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Found 34725 matches. Displaying 121-130
Pavlides C, Donishi T, Ribeiro S, Mello CV, Blanco W, Ogawa S
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Hippocampal functional organization: A microstructure of the place cell network encoding space

A clue to hippocampal function has been the discovery of place cells, leading to the 'spatial map' theory. Although the firing attributes of place cells are well documented, little is known about the organization of the spatial map. Unit recording studies, thus far, have reported a low coherence between neighboring cells and geometric space, leading to the prevalent view that the spatial map is not topographically organized. However, the number of simultaneously recorded units is severely limited, rendering construction of the spatial map nearly impossible. To visualize the functional organization of place cells, we used the activity-dependent immediate early gene Zif268 in combination with behavioral, pharmacological and electrophysiological methods, in mice and rats exploring an environment. Here, we show that in animals confined to a small part of a maze, principal cells in the CA1/CA3 subfields of the dorsal hippocampus immunoreactive (IR) for Zif268 adhere to a 'cluster type' organization. Unit recordings confirmed that the Zif268 IR clusters correspond to active place cells, while blockade of NMDAR (which alters place fields) disrupted the Zif268 IR clusters. Contrary to the prevalent view that the spatial map consists of a non-topographic neural network, our results provide evidence for a 'cluster type' functional organization of hippocampal neurons encoding for space.
Prakash V, Carson BB, Feenstra JM, Dass RA, Sekyrova P, Hoshino A, Petersen J, Guo Y, Parks MM, Kurylo CM, Batchelder JE, Haller K, Hashimoto A, Rundqivst H, Condeelis JS, Allis CD, Drygin D, Nieto MA, Andang M, Percipalle P, Bergh J, Adameyko I, Farrants AKO, Hartman J, Lyden D, Pietras K, Blanchard SC, Vincent CT
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Ribosome biogenesis during cell cycle arrest fuels EMT in development and disease

NATURE COMMUNICATIONS 2019 MAY 8; 10(?):? Article 2110
Ribosome biogenesis is a canonical hallmark of cell growth and proliferation. Here we show that execution of Epithelial-to-Mesenchymal Transition (EMT), a migratory cellular program associated with development and tumor metastasis, is fueled by upregulation of ribosome biogenesis during G1/S arrest. This unexpected EMT feature is independent of species and initiating signal, and is accompanied by release of the repressive nucleolar chromatin remodeling complex (NoRC) from rDNA, together with recruitment of the EMT-driving transcription factor Snai1 (Snail1), RNA Polymerase I (Pol I) and the Upstream Binding Factor (UBF). EMT-associated ribosome biogenesis is also coincident with increased nucleolar recruitment of Rictor, an essential component of the EMT-promoting mammalian target of rapamycin complex 2 (mTORC2). Inhibition of rRNA synthesis in vivo differentiates primary tumors to a benign, Estrogen Receptor-alpha (ER alpha) positive, Rictor-negative phenotype and reduces metastasis. These findings implicate the EMT-associated ribosome biogenesis program with cellular plasticity, de-differentiation, cancer progression and metastatic disease.
Azevedo EP, Pomeranz L, Cheng J, Schneeberger M, Vaughan R, Stem SA, Tan BW, Doerig K, Greengard P, Friedman JM
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A Role of Drd2 Hippocampal Neurons in Context-Dependent Food Intake

NEURON 2019 MAY 22; 102(4):873-886.e5
Associative learning of food cues that link location in space to food availability guides feeding behavior in mammals. However, the function of specific neurons that are elements of the higher-order, cognitive circuitry controlling feeding behavior is largely unexplored. Here, we report that hippocampal dopamine 2 receptor (hD2R) neurons are specifically activated by food and that both acute and chronic modulation of their activity reduces food intake in mice. Upstream projections from the lateral entorhinal cortex (LEC) to the hippocampus activate hD2R cells and can also decrease food intake. Finally, activation of hD2R neurons interferes with the encoding of a spatial memory linking food to a specific location via projections from the hippocampus to the septal area. Altogether these data describe a previously unidentified LEC > hippocampus > septal higher-order circuit that regulates feeding behavior.
Morley-Fletcher S, Mairesse J, Van Camp G, Reynaert ML, Gatta E, Marrocco J, Bouwalerh H, Nicoletti F, Maccari S
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Perinatal Stress Programs Sex Differences in the Behavioral and Molecular Chronobiological Profile of Rats Maintained Under a 12-h Light-Dark Cycle

Stress and the circadian systems play a major role in an organism's adaptation to environmental changes. The adaptive value of the stress system is reactive while that of the circadian system is predictive. Dysfunctions in these two systems may account for many clinically relevant disorders. Despite the evidence that interindividual differences in stress sensitivity and in the functioning of the circadian system are related, there is limited integrated research on these topics. Moreover, sex differences in these systems are poorly investigated. We used the perinatal stress (PRS) rat model, a well-characterized model of maladaptive programming of reactive and predictive adaptation, to monitor the running wheel behavior in male and female adult PRS rats, under a normal light/dark cycle as well as in response to a chronobiological stressor (6-h phase advance/shift). We then analyzed across different time points the expression of genes involved in circadian clocks, stress response, signaling, and glucose metabolism regulation in the suprachiasmatic nucleus (SCN). In the unstressed control group, we found a sex-specific profile that was either enhanced or inverted by PRS. Also, PRS disrupted circadian wheel-running behavior by inducing a phase advance in the activity of males and hypoactivity in females and increased vulnerability to chronobiological stress in both sexes. We also observed oscillations of several genes in the SCN of the unstressed group in both sexes. PRS affected males to greater extent than females, with PRS males displaying a pattern similar to unstressed females. Altogether, our findings provide evidence for a specific profile of dysmasculinization induced by PRS at the behavioral and molecular level, thus advocating the necessity to include sex as a biological variable to study the set-up of circadian system in animal models.
Zeevi D, Korem T, Godneva A, Bar N, Kurilshikov A, Lotan-Pompan M, Weinberger A, Fu JY, Wijmenga C, Zhernakova A, Segal E
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Structural variation in the gut microbiome associates with host health

NATURE 2019 APR 4; 568(7750):43-48
Differences in the presence of even a few genes between otherwise identical bacterial strains may result in critical phenotypic differences. Here we systematically identify microbial genomic structural variants (SVs) and find them to be prevalent in the human gut microbiome across phyla and to replicate in different cohorts. SVs are enriched for CRISPR-associated and antibiotic-producing functions and depleted from housekeeping genes, suggesting that they have a role in microbial adaptation. We find multiple associations between SVs and host disease risk factors, many of which replicate in an independent cohort. Exploring genes that are clustered in the same SV, we uncover several possible mechanistic links between the microbiome and its host, including a region in Anaerostipes hadrus that encodes a composite inositol catabolism-butyrate biosynthesis pathway, the presence of which is associated with lower host metabolic disease risk. Overall, our results uncover a nascent layer of variability in the microbiome that is associated with microbial adaptation and host health.
He H, Guttman-Yassky E
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JAK Inhibitors for Atopic Dermatitis: An Update

Atopic dermatitis (AD) is one of the most common inflammatory skin diseases. AD is driven by barrier dysfunction and abnormal immune activation of Thelper (Th) 2, Th22, and varying degrees of Th1 and Th17 among various subtypes. The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and spleen tyrosine kinase (SYK) pathways are involved in signaling of several AD-related cytokines, such as IFN-gamma, IL-4, IL-13, IL-31, IL-33, IL-23, IL-22, and IL-17, mediating downstream inflammation and barrier alterations. While AD is primarily Th2-driven, the clinical and molecular heterogeneity of AD endotypes highlights the unmet need for effective therapeutic options that target more than one immune axis and are safe for long-term use. The JAK inhibitors, which target different combinations of kinases, have overlapping but distinct mechanisms of action and safety profiles. Several topical and oral JAK inhibitors have been shown to decrease AD severity and symptoms. A review of the JAK and SYK inhibitors that are currently undergoing evaluation for efficacy and safety in the treatment of AD summarizes available data on a promising area of therapeutics and further elucidates the complex molecular interactions that drive AD.
Sarrafzadeh SA, Nourizadeh M, Mahloojirad M, Fazlollahi MR, Shoormasti RS, Badalzadeh M, Deswarte C, Casanova JL, Pourpak Z, Bustamante J, Moin M
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Molecular, Immunological, and Clinical Features of 16 Iranian Patients with Mendelian Susceptibility to Mycobacterial Disease

Purpose Mendelian susceptibility to mycobacterial disease (MSMD) is a rare primary immunodeficiency, triggered by non-tuberculous mycobacteria or Bacillus Calmette-Guerin (BCG) vaccines and characterized by severe diseases. All known genetic etiologies are inborn errors of IFN-gamma-mediated immunity. Here, we report the molecular, cellular, and clinical features of patients from 15 Iranian families with disseminated disease without vaccination (2 patients) or following live BCG vaccination (14 patients). Methods We used whole blood samples from 16 patients and 12 age-matched healthy controls. To measure IL-12 and IFN-gamma, samples were activated by BCG plus recombinant human IFN-gamma or recombinant human IL-12. Immunological assessments and genetic analysis were also done for the patients. Results Eight patients affected as a result of parental first-cousin marriages. Seven patients originated from multiplex kindred with positive history of death because of tuberculosis or finding the MSMD-related gene mutations. Two patients died due to mycobacterial disease at the ages of 8 months and 3.7 years. The remaining patients were alive at the last follow-up and were aged between 2 and 13 years. Patients suffered from infections including chronic mucocutaneous candidiasis (n = 10), salmonellosis (n = 2), and Leishmania (responsible for visceral form) (n = 2). Thirteen patients presented with autosomal recessive (AR) IL-12R beta 1 deficiency, meaning their cells produced low levels of IFN-gamma. Bi-allelic IL12RB1 mutations were detected in nine of patients. Three patients with AR IL-12p40 deficiency (bi-allelic IL12B mutations) produced low levels of both IL-12 and IFN-gamma. Overall, we found five mutations in the IL12RB1 gene and three mutations in the IL12B gene. Except one mutation in exon 5 (c.510C>A) of IL12B, all others were previously reported to be loss-of-function mutations. Conclusions We found low levels of IFN-gamma production and failure to respond to IL12 in 13 Iranian MSMD patients. Due to complicated clinical manifestations in affected children, early cellular and molecular diagnostics is crucial in susceptible patients.
Zhu XG, Puthenveedu SN, Shen YH, La K, Ozlu C, Wang T, Klompstra D, Gultekin Y, Chi JY, Fidelin J, Peng T, Molina H, Hang HC, Min W, Birsoy K
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CHP1 Regulates Compartmentalized Glycerolipid Synthesis by Activating GPAT4

MOLECULAR CELL 2019 APR 4; 74(1):45-58.e7
Cells require a constant supply of fatty acids to survive and proliferate. Fatty acids incorporate into membrane and storage glycerolipids through a series of endoplasmic reticulum (ER) enzymes, but how these enzymes are regulated is not well understood. Here, using a combination of CRISPR-based genetic screens and unbiased lipidomics, we identified calcineurin B homologous protein 1 (CHP1) as a major regulator of ER glycerolipid synthesis. Loss of CHP1 severely reduces fatty acid incorporation and storage in mammalian cells and invertebrates. Mechanistically, CHP1 binds and activates GPAT4, which catalyzes the initial rate-limiting step in glycerolipid synthesis. GPAT4 activity requires CHP1 to be N-myristoylated, forming a key molecular interface between the two proteins. Interestingly, upon CHP1 loss, the peroxisomal enzyme, GNPAT, partially compensates for the loss of ER lipid synthesis, enabling cell proliferation. Thus, our work identifies a conserved regulator of glycerolipid metabolism and reveals plasticity in lipid synthesis of proliferating cells.
Katz M, Corson F, Keil W, Singhal A, Bae A, Lu Y, Liang YP, Shaham S
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Glutamate spillover in C. elegans triggers repetitive behavior through presynaptic activation of MGL-2/mGluR5

NATURE COMMUNICATIONS 2019 APR 23; 10(?):? Article 1882
Glutamate is a major excitatory neurotransmitter, and impaired glutamate clearance following synaptic release promotes spillover, inducing extra-synaptic signaling. The effects of glutamate spillover on animal behavior and its neural correlates are poorly understood. We developed a glutamate spillover model in Caenorhabditis elegans by inactivating the conserved glial glutamate transporter GLT-1. GLT-1 loss drives aberrant repetitive locomotory reversal behavior through uncontrolled oscillatory release of glutamate onto AVA, a major interneuron governing reversals. Repetitive glutamate release and reversal behavior require the glutamate receptor MGL-2/mGluR5, expressed in RIM and other interneurons presynaptic to AVA. mgl-2 loss blocks oscillations and repetitive behavior; while RIM activation is sufficient to induce repetitive reversals in glt-1 mutants. Repetitive AVA firing and reversals require EGL-30/Gaq, an mGluR5 effector. Our studies reveal that cyclic autocrine presynaptic activation drives repetitive reversals following glutamate spillover. That mammalian GLT1 and mGluR5 are implicated in pathological motor repetition suggests a common mechanism controlling repetitive behaviors.