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Search Results: 1 - 10 of 298840 matches for " Fred J. Helmstetter "
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Protein degradation and protein synthesis in long-term memory formation
Timothy J. Jarome,Fred J. Helmstetter
Frontiers in Molecular Neuroscience , 2014, DOI: 10.3389/fnmol.2014.00061
Abstract: Long-term memory (LTM) formation requires transient changes in the activity of intracellular signaling cascades that are thought to regulate new gene transcription and de novo protein synthesis in the brain. Consistent with this, protein synthesis inhibitors impair LTM for a variety of behavioral tasks when infused into the brain around the time of training or following memory retrieval, suggesting that protein synthesis is a critical step in LTM storage in the brain. However, evidence suggests that protein degradation mediated by the ubiquitin-proteasome system may also be a critical regulator of LTM formation and stability following retrieval. This requirement for increased protein degradation has been shown in the same brain regions in which protein synthesis is required for LTM storage. Additionally, increases in the phosphorylation of proteins involved in translational control parallel increases in protein polyubiquitination and the increased demand for protein degradation is regulated by intracellular signaling molecules thought to regulate protein synthesis during LTM formation. In some cases inhibiting proteasome activity can rescue memory impairments that result from pharmacological blockade of protein synthesis, suggesting that protein degradation may control the requirement for protein synthesis during the memory storage process. Results such as these suggest that protein degradation and synthesis are both critical for LTM formation and may interact to properly “consolidate” and store memories in the brain. Here, we review the evidence implicating protein synthesis and degradation in LTM storage and highlight the areas of overlap between these two opposing processes. We also discuss evidence suggesting these two processes may interact to properly form and store memories. LTM storage likely requires a coordinated regulation between protein degradation and synthesis at multiple sites in the mammalian brain.
Memory formation for trace fear conditioning requires ubiquitin-proteasome mediated protein degradation in the prefrontal cortex
David S. Reis,Timothy J. Jarome,Fred J. Helmstetter
Frontiers in Behavioral Neuroscience , 2013, DOI: 10.3389/fnbeh.2013.00150
Abstract: The cellular mechanisms supporting plasticity during memory consolidation have been a subject of considerable interest. De novo protein and mRNA synthesis in several brain areas are critical, and more recently protein degradation, mediated by the ubiquitin-proteasome system (UPS), has been shown to be important. Previous work clearly establishes a relationship between protein synthesis and protein degradation in the amygdala, but it is unclear whether cortical mechanisms of memory consolidation are similar to those in the amygdala. Recent work demonstrating a critical role for prefrontal cortex (PFC) in the acquisition and consolidation of fear memory allows us to address this question. Here we use a PFC-dependent fear conditioning protocol to determine whether UPS mediated protein degradation is necessary for memory consolidation in PFC. Groups of rats were trained with auditory delay or trace fear conditioning and sacrificed 60 min after training. PFC tissue was then analyzed to quantify the amount of polyubiquibated protein. Other animals were trained with similar procedures but were infused with either a proteasome inhibitor (clasto-lactacystin β-lactone) or a translation inhibitor (anisomycin) in the PFC immediately after training. Our results show increased UPS-mediated protein degradation in the PFC following trace but not delay fear conditioning. Additionally, post-training proteasome or translation inhibition significantly impaired trace but not delay fear memory when tested the next day. Our results further support the idea that the PFC is critical for trace but not delay fear conditioning and highlight the role of UPS-mediated degradation as critical for synaptic plasticity.
The Effect of Threat on Novelty Evoked Amygdala Responses
Nicholas L. Balderston, Doug H. Schultz, Fred J. Helmstetter
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0063220
Abstract: A number of recent papers have suggested that the amygdala plays a role in the brain’s novelty detection circuit. In a recent study, we showed that this role may be specific to certain classes of biologically-relevant stimuli, such as human faces. The purpose of the present experiment was to determine whether other biologically-relevant stimuli also evoke novelty specific amygdala responses. To test this idea, we presented novel and repeated images of snakes and flowers while measuring BOLD. Surprisingly, we found that novel images of snakes and flowers evoke more amygdala activity than repeated images of snakes and flowers. Our results further confirm the robustness of the novelty evoked amygdala responses, even when compared with effects more traditionally associated with the amygdala. In addition, our results suggest that threatening stimuli may prime the amygdala to respond to other types of stimuli as well.
Regulation of Extinction-Related Plasticity by Opioid Receptors in the Ventrolateral Periaqueductal Gray Matter
Ryan G. Parsons,Georgette M. Gafford,Fred J. Helmstetter
Frontiers in Behavioral Neuroscience , 2010, DOI: 10.3389/fnbeh.2010.00044
Abstract: Recent work has led to a better understanding of the neural mechanisms underlying the extinction of Pavlovian fear conditioning. Long-term synaptic changes in the medial prefrontal cortex (mPFC) are critical for extinction learning, but very little is currently known about how the mPFC and other brain areas interact during extinction. The current study examined the effect of drugs that impair the extinction of fear conditioning on the activation of the extracellular-related kinase/mitogen-activated protein kinase (ERK/MAPK) in brain regions that likely participate in the consolidation of extinction learning. Inhibitors of opioid and N-methyl-D-aspartic acid (NMDA) receptors were applied to the ventrolateral periaqueductal gray matter (vlPAG) and amygdala shortly before extinction training. Results from these experiments show that blocking opioid receptors in the vlPAG prevented the formation of extinction memory, whereas NMDA receptor blockade had no effect. Conversely, blocking NMDA receptors in the amygdala disrupted the formation of fear extinction memory, but opioid receptor blockade in the same brain area did not. Subsequent experiments tested the effect of these drug treatments on the activation of the ERK/MAPK signaling pathway in various brain regions following extinction training. Only opioid receptor blockade in the vlPAG disrupted ERK phosphorylation in the mPFC and amygdala. These data support the idea that opiodergic signaling derived from the vlPAG affects plasticity across the brain circuit responsible for the formation of extinction memory.
Resting-state connectivity of the amygdala is altered following Pavlovian fear conditioning
Douglas H. Schultz,Nicholas L. Balderston,Fred J. Helmstetter
Frontiers in Human Neuroscience , 2012, DOI: 10.3389/fnhum.2012.00242
Abstract: Neural plasticity in the amygdala is necessary for the acquisition and storage of memory in Pavlovian fear conditioning, but most neuroimaging studies have focused only on stimulus-evoked responses during the conditioning session. This study examined changes in the resting-state functional connectivity (RSFC) of the amygdala before and after Pavlovian fear conditioning, an emotional learning task. Behavioral results from the conditioning session revealed that participants learned normally and fMRI data recorded during learning identified a number of stimulus-evoked changes that were consistent with previous work. A direct comparison between the pre- and post-conditioning amygdala connectivity revealed a region of dorsal prefrontal cortex (PFC) in the superior frontal gyrus that showed a significant increase in connectivity following the conditioning session. A behavioral measure of explicit memory performance was positively correlated with the change in amygdala connectivity within a neighboring region in the superior frontal gyrus. Additionally, an implicit autonomic measure of conditioning was positively correlated with the change in connectivity between the amygdala and the anterior cingulate cortex (ACC). The resting-state data show that amygdala connectivity is altered following Pavlovian fear conditioning and that these changes are also related to behavioral outcomes. These alterations may reflect the operation of a consolidation process that strengthens neural connections to support memory after the learning event.
Time-Dependent Expression of Arc and Zif268 after Acquisition of Fear Conditioning
Mary E. Lonergan,Georgette M. Gafford,Timothy J. Jarome,Fred J. Helmstetter
Neural Plasticity , 2010, DOI: 10.1155/2010/139891
Abstract: Memory consolidation requires transcription and translation of new protein. Arc, an effector immediate early gene, and zif268, a regulatory transcription factor, have been implicated in synaptic plasticity underlying learning and memory. This study explored the temporal expression profiles of these proteins in the rat hippocampus following fear conditioning. We observed a time-dependent increase of Arc protein in the dorsal hippocampus 30-to-90-minute post training, returning to basal levels at 4 h. Zif268 protein levels, however, gradually increased at 30-minute post training before peaking in expression at 60 minute. The timing of hippocampal Arc and zif268 expression coincides with the critical period for protein synthesis-dependent memory consolidation following fear conditioning. However, the expression of Arc protein appears to be driven by context exploration, whereas, zif268 expression may be more specifically related to associative learning. These findings suggest that altered Arc and zif268 expression are related to neural plasticity during the formation of fear memory. 1. Introduction A predominant question in neuroscience is how memory functions are supported by the central nervous system and what cellular processes are necessary. One focus of this research is on protein-dependent synaptic modifications that occur as a consequence of neuronal activity. Signaling cascades activated at the time of learning can induce the transcription of particular genes, ultimately leading to de novo protein synthesis and subsequent structural changes to support long-term memories. Gene expression plays a critical role in these postactivation changes in neurons. Immediate-early genes (IEGs) are induced soon after neuronal activity, and they participate in diverse functions. Some IEGs are regulatory transcription factors (e.g., zif268/Egr1) responsible for inducing transcription of late-response genes, while others are effector IEGs (e.g., Arc/Arg3.1) that are directly involved in cellular changes at locations such as the cytoskeleton or receptors. Many IEGs are translated in the soma. However, the transcripts of some IEGs, such as activity-regulated cytoskeleton-associated protein (Arc), are transported to the dendrites and protein synthesis occurs there [1], thus making Arc a reasonable target for researchers investigating the underlying mechanisms of postsynaptic changes supporting memory formation. Arc (also called Arg3.1) is a plasticity-related gene whose induction occurs soon after synaptic activation [2–4], mRNA transcription is independent of de novo
Activity Dependent Protein Degradation Is Critical for the Formation and Stability of Fear Memory in the Amygdala
Timothy J. Jarome, Craig T. Werner, Janine L. Kwapis, Fred J. Helmstetter
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0024349
Abstract: Protein degradation through the ubiquitin-proteasome system [UPS] plays a critical role in some forms of synaptic plasticity. However, its role in memory formation in the amygdala, a site critical for the formation of fear memories, currently remains unknown. Here we provide the first evidence that protein degradation through the UPS is critically engaged at amygdala synapses during memory formation and retrieval. Fear conditioning results in NMDA-dependent increases in degradation-specific polyubiquitination in the amygdala, targeting proteins involved in translational control and synaptic structure and blocking the degradation of these proteins significantly impairs long-term memory. Furthermore, retrieval of fear memory results in a second wave of NMDA-dependent polyubiquitination that targets proteins involved in translational silencing and synaptic structure and is critical for memory updating following recall. These results indicate that UPS-mediated protein degradation is a major regulator of synaptic plasticity necessary for the formation and stability of long-term memories at amygdala synapses.
CaMKII, but not protein kinase A, regulates Rpt6 phosphorylation and proteasome activity during the formation of long-term memories
Timothy J. Jarome,Janine L. Kwapis,Wendy L. Ruenzel,Fred J. Helmstetter
Frontiers in Behavioral Neuroscience , 2013, DOI: 10.3389/fnbeh.2013.00115
Abstract: CaMKII and Protein Kinase A (PKA) are thought to be critical for synaptic plasticity and memory formation through their regulation of protein synthesis. Consistent with this, numerous studies have reported that CaMKII, PKA and protein synthesis are critical for long-term memory formation. Recently, we found that protein degradation through the ubiquitin-proteasome system is also critical for long-term memory formation in the amygdala. However, the mechanism by which ubiquitin-proteasome activity is regulated during memory formation and how protein degradation interacts with known intracellular signaling pathways important for learning remain unknown. Recently, evidence has emerged suggesting that both CaMKII and PKA are capable of regulating proteasome activity in vitro through the phosphorylation of proteasome regulatory subunit Rpt6 at Serine-120, though whether they regulate Rpt6 phosphorylation and proteasome function in vivo remains unknown. In the present study we demonstrate for the first time that fear conditioning transiently modifies a proteasome regulatory subunit and proteasome catalytic activity in the mammalian brain in a CaMKII-dependent manner. We found increases in the phosphorylation of proteasome ATPase subunit Rpt6 at Serine-120 and an enhancement in proteasome activity in the amygdala following fear conditioning. Pharmacological manipulation of CaMKII, but not PKA, in vivo significantly reduced both the learning-induced increase in Rpt6 Serine-120 phosphorylation and the increase in proteasome activity without directly affecting protein polyubiquitination levels. These results indicate a novel role for CaMKII in memory formation through its regulation of protein degradation and suggest that CaMKII regulates Rpt6 phosphorylation and proteasome function both in vitro and in vivo.
Rapid Amygdala Responses during Trace Fear Conditioning without Awareness
Nicholas L. Balderston, Douglas H. Schultz, Sylvain Baillet, Fred J. Helmstetter
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0096803
Abstract: The role of consciousness in learning has been debated for nearly 50 years. Recent studies suggest that conscious awareness is needed to bridge the gap when learning about two events that are separated in time, as is true for trace fear conditioning. This has been repeatedly shown and seems to apply to other forms of classical conditioning as well. In contrast to these findings, we show that individuals can learn to associate a face with the later occurrence of a shock, even if they are unable to perceive the face. We used a novel application of magnetoencephalography (MEG) to non-invasively record neural activity from the amygdala, which is known to be important for fear learning. We demonstrate rapid (~170–200 ms) amygdala responses during the stimulus free period between the face and the shock. These results suggest that unperceived faces can serve as signals for impending threat, and that rapid, automatic activation of the amygdala contributes to this process. In addition, we describe a methodology that can be applied in the future to study neural activity with MEG in other subcortical structures.
Mainshocks are aftershocks of conditional foreshocks: How do foreshock statistical properties emerge from aftershock laws
A. Helmstetter,D. Sornette,J. -R. Grasso
Physics , 2002, DOI: 10.1029/2002JB001991
Abstract: The inverse Omori law for foreshocks discovered in the 1970s states that the rate of earthquakes prior to a mainshock increases on average as a power law ~ 1/(t_c-t)^p' of the time to the mainshock occurring at t_c. Here, we show that this law results from the direct Omori law for aftershocks describing the power law decay ~ 1/(t-t_c)^p of seismicity after an earthquake, provided that any earthquake can trigger its suit of aftershocks. In this picture, the seismic activity at any time is the sum of the spontaneous tectonic loading and of the activity triggered by all preceding events weighted by their corresponding Omori law. The inverse Omori law then emerges as the expected (in a statistical sense) trajectory of seismicity, conditioned on the fact that it leads to the burst of seismic activity accompanying the mainshock. The often documented apparent decrease of the b-value of the GR law at the approach to the main shock results straightforwardly from the conditioning of the path of seismic activity culminating at the mainshock. In the space domain, we predict that the phenomenon of aftershock diffusion must have its mirror process reflected into an inward migration of foreshocks towards the mainshock. In this model, foreshock sequences are special aftershock sequences which are modified by the condition to end up in a burst of seismicity associated with the mainshock.
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