1 622 199 BIOETHICS IN HUMAN EMBRYOLOGY: THE DOUBLE-EDGED SWORD OF EMBRYO RESEARCH. THERE HAS BEEN A SIGNIFICANT INCREASE IN THE USE OF ASSISTED REPRODUCTIVE THERAPIES (ARTS) OVER THE PAST SEVERAL DECADES, ALLOWING MANY COUPLES WITH INFERTILITY TO CONCEIVE. DESPITE THE ACHIEVEMENTS IN THIS FIELD, A MOUNTING BODY OF EVIDENCE CONCERNING THE EPIGENETIC RISKS ASSOCIATED WITH ART INTERVENTIONS SUCH AS OVARIAN HORMONAL STIMULATION, INTRACYTOPLASMIC SPERM INJECTION (ICSI), AND IN VITRO CULTURE (IVC) OF OOCYTES AND EMBRYOS HAS ALSO EMERGED. INDUCED DEVELOPMENT OF MULTIPLE FOLLICLES, THE IVC MEDIA ITSELF, AND EXTENDED CULTURE MAY ALTER THE EPIGENOME OF BOTH GAMETES AND EMBRYOS, RESULTING IN YET TO BE FULLY UNDERSTOOD DEVELOPMENTAL, POSTNATAL, AND ADULT LIFE HEALTH CONSEQUENCES. INVESTIGATORS HAVE ATTEMPTED TO DECIPHER THE MOLECULAR MECHANISMS MEDIATING ART-INDUCED EPIGENETIC CHANGES USING EITHER HUMAN SAMPLES OR ANIMAL MODELS WITH SOME SUCCESS. AS RESEARCH IN THIS FIELD CONTINUES TO EXPAND, THE ETHICAL RESPONSIBILITIES OF EMBRYOLOGISTS AND RESEARCHERS HAVE BECOME CRITICALLY IMPORTANT. HERE, WE BRIEFLY DISCUSS THE ETHICAL ASPECTS OF ART RESEARCH, CONCENTRATING ON THE CONSTRAINTS ARISING FROM THE PERCEIVED 'UNNATURALNESS' OF MANY OF THESE PROCEDURES. SECONDLY, WE FOCUS ON THE BIOETHICS AND MORALITY OF HUMAN EMBRYO RESEARCH IN GENERAL AND HOW ETHICALLY ACCEPTABLE MODEL SYSTEMS MAY BE USED TO MIMIC EARLY HUMAN EMBRYOGENESIS. LASTLY, WE REVIEW THE 14-DAY CULTURE LIMIT OF HUMAN EMBRYOS AND THE NOTION THAT THIS RULE COULD BE CONSIDERED OF TAKEN INTO ACCOUNT USING NEW TECHNOLOGIES AND CUES FROM ANIMAL MODELS. THE 'BLACK BOX' OF EARLY POST-IMPLANTATION EMBRYOGENESIS MIGHT BE REVEALED USING EMBRYO MODELS. AS LONG AS THIS DISTINCT MORAL LINE HAS BEEN DRAWN AND CLOSELY FOLLOWED, WE SHOULD NOT FEAR SCIENTIFIC GROWTH IN EMBRYO RESEARCH. ALTHOUGH IN VITRO FERTILIZATION (IVF) IS ETHICALLY ACCEPTABLE, RESEARCH WITH HUMAN EMBRYOS TO IMPROVE ITS SUCCESS RAISES SERIOUS ETHICAL CONCERNS THAT ARE IN NEED OF CONSTANT REVISITING.GLOSSARY INDEX: MORAL STATUS: THE ASCRIPTION OF OBLIGATIONS AND RIGHTS TO EMBRYOS ON THE BASIS OF SENTIENCE; SENTIENCE: THE CAPACITY OF THE DEVELOPING EMBRYO TO EXPERIENCE FEELINGS AND SENSATIONS, SUCH AS THE AWARENESS OF PAIN; ECTOGENESIS: THE GROWTH OF THE EMBRYO IN AN ARTIFICIAL ENVIRONMENT OUTSIDE THE MOTHER'S BODY. 2022 2 5444 36 REPEATED TOLUENE EXPOSURE MODIFIES THE ACETYLATION PATTERN OF HISTONES H3 AND H4 IN THE RAT BRAIN. TOLUENE IS A VOLATILE ORGANIC SOLVENT WITH ADDICTIVE POTENTIAL THAT EXHIBITS SIMILARITIES IN ITS PHYSIOLOGICAL EFFECTS AND MODES OF ACTION TO OTHER ADDICTIVE DRUGS. DESPITE ITS WIDESPREAD ABUSE, THE MOLECULAR MECHANISMS DRIVING THE RESPONSE AND ADAPTATION OF THE ORGANISM TO THIS DRUG ARE NOT FULLY UNDERSTOOD. IN RECENT YEARS, DIFFERENT EPIGENETIC MECHANISMS THAT MODULATE GENE EXPRESSION HAVE BEEN SHOWN TO BE ASSOCIATED TO COCAINE, AMPHETAMINE AND ALCOHOL MISUSE-INDUCED ALTERATIONS IN NEURONAL FUNCTION. FOR EXAMPLE, IT HAS BEEN DEMONSTRATED THAT DRUG CONSUMPTION INDUCES VARIATIONS IN HISTONE ACETYLATION LEVELS IN BRAIN REWARD REGIONS AND THESE PLAY A RELEVANT ROLE ON THE ABUSE-ASSOCIATED BEHAVIORAL PLASTICITY. IN ORDER TO DECIPHER WHETHER REPEATED TOLUENE EXPOSURE COULD MEDIATE EPIGENETIC CHANGES IN THE RAT BRAIN, WE HERE ANALYZED THE ACETYLATION PATTERN OF HISTONES H3 AND H4 IN THREE BRAIN AREAS THAT HAVE BEEN PREVIOUSLY ASSOCIATED TO SUBSTANCE ABUSE REWARD PATHWAYS: THE NUCLEUS ACCUMBENS (NAC), THE VENTRAL TEGMENTAL AREA (VTA) AND THE CENTRAL AMYGDALA (CEA). USING IMMUNOFLUORESCENCE ANALYSIS OF BRAIN SECTIONS WITH SPECIFIC ANTIBODIES THAT RECOGNIZE THE ACETYLATED FORMS OF HISTONES H3 AND H4, WE DEMONSTRATE THAT CHRONIC TOLUENE INHALATION DIFFERENTIALLY MODIFIES HISTONE H3 AND H4 ACETYLATION IN THE NAC AND THE VTA WHILE NO EFFECT IS OBSERVED IN THE CEA. OUR RESULTS SUGGEST THAT THE ACTIVITY OF CHROMATIN-MODIFYING ENZYMES SUCH AS HISTONE DE-ACETYLASES (HDACS) IN CERTAIN BRAIN AREAS ARE RESPONSIVE TO TOLUENE INHALATION AND MIGHT BE CRUCIAL MEDIATORS IN THE ADDICTIVE RESPONSE TO TOLUENE. 2011 3 3509 33 IDENTIFYING MECHANISMS OF ENDOMETRIOSIS-ASSOCIATED REDUCED FECUNDITY IN A RAT MODEL: NOVEL INSIGHTS TOWARD UNDERSTANDING HUMAN INFERTILITY. THE EXISTENCE OF ENDOMETRIOSIS HAS BEEN KNOWN SINCE AT LEAST THE NINETEENTH CENTURY, YET THE LACK OF UNDERSTANDING OF CAUSES OF INFERTILITY AND THEREFORE INADEQUATE TREATMENT APPROACHES IN ENDOMETRIOSIS CREATES A SIGNIFICANT CHALLENGE IN REPRODUCTIVE MEDICINE. WOMEN WORLDWIDE SUFFER NOT ONLY PAIN AND INFERTILITY BUT ALSO ECONOMICAL, SOCIETAL, AND PHYSIOLOGICAL BURDENS. STUDIES OF REPRODUCTIVE EVENTS IN WOMEN ARE DIFFICULT TO CONDUCT DUE TO A HOST OF CONFOUNDING PERSONAL AND ENVIRONMENTAL FACTORS AND ETHICALLY LIMITED DUE TO THE VERY NATURE OF WORKING WITH REPRODUCTIVE TISSUES AND CELLS, ESPECIALLY EMBRYOS. ANIMAL MODELS ARE A VIABLE ADJUNCT TO STUDY MECHANISMS CAUSING HUMAN REPRODUCTIVE ANOMALIES AND INFERTILITY IN ENDOMETRIOSIS. THIS CHAPTER DISCUSSES REPRODUCTIVE ANOMALIES CAUSING INFERTILITY IN ENDOMETRIOSIS AND WELL-ESTABLISHED ANIMAL MODELS WHICH HELP DECIPHER THE PROBLEMS AND LEAD TO HERETOFORE UNKNOWN NONSURGICAL, NONHORMONAL METHODS TO MANAGE ENDOMETRIOSIS IN WOMEN. IN ADDITION, STUDIES OF EFFECTS OF DEVELOPMENTAL EXPOSURE TO ENDOMETRIOSIS ARE REVEALING FOR THE FIRST TIME, IN BOTH FEMALE AND MALE OFFSPRING, TRANSGENERATIONAL SUBFERTILITY IN A RAT MODEL PROVIDING INSIGHTS INTO THE FAMILIAL NATURE OF ENDOMETRIOSIS AND POSSIBLE EPIGENETIC INVOLVEMENT. 2020 4 1839 23 EFFECTS OF PRENATAL NICOTINE EXPOSURE ON HEPATIC GLUCOSE AND LIPID METABOLISM IN OFFSPRING RATS AND ITS HEREDITABILITY. PRENATAL NICOTINE EXPOSURE (PNE) COULD INDUCE AN INCREASED SUSCEPTIBILITY TO MULTIPLE CHRONIC DISEASES IN ADULT OFFSPRING, THAT MAINLY CAUSED BY INTRAUTERINE MATERNAL GLUCOCORTICOID (GC) OVER-EXPOSURE. WE INVESTIGATED THE CHANGES AND INHERITABILITY OF HEPATIC GLUCOSE AND LIPID METABOLISM CAUSED BY PNE, TO DECIPHER THE POSSIBLE INTRAUTERINE PROGRAMMING MECHANISM. PREGNANT WISTAR RATS WERE ADMINISTERED SUBCUTANEOUSLY WITH 2 MG/KG.D NICOTINE FROM GESTATIONAL DAY (GD) 9 APPROXIMATELY 20, AND SECOND-GENERATION (F2) WERE SET ACCORDING TO THE MATING BETWEEN CONTROL FEMALES AND PNE MALES. THE RESULTS SHOWED THAT SERUM PHENOTYPES AND HEPATIC ENZYMES OF GLUCOSE AND LIPID METABOLISM WERE LOWER IN F1 FETAL RATS OF PNE BUT HIGHER IN THE F1 ADULT RATS. MEANWHILE, THE ACTIVATED STATES OF HEPATIC GLUCOCORTICOID-ACTIVATION SYSTEM, INCLUDING TYPE 1 AND TYPE 2 11BETA-HYDROXYSTEROID DEHYDROGENASES (HSD11B1/2), NUCLEAR RECEPTOR SUBFAMILY 3, GROUP C, MEMBER 1 (NR3C1) AND CCAAT ENHANCER BINDING PROTEIN ALPHA (CEBPA), WERE POSITIVELY CORRELATED WITH SERUM CORTICOSTERONE LEVELS BUT NEGATIVELY CORRELATED WITH THE HISTONE ACETYLATION (H3K27AC) AND EXPRESSION LEVELS OF INSULIN-LIKE GROWTH FACTOR 1 (IGF1) BEFORE AND AFTER BIRTH. FURTHERMORE, SERUM PHENOTYPES AND HEPATIC ENZYMES OF GLUCOSE AND LIPID METABOLISM WERE LOWER IN BOTH F2 FETAL AND ADULT RATS OF PNE, WHICH WERE CONSISTENT WITH THE HEPATIC CHANGES OF GC-IGF1 AXIS AND THE GLUCOCORTICOID-ACTIVATION SYSTEM. IN CONCLUSION, PNE COULD LEAD TO INHERITABLE CHANGES OF HEPATIC GLUCOSE AND LIPID METABOLISM, WHICH ARE RELATED TO THE INTRAUTERINE PROGRAMMING OF GC-IGF1 AXIS INDUCED BY THE GLUCOCORTICOID-ACTIVATION SYSTEM. 2020 5 6025 39 THE BIOLOGY OF CHRONIC PAIN AND ITS IMPLICATIONS FOR PAIN NEUROSCIENCE EDUCATION: STATE OF THE ART. PAIN IS AN INDIVIDUALIZED EXPERIENCE FOR THE PERSON SUFFERING FROM CHRONIC PAIN. SIGNIFICANT STRIDES HAVE BEEN MADE IN THE LAST FEW DECADES IN UNDERSTANDING VARIOUS BIOLOGICAL CHANGES THAT COINCIDE WITH CHRONIC PAIN. THIS STATE-OF-THE-ART OVERVIEW LOOKS AT THE CURRENT EVIDENCE RELATED TO THE BIOLOGY OF CHRONIC PAIN AND THE IMPLICATIONS THESE FINDINGS HAVE ON THE DELIVERY OF PAIN NEUROSCIENCE EDUCATION (PNE). THE PAPER SUMMARIZES THE VARIOUS (EPI)GENETIC, NEURAL, ENDOCRINE, AND IMMUNE FACTORS DISCOVERED AND EXPLORED IN THE SCIENTIFIC LITERATURE CONCERNING CHRONIC PAIN. EACH OF THESE BIOLOGICAL FACTORS HAS VARIOUS IMPLICATIONS FOR THE CONTENT AND DELIVERY OF PNE. WE DISCUSS THE FUTURE DIRECTIONS THESE BIOLOGICAL FACTORS HAVE FOR THE CLINICAL IMPLEMENTATION OF PNE BY LINKING THE IMPORTANCE OF BEHAVIOR CHANGE, OPTIMIZING THE LEARNING ENVIRONMENT, AND USING AN INDIVIDUALIZED MULTIMODAL TREATMENT APPROACH WITH PNE. IN ADDITION, FUTURE DIRECTIONS FOR RESEARCH OF PNE BASED ON THESE BIOLOGICAL FACTORS ARE PROVIDED WITH IMPORTANCE PLACED ON INDIVIDUALIZED PATIENT-CENTERED CARE AND HOW PNE CAN BE USED WITH TRADITIONAL MODES OF CARE AND GROWING TRENDS WITH OTHER CARE METHODS. PNE WAS ORIGINALLY AND CONTINUES TO BE ROOTED IN UNDERSTANDING CHRONIC PAIN BIOLOGY AND HOW THAT UNDERSTANDING CAN IMPROVE PATIENT CARE AND OUTCOMES. 2023 6 6695 24 VARIANT GENE EXPRESSION AND ANTIGENIC VARIATION BY MALARIA PARASITES. MALARIA IS A SIGNIFICANT THREAT THROUGHOUT THE DEVELOPING WORLD. AMONG THE MOST FASCINATING ASPECTS OF THE PROTOZOAN PARASITES RESPONSIBLE FOR THIS DISEASE ARE THE METHODS THEY EMPLOY TO AVOID THE IMMUNE SYSTEM AND PERPETUATE CHRONIC INFECTIONS. KEY AMONG THESE IS ANTIGENIC VARIATION: BY SYSTEMATICALLY ALTERING ANTIGENS THAT ARE DISPLAYED TO THE HOST'S IMMUNE SYSTEM, THE PARASITE RENDERS THE ADAPTIVE IMMUNE RESPONSE INEFFECTIVE. FOR PLASMODIUM FALCIPARUM, THE SPECIES RESPONSIBLE FOR THE MOST SEVERE FORM OF HUMAN MALARIA, THIS PROCESS INVOLVES A COMPLICATED MOLECULAR MECHANISM THAT RESULTS IN CONTINUOUSLY CHANGING PATTERNS OF VARIANT-ANTIGEN-ENCODING GENE EXPRESSION. ALTHOUGH MANY FEATURES OF THIS PROCESS REMAIN OBSCURE, SIGNIFICANT PROGRESS HAS BEEN MADE IN RECENT YEARS TO DECIPHER VARIOUS MOLECULAR ASPECTS OF THE REGULATORY CASCADE THAT CAUSES CHRONIC INFECTION. 2017 7 2670 40 ETHANOL ACTIONS ON THE VENTRAL TEGMENTAL AREA: NOVEL POTENTIAL TARGETS ON REWARD PATHWAY NEURONS. THE VENTRAL TEGMENTAL AREA (VTA) EVALUATES SALIENCE OF ENVIRONMENTAL STIMULI AND PROVIDES DOPAMINERGIC INNERVATION TO MANY BRAIN AREAS AFFECTED BY ACUTE AND CHRONIC ETHANOL EXPOSURE. WHILE PRIMARILY ASSOCIATED WITH REWARDING AND REINFORCING STIMULI, RECENT EVIDENCE INDICATES A ROLE FOR THE VTA IN AVERSION AS WELL. ETHANOL ACTIONS IN THE VTA MAY TRIGGER NEUROADAPTATION RESULTING IN REDUCTION OF THE AVERSIVE RESPONSES TO ALCOHOL AND A RELATIVE INCREASE IN THE REWARDING RESPONSES. IN SEARCHING FOR EFFECTIVE PHARMACOTHERAPIES FOR THE TREATMENT OF ALCOHOL ABUSE AND ALCOHOLISM, RECOGNITION OF THIS IMBALANCE MAY REVEAL NOVEL STRATEGIES. IN ADDITION TO CONVENTIONAL RECEPTOR/ION CHANNEL PHARMACOTHERAPIES, EPIGENETIC FACTORS THAT CONTROL NEUROADAPTATION TO CHRONIC ETHANOL TREATMENT CAN BE TARGETED AS AN AVENUE FOR DEVELOPMENT OF THERAPEUTIC APPROACHES TO RESTORE THE BALANCE. FURTHERMORE, WHEN EXPLORING THERAPIES TO ADDRESS REWARD/AVERSION IMBALANCE IN THE ACTION OF ALCOHOL IN THE VTA, SEX DIFFERENCES HAVE TO BE TAKEN INTO ACCOUNT TO ENSURE EFFECTIVE TREATMENT FOR BOTH MEN AND WOMEN. THESE PRINCIPLES APPLY TO A VTA-CENTRIC APPROACH TO THERAPIES, BUT SHOULD HOLD TRUE WHEN THINKING ABOUT THE OVERALL APPROACH IN THE DEVELOPMENT OF NEUROACTIVE DRUGS TO TREAT ALCOHOL USE DISORDERS. ALTHOUGH THE FUNCTIONS OF THE VTA ITSELF ARE COMPLEX, IT IS A USEFUL MODEL SYSTEM TO EVALUATE THE REWARD/AVERSION IMBALANCE THAT OCCURS WITH ETHANOL EXPOSURE AND COULD BE USED TO PROVIDE NEW LEADS IN THE EFFORTS TO DEVELOP NOVEL DRUGS TO TREAT ALCOHOLISM. 2018 8 4650 30 NEUROPLASTICITY IN ADDICTION: CELLULAR AND TRANSCRIPTIONAL PERSPECTIVES. DRUG ADDICTION IS A CHRONIC, RELAPSING BRAIN DISORDER WHICH CONSISTS OF COMPULSIVE PATTERNS OF DRUG-SEEKING AND TAKING THAT OCCURS AT THE EXPENSE OF OTHER ACTIVITIES. THE TRANSITION FROM CASUAL TO COMPULSIVE DRUG USE AND THE ENDURING PROPENSITY TO RELAPSE IS THOUGHT TO BE UNDERPINNED BY LONG-LASTING NEUROADAPTATIONS IN SPECIFIC BRAIN CIRCUITRY, ANALOGOUS TO THOSE THAT UNDERLIE LONG-TERM MEMORY FORMATION. RESEARCH SPANNING THE LAST TWO DECADES HAS MADE GREAT PROGRESS IN IDENTIFYING CELLULAR AND MOLECULAR MECHANISMS THAT CONTRIBUTE TO DRUG-INDUCED CHANGES IN PLASTICITY AND BEHAVIOR. ALTERATIONS IN SYNAPTIC TRANSMISSION WITHIN THE MESOCORTICOLIMBIC AND CORTICOSTRIATAL PATHWAYS, AND CHANGES IN THE TRANSCRIPTIONAL POTENTIAL OF CELLS BY EPIGENETIC MECHANISMS ARE TWO IMPORTANT MEANS BY WHICH DRUGS OF ABUSE CAN INDUCE LASTING CHANGES IN BEHAVIOR. IN THIS REVIEW WE PROVIDE A SUMMARY OF MORE RECENT RESEARCH THAT HAS FURTHERED OUR UNDERSTANDING OF DRUG-INDUCED NEUROPLASTIC CHANGES BOTH AT THE LEVEL OF THE SYNAPSE, AND ON A TRANSCRIPTIONAL LEVEL, AND HOW THESE CHANGES MAY RELATE TO THE HUMAN DISEASE OF ADDICTION. 2012 9 2259 23 EPIGENETIC PRIMING IN DRUG ADDICTION. DRUG ADDICTION IS A CHRONIC RELAPSING BRAIN DISORDER THAT IS CHARACTERIZED BY COMPULSIVE DRUG SEEKING AND CONTINUED USE DESPITE NEGATIVE OUTCOMES. CURRENT PHARMACOLOGICAL THERAPIES TARGET NEURONAL RECEPTORS OR TRANSPORTERS UPON WHICH DRUGS OF ABUSE ACT INITIALLY, YET THESE TREATMENTS REMAIN INEFFECTIVE FOR MOST INDIVIDUALS AND DO NOT PREVENT DISEASE RELAPSE AFTER ABSTINENCE. DRUGS OF ABUSE, IN ADDITION TO THEIR ACUTE EFFECTS, CAUSE PERSISTENT PLASTICITY AFTER REPEATED USE, INVOLVING DYSREGULATED GENE EXPRESSION IN THE BRAIN'S REWARD REGIONS, WHICH ARE THOUGHT TO MEDIATE THE PERSISTENT BEHAVIORAL ABNORMALITIES THAT CHARACTERIZE ADDICTION. EMERGING EVIDENCE IMPLICATES EPIGENETIC PRIMING AS A KEY MECHANISM THAT UNDERLIES THE LONG-LASTING ALTERATIONS IN NEURONAL GENE REGULATION, WHICH CAN REMAIN LATENT UNTIL TRIGGERED BY RE-EXPOSURE TO DRUG-ASSOCIATED STIMULI OR THE DRUG ITSELF. THUS, TO EFFECTIVELY TREAT DRUG ADDICTION, WE MUST IDENTIFY THE PRECISE EPIGENETIC MECHANISMS THAT ESTABLISH AND PRESERVE THE DRUG-INDUCED PATHOLOGY OF THE BRAIN REWARD CIRCUITRY. 2018 10 4 31 "MIX OF MICS"- PHENOTYPIC AND BIOLOGICAL HETEROGENEITY OF "MULTIPOTENT" MUSCLE INTERSTITIAL CELLS (MICS). THE CAPACITY OF ADULT SKELETAL MUSCLE FOR REGENERATION APPEARS TO BE LIMITED, WITH PROGRESSIVE IMPAIRMENT IN REPAIR EFFICIENCY OF INJURED MUSCLES OBSERVED IN CHRONIC MUSCULAR DISORDERS AND DURING AGING. WHILE SATELLITE CELLS, THE COMMITTED ADULT MUSCLE STEM CELLS, ARE THE MAIN DIRECT CELL SOURCE SUPPORTING THE REGENERATIVE POTENTIAL OF ADULT SKELETAL MUSCLES, THE CHARACTERIZATION OF THE CELL TYPES AND SIGNALS THAT CONSTITUTE THE FUNCTIONAL "NICHE" OF SATELLITE CELLS IS CURRENTLY THE OBJECT OF INTENSE INVESTIGATION. RECENT STUDIES HAVE IDENTIFIED A FUNCTIONAL RELATIONSHIP BETWEEN SATELLITE CELLS AND VARIOUS CELL TYPES LOCATED IN KEY ANATOMICAL POSITION, SUCH AS THE INTERSTITIUM OF SKELETAL MUSCLES. THIS HETEROGENEOUS POPULATION OF MUSCLE INTERSTITIAL CELLS (MICS) APPEARS TO RETAIN AN INTRINSIC MULTIPOTENCY WITHIN THE MESODERMAL LINEAGE, AND THEIR DIRECT OR INDIRECT CONTRIBUTION TO MYOFIBER TURNOVER, REPAIR AND DEGENERATION HAS BEEN SUGGESTED BY MANY STUDIES THAT WILL BE REVIEWED HERE. GIVEN THE EXISTING GAP OF KNOWLEDGE ON LINEAGE IDENTITY AND FUNCTIONAL PROPERTIES OF MICS, THEIR DETAILED CHARACTERIZATION AT THE SINGLE CELL LEVEL HOLDS THE PROMISE TO PROVIDE KEY INSIGHT INTO THE COMPOSITION OF THIS HETEROGENEOUS POPULATION AND THE DYNAMIC TRANSITION THROUGH DISTINCT SUB-POPULATIONS IN HEALTHY, DISEASED AND AGING MUSCLES. THIS REVIEW PROVIDES AN OVERVIEW OF THE RESULTS OF VARIOUS STUDIES DESCRIBING THE PHENOTYPE AND THE FUNCTION OF CELLS ISOLATED FROM SKELETAL MUSCLE INTERSTITIUM, AND DISCUSSES THE IMPORTANCE OF SINGLE CELL TRANSCRIPTION PROFILING IN ORDER TO DECIPHER THE FUNCTIONAL AND PHENOTYPICAL HETEROGENEITY OF MUSCLE INTERSTITIAL CELLS (MICS). 2012 11 6268 28 THE NEUROEPIGENOME: IMPLICATIONS OF CHEMICAL AND PHYSICAL MODIFICATIONS OF GENOMIC DNA IN SCHIZOPHRENIA. SCHIZOPHRENIA IS A CHRONIC MENTAL ILLNESS WITH A SUBSTANTIAL GENETIC COMPONENT. TO UNFOLD THE COMPLEX ETIOLOGY OF SCHIZOPHRENIA, IT IS IMPORTANT TO UNDERSTAND THE INTERPLAY BETWEEN GENETIC AND NONGENETIC FACTORS. GENETIC FACTORS INVOLVE VARIATION IN THE DNA SEQUENCES OF PROTEIN-CODING GENES, WHICH DIRECTLY CONTRIBUTE TO PHENOTYPIC TRAITS, AND VARIATION IN NONCODING SEQUENCES, WHICH COMPRISE 98% OF THE GENOME AND CONTAIN DNA ELEMENTS KNOWN TO PLAY A ROLE IN REGULATING GENE EXPRESSION. THE EPIGENOME REFERS TO THE CHEMICAL MODIFICATIONS ON BOTH DNA AND THE STRUCTURAL PROTEINS THAT PACKAGE DNA INTO THE NUCLEUS, WHICH TOGETHER REGULATE GENE EXPRESSION IN SPECIFIC CELL TYPES, CONDITIONS, AND DEVELOPMENTAL STAGES. THE DYNAMIC NATURE OF THE EPIGENOME MAKES IT AN IDEAL TOOL TO INVESTIGATE THE RELATIONSHIP BETWEEN INHERITED GENETIC MUTATIONS ASSOCIATED WITH SCHIZOPHRENIA AND ALTERED GENE REGULATION THROUGHOUT THE COURSE OF BRAIN DEVELOPMENT. IN THIS REVIEW, WE FOCUS ON THE CURRENT UNDERSTANDING OF THE ROLE OF EPIGENETIC MARKS AND THEIR THREE-DIMENSIONAL NUCLEAR ORGANIZATION IN THE DEVELOPMENTAL TRAJECTORY OF DISTINCT BRAIN CELL TYPES TO DECIPHER THE COMPLEX GENE REGULATORY MECHANISMS THAT ARE DISRUPTED IN SCHIZOPHRENIA. 2022 12 2140 39 EPIGENETIC INTERACTIONS BETWEEN ALCOHOL AND CANNABINERGIC EFFECTS: FOCUS ON HISTONE MODIFICATION AND DNA METHYLATION. EPIGENETIC STUDIES HAVE LED TO A MORE PROFOUND UNDERSTANDING OF THE MECHANISMS INVOLVED IN CHRONIC CONDITIONS. IN THE CASE OF ALCOHOL ADDICTION, ACCORDING TO THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM, 16 MILLION ADULTS SUFFER FROM ALCOHOL USE DISORDERS (AUDS). EVEN THOUGH THERAPEUTIC INTERVENTIONS LIKE BEHAVIORAL THERAPY AND MEDICATIONS TO PREVENT RELAPSE ARE CURRENTLY AVAILABLE, NO ROBUST CURE EXISTS, WHICH STEMS FROM THE LACK OF UNDERSTANDING THE MECHANISMS OF ACTION OF ALCOHOL AND THE LACK OF DEVELOPMENT OF PRECISION MEDICINE APPROACHES TO TREAT AUDS. ANOTHER COMMON GROUP OF ADDICTIVE SUBSTANCE, CANNABINOIDS, HAVE BEEN STUDIED EXTENSIVELY TO REVEAL THEY WORK THROUGH CANNABINOID RECEPTORS. THERAPEUTIC APPLICATIONS HAVE BEEN FOUND FOR THE CANNABINOIDS AND A DEEPER UNDERSTANDING OF THE ENDOCANNABINOID SYSTEM HAS BEEN GAINED OVER THE YEARS. RECENT REPORTS OF CANNABINERGIC MECHANISMS IN AUDS HAS OPENED AN EXCITING REALM OF RESEARCH THAT SEEKS TO ELUCIDATE THE MOLECULAR MECHANISMS OF ALCOHOL-INDUCED END ORGAN DISEASES AND HOPEFULLY PROVIDE INSIGHT INTO NEW THERAPEUTIC STRATEGIES FOR THE TREATMENT OF AUDS. TO DATE, SEVERAL EPIGENETIC MECHANISMS HAVE BEEN ASSOCIATED WITH ALCOHOL AND CANNABINOIDS INDEPENDENTLY. THEREFORE, THE SCOPE OF THIS REVIEW IS TO COMPILE THE MOST RECENT LITERATURE REGARDING ALCOHOL AND CANNABINOIDS IN TERMS OF A POSSIBLE EPIGENETIC CONNECTION BETWEEN THE ENDOCANNABINOID SYSTEM AND ALCOHOL EFFECTS. FIRST, WE WILL PROVIDE AN OVERVIEW OF EPIGENETICS, FOLLOWED BY AN OVERVIEW OF ALCOHOL AND EPIGENETIC MECHANISMS WITH AN EMPHASIS ON HISTONE MODIFICATIONS AND DNA METHYLATIONS. THEN, WE WILL PROVIDE AN OVERVIEW OF CANNABINOIDS AND EPIGENETIC MECHANISMS. LASTLY, WE WILL DISCUSS EVIDENCE OF INTERACTIONS BETWEEN ALCOHOL AND CANNABINERGIC PATHWAYS AND POSSIBLE INSIGHTS INTO THE NOVEL EPIGENETIC MECHANISMS UNDERLYING ALCOHOL-CANNABINERGIC PATHWAY ACTIVITY. FINALIZING THE REVIEW WILL BE A DISCUSSION OF FUTURE DIRECTIONS AND THERAPEUTIC APPLICATIONS. 2017 13 4591 37 NARRATIVE REVIEW OF THE COMPLEX INTERACTION BETWEEN PAIN AND TRAUMA IN CHILDREN: A FOCUS ON BIOLOGICAL MEMORY, PRECLINICAL DATA, AND EPIGENETIC PROCESSES. THE INCIDENCE AND COLLECTIVE IMPACT OF EARLY ADVERSE EXPERIENCES, TRAUMA, AND PAIN CONTINUE TO INCREASE. THIS UNDERSCORES THE URGENT NEED FOR TRANSLATIONAL EFFORTS BETWEEN CLINICAL AND PRECLINICAL RESEARCH TO BETTER UNDERSTAND THE UNDERLYING MECHANISMS AND DEVELOP EFFECTIVE THERAPEUTIC APPROACHES. AS OUR UNDERSTANDING OF THESE ISSUES IMPROVES FROM STUDIES IN CHILDREN AND ADOLESCENTS, WE CAN CREATE MORE PRECISE PRECLINICAL MODELS AND ULTIMATELY TRANSLATE OUR FINDINGS BACK TO CLINICAL PRACTICE. A MULTIDISCIPLINARY APPROACH IS ESSENTIAL FOR ADDRESSING THE COMPLEX AND WIDE-RANGING EFFECTS OF THESE EXPERIENCES ON INDIVIDUALS AND SOCIETY. THIS NARRATIVE REVIEW AIMS TO (1) DEFINE PAIN AND TRAUMA EXPERIENCES IN CHILDHOOD AND ADOLESCENTS, (2) DISCUSS THE RELATIONSHIP BETWEEN PAIN AND TRAUMA, (3) CONSIDER THE ROLE OF BIOLOGICAL MEMORY, (4) DECIPHER THE RELATIONSHIP BETWEEN PAIN AND TRAUMA USING PRECLINICAL DATA, AND (5) EXAMINE THE ROLE OF THE ENVIRONMENT BY INTRODUCING THE IMPORTANCE OF EPIGENETIC PROCESSES. THE ULTIMATE SCOPE IS TO BETTER UNDERSTAND THE WIDE-RANGING EFFECTS OF TRAUMA, ABUSE, AND CHRONIC PAIN ON CHILDREN AND ADOLESCENTS, HOW THEY OCCUR, AND HOW TO PREVENT OR MITIGATE THEIR EFFECTS AND DEVELOP EFFECTIVE TREATMENT STRATEGIES THAT ADDRESS BOTH THE UNDERLYING CAUSES AND THE ASSOCIATED PHYSIOLOGICAL AND PSYCHOLOGICAL EFFECTS. 2023 14 1252 30 CURRENT PERSPECTIVES ON THE NEUROBIOLOGY OF DRUG ADDICTION: A FOCUS ON GENETICS AND FACTORS REGULATING GENE EXPRESSION. DRUG ADDICTION IS A CHRONIC, RELAPSING DISORDER DEFINED BY CYCLIC PATTERNS OF COMPULSIVE DRUG SEEKING AND TAKING INTERSPERSED WITH EPISODES OF ABSTINENCE. WHILE GENETIC VARIABILITY MAY INCREASE THE RISK OF ADDICTIVE BEHAVIOURS IN AN INDIVIDUAL, EXPOSURE TO A DRUG RESULTS IN NEUROADAPTATIONS IN INTERCONNECTED BRAIN CIRCUITS WHICH, IN SUSCEPTIBLE INDIVIDUALS, ARE BELIEVED TO UNDERLIE THE TRANSITION TO, AND MAINTENANCE OF, AN ADDICTED STATE. THESE ADAPTATIONS CAN OCCUR AT THE CELLULAR, MOLECULAR, OR (EPI)GENETIC LEVEL AND ARE ASSOCIATED WITH SYNAPTIC PLASTICITY AND ALTERED GENE EXPRESSION, THE LATTER BEING MEDIATED VIA BOTH FACTORS AFFECTING TRANSLATION (EPIGENETICS) AND TRANSCRIPTION (NON CODING MICRORNAS) OF THE DNA OR RNA ITSELF. NEW ADVANCES USING TECHNIQUES SUCH AS OPTOGENETICS HAVE THE POTENTIAL TO INCREASE OUR UNDERSTANDING OF THE MICROCIRCUITRY MEDIATING ADDICTIVE BEHAVIOURS. HOWEVER, THE PROCESSES LEADING TO ADDICTION ARE COMPLEX AND MULTIFACTORIAL AND THUS WE FACE A MAJOR CONTEMPORARY CHALLENGE TO ELUCIDATE THE FACTORS IMPLICATED IN THE DEVELOPMENT AND MAINTENANCE OF AN ADDICTED STATE. 2012 15 4653 30 NEUROSCIENCE OF ALCOHOLISM: MOLECULAR AND CELLULAR MECHANISMS. ALCOHOL USE AND ABUSE APPEAR TO BE RELATED TO NEUROADAPTIVE CHANGES AT FUNCTIONAL, NEUROCHEMICAL, AND STRUCTURAL LEVELS. ACUTE AND CHRONIC ETHANOL EXPOSURE HAVE BEEN SHOWN TO MODULATE FUNCTION OF THE ACTIVITY-DEPENDENT GENE TRANSCRIPTION FACTOR, CAMP-RESPONSIVE ELEMENT BINDING (CREB) PROTEIN IN THE BRAIN, WHICH MAY BE ASSOCIATED WITH THE DEVELOPMENT OF ALCOHOLISM. STUDY OF THE DOWNSTREAM EFFECTORS OF CREB HAVE IDENTIFIED SEVERAL IMPORTANT CREB-RELATED GENES, SUCH AS NEUROPEPTIDE Y, BRAIN-DERIVED NEUROTROPHIC FACTOR, ACTIVITY-REGULATED CYTOSKELETON-ASSOCIATED PROTEIN, AND CORTICOTROPHIN-RELEASING FACTOR, THAT MAY PLAY A CRUCIAL ROLE IN THE BEHAVIORAL EFFECTS OF ETHANOL AND MOLECULAR CHANGES IN THE SPECIFIC NEUROCIRCUITRY THAT UNDERLIE BOTH ALCOHOL ADDICTION AND A GENETIC PREDISPOSITION TO ALCOHOLISM. BRAIN CHROMATIN REMODELING DUE TO HISTONE COVALENT MODIFICATIONS MAY ALSO BE INVOLVED IN MEDIATING THE BEHAVIORAL EFFECTS AND NEUROADAPTIVE CHANGES THAT OCCUR DURING ETHANOL EXPOSURE. THIS REVIEW OUTLINES PROGRESSIVE NEUROSCIENCE RESEARCH INTO MOLECULAR AND EPIGENETIC MECHANISMS OF ALCOHOLISM. 2010 16 310 33 ALCOHOL AND NMDA RECEPTOR: CURRENT RESEARCH AND FUTURE DIRECTION. THE BRAIN IS ONE OF THE MAJOR TARGETS OF ALCOHOL ACTIONS. MOST OF THE EXCITATORY SYNAPTIC TRANSMISSION IN THE CENTRAL NERVOUS SYSTEM IS MEDIATED BY N-METHYL-D-ASPARTATE (NMDA) RECEPTORS. HOWEVER, ONE OF THE MOST DEVASTATING EFFECTS OF ALCOHOL LEADS TO BRAIN SHRINKAGE, LOSS OF NERVE CELLS AT SPECIFIC REGIONS THROUGH A MECHANISM INVOLVING EXCITOTOXICITY, OXIDATIVE STRESS. EARLIER STUDIES HAVE INDICATED THAT CHRONIC EXPOSURE TO ETHANOL BOTH IN VIVO AND IN VITRO, INCREASES NR1 AND NR2B GENE EXPRESSION AND THEIR POLYPEPTIDE LEVELS. THE EFFECT OF ALCOHOL AND MOLECULAR CHANGES ON THE REGULATORY PROCESS, WHICH MODULATES NMDAR FUNCTIONS INCLUDING FACTORS ALTERING TRANSCRIPTION, TRANSLATION, POST-TRANSLATIONAL MODIFICATIONS, AND PROTEIN EXPRESSION, AS WELL AS THOSE INFLUENCING THEIR INTERACTIONS WITH DIFFERENT REGULATORY PROTEINS (DOWNSTREAM EFFECTORS) ARE INCESSANTLY INCREASING AT THE CELLULAR LEVEL. FURTHER, I DISCUSS THE VARIOUS GENETICALLY ALTERED MICE APPROACHES THAT HAVE BEEN USED TO STUDY NMDA RECEPTOR SUBUNITS AND THEIR FUNCTIONAL IMPLICATION. IN A RECENT COUNTABLE REVIEW, EPIGENETIC DIMENSION (I.E., HISTONE MODIFICATION-INDUCED CHROMATIN REMODELING AND DNA METHYLATION, IN THE PROCESS OF ALCOHOL RELATED NEUROADAPTATION) IS ONE OF THE KEY MOLECULAR MECHANISMS IN ALCOHOL MEDIATED NMDAR ALTERATION. HERE, I PROVIDE A RECOUNT ON WHAT HAS ALREADY BEEN ACHIEVED, CURRENT TRENDS AND HOW THE FUTURE RESEARCH/STUDIES OF THE NMDA RECEPTOR MIGHT LEAD TO EVEN GREATER ENGAGEMENT WITH MANY POSSIBLE NEW INSIGHTS INTO THE NEUROBIOLOGY AND TREATMENT OF ALCOHOLISM. 2013 17 2608 33 EPIGENETICS: A KEY PARADIGM IN REPRODUCTIVE HEALTH. IT IS WELL ESTABLISHED THAT THERE IS A HERITABLE ELEMENT OF SUSCEPTIBILITY TO CHRONIC HUMAN AILMENTS, YET THERE IS COMPELLING EVIDENCE THAT SOME COMPONENTS OF SUCH HERITABILITY ARE TRANSMITTED THROUGH NON-GENETIC FACTORS. DUE TO THE COMPLEXITY OF REPRODUCTIVE PROCESSES, IDENTIFYING THE INHERITANCE PATTERNS OF THESE FACTORS IS NOT EASY. BUT LITTLE DOUBT EXISTS THAT BESIDES THE GENOMIC BACKBONE, A RANGE OF EPIGENETIC CUES AFFECT OUR GENETIC PROGRAMME. THE INTER-GENERATIONAL TRANSMISSION OF EPIGENETIC MARKS IS BELIEVED TO OPERATE VIA FOUR PRINCIPAL MEANS THAT DRAMATICALLY DIFFER IN THEIR INFORMATION CONTENT: DNA METHYLATION, HISTONE MODIFICATIONS, MICRORNAS AND NUCLEOSOME POSITIONING. THESE EPIGENETIC SIGNATURES INFLUENCE THE CELLULAR MACHINERY THROUGH POSITIVE AND NEGATIVE FEEDBACK MECHANISMS EITHER ALONE OR INTERACTIVELY. UNDERSTANDING HOW THESE MECHANISMS WORK TO ACTIVATE OR DEACTIVATE PARTS OF OUR GENETIC PROGRAMME NOT ONLY ON A DAY-TO-DAY BASIS BUT ALSO OVER GENERATIONS IS AN IMPORTANT AREA OF REPRODUCTIVE HEALTH RESEARCH. 2016 18 3103 26 GENOMIC LANDSCAPE OF HCC. INTRODUCTION: HEPATOCELLULAR CARCINOMA (HCC) IS A LEADING CAUSE OF CANCER RELATED MORTALITY IN THE WORLD AND IT HAS LIMITED TREATMENT OPTIONS. UNDERSTANDING THE MOLECULAR DRIVERS OF HCC IS IMPORTANT TO DEVELOP NOVEL BIOMARKERS AND THERAPEUTICS. PURPOSE OF REVIEW: HCC ARISES IN A COMPLEX BACKGROUND OF CHRONIC HEPATITIS, FIBROSIS AND LIVER REGENERATION WHICH LEAD TO GENOMIC CHANGES. HERE, WE SUMMARIZE STUDIES THAT HAVE EXPANDED OUR UNDERSTANDING OF THE MOLECULAR LANDSCAPE OF HCC. RECENT FINDINGS: RECENT TECHNOLOGICAL ADVANCES IN NEXT GENERATION SEQUENCING (NGS) HAVE ELUCIDATED SPECIFIC GENETIC AND MOLECULAR PROGRAMS INVOLVED IN HEPATOCARCINOGENESIS. WE SUMMARIZE THE MAJOR SOMATIC MUTATIONS AND EPIGENETIC CHANGES HAVE BEEN IDENTIFIED IN NGS-BASED STUDIES. WE ALSO DESCRIBE PROMISING MOLECULAR THERAPIES AND IMMUNOTHERAPIES WHICH TARGET SPECIFIC GENETIC AND EPIGENETIC MOLECULAR EVENTS. SUMMARY: THE GENOMIC LANDSCAPE OF HCC IS INCREDIBLY COMPLEX AND HETEROGENEOUS. PROMISING NEW DEVELOPMENTS ARE HELPING US DECIPHER THE MOLECULAR DRIVERS OF HCC AND LEADING TO NEW THERAPIES. 2020 19 6617 33 UNDERPINNING THE NEUROBIOLOGICAL INTRICACIES ASSOCIATED WITH OPIOID TOLERANCE. THE OPIOID CRISIS IS A MAJOR THREAT OF THE 21ST CENTURY, WITH A REMARKABLE JUXTAPOSITION OF USE AND ABUSE. OPIOIDS ARE THE MOST POTENT AND EFFICACIOUS CLASS OF ANALGESICS, BUT DESPITE THEIR PROVEN THERAPEUTIC EFFICACY, THEY HAVE RECENTLY BEEN DEGRADED TO THIRD-LINE THERAPY FOR THE MANAGEMENT OF CHRONIC PAIN IN CLINICS. THE REASON BEHIND THIS IS THE DEVELOPMENT OF POTENTIAL SIDE EFFECTS AND TOLERANCE AFTER REPEATED DOSING. OPIOID TOLERANCE IS THE MAJOR LIMITING FACTOR LEADING TO THE WITHDRAWAL OF TREATMENT, SEVERE SIDE EFFECTS DUE TO DOSE ESCALATION, AND SOMETIMES EVEN DEATH OF THE PATIENTS. EVERY DAY MORE THAN 90 PEOPLE DIE DUE TO OPIOIDS OVERDOSE IN AMERICA, AND A SIMILAR TREND HAS BEEN SEEN ACROSS THE GLOBE. OVER THE PAST TWO DECADES, RESEARCHERS HAVE BEEN TRYING TO DISSECT THE NEUROBIOLOGICAL MECHANISM OF OPIOID TOLERANCE. RESEARCH ON OPIOID TOLERANCE SHIFTED TOWARD CENTRAL NERVOUS SYSTEM-BASED ADAPTATIONS BECAUSE TOLERANCE IS MUCH MORE THAN JUST A CELLULAR PHENOMENON. THUS, NEUROBIOLOGICAL ADAPTATIONS ASSOCIATED WITH OPIOID TOLERANCE ARE IMPORTANT TO UNDERSTAND IN ORDER TO FIND NEWER PAIN THERAPEUTICS. THESE ADAPTATIONS ARE ASSOCIATED WITH ALTERATIONS IN ASCENDING AND DESCENDING PAIN PATHWAYS, REWARD CIRCUITRY MODULATIONS, RECEPTOR DESENSITIZATION AND DOWN-REGULATION, RECEPTOR INTERNALIZATION, HETERODIMERIZATION, AND ALTERED EPIGENETIC REGULATION. THE PRESENT REVIEW IS FOCUSED ON NOVEL CIRCUITRIES ASSOCIATED WITH OPIOID TOLERANCE IN DIFFERENT AREAS OF THE BRAIN, SUCH AS PERIAQUEDUCTAL GRAY, ROSTRAL VENTROMEDIAL MEDULLA, DORSAL RAPHE NUCLEUS, VENTRAL TEGMENTAL AREA, AND NUCLEUS ACCUMBENS. UNDERSTANDING THE NEUROBIOLOGICAL MODULATIONS ASSOCIATED WITH CHRONIC OPIOID EXPOSURE AND TOLERANCE WILL PAVE THE WAY FOR THE DEVELOPMENT OF NOVEL PHARMACOLOGICAL TOOLS FOR SAFER AND BETTER MANAGEMENT OF CHRONIC PAIN IN PATIENTS. 2020 20 4639 34 NEURONAL EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) ACTIVITY AS MARKER AND MEDIATOR OF ALCOHOL AND OPIOID DEPENDENCE. EARLY PIONEERING WORK IN THE FIELD OF BIOCHEMISTRY IDENTIFIED PHOSPHORYLATION AS A CRUCIAL POST-TRANSLATIONAL MODIFICATION OF PROTEINS WITH THE ABILITY TO BOTH INDICATE AND ARBITRATE COMPLEX PHYSIOLOGICAL PROCESSES. MORE RECENT INVESTIGATIONS HAVE FUNCTIONALLY LINKED PHOSPHORYLATION OF EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK) TO A VARIETY OF NEUROPHYSIOLOGICAL MECHANISMS RANGING FROM ACUTE NEUROTRANSMITTER ACTION TO LONG-TERM GENE EXPRESSION. ERK PHOSPHORYLATION SERVES AS AN INTRACELLULAR BRIDGING MECHANISM THAT FACILITATES NEURONAL COMMUNICATION AND PLASTICITY. DRUGS OF ABUSE, INCLUDING ALCOHOL AND OPIOIDS, ACT AS ARTIFICIAL YET POWERFUL REWARDS THAT IMPINGE UPON NATURAL REINFORCEMENT PROCESSES CRITICAL FOR SURVIVAL. THE GRADED PROGRESSION FROM INITIAL EXPOSURE TO ADDICTION (OR SUBSTANCE DEPENDENCE) IS BELIEVED TO RESULT FROM DRUG- AND DRUG CONTEXT-INDUCED ADAPTATIONS IN NEURONAL SIGNALING PROCESSES ACROSS BRAIN REWARD AND STRESS CIRCUITS FOLLOWING EXCESSIVE DRUG USE. IN THIS REGARD, COMMONLY ABUSED DRUGS AS WELL AS DRUG-ASSOCIATED EXPERIENCES ARE CAPABLE OF MODIFYING THE PHOSPHORYLATION OF ERK WITHIN CENTRAL REINFORCEMENT SYSTEMS. IN ADDITION, CHRONIC DRUG AND ALCOHOL EXPOSURE MAY DRIVE ERK-REGULATED EPIGENETIC AND STRUCTURAL ALTERATIONS THAT UNDERLIE A LONG-TERM PROPENSITY FOR ESCALATING DRUG USE. UNDER THE INFLUENCE OF SUCH A NEUROBIOLOGICAL VULNERABILITY, ENCOUNTERING DRUG-ASSOCIATED CUES AND CONTEXTS CAN PRODUCE SUBSEQUENT ALTERATIONS IN ERK SIGNALING THAT DRIVE RELAPSE TO DRUG AND ALCOHOL SEEKING. CURRENT STUDIES ARE DETERMINING PRECISELY WHICH MOLECULAR AND REGIONAL ERK PHOSPHORYLATION-ASSOCIATED EVENTS CONTRIBUTE TO THE ADDICTION PROCESS, AS WELL AS WHICH NEUROADAPTATIONS NEED TO BE TARGETED IN ORDER TO RETURN DEPENDENT INDIVIDUALS TO A HEALTHY STATE. 2014