation is mainly the outcome of an internal timing mechanism known as the circadian clock. In fish, and other non-mammalian vertebrates, the pineal gland contains an intrinsic circadian oscillator that drives the circadian rhythms of its hormonal signal (melatonin), and has been considered a key element in the circadian system. Employing a dominant-negative strategy we generated a transgenic zebrafish line in which the molecular clock is selectively blocked in the melatonin-producing cells of the pineal gland. As a result, clock-controlled rhythms of melatonin production in the adult pineal gland were disrupted and the rhythmic expression pattern of the majority of clock-controlled genes in the adult pineal gland was abolished. Importantly, the amplitude of behavioral rhythms was substantially reduced, but not completely eliminated. Thus, the pineal clock plays a key role in modulating circadian rhythms of behavior, but it is not the only regulatory component. To determine the role of other tissues in the circadian clock system and the hierarchal relationship among them, we are currently employing the same dominant-negative transgenic approach to block the clock at other tissues and cell types

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Tatyana will describe results showing that neural responses in the hippocampus have a low-dimensional hyperbolic geometry and that their hyperbolic size is optimized for the number of available neurons. It was also possible to analyze how neural representations change with experience. In particular, neural representations continued to be described by a low-dimensional hyperbolic geometry as the animal explored the environment but the radius increased logarithmically with time. This time dependence matches the maximal rate of information acquisition by a maximum entropy discrete Poisson process, further implying that neural representations continue to perform optimally as they change with experience

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Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition with high heritability. Genetic factors are associated with the autistic phenotype in 30–40% of children diagnosed with ASD. Despite substantial advances in genetic research, the precise cause of ASD remains unclear, suggesting that environmental factors may also play a crucial role. Stressors such as ischemia, maternal immune activation (MIA), and toxins have been linked to the development of ASD, either through direct effects on the brain or by inducing mitochondrial dysfunction and endoplasmic reticulum (ER) stress. These processes, in turn, are associated with perturbations in neuronal differentiation, potentially disrupting synaptic protein function and impairing neural circuit formation. Extracellular vesicles (EVs) are membrane-surrounded nanovesicles routinely excreted by cells, containing proteins, lipids, nucleic acids, and metabolites, and play a role in cell-to-cell communication. EVs mainly originate from the Golgi system, ER, or, to a lesser extent, direct exocytosis from cellular or mitochondrial membranes. The content of EVs extracted from plasma reflects physiological processes occurring in body tissues, including the brain. Thus, disrupted processes, in the brain, characteristic of ASD may be evident in their protein profiles.

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The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a GGGGCC repeat expansion in the C9orf72 gene. We developed a platform to interrogate the chromatin accessibility landscape and transcriptional program within neurons during degeneration. We provide evidence that neurons expressing the dipeptide repeat protein poly(proline-arginine), translated from the C9orf72 repeat expansion, activate a highly specific transcriptional program, exemplified by a single transcription factor, p53. Ablating p53 in mice completely rescued neurons from degeneration and markedly increased survival in a C9orf72 mouse model. p53 reduction increased survival of C9orf72 ALS/FTD-patient-induced pluripotent stem cell (iPSC)-derived motor neurons. Together, this demonstrates a neurodegenerative mechanism dynamically regulated through transcription-factor-binding events and provides a framework to apply chromatin accessibility and transcription program profiles to neurodegeneration.

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The brain can form associations between sensory information of inner and/or outer world (e.g. Pavlovian conditioning) but also between sensory information and the immune system. The phenomenon which was described in the last century is termed conditioned immune response (CIR) but very little is known about neuronal mechanisms subserving it.  The conditioned stimulus can be a given taste and the unconditioned stimulus is an agent that induces or reduces a specific immune response.  Over the last years, we and others revealed molecular and cellular mechanisms underlying taste valance representation in the anterior insular cortex (aIC). Recently, a circuit in the posterior insular cortex (pIC) encoding the internal representation of a given immune response was identified. Together, it allowed us to hypothesize and prove that the internal reciprocal connections between the anterior and posterior insula encode CIR.  One can look at CIR as a noon declarative form of Nocebo effect and thus we demonstrate for the first time a detailed circuit mechanism for Placebo/Nocebo effect in the cortex.

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This presentation will examine how astrocytes and microglia, two key types of glial cells, contribute to neurological disorders with particular emphasis on brain injury. I will present published and unpublished findings that reveal sophisticated molecular interactions between plexin and semaphorin proteins, which serve as signaling partners on microglia and astrocytes. While semaphorins typically function as signal-sending molecules (ligands) and plexins as signal-receiving molecules (receptors), our research has uncovered an unexpected "reverse-signaling" mechanism where these roles are reversed. This discovery points to a new framework for understanding how astrocytes and microglia communicate and regulate each other's functions.

Our research demonstrates how these intricate signaling pathways control both inflammatory responses and cellular balance, directly impacting the survival of neurons. These insights suggest promising therapeutic approaches for protecting nerve cells from damage. Additionally, I will present related findings from our study of a specific form of pediatric brain cancer - a high-grade glioma located in the pons - which reveals important roles for microglial cells in this disease.

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Brain activity while performing tasks is closely related to connectivity. Using machine learning we show that connectivity patterns obtained from resting-state scans predict individual differences in brain activation in healthy individuals and psychiatric patients. We further demonstrate that models can be generalized across datasets sites MRI vendors and age groups suggesting that it may be possible to train a model using publicly available datasets and test on smaller ‘boutique’ datasets. Next we show that task-activation maps predicted from functional connectivity can be used to predict individual traits. Therefore predicted task-activation may serve as a novel representation of connectivity that may enhance brain-behavior associations. Finally activity and connectivity are not fixed but undergo modifications following learning. In a series of studies we examined the relations between task-activation and functional connectivity and the predictability of the former from the latter in the learning brain. Participants underwent scans before and after either a piano training or a sign-language course. We show learning-induced modifications in connectivity and activity and their associations with one another and with performance. We conclude that connectivity and task-induced activity may share a common neural representation and that connectivity may play a mechanistic role in brain activity and behavior