1 4632 121 NEUROIMAGING GENETIC APPROACHES TO POSTTRAUMATIC STRESS DISORDER. NEUROIMAGING GENETIC STUDIES THAT ASSOCIATE GENETIC AND EPIGENETIC VARIATION WITH NEURAL ACTIVITY OR STRUCTURE PROVIDE AN OPPORTUNITY TO LINK GENES TO PSYCHIATRIC DISORDERS, OFTEN BEFORE PSYCHOPATHOLOGY IS DISCERNABLE IN BEHAVIOR. HERE WE REVIEW NEUROIMAGING GENETICS STUDIES WITH PARTICIPANTS WHO HAVE POSTTRAUMATIC STRESS DISORDER (PTSD). RESULTS SHOW THAT GENES RELATED TO THE PHYSIOLOGICAL STRESS RESPONSE (E.G., GLUCOCORTICOID RECEPTOR AND ACTIVITY, NEUROENDOCRINE RELEASE), LEARNING AND MEMORY (E.G., PLASTICITY), MOOD, AND PAIN PERCEPTION ARE TIED TO NEURAL INTERMEDIATE PHENOTYPES ASSOCIATED WITH PTSD. THESE GENES ARE ASSOCIATED WITH AND SOMETIMES PREDICT NEURAL STRUCTURE AND FUNCTION IN AREAS INVOLVED IN ATTENTION, EXECUTIVE FUNCTION, MEMORY, DECISION-MAKING, EMOTION REGULATION, SALIENCE OF POTENTIAL THREATS, AND PAIN PERCEPTION. EVIDENCE SUGGESTS THESE RISK POLYMORPHISMS AND NEURAL INTERMEDIATE PHENOTYPES ARE VULNERABILITIES TOWARD DEVELOPING PTSD IN THE AFTERMATH OF TRAUMA, OR VULNERABILITIES TOWARD PARTICULAR SYMPTOMS ONCE PTSD HAS DEVELOPED. WORK DISTINGUISHING BETWEEN THE RE-EXPERIENCING AND DISSOCIATIVE SUB-TYPES OF PTSD, AND EXAMINING OTHER PTSD SYMPTOM CLUSTERS IN ADDITION TO THE RE-EXPERIENCING AND HYPERAROUSAL SYMPTOMS, WILL FURTHER CLARIFY NEUROBIOLOGICAL MECHANISMS AND INCONSISTENT FINDINGS. FURTHERMORE, AN EXCITING POSSIBILITY IS THAT GENETIC ASSOCIATIONS WITH PTSD MAY EVENTUALLY BE UNDERSTOOD THROUGH DIFFERENTIAL INTERMEDIATE PHENOTYPES OF NEURAL CIRCUIT STRUCTURE AND FUNCTION, POSSIBLY UNDERLYING THE DIFFERENT SYMPTOM CLUSTERS SEEN WITHIN PTSD. 2016 2 4937 33 PATERNAL MORPHINE EXPOSURE IN RATS REDUCES SOCIAL PLAY IN ADOLESCENT MALE PROGENY WITHOUT AFFECTING DRUG-TAKING BEHAVIOR IN JUVENILE MALES OR FEMALE OFFSPRING. THE ONGOING OPIOID ADDICTION CRISIS NECESSITATES THE IDENTIFICATION OF NOVEL RISK FACTORS TO IMPROVE PREVENTION AND TREATMENT OF OPIOID USE DISORDER. PARENTAL OPIOID EXPOSURE HAS RECENTLY EMERGED AS A POTENTIAL REGULATOR OF OFFSPRING VULNERABILITY TO OPIOID MISUSE, IN ADDITION TO HERITABLE GENETIC LIABILITY. AN UNDERSTUDIED ASPECT OF THIS "MISSING HERITABILITY" IS THE DEVELOPMENTAL PRESENTATION OF THESE CROSS-GENERATIONAL PHENOTYPES. THIS IS AN ESPECIALLY RELEVANT QUESTION IN THE CONTEXT OF INHERITED ADDICTION-RELATED PHENOTYPES, GIVEN THE PROMINENT ROLE OF DEVELOPMENTAL PROCESSES IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS. PATERNAL MORPHINE SELF-ADMINISTRATION WAS PREVIOUSLY SHOWN TO ALTER THE SENSITIVITY TO THE REINFORCING AND ANTINOCICEPTIVE PROPERTIES OF OPIOIDS IN THE NEXT GENERATION. HERE, PHENOTYPING WAS EXPANDED TO INCLUDE THE ADOLESCENT PERIOD, WITH A FOCUS ON ENDOPHENOTYPES RELATED TO OPIOID USE DISORDERS AND PAIN. PATERNAL MORPHINE EXPOSURE DID NOT ALTER HEROIN OR COCAINE SELF-ADMINISTRATION IN MALE AND FEMALE JUVENILE PROGENY. FURTHER, BASELINE SENSORY REFLEXES RELATED TO PAIN WERE UNALTERED IN MORPHINE-SIRED ADOLESCENT RATS OF EITHER SEX. HOWEVER, MORPHINE-SIRED ADOLESCENT MALES EXHIBITED A REDUCTION IN SOCIAL PLAY BEHAVIOR. OUR FINDINGS SUGGEST THAT, IN MORPHINE-SIRED MALE OFFSPRING, PATERNAL OPIOID EXPOSURE DOES NOT AFFECT OPIOID INTAKE DURING ADOLESCENCE, SUGGESTING THAT THIS PHENOTYPE DOES NOT EMERGE UNTIL LATER IN LIFE. ALTERED SOCIAL BEHAVIORS IN MALE MORPHINE-SIRED ADOLESCENTS INDICATE THAT THE CHANGES IN DRUG-TAKING BEHAVIOR IN ADULTS SIRED BY MORPHINE-EXPOSED SIRES MAY BE DUE TO MORE COMPLEX FACTORS NOT YET FULLY ASSESSED. 2023 3 5310 25 PSYCHOBIOLOGY AND MOLECULAR GENETICS OF RESILIENCE. EVERY INDIVIDUAL EXPERIENCES STRESSFUL LIFE EVENTS. IN SOME CASES ACUTE OR CHRONIC STRESS LEADS TO DEPRESSION AND OTHER PSYCHIATRIC DISORDERS, BUT MOST PEOPLE ARE RESILIENT TO SUCH EFFECTS. RECENT RESEARCH HAS BEGUN TO IDENTIFY THE ENVIRONMENTAL, GENETIC, EPIGENETIC AND NEURAL MECHANISMS THAT UNDERLIE RESILIENCE, AND HAS SHOWN THAT RESILIENCE IS MEDIATED BY ADAPTIVE CHANGES IN SEVERAL NEURAL CIRCUITS INVOLVING NUMEROUS NEUROTRANSMITTER AND MOLECULAR PATHWAYS. THESE CHANGES SHAPE THE FUNCTIONING OF THE NEURAL CIRCUITS THAT REGULATE REWARD, FEAR, EMOTION REACTIVITY AND SOCIAL BEHAVIOUR, WHICH TOGETHER ARE THOUGHT TO MEDIATE SUCCESSFUL COPING WITH STRESS. 2009 4 4402 26 MODULATION OF NOCICEPTION BY SOCIAL FACTORS IN RODENTS: CONTRIBUTION OF THE OPIOID SYSTEM. RATIONALE: THE OPIOID SYSTEM IS INVOLVED IN THE REGULATION OF SEVERAL BEHAVIORAL AND PHYSIOLOGICAL RESPONSES, CONTROLLING PAIN, REWARD, AND ADDICTIVE BEHAVIORS. OPIOID ADMINISTRATION, DEPENDING ON DRUGS AND DOSES, USUALLY AFFECTS SOCIABILITY REDUCING INTERACTIONS BETWEEN CONSPECIFICS, WHEREAS SOME AFFILIATIVE BEHAVIORS SUCH AS SEXUAL ACTIVITY, SOCIAL GROOMING, AND PLAY BEHAVIOR INCREASE THE ENDOGENOUS OPIOID ACTIVITY. OBJECTIVES: THE POSSIBLE INTERACTION BETWEEN ENDOGENOUS OPIOIDS RELEASED DURING SOCIO/SEXUAL BEHAVIOR AND THEIR ANALGESIC EFFECT ON PAIN RESPONSE IS REVIEWED IN THE RODENT LITERATURE. RESULTS: DIRECT EVIDENCE FOR SOCIALLY MEDIATED OPIOID CHANGES RESULTING IN INCREASE IN NOCICEPTIVE THRESHOLD DERIVES FROM STUDIES EXPLORING THE EFFECTS OF DEFEAT EXPERIENCES, SOCIAL ISOLATION, MATERNAL, SEXUAL BEHAVIOR, AND SOCIAL REUNION AMONG KIN OR FAMILIAR ANIMALS IN LABORATORY RODENTS. INDIRECT EVIDENCE FOR ENDOGENOUS ACTIVATION OF THE OPIOID SYSTEM, POSSIBLY AFFECTING PAIN SENSITIVITY, DERIVES FROM STUDIES INVESTIGATING THE RELEVANCE OF NATURAL SOCIAL REWARD USING THE CONDITIONED PLACE PREFERENCE PROTOCOLS OR ANALYZING ULTRASONIC VOCALIZATIONS ASSOCIATED TO POSITIVE AFFECTIVE CONTEXTS. FINALLY, GENETIC AND EPIGENETIC FACTORS THAT AFFECT THE OPIOID SYSTEM DURING DEVELOPMENT ARE REPORTED TO BE INVOLVED IN MODULATING THE RESPONSE TO SOCIAL STIMULI AS WELL AS NOCICEPTION. CONCLUSIONS: ALL STUDIES HIGHLIGHT THE RELEVANCE OF AFFILIATIVE CONTACT BEHAVIOR BETWEEN CONSPECIFICS THAT IS RESPONSIBLE FOR THE ACTIVATION OF THE ENDOGENOUS MU-OPIOID SYSTEM, INDUCING NOCICEPTIVE THRESHOLD INCREASE. 2012 5 5831 38 STRESS-INDUCED CHRONIC VISCERAL PAIN OF GASTROINTESTINAL ORIGIN. VISCERAL PAIN IS GENERALLY POORLY LOCALIZED AND CHARACTERIZED BY HYPERSENSITIVITY TO A STIMULUS SUCH AS ORGAN DISTENSION. IN CONCERT WITH CHRONIC VISCERAL PAIN, THERE IS A HIGH COMORBIDITY WITH STRESS-RELATED PSYCHIATRIC DISORDERS INCLUDING ANXIETY AND DEPRESSION. THE MECHANISMS LINKING VISCERAL PAIN WITH THESE OVERLAPPING COMORBIDITIES REMAIN TO BE ELUCIDATED. EVIDENCE SUGGESTS THAT LONG TERM STRESS FACILITATES PAIN PERCEPTION AND SENSITIZES PAIN PATHWAYS, LEADING TO A FEED-FORWARD CYCLE PROMOTING CHRONIC VISCERAL PAIN DISORDERS SUCH AS IRRITABLE BOWEL SYNDROME (IBS). EARLY LIFE STRESS (ELS) IS A RISK-FACTOR FOR THE DEVELOPMENT OF IBS, HOWEVER THE MECHANISMS RESPONSIBLE FOR THE PERSISTENT EFFECTS OF ELS ON VISCERAL PERCEPTION IN ADULTHOOD REMAIN INCOMPLETELY UNDERSTOOD. IN RODENT MODELS, STRESS IN ADULT ANIMALS INDUCED BY RESTRAINT AND WATER AVOIDANCE HAS BEEN EMPLOYED TO INVESTIGATE THE MECHANISMS OF STRESS-INDUCE PAIN. ELS MODELS SUCH AS MATERNAL SEPARATION, LIMITED NESTING, OR ODOR-SHOCK CONDITIONING, WHICH ATTEMPT TO MODEL EARLY CHILDHOOD EXPERIENCES SUCH AS NEGLECT, POVERTY, OR AN ABUSIVE CAREGIVER, CAN PRODUCE CHRONIC, SEXUALLY DIMORPHIC INCREASES IN VISCERAL SENSITIVITY IN ADULTHOOD. CHRONIC VISCERAL PAIN IS A CLASSIC EXAMPLE OF GENE X ENVIRONMENT INTERACTION WHICH RESULTS FROM MALADAPTIVE CHANGES IN NEURONAL CIRCUITRY LEADING TO NEUROPLASTICITY AND ABERRANT NEURONAL ACTIVITY-INDUCED SIGNALING. ONE POTENTIAL MECHANISM UNDERLYING THE PERSISTENT EFFECTS OF STRESS ON VISCERAL SENSITIVITY COULD BE EPIGENETIC MODULATION OF GENE EXPRESSION. WHILE THERE ARE RELATIVELY FEW STUDIES EXAMINING EPIGENETICALLY MEDIATED MECHANISMS INVOLVED IN VISCERAL NOCICEPTION, STRESS-INDUCED VISCERAL PAIN HAS BEEN LINKED TO ALTERATIONS IN DNA METHYLATION AND HISTONE ACETYLATION PATTERNS WITHIN THE BRAIN, LEADING TO INCREASED EXPRESSION OF PRO-NOCICEPTIVE NEUROTRANSMITTERS. THIS REVIEW WILL DISCUSS THE POTENTIAL NEURONAL PATHWAYS AND MECHANISMS RESPONSIBLE FOR STRESS-INDUCED EXACERBATION OF CHRONIC VISCERAL PAIN. ADDITIONALLY, WE WILL REVIEW THE IMPORTANCE OF SPECIFIC EXPERIMENTAL MODELS OF ADULT STRESS AND ELS IN ENHANCING OUR UNDERSTANDING OF THE BASIC MOLECULAR MECHANISMS OF PAIN PROCESSING. 2017 6 5466 35 RESILIENCE: SAFETY IN THE AFTERMATH OF TRAUMATIC STRESSOR EXPERIENCES. THE RELATIONSHIP BETWEEN ADVERSE EXPERIENCES AND THE EMERGENCE OF PATHOLOGY HAS OFTEN FOCUSED ON CHARACTERISTICS OF THE STRESSOR OR OF THE INDIVIDUAL (STRESSOR APPRAISALS, COPING STRATEGIES). THESE FEATURES ARE THOUGHT TO INFLUENCE MULTIPLE BIOLOGICAL PROCESSES THAT FAVOR THE DEVELOPMENT OF MENTAL AND PHYSICAL ILLNESSES. LESS OFTEN HAS ATTENTION FOCUSED ON THE AFTERMATH OF TRAUMATIC EXPERIENCES, AND THE IMPORTANCE OF SAFETY AND REASSURANCE THAT IS NECESSARY FOR LONGER-TERM WELL-BEING. IN SOME CASES (E.G., POST-TRAUMATIC STRESS DISORDER) THIS MAY BE REFLECTED BY A FAILURE OF FEAR EXTINCTION, WHEREAS IN OTHER INSTANCES (E.G., HISTORICAL TRAUMA), THE UNCERTAINTY ABOUT THE FUTURE MIGHT FOSTER CONTINUED ANXIETY. IN ESSENCE, THE QUESTION BECOMES ONE OF HOW INDIVIDUALS ATTAIN FEELINGS OF SAFETY WHEN IT IS FULLY UNDERSTOOD THAT THE WORLD IS NOT NECESSARILY A SAFE PLACE, UNCERTAINTIES ABOUND, AND FEELINGS OF AGENCY ARE OFTEN ILLUSORY. WE CONSIDER HOW INDIVIDUALS ACQUIRE RESILIENCE IN THE AFTERMATH OF TRAUMATIC AND CHRONIC STRESSORS. IN THIS RESPECT, WE REVIEW CHARACTERISTICS OF STRESSORS THAT MAY TRIGGER PARTICULAR BIOLOGICAL AND BEHAVIORAL COPING RESPONSES, AS WELL AS FACTORS THAT UNDERMINE THEIR EFFICACY. TO THIS END, WE EXPLORE STRESSOR DYNAMICS AND SOCIAL PROCESSES THAT FOSTER RESILIENCE IN RESPONSE TO SPECIFIC TRAUMATIC, CHRONIC, AND UNCONTROLLABLE STRESSOR CONTEXTS (INTIMATE PARTNER ABUSE; REFUGEE MIGRATION; COLLECTIVE HISTORICAL TRAUMA). WE POINT TO RESILIENCE FACTORS THAT MAY COMPRISE NEUROBIOLOGICAL CHANGES, SUCH AS THOSE RELATED TO VARIOUS STRESSOR-PROVOKED HORMONES, NEUROTROPHINS, INFLAMMATORY IMMUNE, MICROBIAL, AND EPIGENETIC PROCESSES. THESE BEHAVIORAL AND BIOLOGICAL STRESS RESPONSES MAY INFLUENCE, AND BE INFLUENCED BY, FEELINGS OF SAFETY THAT COME ABOUT THROUGH RELATIONSHIPS WITH OTHERS, SPIRITUAL AND PLACE-BASED CONNECTIONS. 2020 7 5804 26 STRAIN AND SEX DEPENDENT EFFECTS OF ISOLATION HOUSING RELATIVE TO ENVIRONMENTAL ENRICHMENT ON OPERANT SENSATION SEEKING IN MICE. SENSATION SEEKING IS A MULTIDIMENSIONAL PHENOTYPE THAT PREDICTS THE DEVELOPMENT OF DRUG ADDICTION IN HUMANS AND ADDICTION-LIKE DRUG SEEKING IN RODENTS. SEVERAL LINES OF EVIDENCE SUGGEST THAT CHRONIC STRESS INCREASES SENSATION SEEKING AND ADDICTION-LIKE DRUG SEEKING THROUGH COMMON GENETIC MECHANISMS. DISCOVERY AND CHARACTERIZATION OF THESE MECHANISMS WOULD REVEAL HOW CHRONIC STRESS INTERACTS WITH THE GENOME TO INFLUENCE SENSATION SEEKING AND HOW DRUGS OF ABUSE HIJACK THESE FUNDAMENTAL REWARD MECHANISMS TO DRIVE ADDICTION. TO THIS END, WE TESTED THE HYPOTHESIS THAT CHRONIC ISOLATION HOUSING STRESS (RELATIVE TO ENVIRONMENTAL ENRICHMENT) INFLUENCES OPERANT SENSATION SEEKING AS A FUNCTION OF STRAIN, SEX, OR THEIR INTERACTION. TO DETERMINE IF THE BXD RECOMBINANT INBRED PANEL COULD BE USED TO IDENTIFY GENETIC AND EPIGENETIC MECHANISMS UNDERLYING ANY IDENTIFIED GENE-BY-ENVIRONMENT INTERACTIONS, WE USED MICE FROM THE TWO BXD FOUNDER STRAINS. FOLLOWING 10 WEEKS OF DIFFERENTIAL HOUSING, WE ASSESSED OPERANT SENSATION SEEKING USING SEVERAL REINFORCEMENT SCHEDULES. THE PRIMARY FINDING FROM THIS STUDY WAS THAT DBA/2J BUT NOT C57BL/6J MICE WERE SIGNIFICANTLY VULNERABLE TO AN ISOLATION-INDUCED INCREASE (RELATIVE TO ENVIRONMENTAL ENRICHMENT) IN SENSATION SEEKING DURING EXTINCTION WHEN THE SENSORY REWARD WAS NO LONGER AVAILABLE; THIS EFFECT WAS SIGNIFICANTLY MORE ROBUST IN FEMALES. THESE DATA REVEAL A PREVIOUSLY UNKNOWN ISOLATION-INDUCED EFFECT ON EXTINCTION OF OPERANT SENSATION SEEKING THAT IS SEX-DEPENDENT, ADDICTION-RELEVANT, AND THAT CAN BE DISSECTED USING THE BXD RECOMBINANT INBRED PANEL. 2021 8 4622 31 NEUROBIOLOGICAL DEVELOPMENT IN THE CONTEXT OF CHILDHOOD TRAUMA. NEUROBIOLOGICAL SYSTEMS MAY BE PARTICULARLY SUSCEPTIBLE TO DELETERIOUS IMPACT OF CHILDHOOD TRAUMA, AND THE IMPACT OF CHILDHOOD TRAUMA ON DEVELOPMENT AND SUBSEQUENT FUNCTIONAL OUTCOMES ACROSS THE LIFESPAN HAS BEEN WELL-DOCUMENTED. THE CURRENT REVIEW ADDRESSES THE NEUROBIOLOGICAL IMPACT OF EXPOSURE TO INTERPERSONAL TRAUMA IN CHILDHOOD IN THE CONTEXT OF EXECUTIVE FUNCTION, EMOTION REGULATION, AND DISSOCIATION/INTEROCEPTIVE AWARENESS. SUBSEQUENT RISK FOR PTSD AND DEPRESSION IS ALSO DISCUSSED. THE PATHWAY OF RISK FROM CHILDHOOD TRAUMA TO THESE COGNITIVE, EMOTIONAL, AND PSYCHIATRIC OUTCOMES IS ADDRESSED IN TERMS OF POTENTIAL STRUCTURAL AND FUNCTIONAL ALTERATIONS WITHIN THE HIPPOCAMPUS, PREFRONTAL CORTEX, AND AMYGDALA RESULTING FROM CHRONIC OR REPEATED ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS AND ITS INTERACTION WITH AND INFLUENCE ON GENETIC AND EPIGENETIC PROCESSES DURING SENSITIVE PERIODS OF DEVELOPMENT. IMPLICATIONS FOR PRACTICE ARE DISCUSSED. 2017 9 1750 29 EARLY LIFE STRESS AND PEDIATRIC POSTTRAUMATIC STRESS DISORDER. TRAUMATIC STRESS EXPOSURE DURING CRITICAL PERIODS OF DEVELOPMENT MAY HAVE ESSENTIAL AND LONG-LASTING EFFECTS ON THE PHYSICAL AND MENTAL HEALTH OF INDIVIDUALS. TWO THIRDS OF YOUTH ARE EXPOSED TO POTENTIALLY TRAUMATIC EXPERIENCES BY THE AGE OF 17, AND APPROXIMATELY 5% OF ADOLESCENTS MEET LIFETIME CRITERIA FOR POSTTRAUMATIC STRESS DISORDER (PTSD). THE ROLE OF THE STRESS SYSTEM IS THE MAINTENANCE OF HOMEOSTASIS IN THE PRESENCE OF REAL/PERCEIVED AND ACUTE/CHRONIC STRESSORS. EARLY-LIFE STRESS (ELS) HAS AN IMPACT ON NEURONAL BRAIN NETWORKS INVOLVED IN STRESS REACTIONS, AND COULD EXERT A PROGRAMMING EFFECT ON GLUCOCORTICOID SIGNALING. STUDIES ON PEDIATRIC PTSD REVEAL DIVERSE NEUROENDOCRINE RESPONSES TO ADVERSE EVENTS AND RELATED LONG-TERM NEUROENDOCRINE AND EPIGENETIC ALTERATIONS. NEUROENDOCRINE, NEUROIMAGING, AND GENETIC STUDIES IN CHILDREN WITH PTSD AND ELS EXPERIENCES ARE CRUCIAL IN UNDERSTANDING RISK AND RESILIENCE FACTORS, AND ALSO THE NATURAL HISTORY OF PTSD. 2020 10 2509 28 EPIGENETICS AND PAIN: NEW INSIGHTS TO AN OLD PROBLEM. PHYSICIANS AND NEUROSCIENTISTS HAVE LONG OBSERVED THAT FACTORS SUCH AS THOUGHTS, EMOTIONS, AND EXPECTATIONS CAN INFLUENCE THE PERCEPTION OF PAIN. PAIN CAN BE DESCRIBED AS AN UNPLEASANT SENSATION THAT CAUSES PHYSICAL DISCOMFORT AND EMOTIONAL DISTRESS. IT ALERTS AN INDIVIDUAL TO SEEK HELP AND IS THE MAIN COMPLAINT THAT BRINGS INDIVIDUALS TO PHYSICIANS. THOUGH IT IS ASSOCIATED WITH PROBABLE TISSUE DAMAGE, SUCH DAMAGE MAY BE SUBTLE, SOMETIMES INVOLVING THE RELEASE OF ALGESIC CHEMICALS, AND ALSO INFLUENCED BY ATTITUDES, BELIEFS, PERSONALITY, AND SOCIAL FACTORS. THE PERCEPTION OF PAIN MAY VARY DUE TO A MULTITUDE OF THESE FACTORS INFLUENCING THE ASCENDING SENSORY IMPULSE PROPAGATION TO THE PRIMARY SOMATOSENSORY CORTEX. THE GENETICS AND EPIGENETICS OF PAIN MODULATORS HAVE BEEN PREVIOUSLY STUDIED, BUT THERE IS A LACK OF APPLICATION IN THE EVERYDAY MANAGEMENT AND TREATMENT OF PAIN DUE TO THE PAUCITY OF VALID EVIDENCE-BASED DATA. WE USED THE PUBMED DATABASE AS OUR PRIMARY TOOL FOR RESEARCHING CURRENT LITERATURE ON THIS TOPIC. THE MESH TERMS USED INCLUDED: GENE MODIFICATION, EPIGENETICS, GENES, PAIN, ANALGESIA, "TYPES OF PAIN, AND THEORIES OF PAIN. THE RESULTS WERE FILTERED AS FOLLOWS: PUBLICATIONS WITHIN THE LAST 10 YEARS, GENERALIZED PAIN STUDIES REGARDING THE BIOPSYCHOSOCIAL ASPECT OF PAIN, PERTINENT GENES, AND EPIGENETIC MODULATION OF THOSE GENES; 52 PUBLICATIONS WERE SELECTED FOR REVIEW. BY ADDRESSING THE EXTERNAL FACTORIAL CAUSES AND THE APPROPRIATE APPLICATION OF EPIGENETIC PRINCIPLES WHICH AFFECT PAIN PERCEPTION, IT IS HOPED THAT THIS REVIEW WILL MOTIVATE FUTURE ADVANCEMENTS IN THE MANAGEMENT OF ACUTE AND/OR CHRONIC PAIN. 2022 11 4701 32 NICOTINE AND THE ADOLESCENT BRAIN. ADOLESCENCE ENCOMPASSES A SENSITIVE DEVELOPMENTAL PERIOD OF ENHANCED CLINICAL VULNERABILITY TO NICOTINE, TOBACCO, AND E-CIGARETTES. WHILE THERE ARE SOCIOCULTURAL INFLUENCES, DATA AT PRECLINICAL AND CLINICAL LEVELS INDICATE THAT THIS ADOLESCENT SENSITIVITY HAS STRONG NEUROBIOLOGICAL UNDERPINNINGS. ALTHOUGH DEFINITIONS OF ADOLESCENCE VARY, THE HALLMARK OF THIS PERIOD IS A PROFOUND REORGANIZATION OF BRAIN REGIONS NECESSARY FOR MATURE COGNITIVE AND EXECUTIVE FUNCTION, WORKING MEMORY, REWARD PROCESSING, EMOTIONAL REGULATION, AND MOTIVATED BEHAVIOR. REGULATING CRITICAL FACETS OF BRAIN MATURATION ARE NICOTINIC ACETYLCHOLINE RECEPTORS (NACHRS). HOWEVER, PERTURBATIONS OF CHOLINERGIC SYSTEMS DURING THIS TIME WITH NICOTINE, VIA TOBACCO OR E-CIGARETTES, HAVE UNIQUE CONSEQUENCES ON ADOLESCENT DEVELOPMENT. IN THIS REVIEW, WE HIGHLIGHT RECENT CLINICAL AND PRECLINICAL DATA EXAMINING THE ADOLESCENT BRAIN'S DISTINCT NEUROBIOLOGY AND UNIQUE SENSITIVITY TO NICOTINE. FIRST, WE DISCUSS WHAT DEFINES ADOLESCENCE BEFORE REVIEWING NORMATIVE STRUCTURAL AND NEUROCHEMICAL ALTERATIONS THAT PERSIST UNTIL EARLY ADULTHOOD, WITH AN EMPHASIS ON DOPAMINERGIC SYSTEMS. WE REVIEW HOW ACUTE EXPOSURE TO NICOTINE IMPACTS BRAIN DEVELOPMENT AND HOW DRUG RESPONSES DIFFER FROM THOSE SEEN IN ADULTS. FINALLY, WE DISCUSS THE PERSISTENT ALTERATIONS IN NEURONAL SIGNALING AND COGNITIVE FUNCTION THAT RESULT FROM CHRONIC NICOTINE EXPOSURE, WHILE HIGHLIGHTING A LOW DOSE, SEMI-CHRONIC EXPOSURE PARADIGM THAT MAY BETTER MODEL ADOLESCENT TOBACCO USE. WE ARGUE THAT NICOTINE EXPOSURE, INCREASINGLY OCCURRING AS A RESULT OF E-CIGARETTE USE, MAY INDUCE EPIGENETIC CHANGES THAT SENSITIZE THE BRAIN TO OTHER DRUGS AND PRIME IT FOR FUTURE SUBSTANCE ABUSE. 2015 12 242 32 ADOLESCENT CANNABINOID EXPOSURE MODULATES THE VULNERABILITY TO COCAINE-INDUCED CONDITIONED PLACE PREFERENCE AND DNMT3A EXPRESSION IN THE PREFRONTAL CORTEX IN SWISS MICE. RATIONALE: CANNABIS SATIVA IS THE MOST WIDELY USED DRUG BY ADOLESCENTS GLOBALLY. THE RECREATIONAL USE OF SYNTHETIC CANNABINOIDS BY TEENAGERS HAS ALSO GROWN IN RECENT YEARS. DESPITE THE WRONG PERCEPTION THAT EXPOSURE TO THESE DRUGS DOES NOT CAUSE HARM, REPEATED EXPOSURE TO CANNABINOIDS AT EARLY STAGES OF LIFE COMPROMISES IMPORTANT MATURATION PROCESSES AND BRAIN DEVELOPMENT. CHRONIC EARLY CANNABINOID USE HAS BEEN RELATED TO A HIGHER RISK OF PSYCHIATRIC OUTCOMES, INCLUDING COCAINE ADDICTION. EVIDENCE SUGGESTS THAT EXPOSURE TO NATURAL AND SYNTHETIC CANNABINOIDS DURING ADOLESCENCE MODIFIES MOLECULAR AND BEHAVIORAL EFFECTS OF COCAINE IN ADULTHOOD. RESPONSES TO COCAINE ARE REGULATED BY EPIGENETIC MECHANISMS, SUCH AS DNA METHYLATION, IN THE BRAIN'S REWARD REGIONS. HOWEVER, THE INVOLVEMENT OF THESE PROCESSES IN MODULATION OF THE VULNERABILITY TO THE EFFECTS OF COCAINE INDUCED BY PRIOR EXPOSURE TO CANNABINOIDS REMAINS POORLY UNDERSTOOD. OBJECTIVES: INVESTIGATE WHETHER EXPOSURE TO THE SYNTHETIC CANNABINOID WIN55,212-2 DURING ADOLESCENCE MODULATES ANXIETY- AND DEPRESSION-LIKE BEHAVIOR, MEMORY, AND COCAINE REWARD IN ADULT MICE. WE ALSO EVALUATED WHETHER EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE MODULATES THE EXPRESSION OF ENZYMES THAT ARE INVOLVED IN DNA METHYLATION. RESULTS: EXPOSURE TO WIN55,212-2 DURING ADOLESCENCE DID NOT ALTER ANXIETY- OR DEPRESSIVE-LIKE BEHAVIOR. HOWEVER, PRIOR EXPOSURE TO CANNABINOIDS INHIBITED COCAINE-INDUCED CONDITIONED PLACE PREFERENCE WITHOUT MODULATING COCAINE-INDUCED HYPERLOCOMOTION, ACCOMPANIED BY AN INCREASE IN EXPRESSION OF THE ENZYME DNA METHYLTRANSFERASE 3A (DNMT3A) IN THE PREFRONTAL CORTEX. CONCLUSIONS: OUR FINDINGS SUGGEST THAT EXPOSURE TO WIN55,212-2 DURING ADOLESCENCE LEADS TO CHANGES IN DNMT3A EXPRESSION, AND THIS PATHWAY APPEARS TO BE RELEVANT TO MODULATING THE REWARDING EFFECTS OF COCAINE. 2021 13 4938 33 PATERNAL NICOTINE ENHANCES FEAR MEMORY, REDUCES NICOTINE ADMINISTRATION, AND ALTERS HIPPOCAMPAL GENETIC AND NEURAL FUNCTION IN OFFSPRING. NICOTINE USE REMAINS HIGHLY PREVALENT WITH TOBACCO AND E-CIGARETTE PRODUCTS CONSUMED WORLDWIDE. HOWEVER, INCREASING EVIDENCE OF TRANSGENERATIONAL EPIGENETIC INHERITANCE SUGGESTS THAT NICOTINE USE MAY ALTER BEHAVIOR AND NEUROBIOLOGY IN SUBSEQUENT GENERATIONS. WE TESTED THE EFFECTS OF CHRONIC PATERNAL NICOTINE EXPOSURE IN C57BL6/J MICE ON FEAR CONDITIONING IN F1 AND F2 OFFSPRING, AS WELL AS CONDITIONED FEAR EXTINCTION AND SPONTANEOUS RECOVERY, NICOTINE SELF-ADMINISTRATION, HIPPOCAMPAL CHOLINERGIC FUNCTIONING, RNA EXPRESSION, AND DNA METHYLATION IN F1 OFFSPRING. PATERNAL NICOTINE EXPOSURE WAS ASSOCIATED WITH ENHANCED CONTEXTUAL AND CUED FEAR CONDITIONING AND SPONTANEOUS RECOVERY OF EXTINGUISHED FEAR MEMORIES. FURTHER, NICOTINE REINFORCEMENT WAS REDUCED IN NICOTINE-SIRED MICE, AS ASSESSED IN A SELF-ADMINISTRATION PARADIGM. THESE BEHAVIORAL PHENOTYPES WERE COUPLED WITH ALTERED RESPONSE TO NICOTINE, UPREGULATED HIPPOCAMPAL NICOTINIC ACETYLCHOLINE RECEPTOR BINDING, REDUCED EVOKED HIPPOCAMPAL CHOLINERGIC CURRENTS, AND ALTERED METHYLATION AND EXPRESSION OF HIPPOCAMPAL GENES RELATED TO NEURAL DEVELOPMENT AND PLASTICITY. GENE EXPRESSION ANALYSIS SUGGESTS MULTIGENERATIONAL EFFECTS ON BROADER GENE NETWORKS POTENTIALLY INVOLVED IN NEUROPLASTICITY AND MENTAL DISORDERS. THE CHANGES IN FEAR CONDITIONING SIMILARLY SUGGEST PHENOTYPES ANALOGOUS TO ANXIETY DISORDERS SIMILAR TO POST-TRAUMATIC STRESS. 2021 14 4500 30 MORPHINE-WITHDRAWAL AVERSIVE MEMORIES AND THEIR EXTINCTION MODULATE H4K5 ACETYLATION AND BRD4 ACTIVATION IN THE RAT HIPPOCAMPUS AND BASOLATERAL AMYGDALA. CHROMATIN MODIFICATION IS A CRUCIAL MECHANISM IN SEVERAL IMPORTANT PHENOMENA IN THE BRAIN, INCLUDING DRUG ADDICTION. PERSISTENCE OF DRUG CRAVING AND RISK OF RELAPSE COULD BE ATTRIBUTED TO DRUG-INDUCED EPIGENETIC MECHANISMS THAT SEEM TO BE CANDIDATES EXPLAINING LONG-LASTING DRUG-INDUCED BEHAVIOUR AND MOLECULAR ALTERATIONS. HISTONE ACETYLATION HAS BEEN PROPOSED TO REGULATE DRUG-SEEKING BEHAVIOURS AND THE EXTINCTION OF REWARDING MEMORY OF DRUG TAKING. IN THIS WORK, WE STUDIED THE EPIGENETIC REGULATION DURING CONDITIONED PLACE AVERSION AND AFTER EXTINCTION OF AVERSIVE MEMORY OF OPIATE WITHDRAWAL. THROUGH IMMUNOFLUORESCENCE ASSAYS, WE ASSESSED SOME EPIGENETIC MARKS (H4K5AC AND P-BRD4) IN CRUCIAL AREAS RELATED TO MEMORY RETRIEVAL -BASOLATERAL AMYGDALA (BLA) AND HIPPOCAMPUS-. ADDITIONALLY, TO TEST THE DEGREE OF TRANSCRIPTIONAL ACTIVATION, WE EVALUATED THE IMMEDIATE EARLY GENES (IEGS) RESPONSE (ARC, BDNF, CREB, EGR-1, FOS AND NFKB) AND SMARCC1 (CHROMATIN REMODELER) THROUGH RT-QPCR IN THESE NUCLEI. OUR RESULTS SHOWED INCREASED P-BRD4 AND H4K5AC LEVELS DURING AVERSIVE MEMORY RETRIEVAL, SUGGESTING A MORE OPEN CHROMATIN STATE. HOWEVER, TRANSCRIPTIONAL ACTIVATION OF THESE IEGS WAS NOT FOUND, THEREFORE SUGGESTING THAT OTHER SECONDARY RESPONSE MAY ALREADY BE HAPPENING. ADDITIONALLY, SMARCC1 LEVELS WERE REDUCED DUE TO MORPHINE CHRONIC ADMINISTRATION IN BLA AND DENTATE GYRUS. THE ACTIVATION MARKERS RETURNED TO CONTROL LEVELS AFTER THE RETRIEVAL OF AVERSIVE MEMORIES, REVEALING A MORE REPRESSED CHROMATIN STATE. TAKEN TOGETHER, OUR RESULTS SHOW A MAJOR ROLE OF THE TANDEM H4K5AC/P-BRD4 DURING THE RETRIEVAL OF AVERSIVE MEMORIES. THESE RESULTS MIGHT BE USEFUL TO ELUCIDATE NEW MOLECULAR TARGETS TO IMPROVE AND DEVELOP PHARMACOLOGICAL TREATMENTS TO ADDRESS ADDICTION AND TO AVOID DRUG RELAPSE. 2023 15 4848 38 OPIOID-INDUCED STRUCTURAL AND FUNCTIONAL PLASTICITY OF MEDIUM-SPINY NEURONS IN THE NUCLEUS ACCUMBENS. OPIOID USE DISORDER (OUD) IS A CHRONIC RELAPSING CLINICAL CONDITION WITH TREMENDOUS MORBIDITY AND MORTALITY THAT FREQUENTLY PERSISTS, DESPITE TREATMENT, DUE TO AN INDIVIDUAL'S UNDERLYING PSYCHOLOGICAL, NEUROBIOLOGICAL, AND GENETIC VULNERABILITIES. EVIDENCE SUGGESTS THAT THESE VULNERABILITIES MAY HAVE NEUROCHEMICAL, CELLULAR, AND MOLECULAR BASES. KEY NEUROPLASTIC EVENTS WITHIN THE MESOCORTICOLIMBIC SYSTEM THAT EMERGE THROUGH CHRONIC EXPOSURE TO OPIOIDS MAY HAVE A DETERMINATIVE INFLUENCE ON BEHAVIORAL SYMPTOMS ASSOCIATED WITH OUD. IN PARTICULAR, STRUCTURAL AND FUNCTIONAL ALTERATIONS IN THE DENDRITIC SPINES OF MEDIUM SPINY NEURONS (MSNS) WITHIN THE NUCLEUS ACCUMBENS (NAC) AND ITS DOPAMINERGIC PROJECTIONS FROM THE VENTRAL TEGMENTAL AREA (VTA) ARE BELIEVED TO FACILITATE THESE BEHAVIORAL SEQUELAE. ADDITIONALLY, GLUTAMATERGIC NEURONS FROM THE PREFRONTAL CORTEX, THE BASOLATERAL AMYGDALA, THE HIPPOCAMPUS, AND THE THALAMUS PROJECT TO THESE SAME MSNS, PROVIDING AN ENRICHED TARGET FOR SYNAPTIC PLASTICITY. HERE, WE REVIEW LITERATURE RELATED TO NEUROADAPTATIONS IN NAC MSNS FROM DOPAMINERGIC AND GLUTAMATERGIC PATHWAYS IN OUD. WE ALSO DESCRIBE NEW FINDINGS RELATED TO TRANSCRIPTIONAL, EPIGENETIC, AND MOLECULAR MECHANISMS IN MSN PLASTICITY IN THE DIFFERENT STAGES OF OUD. 2021 16 5812 39 STRESS AND ANXIETY: STRUCTURAL PLASTICITY AND EPIGENETIC REGULATION AS A CONSEQUENCE OF STRESS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR. THE ADULT, AS WELL AS DEVELOPING BRAIN, POSSESS A REMARKABLE ABILITY TO SHOW REVERSIBLE STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESSFUL AND OTHER EXPERIENCES, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING, AND SYNAPSE TURNOVER. THIS IS PARTICULARLY EVIDENT IN THE HIPPOCAMPUS, WHERE ALL THREE TYPES OF STRUCTURAL PLASTICITY HAVE BEEN RECOGNIZED AND INVESTIGATED, USING A COMBINATION OF MORPHOLOGICAL, MOLECULAR, PHARMACOLOGICAL, ELECTROPHYSIOLOGICAL AND BEHAVIORAL APPROACHES. THE AMYGDALA AND THE PREFRONTAL CORTEX, BRAIN REGIONS INVOLVED IN ANXIETY AND FEAR, MOOD, COGNITIVE FUNCTION AND BEHAVIORAL CONTROL, ALSO SHOW STRUCTURAL PLASTICITY. ACUTE AND CHRONIC STRESS CAUSE AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION MAKING, ANXIETY AND MOOD THAT CAN INCREASE OR DECREASE EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. IN THE SHORT TERM, SUCH AS FOR INCREASED FEARFUL VIGILANCE AND ANXIETY IN A THREATENING ENVIRONMENT, THESE CHANGES MAY BE ADAPTIVE; BUT, IF THE DANGER PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION MAY NEED INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES, AS IS THE CASE FOR CHRONIC OR MOOD ANXIETY DISORDERS. WE SHALL REVIEW CELLULAR AND MOLECULAR MECHANISMS, AS WELL AS RECENT WORK ON INDIVIDUAL DIFFERENCES IN ANXIETY-LIKE BEHAVIOR AND ALSO DEVELOPMENTAL INFLUENCES THAT BIAS HOW THE BRAIN RESPONDS TO STRESSORS. FINALLY, WE SUGGEST THAT SUCH AN APPROACH NEEDS TO BE EXTENDED TO OTHER BRAIN AREAS THAT ARE ALSO INVOLVED IN ANXIETY AND MOOD. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED 'ANXIETY AND DEPRESSION'. 2012 17 1677 33 DRUG ADDICTION: HYPERKATIFEIA/NEGATIVE REINFORCEMENT AS A FRAMEWORK FOR MEDICATIONS DEVELOPMENT. COMPULSIVE DRUG SEEKING THAT IS ASSOCIATED WITH ADDICTION IS HYPOTHESIZED TO FOLLOW A HEURISTIC FRAMEWORK THAT INVOLVES THREE STAGES (BINGE/INTOXICATION, WITHDRAWAL/NEGATIVE AFFECT, AND PREOCCUPATION/ANTICIPATION) AND THREE DOMAINS OF DYSFUNCTION (INCENTIVE SALIENCE/PATHOLOGIC HABITS, NEGATIVE EMOTIONAL STATES, AND EXECUTIVE FUNCTION, RESPECTIVELY) VIA CHANGES IN THE BASAL GANGLIA, EXTENDED AMYGDALA/HABENULA, AND FRONTAL CORTEX, RESPECTIVELY. THIS REVIEW FOCUSES ON NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS THAT CONTRIBUTE TO HYPERKATIFEIA, DEFINED AS A GREATER INTENSITY OF NEGATIVE EMOTIONAL/MOTIVATIONAL SIGNS AND SYMPTOMS DURING WITHDRAWAL FROM DRUGS OF ABUSE IN THE WITHDRAWAL/NEGATIVE AFFECT STAGE OF THE ADDICTION CYCLE. HYPERKATIFEIA PROVIDES AN ADDITIONAL SOURCE OF MOTIVATION FOR COMPULSIVE DRUG SEEKING VIA NEGATIVE REINFORCEMENT. NEGATIVE REINFORCEMENT REFLECTS AN INCREASE IN THE PROBABILITY OF A RESPONSE TO REMOVE AN AVERSIVE STIMULUS OR DRUG SEEKING TO REMOVE HYPERKATIFEIA THAT IS AUGMENTED BY GENETIC/EPIGENETIC VULNERABILITY, ENVIRONMENTAL TRAUMA, AND PSYCHIATRIC COMORBIDITY. NEUROBIOLOGICAL TARGETS FOR HYPERKATIFEIA IN ADDICTION INVOLVE NEUROCIRCUITRY OF THE EXTENDED AMYGDALA AND ITS CONNECTIONS VIA WITHIN-SYSTEM NEUROADAPTATIONS IN DOPAMINE, ENKEPHALIN/ENDORPHIN OPIOID PEPTIDE, AND GAMMA-AMINOBUTYRIC ACID/GLUTAMATE SYSTEMS AND BETWEEN-SYSTEM NEUROADAPTATIONS IN PROSTRESS CORTICOTROPIN-RELEASING FACTOR, NOREPINEPHRINE, GLUCOCORTICOID, DYNORPHIN, HYPOCRETIN, AND NEUROIMMUNE SYSTEMS AND ANTISTRESS NEUROPEPTIDE Y, NOCICEPTIN, ENDOCANNABINOID, AND OXYTOCIN SYSTEMS. SUCH NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS ARE HYPOTHESIZED TO MEDIATE A NEGATIVE HEDONIC SET POINT THAT GRADUALLY GAINS ALLOSTATIC LOAD AND SHIFTS FROM A HOMEOSTATIC HEDONIC STATE TO AN ALLOSTATIC HEDONIC STATE. BASED ON PRECLINICAL STUDIES AND TRANSLATIONAL STUDIES TO DATE, MEDICATIONS AND BEHAVIORAL THERAPIES THAT RESET BRAIN STRESS, ANTISTRESS, AND EMOTIONAL PAIN SYSTEMS AND RETURN THEM TO HOMEOSTASIS WOULD BE PROMISING NEW TARGETS FOR MEDICATION DEVELOPMENT. SIGNIFICANCE STATEMENT: THE FOCUS OF THIS REVIEW IS ON NEUROCHEMICAL/NEUROCIRCUITRY DYSREGULATIONS THAT CONTRIBUTE TO HYPERKATIFEIA, DEFINED AS A GREATER INTENSITY OF NEGATIVE EMOTIONAL/MOTIVATIONAL SIGNS AND SYMPTOMS DURING WITHDRAWAL FROM DRUGS OF ABUSE IN THE WITHDRAWAL/NEGATIVE AFFECT STAGE OF THE DRUG ADDICTION CYCLE AND A DRIVING FORCE FOR NEGATIVE REINFORCEMENT IN ADDICTION. MEDICATIONS AND BEHAVIORAL THERAPIES THAT REVERSE HYPERKATIFEIA BY RESETTING BRAIN STRESS, ANTISTRESS, AND EMOTIONAL PAIN SYSTEMS AND RETURNING THEM TO HOMEOSTASIS WOULD BE PROMISING NEW TARGETS FOR MEDICATION DEVELOPMENT. 2021 18 5876 23 SYNAPTIC PLASTICITY AND PAIN AVERSION. NEGATIVE AFFECTIVE EMOTIONS ARE DEFINED AS THE CONCEPTUAL FEATURE OF PAIN. A NUMBER OF CLINICAL AND ANIMAL STUDIES HAVE INDICATED THAT THE LIMBIC SYSTEM INCLUDING THE ANTERIOR CINGULATE CORTEX (ACC) AND AMYGDALA PLAYS A CRITICAL ROLE IN THE PROCESSING OF AFFECTIVE COMPONENTS OF PAIN. GLUTAMATERGIC TRANSMISSION PLAYS AN IMPORTANT ROLE IN THE PROCESSING OF AFFECTIVE ASPECTS OF PAIN. LONG-TERM CHANGES ON GLUTAMATERGIC SYNAPSES CONTRIBUTE TO THE EXPRESSION OF AVERSION BEHAVIOR INDUCED BY PAIN. IN THIS ARTICLE, THE NEUROCIRCUITS INVOLVED IN THE PROCESSING OF AFFECTIVE ASPECTS OF PAIN, THE GLUTAMATERGIC SYNAPTIC PLASTICITY IN THESE BRAIN REGIONS, AND THE EPIGENETIC MECHANISMS UNDERLYING PAIN-RELATED SYNAPTIC PLASTICITY WILL BE REVIEWED AND DISCUSSED. NEW DISCOVERIES REGARDING THE INTERACTION BETWEEN THE SYNAPTIC PLASTICITY AND AFFECTIVE COMPONENTS OF PAIN MAY ADVANCE OUR UNDERSTANDING ON THE PAIN MECHANISM, AND LEAD TO NEW STRATEGIES FOR PAIN TREATMENT. 2011 19 2576 27 EPIGENETICS OF FEAR, ANXIETY AND STRESS - FOCUS ON HISTONE MODIFICATIONS. FEAR-, ANXIETY- AND STRESS-RELATED DISORDERS ARE AMONG THE MOST FREQUENT MENTAL DISORDERS. GIVEN SUBSTANTIAL RATES OF INSUFFICIENT TREATMENT RESPONSE AND OFTEN A CHRONIC COURSE, A BETTER UNDER-STANDING OF THE PATHOMECHANISMS OF FEAR-, ANXIETY- AND STRESS-RELATED DISORDERS IS URGENTLY WARRANTED. EPIGENETIC MECHANISMS SUCH AS HISTONE MODIFICATIONS - POSITIONED AT THE INTERFACE BETWEEN THE BIOLOGICAL AND THE ENVIRONMENTAL LEVEL IN THE COMPLEX PATHOGENESIS OF MENTAL DISORDERS - MIGHT BE HIGHLY INFORMATIVE IN THIS CONTEXT. THE CURRENT STATE OF KNOWLEDGE ON HISTONE MODIFICATIONS, CHROMATIN-RELATED PHARMACOLOGY AND ANIMAL MODELS MODIFIED FOR GENES INVOLVED IN THE HISTONE-RELATED EPIGENETIC MA-CHINERY WILL BE REVIEWED WITH RESPECT TO FEAR-, ANXIETY- AND STRESS-RELATED STATES. RELEVANT STUDIES, PUBLISHED UNTIL 30TH JUNE 2022, WERE IDENTIFIED USING A MULTI-STEP SYSTEMATIC LITERATURE SEARCH OF THE PUB-MED AND WEB OF SCIENCE DATABASES. ANIMAL STUDIES POINT TOWARDS HISTONE MODIFICATIONS (E.G., H3K4ME3, H3K9ME1/2/3, H3K27ME2/3, H3K9AC, H3K14AC AND H4K5AC) TO BE DYNAMICALLY AND MOSTLY BRAIN REGION-, TASK- AND TIME-DEPENDENTLY ALTERED ON A GENOME-WIDE LEVEL OR GENE-SPECIFICALLY (E.G., BDNF) IN MODELS OF FEAR CONDITIONING, RETRIEVAL AND EXTINCTION, ACUTE AND (SUB-)CHRONIC STRESS. SINGULAR AND UNDERPOWERED STUDIES ON HISTONE MODIFICATIONS IN HUMAN FEAR-, ANXIETY- OR STRESS-RELATED PHENOTYPES ARE CURRENTLY RESTRICTED TO THE PHENOTYPE OF PTSD. PROVIDED CONSISTENT VALIDATION IN HUMAN PHENOTYPES, EPIGENETIC BIOMARKERS MIGHT ULTIMATELY INFORM INDICATED PREVENTIVE INTERVENTIONS AS WELL AS PERSONALIZED TREATMENT APPROACHES, AND COULD INSPIRE FUTURE INNOVATIVE PHARMACOLOGICAL TREATMENT OPTIONS TARGETING THE EPIGENETIC MACHINERY IMPROVING TREATMENT RESPONSE IN FEAR-, ANXIETY- AND STRESS RELATED DISORDERS. 2023 20 23 33 60 YEARS OF NEUROENDOCRINOLOGY: REDEFINING NEUROENDOCRINOLOGY: STRESS, SEX AND COGNITIVE AND EMOTIONAL REGULATION. THE DISCOVERY OF STEROID HORMONE RECEPTORS IN BRAIN REGIONS THAT MEDIATE EVERY ASPECT OF BRAIN FUNCTION HAS BROADENED THE DEFINITION OF 'NEUROENDOCRINOLOGY' TO INCLUDE THE RECIPROCAL COMMUNICATION BETWEEN THE BRAIN AND THE BODY VIA HORMONAL AND NEURAL PATHWAYS. THE BRAIN IS THE CENTRAL ORGAN OF STRESS AND ADAPTATION TO STRESS BECAUSE IT PERCEIVES AND DETERMINES WHAT IS THREATENING, AS WELL AS THE BEHAVIORAL AND PHYSIOLOGICAL RESPONSES TO THE STRESSOR. THE ADULT AND DEVELOPING BRAIN POSSESS REMARKABLE STRUCTURAL AND FUNCTIONAL PLASTICITY IN RESPONSE TO STRESS, INCLUDING NEURONAL REPLACEMENT, DENDRITIC REMODELING, AND SYNAPSE TURNOVER. STRESS CAUSES AN IMBALANCE OF NEURAL CIRCUITRY SUBSERVING COGNITION, DECISION-MAKING, ANXIETY AND MOOD THAT CAN ALTER EXPRESSION OF THOSE BEHAVIORS AND BEHAVIORAL STATES. THIS IMBALANCE, IN TURN, AFFECTS SYSTEMIC PHYSIOLOGY VIA NEUROENDOCRINE, AUTONOMIC, IMMUNE AND METABOLIC MEDIATORS. IN THE SHORT TERM, AS FOR INCREASED FEARFUL VIGILANCE AND ANXIETY IN A THREATENING ENVIRONMENT, THESE CHANGES MAY BE ADAPTIVE. BUT, IF THE DANGER PASSES AND THE BEHAVIORAL STATE PERSISTS ALONG WITH THE CHANGES IN NEURAL CIRCUITRY, SUCH MALADAPTATION MAY NEED INTERVENTION WITH A COMBINATION OF PHARMACOLOGICAL AND BEHAVIORAL THERAPIES, AS IS THE CASE FOR CHRONIC ANXIETY AND DEPRESSION. THERE ARE IMPORTANT SEX DIFFERENCES IN THE BRAIN RESPONSES TO STRESSORS THAT ARE IN URGENT NEED OF FURTHER EXPLORATION. MOREOVER, ADVERSE EARLY-LIFE EXPERIENCE, INTERACTING WITH ALLELES OF CERTAIN GENES, PRODUCE LASTING EFFECTS ON BRAIN AND BODY OVER THE LIFE-COURSE VIA EPIGENETIC MECHANISMS. WHILE PREVENTION IS MOST IMPORTANT, THE PLASTICITY OF THE BRAIN GIVES HOPE FOR THERAPIES THAT TAKE INTO CONSIDERATION BRAIN-BODY INTERACTIONS. 2015