19 results on '"Alaghband Y"'
Search Results
2. IS011 - FLASH Mechanisms Track NEW HORIZONS RELATED TO THE BIOLOGY OF FLASH-RT
- Author
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Limoli, C., Alaghband, Y., Allen, B., and Vozenin, M.-C.
- Published
- 2022
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3. Specific exercise patterns generate an epigenetic molecular memory window that drives long-term memory formation and identifies ACVR1C as a bidirectional regulator of memory in mice.
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Keiser AA, Dong TN, Kramár EA, Butler CW, Chen S, Matheos DP, Rounds JS, Rodriguez A, Beardwood JH, Augustynski AS, Al-Shammari A, Alaghband Y, Alizo Vera V, Berchtold NC, Shanur S, Baldi P, Cotman CW, and Wood MA
- Subjects
- Animals, Female, Humans, Male, Mice, Aging genetics, Aging physiology, Mice, Inbred C57BL, Neuronal Plasticity genetics, Promoter Regions, Genetic, Activin Receptors, Type I genetics, Activin Receptors, Type I metabolism, Epigenesis, Genetic, Hippocampus metabolism, Memory, Long-Term physiology, Physical Conditioning, Animal physiology
- Abstract
Exercise has beneficial effects on cognition throughout the lifespan. Here, we demonstrate that specific exercise patterns transform insufficient, subthreshold training into long-term memory in mice. Our findings reveal a potential molecular memory window such that subthreshold training within this window enables long-term memory formation. We performed RNA-seq on dorsal hippocampus and identify genes whose expression correlate with conditions in which exercise enables long-term memory formation. Among these genes we found Acvr1c, a member of the TGF ß family. We find that exercise, in any amount, alleviates epigenetic repression at the Acvr1c promoter during consolidation. Additionally, we find that ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice. Furthermore, Acvr1c expression is impaired in the aging human and mouse brain, as well as in the 5xFAD mouse model, and over-expression of Acvr1c enables learning and facilitates plasticity in mice. These data suggest that promoting ACVR1C may protect against cognitive impairment., (© 2024. The Author(s).)
- Published
- 2024
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4. More May Not be Better: Enhanced Spacecraft Shielding May Exacerbate Cognitive Decrements by Increasing Pion Exposures during Deep Space Exploration.
- Author
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Vozenin MC, Alaghband Y, Drayson OGG, Piaget F, Leavitt R, Allen BD, Doan NL, Rostomyan T, Stabilini A, Reggiani D, Hajdas W, Yukihara EG, Norbury JW, Bailat C, Desorgher L, Baulch JE, and Limoli CL
- Subjects
- Humans, Spacecraft, Astronauts, Cognition, Radiation Dosage, Mesons, Cosmic Radiation adverse effects, Radiation Protection methods, Space Flight
- Abstract
The pervasiveness of deep space radiation remains a confounding factor for the transit of humans through our solar system. Spacecraft shielding both protects astronauts but also contributes to absorbed dose through galactic cosmic ray interactions that produce secondary particles. The resultant biological effects drop to a minimum for aluminum shielding around 20 g/cm2 but increase with additional shielding. The present work evaluates for the first time, the impact of secondary pions on central nervous system functionality. The fractional pion dose emanating from thicker shielded spacecraft regions could contribute up to 10% of the total absorbed radiation dose. New results from the Paul Scherrer Institute have revealed that low dose exposures to 150 MeV positive and negative pions, akin to a Mars mission, result in significant, long-lasting cognitive impairments. These surprising findings emphasize the need to carefully evaluate shielding configurations to optimize safe exposure limits for astronauts during deep space travel., (© 2024 by Radiation Research Society.)
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- 2024
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5. Elucidating the neurological mechanism of the FLASH effect in juvenile mice exposed to hypofractionated radiotherapy.
- Author
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Allen BD, Alaghband Y, Kramár EA, Ru N, Petit B, Grilj V, Petronek MS, Pulliam CF, Kim RY, Doan NL, Baulch JE, Wood MA, Bailat C, Spitz DR, Vozenin MC, and Limoli CL
- Subjects
- Humans, Child, Male, Female, Animals, Mice, Disease Models, Animal, Radiotherapy Dosage, Radiotherapy adverse effects, Brain Neoplasms radiotherapy, Brain Neoplasms etiology
- Abstract
Background: Ultrahigh dose-rate radiotherapy (FLASH-RT) affords improvements in the therapeutic index by minimizing normal tissue toxicities without compromising antitumor efficacy compared to conventional dose-rate radiotherapy (CONV-RT). To investigate the translational potential of FLASH-RT to a human pediatric medulloblastoma brain tumor, we used a radiosensitive juvenile mouse model to assess adverse long-term neurological outcomes., Methods: Cohorts of 3-week-old male and female C57Bl/6 mice exposed to hypofractionated (2 × 10 Gy, FLASH-RT or CONV-RT) whole brain irradiation and unirradiated controls underwent behavioral testing to ascertain cognitive status four months posttreatment. Animals were sacrificed 6 months post-irradiation and tissues were analyzed for neurological and cerebrovascular decrements., Results: The neurological impact of FLASH-RT was analyzed over a 6-month follow-up. FLASH-RT ameliorated neurocognitive decrements induced by CONV-RT and preserved synaptic plasticity and integrity at the electrophysiological (long-term potentiation), molecular (synaptophysin), and structural (Bassoon/Homer-1 bouton) levels in multiple brain regions. The benefits of FLASH-RT were also linked to reduced neuroinflammation (activated microglia) and the preservation of the cerebrovascular structure, by maintaining aquaporin-4 levels and minimizing microglia colocalized to vessels., Conclusions: Hypofractionated FLASH-RT affords significant and long-term normal tissue protection in the radiosensitive juvenile mouse brain when compared to CONV-RT. The capability of FLASH-RT to preserve critical cognitive outcomes and electrophysiological properties over 6-months is noteworthy and highlights its potential for resolving long-standing complications faced by pediatric brain tumor survivors. While care must be exercised before clinical translation is realized, present findings document the marked benefits of FLASH-RT that extend from synapse to cognition and the microvasculature., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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6. Uncovering the Protective Neurologic Mechanisms of Hypofractionated FLASH Radiotherapy.
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Alaghband Y, Allen BD, Kramár EA, Zhang R, Drayson OGG, Ru N, Petit B, Almeida A, Doan NL, Wood MA, Baulch JE, Ballesteros-Zebadua P, Vozenin MC, and Limoli CL
- Subjects
- Male, Mice, Female, Animals, Neuronal Plasticity, Radiation Dose Hypofractionation, Neuroinflammatory Diseases, Long-Term Potentiation
- Abstract
Implementation of ultra-high dose-rate FLASH radiotherapy (FLASH-RT) is rapidly gaining traction as a unique cancer treatment modality able to dramatically minimize normal tissue toxicity while maintaining antitumor efficacy compared with standard-of-care radiotherapy at conventional dose rate (CONV-RT). The resultant improvements in the therapeutic index have sparked intense investigations in pursuit of the underlying mechanisms. As a preamble to clinical translation, we exposed non-tumor-bearing male and female mice to hypofractionated (3 × 10 Gy) whole brain FLASH- and CONV-RT to evaluate differential neurologic responses using a comprehensive panel of functional and molecular outcomes over a 6-month follow-up. In each instance, extensive and rigorous behavioral testing showed FLASH-RT to preserve cognitive indices of learning and memory that corresponded to a similar protection of synaptic plasticity as measured by long-term potentiation (LTP). These beneficial functional outcomes were not found after CONV-RT and were linked to a preservation of synaptic integrity at the molecular (synaptophysin) level and to reductions in neuroinflammation (CD68
+ microglia) throughout specific brain regions known to be engaged by our selected cognitive tasks (hippocampus, medial prefrontal cortex). Ultrastructural changes in presynaptic/postsynaptic bouton (Bassoon/Homer-1 puncta) within these same regions of the brain were not found to differ in response to dose rate. With this clinically relevant dosing regimen, we provide a mechanistic blueprint from synapse to cognition detailing how FLASH-RT reduces normal tissue complications in the irradiated brain., Significance: Functional preservation of cognition and LTP after hypofractionated FLASH-RT are linked to a protection of synaptic integrity and a reduction in neuroinflammation over protracted after irradiation times., (© 2023 The Authors; Published by the American Association for Cancer Research.)- Published
- 2023
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7. Galactic cosmic radiation exposure causes multifaceted neurocognitive impairments.
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Alaghband Y, Klein PM, Kramár EA, Cranston MN, Perry BC, Shelerud LM, Kane AE, Doan NL, Ru N, Acharya MM, Wood MA, Sinclair DA, Dickstein DL, Soltesz I, Limoli CL, and Baulch JE
- Subjects
- Female, Mice, Male, Animals, Synapses, Long-Term Potentiation, Neuronal Plasticity, Hippocampus, Radiation Exposure
- Abstract
Technological advancements have facilitated the implementation of realistic, terrestrial-based complex 33-beam galactic cosmic radiation simulations (GCR Sim) to now probe central nervous system functionality. This work expands considerably on prior, simplified GCR simulations, yielding new insights into responses of male and female mice exposed to 40-50 cGy acute or chronic radiations relevant to deep space travel. Results of the object in updated location task suggested that exposure to acute or chronic GCR Sim induced persistent impairments in hippocampus-dependent memory formation and reconsolidation in female mice that did not manifest robustly in irradiated male mice. Interestingly, irradiated male mice, but not females, were impaired in novel object recognition and chronically irradiated males exhibited increased aggressive behavior on the tube dominance test. Electrophysiology studies used to evaluate synaptic plasticity in the hippocampal CA1 region revealed significant reductions in long-term potentiation after each irradiation paradigm in both sexes. Interestingly, network-level disruptions did not translate to altered intrinsic electrophysiological properties of CA1 pyramidal cells, whereas acute exposures caused modest drops in excitatory synaptic signaling in males. Ultrastructural analyses of CA1 synapses found smaller postsynaptic densities in larger spines of chronically exposed mice compared to controls and acutely exposed mice. Myelination was also affected by GCR Sim with acutely exposed mice exhibiting an increase in the percent of myelinated axons; however, the myelin sheathes on small calibur (< 0.3 mm) and larger (> 0.5 mm) axons were thinner when compared to controls. Present findings might have been predicted based on previous studies using single and mixed beam exposures and provide further evidence that space-relevant radiation exposures disrupt critical cognitive processes and underlying neuronal network-level plasticity, albeit not to the extent that might have been previously predicted., (© 2023. The Author(s).)
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- 2023
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8. Acute, Low-Dose Neutron Exposures Adversely Impact Central Nervous System Function.
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Klein PM, Alaghband Y, Doan NL, Ru N, Drayson OGG, Baulch JE, Kramár EA, Wood MA, Soltesz I, and Limoli CL
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- Animals, Behavior, Animal radiation effects, Male, Memory radiation effects, Mice, Neuronal Plasticity radiation effects, Cosmic Radiation adverse effects, Hippocampus radiation effects, Neutrons adverse effects
- Abstract
A recognized risk of long-duration space travel arises from the elevated exposure astronauts face from galactic cosmic radiation (GCR), which is composed of a diverse array of energetic particles. There is now abundant evidence that exposures to many different charged particle GCR components within acute time frames are sufficient to induce central nervous system deficits that span from the molecular to the whole animal behavioral scale. Enhanced spacecraft shielding can lessen exposures to charged particle GCR components, but may conversely elevate neutron radiation levels. We previously observed that space-relevant neutron radiation doses, chronically delivered at dose-rates expected during planned human exploratory missions, can disrupt hippocampal neuronal excitability, perturb network long-term potentiation and negatively impact cognitive behavior. We have now determined that acute exposures to similar low doses (18 cGy) of neutron radiation can also lead to suppressed hippocampal synaptic signaling, as well as decreased learning and memory performance in male mice. Our results demonstrate that similar nervous system hazards arise from neutron irradiation regardless of the exposure time course. While not always in an identical manner, neutron irradiation disrupts many of the same central nervous system elements as acute charged particle GCR exposures. The risks arising from neutron irradiation are therefore important to consider when determining the overall hazards astronauts will face from the space radiation environment.
- Published
- 2021
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9. Neuroprotection of Radiosensitive Juvenile Mice by Ultra-High Dose Rate FLASH Irradiation.
- Author
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Alaghband Y, Cheeks SN, Allen BD, Montay-Gruel P, Doan NL, Petit B, Jorge PG, Giedzinski E, Acharya MM, Vozenin MC, and Limoli CL
- Abstract
Major advances in high precision treatment delivery and imaging have greatly improved the tolerance of radiotherapy (RT); however, the selective sparing of normal tissue and the reduction of neurocognitive side effects from radiation-induced toxicities remain significant problems for pediatric patients with brain tumors. While the overall survival of pediatric patients afflicted with medulloblastoma (MB), the most common type primary brain cancer in children, remains high (≥80%), lifelong neurotoxic side-effects are commonplace and adversely impact patients' quality of life. To circumvent these clinical complications, we have investigated the capability of ultra-high dose rate FLASH-radiotherapy (FLASH-RT) to protect the radiosensitive juvenile mouse brain from normal tissue toxicities. Compared to conventional dose rate (CONV) irradiation, FLASH-RT was found to ameliorate radiation-induced cognitive dysfunction in multiple independent behavioral paradigms, preserve developing and mature neurons, minimize microgliosis and limit the reduction of the plasmatic level of growth hormone. The protective "FLASH effect" was pronounced, especially since a similar whole brain dose of 8 Gy delivered with CONV-RT caused marked reductions in multiple indices of behavioral performance (objects in updated location, novel object recognition, fear extinction, light-dark box, social interaction), reductions in the number of immature (doublecortin
+ ) and mature (NeuN+ ) neurons and increased neuroinflammation, adverse effects that were not found with FLASH-RT. Our data point to a potentially innovative treatment modality that is able to spare, if not prevent, many of the side effects associated with long-term treatment that disrupt the long-term cognitive and emotional well-being of medulloblastoma survivors.- Published
- 2020
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10. Aging mice show impaired memory updating in the novel OUL updating paradigm.
- Author
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Kwapis JL, Alaghband Y, Keiser AA, Dong TN, Michael CM, Rhee D, Shu G, Dang RT, Matheos DP, and Wood MA
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- Animals, Male, Memory Disorders physiopathology, Mice, Mice, Inbred C57BL, Aging physiology, Aging psychology, Memory physiology, Memory Disorders psychology, Recognition, Psychology physiology
- Abstract
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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- 2020
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11. HDAC3-Mediated Repression of the Nr4a Family Contributes to Age-Related Impairments in Long-Term Memory.
- Author
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Kwapis JL, Alaghband Y, López AJ, Long JM, Li X, Shu G, Bodinayake KK, Matheos DP, Rapp PR, and Wood MA
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- Aging metabolism, Animals, Disease Models, Animal, Gene Expression Regulation, Histone Deacetylases metabolism, Memory Disorders metabolism, Nuclear Receptor Subfamily 4, Group A, Member 1 metabolism, Nuclear Receptor Subfamily 4, Group A, Member 2 metabolism, Rats, Aging genetics, Histone Deacetylases genetics, Memory Disorders genetics, Memory, Long-Term physiology, Nuclear Receptor Subfamily 4, Group A, Member 1 genetics, Nuclear Receptor Subfamily 4, Group A, Member 2 genetics
- Abstract
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 Nr4a 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 Nr4a1 and Nr4a2 in age-related memory impairments. Using a rat model designed to identify individual differences in age-related memory impairments, we first identified Nr4a2 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 Nr4a2 in the aged male and female hippocampus. Finally, we show that overexpression of Nr4a1 , Nr4a2 , or both transcripts in the male mouse dorsal hippocampus can ameliorate age-related impairments in object location memory. Together, our results suggest that Nr4a2 may be a key mechanism that promotes preserved cognitive function in old age, with HDAC3-mediated repression of Nr4a2 contributing to age-related cognitive decline. More broadly, these results indicate that therapeutic strategies to promote Nr4a gene expression or function may be an effective strategy to improve cognitive function in old age. SIGNIFICANCE STATEMENT 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 Nr4a2 is selectively impaired in aged rats with memory impairments. Further, we show that Nr4a2 is regulated by histone deacetylase HDAC3 in the aged mouse hippocampus. Finally, we demonstrate that hippocampal overexpression of either Nr4a2 or its family member, Nr4a1 , can ameliorate age-related memory impairments. This suggests that promoting Nr4a expression may be a novel strategy to improve memory in aging individuals., (Copyright © 2019 the authors.)
- Published
- 2019
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12. Medial habenula cholinergic signaling regulates cocaine-associated relapse-like behavior.
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López AJ, Jia Y, White AO, Kwapis JL, Espinoza M, Hwang P, Campbell R, Alaghband Y, Chitnis O, Matheos DP, Lynch G, and Wood MA
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- Analysis of Variance, Animals, Cholinergic Neurons physiology, Conditioning, Psychological drug effects, Female, Male, Mice, Inbred C57BL, Recurrence, Signal Transduction drug effects, Cocaine pharmacology, Dopamine Uptake Inhibitors pharmacology, Habenula physiology
- Abstract
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., (© 2018 The Authors.Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.)
- Published
- 2019
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13. CREST in the Nucleus Accumbens Core Regulates Cocaine Conditioned Place Preference, Cocaine-Seeking Behavior, and Synaptic Plasticity.
- Author
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Alaghband Y, Kramár E, Kwapis JL, Kim ES, Hemstedt TJ, López AJ, White AO, Al-Kachak A, Aimiuwu OV, Bodinayake KK, Oparaugo NC, Han J, Lattal KM, and Wood MA
- Subjects
- Animals, Conditioning, Operant drug effects, Male, Mice, Mice, Inbred C57BL, Neuronal Plasticity drug effects, Nucleus Accumbens drug effects, RNA, Messenger biosynthesis, RNA, Messenger genetics, Rats, Rats, Long-Evans, Trans-Activators deficiency, Trans-Activators genetics, Cocaine administration & dosage, Conditioning, Operant physiology, Drug-Seeking Behavior physiology, Neuronal Plasticity physiology, Nucleus Accumbens metabolism, Trans-Activators biosynthesis
- Abstract
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. SIGNIFICANCE STATEMENT 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., (Copyright © 2018 the authors 0270-6474/18/389515-13$15.00/0.)
- Published
- 2018
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14. Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory.
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Kwapis JL, Alaghband Y, Kramár EA, López AJ, Vogel Ciernia A, White AO, Shu G, Rhee D, Michael CM, Montellier E, Liu Y, Magnan CN, Chen S, Sassone-Corsi P, Baldi P, Matheos DP, and Wood MA
- Subjects
- Animals, Gene Deletion, Gene Knockdown Techniques, Histone Deacetylases metabolism, Long-Term Potentiation, Memory Disorders genetics, Memory Disorders physiopathology, Mice, Inbred C57BL, Neuronal Plasticity genetics, Period Circadian Proteins metabolism, Aging physiology, Circadian Rhythm genetics, Epigenesis, Genetic, Hippocampus physiology, Memory physiology, Period Circadian Proteins genetics
- Abstract
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.
- Published
- 2018
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15. Distinct roles for the deacetylase domain of HDAC3 in the hippocampus and medial prefrontal cortex in the formation and extinction of memory.
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Alaghband Y, Kwapis JL, López AJ, White AO, Aimiuwu OV, Al-Kachak A, Bodinayake KK, Oparaugo NC, Dang R, Astarabadi M, Matheos DP, and Wood MA
- Subjects
- Animals, Cocaine administration & dosage, Conditioning, Classical, Drug-Seeking Behavior, Male, Mice, Inbred C57BL, Recognition, Psychology physiology, Spatial Learning physiology, Extinction, Psychological physiology, Hippocampus physiology, Histone Deacetylases physiology, Memory physiology, Prefrontal Cortex physiology
- Abstract
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., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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16. Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala.
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Kwapis JL, Alaghband Y, López AJ, White AO, Campbell RR, Dang RT, Rhee D, Tran AV, Carl AE, Matheos DP, and Wood MA
- Subjects
- Animals, Auditory Perception drug effects, Auditory Perception physiology, Basolateral Nuclear Complex drug effects, Basolateral Nuclear Complex metabolism, Conditioning, Classical drug effects, Fear drug effects, Hippocampus drug effects, Hippocampus metabolism, Male, Memory drug effects, Mice, Mice, Inbred C57BL, Basolateral Nuclear Complex physiology, Conditioning, Classical physiology, Fear physiology, Hippocampus physiology, Histone Deacetylase Inhibitors pharmacology, Histone Deacetylases physiology, Memory physiology
- Abstract
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.
- Published
- 2017
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17. The role of active DNA demethylation and Tet enzyme function in memory formation and cocaine action.
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Alaghband Y, Bredy TW, and Wood MA
- Subjects
- Animals, Drug-Seeking Behavior physiology, Epigenesis, Genetic, Gene Expression Regulation, Humans, Cocaine genetics, DNA Methylation, DNA-Binding Proteins genetics, Dioxygenases genetics, Memory physiology, Mixed Function Oxygenases genetics, Proto-Oncogene Proteins genetics, Substance-Related Disorders genetics
- Abstract
Active DNA modification is a major epigenetic mechanism that regulates gene expression in an experience-dependent manner, which is thought to establish stable changes in neuronal function and behavior. Recent discoveries regarding the Ten eleven translocation (Tet1-3) family of DNA hydroxylases have provided a new avenue for the study of active DNA demethylation, and may thus help to advance our understanding of how dynamic DNA modifications lead to long-lasting changes in brain regions underlying learning and memory, as well as drug-seeking and propensity for relapse following abstinence. Drug addiction is a complex, relapsing disorder in which compulsive drug-seeking behavior can persist despite aversive consequences. Therefore, understanding the molecular mechanisms that underlie the onset and persistence of drug addiction, as well as the pronounced propensity for relapse observed in addicts, is necessary for the development of selective treatments and therapies. In this mini-review, we provide an overview of the involvement of active DNA demethylation with an emphasis on the Tet family of enzymes and 5-hydroxymethylcytosine (5-hmC) in learning and memory, as well as in drug-seeking behavior. Memory and addiction share overlapping molecular, cellular, and circuit functions allowing research in one area to inform the other. Current discrepancies and directions for future studies focusing on the dynamic interplay between DNA methylation and demethylation, and how they orchestrate gene expression required for neuronal plasticity underlying memory formation, are discussed., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)
- Published
- 2016
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18. BDNF rescues BAF53b-dependent synaptic plasticity and cocaine-associated memory in the nucleus accumbens.
- Author
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White AO, Kramár EA, López AJ, Kwapis JL, Doan J, Saldana D, Davatolhagh MF, Alaghband Y, Blurton-Jones M, Matheos DP, and Wood MA
- Subjects
- Animals, Cell Line, Chromosomal Proteins, Non-Histone genetics, Cocaine, Cocaine-Related Disorders physiopathology, Female, Long-Term Potentiation physiology, Male, Memory Disorders chemically induced, Memory Disorders physiopathology, Mice, Knockout, Mice, Transgenic, Nucleus Accumbens physiopathology, Receptor, trkB metabolism, Brain-Derived Neurotrophic Factor metabolism, Chromosomal Proteins, Non-Histone metabolism, Cocaine-Related Disorders metabolism, Memory Disorders metabolism, Nucleus Accumbens metabolism
- Abstract
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.
- Published
- 2016
- Full Text
- View/download PDF
19. Retrieval-induced NMDA receptor-dependent Arc expression in two models of cocaine-cue memory.
- Author
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Alaghband Y, O'Dell SJ, Azarnia S, Khalaj AJ, Guzowski JF, and Marshall JF
- Subjects
- Animals, Brain drug effects, Cues, Dizocilpine Maleate pharmacology, Excitatory Amino Acid Antagonists pharmacology, Male, Memantine pharmacology, Memory drug effects, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate antagonists & inhibitors, Signal Transduction drug effects, Brain metabolism, Cocaine pharmacology, Cytoskeletal Proteins metabolism, Dopamine Uptake Inhibitors pharmacology, Memory physiology, Nerve Tissue Proteins metabolism, Receptors, N-Methyl-D-Aspartate metabolism
- Abstract
The association of environmental cues with drugs of abuse results in persistent drug-cue memories. These memories contribute significantly to relapse among addicts. While conditioned place preference (CPP) is a well-established paradigm frequently used to examine the modulation of drug-cue memories, very few studies have used the non-preference-based model conditioned activity (CA) for this purpose. Here, we used both experimental approaches to investigate the neural substrates of cocaine-cue memories. First, we directly compared, in a consistent setting, the involvement of cortical and subcortical brain regions in cocaine-cue memory retrieval by quantifying activity-regulated cytoskeletal-associated (Arc) protein expression in both the CPP and CA models. Second, because NMDA receptor activation is required for Arc expression, we investigated the NMDA receptor dependency of memory persistence using the CA model. In both the CPP and CA models, drug-paired animals showed significant increases in Arc immunoreactivity in regions of the frontal cortex and amygdala compared to unpaired controls. Additionally, administration of a NMDA receptor antagonist (MK-801 or memantine) immediately after cocaine-CA memory reactivation impaired the subsequent conditioned locomotion associated with the cocaine-paired environment. The enhanced Arc expression evident in a subset of corticolimbic regions after retrieval of a cocaine-context memory, observed in both the CPP and CA paradigms, likely signifies that these regions: (i) are activated during retrieval of these memories irrespective of preference-based decisions, and (ii) undergo neuroplasticity in order to update information about cues previously associated with cocaine. This study also establishes the involvement of NMDA receptors in maintaining memories established using the CA model, a characteristic previously demonstrated using CPP. Overall, these results demonstrate the utility of the CA model for studies of cocaine-context memory and suggest the involvement of an NMDA receptor-dependent Arc induction pathway in drug-cue memory interference., (Copyright © 2014 Elsevier Inc. All rights reserved.)
- Published
- 2014
- Full Text
- View/download PDF
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