Publications by authors named "Marcelo A Wood"

82 Publications

Cocaine induces paradigm-specific changes to the transcriptome within the ventral tegmental area.

Neuropsychopharmacology 2021 Jun 21. Epub 2021 Jun 21.

Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, CA, USA.

During the initial stages of drug use, cocaine-induced neuroadaptations within the ventral tegmental area (VTA) are critical for drug-associated cue learning and drug reinforcement processes. These neuroadaptations occur, in part, from alterations to the transcriptome. Although cocaine-induced transcriptional mechanisms within the VTA have been examined, various regimens and paradigms have been employed to examine candidate target genes. In order to identify key genes and biological processes regulating cocaine-induced processes, we employed genome-wide RNA-sequencing to analyze transcriptional profiles within the VTA from male mice that underwent one of four commonly used paradigms: acute home cage injections of cocaine, chronic home cage injections of cocaine, cocaine-conditioning, or intravenous-self administration of cocaine. We found that cocaine alters distinct sets of VTA genes within each exposure paradigm. Using behavioral measures from cocaine self-administering mice, we also found several genes whose expression patterns corelate with cocaine intake. In addition to overall gene expression levels, we identified several predicted upstream regulators of cocaine-induced transcription shared across all paradigms. Although distinct gene sets were altered across cocaine exposure paradigms, we found, from Gene Ontology (GO) term analysis, that biological processes important for energy regulation and synaptic plasticity were affected across all cocaine paradigms. Coexpression analysis also identified gene networks that are altered by cocaine. These data indicate that cocaine alters networks enriched with glial cell markers of the VTA that are involved in gene regulation and synaptic processes. Our analyses demonstrate that transcriptional changes within the VTA depend on the route, dose and context of cocaine exposure, and highlight several biological processes affected by cocaine. Overall, these findings provide a unique resource of gene expression data for future studies examining novel cocaine gene targets that regulate drug-associated behaviors.
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http://dx.doi.org/10.1038/s41386-021-01031-4DOI Listing
June 2021

Model organism development and evaluation for late-onset Alzheimer's disease: MODEL-AD.

Alzheimers Dement (N Y) 2020 23;6(1):e12110. Epub 2020 Nov 23.

Indiana University School of Medicine Indianapolis Indiana USA.

Alzheimer's disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of the basic biological mechanisms underlying AD, we do not know how to prevent it, nor do we have an approved disease-modifying intervention. Both are essential to slow or stop the growth in dementia prevalence. While our current animal models of AD have provided novel insights into AD disease mechanisms, thus far, they have not been successfully used to predict the effectiveness of therapies that have moved into AD clinical trials. The Model Organism Development and Evaluation for Late-onset Alzheimer's Disease (MODEL-AD; www.model-ad.org) Consortium was established to maximize human datasets to identify putative variants, genes, and biomarkers for AD; to generate, characterize, and validate the next generation of mouse models of AD; and to develop a preclinical testing pipeline. MODEL-AD is a collaboration among Indiana University (IU); The Jackson Laboratory (JAX); University of Pittsburgh School of Medicine (Pitt); Sage BioNetworks (Sage); and the University of California, Irvine (UCI) that will generate new AD modeling processes and pipelines, data resources, research results, standardized protocols, and models that will be shared through JAX's and Sage's proven dissemination pipelines with the National Institute on Aging-supported AD Centers, academic and medical research centers, research institutions, and the pharmaceutical industry worldwide.
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http://dx.doi.org/10.1002/trc2.12110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7683958PMC
November 2020

Modeling suggests combined-drug treatments for disorders impairing synaptic plasticity via shared signaling pathways.

J Comput Neurosci 2021 02 11;49(1):37-56. Epub 2020 Nov 11.

Department of Neurobiology and Anatomy, W.M. Keck Center for the Neurobiology of Learning and Memory, McGovern Medical School of the University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.

Genetic disorders such as Rubinstein-Taybi syndrome (RTS) and Coffin-Lowry syndrome (CLS) cause lifelong cognitive disability, including deficits in learning and memory. Can pharmacological therapies be suggested that improve learning and memory in these disorders? To address this question, we simulated drug effects within a computational model describing induction of late long-term potentiation (L-LTP). Biochemical pathways impaired in these and other disorders converge on a common target, histone acetylation by acetyltransferases such as CREB binding protein (CBP), which facilitates gene induction necessary for L-LTP. We focused on four drug classes: tropomyosin receptor kinase B (TrkB) agonists, cAMP phosphodiesterase inhibitors, histone deacetylase inhibitors, and ampakines. Simulations suggested each drug type alone may rescue deficits in L-LTP. A potential disadvantage, however, was the necessity of simulating strong drug effects (high doses), which could produce adverse side effects. Thus, we investigated the effects of six drug pairs among the four classes described above. These combination treatments normalized impaired L-LTP with substantially smaller individual drug 'doses'. In addition three of these combinations, a TrkB agonist paired with an ampakine and a cAMP phosphodiesterase inhibitor paired with a TrkB agonist or an ampakine, exhibited strong synergism in L-LTP rescue. Therefore, we suggest these drug combinations are promising candidates for further empirical studies in animal models of genetic disorders that impair histone acetylation, L-LTP, and learning.
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http://dx.doi.org/10.1007/s10827-020-00771-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878405PMC
February 2021

Attenuation of M-Current Suppression Impairs Consolidation of Object Recognition Memory.

J Neurosci 2020 07 17;40(30):5847-5856. Epub 2020 Jun 17.

Department of Pharmacology, University of California, Irvine, Irvine, California 92697

The M-current is a low voltage-activated potassium current generated by neuronal Kv7 channels. A prominent role of the M-current is to a create transient increase of neuronal excitability in response to neurotransmitters through the suppression of this current. Accordingly, M-current suppression is assumed to be involved in higher brain functions including learning and memory. However, there is little evidence supporting such a role to date. To address this gap, we examined behavioral tasks to assess learning and memory in homozygous Kv7.2 knock-in mice, Kv7.2(S559A), which show reduced M-current suppression while maintaining a normal basal M-current activity in neurons. We found that Kv7.2(S559A) mice had normal object location memory and contextual fear memory, but impaired long-term object recognition memory. Furthermore, short-term memory for object recognition was intact in Kv7.2(S559A) mice. The deficit in long-term object recognition memory was restored by the administration of a selective Kv7 channel inhibitor, XE991, when delivered during the memory consolidation phase. Lastly, c-Fos induction 2 h after training in Kv7.2(S559A) mice was normal in the hippocampus, which corresponds to intact object location memory, but was reduced in the perirhinal cortex, which corresponds to impaired long-term object recognition memory. Together, these results support the overall conclusion that M-current suppression is important for memory consolidation of specific types of memories. Dynamic regulation of neuronal excitation is a fundamental mechanism for information processing in the brain, which is mediated by changes in synaptic transmissions or by changes in ion channel activity. Some neurotransmitters can facilitate action potential firing by suppression of a low voltage-activated potassium current, M-current. We demonstrate that M-current suppression is critical for establishment of long-term object recognition memory, but is not required for establishment of hippocampus-dependent location memory or contextual memory. This study suggests that M-current suppression is important for stable encoding of specific types of memories.
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http://dx.doi.org/10.1523/JNEUROSCI.0348-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380971PMC
July 2020

Optogenetic intervention of seizures improves spatial memory in a mouse model of chronic temporal lobe epilepsy.

Epilepsia 2020 03 18;61(3):561-571. Epub 2020 Feb 18.

Department of Neurosurgery, Stanford University, Stanford, California.

Objective: To determine if closed-loop optogenetic seizure intervention, previously shown to reduce seizure duration in a well-established mouse model chronic temporal lobe epilepsy (TLE), also improves the associated comorbidity of impaired spatial memory.

Methods: Mice with chronic, spontaneous seizures in the unilateral intrahippocampal kainic acid model of TLE, expressing channelrhodopsin in parvalbumin-expressing interneurons, were implanted with optical fibers and electrodes, and tested for response to closed-loop light intervention of seizures. Animals that responded to closed-loop optogenetic curtailment of seizures were tested in the object location memory test and then given closed-loop optogenetic intervention on all detected seizures for 2 weeks. Following this, they were tested with a second object location memory test, with different objects and contexts than used previously, to assess if seizure suppression can improve deficits in spatial memory.

Results: Animals that received closed-loop optogenetic intervention performed significantly better in the second object location memory test compared to the first test. Epileptic controls with no intervention showed stable frequency and duration of seizures, as well as stable spatial memory deficits, for several months after the precipitating insult.

Significance: Many currently available treatments for epilepsy target seizures but not the associated comorbidities, therefore there is a need to investigate new potential therapies that may be able to improve both seizure burden and associated comorbidities of epilepsy. In this study, we showed that optogenetic intervention may be able to both shorten seizure duration and improve cognitive outcomes of spatial memory.
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http://dx.doi.org/10.1111/epi.16445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7708390PMC
March 2020

Exercise opens a temporal window for enhanced cognitive improvement from subsequent physical activity.

Learn Mem 2019 12 15;26(12):485-492. Epub 2019 Nov 15.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, California 92617, USA.

The beneficial effects of exercise on cognition are well established; however specific exercise parameters regarding the frequency and duration of physical activity that provide optimal cognitive health have not been well defined. Here, we explore the effects of the duration of exercise and sedentary periods on long-term object location memory (OLM) in mice. We use a weak object location training paradigm that is subthreshold for long-term memory formation in sedentary controls, and demonstrate that exercise enables long-term memories to form. We show that 14- and 21-d of running wheel access enables mice to discriminate between familiar and novel object locations after a 24 h delay, while 2- or 7-d running wheel access provides insufficient exercise for such memory enhancement using the subthreshold learning paradigm. After 14- and 21-d of wheel running, exercise-induced cognitive enhancement then decays back to baseline performance following 3-d of sedentary activity. However, exercise-induced cognitive enhancement can be reactivated by an additional period of just 2 d exercise, previously shown to be insufficient to induce cognitive enhancement on its own. The reactivating period of exercise is capable of enhancing memory after three- or seven-sedentary days, but not 14-d. These data suggest a type of "molecular memory" for the exercise stimulus, in that once exercise duration reaches a certain threshold, it establishes a temporal window during which subsequent low-level exercise can capitalize on the neurobiological adaptations induced by the initial period of exercise, enabling it to maintain the benefits on cognitive function. These findings provide new information that may help to guide future clinical studies in exercise.
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http://dx.doi.org/10.1101/lm.050278.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6859826PMC
December 2019

Examining the contribution of histone modification to sex differences in learning and memory.

Learn Mem 2019 09 15;26(9):318-331. Epub 2019 Aug 15.

Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, California 92697, USA.

The epigenome serves as a signal integration platform that encodes information from experience and environment that adds tremendous complexity to the regulation of transcription required for memory, beyond the directions encoded in the genome. To date, our understanding of how epigenetic mechanisms integrate information to regulate gene expression required for memory is primarily obtained from male derived data despite sex-specific life experiences and sex differences in consolidation and retrieval of memory, and in the molecular mechanisms that mediate these processes. In this review, we examine the contribution of chromatin modification to learning and memory in both sexes. We provide examples of how exposure to a number of internal and external factors influence the epigenome in sex-similar and sex-specific ways that may ultimately impact transcription required for memory processes. We also pose a number of key open questions and identify areas requiring further investigation as we seek to understand how histone modifying mechanisms shape memory in females.
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http://dx.doi.org/10.1101/lm.048850.118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6699407PMC
September 2019

Innovative approaches in cognitive aging.

Neurobiol Aging 2019 11 30;83:150-154. Epub 2019 Apr 30.

Department of Neurology, The Johns Hopkins School of Medicine, Baltimore, MD, USA. Electronic address:

Novel approaches to address cognitive aging and to delay or prevent cognitive decline in older individuals will require a better understanding of the biological and environmental factors that contribute to it. Studies in animal models-in particular, animals whose cognitive trajectory across their life span closely tracks that of humans-can provide important insights into the factors that contribute to the accumulation of reserve and ways in which it is preserved or depleted. A better understanding of the molecular processes that underlie these elements would enhance and guide not only research but also treatment approaches to these issues. These treatment approaches may include noninvasive brain stimulation and drug treatments to promote youthfulness or combat the aging process. It is important to realize, however, that these processes occur in the context of the human experience, and studies of them must consider the complexity and individuality of each person's life.
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http://dx.doi.org/10.1016/j.neurobiolaging.2019.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7039185PMC
November 2019

PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.

EMBO J 2019 07 22;38(13):e101032. Epub 2019 May 22.

Department of Medicine, Division of Brain Sciences, Molecular Neuroregeneration, Imperial College London, London, UK.

The molecular mechanisms discriminating between regenerative failure and success remain elusive. While a regeneration-competent peripheral nerve injury mounts a regenerative gene expression response in bipolar dorsal root ganglia (DRG) sensory neurons, a regeneration-incompetent central spinal cord injury does not. This dichotomic response offers a unique opportunity to investigate the fundamental biological mechanisms underpinning regenerative ability. Following a pharmacological screen with small-molecule inhibitors targeting key epigenetic enzymes in DRG neurons, we identified HDAC3 signalling as a novel candidate brake to axonal regenerative growth. In vivo, we determined that only a regenerative peripheral but not a central spinal injury induces an increase in calcium, which activates protein phosphatase 4 that in turn dephosphorylates HDAC3, thus impairing its activity and enhancing histone acetylation. Bioinformatics analysis of ex vivo H3K9ac ChIPseq and RNAseq from DRG followed by promoter acetylation and protein expression studies implicated HDAC3 in the regulation of multiple regenerative pathways. Finally, genetic or pharmacological HDAC3 inhibition overcame regenerative failure of sensory axons following spinal cord injury. Together, these data indicate that PP4-dependent HDAC3 dephosphorylation discriminates between axonal regeneration and regenerative failure.
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http://dx.doi.org/10.15252/embj.2018101032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600644PMC
July 2019

Aging mice show impaired memory updating in the novel OUL updating paradigm.

Neuropsychopharmacology 2020 01 15;45(2):337-346. Epub 2019 Jun 15.

Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA, 92697, USA.

Memories do not persist in a permanent, static state but instead must be dynamically modified in response to new information. Although new memory formation is typically studied in a laboratory setting, most real-world associations are modifications to existing memories, particularly in the aging, experienced brain. To date, the field has lacked a simple behavioral paradigm that can measure whether original and updated information is remembered in a single test session. To address this gap, we have developed a novel memory updating paradigm, called the Objects in Updated Locations (OUL) task that is capable of assessing memory updating in a non-stressful task that is appropriate for both young and old rodents. We first show that young mice successfully remember both the original memory and the updated information in OUL. Next, we demonstrate that intrahippocampal infusion of the protein synthesis inhibitor anisomycin disrupts both the updated information and the original memory at test, suggesting that memory updating in OUL engages the original memory. To verify this, we used the Arc CatFISH technique to show that the OUL update session reactivates a largely overlapping set of neurons as the original memory. Finally, using OUL, we show that memory updating is impaired in aging, 18-m.o. mice. Together, these results demonstrate that hippocampal memory updating is impaired with aging and establish that the OUL paradigm is an effective, sensitive method of assessing memory updating in rodents.
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http://dx.doi.org/10.1038/s41386-019-0438-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6901557PMC
January 2020

Nicotine excites VIP interneurons to disinhibit pyramidal neurons in auditory cortex.

Synapse 2019 09 17;73(9):e22116. Epub 2019 May 17.

Department of Neurobiology and Behavior, Center for Hearing Research, University of California, Irvine, Irvine, California.

Nicotine activates nicotinic acetylcholine receptors and improves cognitive and sensory function, in part by its actions in cortical regions. Physiological studies show that nicotine amplifies stimulus-evoked responses in sensory cortex, potentially contributing to enhancement of sensory processing. However, the role of specific cell types and circuits in the nicotinic modulation of sensory cortex remains unclear. Here, we performed whole-cell recordings from pyramidal (Pyr) neurons and inhibitory interneurons expressing parvalbumin (PV), somatostatin (SOM), and vasoactive intestinal peptide (VIP) in mouse auditory cortex, in vitro. Bath application of nicotine strongly depolarized and excited VIP neurons, weakly depolarized Pyr neurons, and had no effect on the membrane potential of SOM or PV neurons. The use of receptor antagonists showed that nicotine's effects on VIP and Pyr neurons were direct and indirect, respectively. Nicotine also enhanced the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in Pyr, VIP, and SOM, but not PV, cells. Using Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), we show that chemogenetic inhibition of VIP neurons prevents nicotine's effects on Pyr neurons. Since VIP cells preferentially contact other inhibitory interneurons, we suggest that nicotine drives VIP cell firing to disinhibit Pyr cell somata, potentially making Pyr cells more responsive to auditory stimuli. In parallel, activation of VIP cells also directly inhibits Pyr neurons, likely altering integration of other synaptic inputs. These cellular and synaptic mechanisms likely contribute to nicotine's beneficial effects on cognitive and sensory function.
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http://dx.doi.org/10.1002/syn.22116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6767604PMC
September 2019

HDAC3-Mediated Repression of the Family Contributes to Age-Related Impairments in Long-Term Memory.

J Neurosci 2019 06 18;39(25):4999-5009. Epub 2019 Apr 18.

Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, California 92697, and

Aging is accompanied by cognitive deficits, including impairments in long-term memory formation. Understanding the molecular mechanisms that support preserved cognitive function in aged animals is a critical step toward identifying novel therapeutic targets that could improve memory in aging individuals. One potential mechanism is the family of genes, a group of CREB-dependent nuclear orphan receptors that have previously been shown to be important for hippocampal memory formation. Here, using a cross-species approach, we tested the role of and in age-related memory impairments. Using a rat model designed to identify individual differences in age-related memory impairments, we first identified as a key gene that fails to be induced by learning in cognitively impaired male aged rats. Next, using a mouse model that allows for genetic manipulations, we determined that histone deacetylase 3 (HDAC3) negatively regulates in the aged male and female hippocampus. Finally, we show that overexpression of , , or both transcripts in the male mouse dorsal hippocampus can ameliorate age-related impairments in object location memory. Together, our results suggest that may be a key mechanism that promotes preserved cognitive function in old age, with HDAC3-mediated repression of contributing to age-related cognitive decline. More broadly, these results indicate that therapeutic strategies to promote gene expression or function may be an effective strategy to improve cognitive function in old age. Aging is accompanied by memory impairments, although there is a great deal of variability in the severity of these impairments. Identifying molecular mechanisms that promote preserved memory or participate in cognitive reserve in old age is important to develop strategies that promote healthy cognitive aging. Here, we show that learning-induced expression of the CREB-regulated nuclear receptor gene is selectively impaired in aged rats with memory impairments. Further, we show that is regulated by histone deacetylase HDAC3 in the aged mouse hippocampus. Finally, we demonstrate that hippocampal overexpression of either or its family member, , can ameliorate age-related memory impairments. This suggests that promoting expression may be a novel strategy to improve memory in aging individuals.
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http://dx.doi.org/10.1523/JNEUROSCI.2799-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6670247PMC
June 2019

Epigenetic regulation of immediate-early gene Nr4a2/Nurr1 in the medial habenula during reinstatement of cocaine-associated behavior.

Neuropharmacology 2019 07 15;153:13-19. Epub 2019 Apr 15.

Department of Neurobiology and Behavior, School of Biological Sciences University of California, Irvine, USA; UC Irvine Center for Addiction Neuroscience, School of Biological Sciences, University of California, Irvine, USA; Center for the Neurobiology of Learning and Memory, School of Biological Sciences, University of California, Irvine, USA. Electronic address:

Propensity to relapse following long periods of abstinence is a key feature of substance use disorder. Drugs of abuse, such as cocaine, cause long-term changes in the neural circuitry regulating reward, motivation, and memory processes through dysregulation of various molecular mechanisms, including epigenetic regulation of activity-dependent gene expression. Underlying drug-induced changes to neural circuit function are the molecular mechanisms regulating activity-dependent gene expression. Of note, histone acetyltransferases and histone deacetylases (HDACs), powerful epigenetic regulators of gene expression, are dysregulated following both acute and chronic cocaine exposure and are linked to cocaine-induced changes in neural circuit function. To better understand the effect of drug-induced changes on epigenetic function and behavior, we investigated HDAC3-mediated regulation of Nr4a2/Nurr1 in the medial habenula, an understudied pathway in cocaine-associated behaviors. Nr4a2, a transcription factor critical in cocaine-associated behaviors and necessary for MHb development, is enriched in the cholinergic cell-population of the MHb; yet, the role of NR4A2 within the MHb in the adult brain remains elusive. Here, we evaluated whether epigenetic regulation of Nr4a2 in the MHb has a role in reinstatement of cocaine-associated behaviors. We found that HDAC3 disengages from Nr4a2 in the MHb in response to cocaine-primed reinstatement. Whereas enhancing HDAC3 function in the MHb had no effect on reinstatement, we found, using a dominant-negative splice variant (NURR2C), that loss of NR4A2 function in the MHb blocked reinstatement behaviors. These results show for the first time that regulation of NR4A2 function in the MHb is critical in relapse-like behaviors.
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http://dx.doi.org/10.1016/j.neuropharm.2019.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581582PMC
July 2019

How the epigenome integrates information and reshapes the synapse.

Nat Rev Neurosci 2019 03;20(3):133-147

Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, Center for Addiction Neuroscience, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA.

In the past few decades, the field of neuroepigenetics has investigated how the brain encodes information to form long-lasting memories that lead to stable changes in behaviour. Activity-dependent molecular mechanisms, including, but not limited to, histone modification, DNA methylation and nucleosome remodelling, dynamically regulate the gene expression required for memory formation. Recently, the field has begun to examine how a learning experience is integrated at the level of both chromatin structure and synaptic physiology. Here, we provide an overview of key established epigenetic mechanisms that are important for memory formation. We explore how epigenetic mechanisms give rise to stable alterations in neuronal function by modifying synaptic structure and function, and highlight studies that demonstrate how manipulating epigenetic mechanisms may push the boundaries of memory.
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http://dx.doi.org/10.1038/s41583-019-0121-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7032043PMC
March 2019

Extinction Versus Epigenetic Intergenerational Inheritance: Who Wins?

Biol Psychiatry 2019 02;85(3):184-186

Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, Center for Addiction Neuroscience, Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, California. Electronic address:

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http://dx.doi.org/10.1016/j.biopsych.2018.11.016DOI Listing
February 2019

Effects of a histone deacetylase 3 inhibitor on extinction and reinstatement of cocaine self-administration in rats.

Psychopharmacology (Berl) 2019 Jan 28;236(1):517-529. Epub 2018 Nov 28.

Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR, USA.

Rationale: A challenge in treating substance use disorder is that successful treatment often does not persist, resulting in relapse and continued drug seeking. One approach to persistently weaken drug-seeking behaviors is to pair exposure to drug-associated cues or behaviors with delivery of a compound that may strengthen the inhibition of the association between drug cues and behavior.

Objectives: We evaluated whether a selective histone deacetylase 3 (HDAC3) inhibitor could promote extinction and weaken contextual control of operant drug seeking after intravenous cocaine self-administration.

Methods: Male Long-Evans rats received a systemic injection of the HDAC3 inhibitor RGFP966 either before or immediately after the first extinction session. Persistence of extinction was tested over subsequent extinction sessions, as well as tests of reinstatement that included cue-induced reinstatement, contextual renewal, and cocaine-primed reinstatement. Additional extinction sessions occurred between each reinstatement test. We also evaluated effects of RGFP966 on performance and motivation during stable fixed ratio operant responding for cocaine and during a progressive ratio of reinforcement.

Results: RGFP966 administered before the first extinction session led to significantly less responding during subsequent extinction and reinstatement tests compared to vehicle-injected rats. Follow-up studies found that these effects were not likely due to a performance deficit or a change in motivation to self-administer cocaine, as injections of RGFP966 had no effect on stable responding during a fixed or progressive ratio schedule. In addition, RGFP966 administered just after the first extinction session had no effect during early extinction and reinstatement tests, but weakened long-term responding during later extinction sessions.

Conclusions: These results suggest that a systemic injection of a selective HDAC3 inhibitor can enhance extinction and suppress reinstatement after cocaine self-administration. The finding that behavioral and pharmacological manipulations can be combined to decrease drug seeking provides further potential for treatment by epigenetic modulation.
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http://dx.doi.org/10.1007/s00213-018-5122-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459190PMC
January 2019

Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice.

Aging Cell 2018 Dec 2;17(6):e12832. Epub 2018 Oct 2.

Department of Neurobiology and Behavior, University of California, Irvine, California.

Microglia, the resident immune cell of the brain, can be eliminated via pharmacological inhibition of the colony-stimulating factor 1 receptor (CSF1R). Withdrawal of CSF1R inhibition then stimulates microglial repopulation, effectively replacing the microglial compartment. In the aged brain, microglia take on a "primed" phenotype and studies indicate that this coincides with age-related cognitive decline. Here, we investigated the effects of replacing the aged microglial compartment with new microglia using CSF1R inhibitor-induced microglial repopulation. With 28 days of repopulation, replacement of resident microglia in aged mice (24 months) improved spatial memory and restored physical microglial tissue characteristics (cell densities and morphologies) to those found in young adult animals (4 months). However, inflammation-related gene expression was not broadly altered with repopulation nor the response to immune challenges. Instead, microglial repopulation resulted in a reversal of age-related changes in neuronal gene expression, including expression of genes associated with actin cytoskeleton remodeling and synaptogenesis. Age-related changes in hippocampal neuronal complexity were reversed with both microglial elimination and repopulation, while microglial elimination increased both neurogenesis and dendritic spine densities. These changes were accompanied by a full rescue of age-induced deficits in long-term potentiation with microglial repopulation. Thus, several key aspects of the aged brain can be reversed by acute noninvasive replacement of microglia.
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http://dx.doi.org/10.1111/acel.12832DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6260908PMC
December 2018

CREST in the Nucleus Accumbens Core Regulates Cocaine Conditioned Place Preference, Cocaine-Seeking Behavior, and Synaptic Plasticity.

J Neurosci 2018 10 18;38(44):9514-9526. Epub 2018 Sep 18.

Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory,

Epigenetic mechanisms result in persistent changes at the cellular level that can lead to long-lasting behavioral adaptations. Nucleosome remodeling is a major epigenetic mechanism that has not been well explored with regards to drug-seeking behaviors. Nucleosome remodeling is performed by multi-subunit complexes that interact with DNA or chromatin structure and possess an ATP-dependent enzyme to disrupt nucleosome-DNA contacts and ultimately regulate gene expression. Calcium responsive transactivator (CREST) is a transcriptional activator that interacts with enzymes involved in both histone acetylation and nucleosome remodeling. Here, we examined the effects of knocking down CREST in the nucleus accumbens (NAc) core on drug-seeking behavior and synaptic plasticity in male mice as well as drug-seeking in male rats. Knocking down CREST in the NAc core results in impaired cocaine-induced conditioned place preference (CPP) as well as theta-induced long-term potentiation in the NAc core. Further, similar to the CPP findings, using a self-administration procedure, we found that CREST knockdown in the NAc core of male rats had no effect on instrumental responding for cocaine itself on a first-order schedule, but did significantly attenuate responding on a second-order chain schedule, in which responding has a weaker association with cocaine. Together, these results suggest that CREST in the NAc core is required for cocaine-induced CPP, synaptic plasticity, as well as cocaine-seeking behavior. This study demonstrates a key role for the role of Calcium responsive transactivator (CREST), a transcriptional activator, in the nucleus accumbens (NAc) core with regard to cocaine-induced conditioned place preference (CPP), self-administration (SA), and synaptic plasticity. CREST is a unique transcriptional regulator that can recruit enzymes from two different major epigenetic mechanisms: histone acetylation and nucleosome remodeling. In this study we also found that the level of potentiation in the NAc core correlated with whether or not animals formed a CPP. Together the results indicate that CREST is a key downstream regulator of cocaine action in the NAc.
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http://dx.doi.org/10.1523/JNEUROSCI.2911-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209848PMC
October 2018

Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory.

Nat Commun 2018 08 20;9(1):3323. Epub 2018 Aug 20.

Department of Neurobiology and Behavior, University of California, Irvine, CA, 92697, USA.

Aging is accompanied by impairments in both circadian rhythmicity and long-term memory. Although it is clear that memory performance is affected by circadian cycling, it is unknown whether age-related disruption of the circadian clock causes impaired hippocampal memory. Here, we show that the repressive histone deacetylase HDAC3 restricts long-term memory, synaptic plasticity, and experience-induced expression of the circadian gene Per1 in the aging hippocampus without affecting rhythmic circadian activity patterns. We also demonstrate that hippocampal Per1 is critical for long-term memory formation. Together, our data challenge the traditional idea that alterations in the core circadian clock drive circadian-related changes in memory formation and instead argue for a more autonomous role for circadian clock gene function in hippocampal cells to gate the likelihood of long-term memory formation.
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http://dx.doi.org/10.1038/s41467-018-05868-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6102273PMC
August 2018

Habits Are Negatively Regulated by Histone Deacetylase 3 in the Dorsal Striatum.

Biol Psychiatry 2018 09 8;84(5):383-392. Epub 2018 Feb 8.

Department of Psychology, University of California, Los Angeles, California; Brain Research Institute, University of California, Los Angeles, Los Angeles, California. Electronic address:

Background: Optimal behavior and decision making result from a balance of control between two strategies, one cognitive/goal-directed and one habitual. These systems are known to rely on the anatomically distinct dorsomedial and dorsolateral striatum, respectively. However, the transcriptional regulatory mechanisms required to learn and transition between these strategies are unknown. Here we examined the role of one chromatin-based transcriptional regulator, histone modification via histone deacetylases (HDACs), in this process.

Methods: We combined procedures that diagnose behavioral strategy in rats with pharmacological and viral-mediated HDAC manipulations, chromatin immunoprecipitation, and messenger RNA quantification.

Results: The results indicate that dorsal striatal HDAC3 activity constrains habit formation. Systemic HDAC inhibition following instrumental (lever press → reward) conditioning increased histone acetylation throughout the dorsal striatum and accelerated habitual control of behavior. HDAC3 was removed from the promoters of key learning-related genes in the dorsal striatum as habits formed with overtraining and with posttraining HDAC inhibition. Decreasing HDAC3 function, either by selective pharmacological inhibition or by expression of dominant-negative mutated HDAC3, in either the dorsolateral striatum or the dorsomedial striatum accelerated habit formation, while HDAC3 overexpression in either region prevented habit.

Conclusions: These results challenge the strict dissociation between dorsomedial striatum and dorsolateral striatum function in goal-directed versus habitual behavioral control and identify dorsostriatal HDAC3 as a critical molecular directive of the transition to habit. Because this transition is disrupted in many neurodegenerative and psychiatric diseases, these data suggest a potential molecular mechanism for the negative behavioral symptoms of these conditions and a target for therapeutic intervention.
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http://dx.doi.org/10.1016/j.biopsych.2018.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082729PMC
September 2018

Deleting HDAC3 rescues long-term memory impairments induced by disruption of the neuron-specific chromatin remodeling subunit BAF53b.

Learn Mem 2018 03 15;25(3):109-114. Epub 2018 Feb 15.

Department of Neurobiology and Behavior, University of California, Irvine, California, 92697, USA.

Multiple epigenetic mechanisms, including histone acetylation and nucleosome remodeling, are known to be involved in long-term memory formation. Enhancing histone acetylation by deleting histone deacetylases, like HDAC3, typically enhances long-term memory formation. In contrast, disrupting nucleosome remodeling by blocking the neuron-specific chromatin remodeling subunit BAF53b impairs long-term memory. Here, we show that deleting HDAC3 can ameliorate the impairments in both long-term memory and synaptic plasticity caused by BAF53b mutation. This suggests a dynamic interplay exists between histone acetylation/deacetylation and nucleosome remodeling mechanisms in the regulation of memory formation.
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http://dx.doi.org/10.1101/lm.046920.117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5817283PMC
March 2018

Medial habenula cholinergic signaling regulates cocaine-associated relapse-like behavior.

Addict Biol 2019 05 12;24(3):403-413. Epub 2018 Feb 12.

Department of Neurobiology and Behavior, Ayala School of Biological Sciences, University of California, Irvine, CA, USA.

Propensity to relapse, even following long periods of abstinence, is a key feature in substance use disorders. Relapse and relapse-like behaviors are known to be induced, in part, by re-exposure to drug-associated cues. Yet, while many critical nodes in the neural circuitry contributing to relapse have been identified and studied, a full description of the networks driving reinstatement of drug-seeking behaviors is lacking. One area that may provide further insight to the mechanisms of relapse is the habenula complex, an epithalamic region composed of lateral and medial (MHb) substructures, each with unique cell and target populations. Although well conserved across vertebrate species, the functions of the MHb are not well understood. Recent research has demonstrated that the MHb regulates nicotine aversion and withdrawal. However, it remains undetermined whether MHb function is limited to nicotine and aversive stimuli or if MHb circuit regulates responses to other drugs of abuse. Advances in circuit-level manipulations now allow for cell-type and temporally specific manipulations during behavior, specifically in spatially restrictive brain regions, such as the MHb. In this study, we focus on the response of the MHb to reinstatement of cocaine-associated behavior, demonstrating that cocaine-primed reinstatement of conditioned place preference engages habenula circuitry. Using chemogenetics, we demonstrate that MHb activity is sufficient to induce reinstatement behavior. Together, these data identify the MHb as a key hub in the circuitry underlying reinstatement and may serve as a target for regulating relapse-like behaviors.
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http://dx.doi.org/10.1111/adb.12605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6087687PMC
May 2019

Distinct roles for the deacetylase domain of HDAC3 in the hippocampus and medial prefrontal cortex in the formation and extinction of memory.

Neurobiol Learn Mem 2017 Nov 8;145:94-104. Epub 2017 Sep 8.

301 Qureshey Research Lab, Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, CA 92697, United States; Center for the Neurobiology of Learning and Memory (CNLM), Irvine, CA 92697, United States; Irvine Center for Addiction Neuroscience (ICAN), University of California, Irvine, CA 92697, United States; Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, Irvine, CA 92697, United States. Electronic address:

Histone deacetylases (HDACs) are chromatin modifying enzymes that have been implicated as powerful negative regulators of memory processes. HDAC3has been shown to play a pivotal role in long-term memory for object location as well as the extinction of cocaine-associated memory, but it is unclear whether this function depends on the deacetylase domain of HDAC3. Here, we tested whether the deacetylase domain of HDAC3has a role in object location memory formation as well as the formation and extinction of cocaine-associated memories. Using a deacetylase-dead point mutant of HDAC3, we found that selectively blocking HDAC3 deacetylase activity in the dorsal hippocampus enhanced long-term memory for object location, but had no effect on the formation of cocaine-associated memory. When this same point mutant virus of HDAC3 was infused into the prelimbic cortex, it failed to affect cocaine-associated memory formation. With regards to extinction, impairing the HDAC3 deacetylase domain in the infralimbic cortex had no effect on extinction, but a facilitated extinction effect was observed when the point mutant virus was delivered to the dorsal hippocampus. These results suggest that the deacetylase domain of HDAC3 plays a selective role in specific brain regions underlying long-term memory formation of object location as well as cocaine-associated memory formation and extinction.
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http://dx.doi.org/10.1016/j.nlm.2017.09.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5698127PMC
November 2017

Mutation of neuron-specific chromatin remodeling subunit BAF53b: rescue of plasticity and memory by manipulating actin remodeling.

Learn Mem 2017 05 17;24(5):199-209. Epub 2017 Apr 17.

Department of Neurobiology and Behavior, University of California, Irvine, California 92697, USA.

Recent human exome-sequencing studies have implicated polymorphic Brg1-associated factor (BAF) complexes (mammalian SWI/SNF chromatin remodeling complexes) in several intellectual disabilities and cognitive disorders, including autism. However, it remains unclear how mutations in BAF complexes result in impaired cognitive function. Post-mitotic neurons express a neuron-specific assembly, nBAF, characterized by the neuron-specific subunit BAF53b. Subdomain 2 of BAF53b is essential for the differentiation of neuronal precursor cells into neurons. We generated transgenic mice lacking subdomain 2 of Baf53b (BAF53bΔSB2). Long-term synaptic potentiation (LTP) and long-term memory, both of which are associated with phosphorylation of the actin severing protein cofilin, were assessed in these animals. A phosphorylation mimic of cofilin was stereotaxically delivered into the hippocampus of BAF53bΔSB2 mice in an effort to rescue LTP and memory. BAF53bΔSB2 mutant mice show impairments in phosphorylation of synaptic cofilin, LTP, and memory. Both the synaptic plasticity and memory deficits are rescued by overexpression of a phosphorylation mimetic of cofilin. Baseline physiology and behavior were not affected by the mutation or the experimental treatment. This study suggests a potential link between nBAF function, actin cytoskeletal remodeling at the dendritic spine, and memory formation. This work shows that a targeted manipulation of synaptic function can rescue adult plasticity and memory deficits caused by manipulations of nBAF, and thereby provides potential novel avenues for therapeutic development for multiple intellectual disability disorders.
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http://dx.doi.org/10.1101/lm.044602.116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5397687PMC
May 2017

Reconsolidation and extinction: Using epigenetic signatures to challenge conventional wisdom.

Neurobiol Learn Mem 2017 Jul 21;142(Pt A):55-65. Epub 2017 Jan 21.

Department of Neurobiology and Behavior, University of California, Irvine, CA, USA; Center for the Neurobiology of Learning and Memory, Irvine, CA, USA. Electronic address:

Epigenetic mechanisms have the potential to give rise to lasting changes in cell function that ultimately can affect behavior persistently. This concept is especially interesting with respect to fear reconsolidation and fear memory extinction. These two behavioral approaches are used in the laboratory to investigate how fear memory can be attenuated, which becomes important when searching for therapeutic intervention to treat anxiety disorders and post-traumatic stress disorder. Here we review the role of several key epigenetic mechanisms in reconsolidation and extinction of learned fear and their potential to persistently alter behavioral responses to conditioned cues. We also briefly discuss how epigenetic mechanisms may establish persistent behaviors that challenge our definitions of extinction and reconsolidation.
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http://dx.doi.org/10.1016/j.nlm.2017.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5457345PMC
July 2017

Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala.

Neuropsychopharmacology 2017 May 7;42(6):1284-1294. Epub 2016 Dec 7.

Department of Neurobiology and Behavior, Center for the Neurobiology of Learning and Memory, University of California, Irvine, California, USA.

Histone acetylation is a fundamental epigenetic mechanism that is dynamically regulated during memory formation. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) compete to modulate histone acetylation, allowing for rapid changes in acetylation in response to a learning event. HDACs are known to be powerful negative regulators of memory formation, but it is not clear whether this function depends on HDAC enzymatic activity per se. Here, we tested whether the enzymatic activity of an individual Class I HDAC, HDAC3, has a role in fear memory formation in subregions of the hippocampus and amygdala. We found that fear conditioning drove expression of the immediate early genes cFos and Nr4a2 in the hippocampus, which coincided with reduced HDAC3 occupancy at these promoters. Using a dominant-negative, deacetylase-dead point mutant virus (AAV-HDAC3(Y298H)-v5), we found that selectively blocking HDAC3 deacetylase activity in either the dorsal hippocampus or basal nucleus of the amygdala enhanced context fear without affecting tone fear. Blocking HDAC3 activity in the lateral nucleus of the amygdala, on the other hand, enhanced tone, but not context fear memory. These results show for the first time that the enzymatic activity of HDAC3 functions to negatively regulate fear memory formation. Further, HDAC3 activity regulates different aspects of fear memory in the basal and lateral subregions of the amygdala. Thus, the deacetylase activity of HDAC3 is a powerful negative regulator of fear memory formation in multiple subregions of the fear circuit.
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http://dx.doi.org/10.1038/npp.2016.274DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437888PMC
May 2017

Impaired function of α2-containing nicotinic acetylcholine receptors on oriens-lacunosum moleculare cells causes hippocampus-dependent memory impairments.

Neurobiol Learn Mem 2016 Dec 19;136:13-20. Epub 2016 Sep 19.

Department of Neurobiology and Behavior, University of California Irvine, Irvine, CA 92697-4550, USA. Electronic address:

Children of mothers who smoked during pregnancy are at significantly greater risk for cognitive impairments including memory deficits, but the mechanisms underlying this effect remain to be understood. In rodent models of smoking during pregnancy, early postnatal nicotine exposure results in impaired long-term hippocampus-dependent memory, functional loss of α2-containing nicotinic acetylcholine receptors (α2 nAChRs) in oriens-lacunosum moleculare (OLM) cells, increased CA1 network excitation, and unexpected facilitation of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses. Here we demonstrate that α2 knockout mice show the same pattern of memory impairment as previously observed in wild-type mice exposed to early postnatal nicotine. However, α2 knockout mice and α2 knockout mice exposed to early postnatal nicotine did not share all of the anomalies in hippocampal function observed in wild-type mice treated with nicotine during development. Unlike nicotine-treated wild-type mice, α2 knockout mice and nicotine-exposed α2 knockout mice did not demonstrate increased CA1 network excitation following Schaffer collateral stimulation and facilitated LTP, indicating that the effects are likely adaptive changes caused by activation of α2 nAChRs during nicotine exposure and are unlikely related to the associated memory impairment. Thus, the functional loss of α2 nAChRs in OLM cells likely plays a critical role in mediating this developmental-nicotine-induced hippocampal memory deficit.
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http://dx.doi.org/10.1016/j.nlm.2016.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5124391PMC
December 2016

Longitudinal assessment of neuronal 3D genomes in mouse prefrontal cortex.

Nat Commun 2016 09 6;7:12743. Epub 2016 Sep 6.

Department of Psychiatry, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1470 Madison Avenue, New York, New York 10029, USA.

Neuronal epigenomes, including chromosomal loopings moving distal cis-regulatory elements into proximity of target genes, could serve as molecular proxy linking present-day-behaviour to past exposures. However, longitudinal assessment of chromatin state is challenging, because conventional chromosome conformation capture assays essentially provide single snapshots at a given time point, thus reflecting genome organization at the time of brain harvest and therefore are non-informative about the past. Here we introduce 'NeuroDam' to assess epigenome status retrospectively. Short-term expression of the bacterial DNA adenine methyltransferase Dam, tethered to the Gad1 gene promoter in mouse prefrontal cortex neurons, results in stable G(methyl)ATC tags at Gad1-bound chromosomal contacts. We show by NeuroDam that mice with defective cognition 4 months after pharmacological NMDA receptor blockade already were affected by disrupted chromosomal conformations shortly after drug exposure. Retrospective profiling of neuronal epigenomes is likely to illuminate epigenetic determinants of normal and diseased brain development in longitudinal context.
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http://dx.doi.org/10.1038/ncomms12743DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5025847PMC
September 2016

BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens.

Nat Commun 2016 05 26;7:11725. Epub 2016 May 26.

301 Qureshey Research Lab, Department of Neurobiology and Behavior, University of California, Irvine, California 92697, USA.

Recent evidence implicates epigenetic mechanisms in drug-associated memory processes. However, a possible role for one major epigenetic mechanism, nucleosome remodelling, in drug-associated memories remains largely unexplored. Here we examine mice with genetic manipulations targeting a neuron-specific nucleosome remodelling complex subunit, BAF53b. These mice display deficits in cocaine-associated memory that are more severe in BAF53b transgenic mice compared with BAF53b heterozygous mice. Similar to the memory deficits, theta-induced long-term potentiation (theta-LTP) in the nucleus accumbens (NAc) is significantly impaired in slices taken from BAF53b transgenic mice but not heterozygous mice. Further experiments indicate that theta-LTP in the NAc is dependent on TrkB receptor activation, and that BDNF rescues theta-LTP and cocaine-associated memory deficits in BAF53b transgenic mice. Together, these results suggest a role for BAF53b in NAc neuronal function required for cocaine-associated memories, and also that BDNF/TrkB activation in the NAc may overcome memory and plasticity deficits linked to BAF53b mutations.
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http://dx.doi.org/10.1038/ncomms11725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4894971PMC
May 2016

Promoter-Specific Effects of DREADD Modulation on Hippocampal Synaptic Plasticity and Memory Formation.

J Neurosci 2016 Mar;36(12):3588-99

Department of Neurobiology and Behavior and Center for the Neurobiology of Learning and Memory, University of California, Irvine, Irvine, California 92697, UC Irvine Center for Addiction Neuroscience, and

Unlabelled: Designer receptors exclusively activated by designer drug (DREADDs) are a novel tool with the potential to bidirectionally drive cellular, circuit, and ultimately, behavioral changes. We used DREADDs to evaluate memory formation in a hippocampus-dependent task in mice and effects on synaptic physiology in the dorsal hippocampus. We expressed neuron-specific (hSyn promoter) DREADDs that were either excitatory (HM3D) or inhibitory (HM4D) in the dorsal hippocampus. As predicted, hSyn-HM3D was able to transform a subthreshold learning event into long-term memory (LTM), and hSyn-HM4D completely impaired LTM formation. Surprisingly, the opposite was observed during experiments examining the effects on hippocampal long-term potentiation (LTP). hSyn-HM3D impaired LTP and hSyn-HM4D facilitated LTP. Follow-up experiments indicated that the hSyn-HM3D-mediated depression of fEPSP appears to be driven by presynaptic activation of inhibitory currents, whereas the hSyn-HM4D-mediated increase of fEPSP is induced by a reduction in GABAA receptor function. To determine whether these observations were promoter specific, we next examined the effects of using the CaMKIIα promoter that limits expression to forebrain excitatory neurons. CaMKIIα-HM3D in the dorsal hippocampus led to the transformation of a subthreshold learning event into LTM, whereas CaMKIIα-HM4D blocked LTM formation. Consistent with these findings, baseline synaptic transmission and LTP was increased in CaMKIIα-HM3D hippocampal slices, whereas slices from CaMKIIα-HM4D mice produced expected decreases in baseline synaptic transmission and LTP. Together, these experiments further demonstrate DREADDs as being a robust and reliable means of modulating neuronal function to manipulate long-term changes in behavior, while providing evidence for specific dissociations between LTM and LTP.

Significance Statement: This study evaluates the efficacy of designer receptors exclusively activated by designer drug (DREADDs) as a means of bidirectionally modulating the hippocampus in not only a hippocampus-dependent task but also in hippocampal synaptic plasticity. This is the first study to evaluate the effects of DREADD-mediated inhibition and excitation in hippocampal long-term potentiation. More specifically, this study evaluates the effect of promoter-specific expression of DREADD viruses in a heterogenic cell population, which revealed surprising effects of different promoters. With chemogenetics becoming a more ubiquitous tool throughout studies investigating circuit-specific function, these data are of broad interest to the neuroscientific community because we have shown that promoter-specific effects can drastically alter synaptic function within a specific region, without parallel changes at the level of behavior.
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http://dx.doi.org/10.1523/JNEUROSCI.3682-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4804014PMC
March 2016
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