1 1677 158 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 2 4500 23 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 3 800 29 CELLULAR, MOLECULAR, AND EPIGENETIC MECHANISMS IN NON-ASSOCIATIVE CONDITIONING: IMPLICATIONS FOR PAIN AND MEMORY. SENSITIZATION IS A FORM OF NON-ASSOCIATIVE CONDITIONING IN WHICH AMPLIFICATION OF BEHAVIORAL RESPONSES CAN OCCUR FOLLOWING PRESENTATION OF AN AVERSIVE OR NOXIOUS STIMULUS. UNDERSTANDING THE CELLULAR AND MOLECULAR UNDERPINNINGS OF SENSITIZATION HAS BEEN AN OVERARCHING THEME SPANNING THE FIELD OF LEARNING AND MEMORY AS WELL AS THAT OF PAIN RESEARCH. IN THIS REVIEW WE EXAMINE HOW SENSITIZATION, BOTH IN THE CONTEXT OF LEARNING AS WELL AS PAIN PROCESSING, SHARES EVOLUTIONARILY CONSERVED BEHAVIORAL, CELLULAR/SYNAPTIC, AND EPIGENETIC MECHANISMS ACROSS PHYLA. FIRST, WE CHARACTERIZE THE BEHAVIORAL PHENOMENON OF SENSITIZATION BOTH IN INVERTEBRATES AND VERTEBRATES. PARTICULAR EMPHASIS IS PLACED ON LONG-TERM SENSITIZATION (LTS) OF WITHDRAWAL REFLEXES IN APLYSIA FOLLOWING AVERSIVE STIMULATION OR INJURY, ALTHOUGH ADDITIONAL INVERTEBRATE MODELS ARE ALSO COVERED. IN THE CONTEXT OF VERTEBRATES, SENSITIZATION OF MAMMALIAN HYPERAROUSAL IN A MODEL OF POST-TRAUMATIC STRESS DISORDER (PTSD), AS WELL AS MAMMALIAN MODELS OF INFLAMMATORY AND NEUROPATHIC PAIN IS CHARACTERIZED. SECOND, WE INVESTIGATE THE CELLULAR AND SYNAPTIC MECHANISMS UNDERLYING THESE BEHAVIORS. WE FOCUS OUR DISCUSSION ON SEROTONIN-MEDIATED LONG-TERM FACILITATION (LTF) AND AXOTOMY-MEDIATED LONG-TERM HYPEREXCITABILITY (LTH) IN REDUCED APLYSIA SYSTEMS, AS WELL AS MAMMALIAN SPINAL PLASTICITY MECHANISMS OF CENTRAL SENSITIZATION. THIRD, WE EXPLORE RECENT EVIDENCE IMPLICATING EPIGENETIC MECHANISMS IN LEARNING- AND PAIN-RELATED SENSITIZATION. THIS REVIEW ILLUSTRATES THE FUNDAMENTAL AND FUNCTIONAL OVERLAY OF THE LEARNING AND MEMORY FIELD WITH THE PAIN FIELD WHICH ARGUES FOR HOMOLOGOUS PERSISTENT PLASTICITY MECHANISMS IN RESPONSE TO SENSITIZING STIMULI OR INJURY ACROSS PHYLA. 2013 4 248 29 ADVANCE IN STRESS FOR DEPRESSIVE DISORDER. STRESS IS AN ADAPTIVE RESPONSE TO ENVIRONMENT AVERSIVE STIMULI AND A COMMON LIFE EXPERIENCE OF ONE'S DAILY LIFE. CHRONIC OR EXCESSIVE STRESS ESPECIALLY THAT HAPPENED IN EARLY LIFE IS FOUND TO BE DELETERIOUS TO INDIVIDUAL'S PHYSICAL AND MENTAL HEALTH, WHICH IS HIGHLY RELATED TO DEPRESSIVE DISORDERS ONSET. STRESSFUL LIFE EVENTS ARE CONSISTENTLY CONSIDERED TO BE THE HIGH-RISK FACTORS OF ENVIRONMENT FOR PREDISPOSING DEPRESSIVE DISORDERS. IN LINKING STRESSFUL LIFE EVENTS WITH DEPRESSIVE DISORDER ONSET, DYSREGULATED HPA AXIS ACTIVITY IS SUPPOSED TO PLAY AN IMPORTANT ROLE IN MEDIATING AVERSIVE IMPACTS OF LIFE STRESS ON BRAIN STRUCTURE AND FUNCTION. INCREASING EVIDENCE HAVE INDICATED THE STRONG ASSOCIATION OF STRESS, ESPECIALLY THE CHRONIC STRESS AND EARLY LIFE STRESS, WITH DEPRESSIVE DISORDERS DEVELOPMENT, WHILE THE ASSOCIATION OF STRESS WITH DEPRESSION IS MODERATED BY GENETIC RISK FACTORS, INCLUDING POLYMORPHISM OF SERT, BDNF, GR, FKBP5, MR, AND CRHR1. MEANWHILE, STRESSFUL LIFE EXPERIENCE PARTICULARLY EARLY LIFE STRESS WILL EXERT EPIGENETIC MODIFICATION IN THESE RISK GENES VIA DNA METHYLATION AND MIRNA REGULATION TO GENERATE LONG-LASTING EFFECTS ON THESE GENES EXPRESSION, WHICH IN TURN CAUSE BRAIN STRUCTURAL AND FUNCTIONAL ALTERATION, AND FINALLY INCREASE THE VULNERABILITY TO DEPRESSIVE DISORDERS. THEREFORE, THE INTERACTION OF ENVIRONMENT WITH GENE, IN WHICH STRESSFUL LIFE EXPOSURE INTERPLAY WITH GENETIC RISK FACTORS AND EPIGENETIC MODIFICATION, IS ESSENTIAL IN PREDICTING DEPRESSIVE DISORDERS DEVELOPMENT. AS THE MEDIATOR OF ENVIRONMENTAL RISK FACTORS, STRESS WILL FUNCTION TOGETHER WITH GENETIC AND EPIGENETIC MECHANISM TO INFLUENCE BRAIN STRUCTURE AND FUNCTION, PHYSIOLOGY AND PSYCHOLOGY, AND FINALLY THE VULNERABILITY TO DEPRESSIVE DISORDERS. 2019 5 2670 36 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 6 4632 33 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 7 4848 32 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 8 5310 20 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 9 1750 23 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 4846 26 OPIATE ADDICTION AND COCAINE ADDICTION: UNDERLYING MOLECULAR NEUROBIOLOGY AND GENETICS. ADDICTIVE DISEASES, INCLUDING ADDICTION TO HEROIN, PRESCRIPTION OPIOIDS, OR COCAINE, POSE MASSIVE PERSONAL AND PUBLIC HEALTH COSTS. ADDICTIONS ARE CHRONIC RELAPSING DISEASES OF THE BRAIN CAUSED BY DRUG-INDUCED DIRECT EFFECTS AND PERSISTING NEUROADAPTATIONS AT THE EPIGENETIC, MRNA, NEUROPEPTIDE, NEUROTRANSMITTER, OR PROTEIN LEVELS. THESE NEUROADAPTATIONS, WHICH CAN BE SPECIFIC TO DRUG TYPE, AND THEIR RESULTANT BEHAVIORS ARE MODIFIED BY VARIOUS INTERNAL AND EXTERNAL ENVIRONMENTAL FACTORS, INCLUDING STRESS RESPONSIVITY, ADDICT MINDSET, AND SOCIAL SETTING. SPECIFIC GENE VARIANTS, INCLUDING VARIANTS ENCODING PHARMACOLOGICAL TARGET PROTEINS OR GENES MEDIATING NEUROADAPTATIONS, ALSO MODIFY VULNERABILITY AT PARTICULAR STAGES OF ADDICTION. GREATER UNDERSTANDING OF THESE INTERACTING FACTORS THROUGH LABORATORY-BASED AND TRANSLATIONAL STUDIES HAVE THE POTENTIAL TO OPTIMIZE EARLY INTERVENTIONS FOR THE THERAPY OF CHRONIC ADDICTIVE DISEASES AND TO REDUCE THE BURDEN OF RELAPSE. HERE, WE REVIEW THE MOLECULAR NEUROBIOLOGY AND GENETICS OF OPIATE ADDICTION, INCLUDING HEROIN AND PRESCRIPTION OPIOIDS, AND COCAINE ADDICTION. 2012 11 1088 31 COCAINE DIRECTLY IMPAIRS MEMORY EXTINCTION AND ALTERS BRAIN DNA METHYLATION DYNAMICS IN HONEY BEES. DRUG ADDICTION IS A CHRONIC RELAPSING BEHAVIORAL DISORDER. THE HIGH RELAPSE RATE HAS OFTEN BEEN ATTRIBUTED TO THE PERSEVERANCE OF DRUG-ASSOCIATED MEMORIES DUE TO HIGH INCENTIVE SALIENCE OF STIMULI LEARNT UNDER THE INFLUENCE OF DRUGS. DRUG ADDICTION HAS ALSO BEEN INTERPRETED AS A MEMORY DISORDER SINCE DRUG ASSOCIATED MEMORIES ARE UNUSUALLY ENDURING AND SOME DRUGS, SUCH AS COCAINE, INTERFERE WITH NEUROEPIGENETIC MACHINERY KNOWN TO BE INVOLVED IN MEMORY PROCESSING. HERE WE USED THE HONEY BEE (AN ESTABLISHED INVERTEBRATE MODEL FOR EPIGENOMICS AND BEHAVIORAL STUDIES) TO EXAMINE WHETHER OR NOT COCAINE AFFECTS MEMORY PROCESSING INDEPENDENTLY OF ITS EFFECT ON INCENTIVE SALIENCE. USING THE PROBOSCIS EXTENSION REFLEX TRAINING PARADIGM WE FOUND THAT COCAINE STRONGLY IMPAIRS CONSOLIDATION OF EXTINCTION MEMORY. BASED ON CORRELATION BETWEEN THE OBSERVED EFFECT OF COCAINE ON LEARNING AND EXPRESSION OF EPIGENETIC PROCESSES, WE PROPOSE THAT COCAINE INTERFERES WITH MEMORY PROCESSING INDEPENDENTLY OF INCENTIVE SALIENCE BY DIRECTLY ALTERING DNA METHYLATION DYNAMICS. OUR FINDINGS EMPHASIZE THE IMPACT OF COCAINE ON MEMORY SYSTEMS, WITH RELEVANCE FOR UNDERSTANDING HOW COCAINE CAN HAVE SUCH AN ENDURING IMPACT ON BEHAVIOR. 2018 12 6626 30 UNDERSTANDING RESILIENCE. RESILIENCE IS THE ABILITY TO ADAPT SUCCESSFULLY IN THE FACE OF STRESS AND ADVERSITY. STRESSFUL LIFE EVENTS, TRAUMA, AND CHRONIC ADVERSITY CAN HAVE A SUBSTANTIAL IMPACT ON BRAIN FUNCTION AND STRUCTURE, AND CAN RESULT IN THE DEVELOPMENT OF POSTTRAUMATIC STRESS DISORDER (PTSD), DEPRESSION AND OTHER PSYCHIATRIC DISORDERS. HOWEVER, MOST INDIVIDUALS DO NOT DEVELOP SUCH ILLNESSES AFTER EXPERIENCING STRESSFUL LIFE EVENTS, AND ARE THUS THOUGHT TO BE RESILIENT. RESILIENCE AS SUCCESSFUL ADAPTATION RELIES ON EFFECTIVE RESPONSES TO ENVIRONMENTAL CHALLENGES AND ULTIMATE RESISTANCE TO THE DELETERIOUS EFFECTS OF STRESS, THEREFORE A GREATER UNDERSTANDING OF THE FACTORS THAT PROMOTE SUCH EFFECTS IS OF GREAT RELEVANCE. THIS REVIEW FOCUSES ON RECENT FINDINGS REGARDING GENETIC, EPIGENETIC, DEVELOPMENTAL, PSYCHOSOCIAL, AND NEUROCHEMICAL FACTORS THAT ARE CONSIDERED ESSENTIAL CONTRIBUTORS TO THE DEVELOPMENT OF RESILIENCE. NEURAL CIRCUITS AND PATHWAYS INVOLVED IN MEDIATING RESILIENCE ARE ALSO DISCUSSED. THE GROWING UNDERSTANDING OF RESILIENCE FACTORS WILL HOPEFULLY LEAD TO THE DEVELOPMENT OF NEW PHARMACOLOGICAL AND PSYCHOLOGICAL INTERVENTIONS FOR ENHANCING RESILIENCE AND MITIGATING THE UNTOWARD CONSEQUENCES. 2013 13 6266 27 THE NEUROBIOLOGY OF SUICIDE. THE STRESS-DIATHESIS MODEL POSITS THAT SUICIDE IS THE RESULT OF AN INTERACTION BETWEEN STATE-DEPENDENT (ENVIRONMENTAL) STRESSORS AND A TRAIT-LIKE DIATHESIS OR SUSCEPTIBILITY TO SUICIDAL BEHAVIOUR, INDEPENDENT OF PSYCHIATRIC DISORDERS. FINDINGS FROM POST-MORTEM STUDIES OF THE BRAIN AND FROM GENOMIC AND IN-VIVO NEUROIMAGING STUDIES INDICATE A BIOLOGICAL BASIS FOR THIS DIATHESIS, INDICATING THE IMPORTANCE OF NEUROBIOLOGICAL SCREENING AND INTERVENTIONS, IN ADDITION TO COGNITIVE AND MOOD INTERVENTIONS, IN THE PREVENTION OF SUICIDE. EARLY-LIFE ADVERSITY AND EPIGENETIC MECHANISMS MIGHT EXPLAIN SOME OF THE LINK BETWEEN SUICIDE RISK AND BRAIN CIRCUITRY AND NEUROCHEMISTRY ABNORMALITIES. RESULTS FROM A RANGE OF STUDIES USING DIVERSE DESIGNS AND POST-MORTEM AND IN-VIVO TECHNIQUES SHOW IMPAIRMENTS OF THE SEROTONIN NEUROTRANSMITTER SYSTEM AND THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS STRESS-RESPONSE SYSTEM IN THE DIATHESIS FOR SUICIDAL BEHAVIOUR. THESE IMPAIRMENTS MANIFEST AS IMPAIRED COGNITIVE CONTROL OF MOOD, PESSIMISM, REACTIVE AGGRESSIVE TRAITS, IMPAIRED PROBLEM SOLVING, OVER-REACTIVITY TO NEGATIVE SOCIAL SIGNS, EXCESSIVE EMOTIONAL PAIN, AND SUICIDAL IDEATION, LEADING TO SUICIDAL BEHAVIOUR. BIOMARKERS RELATED TO THE DIATHESIS MIGHT HELP TO INFORM RISK-ASSESSMENT PROCEDURES AND TREATMENT CHOICE IN THE PREVENTION OF SUICIDE. 2014 14 3092 26 GENOMIC AND EPIGENOMIC MECHANISMS OF GLUCOCORTICOIDS IN THE BRAIN. FOLLOWING THE DISCOVERY OF GLUCOCORTICOID RECEPTORS IN THE HIPPOCAMPUS AND OTHER BRAIN REGIONS, RESEARCH HAS FOCUSED ON UNDERSTANDING THE EFFECTS OF GLUCOCORTICOIDS IN THE BRAIN AND THEIR ROLE IN REGULATING EMOTION AND COGNITION. GLUCOCORTICOIDS ARE ESSENTIAL FOR ADAPTATION TO STRESSORS (ALLOSTASIS) AND IN MALADAPTATION RESULTING FROM ALLOSTATIC LOAD AND OVERLOAD. ALLOSTATIC OVERLOAD, WHICH CAN OCCUR DURING CHRONIC STRESS, CAN RESHAPE THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS THROUGH EPIGENETIC MODIFICATION OF GENES IN THE HIPPOCAMPUS, HYPOTHALAMUS AND OTHER STRESS-RESPONSIVE BRAIN REGIONS. GLUCOCORTICOIDS EXERT THEIR EFFECTS ON THE BRAIN THROUGH GENOMIC MECHANISMS THAT INVOLVE BOTH GLUCOCORTICOID RECEPTORS AND MINERALOCORTICOID RECEPTORS DIRECTLY BINDING TO DNA, AS WELL AS BY NON-GENOMIC MECHANISMS. FURTHERMORE, GLUCOCORTICOIDS SYNERGIZE BOTH GENOMICALLY AND NON-GENOMICALLY WITH NEUROTRANSMITTERS, NEUROTROPHIC FACTORS, SEX HORMONES AND OTHER STRESS MEDIATORS TO SHAPE AN ORGANISM'S PRESENT AND FUTURE RESPONSES TO A STRESSFUL ENVIRONMENT. HERE, WE DISCUSS THE MECHANISMS OF GLUCOCORTICOID ACTION IN THE BRAIN AND REVIEW HOW GLUCOCORTICOIDS INTERACT WITH STRESS MEDIATORS IN THE CONTEXT OF ALLOSTASIS, ALLOSTATIC LOAD AND STRESS-INDUCED NEUROPLASTICITY. 2017 15 1774 31 EARLY-LIFE STRESS: FROM NEUROENDOCRINE MECHANISMS TO STRESS-RELATED DISORDERS. STRESS EXPOSURE IS HIGHLY PREVALENT IN THE GENERAL POPULATION; HOWEVER, THE EXPERIENCE OF STRESS DURING VULNERABLE PERIODS OF DEVELOPMENT HAS SUBSTANTIAL AND PERMANENT EFFECTS ON BRAIN STRUCTURE AND FUNCTION AND PHYSICAL HEALTH IN ADULTHOOD. STRESS, THE STATE OF THREATENED HOMEOSTASIS, IS GENERALLY ASSOCIATED WITH A TIME-LIMITED ACTIVATION OF THE STRESS SYSTEM, I.E., THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE AROUSAL/SYMPATHETIC NERVOUS SYSTEM, TAILORED TO THE STRESSFUL STIMULUS ALSO KNOWN AS THE STRESSOR. ON THE OTHER HAND, CHRONIC STRESS MAY BE ASSOCIATED WITH LINGERING HYPER- OR HYPOSECRETION OF MEDIATORS OF THE STRESS SYSTEM. THIS CHRONIC CONDITION IS CALLED DYSHOMEOSTASIS, ALLOSTASIS, OR CACOSTASIS AND IS ASSOCIATED WITH INCREASED MENTAL AND PHYSICAL MORBIDITY IN THE LONG TERM. STRESSFUL OR TRAUMATIC EXPERIENCES DURING FETAL LIFE, EARLY CHILDHOOD, AND ADOLESCENCE HAVE BEEN RELATED TO PERSISTENT NEUROENDOCRINE AND EPIGENETIC CHANGES. FURTHER, BRAIN STRUCTURES INVOLVED IN THE STRESS RESPONSE, SUCH AS THOSE OF THE STRESS SYSTEM, THE HIPPOCAMPUS, AND THE AMYGDALA, MAY BE PROGRAMMED EARLY ON FOR A LIFE OF ADVERSITY. 2018 16 5812 36 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 4622 26 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 18 3534 30 IMMEDIATE-EARLY GENES MODULATION BY ANTIPSYCHOTICS: TRANSLATIONAL IMPLICATIONS FOR A PUTATIVE GATEWAY TO DRUG-INDUCED LONG-TERM BRAIN CHANGES. AN INCREASING AMOUNT OF RESEARCH AIMS AT RECOGNIZING THE MOLECULAR MECHANISMS INVOLVED IN LONG-LASTING BRAIN ARCHITECTURAL CHANGES INDUCED BY ANTIPSYCHOTIC TREATMENTS. ALTHOUGH BOTH STRUCTURAL AND FUNCTIONAL MODIFICATIONS HAVE BEEN IDENTIFIED FOLLOWING ACUTE ANTIPSYCHOTIC ADMINISTRATION IN HUMANS, CURRENTLY THERE IS SCARCE KNOWLEDGE ON THE ENDURING CONSEQUENCES OF THESE ACUTE CHANGES. NEW INSIGHTS IN IMMEDIATE-EARLY GENES (IEGS) MODULATION FOLLOWING ACUTE OR CHRONIC ANTIPSYCHOTIC ADMINISTRATION MAY HELP TO FILL THE GAP BETWEEN PRIMARY MOLECULAR RESPONSE AND PUTATIVE LONG-TERM CHANGES. MOREOVER, A CRITICAL APPRAISAL OF THE SPATIAL AND TEMPORAL PATTERNS OF IEGS EXPRESSION MAY SHED LIGHT ON THE FUNCTIONAL "SIGNATURE" OF ANTIPSYCHOTICS, SUCH AS THE PROPENSITY TO INDUCE MOTOR SIDE EFFECTS, THE POTENTIAL NEUROBIOLOGICAL MECHANISMS UNDERLYING THE DIFFERENCES BETWEEN ANTIPSYCHOTICS BEYOND D2 DOPAMINE RECEPTOR AFFINITY, AS WELL AS THE RELEVANT EFFECTS OF BRAIN REGION-SPECIFICITY IN THEIR MECHANISMS OF ACTION. THE INTEREST FOR BRAIN IEGS MODULATION AFTER ANTIPSYCHOTIC TREATMENTS HAS BEEN REVITALIZED BY BREAKTHROUGH FINDINGS SUCH AS THE ROLE OF EARLY GENES IN SCHIZOPHRENIA PATHOPHYSIOLOGY, THE INVOLVEMENT OF IEGS IN EPIGENETIC MECHANISMS RELEVANT FOR COGNITION, AND IN NEURONAL MAPPING BY MEANS OF IEGS EXPRESSION PROFILING. HERE WE CRITICALLY REVIEW THE EVIDENCE ON THE DIFFERENTIAL MODULATION OF IEGS BY ANTIPSYCHOTICS, HIGHLIGHTING THE ASSOCIATION BETWEEN IEGS EXPRESSION AND NEUROPLASTICITY CHANGES IN BRAIN REGIONS IMPACTED BY ANTIPSYCHOTICS, TRYING TO ELUCIDATE THE MOLECULAR MECHANISMS UNDERPINNING THE EFFECTS OF THIS CLASS OF DRUGS ON PSYCHOTIC, COGNITIVE AND BEHAVIORAL SYMPTOMS. 2017 19 2949 25 GENETIC AND EPIGENETIC CONSEQUENCE OF EARLY-LIFE SOCIAL STRESS ON DEPRESSION: ROLE OF SEROTONIN-ASSOCIATED GENES. EARLY-LIFE ADVERSITY CAUSED BY POOR SOCIAL BONDING AND DEPRIVED MATERNAL CARE IS KNOWN TO AFFECT MENTAL WELLBEING AND PHYSICAL HEALTH. IT IS A FORM OF CHRONIC SOCIAL STRESS THAT PERSISTS BECAUSE OF A NEGATIVE ENVIRONMENT, AND THE CONSEQUENCES ARE LONG-LASTING ON MENTAL HEALTH. THE PRESENCE OF SOCIAL STRESS DURING EARLY LIFE CAN HAVE AN EPIGENETIC EFFECT ON THE BODY, POSSIBLY RESULTING IN MANY COMPLEX MENTAL DISORDERS, INCLUDING DEPRESSION IN LATER LIFE. HERE, WE REVIEW THE EVIDENCE FOR EARLY-LIFE SOCIAL STRESS-INDUCED EPIGENETIC CHANGES THAT MODULATE JUVENILE AND ADULT SOCIAL BEHAVIOR (DEPRESSION AND ANXIETY). THIS REVIEW HAS A PARTICULAR EMPHASIS ON THE INTERACTION BETWEEN EARLY-LIFE SOCIAL STRESS AND GENETIC VARIATION OF SEROTONIN ASSOCIATE GENES INCLUDING THE SEROTONIN TRANSPORTER GENE (5-HTT; ALSO KNOWN AS SLC6A4), WHICH ARE KEY MOLECULES INVOLVED IN DEPRESSION. 2020 20 23 31 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