Biology subjects

Wood, M. A.

Publications and source records attributed to Wood, M. A..

18 recordsLinked to original sources

bioRxiv2026

Neuroprotection following FLASH-RT may be mediated by sustained glutamate receptor AMPAR activation in CA3 neurons

To elucidate the early mechanisms underlying the long-term neuroprotective effect of FLASH-RT in the normal brain, spatial transcriptomics (Nanostring) were performed after whole-brain irradiation of C57BL/6J mice with either 1 or 3 fractions of 10 Gy at 5.6x106 Gy/s (1 pulse-FLASH) or at conventional dose-rate 0.1 Gy/s. FLASH -RT induced a distinct transcriptomic signature in the CA3 and DG neurons, with upregulation of genes encoding glutamate receptors, involved in calcium signaling, long-term potentiation and mitochondrial OXPHOS. Early transcriptional upregulation of Gria gene translated into increased AMPAR protein levels at 48h in the DG and CA3 region and sustained higher AMPAR expression at 2 and 4 weeks post-FLASH. These findings support a durable activation of AMPAR. We propose a mechanism to explain FLASH-induced neuroprotection initiated by early calcium influx and subsequent sustained expression of glutamate receptor AMPAR in neurons and/or neural progenitors of the CA3, potentially contributing to long-term cognitive sparing. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/725423v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@1ae125forg.highwire.dtl.DTLVardef@138357aorg.highwire.dtl.DTLVardef@13f128dorg.highwire.dtl.DTLVardef@1db1cf6_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIFLASH-RT induces a stronger transcriptional response in the hippocampus than the cortex. C_LIO_LIFLASH-RT induces calcium signaling, LTP and mitochondrial OXPHOS genes. C_LIO_LIEarly AMPAR upregulation leads to sustained protein expression. C_LIO_LIFLASH-RT induces a AMPAR-dependent signaling program in CA3 neurons. C_LI

cancer biology↗

bioRxiv2025

In-vivo dendrite injury drives local mitochondrial contraction and dendrite branching

Mitochondria regulate cellular homeostasis in development and disease, and mitochondrial morphology plays a role in local injury signaling and wound repair. How mitochondria respond during dendrite injury remains an open fundamental question. Here we show that mitochondria contract rapidly and locally after laser dendrotomy. In the proximal intact dendrite, the extent of mitochondrial contraction diminishes with increasing distance from the injury site. We report that mitochondrial contraction is dependent on injury severity and that immediate contraction after injury results in a spatiotemporal increase in dendrite branching. Additionally, we find that mitochondrial contraction is inhibited by KCNJ2 (potassium inwardly rectifying channel subfamily J member 2), providing evidence that mitochondrial contraction is regulated by electrical activity. Mechanistically, we find that injury-induced mitochondrial contraction requires Drp1 (Dynamin related protein 1). In conclusion, these in-vivo findings characterize a dendrite response for mitochondria in neurons and provide insight into the regenerative outcomes of dendrites after injury. Graphical abstractIn-vivo dendrite injury drives local mitochondrial contraction and dendrite branching O_FIG O_LINKSMALLFIG WIDTH=175 HEIGHT=200 SRC="FIGDIR/small/658131v1_ufig1.gif" ALT="Figure 1"> View larger version (17K): org.highwire.dtl.DTLVardef@e4c767org.highwire.dtl.DTLVardef@1df4f23org.highwire.dtl.DTLVardef@1c4bf4aorg.highwire.dtl.DTLVardef@1ea9f76_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2025

Cocaine Blocks Cholinergic Activity in the Medial Habenula Prior to But Not After Induced Preference for the Drug

Descending projections from the medial habenula potently influence brainstem systems associated with reward and mood. Relatedly, the ventral, cholinergic segment of the nucleus has been linked to nicotine and cocaine addiction. Here we report that cocaine has no effect on baseline firing in the ventral medial habenula but entirely blocks the self-sustained activity initiated by endogenous acetylcholine. This effect was not altered by antagonists to dopamine receptors and thus presumably reflects a direct action on cholinergic receptors. Remarkably, cocaine had no effect on endogenous cholinergic activity in mice that had been extinguished from an induced cocaine preference. In all, the drug has potent effects, albeit through an exotic mode of action, on the medial habenula and these are eliminated by prior experience with the drug. These results describe a novel target for cocaine that is plausibly related to the psychological effects of the drug, and an unexpected consequence of earlier use.

neuroscience↗

bioRxiv2024

The GluA1 cytoplasmic tail regulates intracellular AMPA receptor trafficking and synaptic transmission onto dentate gyrus GABAergic interneurons, gating response to novelty

The GluA1 subunit, encoded by the putative schizophrenia-associated gene GRIA1, is required for activity-regulated AMPA receptor (AMPAR) trafficking, and plays a key role in cognitive and affective function. The cytoplasmic, carboxy-terminal domain (CTD) is the most divergent region across AMPAR subunits. The GluA1 CTD has received considerable attention for its role during long-term potentiation (LTP) at CA1 pyramidal neuron synapses. However, its function at other synapses and, more broadly, its contribution to different GluA1-dependent processes, is poorly understood. Here, we used mice with a constitutive truncation of the GluA1 CTD to dissect its role regulating AMPAR localization and function as well as its contribution to cognitive and affective processes. We found that GluA1 CTD truncation affected AMPAR subunit levels and intracellular trafficking. {Delta}CTD GluA1 mice exhibited no memory deficits, but presented exacerbated novelty-induced hyperlocomotion and dentate gyrus granule cell (DG GC) hyperactivity, among other behavioral alterations. Mechanistically, we found that AMPAR EPSCs onto DG GABAergic interneurons were significantly reduced, presumably underlying, at least in part, the observed changes in neuronal activity and behavior. In summary, this study dissociates CTD-dependent from CTD-independent GluA1 functions, unveiling the GluA1 CTD as a crucial hub regulating AMPAR function in a cell type-specific manner.

neuroscience↗

bioRxiv2024

Long term rescue of Alzheimer deficits in vivo by one-time gene-editing of App C-terminus.

Gene-editing technologies promise to create a new class of therapeutics that can achieve permanent correction with a single intervention. Besides eliminating mutant alleles in familial disease, gene-editing can manipulate upstream pathophysiologic events and alter disease-course in wider patient populations. Here we use CRISPR-Cas9 to edit the last exon of amyloid precursor protein (App), relevant for Alzheimers disease (AD). Our strategy effectively eliminates an endocytic (YENPTY) motif at APP C-terminus in mouse and human neurons, while preserving N-terminus and compensatory APP-homologues. This manipulation favorably alters events along the amyloid-pathway; inhibiting toxic APP-beta-cleavage fragments (including Abeta) and upregulating neuroprotective APP-alpha-cleavage. AAV-editing ameliorates neuropathologic, electrophysiologic, and behavioral deficits in an AD knockin mouse model. Effects persist for many months with no detectable abnormalities in germline-edited WT mice, and pathologic alterations in glial-transcriptomes are also normalized. Our strategy takes advantage of innate transcriptional rules that render terminal exons insensitive to nonsense-decay, and this upstream manipulation is expected to be effective for all forms of AD.

neuroscience↗

bioRxiv2023

C5aR1 signaling promotes region and age dependent synaptic pruning in models of Alzheimers Disease

INTRODUCTIONSynaptic loss is a hallmark of Alzheimers disease (AD) that correlates with cognitive decline in AD patients. Complement-mediated synaptic pruning has been associated with this excessive loss of synapses in AD. Here, we investigated the effect of C5aR1 inhibition on microglial and astroglial synaptic pruning in two mouse models of AD. METHODSA combination of super-resolution and confocal and tridimensional image reconstruction was used to assess the effect of genetic ablation or pharmacological inhibition of C5aR1 on the Arctic48 and Tg2576 models of AD. RESULTSGenetic ablation or pharmacological inhibition of C5aR1 rescues the excessive pre-synaptic pruning and synaptic loss in an age and region dependent fashion in two mouse models of AD, which correlates with improved long-term potentiation (LTP). DISCUSSIONReduction of excessive synaptic pruning is an additional beneficial outcome of the suppression of C5a-C5aR1 signaling, further supporting its potential as an effective targeted therapy to treat AD.

neuroscience↗

bioRxiv2023

Inhibition of CPEB3 ribozyme elevates CPEB3 protein expression and polyadenylation of its target mRNAs, and enhances object location memory

A self-cleaving ribozyme that maps to an intron of the cytoplasmic polyadenylation element binding protein 3 (CPEB3) gene is thought to play a role in human episodic memory, but the underlying mechanisms mediating this effect are not known. We tested the activity of the murine sequence and found that the ribozymes self-scission half-life matches the time it takes an RNA polymerase to reach the immediate downstream exon, suggesting that the ribozyme-dependent intron cleavage is tuned to co-transcriptional splicing of the CPEB3 mRNA. Our studies also reveal that the murine ribozyme modulates maturation of its harboring mRNA in both cultured cortical neurons and the hippocampus: inhibition of the ribozyme using an antisense oligonucleotide leads to increased CPEB3 protein expression, which enhances polyadenylation and translation of localized plasticity-related target mRNAs, and subsequently strengthens hippocampal-dependent long-term memory. These findings reveal a previously unknown role for self-cleaving ribozyme activity in regulating experience-induced co-transcriptional and local translational processes required for learning and memory. Significance StatementCytoplasmic polyadenylation-induced translation is one of the key steps for regulating protein synthesis and neuroplasticity in the hippocampus. The CPEB3 ribozyme is a highly conserved mammalian self-cleaving catalytic RNA with unknown biological roles. In this study, we investigated how the intronic ribozyme affects the CPEB3 mRNA maturation and translation, and its subsequent effect on memory formation. Our findings show that the ribozyme activity is anti-correlated with CPEB3 mRNA splicing: inhibition of the ribozyme results in higher mRNA and protein levels, which contribute to long-term memory. Our studies offer new insights into the role of the CPEB3 ribozyme in neuronal translational control for the activity-dependent synaptic functions that underlie long-term memory and demonstrate a novel biological role for self-cleaving ribozymes.

neuroscience↗

bioRxiv2022

Targeting acetyl-CoA metabolism attenuates the formation of fear memories through reduced activity-dependent histone acetylation

Histone acetylation is a key component in the consolidation of long-term fear memories. Epigenetic enzymes involved in histone acetylation, including histone acetyltransferases and deacetylases, have been put forward as potential pharmacological targets in the treatment of pathological fear memories, such as those that underlie post-traumatic stress disorder (PTSD). However, these enzymes typically play a ubiquitous role in gene regulation, which precludes the clinical use of systemic manipulations. Recently, we have found that a nuclear-localized metabolic enzyme, Acetyl-coA synthetase 2 (Acss2), modulates histone acetylation during learning and memory. Loss of Acss2 is well-tolerated in mice, with no impact on general health or baseline behavior. Here, we show that an Acss2 null mouse model shows reduced acquisition of long-term fear memories in assays of contextual and cued fear conditioning. We find that loss of Acss2 leads to consolidation-specific reductions in both histone acetylation and the expression of critical learning and memory-related genes in the dorsal hippocampus. Further, we show that systemic administration of blood-brain-barrier (BBB)-permeable Acss2 inhibitors during the consolidation window reduces fear memory formation in mice and rats, and also reduces anxiety in a predator-scent-stress (PSS) paradigm. Our findings suggest that Acss2 plays a critical role in the formation of fear memories, and represents a potential pharmacological target in the treatment of PTSD.

neuroscience↗

bioRxiv2022

A Trem2*R47H mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques

Genome-Wide Association Studies revealed the TREM2 R47H variant as one of the strongest genetic risk factors for late-onset Alzheimers Disease (AD). Unfortunately, many current TREM2*R47H mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. We have developed the Trem2R47H NSS (Normal Splice Site) mouse model where the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele, without evidence of cryptic splicing products, and appropriate inflammatory responses to cuprizone challenge. Utilizing the 5xFAD mouse model, we report age- and disease-dependent changes in response to pathology. At an early disease stage (4 mo), homozygous Trem2R47H NSS; hemizygous 5xFAD (Trem2R47H NSS ; 5xFAD) mice have reduced size and number of microglia plus impaired interaction with plaques, that is associated with increased dystrophic neurites and axonal damage detected through plasma neurofilament light chain (NfL) level and suppressed inflammation. However, homozygosity for Trem2R47H NSS suppressed LTP deficits and presynaptic puncta loss caused by the 5xFAD transgene array. At a more advanced disease stage (12 mo,) Trem2R47H NSS ; 5xFAD mice no longer display impaired plaque-microglia interaction or suppressed inflammatory gene expression, although NfL levels remain elevated, and a unique interferon-related gene expression signature is seen. Furthermore, Trem2R47H NSS ; 5xFAD mice also display robust LTP deficits and exacerbated presynaptic loss. Collectively, we provide a Trem2R47H variant mouse without cryptic splicing, and demonstrate it has disease stage dependent effects when combined with a plaque bearing model, with an initial loss of function that ultimately resolves, giving rise to a unique interferon signature and associated tissue damage.

neuroscience↗

bioRxiv2022

Retained introns in long RNA-seq reads are not reliably detected in sample-matched short reads

There is growing interest in retained introns in a variety of disease contexts including cancer and aging. Many software tools have been developed to detect retained introns from short RNA-seq reads, but reliable detection is complicated by overlapping genes and transcripts as well as the presence of unprocessed or partially processed RNAs. We compared introns detected by 5 tools using short RNA-seq reads with introns observed in long RNA-seq reads from the same biological specimens and found: (1) significant disagreement among tools (Fleiss{kappa} = 0.231) such that 52.4% of all detected intron retentions were not called by more than one tool; (2) that no tool achieved greater than 20% precision or 35% recall under generous conditions; and (3) that retained intron detectability was adversely affected by greater intron length and overlap with annotated exons.

genomics↗

bioRxiv2021

Systematic Phenotyping and Characterization of the 5xFAD mouse model of Alzheimer's Disease

Mouse models of human diseases are invaluable tools for studying pathogenic mechanisms and testing interventions and therapeutics. For disorders such as Alzheimers disease in which numerous models are being generated, a challenging first step is to identify the most appropriate model and age to effectively evaluate new therapeutic approaches. Here we conducted a detailed phenotypic characterization of the 5xFAD model on a congenic C57BL/6J strain background, across its lifespan - including a seldomly analyzed 18-month old time point to provide temporally correlated phenotyping of this model and a template for characterization of new models of LOAD as they are generated. This comprehensive analysis included quantification of plaque burden, A{beta} biochemical levels, and neuropathology, neurophysiological measurements and behavioral and cognitive assessments, and evaluation of microglia, astrocytes, and neurons. Analysis of transcriptional changes was conducted using bulk-tissue generated RNA-seq data from microdissected cortices and hippocampi as a function of aging, which can be explored at the UCI Mouse Explorer and AD Knowledge Portal. This deep-phenotyping pipeline identified novel aspects of age-related pathology in the 5xFAD model.

neuroscience↗

bioRxiv2021

The CPEB3 ribozyme modulates hippocampal-dependent memory

A self-cleaving ribozyme mapping to an intron of the cytoplasmic polyadenylation element binding protein 3 (CPEB3) gene has been suggested to play a role in human episodic memory, but the underlying mechanisms mediating this effect are not known. The ribozymes self-scission half-life matches the time it takes an RNA polymerase to reach the immediate downstream exon, suggesting that the ribozyme-dependent intron cleavage is tuned to co-transcriptional splicing of the CPEB3 mRNA. Here we report that the murine ribozyme modulates its own host mRNA maturation in both cultured cortical neurons and the hippocampus. Inhibition of the ribozyme using an antisense oligonucleotide leads to increased CPEB3 protein expression, which enhances polyadenylation and translation of localized plasticity-related target mRNAs, and subsequently strengthens hippocampal-dependent long-term memory. These findings reveal a previously unknown role for self-cleaving ribozyme activity in regulating experience-induced co-transcriptional and local translational processes required for learning and memory.

molecular biology↗

bioRxiv2019

Burden of tumor mutations, neoepitopes, and other variants are cautionary predictors of cancer immunotherapy response and overall survival

BackgroundTumor mutational burden (TMB, the quantity of aberrant nucleotide sequences a given tumor may harbor) has been associated with response to immune checkpoint inhibitor therapy and is gaining broad acceptance as a result. However, TMB harbors intrinsic variability across cancer types, and its assessment and interpretation are poorly standardized. MethodsUsing a standardized approach, we quantify the robustness of TMB as a metric and its potential as a predictor of immunotherapy response and survival among a diverse cohort of cancer patients. We also explore the additive predictive potential of RNA-derived variants and neoepitope burden, incorporating several novel metrics of immunogenic potential. ResultsWe find that TMB is a partial predictor of immunotherapy response in melanoma and non-small cell lung cancer, but not renal cell carcinoma. We find that TMB is predictive of overall survival in melanoma patients receiving immunotherapy, but not in an immunotherapy-naive population. We also find that it is an unstable metric with potentially problematic repercussions for clinical cohort classification. We finally note minimal additional predictive benefit to assessing neoepitope burden or its bulk derivatives, including RNA-derived sources of neoepitopes. ConclusionsWe find sufficient cause to suggest that the predictive clinical value of TMB should not be overstated or oversimplified. While it is readily quantified, TMB is at best a limited surrogate biomarker of immunotherapy response. The data do not support isolated use of TMB in renal cell carcinoma.

cancer biology↗

bioRxiv2018

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

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.\n\n\n\nO_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC=\"FIGDIR/small/446963_ufig1.gif\" ALT=\"Figure 1\">\nView larger version (40K):\norg.highwire.dtl.DTLVardef@1bd577corg.highwire.dtl.DTLVardef@1ba990aorg.highwire.dtl.DTLVardef@195813corg.highwire.dtl.DTLVardef@57abc7_HPS_FORMAT_FIGEXP M_FIG Graphical AbstractFollowing central nervous system (CNS) spinal injury, protein phosphatase 4/2 activity is not induced since calcium levels remain unchanged compared to uninjured conditions. HDAC3 remains phosphorylated and occupies deacetylated chromatin contributing to its compaction inhibiting gene expression. Following peripheral nervous system (PNS) sciatic injury, protein phosphatase 4/2 activity is induced by calcium. HDAC3 is dephosphorylated leading to its inhibition and release from chromatin sites contributing to increase in histone acetylation and in the expression of regeneration associated genes (RAGs).\n\nC_FIG

neuroscience↗

bioRxiv2018

neoepiscope Improves Neoepitope Prediction with Multi-variant Phasing

The vast majority of tools for neoepitope prediction from DNA sequencing of complementary tumor and normal patient samples do not consider germline context or the potential for co-occurrence of two or more somatic variants on the same mRNA transcript. Without consideration of these phenomena, existing approaches are likely to produce both false positive and false negative results, resulting in an inaccurate and incomplete picture of the cancer neoepitope landscape. We developed neoepiscope chiefly to address this issue for single nucleotide variants (SNVs) and insertions/deletions (indels), and herein illustrate how germline and somatic variant phasing affects neoepitope prediction across multiple datasets. We estimate that up to [~]5% of neoepitopes arising from SNVs and indels may require variant phasing for their accurate assessment. neoepiscope is performant, flexible, and supports several major histocompatibility complex binding affinity prediction tools. We have released neoepiscope as open-source software (MIT license, https://github.com/pdxgx/neoepiscope) for broad use.\n\nKEY POINTSO_LIGermline context and somatic variant phasing are important for neoepitope prediction\nC_LIO_LIMany popular neoepitope prediction tools have issues of performance and reproducibility\nC_LIO_LIWe describe and provide performant software for accurate neoepitope prediction from DNA-seq data\nC_LI

bioinformatics↗

bioRxiv2018

Epigenetic regulation of the circadian gene Per1 in the hippocampus mediates age-related changes in memory and synaptic plasticity

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 learning-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.

neuroscience↗

bioRxiv2017

Population-level distribution and putative immunogenicity of cancer neoepitopes

BackgroundTumor neoantigens are a driver of cancer immunotherapy response; however, current neoantigen prediction tools produce many candidates that require further prioritization for research/clinical applications. Additional filtration criteria and population-level understanding may help to produce refined lists of putative neoantigens. Herein, we show neoepitope immunogenicity is likely related to measures of peptide novelty and report population-level behavior of these and other metrics.\n\nMethodsWe propose four peptide novelty metrics to refine predicted neoantigenicity: tumor vs. paired normal peptide binding affinity difference, tumor vs. paired normal peptide sequence similarity, tumor vs. closest human peptide sequence similarity, and tumor vs. closest microbial peptide sequence similarity. We apply these metrics to tumor neoepitopes predicted from somatic missense mutations in The Cancer Genome Atlas (TCGA) and a cohort of melanoma patients, as well as to a group of peptides with neoepitope-specific immune response data using an extension of pVAC-Seq [1].\n\nResultsWe show neoepitope burden varies across TCGA disease sites and HLA alleles, with surprisingly low repetition of neoepitope sequences across patients or neoepitope preferences among sets of HLA alleles. Only 20.3% of predicted neoepitopes across TCGA patients displayed novel binding change based on our binding affinity difference criteria. Similarity of amino acid sequence was typically high between paired tumor-normal epitopes, but in 24.6% of cases, neoepitopes were more similar to other human peptides, or even to bacterial (56.8% of cases) or viral peptides (15.5% of cases), than their paired normal counterparts. Applied to peptides with neoepitope-specific immune response, a linear model incorporating neoepitope binding affinity, protein sequence similarity between neoepitopes and their closest viral peptides, and paired binding affinity difference was able to predict immunogenicity with an AUROC of 0.66.\n\nConclusionsOur proposed neoepitope prioritization criteria emphasize neoepitope novelty and refine patient neoepitope predictions for focus on biologically meaningful candidate neoantigens. We have demonstrated that neoepitopes should be considered not only with respect to their paired normal epitope, but with respect to the entire human proteome, as well as bacterial and viral peptides, with potential implications for neoepitope immunogenicity and personalized vaccines for cancer treatment. We conclude that putative neoantigens are highly variable across individuals as a function of both cancer genetics and personalized HLA repertoire, while the overall behavior of filtration criteria reflects predictable patterns.

cancer biology↗

bioRxiv2017

Habits are negatively regulated by HDAC3 in the dorsal striatum

Optimal behavior results from a balance of control between two strategies, one cognitive/goal-directed and one habitual, which rely on the anatomically distinct dorsomedial (DMS) and dorsolateral (DLS) striatum, respectively. The transcriptional regulatory mechanisms required to learn and transition between these strategies are unknown. Here we identified a critical negative regulator of habit learning. Histone deacetylase (HDAC) inhibition following instrumental conditioning accelerated habitual control of behavior. HDAC3, a transcriptional repressor, was removed from the promoters of learning-related genes in the dorsal striatum as habits formed with overtraining and with post-training HDAC inhibition. Decreasing HDAC3 function in the DLS accelerated habit formation, while DLS HDAC3 overexpression prevented habit. HDAC3 activity in the DMS was also found to constrain habit formation. These results challenge the strict dissociation between DMS and DLS function in goal-directed v. habitual behavioral control and identify dorsal striatal HDAC3 as a critical molecular substrate of the transition to habit.

neuroscience↗