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1.
Nat Rev Mol Cell Biol ; 19(9): 563-578, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29930302

RESUMEN

Metabolism and gene expression, which are two fundamental biological processes that are essential to all living organisms, reciprocally regulate each other to maintain homeostasis and regulate cell growth, survival and differentiation. Metabolism feeds into the regulation of gene expression via metabolic enzymes and metabolites, which can modulate chromatin directly or indirectly - through regulation of the activity of chromatin trans-acting proteins, including histone-modifying enzymes, chromatin-remodelling complexes and transcription regulators. Deregulation of these metabolic activities has been implicated in human diseases, prominently including cancer.


Asunto(s)
Cromatina/fisiología , Regulación de la Expresión Génica/fisiología , Factores de Transcripción/metabolismo , Animales , Código de Histonas/fisiología , Histonas/metabolismo , Humanos
2.
Nature ; 605(7908): 160-165, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35477756

RESUMEN

Colorectal cancer (CRC) is among the most frequent forms of cancer, and new strategies for its prevention and therapy are urgently needed1. Here we identify a metabolite signalling pathway that provides actionable insights towards this goal. We perform a dietary screen in autochthonous animal models of CRC and find that ketogenic diets exhibit a strong tumour-inhibitory effect. These properties of ketogenic diets are recapitulated by the ketone body ß-hydroxybutyrate (BHB), which reduces the proliferation of colonic crypt cells and potently suppresses intestinal tumour growth. We find that BHB acts through the surface receptor Hcar2 and induces the transcriptional regulator Hopx, thereby altering gene expression and inhibiting cell proliferation. Cancer organoid assays and single-cell RNA sequencing of biopsies from patients with CRC provide evidence that elevated BHB levels and active HOPX are associated with reduced intestinal epithelial proliferation in humans. This study thus identifies a BHB-triggered pathway regulating intestinal tumorigenesis and indicates that oral or systemic interventions with a single metabolite may complement current prevention and treatment strategies for CRC.


Asunto(s)
Neoplasias Colorrectales , Transducción de Señal , Ácido 3-Hidroxibutírico/metabolismo , Ácido 3-Hidroxibutírico/farmacología , Animales , Proliferación Celular , Transformación Celular Neoplásica , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/prevención & control , Humanos
3.
Proc Natl Acad Sci U S A ; 119(32): e2114758119, 2022 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-35921439

RESUMEN

Histone acetylation is a key component in the consolidation of long-term fear memories. Histone acetylation is fueled by acetyl-coenzyme A (acetyl-CoA), and recently, nuclear-localized metabolic enzymes that produce this metabolite have emerged as direct and local regulators of chromatin. In particular, acetyl-CoA synthetase 2 (ACSS2) mediates histone acetylation in the mouse hippocampus. However, whether ACSS2 regulates long-term fear memory remains to be determined. Here, we show that Acss2 knockout is well tolerated in mice, yet the Acss2-null mouse exhibits reduced acquisition of long-term fear memory. Loss of Acss2 leads to reductions in both histone acetylation and expression of critical learning and memory-related genes in the dorsal hippocampus, specifically following fear conditioning. Furthermore, systemic administration of blood-brain barrier-permeable Acss2 inhibitors during the consolidation window reduces fear-memory formation in mice and rats and reduces anxiety in a predator-scent stress paradigm. Our findings suggest that nuclear acetyl-CoA metabolism via ACSS2 plays a critical, previously unappreciated, role in the formation of fear memories.


Asunto(s)
Acetato CoA Ligasa , Acetilcoenzima A , Condicionamiento Clásico , Miedo , Histonas , Consolidación de la Memoria , Acetato CoA Ligasa/genética , Acetato CoA Ligasa/metabolismo , Acetilcoenzima A/metabolismo , Acetilación , Animales , Condicionamiento Clásico/fisiología , Miedo/fisiología , Hipocampo/enzimología , Histonas/metabolismo , Ratones , Ratones Noqueados , Ratas
4.
Genome Res ; 28(8): 1243-1252, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29945882

RESUMEN

Most common genetic risk variants associated with neuropsychiatric disease are noncoding and are thought to exert their effects by disrupting the function of cis regulatory elements (CREs), including promoters and enhancers. Within each cell, chromatin is arranged in specific patterns to expose the repertoire of CREs required for optimal spatiotemporal regulation of gene expression. To further understand the complex mechanisms that modulate transcription in the brain, we used frozen postmortem samples to generate the largest human brain and cell-type-specific open chromatin data set to date. Using the Assay for Transposase Accessible Chromatin followed by sequencing (ATAC-seq), we created maps of chromatin accessibility in two cell types (neurons and non-neurons) across 14 distinct brain regions of five individuals. Chromatin structure varies markedly by cell type, with neuronal chromatin displaying higher regional variability than that of non-neurons. Among our findings is an open chromatin region (OCR) specific to neurons of the striatum. When placed in the mouse, a human sequence derived from this OCR recapitulates the cell type and regional expression pattern predicted by our ATAC-seq experiments. Furthermore, differentially accessible chromatin overlaps with the genetic architecture of neuropsychiatric traits and identifies differences in molecular pathways and biological functions. By leveraging transcription factor binding analysis, we identify protein-coding and long noncoding RNAs (lncRNAs) with cell-type and brain region specificity. Our data provide a valuable resource to the research community and we provide this human brain chromatin accessibility atlas as an online database "Brain Open Chromatin Atlas (BOCA)" to facilitate interpretation.


Asunto(s)
Encéfalo/metabolismo , Cromatina/genética , Elementos Reguladores de la Transcripción/genética , Animales , Regulación de la Expresión Génica/genética , Humanos , Ratones , Regiones Promotoras Genéticas , Unión Proteica , Análisis de Secuencia de ADN , Transposasas
5.
Neurobiol Learn Mem ; 181: 107438, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33845131

RESUMEN

Epigenetic mechanisms have recently emerged as critical regulators of brain function in health and disease. By controlling the accessibility and the expression of specific genes, these pathways can mediate transient and long-lasting changes in neuronal function in both physiological and pathological contexts. Due to the extreme complexity of the epigenetic regulatory landscape, emerging methods that directly assay chromatin accessibility are of particular interest. Here, I review recent insights gained on open and closed chromatin states in the brain, with emphasis on neuropsychiatric disorders. These advances generated an invaluable wealth of information that can help us better understand gene regulation in the brain and its impairments that contribute to the development of disease.


Asunto(s)
Encéfalo/metabolismo , Cromatina/metabolismo , Epigénesis Genética , Regulación de la Expresión Génica , Trastornos Mentales/genética , Ensamble y Desensamble de Cromatina , Humanos
6.
Mol Psychiatry ; 25(9): 2058-2069, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-29955167

RESUMEN

Consumption of high fat, high sugar (western) diets is a major contributor to the current high levels of obesity. Here, we used a multidisciplinary approach to gain insight into the molecular mechanisms underlying susceptibility to diet-induced obesity (DIO). Using positron emission tomography (PET), we identified the dorsal striatum as the brain area most altered in DIO-susceptible rats and molecular studies within this region highlighted regulator of G-protein signaling 4 (Rgs4) within laser-capture micro-dissected striatonigral (SN) and striatopallidal (SP) medium spiny neurons (MSNs) as playing a key role. Rgs4 is a GTPase accelerating enzyme implicated in plasticity mechanisms of SP MSNs, which are known to regulate feeding and disturbances of which are associated with obesity. Compared to DIO-resistant rats, DIO-susceptible rats exhibited increased striatal Rgs4 with mRNA expression levels enriched in SP MSNs. siRNA-mediated knockdown of striatal Rgs4 in DIO-susceptible rats decreased food intake to levels comparable to DIO-resistant animals. Finally, we demonstrated that the human Rgs4 gene locus is associated with increased body weight and obesity susceptibility phenotypes, and that overweight humans exhibit increased striatal Rgs4 protein. Our findings highlight a novel role for involvement of Rgs4 in SP MSNs in feeding and DIO-susceptibility.


Asunto(s)
Obesidad , Aumento de Peso , Animales , Cuerpo Estriado , Dieta Occidental , Susceptibilidad a Enfermedades , Obesidad/genética , Ratas
7.
Mol Psychiatry ; 24(5): 653-673, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-29955163

RESUMEN

Delineating the pathophysiology of psychiatric disorders has been extremely challenging but technological advances in recent decades have facilitated a deeper interrogation of molecular processes in the human brain. Initial candidate gene expression studies of the postmortem brain have evolved into genome wide profiling of the transcriptome and the epigenome, a critical regulator of gene expression. Here, we review the potential and challenges of direct molecular characterization of the postmortem human brain, and provide a brief overview of recent transcriptional and epigenetic studies with respect to neuropsychiatric disorders. Such information can now be leveraged and integrated with the growing number of genome-wide association databases to provide a functional context of trait-associated genetic variants linked to psychiatric illnesses and related phenotypes. While it is clear that the field is still developing and challenges remain to be surmounted, these recent advances nevertheless hold tremendous promise for delineating the neurobiological underpinnings of mental diseases and accelerating the development of novel medication strategies.


Asunto(s)
Encéfalo/fisiopatología , Trastornos Mentales/genética , Trastornos Mentales/fisiopatología , Autopsia/métodos , Epigénesis Genética/genética , Regulación de la Expresión Génica/genética , Predisposición Genética a la Enfermedad/genética , Genoma/genética , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Fenotipo , Transcriptoma/genética
8.
Mol Psychiatry ; 24(4): 588-600, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30283037

RESUMEN

Neuronal circuits within the prefrontal cortex (PFC) mediate higher cognitive functions and emotional regulation that are disrupted in psychiatric disorders. The PFC undergoes significant maturation during adolescence, a period when cannabis use in humans has been linked to subsequent vulnerability to psychiatric disorders such as addiction and schizophrenia. Here, we investigated in a rat model the effects of adolescent exposure to Δ9-tetrahydrocannabinol (THC), a psychoactive component of cannabis, on the morphological architecture and transcriptional profile of layer III pyramidal neurons-using cell type- and layer-specific high-resolution microscopy, laser capture microdissection and next-generation RNA-sequencing. The results confirmed known normal expansions in basal dendritic arborization and dendritic spine pruning during the transition from late adolescence to early adulthood that were accompanied by differential expression of gene networks associated with neurodevelopment in control animals. In contrast, THC exposure disrupted the normal developmental process by inducing premature pruning of dendritic spines and allostatic atrophy of dendritic arborization in early adulthood. Surprisingly, there was minimal overlap of the developmental transcriptomes between THC- and vehicle-exposed rats. THC altered functional gene networks related to cell morphogenesis, dendritic development, and cytoskeleton organization. Marked developmental network disturbances were evident for epigenetic regulators with enhanced co-expression of chromatin- and dendrite-related genes in THC-treated animals. Dysregulated PFC co-expression networks common to both the THC-treated animals and patients with schizophrenia were enriched for cytoskeletal and neurite development. Overall, adolescent THC exposure altered the morphological and transcriptional trajectory of PFC pyramidal neurons, which could enhance vulnerability to psychiatric disorders.


Asunto(s)
Dendritas/efectos de los fármacos , Dronabinol/efectos adversos , Células Piramidales/efectos de los fármacos , Factores de Edad , Animales , Espinas Dendríticas/fisiología , Dronabinol/metabolismo , Masculino , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Long-Evans
9.
bioRxiv ; 2024 Aug 27.
Artículo en Inglés | MEDLINE | ID: mdl-39253503

RESUMEN

Metabolic control of chromatin and gene expression is emerging as a key, but largely unexplored aspect of gene regulation. In the brain, metabolic-epigenetic interactions can influence critical neuronal functions. Here, we use a combination of behavioral, proteomic and genomic approaches to demonstrate that the intermediary metabolite acetate enhances memory in a brain region- and sex-specific manner. We show that acetate facilitates the formation of dorsal hippocampus-dependent spatial memories in female but not in male mice, while having no effect on cortex-dependent non-spatial memories in either sex. Acetate-enhanced spatial memory is driven by increased acetylation of histone variant H2A.Z, and upregulation of genes implicated in spatial learning in the dorsal hippocampus of female mice. In line with the sex-specific behavioral outcomes, the effect of acetate on dorsal hippocampal histone modifications and gene expression shows marked differences between the sexes during critical windows of memory formation (consolidation and recall). Overall, our findings elucidate a novel role for acetate, a ubiquitous and abundant metabolite, in regulating dorsal hippocampal chromatin, gene expression and learning, and outline acetate exposure as a promising new approach to enhance memory formation.

10.
Nat Aging ; 3(4): 402-417, 2023 04.
Artículo en Inglés | MEDLINE | ID: mdl-37117791

RESUMEN

Mammalian aging is characterized by the progressive loss of tissue function and increased risk for disease. Accumulation of senescent cells in aging tissues partly contributes to this decline, and targeted depletion of senescent cells in vivo ameliorates many age-related phenotypes. The fundamental molecular mechanisms responsible for the decline of cellular health and fitness during senescence and aging are largely unknown. In this study, we investigated whether chromatin-mediated loss of transcriptional fidelity, known to contribute to fitness and survival in yeast and worms, also occurs during human cellular senescence and mouse aging. Our findings reveal aberrant transcription initiation inside genes during senescence and aging that co-occurs with changes in the chromatin landscape. Interventions that alter these spurious transcripts have profound consequences on cellular health, primarily affecting intracellular signal transduction pathways. We propose that age-related spurious transcription promotes a noisy transcriptome and degradation of coherent transcriptional networks.


Asunto(s)
Envejecimiento , Senescencia Celular , Humanos , Animales , Ratones , Envejecimiento/genética , Senescencia Celular/genética , Cromatina/genética , Transcriptoma , Fenotipo , Mamíferos/genética
13.
Sci Adv ; 8(3): eabj5688, 2022 Jan 21.
Artículo en Inglés | MEDLINE | ID: mdl-35061542

RESUMEN

Histone acetylation is governed by nuclear acetyl-CoA pools generated, in part, from local acetate by metabolic enzyme acetyl-CoA synthetase 2 (ACSS2). We hypothesize that during gene activation, a local transfer of intact acetate occurs via sequential action of epigenetic and metabolic enzymes. Using stable isotope labeling, we detect transfer between histone acetylation sites both in vitro using purified mammalian enzymes and in vivo using quiescence exit in Saccharomyces cerevisiae as a change-of-state model. We show that Acs2, the yeast ortholog of ACSS2, is recruited to chromatin during quiescence exit and observe dynamic histone acetylation changes proximal to Acs2 peaks. We find that Acs2 is preferentially associated with the most up-regulated genes, suggesting that acetyl group transfer plays an important role in gene activation. Overall, our data reveal direct transfer of acetate between histone lysine residues to facilitate rapid transcriptional induction, an exchange that may be critical during changes in nutrient availability.

14.
Histochem Cell Biol ; 135(4): 409-17, 2011 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-21424608

RESUMEN

Growth factors and mitogens influence signaling pathways and often induce the activity of p70S6 kinase (p70S6K), which in turn phosphorylates the ribosomal S6 protein (S6). Although recent data are rather conflicting, the overall view suggests that phosphorylated S6 is a regulator of global protein synthesis, cell proliferation, cell size and glucose homeostasis. In the present work, emphasis was given to cell cycle-dependent activation of S6 focusing mainly on human lymphoid and lymphoma cells. Paraffin-embedded human tissue blocks from lymph node and different tumor biopsies as well as in vitro cell lines were investigated by immunohistochemistry, immunocytochemistry, flow cytometry and Western blotting using antibodies directed against phospho-S6, phospho-mTOR, phospho-p70S6K and phospho-Histone H3. To enrich the cell number in different phases of the cell cycle, nocodazole, staurosporine or rapamycin were used in cell cultures. We observed strong phospho-S6 positivity by immunostainings in the dividing lymphoid cells of reactive lymph nodes and in lymphoma cells cultured in vitro. Phospho-S6 protein levels were shown to be elevated throughout mitosis in lymphoma cells; however, the high expression of phospho-S6 in mitotic cells was not a general hallmark of tumor cell types studied so far: phospho-S6-negative mitotic cells were detected in several carcinoma and sarcoma biopsies. These observations may have practical implications as they raise the possibility to consider p70S6K and/or S6 as a potential therapeutic target-besides mTOR-in certain lymphomas and perhaps in clinical immunosuppression.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Linfoma/metabolismo , Linfoma/patología , Mitosis , Proteína S6 Ribosómica/química , Proteína S6 Ribosómica/metabolismo , Western Blotting , Citometría de Flujo , Humanos , Inmunohistoquímica , Fosforilación , Proteína S6 Ribosómica/análisis , Proteína S6 Ribosómica/biosíntesis , Células Tumorales Cultivadas
15.
Trends Neurosci ; 44(12): 1004-1015, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34702580

RESUMEN

Alcohol use produces wide-ranging and diverse effects on the central nervous system. It influences intracellular signaling mechanisms, leading to changes in gene expression, chromatin remodeling, and translation. As a result of these molecular alterations, alcohol affects the activity of neuronal circuits. Together, these mechanisms produce long-lasting cellular adaptations in the brain that in turn can drive the development and maintenance of alcohol use disorder (AUD). We provide an update on alcohol research, focusing on multiple levels of alcohol-induced adaptations, from intracellular changes to changes in neural circuits. A better understanding of how alcohol affects these diverse and interlinked mechanisms may lead to the identification of novel therapeutic targets and to the development of much-needed novel and efficacious treatment options.


Asunto(s)
Alcoholismo , Etanol , Alcoholismo/tratamiento farmacológico , Alcoholismo/genética , Alcoholismo/metabolismo , Encéfalo/metabolismo , Ensamble y Desensamble de Cromatina , Etanol/metabolismo , Etanol/farmacología , Etanol/uso terapéutico , Humanos , Neuronas/metabolismo
16.
Nat Commun ; 11(1): 4634, 2020 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-32929078

RESUMEN

The current opioid epidemic necessitates a better understanding of human addiction neurobiology to develop efficacious treatment approaches. Here, we perform genome-wide assessment of chromatin accessibility of the human striatum in heroin users and matched controls. Our study reveals distinct neuronal and non-neuronal epigenetic signatures, and identifies a locus in the proximity of the gene encoding tyrosine kinase FYN as the most affected region in neurons. FYN expression, kinase activity and the phosphorylation of its target Tau are increased by heroin use in the post-mortem human striatum, as well as in rats trained to self-administer heroin and primary striatal neurons treated with chronic morphine in vitro. Pharmacological or genetic manipulation of FYN activity significantly attenuates heroin self-administration and responding for drug-paired cues in rodents. Our findings suggest that striatal FYN is an important driver of heroin-related neurodegenerative-like pathology and drug-taking behavior, making FYN a promising therapeutic target for heroin use disorder.


Asunto(s)
Cromatina/metabolismo , Cuerpo Estriado/enzimología , Dependencia de Heroína/enzimología , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas c-fyn/metabolismo , Animales , Secuencia de Bases , Conducta Animal/efectos de los fármacos , Señales (Psicología) , Genoma , Células HEK293 , Heroína/efectos adversos , Humanos , Masculino , Neuronas/metabolismo , Fosforilación/efectos de los fármacos , Regiones Promotoras Genéticas/genética , Proteínas Proto-Oncogénicas c-fyn/antagonistas & inhibidores , Ratas Long-Evans , Autoadministración , Transcripción Genética/efectos de los fármacos , Proteínas tau/metabolismo
17.
Neurosci Biobehav Rev ; 85: 117-125, 2018 02.
Artículo en Inglés | MEDLINE | ID: mdl-28571877

RESUMEN

Substance use disorders continue to impose increasing medical, financial and emotional burdens on society in the form of morbidity and overdose, family disintegration, loss of employment and crime, while advances in prevention and treatment options remain limited. Importantly, not all individuals exposed to abused substances effectively develop the disease. Genetic factors play a significant role in determining addiction vulnerability and interactions between innate predisposition, environmental factors and personal experiences are also critical. Thus, understanding individual differences that contribute to the initiation of substance use as well as on long-term maladaptations driving compulsive drug use and relapse propensity is of critical importance to reduce this devastating disorder. In this paper, we discuss current topics in the field of addiction regarding individual vulnerability related to behavioral endophenotypes, neural circuits, as well as genetics and epigenetic mechanisms. Expanded knowledge of these factors is of importance to improve and personalize prevention and treatment interventions in the future.


Asunto(s)
Conducta Adictiva/genética , Epigénesis Genética/genética , Predisposición Genética a la Enfermedad/genética , Trastornos Relacionados con Sustancias/genética , Animales , Endofenotipos/metabolismo , Humanos , Individualidad
18.
Biol Psychiatry ; 81(7): 585-594, 2017 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-27863698

RESUMEN

BACKGROUND: Opiate abuse and overdose reached epidemic levels in the United States. However, despite significant advances in animal and in vitro models, little knowledge has been directly accrued regarding the neurobiology of the opiate-addicted human brain. METHODS: We used postmortem human brain specimens from a homogeneous European Caucasian population of heroin users for transcriptional and epigenetic profiling, as well as direct assessment of chromatin accessibility in the striatum, a brain region central to reward and emotion. A rat heroin self-administration model was used to obtain translational molecular and behavioral insights. RESULTS: Our transcriptome approach revealed marked impairments related to glutamatergic neurotransmission and chromatin remodeling in the human striatum. A series of biochemical experiments tracked the specific location of the epigenetic disturbances to hyperacetylation of lysine 27 of histone H3, showing dynamic correlations with heroin use history and acute opiate toxicology. Targeted investigation of GRIA1, a glutamatergic gene implicated in drug-seeking behavior, verified the increased enrichment of lysine-27 acetylated histone H3 at discrete loci, accompanied by enhanced chromatin accessibility at hyperacetylated regions in the gene body. Analogous epigenetic impairments were detected in the striatum of heroin self-administering rats. Using this translational model, we showed that bromodomain inhibitor JQ1, which blocks the functional readout of acetylated lysines, reduced heroin self-administration and cue-induced drug-seeking behavior. CONCLUSIONS: Overall, our data suggest that heroin-related histone H3 hyperacetylation contributes to glutamatergic transcriptional changes that underlie addiction behavior and identify JQ1 as a promising candidate for targeted clinical interventions in heroin use disorder.


Asunto(s)
Encéfalo/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Epigénesis Genética , Dependencia de Heroína/genética , Dependencia de Heroína/metabolismo , Histonas/metabolismo , Receptores AMPA/genética , Acetilación , Animales , Azepinas/administración & dosificación , Encéfalo/efectos de los fármacos , Ensamble y Desensamble de Cromatina , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Epigenómica , Perfilación de la Expresión Génica , Humanos , Masculino , Ratas , Ratas Long-Evans , Receptores AMPA/metabolismo , Autoadministración , Triazoles/administración & dosificación , Población Blanca
19.
Neuropsychopharmacology ; 42(12): 2365-2376, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28580946

RESUMEN

Appetitive drive is influenced by coordinated interactions between brain circuits that regulate reinforcement and homeostatic signals that control metabolism. Glucose modulates striatal dopamine (DA) and regulates appetitive drive and reinforcement learning. Striatal DA D2 receptors (D2Rs) also regulate reinforcement learning and are implicated in glucose-related metabolic disorders. Nevertheless, interactions between striatal D2R and peripheral glucose have not been previously described. Here we show that manipulations involving striatal D2R signaling coincide with perseverative and impulsive-like responding for sucrose, a disaccharide consisting of fructose and glucose. Fructose conveys orosensory (ie, taste) reinforcement but does not convey metabolic (ie, nutrient-derived) reinforcement. Glucose however conveys orosensory reinforcement but unlike fructose, it is a major metabolic energy source, underlies sustained reinforcement, and activates striatal circuitry. We found that mice with deletion of dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32) exclusively in D2R-expressing cells exhibited preferential D2R changes in the nucleus accumbens (NAc), a striatal region that critically regulates sucrose reinforcement. These changes coincided with perseverative and impulsive-like responding for sucrose pellets and sustained reinforcement learning of glucose-paired flavors. These mice were also characterized by significant glucose intolerance (ie, impaired glucose utilization). Systemic glucose administration significantly attenuated sucrose operant responding and D2R activation or blockade in the NAc bidirectionally modulated blood glucose levels and glucose tolerance. Collectively, these results implicate NAc D2R in regulating both peripheral glucose levels and glucose-dependent reinforcement learning behaviors and highlight the notion that glucose metabolic impairments arising from disrupted NAc D2R signaling are involved in compulsive and perseverative feeding behaviors.


Asunto(s)
Cognición/fisiología , Glucosa/metabolismo , Núcleo Accumbens/metabolismo , Receptores de Dopamina D2/metabolismo , Refuerzo en Psicología , Transducción de Señal/fisiología , Animales , Condicionamiento Operante/fisiología , Prueba de Tolerancia a la Glucosa/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Tiempo de Reacción/fisiología
20.
Neurotoxicol Teratol ; 58: 107-114, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27221226

RESUMEN

Cannabis (Cannabis sativa, Cannabis indica) is the illicit drug most frequently abused by young men and women. The growing use of the drug has raised attention not only on the impact of direct exposure on the developing brain and behavior later in life, but also on potential cross-generational consequences. Our previous work demonstrated that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, affects reward-related behavior and striatal gene expression in male offspring that were unexposed to the drug during their own lifespan. The significant sex differences documented for most addiction and psychiatric disorders suggest that understanding the perturbation of the brain in the two sexes due to cannabis could provide insights about neuronal systems underpinning vulnerability to psychiatric illnesses. In the current study, we expanded our previous observations in males by analyzing the female brain for specific aberrations associated with cross-generational THC exposure. Based on the impact of adolescent development on subsequent adult behavioral pathology, we examined molecular patterns during both adolescence and adulthood. The results revealed a switch from the ventral striatum during adolescence to the dorsal striatum in adulthood in alterations of gene expression related to synaptic plasticity in both sexes. Females, however, exhibited stronger correlation patterns between genes and also showed locomotor disturbances not evident in males. Overall, the findings demonstrate cross-generational consequences of parental THC exposure in both male and female offspring.


Asunto(s)
Cuerpo Estriado/crecimiento & desarrollo , Cuerpo Estriado/metabolismo , Dronabinol/administración & dosificación , Expresión Génica/efectos de los fármacos , Exposición Materna , Exposición Paterna , Animales , Conducta Exploratoria , Femenino , Locomoción/efectos de los fármacos , Masculino , Plasticidad Neuronal , ARN Mensajero/metabolismo , Ratas Long-Evans
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