44 results on '"Radulovic, Jelena"'
Search Results
2. Formation of memory assemblies through the DNA-sensing TLR9 pathway.
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Jovasevic, Vladimir, Wood, Elizabeth M., Cicvaric, Ana, Zhang, Hui, Petrovic, Zorica, Carboncino, Anna, Parker, Kendra K., Bassett, Thomas E., Moltesen, Maria, Yamawaki, Naoki, Login, Hande, Kalucka, Joanna, Sananbenesi, Farahnaz, Zhang, Xusheng, Fischer, Andre, and Radulovic, Jelena
- Abstract
As hippocampal neurons respond to diverse types of information1, a subset assembles into microcircuits representing a memory2. Those neurons typically undergo energy-intensive molecular adaptations, occasionally resulting in transient DNA damage3–5. Here we found discrete clusters of excitatory hippocampal CA1 neurons with persistent double-stranded DNA (dsDNA) breaks, nuclear envelope ruptures and perinuclear release of histone and dsDNA fragments hours after learning. Following these early events, some neurons acquired an inflammatory phenotype involving activation of TLR9 signalling and accumulation of centrosomal DNA damage repair complexes6. Neuron-specific knockdown of Tlr9 impaired memory while blunting contextual fear conditioning-induced changes of gene expression in specific clusters of excitatory CA1 neurons. Notably, TLR9 had an essential role in centrosome function, including DNA damage repair, ciliogenesis and build-up of perineuronal nets. We demonstrate a novel cascade of learning-induced molecular events in discrete neuronal clusters undergoing dsDNA damage and TLR9-mediated repair, resulting in their recruitment to memory circuits. With compromised TLR9 function, this fundamental memory mechanism becomes a gateway to genomic instability and cognitive impairments implicated in accelerated senescence, psychiatric disorders and neurodegenerative disorders. Maintaining the integrity of TLR9 inflammatory signalling thus emerges as a promising preventive strategy for neurocognitive deficits.Learning results in persistent double-stranded DNA breaks, nuclear rupture and release of DNA fragments and histones within hippocampal CA1 neurons that, following TLR9-mediated DNA damage repair, results in their recruitment to memory circuits. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Activation of the dorsal, but not the ventral, hippocampus relieves neuropathic pain in rodents.
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Wei, Xuhong, Centeno, Maria Virginia, Ren, Wenjie, Borruto, Anna Maria, Procissi, Daniele, Xu, Ting, Jabakhanji, Rami, Mao, Zuchao, Kim, Haram, Li, Yajing, Yang, Yiyuan, Gutruf, Philipp, Rogers, John A., Surmeier, D. James, Radulovic, Jelena, Liu, Xianguo, Martina, Marco, and Apkarian, Apkar Vania
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- 2021
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4. Stress-related memories disrupt sociability and associated patterning of hippocampal activity: a role of hilar oxytocin receptor-positive interneurons.
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Meyer, Mariah A. A., Anstötz, Max, Ren, Lynn Y., Fiske, Michael P., Guedea, Anita L., Grayson, Viktoriya S., Schroth, Samantha L., Cicvaric, Ana, Nishimori, Katsuhiko, Maccaferri, Gianmaria, and Radulovic, Jelena
- Published
- 2020
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5. Excitatory VTA to DH projections provide a valence signal to memory circuits.
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Han, Yuan, Zhang, Yi, Kim, Haram, Grayson, Viktoriya S., Jovasevic, Vladimir, Ren, Wenjie, Centeno, Maria V., Guedea, Anita L., Meyer, Mariah A. A., Wu, Yixin, Gutruf, Philipp, Surmeier, Dalton J., Gao, Can, Martina, Marco, Apkarian, Apkar V., Rogers, John A., and Radulovic, Jelena
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DRUG-seeking behavior ,EPISODIC memory ,MEMORY ,ADAPTABILITY (Personality) ,INTEGRATING circuits - Abstract
The positive or negative value (valence) of past experiences is normally integrated into neuronal circuits that encode episodic memories and plays an important role in guiding behavior. Here, we show, using mouse behavioral models, that glutamatergic afferents from the ventral tegmental area to the dorsal hippocampus (VTA→DH) signal negative valence to memory circuits, leading to the formation of fear-inducing context memories and to context-specific reinstatement of fear. To a lesser extent, these projections also contributed to opioid-induced place preference, suggesting a role in signaling positive valence as well, and thus a lack of dedicated polarity. Manipulations of VTA terminal activity were more effective in females and paralleled by sex differences in glutamatergic signaling. By prioritizing retrieval of negative and positive over neutral memories, the VTA→DH circuit can facilitate the selection of adaptive behaviors when current and past experiences are valence congruent. The neuronal pathway that signals the positive or negative value of memories is not well understood. Here, the authors report that an excitatory projection from the ventral tegmental area to the dorsal hippocampus carries the valence information, contributing, especially in females, to the recurrence of fear and to drug seeking behavior. [ABSTRACT FROM AUTHOR]
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- 2020
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6. Differential Contributions of Glutamatergic Hippocampal→Retrosplenial Cortical Projections to the Formation and Persistence of Context Memories.
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Yamawaki, Naoki, Corcoran, Kevin A, Guedea, Anita L, Shepherd, Gordon M G, and Radulovic, Jelena
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- 2019
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7. N-Methyl D-aspartate receptor subunit signaling in fear extinction.
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Radulovic, Jelena, Ren, Lynn Y., and Gao, Can
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METHYL aspartate receptors ,FEAR ,EXTINCTION (Psychology) ,MEMORY ,ANXIETY disorders ,POST-traumatic stress disorder ,NEUROPLASTICITY ,COGNITION - Abstract
N-Methyl D-aspartate receptors (NMDAR) are central mediators of glutamate actions underlying learning and memory processes including those required for extinction of fear and fear-related behaviors. Consistent with this view, in animal models, antagonists of NMDAR typically impair fear extinction, whereas partial agonists have facilitating effects. Promoting NMDAR function has thus been recognized as a promising strategy towards reduction of fear symptoms in patients suffering from anxiety disorders and post-traumatic disorder (PTSD). Nevertheless, application of these drugs in clinical trials has proved of limited utility. Here we summarize recent advances in our knowledge of NMDAR pharmacology relevant for fear extinction, focusing on molecular, cellular, and circuit aspects of NMDAR function as they relate to fear extinction at the level of behavior and cognition. We also discuss how these advances from animal models might help to understand and overcome the limitations of existing approaches in human anxiety disorders and how novel, more specific, and personalized approaches might help advance future therapeutic strategies. [ABSTRACT FROM AUTHOR]
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- 2019
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8. State-Dependent Memory: Neurobiological Advances and Prospects for Translation to Dissociative Amnesia.
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Radulovic, Jelena, Lee, Royce, and Ortony, Andrew
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- 2018
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9. Using New Approaches in Neurobiology to Rethink Stress-Induced Amnesia.
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Radulovic, Jelena
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- 2017
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10. A Corticocortical Circuit Directly Links Retrosplenial Cortex to M2 in the Mouse.
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Yamawaki, Naoki, Radulovic, Jelena, and Shepherd, Gordon M. G.
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CEREBRAL cortex ,COGNITION ,HIPPOCAMPUS (Brain) ,MOTOR cortex ,PYRAMIDAL neurons - Abstract
Retrosplenial cortex (RSC) is a dorsomedial parietal area involved in a range of cognitive functions, including episodic memory, navigation, and spatial memory. Anatomically, the RSC receives inputs from dorsal hippocampal networks and in turn projects to medial neocortical areas. A particularly prominent projection extends rostrally to the posterior secondary motor cortex (M2), suggesting a functional corticocortical link from the RSC to M2 and thus a bridge between hippocampal and neocortical networks involved in mnemonic and sensorimotor aspects of navigation. We investigated the cellular connectivity in this RSC→M2 projection in the mouse using optogenetic photostimulation, retrograde labeling, and electrophysiology. Axons from RSC formed monosynaptic excitatory connections onto M2 pyramidal neurons across layers and projection classes, including corticocortical/intratelencephalic neurons (reciprocally and callosally projecting) in layers 2-6, pyramidal tract neurons (corticocollicular, corticopontine) in layer 5B, and, to a lesser extent, corticothalamic neurons in layer 6. In addition to these direct connections, disynaptic connections were made via posterior parietal cortex (RSC→PPC→M2) and anteromedial thalamus (RSC→AM→M2). In the reverse direction, axons from M2 monosynaptically excited M2-projecting corticocortical neurons in the RSC, especially in the superficial layers of the dysgranular region. These findings establish an excitatory RSC→M2 corticocortical circuit that engages diverse types of excitatory projection neurons in the downstream area, suggesting a basis for direct communication from dorsal hippocampal networks involved in spatial memory and navigation to neocortical networks involved in diverse aspects of sensorimotor integration and motor control. [ABSTRACT FROM AUTHOR]
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- 2016
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11. Role of adult hippocampal neurogenesis in persistent pain.
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Apkarian, A. Vania, Mutso, Amelia A., Centeno, Maria V., Kan, Lixin, Wu, Melody, Levinstein, Marjorie, Banisadr, Ghazal, Gobeske, Kevin T., Miller, Richard J., Radulovic, Jelena, Hen, René, and Kessler, John A.
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- 2016
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12. Correction to: Sex-specific roles of hippocampal microRNAs in stress vulnerability and resilience.
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Krispil-Alon, Maayan, Jovasevic, Vladimir, Radulovic, Jelena, and Richter-Levin, Gal
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- 2023
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13. Double Dissociation of the Roles of Metabotropic Glutamate Receptor 5 and Oxytocin Receptor in Discrete Social Behaviors.
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Mesic, Ivana, Guzman, Yomayra F, Guedea, Anita L, Jovasevic, Vladimir, Corcoran, Kevin A, Leaderbrand, Katherine, Nishimori, Katsuhiko, Contractor, Anis, and Radulovic, Jelena
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SOCIAL interaction ,GLUTAMATE receptors ,NEUROTRANSMITTER receptors ,OXYTOCIN receptors ,COLLECTIVE memory ,IMMUNOSTAINING - Abstract
Social interactions in vertebrates are complex phenomena based on affective and cognitive processes. Multiple brain regions and neurotransmitter systems are involved in the expression of social behaviors, but their individual roles in specific aspects of social interactions are not well understood. Here we investigated how Gq-protein-coupled metabotropic glutamate receptor 5 (mGluR5) and oxytocin receptor (Oxtr) affect social affiliation and social memory. We used conditional genetic approaches in which the genes coding for these receptors were knocked out in the lateral septum by infusion of recombinant adeno-associated viral vectors containing Cre recombinase (AAV-Cre). Social behavior was assessed 2 weeks later using a three-chamber paradigm for sociability and preference for social novelty. Septal deletion of mGluR5 abolished sociability while leaving preference for social novelty intact. In contrast, deletion of Oxtr did not affect sociability but significantly impaired preference for social novelty. Nonsocial behaviors or memories, including novel object recognition or fear conditioning, were not affected by these genetic manipulations. Immunohistochemical analyses of the distribution of mGluR5 and Oxtr revealed non-overlapping localization of these receptors within the lateral septum, suggesting that not only different neurotransmitters but also different neuronal types contribute to sociability versus preference for social novelty. Our findings identify highly specialized roles of lateral septal mGluR5 and Oxtr in the the regulation of discrete social behaviors, and suggest that deficits in social interactions, which accompany many mental illnesses, would benefit from comprehensive treatments targeting different components of social functioning. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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14. GABAergic mechanisms regulated by miR-33 encode state-dependent fear.
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Jovasevic, Vladimir, Corcoran, Kevin A, Leaderbrand, Katherine, Yamawaki, Naoki, Guedea, Anita L, Chen, Helen J, Shepherd, Gordon M G, and Radulovic, Jelena
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GABA ,NEUROTRANSMITTERS ,MEMORY ,PATHOLOGICAL psychology ,HIPPOCAMPUS (Brain) ,THERAPEUTICS - Abstract
Fear-inducing memories can be state dependent, meaning that they can best be retrieved if the brain states at encoding and retrieval are similar. Restricted access to such memories can present a risk for psychiatric disorders and hamper their treatment. To better understand the mechanisms underlying state-dependent fear, we used a mouse model of contextual fear conditioning. We found that heightened activity of hippocampal extrasynaptic GABA
A receptors, believed to impair fear and memory, actually enabled their state-dependent encoding and retrieval. This effect required protein kinase C-βII and was influenced by miR-33, a microRNA that regulates several GABA-related proteins. In the extended hippocampal circuit, extrasynaptic GABAA receptors promoted subcortical, but impaired cortical, activation during memory encoding of context fear. Moreover, suppression of retrosplenial cortical activity, which normally impairs retrieval, had an enhancing effect on the retrieval of state-dependent fear. These mechanisms can serve as treatment targets for managing access to state-dependent memories of stressful experiences. [ABSTRACT FROM AUTHOR]- Published
- 2015
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15. Accumulation of Cytoplasmic Glucocorticoid Receptor Is Related to Elevation of FKBP5 in Lymphocytes of Depressed Patients.
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Lukic, Iva, Mitic, Milos, Soldatovic, Ivan, Jovicic, Milica, Maric, Nadja, Radulovic, Jelena, and Adzic, Miroslav
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We have previously shown that patients with the major depressive disorder (MDD) exhibited elevated phosphorylation of the lymphocyte glucocorticoid receptor (GR) at serine 226 (S226). Here, we further analyse potential alterations of GR signalization in lymphocytes of MDD patients, i.e. the cytoplasmic/nuclear distribution of GR, levels of FK506-binding protein 5 (FKBP5) and glucocorticoid-induced leucine zipper (GILZ). The FKBP5 acts as an important regulator of GR activation, by decreasing ligand binding and impeding translocation of the receptor to the nucleus, while GILZ mediates glucocorticoid anti-inflammatory effects. Our result showed that the depressed patients had significantly higher GR levels in the cytoplasm compared to controls, which was accompanied by higher FKBP5 levels. Linear regression model demonstrated significantly higher correlation between FKBP5 and cytoplasmic GR than the presence of MDD itself or phosphorylation of nuclear GR at S226. There were no differences in the levels of GILZ isoforms. Therefore, the results suggest that accumulation of the GR in cytoplasm is related to the elevation of FKBP5, adding one more step in understanding altered GR signalling in lymphocytes, and potentially brain tissue, of MDD patients. [ABSTRACT FROM AUTHOR]
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- 2015
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16. Role of oxytocin receptors in modulation of fear by social memory.
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Guzmán, Yomayra, Tronson, Natalie, Sato, Keisuke, Mesic, Ivana, Guedea, Anita, Nishimori, Katsuhiko, and Radulovic, Jelena
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PSYCHOPHARMACOLOGICAL research ,DRUG receptors ,OXYTOCIN receptors ,COLLECTIVE memory ,FEAR ,LABORATORY mice ,CLASSICAL conditioning ,CONDITIONED response - Abstract
Rationale: Oxytocin receptors (Oxtr) are important mediators of social learning and emotion, with bidirectional effects on fear and anxiety. Contrary to the anxiolytic actions of Oxtr in the amygdala, we recently showed that Oxtr in the lateral septum mediate the enhancement of fear conditioning by social defeat in mice. Objectives: Using positive social interactions, which impair fear conditioning, here we attempted to delineate whether the role of septal Oxtr in fear regulation depends on the valence of the social memory. Methods: Pharmacological and genetic manipulations of lateral septal Oxtr were combined with the social buffering of fear paradigm, in which pre-exposure to nonfearful conspecifics reduces subsequent contextual fear conditioning, as revealed by decreased freezing behavior. Results: Antagonism and down-regulation of Oxtr in the lateral septum abolished, while oxytocin (Oxt) administration before pre-exposure to nonfearful conspecifics facilitated the decrease of freezing behavior. Conclusions: The septal oxytocin system enhances memory of social interactions regardless of their valence, reducing fear after positive and enhancing fear after negative social encounters. These findings explain, at least in part, the seemingly bidirectional role of Oxt in fear regulation. [ABSTRACT FROM AUTHOR]
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- 2014
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17. Extinction of Remotely Acquired Fear Depends on an Inhibitory NR2B/PKA Pathway in the Retrosplenial Cortex.
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Corcoran, Kevin A., Leaderbrand, Katherine, and Radulovic, Jelena
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FEAR ,BIOLOGICAL extinction ,METHYL aspartate receptors ,CYCLIC-AMP-dependent protein kinase ,MEMORY ,HIPPOCAMPUS (Brain) - Abstract
As memories age, their processing increasingly relies upon cortical rather than hippocampal circuits, but the adaptive significance and mechanisms of this shift are not fully understood. Here we investigated the behavioral features and cortical mechanisms underlying extinction of remotely versus recently acquired context fear in mice. Behaviorally, extinction and reinstatement were similar, but re-extinction of remote fear was significantly faster, suggesting time-dependent engagement of mechanisms specific for processing remote memory. Using pharmacological manipulations of NMDA receptors and associated signaling pathways in the in the retrosplenial cortex, we demonstrated that extinction of remote fear uniquely required NR2B-mediated downregulation of the cAMP-dependent protein kinase (PKA)/cAMP response element-binding protein pathway. Interestingly, NR2B/PKA interactions weakened independently of the age of the memory, but the functional significance of this molecular change was evident only as memory retrieval became PKA-dependent over time. Thus, cortical PKA signaling may provide a molecular signature of when a memory has become "remote," and inhibition of this pathway may open the door for modulation of remote memories. [ABSTRACT FROM AUTHOR]
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- 2013
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18. Abnormalities in Hippocampal Functioning with Persistent Pain.
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Mutso, Amelia A., Radzicki, Daniel, Baliki, Marwan N., Huang, Lejian, Banisadr, Ghazal, Centeno, Maria V., Radulovic, Jelena, Martina, Marco, Miller, Richard J., and Apkarian, A. Vania
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CHRONIC pain ,HIPPOCAMPUS (Brain) ,NEUROPLASTICITY ,PHOSPHORYLATION ,DEVELOPMENTAL neurobiology ,LABORATORY mice ,PATIENTS - Abstract
Chronic pain patients exhibit increased anxiety, depression, and deficits in learning and memory. Yet how persistent pain affects the key brain area regulating these behaviors, the hippocampus, has remained minimally explored. In this study we investigated the impact of spared nerve injury (SNI) neuropathic pain in mice on hippocampal-dependent behavior and underlying cellular and molecular changes. In parallel, we measured the hippocampal volume of three groups of chronic pain patients. We found that SNI animals were unable to extinguish contextual fear and showed increased anxiety-like behavior. Additionally, SNI mice compared with Sham animals exhibited hippocampal (1) reduced extracellular signal-regulated kinase expression and phosphorylation, (2) decreased neurogenesis, and (3) altered short-term synaptic plasticity. To relate the observed hippocampal abnormalities with human chronic pain, we measured the volume of human hippocampus in chronic back pain (CBP), complex regional pain syndrome (CRPS), and osteoarthritis patients (OA). Compared with controls, CBP and CRPS, but not OA, had significantly less bilateral hippocampal volume. These results indicate that hippocampus-mediated behavior, synaptic plasticity, and neurogenesis are abnormal in neuropathic rodents. The changes may be related to the reduction in hippocampal volume we see in chronic pain patients, and these abnormalities may underlie learning and emotional deficits commonly observed in such patients. [ABSTRACT FROM AUTHOR]
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- 2012
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19. NMDA Receptors in Retrosplenial Cortex Are Necessary for Retrieval of Recent and Remote Context Fear Memory.
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Corcoran, Kevin A., Donnan, Michael D., Tronson, Natalie C., Guzmán, Yomayra F., Can Gao, Jovasevic, Vladimir, Guedea, Anita L., and Radulovic, Jelena
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NEUROTRANSMITTER receptors ,POST-traumatic stress disorder ,METHYL aspartate ,HIPPOCAMPUS (Brain) ,LABORATORY mice ,PATIENTS - Abstract
Over time, memory retrieval is thought to transfer from the hippocampus to a distributed network of neocortical sites. Of these sites, the retrosplenial cortex (RSC) is robustly activated during retrieval of remotely acquired, emotionally valenced memories. It is unclear, however, whether RSC is specifically involved in memory storage or retrieval, and which neurotransmitter receptor mechanisms serve its function. We addressed these questions by inhibiting NMDARs in RSC via infusions of APV before tests for context fear in mice. Anterior cingulate cortex (ACC) and dorsal hippocampus (DH), which have been implicated in the retrieval of remote and recent memory, respectively, served as neuroanatomical controls. Surprisingly, infusion of APV only into RSC, but not ACC or DH, abolished retrieval of remote memory, as revealed by lack of freezing to the conditioning context. APV infused into RSC also impaired retrieval of recent memory, but had no effect on conditioning or memory storage. Within-subject experiments confirmed that the role of RSC in memory retrieval is not time limited. RSC-dependent context fear memory retrieval was mediated by NR2A, but not NR2B, subunit-containing NMDARs. Collectively, these data are the first demonstration that NMDARs in RSC are necessary for the retrieval of remote and recent memories of fear-evoking contexts. Dysfunction of RSC may thereby contribute significantly to the reexperiencing of traumatic memories in patients with posttraumatic stress disorder. [ABSTRACT FROM AUTHOR]
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- 2011
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20. IQGAP1 Regulates NR2A Signaling, Spine Density, and Cognitive Processes.
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Gao, Can, Frausto, Shanti F., Guedea, Anita L., Tronson, Natalie C., Jovasevic, Vladimir, Leaderbrand, Katie, Corcoran, Kevin A., Guzmán, Yomayra F., Swanson, Geoffrey T., and Radulovic, Jelena
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NEUROBEHAVIORAL disorders ,BRAIN diseases ,DEMENTIA ,NERVOUS system ,PSYCHOSES - Abstract
General or brain-region-specific decreases in spine number or morphology accompany major neuropsychiatric disorders. It is unclear, however, whether changes in spine density are specific for an individual mental process or disorder and, if so, which molecules confer such specificity. Here we identify the scaffolding protein IQGAP1 as a key regulator of dendritic spine number with a specific role in cognitive but not emotional or motivational processes. We show that IQGAP1 is an important component of NMDAR multiprotein complexes and functionally interacts with the NR2A subunits and the extracellular signal-regulated kinase 1 (ERK1) and ERK2 signaling pathway. Mice lacking the IQGAP1 gene exhibited significantly lower levels of surface NR2A and impaired ERK activity compared to their wild-type littermates. Accordingly, primary hippocampal cultures of IQGAP1
-/- neurons exhibited reduced surface expression of NR2A and disrupted ERK signaling in response to NR2A-dependent NMDAR stimulation. These molecular changes were accompanied by region-specific reductions of dendritic spine density in key brain areas involved in cognition, emotion, and motivation. IQGAP1 knock-outs exhibited marked long-term memory deficits accompanied by impaired hippocampal long-term potentiation (LTP) in a weak cellular learning model; in contrast, LTP was unaffected when induced with stronger stimulation paradigms. Anxiety- and depression like behavior remained intact. On the basis of these findings, we propose that a dysfunctional IQGAP1 gene contributes to the cognitive deficits in brain disorders characterized by fewer dendritic spines. [ABSTRACT FROM AUTHOR]- Published
- 2011
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21. Hippocampal NMDA receptor subunits differentially regulate fear memory formation and neuronal signal propagation.
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Gao, Can, Gill, Martin B., Tronson, Natalie C., Guedea, Anita L., Guzmán, Yomayra F., Huh, Kyu Hwan, Corcoran, Kevin A., Swanson, Geoffrey T., and Radulovic, Jelena
- Abstract
Activation of NMDA receptors (NMDAR) in the hippocampus is essential for the formation of contextual and trace memory. However, the role of individual NMDAR subunits in the molecular mechanisms contributing to these memory processes is not known. Here we demonstrate, using intrahippocampal injection of subunit-selective compounds, that the NR2A-preferring antagonist impaired contextual and trace fear conditioning as well as learning-induced increase of the nuclear protein c-Fos. The NR2B-specific antagonist, on the other hand, selectively blocked trace fear conditioning without affecting c-Fos levels. Studies with cultured primary hippocampal neurons, further showed that synaptic and extrasynaptic NR2A and NR2B differentially regulate the extracellular signal-regulated kinase 1 and 2/mitogen- and stress-activated protein kinase 1 (ERK1/2/MSK1)/c-Fos pathway. Activation of the synaptic population of NMDAR induced cytosolic, cytoskeletal, and perinuclear phosphorylation of ERK1/2 (pERK1/2). The nuclear propagation of pERK1/2 signals, revealed by upregulation of the downstream nuclear targets pMSK1 and c-Fos, was blocked by a preferential NR2A but not by a specific NR2B antagonist. Conversely, activation of total (synaptic and extrasynaptic) NMDAR engaged receptors with NR2B subunits, and resulted in membrane retention of pERK1/2 without inducing pMSK1 and c-Fos. Stimulation of extrasynaptic NMDAR alone was consistently ineffective at activating ERK signaling. The discrete contribution of synaptic and total NR2A- and NR2B-containing NMDAR to nuclear transmission vs. membrane retention of ERK signaling may underlie their specific roles in the formation of contextual and trace fear memory. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2010
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22. BMP Signaling Mediates Effects of Exercise on Hippocampal Neurogenesis and Cognition in Mice.
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Gobeske, Kevin T., Das, Sunit, Bonaguidi, Michael A., Weiss, Craig, Radulovic, Jelena, Disterhoft, John F., and Kessler, John A.
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DEVELOPMENTAL neurobiology ,RODENTS ,TRANSGENIC mice ,TRANSGENIC animals ,COGNITION ,NERVOUS system ,GROWTH factors ,BONE morphogenetic proteins ,MAMMALS - Abstract
Exposure to exercise or to environmental enrichment increases the generation of new neurons in the adult hippocampus and promotes certain kinds of learning and memory. While the precise role of neurogenesis in cognition has been debated intensely, comparatively few studies have addressed the mechanisms linking environmental exposures to cellular and behavioral outcomes. Here we show that bone morphogenetic protein (BMP) signaling mediates the effects of exercise on neurogenesis and cognition in the adult hippocampus. Elective exercise reduces levels of hippocampal BMP signaling before and during its promotion of neurogenesis and learning. Transgenic mice with decreased BMP signaling or wild type mice infused with a BMP inhibitor both exhibit remarkable gains in hippocampal cognitive performance and neurogenesis, mirroring the effects of exercise. Conversely, transgenic mice with increased BMP signaling have diminished hippocampal neurogenesis and impaired cognition. Exercise exposure does not rescue these deficits, suggesting that reduced BMP signaling is required for environmental effects on neurogenesis and learning. Together, these observations show that BMP signaling is a fundamental mechanism linking environmental exposure with changes in cognitive function and cellular properties in the hippocampus. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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23. Kalirin regulates cortical spine morphogenesis and disease-related behavioral phenotypes.
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Cahill, Michael E., Zhong Xie, Day, Michelle, Barbolina, Maria V., Miller, Courtney A., Weiss, Craig, Radulovic, Jelena, Sweatt, J. David, Disterhoft, John F., Surmeier, D. James, and Penzes, Peter
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MORPHOGENESIS ,PATHOLOGICAL psychology ,SPINE abnormalities ,GENETIC regulation ,CLOZAPINE ,COGNITIVE ability - Abstract
Dendritic spine morphogenesis contributes to brain function, cognition, and behavior, and is altered in psychiatric disorders. Kalirin is a brain-specific guanine-nucleotide exchange factor (GEF) for Rac-like GTPases and is a key regulator of spine morphogenesis. Here, we show that KALRN-knockout mice have specific reductions in cortical, but not hippocampal, Rac1 signaling and spine density, and exhibit reduced cortical glutamatergic transmission. These mice exhibit robust deficits in working memory, sociability, and prepulse inhibition, paralleled by locomotor hyperactivity reversible by clozapine in a kalirin-dependent manner. Several of these deficits are delayed and age-dependent. Our study thus links spine morphogenic signaling with age-dependent, delayed, disease-related phenotypes, including cognitive dysfunction. [ABSTRACT FROM AUTHOR]
- Published
- 2009
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24. Segregated Populations of Hippocampal Principal CA1 Neurons Mediating Conditioning and Extinction of Contextual Fear.
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Tronson, Natalie C., Schrick, Christina, Guzman, Yomayra F., Kyu Hwan Huh, Srivastava, Deepak P., Penzes, Peter, Guedea, Anita L., Can Gao, and Radulovic, Jelena
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NERVOUS system ,IMMUNOFLUORESCENCE ,NEURONS ,IMMUNOCYTOCHEMISTRY ,PROTEIN kinases - Abstract
Learning processes mediating conditioning and extinction of contextual fear require activation of several key signaling pathways in the hippocampus. Principal hippocampal CA1 neurons respond to fear conditioning by a coordinated activation of multiple protein kinases and immediate early genes, such as cFos, enabling rapid and lasting consolidation of contextual fear memory. The extracellular signal-regulated kinase (Erk) additionally acts as a central mediator of fear extinction. It is not known however, whether these molecular events take place in overlapping or nonoverlapping neuronal populations. By using mouse models of conditioning and extinction of fear, we set out to determine the time course of cFos and Erk activity, their cellular overlap, and regulation by afferent cholinergic input from the medial septum. Analyses of cFos
+ and pErk+ cells by immunofluorescence revealed predominant nuclear activation of either protein during conditioning and extinction of fear, respectively. Transgenic cFos-LacZ mice were further used to label in vivo Fos+ hippocampal cells during conditioning followed by pErk immunostaining after extinction. The results showed that these signaling molecules were activated in segregated populations of hippocampal principal neurons. Furthermore, immunotoxin-induced lesions of medial septal neurons, providing cholinergic input into the hippocampus, selectively abolished Erk activation and extinction of fear without affecting cFos responses and conditioning. These results demonstrate that extinction mechanisms based on Erk signaling involve a specific population of CA1 principal neurons distinctively regulated by afferent cholinergic input from the medial septum. [ABSTRACT FROM AUTHOR]- Published
- 2009
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25. Regulatory Mechanisms of Fear Extinction and Depression-Like Behavior.
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Tronson, Natalie C., Schrick, Christina, Fischer, Andre, Sananbenesi, Farahnaz, Pagès, Gilles, Pouysségur, Jacques, and Radulovic, Jelena
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ANXIETY ,MENTAL depression ,AFFECTIVE disorders ,PSYCHOLOGICAL stress ,PROTEIN kinases ,DEPRESSED persons ,NEUROPSYCHOPHARMACOLOGY - Abstract
Human anxiety is frequently accompanied by depression, and when they co-occur both conditions exhibit greater severity and resistance to treatment. Little is known, however, about the molecular processes linking these emotional and mood disorders. Based on previously reported phosphorylation patterns of extracellular signal-regulated kinase (ERK) in the brain, we hypothesized that ERK's upstream activators intertwine fear and mood regulation through their hippocampal actions. We tested this hypothesis by studying the upstream regulation of ERK signaling in behavioral models of fear and depression. Wild-type and ERK1-deficient mice were used to study the dorsohippocampal actions of the putative ERK activators: mitogen-activated and extracellular signal-regulated kinase (MEK), protein kinase C (PKC), and cAMP-dependent protein kinase (PKA). Mice lacking ERK1 exhibited enhanced fear extinction and reduced depression caused by overactivation of ERK2. Both behaviors were reversed by inhibition of MEK, however the extinction phenotype depended on hippocampal, whereas the depression phenotype predominantly involved extrahippocampal MEK. Unexpectedly, inhibition of PKC accelerated extinction and decreased depression by ERK-independent mechanisms, whereas inhibition of PKA did not produce detectable molecular or behavioral effects in the employed paradigm. These results indicate that, contrary to fear conditioning but similar to mood stabilization, extinction of fear required upregulation of MEK/ERK and downregulation of ERK-independent PKC signaling. The dissociation of these pathways may thus represent a common mechanism for fear and mood regulation, and a potential therapeutic option for comorbid anxiety and depression.Neuropsychopharmacology (2008) 33, 1570–1583; doi:10.1038/sj.npp.1301550; published online 22 August 2007 [ABSTRACT FROM AUTHOR]
- Published
- 2008
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26. A hippocampal Cdk5 pathway regulates extinction of contextual fear.
- Author
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Sananbenesi, Farahnaz, Fischer, Andre, Xinyu Wang, Schrick, Christina, Neve, Rachael, Radulovic, Jelena, and Li-Huei Tsai
- Subjects
FEAR ,EMOTIONS ,PERSONALITY & emotions ,CYCLIN-dependent kinases ,PROTEIN kinases ,CYTOSOL - Abstract
Treatment of emotional disorders involves the promotion of extinction processes, which are defined as the learned reduction of fear. The molecular mechanisms underlying extinction have only begun to be elucidated. By employing genetic and pharmacological approaches in mice, we show here that extinction requires downregulation of Rac-1 and cyclin-dependent kinase 5 (Cdk5), and upregulation of p21 activated kinase-1 (PAK-1) activity. This is physiologically achieved by a Rac-1–dependent relocation of the Cdk5 activator p35 from the membrane to the cytosol and dissociation of p35 from PAK-1. Moreover, our data suggest that Cdk5/p35 activity prevents extinction in part by inhibition of PAK-1 activity in a Rac-1–dependent manner. We propose that extinction of contextual fear is regulated by counteracting components of a molecular pathway involving Rac-1, Cdk5 and PAK-1. Our data suggest that this pathway could provide a suitable target for therapeutic treatment of emotional disorders. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
27. Differential activation of CRF receptor subtypes removes stress-induced memory deficit and anxiety.
- Author
-
Todorovic, Cedomir, Radulovic, Jelena, Jahn, Olaf, Radulovic, Marko, Sherrin, Tessi, Hippel, Cathrin, and Spiess, Joachim
- Subjects
CORTICOTROPIN releasing hormone ,HIPPOCAMPUS (Brain) ,SEPTUM (Brain) ,ANIMAL immobilization ,ANXIETY ,LABORATORY mice - Abstract
The objective of this study was to investigate the role of corticotropin-releasing factor receptors 1 (CRF
1 ) and 2 (CRF2 ) in anxiety-like behavior and learning of C57BL/6J mice after exposure to a stressful stimulus. When C57BL/6J mice were exposed to immobilization (1 h) serving as stressful stimulus, context- and tone-dependent fear conditioning were impaired if the training followed immediately after immobilization. The stress-induced impairment of context-dependent fear conditioning was prevented by specific blockade of CRF2 of the lateral septum (LS) with anti-sauvagine-30. Immobilization did not only affect conditioned fear, but also enhanced, through CRF2 of the LS, anxiety-like behavior determined with the elevated plus maze. Recovery from stress-induced anxiety and impairment of context-dependent fear conditioning was observed after 1 h delay of training and required hippocampal CRF1 , as indicated by the finding that this recovery was prevented by blockade of intrahippocampal CRF1 . It was concluded that exposure to a stressor initially affected both anxiety-like behavior and contextual conditioned fear through septal CRF2 , while the later activation of hippocampal CRF1 resulted in the return to baseline levels of both processes. Intraventricular injection of mouse urocortin 2, a CRF2 -selective agonist, removed the stress-induced anxiety and learning impairment, but did not reduce the activation of the hypothalamic pituitary adrenal axis indicative of the hormonal stress response. We propose that the enhanced anxiety is the component of the stress response responsible for the memory deficit. [ABSTRACT FROM AUTHOR]- Published
- 2007
- Full Text
- View/download PDF
28. Distinct Roles of Hippocampal De Novo Protein Synthesis and Actin Rearrangement in Extinction of Contextual Fear.
- Author
-
Fischer, André, Sananbenesi, Farahnaz, Schrick, Christina, Spiess, Joachim, and Radulovic, Jelena
- Subjects
NEURAL circuitry ,CONDITIONED response ,NEUROPLASTICITY ,CYTOCHALASINS ,HIPPOCAMPUS (Brain) ,PROTEIN synthesis - Abstract
It is believed that de novo protein synthesis is fundamentally linked to synaptic changes in neuronal circuits involved in acquisition and extinction of conditioned responses. Recent studies show that neuronal plasticity may be also altered by cytoskeletal rearrangement independently of protein synthesis. We investigated the role of these processes in the hippocampus during acquisition and extinction of context-dependent conditioned fear in mice. Intrahippocampal injections of the protein synthesis inhibitors anisomycin and puromycin, or of the actin rearrangement inhibitors cytochalasin D and latrunculin A, prevented the acquisition of context-dependent fear. Unexpectedly, anisomycin and puromycin enhanced extinction without erasing the fear memory. In contrast, cytochalasin D and latrunculin A prevented extinction of context-dependent freezing. On the basis of these findings, it is suggested that certain hippocampal mechanisms mediating extinction of conditioned contextual fear are inhibited by protein synthesis and involve actin rearrangement. Such mechanisms might predominandy elicit modifications of hippocampal circuits that store the conditioning memory. [ABSTRACT FROM AUTHOR]
- Published
- 2004
- Full Text
- View/download PDF
29. Mitogen-Activated Protein Kinase Signaling in the Hippocampus and Its Modulation by Corticotropin-Releasing Factor Receptor 2: A Possible Link between Stress and Fear Memory.
- Author
-
Sananbenesi, Farahnaz, Fischer, André, Schrick, Christina, Spiess, Joachim, and Radulovic, Jelena
- Subjects
PROTEIN kinases ,MITOGENS ,ADRENOCORTICOTROPIC hormone ,PEPTIDE hormones ,EMOTIONS - Abstract
A coordinated activation of multiple interlinked signaling pathways involving cAMP-dependent protein kinase (PKA) and mitogen-activated extracellular signal-regulated kinases (Mek-½) regulates gene expression and neuronal changes underlying memory consolidation. In the present study we investigated whether these molecular cascades might mediate the effects of stress on memory formation. We also investigated the role of hippocampal corticotropin-releasing factor receptor 2 (CRF[sub2]) in stress-enhanced learning and molecular signaling mediated by PKA, Mek-½, and their downstream targets extracellularly regulated kinases 1 and 2 (Erk-½) and p90-ribosomal-s-kinase-1 (p90Rsk-1). Acute 1 hr immobilization was used as a stressful stimulus, and one-trial context-dependent fear conditioning was used as a model for associative learning. Training of BALB/c mice 3 hr after the end of immobilization resulted in an enhancement of conditioned fear, as indicated by significantly increased freezing behavior of stressed when compared with nonstressed mice. Interestingly, Erk-½ phosphorylation after conditioning of nonstressed and stressed mice depended on PKA and Mek-½, respectively. Intrahippocampal injection of the selective Mek-½ inhibitor U0126 or CRF[sub2] antagonist antisauvagine-30 (aSvg-30) prevented stress-enhanced fear conditioning and Mek-½-dependent activation of Erk-½ and p90Rsk-1. aSvg-30 did not affect the phosphorylation of the PKA regulatory subunit II of stressed mice. The molecular and behavioral effects of CRF[sub2] coincided with stress-induced upregulation of CRF[sub2] mRNA. These results suggest that modulation of Mek-½-dependent signaling by hippocampal CRF[sub2] can be selectively involved in the delayed effects of stress on memory consolidation. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
30. Stress Applied During Primary Immunization Affects the Secondary Humoral Immune Response in the Rat: Involvement of Opioid Peptides.
- Author
-
Stanojevic, Stanislava, Dimitrijevic, Mirjana, Kovacevic-Jovanovic, Vesna, Miletic, Tatjana, Vujic, Vesna, and Radulovic, Jelena
- Subjects
ELECTRIC shock ,IMMUNE response ,SERUM albumin ,IMMUNOGLOBULINS ,PHYSIOLOGICAL stress - Abstract
The effect of unpredictable, inescapable and uncontrollable electric tail shocks (ES) on the humoral immune response to bovine serum albumin (BSA) was investigated in the rat. Contributions of the procedures that accompany shock delivery, such as witnessing the ES procedure (stress witnessing, SW) and exposure to the apparatus for shock delivery (apparatus control, AC) to the changes in specific immunity induced by ES were also tested. All procedures were applied during primary and/or secondary immunization. It was demonstrated that exposure to ES during primary immunization with BSA significantly suppressed specific anti-BSA antibody production after secondary and tertiary immunization with the same antigen. Exposure to the SW procedure during primary immunization with BSA enhanced the specific antibody level after secondary immunization, while exposure to the apparatus alone did not influence the development of either the primary or secondary humoral immune response to BSA. Both ES-induced suppression and SW-induced potentiation of the humoral immune response were partially inhibited by prior treatment with the opioid receptor antagonist naloxone. Additionally, treatments with the opioid peptides methionine- and leucine-enkephalin decreased anti-BSA antibody level, mimicking to some extent the effects of ES. It is suggested that ES and endogenous opioid peptides had long-term effects on humoral immunity through mechanisms involving immunologic memory. [ABSTRACT FROM AUTHOR]
- Published
- 2003
- Full Text
- View/download PDF
31. Cdk5: A Novel Role in Learning and Memory.
- Author
-
Fischer, André, Sananbenesi, Farahnaz, Spiess, Joachim, and Radulovic, Jelena
- Published
- 2003
- Full Text
- View/download PDF
32. A single amino acid serves as an affinity switch between the receptor and the binding protein of...
- Author
-
Eckart, Klaus, Jahn, Olaf, Radulovic, Jelena, Tezval, Hossein, van Werven, Lars, and Spiess, Joachim
- Subjects
CORTICOTROPIN releasing hormone ,AMINO acids ,CARRIER proteins - Abstract
Reports that a single amino acid serves as an affinity switch between the receptor and the binding protein of corticotropin-releasing factor(CRF). Effect of CRF on brain functions through at least two subtypes of G protein-dependent receptors and a binding protein; Pharmacological relevance of residue 22 h/rCRF; Solubility and in vivo potency of Ast analogs.
- Published
- 2001
- Full Text
- View/download PDF
33. Deletion of Crhr2 reveals an anxiolytic role for corticotropin-releasing hormone receptor-2.
- Author
-
Kishimoto, Toshimitsu, Radulovic, Jelena, Radulovic, Marko, Lin, Chijen R., Schrick, Christina, Hooshmand, Farideh, Hermanson, Ola, Rosenfeld, Michael G., and Spiess, Joachim
- Subjects
G proteins ,CORTICOTROPIN releasing hormone ,ANIMAL locomotion - Abstract
Corticotropin-releasing hormone (Crh), a 41-residue polypeptide, activates two G-protein?coupled receptors, Crhr1 (refs 3?5) and Crhr2 (refs 6?9), causing (among other transductional events) phosphorylation of the transcription factor Creb (ref. 10). The physiologic role of these receptors is only partially understood. Here we report that male, but not female, Crhr2-deficient mice exhibit enhanced anxious behaviour in several tests of anxiety in contrast to mice lacking Crhr1 (refs 11,12). The enhanced anxiety of Crhr2-deficient mice is not due to changes in hypothalamic-pituitary-adrenal (HPA) axis activity, but rather reflects impaired responses in specific brain regions involved in emotional and autonomic function, as monitored by a reduction of Creb phosphorylation in male, but not female, Crhr2
-/- mice. We propose that Crhr2 predominantly mediates a central anxiolytic response, opposing the general anxiogenic effect of Crh mediated by Crhr1. Neither male nor female Crhr2-deficient mice show alterations of baseline feeding behaviour. Both respond with increased edema formation in response to thermal exposure, however, indicating that in contrast to its central role in anxiety, the peripheral role of Crhr2 in vascular permeability is independent of gender. [ABSTRACT FROM AUTHOR]- Published
- 2000
- Full Text
- View/download PDF
34. STRESS-INDUCED RISE IN SERUM ANTI-BRAIN AUTOANTIBODY LEVELS IN THE RAT.
- Author
-
Andrejević, Sladjana, Bukilica, Mirjana, Dimitrijević, Mirjana, Laban, Olgica, Radulovic, Jelena, Kovacevic-Jovanovic, Vesna, Stanojevic, Stanislava, Vasiljevic, Tatjana, and Marković, Branislav M.
- Subjects
AUTOANTIBODIES ,ENOLASE - Abstract
Studies the stress-induced rise in serum anti-brain autoantibody levels in the rat. Presence of autoantibodies with specificity for neuron-specific enolase (NSE) and S100 protein that are preferentially localized in neurons and glia; Presence of autoantibodies in sera of animals before exposure to stress; Differences between stressed and control animals.
- Published
- 1997
35. Tumor Necrosis Factor Alpha Differentially Regulates Beta-Endorphin Concentrations and Proopiomelanocortin RNA in the Anterior and Neurointermediate Pituitary in vivo.
- Author
-
Sacerdote, Paola, Brini, Anna T., Locatelli, Luisa, Radulovic, Jelena, and Panerai, Alberto E.
- Published
- 1994
- Full Text
- View/download PDF
36. Centrally applied NPY mimics immunoactivation induced by non-analgesic doses of met-enkephalin.
- Author
-
von Hörsten, Stephan, Nave, Heike, Ballof, Jan, Helfritz, Fabian, Meyer, Dirk, Schmidt, Reinhold E., Stalp, Michael, Exton, Natalie G., Exton, Michael S., Straub, Rainer H., Radulovic, Jelena, and Pabst, Reinhard
- Published
- 1998
- Full Text
- View/download PDF
37. Characterization of native corticotropin-releasing factor receptor type 1 (cRFR1) in the rat and mouse central nervous system.
- Author
-
Radulovic, Jelena, Sydow, Sabine, and Spiess, Joachim
- Published
- 1998
- Full Text
- View/download PDF
38. Orai1 channels are essential for amplification of glutamate-evoked Ca2+ signals in dendritic spines to regulate working and associative memory.
- Author
-
Maneshi, Mohammad Mehdi, Toth, Anna B., Ishii, Toshiyuki, Hori, Kotaro, Tsujikawa, Shogo, Shum, Andrew K., Shrestha, Nisha, Yamashita, Megumi, Miller, Richard J., Radulovic, Jelena, Swanson, Geoffrey T., and Prakriya, Murali
- Published
- 2021
- Full Text
- View/download PDF
39. Fear-enhancing effects of septal oxytocin receptors.
- Author
-
Guzmán, Yomayra F, Tronson, Natalie C, Jovasevic, Vladimir, Sato, Keisuke, Guedea, Anita L, Mizukami, Hiroaki, Nishimori, Katsuhiko, and Radulovic, Jelena
- Subjects
SEPTUM (Brain) ,OXYTOCIN receptors ,FEAR ,PROTEIN kinases ,PROSOCIAL behavior ,TRANQUILIZING drugs - Abstract
The nonapeptide oxytocin is considered beneficial to mental health due to its anxiolytic, prosocial and antistress effects, but evidence for anxiogenic actions of oxytocin in humans has recently emerged. Using region-specific manipulations of the mouse oxytocin receptor (Oxtr) gene (Oxtr), we identified the lateral septum as the brain region mediating fear-enhancing effects of Oxtr. These effects emerge after social defeat and require Oxtr specifically coupled to the extracellular signal-regulated protein kinase pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
40. Preso1, mGluR5 and the machinery of pain.
- Author
-
Radulovic, Jelena and Tronson, Natalie C
- Subjects
GLUTAMATE receptors ,BEHAVIOR ,PAIN ,SCAFFOLD proteins ,KINASES ,CALCIUM - Abstract
The article offers information that the type I metabotropic glutamate receptors mGluR1 and mGluR5 regulate complex behaviors ranging from pain to emotion. Anchoring specific kinases close to membrane receptors, scaffold proteins incorporate input specificity into a system in which a signaling pathways is required for functional outcomes. By bringing mGluR1/5 and proline-directed kinases together, the scaffold protein Preso1 stabilize the interaction and attenuate calcium influx and reduce pain.
- Published
- 2012
- Full Text
- View/download PDF
41. Receptors in (e)motion.
- Author
-
Radulovic, Jelena and Tronson, Natalie C
- Subjects
FEAR ,AVERSIVE stimuli ,EMOTIONAL conditioning ,ANXIETY disorders ,APPEAL to fear (Logical fallacy) ,PSYCHOLOGY - Abstract
The article discusses the study on alpha-amino-3-hydroxy-5-methyl-4- isoxazole-propionic acid (AMPA) receptor which shows that AMPA-type glutamate receptor (AMPA) trafficking protects the memory modification which causes excessive fear. It says that fears responses are learned when normal situations are paired with aversive events. It adds that human studies suggest that reconsolidation may provoke fear and certain mechanisms may trigger the fear phenomenon in individuals with anxiety disorder.
- Published
- 2011
- Full Text
- View/download PDF
42. Small-conductance, Ca2+-activated K+ channel SK3 generates age-related memory and LTP deficits.
- Author
-
Blank, Thomas, Nijholt, Ingrid, Min-jeong Kye, Radulovic, Jelena, and Spiess, Joachim
- Subjects
AGE factors in cognition ,HIPPOCAMPUS (Brain) ,MEMORY disorders ,LABORATORY mice - Abstract
Cognitive deficits are among the most devastating changes associated with the aging process. Age-related decrement in performance on learning tasks is correlated with substantial changes in neuronal signal processing in the hippocampus. Here we show that elevated expression of small-conductance Ca
2+ -activated K+ channels (SK channels) of the SK3 type in hippocampi of aged mice contributes to reduced long-term potentiation (LTP) and impaired trace fear conditioning, a hippocampus-dependent learning task. [ABSTRACT FROM AUTHOR]- Published
- 2003
- Full Text
- View/download PDF
43. PATHWAYS TO FEAR.
- Author
-
Radulovic, Jelena
- Subjects
FEAR ,AMNESIA ,DISEASES ,PSYCHOLOGICAL stress ,EXCITATORY amino acid agents ,PATIENTS - Abstract
In some individuals, traumatic stressful experiences leave lasting painful memories. In others, they cause dissociative amnesia-an inability to consciously access memories of the traumatic events. Nevertheless, both accessible and inaccessible stress-related memories can profoundly disrupt affective and social functioning. Using mouse models, we have identified some of the pathways contributing to these phenomena. Glutamatergic signaling complexes underlie the formation, retrieval and extinction of accessible fear-inducing episodic memories. Extrasynaptic GABAergic mechanisms, on the other hand, lead to the formation of state-dependent, normally inaccessible memories. The translational implications of our findings for patients suffering from stress-related disorders will be discussed. [ABSTRACT FROM AUTHOR]
- Published
- 2016
44. ChemInform Abstract: Actions of CRF and Its Analogues.
- Author
-
Eckart, Klaus, Radulovic, Jelena, Radulovic, Marko, Jahn, Olaf, Blank, Thomas, Stiedl, Oliver, and Spiess, Joachim
- Published
- 1999
- Full Text
- View/download PDF
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