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Clive R. Bramham - One of the best experts on this subject based on the ideXlab platform.
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Arc Protein: a flexible hub for synaptic plasticity and cognition
Seminars in cell & developmental biology, 2017Co-Authors: Oleksii Nikolaienko, Sudarshan Patil, Maria S. Eriksen, Clive R. BramhamAbstract:Mammalian excitatory synapses express diverse types of synaptic plasticity. A major challenge in neuroscience is to understand how a neuron utilizes different types of plasticity to sculpt brain development, function, and behavior. Neuronal activity-induced expression of the immediate early Protein, Arc, is critical for long-term potentiation and depression of synaptic transmission, homeostatic synaptic scaling, and adaptive functions such as long-term memory formation. However, the molecular basis of Arc Protein function as a regulator of synaptic plasticity and cognition remains a puzzle. Recent work on the biophysical and structural properties of Arc, its Protein-Protein interactions and post-translational modifications have shed light on the issue. Here, we present Arc Protein as a flexible, multifunctional and interactive hub. Arc interacts with specific effector Proteins in neuronal compartments (dendritic spines, nuclear domains) to bidirectionally regulate synaptic strength by distinct molecular mechanisms. Arc stability, subcellular localization, and interactions are dictated by synaptic activity and post-translational modification of Arc. This functional versatility and context-dependent signaling supports a view of Arc as a highly specialized master organizer of long-term synaptic plasticity, critical for information storage and cognition.
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Stimulus-evoked ERK-dependent phosphorylation of activity-regulated cytoskeleton-associated Protein (Arc) regulates its neuronal subcellular localization
Neuroscience, 2017Co-Authors: Oleksii Nikolaienko, Sudarshan Patil, Maria S. Eriksen, Haruhiko Bito, Clive R. BramhamAbstract:Abstract Activity-regulated cytoskeletal-associated Protein (Arc) is implicated as a master regulator of long-term synaptic plasticity and memory formation in mammalian brain. Arc acts at synapses and within the nucleus, but the mechanisms controlling Arc localization and function are little known. As Arc transcription and translation are regulated by extracellularsignal-regulated kinase (ERK) signaling, we asked whether Arc Protein itself is phosphorylated by ERK. GST-fused Arc of rat origin was able to pull down endogenous ERK2 from rat hippocampal lysates. Using a peptide array, we show that ERK binds a non-canonical docking (D) motif in the C-terminal domain of Arc, and this interaction is abolished by phosphorylation of Tyr309. Activated ERK2 phosphorylated bacterially expressed Arc in vitro at all five predicted sites, as confirmed by phospho-specific Protein staining and LC–MS/MS analysis. In neuroblastoma cells expressing epitope tagged-Arc, we demonstrate ERK-dependent phosphorylation of Arc in response to activation of muscarinic cholinergic receptors with carbachol. Using phosphosite-specific antibodies, this stimulus-evoked phosphorylation was shown to occur on Ser206 located within the central hinge region of Arc. In cultured hippocampal neurons expressing phosphomutant Arc under control of the activity-dependent promoter, we show that Ser206 phosphorylation regulates the nuclear:cytosolic localization of Arc. Thus, the neuronal activity-induced phosphomimic exhibits enhanced cytosolic localization relative to phosphodeficient and wild-type Arc. Furthermore, enhanced Ser206 phosphorylation of endogenous Arc was detected in the dentate gyrus cytoskeletal fraction after induction of long-term potentiation (LTP) in live rats. Taken together, this work demonstrates stimulus-evoked ERK-dependent phosphorylation and regulation of Arc Protein.
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Dynamic Arc SUMOylation and Selective Interaction with F-Actin-Binding Protein Drebrin A in LTP Consolidation In Vivo.
Frontiers in synaptic neuroscience, 2017Co-Authors: Rajeevkumar R. Nair, Sudarshan Patil, Tambudzai Kanhema, Debabrata Panja, Adrian Tiron, Lars Schiro, Kamil Parobczak, Grzegorz M. Wilczynski, Clive R. BramhamAbstract:Activity-regulatedcytoskeleton-associated Protein (Arc) Protein is implicated as a master regulator of long-term forms of synaptic plasticity and memory formation, but the mechanisms controlling Arc Protein function are little known. Post-translation modification by small ubiquitin-like modifier (SUMO) Proteins has emerged as a major mechanism for regulating Protein-Protein interactions and function. We first show in cell lines that ectopically expressed Arc undergoes mono-SUMOylation. The covalent addition of a single SUMO1 Protein was confirmed by in vitro SUMOylation of immunoprecipitated Arc. To explore regulation of endogenous Arc during synaptic plasticity, we induced long-term potentiation (LTP) in the dentate gyrus of live anesthetized rats. Using coimmunoprecipitation of native Proteins, we show that Arc synthesized during the maintenance phase of LTP undergoes dynamic mono-SUMO1-ylation. Levels of unmodified Arc increase in multiple subcellular fractions (cytosol, membrane, nuclear and cytoskeletal), whereas enhanced Arc SUMOylation was specific to the synaptoneurosomal and the cytoskeletal fractions. Dentate gyrus LTP consolidation requires a period of sustained Arc synthesis driven by brain-derived neurotrophic factor (BDNF) signaling. Local infusion of the BDNF scavenger, TrkB-Fc, during LTP maintenance resulted in rapid reversion of LTP, inhibition of Arc synthesis and loss of enhanced Arc SUMO1ylation. Furthermore, coimmunoprecipitation analysis showed that SUMO1-ylated Arc forms a complex with the F-actin-binding Protein drebrin A, a major regulator of cytoskeletal dynamics in dendritic spines. Although Arc also interacted with dynamin 2, calcium/calmodulindependentProtein kinase II-beta (CaMKIIβ), and postsynaptic density Protein-95 (PSD-95), these complexes lacked SUMOylated Arc. The results support a model in which newly synthesized Arc is SUMOylated and targeted for actin cytoskeletal regulation during in vivo LTP.
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Balancing Arc Synthesis, mRNA Decay, and Proteasomal Degradation MAXIMAL Protein EXPRESSION TRIGGERED BY RAPID EYE MOVEMENT SLEEP-LIKE BURSTS OF MUSCARINIC CHOLINERGIC RECEPTOR STIMULATION
The Journal of biological chemistry, 2012Co-Authors: Jonathan Soule, Maria Nordheim Alme, Craig Myrum, Manja Schubert, Tambudzai Kanhema, Clive R. BramhamAbstract:Abstract Cholinergic signaling induces Arc/Arg3.1, an immediate early gene crucial for synaptic plasticity. However, the molecular mechanisms that dictate Arc mRNA and Protein dynamics during and after cholinergic epochs are little understood. Using human SH-SY5Y neuroblastoma cells, we show that muscarinic cholinergic receptor (mAchR) stimulation triggers Arc synthesis, whereas translation-dependent RNA decay and proteasomal degradation strictly limit the amount and duration of Arc expression. Chronic application of the mAchR agonist, carbachol (Cch), induces Arc transcription via ERK signaling and release of calcium from IP3-sensitive stores. Arc translation requires ERK activation, but not changes in intracellular calcium. Proteasomal degradation of Arc (half-life ∼37 min) was enhanced by thapsigargin, an inhibitor of the endoplasmic calcium-ATPase pump. Similar mechanisms of Arc Protein regulation were observed in cultured rat hippocampal slices. Functionally, we studied the impact of cholinergic epoch duration and temporal pattern on Arc Protein expression. Acute Cch treatment (as short as 2 min) induces transient, moderate Arc expression, whereas continuous treatment of more than 30 min induces maximal expression, followed by rapid decline. Cholinergic activity associated with rapid eye movement sleep may function to facilitate long term synaptic plasticity and memory. Employing a paradigm designed to mimic intermittent rapid eye movement sleep epochs, we show that application of Cch in a series of short bursts generates persistent and maximal Arc Protein expression. The results demonstrate dynamic, multifaceted control of Arc synthesis during mAchR signaling, and implicate cholinergic epoch duration and repetition as critical determinants of Arc expression and function in synaptic plasticity and behavior.
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The Arc of synaptic memory
Experimental Brain Research, 2010Co-Authors: Clive R. Bramham, Jonathan Soule, Manja Schubert, Debabrata Panja, Rajeevkumar R. Nair, Adrian Tiron, Maria N. Alme, Margarethe Bittins, Sjoukje D. Kuipers, Karin WibrandAbstract:The immediate early gene Arc is emerging as a versatile, finely tuned system capable of coupling changes in neuronal activity patterns to synaptic plasticity, thereby optimizing information storage in the nervous system. Here, we attempt to overview the Arc system spanning from transcriptional regulation of the Arc gene, to dendritic transport, metabolism, and translation of Arc mRNA, to post-translational modification, localization, and degradation of Arc Protein. Within this framework we discuss the function of Arc in regulation of actin cytoskeletal dynamics underlying consolidation of long-term potentiation (LTP) and regulation of AMPA-type glutamate receptor endocytosis underlying long-term depression (LTD) and homeostatic plasticity. Behaviorally, Arc has a key role in consolidation of explicit and implicit forms of memory, with recent work implicating Arc in adaptation to stress as well as maladaptive plasticity connected to drug addiction. Arc holds considerable promise as a “master regulator” of Protein synthesis-dependent forms of synaptic plasticity, but the mechanisms that modulate and switch Arc function are only beginning to be elucidated.
Martin Scheffner - One of the best experts on this subject based on the ideXlab platform.
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role of the ubiquitin ligase e6ap ube3a in controlling levels of the synaptic Protein Arc
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Simone Kühnle, Benedikt Mothes, Konstantin Matentzoglu, Martin ScheffnerAbstract:Inactivation of the ubiquitin ligase E6 associated Protein (E6AP) encoded by the UBE3A gene has been associated with development of the Angelman syndrome. Recently, it was reported that in mice, loss of E6AP expression results in increased levels of the synaptic Protein Arc and a concomitant impaired synaptic function, providing an explanation for some phenotypic features of Angelman syndrome patients. Accordingly, E6AP has been shown to negatively regulate activity-regulated cytoskeleton-associated Protein (Arc) and it has been suggested that E6AP targets Arc for ubiquitination and degradation. In our study, we provide evidence that Arc is not a direct substrate for E6AP and binds only weakly to E6AP, if at all. Furthermore, we show that down-regulation of E6AP expression stimulates estradiol-induced transcription of the Arc gene. Thus, we propose that Arc Protein levels are controlled by E6AP at the transcriptional rather than at the posttranslational level.
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Role of the ubiquitin ligase E6AP/UBE3A in controlling levels of the synaptic Protein Arc
Proceedings of the National Academy of Sciences of the United States of America, 2013Co-Authors: Simone Kühnle, Benedikt Mothes, Konstantin Matentzoglu, Martin ScheffnerAbstract:Inactivation of the ubiquitin ligase E6 associated Protein (E6AP) encoded by the UBE3A gene has been associated with development of the Angelman syndrome. Recently, it was reported that in mice, loss of E6AP expression results in increased levels of the synaptic Protein Arc and a concomitant impaired synaptic function, providing an explanation for some phenotypic features of Angelman syndrome patients. Accordingly, E6AP has been shown to negatively regulate activity-regulated cytoskeleton-associated Protein (Arc) and it has been suggested that E6AP targets Arc for ubiquitination and degradation. In our study, we provide evidence that Arc is not a direct substrate for E6AP and binds only weakly to E6AP, if at all. Furthermore, we show that down-regulation of E6AP expression stimulates estradiol-induced transcription of the Arc gene. Thus, we propose that Arc Protein levels are controlled by E6AP at the transcriptional rather than at the posttranslational level.
Christa K. Mcintyre - One of the best experts on this subject based on the ideXlab platform.
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Optogenetic stimulation of the basolateral amygdala-medial entorhinal cortex pathway after spatial training has sex-specific effects on downstream activity-regulated cytoskeletal-associated Protein expression
2020Co-Authors: Krista L Wahlstrom, Christa K. Mcintyre, Amanda C. Alvarez-dieppa, Ryan T. LalumiereAbstract:Previous work from our laboratory suggests that projections from the basolateral amygdala (BLA) to the medial entorhinal cortex (mEC) are a critical pathway by which the BLA modulates the consolidation of spatial learning. Posttraining optogenetic stimulation of this pathway enhances retention of spatial memories. Evidence also indicates that intra-BLA administration of memory-enhancing drugs increases Protein levels of activity-regulated cytoskeletal-associated Protein (Arc) in the dorsal hippocampus (DH) and that blocking Arc in the DH impairs spatial memory consolidation. Yet, whether optical manipulations of the BLA-mEC pathway after spatial training also alter Arc in the DH is unknown. To address this question, male and female Sprague-Dawley rats received optogenetic stimulation of the BLA-mEC pathway immediately after spatial training using a Barnes maze and, 45 min later, were sacrificed for Arc analysis. Initial experiments found that spatial training increased Arc levels in the DH of rats above those observed in control rats and rats that underwent a cued-response version of the task. Optogenetic stimulation of the BLA-mEC pathway following spatial training, using parameters effective at enhancing spatial memory consolidation, enhanced Arc Protein levels in the DH of male rats without affecting Arc levels in the dorsolateral striatum (DLS) or somatosensory cortex. In contrast, similar optical stimulation decreased Arc Protein levels in the DLS of female rats without altering Arc in the DH or somatosensory cortex. Together, the present findings suggest a mechanism by which BLA-mEC stimulation enhances spatial memory consolidation in rats and reveals a possible sex-difference in this mechanism.
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Vagus Nerve Stimulation Enhances Extinction of Conditioned Fear in Rats and Modulates Arc Protein, CaMKII, and GluN2B-Containing NMDA Receptors in the Basolateral Amygdala.
Neural plasticity, 2016Co-Authors: Amanda C. Alvarez-dieppa, Kimberly Griffin, Sheridan Cavalier, Christa K. McintyreAbstract:Vagus nerve stimulation (VNS) enhances the consolidation of extinction of conditioned fear. High frequency stimulation of the infralimbic cortex (IL) produces long-term potentiation in the basolateral amygdala (BLA) in rats given VNS-paired extinction training, whereas the same stimulation produces long-term depression in sham-treated rats. The present study investigated the state of synaptic plasticity-associated Proteins in the BLA that could be responsible for this shift. Male Sprague-Dawley rats were separated into 4 groups: auditory fear conditioning only (fear-conditioned); fear conditioning + 20 extinction trials (extended-extinction); fear conditioning + 4 extinction trials paired with sham stimulation (sham-extinction); fear conditioning + 4 extinction trials paired with VNS (VNS-extinction). Freezing was significantly reduced in extended-extinction and VNS-extinction rats. Western blots were used to quantify expression and phosphorylation state of synaptic plasticity-associated Proteins such as Arc, CaMKII, ERK, PKA, and AMPA and NMDA receptors. Results show significant increases in GluN2B expression and phosphorylated CaMKII in BLA samples from VNS- and extended-extinction rats. Arc expression was significantly reduced in VNS-extinction rats compared to all groups. Administration of the GluN2B antagonist ifenprodil immediately after fear extinction training blocked consolidation of extinction learning. Results indicate a role for BLA CaMKII-induced GluN2B expression and reduced Arc Protein in VNS-enhanced extinction.
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Noradrenergic actions in the basolateral complex of the amygdala modulate Arc expression in hippocampal synapses and consolidation of aversive and non-aversive memory.
Neurobiology of learning and memory, 2014Co-Authors: Jayme R. Mcreynolds, Kyle M. Donowho, Kelly M. Anderson, Christa K. McintyreAbstract:The basolateral complex of the amygdala (BLA) plays a role in the modulation of emotional memory consolidation through its interactions with other brain regions. In rats, memory enhancing infusions of the β-adrenergic receptor agonist clenbuterol into the BLA immediately after training enhances expression of the Protein product of the immediate early gene Arc in the dorsal hippocampus and memory-impairing intra-BLA treatments reduce hippocampal Arc expression. We have proposed that the BLA may modulate memory consolidation through an influence on the local translation of synaptic plasticity Proteins, like Arc, in recently active synapses in efferent brain regions. To date, all work related to this hypothesis is based on aversive memory tasks such as inhibitory avoidance (IA). To determine whether BLA modulation of hippocampal Arc Protein expression is specific to plasticity associated with inhibitory avoidance memory, or a common mechanism for multiple types of memory, we tested the effect of intra-BLA infusions of clenbuterol on memory and hippocampal synaptic Arc expression following IA or object recognition training. Results indicate that intra-BLA infusions of clenbuterol enhance memory for both tasks; however, Arc expression in hippocampal synaptoneurosomes was significantly elevated only in rats trained on the aversive IA task. These findings suggest that regulation of Arc expression in hippocampal synapses may depend on co-activation of arousal systems. To test this hypothesis, a “high arousal” version of the OR task was used where rats were not habituated to the testing conditions. Posttraining intra-BLA infusions of clenbuterol enhanced consolidation of the high-arousing version of the task and significantly increased Arc Protein levels in dorsal hippocampus synaptic fractions. These findings suggest that the BLA modulates multiple forms of memory and affects the synaptic plasticity-associated Protein Arc in synapses of the dorsal hippocampus when emotional arousal is elevated.
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Corticosterone-induced enhancement of memory and synaptic Arc Protein in the medial prefrontal cortex
Neurobiology of learning and memory, 2014Co-Authors: Jayme R. Mcreynolds, Crystal M. Holloway-erickson, Tulja U. Parmar, Christa K. McintyreAbstract:Acute administration of the stress hormone corticosterone enhances memory consolidation in a manner that is dependent upon the modulatory effects of the basolateral complex of the amygdala (BLA). Posttraining administration of corticosterone increases expression of the activity-regulated cytoskeletal-associated Protein (Arc) in hippocampal synaptic-enriched fractions. Interference with hippocampal Arc expression impairs memory, suggesting that the corticosterone-induced increase in hippocampal Arc plays a role in the memory enhancing effect of the hormone. Blockade of β-adrenoceptors in the BLA attenuates the corticosterone-induced increase in hippocampal Arc expression and blocks corticosterone-induced memory enhancement. To determine whether posttraining corticosterone treatment affects Arc Protein expression in synapses of other areas of the brain that are involved in memory processing, a memory-enhancing dose of corticosterone was administered to rats immediately after inhibitory avoidance training. As seen in the hippocampus, Arc Protein expression was increased in synaptic fractions taken from the prelimbic region of the medial prefrontal cortex (mPFC). Blockade of Arc Protein expression significantly impaired memory, indicating that the Protein is necessary in the mPFC for long-term memory formation. To test the hypothesis that blockade of β-adrenoceptors in the BLA would block the effect of systemic corticosterone on memory and attenuate mPFC Arc expression, as it does in the hippocampus, posttraining intra-BLA microinfusions of the β-adrenoceptor antagonist propranolol were given concurrently with the systemic corticosterone injection. Although this treatment blocked corticosterone-induced memory enhancement, it increased corticosterone-induced Arc Protein expression in mPFC synaptic fractions. These findings suggest that the BLA mediates stress hormone effects on memory by participating in the negative or positive regulation of corticosterone-induced synaptic plasticity in efferent brain regions.
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Memory-enhancing intra-basolateral amygdala infusions of clenbuterol increase Arc and CaMKIIα Protein expression in the rostral anterior cingulate cortex.
Frontiers in behavioral neuroscience, 2012Co-Authors: Crystal M. Holloway-erickson, Jayme R. Mcreynolds, Christa K. McintyreAbstract:Activation of β-adrenoceptors in the basolateral complex of the amygdala (BLA) modulates memory through interactions with multiple memory systems. The cellular mechanisms for this interaction remain unresolved. Memory-modulating BLA manipulations influence expression of the Protein product of the immediate early gene activity-regulated cytoskeletal-associated Protein (Arc) in the dorsal hippocampus, and hippocampal expression of Arc Protein is critically involved in memory consolidation and long-term potentiation. The present studies examined whether this influence of the BLA is specific to the hippocampus and to Arc Protein. Like the hippocampus, the rostral portion of the anterior cingulate cortex (rACC) is involved in the consolidation of inhibitory avoidance (IA) memory, and IA training increases Arc Protein in the rACC. Because the BLA interacts with the rACC in the consolidation of IA memory, the rACC is a potential candidate for further studies of BLA modulation of synaptic plasticity. The alpha isoform of the Calcium/Calmodulin-dependent Protein kinase II (CaMKIIα) and the immediate early gene c-Fos are involved in long-term potentiation and memory. Both Arc and CaMKIIα Proteins can be translated in isolated synapses, where the mRNA is localized, but c-Fos Protein remains in the soma. To examine the influence of memory-modulating manipulations of the BLA on expression of these memory and plasticity-associated Proteins in the rACC, male Sprague-Dawley rats were trained on an IA task and given intra-BLA infusions of either clenbuterol or lidocaine immediately after training. Findings suggest that noradrenergic stimulation of the BLA may modulate memory consolidation through effects on both synaptic Proteins Arc and CaMKIIα, but not the somatic Protein c-Fos. Furthermore, Protein changes observed in the rACC following BLA manipulations suggest that the influence of the BLA on synaptic Proteins is not limited to those in the dorsal hippocampus.
P. Segura-torres - One of the best experts on this subject based on the ideXlab platform.
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Arc Protein expression after unilateral intracranial self-stimulation of the medial forebrain bundle is upregulated in specific nuclei of memory-related areas.
BMC neuroscience, 2018Co-Authors: Elisabet Kádár, L. Aldavert-vera, Ignacio Morgado-bernal, Eva Vico Varela, Gemma Huguet, P. Segura-torresAbstract:Intracranial Self-Stimulation (ICSS) of the medial forebrain bundle (MFB) is a deep brain stimulation procedure, which has a powerful enhancement effect on explicit and implicit memory. However, the downstream synaptic plasticity events of MFB-ICSS in memory related areas have not been described thoroughly. This study complements previous work studying the effect of MFB-ICSS on the expression of the activity-regulated cytoskeleton-associated (Arc) Protein, which has been widely established as a synaptic plasticity marker. We provide new integrated measurements from memory related regions and take possible regional hemispheric differences into consideration. Arc Protein expression levels were analyzed 4.5 h after MFB-ICSS by immunohistochemistry in the hippocampus, habenula, and memory related amygdalar and thalamic nuclei, in both the ipsilateral and contralateral hemispheres to the stimulating electrode location. MFB-ICSS was performed using the same paradigm which has previously been shown to facilitate memory. Our findings illustrate that MFB-ICSS upregulates the expression of Arc Protein in the oriens and radiatum layers of ipsilateral CA1 and contralateral CA3 hippocampal regions; the hilus bilaterally, the lateral amygdala and dorsolateral thalamic areas as well as the central medial thalamic nucleus. In contrast, the central amygdala, mediodorsal and paraventricular thalamic nuclei, and the habenular complex did not show changes in Arc expression after MFB-ICSS. Our results expand our knowledge of which specific memory related areas MFB-ICSS activates and, motivates the definition of three functionally separate groups according to their Arc-related synaptic plasticity response: (1) the hippocampus and dorsolateral thalamic area, (2) the central medial thalamic area and (3) the lateral amygdala.
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Arc Protein expression after unilateral intracranial self-stimulation of the medial forebrain bundle is upregulated in specific nuclei of memory-related areas
BMC, 2018Co-Authors: Elisabet Kádár, L. Aldavert-vera, Ignacio Morgado-bernal, Eva Vico Varela, Gemma Huguet, P. Segura-torresAbstract:Abstract Background Intracranial Self-Stimulation (ICSS) of the medial forebrain bundle (MFB) is a deep brain stimulation procedure, which has a powerful enhancement effect on explicit and implicit memory. However, the downstream synaptic plasticity events of MFB-ICSS in memory related areas have not been described thoroughly. This study complements previous work studying the effect of MFB-ICSS on the expression of the activity-regulated cytoskeleton-associated (Arc) Protein, which has been widely established as a synaptic plasticity marker. We provide new integrated measurements from memory related regions and take possible regional hemispheric differences into consideration. Results Arc Protein expression levels were analyzed 4.5 h after MFB-ICSS by immunohistochemistry in the hippocampus, habenula, and memory related amygdalar and thalamic nuclei, in both the ipsilateral and contralateral hemispheres to the stimulating electrode location. MFB-ICSS was performed using the same paradigm which has previously been shown to facilitate memory. Our findings illustrate that MFB-ICSS upregulates the expression of Arc Protein in the oriens and radiatum layers of ipsilateral CA1 and contralateral CA3 hippocampal regions; the hilus bilaterally, the lateral amygdala and dorsolateral thalamic areas as well as the central medial thalamic nucleus. In contrast, the central amygdala, mediodorsal and paraventricular thalamic nuclei, and the habenular complex did not show changes in Arc expression after MFB-ICSS. Conclusions Our results expand our knowledge of which specific memory related areas MFB-ICSS activates and, motivates the definition of three functionally separate groups according to their Arc-related synaptic plasticity response: (1) the hippocampus and dorsolateral thalamic area, (2) the central medial thalamic area and (3) the lateral amygdala
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Increase in c-Fos and Arc Protein in retrosplenial cortex after memory-improving lateral hypothalamic electrical stimulation treatment.
Neurobiology of learning and memory, 2016Co-Authors: Elisabeth Kádár, L. Aldavert-vera, Ignacio Morgado-bernal, Gemma Huguet, Eva Vico-varela, P. Segura-torresAbstract:Post-training Intracranial self-stimulation (ICSS) of the lateral hypothalamus (LH), a kind of rewarding deep-brain stimulation, potentiates learning and memory and increases c-Fos Protein expression in specific memory-related brain regions. In a previous study, Aldavert-Vera et al. (2013) reported that post-acquisition LH-ICSS improved 48 h retention of a delay two-way active avoidance conditioning (TWAA) and induced c-Fos expression increase in CA3 at 90 min after administration. Nevertheless, this c-Fos induction was only observed after the acquisition session and not after the retention test at 48 h, when the ICSS improving effect was observed on memory. This current study aims to examine the hypothesis that post-training ICSS treatment may stimulate c-Fos expression at the time of the TWAA retention test in retrosplenial cortex (RSC), a hippocampus-related brain region more closely related with long-lasting memory storage. Effects of ICSS on Arc Protein, a marker of memory-associated synaptic plasticity, were also measured by immunohistochemistry in granular and agranular RSC. The most innovative results are that the ICSS treatment potentiates the c-Fos induction across TWAA conditions (no conditioning, acquisition and retention), specifically in layer V of the granular RSC, along with increases of Arc Protein levels in the granular but not in agranular areas of RSC ipsilaterally few hours after ICSS. This leads us to suggest that plasticity-related Protein activation in the granular RSC could be involved in the positive modulatory effects of ICSS on TWAA memory consolidation, opening a new approach for future reseArch in ICSS memory facilitation.
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Intracranial self stimulation upregulates the expression of synaptic plasticity related genes and Arc Protein expression in rat hippocampus
Genes Brain and Behavior, 2013Co-Authors: Eniko Kadar, L. Aldavert-vera, Guillaume Huguet, Ignacio Morgado-bernal, P. Segura-torresAbstract:Post-training lateral hypothalamus (LH) intracranial self stimulation (ICSS) has a reliable enhancing effect on explicit memory formation evaluated in hippocampus-dependent tasks such as the Morris water maze. In this study, the effects of ICSS on gene expression in the hippocampus are examined 4.5 h post treatment by using oligonucleotide microarray and real-time PCR, and by measuring Arc Protein levels in the different layers of hippocampal subfields through immunofluorescence. The microarray data analysis resulted in 65 significantly regulated genes in rat ICSS hippocampi compared to sham, including cAMP-mediated signaling as one of the most significantly enriched Database for Annotation, Visualization and Integrated Discovery (DAVID) functional categories. In particular, expression of CREB-dependent synaptic plasticity related genes (c-Fos, Arc, Bdnf, Ptgs-2 and Crem and Icer) was regulated in a time-dependent manner following treatment administration. Immunofluorescence results showed that ICSS treatment induced a significant increase in Arc Protein expression in CA1 and DG hippocampal subfields. This empirical evidence supports our hypothesis that the effect of ICSS on improved or restored memory functions might be mediated by increased hippocampal expression of activity-dependent synaptic plasticity related genes, including Arc Protein expression, as neural mechanisms related to memory consolidation.
Paul F Worley - One of the best experts on this subject based on the ideXlab platform.
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Real-Time Imaging Reveals Properties of Glutamate-Induced Arc/Arg 3.1 Translation in Neuronal Dendrites
Neuron, 2016Co-Authors: Sungjin Park, Changhee Lee, Kim Dongkyu, Joo Min Park, Shanthini Sockanathan, Richard L. Huganir, Paul F WorleyAbstract:The immediate early gene Arc (also Arg3.1) produces rapid changes in synaptic properties that are linked to de novo translation. Here we develop a novel translation reporter that exploits the rapid maturation and "flash" kinetics of Gaussia luciferase (Gluc) to visualize Arc translation. Following glutamate stimulation, discrete Arc-Gluc bioluminescent flashes representing sites of de novo translation are detected within 15 s at distributed sites in dendrites, but not spines. Flashes are episodic, lasting ∼20 s, and may be unitary or repeated at ∼minute intervals at the same sites. Analysis of flash amplitudes suggests they represent the quantal product of one or more polyribosomes, while inter-flash intervals appear random, suggesting they arise from a stochastic process. Surprisingly, glutamate-induced translation is dependent on Arc open reading frame. Combined observations support a model in which stalled ribosomes are reactivated to rapidly generate Arc Protein.
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Spatial Exploration-Induced Arc mRNA and Protein Expression: Evidence for Selective, Network-Specific Reactivation
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2005Co-Authors: Víctor Ramírez-amaya, Paul F Worley, Almira Vazdarjanova, Dalia M. Mikhael, Susanna Rosi, Carol A BarnesAbstract:The immediate-early gene Arc is transcribed in neurons that are part of stable neural networks activated during spatial exploratory behaviors. Arc Protein has been demonstrated to regulate AMPA-type glutamate receptor trafficking by recruiting endosomal pathways, suggesting a direct role in synaptic plasticity. The purpose of the present study is to examine the fidelity of Arc mRNA translation and the temporal dynamics of behaviorally induced Arc Protein expression after rats explore a novel environment. These experiments reveal two waves of Arc Protein expression after a single exploration session. In the initial wave, virtually all cells that express Arc mRNA in the hippocampus and parietal cortex also express Arc Protein, indicating, at a cellular level, that mRNA transcription and translation are closely correlated from 30 min to 2 h in hippocampal CA and parietal neurons. A second wave of Protein expression spans the interval from 8 to 24 h and is also remarkably specific to cells active in the original behavior-induced network. This second wave is detected in a subset of the original active network and displays the novel property that the proportions of Arc-positive neurons become correlated among regions at 24 h. This suggests that the second expression wave is driven by network activity, and the stabilization of circuits reflecting behavioral experience may occur in temporally discrete phases, as memories become consolidated. This is the first demonstration of network-selective translational events consequent to spatial behavior and suggests a role for immediate-early genes in circuit-specific, late-phase synaptic biology.
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Activity-regulated cytoskeletal-associated Protein is localized to recently activated excitatory synapses.
Neuroscience, 2004Co-Authors: Diana Moga, Paul F Worley, M.e. Calhoun, A. Chowdhury, John H. Morrison, M.l. ShapiroAbstract:Activity-regulated, cytoskeletal-associated Protein (Arc) is an immediate early gene induced in excitatory circuits following behavioral episodes. Arc mRNA is targeted to activated regions of the dendrite after long-term potentiation (LTP) of the dentate gyrus, a process dependent on NMDA receptor activation. We used post-embedding immunogold electron microscopy (EM) to test whether synaptic Arc expression patterns are selectively modified by plasticity. Consistent with previous light microscopic observations, Arc Protein was rapidly induced in the dentate gyrus following LTP-producing stimulation of the perforant path and was detectable in granule cell nuclei, somata and dendrites after two hours of high frequency stimulation. Post-embedding EM revealed Arc immunogold labeling in three times as many spines in the middle molecular layer of the stimulated dentate gyrus than in either the ipsilateral outer molecular layer or the contralateral middle and outer molecular layers. This upregulation did not occur with low frequency stimulation of the perforant path. Therefore Arc Protein localization may be a powerful tool to isolate recently activated dendritic spines.
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local synthesis of Proteins at synaptic sites on dendrites role in synaptic plasticity and memory consolidation
Neurobiology of Learning and Memory, 2002Co-Authors: Oswald Steward, Paul F WorleyAbstract:Long-lasting forms of memory are thought to be mediated by modifications in synapses that are induced by particular patterns of activity, take time to be established (consolidated), and involve new gene expression. The molecular mechanisms underlying such long-lasting synaptic modifications remain to be defined. Here, we focus on new findings regarding synapse-specific gene expression and especially the intracellular transport and synaptic targeting of the mRNA for a recently identified immediate early gene called activity-regulated cytoskeleton-associated Protein (Arc). Arc mRNA is transported into dendrites after episodes of neuronal activation. The newly synthesized Arc mRNA localizes selectively at synapses that have experienced particular patterns of activity, and this targeting depends on NMDA receptor activation. Arc Protein is assembled into the postsynaptic junction, and Arc expression is strongly induced by brief behavioral experiences in select populations of neurons. These features of Arc induction and trafficking reveal novel cellular mechanisms that are well suited to mediate long-term synapse-specific modifications. We will review findings from other laboratories that both LTP and memory are disrupted when Arc induction is blocked, and we will discuss the possibility that Arc Protein may play a key role in activity-dependent synaptic modification.
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Response: Arc mRNA dynamics: a Rosetta stone for deciphering cellular and systems mechanisms in history
Trends in Neurosciences, 2001Co-Authors: Oswald Steward, Paul F WorleyAbstract:Abstract We appreciate the thoughtful review of our work by Martin. Indeed, Arc is a tool par excellence for studying mRNA localization in response to localized synaptic stimulation. We would additionally like to note two other lines of investigation. The first suggests that Arc might be a useful marker for individual neurons and perhaps individual synapses that are undergoing activity-dependent modifications (LTP and LTD). The second implicates Arc Protein in synapse-specific plasticity and memory.