1 4633 115 NEUROIMMUNE ACTIVATION DRIVES MULTIPLE BRAIN STATES. NEUROIMMUNE SIGNALING IS INCREASINGLY IDENTIFIED AS A CRITICAL COMPONENT OF NEURONAL PROCESSES UNDERLYING MEMORY, EMOTION AND COGNITION. THE INTERACTIONS OF MICROGLIA AND ASTROCYTES WITH NEURONS AND SYNAPSES, AND THE INDIVIDUAL CYTOKINES AND IMMUNE SIGNALING MOLECULES THAT MEDIATE THESE INTERACTIONS ARE A CURRENT FOCUS OF MUCH RESEARCH. HERE, WE DISCUSS NEUROIMMUNE ACTIVATION AS A MECHANISM TRIGGERING DIFFERENT STATES THAT MODULATE COGNITIVE AND AFFECTIVE PROCESSES TO ALLOW FOR APPROPRIATE BEHAVIOR DURING AND AFTER ILLNESS OR INJURY. WE PROPOSE THAT THESE STATES LIE ON A CONTINUUM FROM A NAIVE HOMEOSTATIC BASELINE STATE IN THE ABSENCE OF STIMULATION, TO ACUTE NEUROIMMUNE ACTIVITY AND CHRONIC ACTIVATION. IMPORTANTLY, CONSEQUENCES OF ILLNESS OR INJURY INCLUDING COGNITIVE DEFICITS AND MOOD IMPAIRMENTS CAN PERSIST LONG AFTER RESOLUTION OF IMMUNE SIGNALING. THIS SUGGESTS THAT NEUROIMMUNE ACTIVATION ALSO RESULTS IN AN ENDURING SHIFT IN THE HOMEOSTATIC BASELINE STATE WITH LONG LASTING CONSEQUENCES FOR NEURAL FUNCTION AND BEHAVIOR. SUCH DIFFERENT STATES CAN BE IDENTIFIED IN A MULTIDIMENSIONAL WAY, USING PATTERNS OF CYTOKINE AND GLIAL ACTIVATION, BEHAVIORAL AND COGNITIVE CHANGES, AND EPIGENETIC SIGNATURES. IDENTIFYING DISTINCT NEUROIMMUNE STATES AND THEIR CONSEQUENCES FOR NEURAL FUNCTION WILL PROVIDE A FRAMEWORK FOR PREDICTING VULNERABILITY TO DISORDERS OF MEMORY, COGNITION AND EMOTION BOTH DURING AND LONG AFTER RECOVERY FROM ILLNESS. 2018 2 4642 37 NEURONAL PLASTICITY: A LINK BETWEEN STRESS AND MOOD DISORDERS. ALTHOUGH STRESS REPRESENTS THE MAJOR ENVIRONMENTAL ELEMENT OF SUSCEPTIBILITY FOR MOOD DISORDERS, THE RELATIONSHIP BETWEEN STRESS AND DISEASE REMAINS TO BE FULLY ESTABLISHED. IN THE PRESENT ARTICLE WE REVIEW THE EVIDENCE IN SUPPORT FOR A ROLE OF NEURONAL PLASTICITY, AND IN PARTICULAR OF NEUROTROPHIC FACTORS. EVEN THOUGH DECREASED LEVELS OF NOREPINEPHRINE AND SEROTONIN MAY UNDERLIE DEPRESSIVE SYMPTOMS, COMPELLING EVIDENCE NOW SUGGESTS THAT MOOD DISORDERS ARE CHARACTERIZED BY REDUCED NEURONAL PLASTICITY, WHICH CAN BE BROUGHT ABOUT BY EXPOSURE TO STRESS AT DIFFERENT STAGES OF LIFE. INDEED THE EXPRESSION OF NEUROTROPHIC MOLECULES, SUCH AS THE NEUROTROPHIN BDNF, IS REDUCED IN DEPRESSED SUBJECTS AS WELL AS IN EXPERIMENTAL ANIMALS EXPOSED TO ADVERSE EXPERIENCE AT EARLY STAGES OF LIFE OR AT ADULTHOOD. THESE CHANGES SHOW AN ANATOMICAL SPECIFICITY AND MIGHT BE SUSTAINED BY EPIGENETIC MECHANISMS. PHARMACOLOGICAL INTERVENTION MAY NORMALIZE SUCH DEFECTS AND IMPROVE NEURONAL FUNCTION THROUGH THE MODULATION OF THE SAME FACTORS THAT ARE DEFECTIVE IN DEPRESSION. SEVERAL STUDIES HAVE DEMONSTRATED THAT CHRONIC, BUT NOT ACUTE, ANTIDEPRESSANT TREATMENT INCREASES THE EXPRESSION OF BDNF AND MAY ENHANCE ITS LOCALIZATION AT SYNAPTIC LEVEL. ANTIDEPRESSANT TREATMENT CAN NORMALIZE DEFICITS IN NEUROTROPHIN EXPRESSION PRODUCED BY CHRONIC STRESS PARADIGMS, BUT MAY ALSO ALTER THE MODULATION OF BDNF UNDER ACUTE STRESSFUL CONDITIONS. IN SUMMARY, THERE IS GOOD AGREEMENT IN CONSIDERING NEURONAL PLASTICITY, AND THE EXPRESSION OF KEY PROTEINS SUCH AS THE NEUROTROPHIN BDNF, AS A CENTRAL PLAYER FOR THE EFFECTS OF STRESS ON BRAIN FUNCTION AND ITS IMPLICATION FOR PSYCHOPATHOLOGY. ACCORDINGLY, EFFECTIVE TREATMENTS SHOULD NOT LIMIT THEIR EFFECTS TO THE CONTROL OF NEUROTRANSMITTER AND HORMONAL DYSFUNCTIONS, BUT SHOULD BE ABLE TO NORMALIZE DEFECTIVE MECHANISMS THAT SUSTAIN THE IMPAIRMENT OF NEURONAL PLASTICITY. 2009 3 6414 33 THE STRESSED SYNAPSE 2.0: PATHOPHYSIOLOGICAL MECHANISMS IN STRESS-RELATED NEUROPSYCHIATRIC DISORDERS. STRESS IS A PRIMARY RISK FACTOR FOR SEVERAL NEUROPSYCHIATRIC DISORDERS. EVIDENCE FROM PRECLINICAL MODELS AND CLINICAL STUDIES OF DEPRESSION HAVE REVEALED AN ARRAY OF STRUCTURAL AND FUNCTIONAL MALADAPTIVE CHANGES, WHEREBY ADVERSE ENVIRONMENTAL FACTORS SHAPE THE BRAIN. THESE CHANGES, OBSERVED FROM THE MOLECULAR AND TRANSCRIPTIONAL LEVELS THROUGH TO LARGE-SCALE BRAIN NETWORKS, TO THE BEHAVIOURS REVEAL A COMPLEX MATRIX OF INTERRELATED PATHOPHYSIOLOGICAL PROCESSES THAT DIFFER BETWEEN SEXES, PROVIDING INSIGHT INTO THE POTENTIAL UNDERPINNINGS OF THE SEX BIAS OF NEUROPSYCHIATRIC DISORDERS. ALTHOUGH MANY PRECLINICAL STUDIES USE CHRONIC STRESS PROTOCOLS, LONG-TERM CHANGES ARE ALSO INDUCED BY ACUTE EXPOSURE TO TRAUMATIC STRESS, OPENING A PATH TO IDENTIFY DETERMINANTS OF RESILIENT VERSUS SUSCEPTIBLE RESPONSES TO BOTH ACUTE AND CHRONIC STRESS. EPIGENETIC REGULATION OF GENE EXPRESSION HAS EMERGED AS A KEY PLAYER UNDERLYING THE PERSISTENT IMPACT OF STRESS ON THE BRAIN. INDEED, HISTONE MODIFICATION, DNA METHYLATION AND MICRORNAS ARE CLOSELY INVOLVED IN MANY ASPECTS OF THE STRESS RESPONSE AND REVEAL THE GLUTAMATE SYSTEM AS A KEY PLAYER. THE SUCCESS OF KETAMINE HAS STIMULATED A WHOLE LINE OF RESEARCH AND DEVELOPMENT ON DRUGS DIRECTLY OR INDIRECTLY TARGETING GLUTAMATE FUNCTION. HOWEVER, THE CHALLENGE OF TRANSLATING THE EMERGING UNDERSTANDING OF STRESS PATHOPHYSIOLOGY INTO EFFECTIVE CLINICAL TREATMENTS REMAINS A MAJOR CHALLENGE. 2022 4 534 31 ASTROGLIA IN THE VULNERABILITY TO AND MAINTENANCE OF STRESS-MEDIATED NEUROPATHOLOGY AND DEPRESSION. SIGNIFICANT STRESS EXPOSURE AND PSYCHIATRIC DEPRESSION ARE ASSOCIATED WITH MORPHOLOGICAL, BIOCHEMICAL, AND PHYSIOLOGICAL DISTURBANCES OF ASTROCYTES IN SPECIFIC BRAIN REGIONS RELEVANT TO THE PATHOPHYSIOLOGY OF THOSE DISORDERS, SUGGESTING THAT ASTROCYTES ARE INVOLVED IN THE MECHANISMS UNDERLYING THE VULNERABILITY TO OR MAINTENANCE OF STRESS-RELATED NEUROPATHOLOGY AND DEPRESSION. TO UNDERSTAND THOSE MECHANISMS A VARIETY OF STUDIES HAVE PROBED THE EFFECT OF VARIOUS MODALITIES OF STRESS EXPOSURE ON THE METABOLISM, GENE EXPRESSION AND PLASTICITY OF ASTROCYTES. THESE STUDIES HAVE UNCOVERED THE PARTICIPATION OF VARIOUS CELLULAR PATHWAYS, SUCH AS THOSE FOR INTRACELLULAR CALCIUM REGULATION, NEUROIMMUNE RESPONSES, EXTRACELLULAR IONIC REGULATION, GAP JUNCTIONS-BASED CELLULAR COMMUNICATION, AND REGULATION OF NEUROTRANSMITTER AND GLIOTRANSMITTER RELEASE AND UPTAKE. MORE RECENTLY EPIGENETIC MODIFICATIONS RESULTING FROM EXPOSURE TO CHRONIC FORMS OF STRESS OR TO EARLY LIFE ADVERSITY HAVE BEEN SUGGESTED TO AFFECT NOT ONLY NEURONAL MECHANISMS BUT ALSO GENE EXPRESSION AND PHYSIOLOGY OF ASTROCYTES AND OTHER GLIAL CELLS. HOWEVER, MUCH REMAINS TO BE LEARNED TO UNDERSTAND THE SPECIFIC ROLE OF THOSE AND OTHER MODIFICATIONS IN THE ASTROGLIAL CONTRIBUTION TO THE VULNERABILITY TO AND MAINTENANCE OF STRESS-RELATED DISORDERS AND DEPRESSION, AND FOR LEVERAGING THAT KNOWLEDGE TO ACHIEVE MORE EFFECTIVE PSYCHIATRIC THERAPIES. 2022 5 110 29 A ROLE FOR ACTIVITY-DEPENDENT EPIGENETICS IN THE DEVELOPMENT AND TREATMENT OF MAJOR DEPRESSIVE DISORDER. CHRONIC STRESSORS, DURING DEVELOPMENTAL SENSITIVE PERIODS AND BEYOND, CONTRIBUTE TO THE RISK OF DEVELOPING PSYCHIATRIC CONDITIONS, INCLUDING MAJOR DEPRESSIVE DISORDER (MDD). EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS, AT KEY STRESS RESPONSE AND NEUROTROPHIN GENES, ARE INCREASINGLY IMPLICATED IN MEDIATING THIS RISK. ALTHOUGH THE EXACT MECHANISMS THROUGH WHICH STRESSFUL ENVIRONMENTAL STIMULI ALTER THE EPIGENOME ARE STILL UNCLEAR, RESEARCH FROM THE LEARNING AND MEMORY FIELDS INDICATES THAT EPIGENOMIC MARKS CAN BE ALTERED, AT LEAST IN PART, THROUGH CALCIUM-DEPENDENT SIGNALING CASCADES IN DIRECT RESPONSE TO NEURONAL ACTIVITY. IN THIS REVIEW, WE HIGHLIGHT KEY FINDINGS FROM THE STRESS, MDD, AND LEARNING AND MEMORY FIELDS TO PROPOSE A MODEL WHERE STRESS REGULATES DOWNSTREAM CELLULAR FUNCTIONING THROUGH ACTIVITY-DEPENDENT EPIGENETIC CHANGES. FURTHERMORE, WE SUGGEST THAT BOTH TYPICAL AND NOVEL ANTIDEPRESSANT TREATMENTS MAY EXERT POSITIVE INFLUENCE THROUGH SIMILAR, ACTIVITY-DEPENDENT PATHWAYS. 2018 6 6228 30 THE LINKS BETWEEN STRESS AND DEPRESSION: PSYCHONEUROENDOCRINOLOGICAL, GENETIC, AND ENVIRONMENTAL INTERACTIONS. THE ROLE OF STRESS IN THE ORIGIN AND DEVELOPMENT OF DEPRESSION MAY BE CONCEIVED AS THE RESULT OF MULTIPLE CONVERGING FACTORS, INCLUDING THE CHRONIC EFFECT OF ENVIRONMENTAL STRESSORS AND THE LONG-LASTING EFFECTS OF STRESSFUL EXPERIENCES DURING CHILDHOOD, ALL OF WHICH MAY INDUCE PERSISTENT HYPERACTIVITY OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS. THESE CHANGES, INCLUDING INCREASED AVAILABILITY OF CORTICOTROPIN-RELEASING FACTOR AND CORTISOL, ARE ALSO ASSOCIATED WITH HYPERACTIVITY OF THE AMYGDALA, HYPOACTIVITY OF THE HIPPOCAMPUS, AND DECREASED SEROTONERGIC NEUROTRANSMISSION, WHICH TOGETHER RESULT IN INCREASED VULNERABILITY TO STRESS. THE ROLE OF OTHER MONOAMINERGIC NEUROTRANSMITTERS, GENETIC POLYMORPHISMS, EPIGENETIC MECHANISMS, INFLAMMATORY PROCESSES, AND ALTERED COGNITIVE PROCESSING HAS ALSO BEEN CONSIDERED IN THE DEVELOPMENT OF A COMPREHENSIVE MODEL OF THE INTERACTIONS BETWEEN DIFFERENT FACTORS OF VULNERABILITY. FURTHER UNDERSTANDING OF THE UNDERLYING MECHANISMS THAT LINK THESE FACTORS MAY CONTRIBUTE SIGNIFICANTLY TO THE DEVELOPMENT OF MORE EFFECTIVE TREATMENTS AND PREVENTIVE STRATEGIES IN THE INTERFACE BETWEEN STRESS AND MOOD DISORDERS. 2016 7 6866 34 [PAIN AND EMOTIONAL DYSREGULATION: CELLULAR MEMORY DUE TO PAIN]. GENETIC FACTORS ARE INVOLVED IN DETERMINANTS FOR THE RISK OF PSYCHIATRIC DISORDERS, AND NEUROLOGICAL AND NEURODEGENERATIVE DISEASES. CHRONIC PAIN STIMULI AND INTENSE PAIN HAVE EFFECTS AT A CELLULAR AND/OR GENE EXPRESSION LEVEL, AND WILL EVENTUALLY INDUCE "CELLULAR MEMORY DUE TO PAIN", WHICH MEANS THAT TISSUE DAMAGE, EVEN IF ONLY TRANSIENT, CAN ELICIT EPIGENETICALLY ABNORMAL TRANSCRIPTION/TRANSLATION AND POST-TRANSLATIONAL MODIFICATION IN RELATED CELLS DEPENDING ON THE DEGREE OR KIND OF INJURY OR ASSOCIATED CONDITIONS. SUCH CELL MEMORY/TRANSFORMATION DUE TO PAIN CAN CAUSE AN ABNORMALITY IN A FUNDAMENTAL INTRACELLULAR RESPONSE, SUCH AS A CHANGE IN THE THREE-DIMENSIONAL STRUCTURE OF DNA, TRANSCRIPTION, OR TRANSLATION. ON THE OTHER HAND, PAIN IS A MULTIDIMENSIONAL EXPERIENCE WITH SENSORY-DISCRIMINATIVE AND MOTIVATIONAL-AFFECTIVE COMPONENTS. RECENT HUMAN BRAIN IMAGING STUDIES HAVE EXAMINED DIFFERENCES IN ACTIVITY IN THE NUCLEUS ACCUMBENS BETWEEN CONTROLS AND PATIENTS WITH CHRONIC PAIN, AND HAVE REVEALED THAT THE NUCLEUS ACCUMBENS PLAYS A ROLE IN PREDICTING THE VALUE OF A NOXIOUS STIMULUS AND ITS OFFSET, AND IN THE CONSEQUENT CHANGES IN THE MOTIVATIONAL STATE. IN THIS REVIEW, WE PROVIDE A VERY BRIEF OVERVIEW OF A COMPREHENSIVE UNDERSTANDING OF CHRONIC PAIN ASSOCIATED WITH EMOTIONAL DYSREGULATION DUE TO TRANSCRIPTIONAL REGULATION, EPIGENETIC MODIFICATION AND MIRNA REGULATION. 2015 8 2011 35 EPIGENETIC BASIS OF MENTAL ILLNESS. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL ILLNESSES INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION AS WELL AS LIKELY ABNORMALITIES IN GLIAL CELLS. WHILE GENETIC FACTORS ARE IMPORTANT IN THE ETIOLOGY OF MOST MENTAL DISORDERS, THE RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS, PARTICULARLY FOR DEPRESSION AND OTHER STRESS-RELATED SYNDROMES, CLEARLY INDICATE THE IMPORTANCE OF ADDITIONAL MECHANISMS. ENVIRONMENTAL FACTORS SUCH AS STRESS ARE KNOWN TO PLAY A ROLE IN THE ONSET OF THESE ILLNESSES. EXPOSURE TO SUCH ENVIRONMENTAL INSULTS INDUCES STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR, AND THESE MALADAPTATIONS APPEAR DISTINCT BETWEEN DEVELOPMENTAL VERSUS ADULT EXPOSURES. INCREASING EVIDENCE INDICATES THAT THESE SUSTAINED ABNORMALITIES ARE MAINTAINED BY EPIGENETIC MODIFICATIONS IN SPECIFIC BRAIN REGIONS. INDEED, TRANSCRIPTIONAL DYSREGULATION AND THE ABERRANT EPIGENETIC REGULATION THAT UNDERLIES THIS DYSREGULATION IS A UNIFYING THEME IN PSYCHIATRIC DISORDERS. HERE, WE PROVIDE A PROGRESS REPORT OF EPIGENETIC STUDIES OF THE THREE MAJOR PSYCHIATRIC SYNDROMES, DEPRESSION, SCHIZOPHRENIA, AND BIPOLAR DISORDER. WE REVIEW THE LITERATURE DERIVED FROM ANIMAL MODELS OF THESE DISORDERS AS WELL AS FROM STUDIES OF POSTMORTEM BRAIN TISSUE FROM HUMAN PATIENTS. WHILE EPIGENETIC STUDIES OF MENTAL ILLNESS REMAIN AT EARLY STAGES, UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY WITHIN SPECIFIC BRAIN REGIONS TO CAUSE LASTING CHANGES IN DISEASE SUSCEPTIBILITY AND PATHOPHYSIOLOGY IS REVEALING NEW INSIGHT INTO THE ETIOLOGY AND TREATMENT OF THESE CONDITIONS. 2016 9 291 31 AGING AND STRESS: PAST HYPOTHESES, PRESENT APPROACHES AND PERSPECTIVES. BRAIN AGING HAS BEEN SUGGESTED TO BE CONDITIONED BY AN EXCESSIVE GLUCOCORTIOID SECRETION LEADING TO DAMAGES ON BRAIN AREAS INVOLVED NOT ONLY IN COGNITIVE AND EMOTIONAL PROCESSES BUT ALSO IN THE CONTROL OF THE ACTIVITY OF THE HYPOTHALAMIC-PITUITARY ADRENAL AXIS. THIS REVIEW DESCRIBES SOME OF THE HYPOTHESIS THAT TRY TO EXPLAIN THE RELATION BETWEEN THE DYSREGULATION OF THE STRESS RESPONSE AND BRAIN AGING, FOCUSING ON CORTICOSTERONE BUT ALSO ON NEUROTRANSMISSION IN THE HIPPOCAMPUS, THE PREFRONTAL CORTEX AND THE AMYGDALA. MOREOVER, DIFFERENT MOLECULAR FACTORS CAN ACCOUNT FOR AN ENHANCED VULNERABILITY OF THE AGED BRAIN TO STRESS EXPOSURE, SPECIALLY FOR RESILIENCE. AMONG THEM, GOOD CANDIDATES COULD BE THOSE MECHANISMS DETERMINING THE LEVELS OF CORTICOSTERONE IN THE BRAIN, SEVERAL MOLECULES DOWNSTREAM GLUCOCORTICOID RECEPTOR ACTIVATION (IE: HEAT SHOCK PROTEINS, BAG-1) OR EVEN THE EPIGENETIC PROGRAMMING OF THE HPA AXIS IN EARLY STAGES. IN CONCLUSION, GENETIC AND ENVIRONMENTAL FACTORS (EARLY LIFE STRESS, CHRONIC STRESS DURING ADULTHOOD) CAN PRODUCE AN ENHANCED VULNERABILITY AND A REDUCED RESILIENCE OF THE BRAIN TO SUBSEQUENT STRESS EXPOSURES OR TO METABOLIC CHALLENGES LEADING, IN TURN, TO AN UNSUCCESSFUL AGING OF THE BRAIN. HOWEVER, RESULTS OBTAINED WITH THE USE OF THE ENVIRONMENTAL ENRICHMENT MODEL IN ANIMALS, ADDED TO SEVERAL RESULTS IN HUMANS ALSO DESCRIBED IN THIS REVIEW SUGGEST THAT POSITIVE ENVIRONMENTAL FACTORS (COGNITIVE-DEMANDING TASKS OR PHYSICAL EXERCISE) CAN HELP TO MAINTAIN NEURONAL PLASTICITY DURING AGING AND TO PROTECT THE BRAIN AGAINST THE DAMAGING EFFECTS OF STRESS EXPOSURE. 2011 10 1981 31 EPIGENETIC ALTERATIONS IN DNA AND HISTONE MODIFICATIONS CAUSED BY DEPRESSION AND ANTIDEPRESSANT DRUGS: LESSONS FROM THE RODENT MODELS. EPIGENETIC MODIFICATIONS REGULATE CHROMATIN FOLDING AND FUNCTION. EPIGENETIC MECHANISMS REGULATE TRANSCRIPTION MEDIATING EFFECTS OF VARIOUS STIMULI ON GENE EXPRESSION. THESE MECHANISMS ARE INVOLVED IN TRANSCRIPTIONAL CONTROL IN VARIOUS PHYSIOLOGICAL AND PATHOLOGICAL CONDITIONS INCLUDING NEUROPSYCHIATRIC DISORDERS AND BEHAVIORAL ABNORMALITIES SUCH AS DEPRESSION. IN RODENTS, EXPOSURE TO CHRONIC SOCIAL STRESS WAS SHOWN TO INDUCE BEHAVIORAL IMPAIRMENTS AND MEMORY/LEARNING DEFICITS THAT RESEMBLE DEPRESSIVE-LIKE PHENOTYPE IN HUMANS. THE RODENT MODELS OF CHRONIC STRESS WERE WIDELY USED TO STUDY MOLECULAR MECHANISMS OF DEPRESSION. IN THESE MODELS, EARLY EXPOSURE TO CHRONIC STRESS SUCH AS PRENATAL OR POSTNATAL STRESS INDUCES LONG-TERM HYPERACTIVE STRESS RESPONSES, BEHAVIORAL ABNORMALITIES, AND FUNCTIONAL IMPAIRMENTS IN BRAIN FUNCTION THAT PERSIST IN ADULTHOOD. FURTHERMORE, THESE ALTERATIONS CAN BE TRANSMITTED TO OFFSPRING OF CHRONICALLY STRESSED ANIMALS ACROSS SEVERAL GENERATIONS. MOLECULAR STUDIES IN ANIMAL MODELS SHOWED THAT CHRONIC STRESS INDUCES STABLE EPIGENETIC CHANGES IN SPECIFIC BRAIN REGIONS, PRIMARILY IN THE LIMBIC SYSTEM. THESE CHANGES LEAD TO LONG-LASTING ABNORMALITIES IN BEHAVIOR THAT PERSIST IN ADULTHOOD AND CAN BE TRANSMITTED TO OFFSPRING. TREATMENT WITH EPIGENETICALLY ACTIVE ANTIDEPRESSANTS DISRUPTS THE ABNORMAL STRESS-INDUCED EPIGENETIC PROGRAMMING AND PROVIDES EPIGENETIC PATTERNS THAT RESEMBLE EPIGENETIC BACKGROUND OF STRESS RESILIENT INDIVIDUALS. 2017 11 1181 26 CONVERGENT ACTIONS OF STRESS AND STIMULANTS VIA EPIGENETIC REGULATION OF NEURAL CIRCUITRY. THE DORSAL STRIATUM INTEGRATES PRIOR AND CURRENT INFORMATION TO GUIDE APPROPRIATE DECISION-MAKING. CHRONIC STRESS AND STIMULANT EXPOSURE INTERFERES WITH DECISION-MAKING, AND CAN CONFER SIMILAR COGNITIVE AND BEHAVIORAL INFLEXIBILITIES. THIS REVIEW EXAMINES THE LITERATURE ON ACUTE AND CHRONIC REGULATION OF THE EPIGENOME BY STRESS AND STIMULANTS. RECENT EVIDENCE SUGGESTS THAT EXPOSURES TO STRESS AND STIMULANTS SHARE SIMILARITIES IN THE MANNERS IN WHICH THEY REGULATE THE DORSAL STRIATUM EPIGENOME THROUGH DNA METHYLATION, TRANSPOSABLE ELEMENT ACTIVITY, AND HISTONE POST-TRANSLATIONAL MODIFICATIONS. THESE FINDINGS SUGGEST THAT CHRONIC STRESS AND STIMULANT EXPOSURE LEADS TO THE ACCUMULATION OF EPIGENETIC MODIFICATIONS THAT IMPAIR IMMEDIATE AND FUTURE NEURON FUNCTION AND ACTIVITY. SUCH EPIGENETIC MECHANISMS REPRESENT POTENTIAL THERAPEUTIC TARGETS FOR AMELIORATING CONVERGENT SYMPTOMS OF STRESS AND ADDICTION. 2022 12 6174 41 THE HIPPOCAMPUS, NEUROTROPHIC FACTORS AND DEPRESSION: POSSIBLE IMPLICATIONS FOR THE PHARMACOTHERAPY OF DEPRESSION. DEPRESSION IS A PREVALENT, HIGHLY DEBILITATING MENTAL DISORDER AFFECTING UP TO 15% OF THE POPULATION AT LEAST ONCE IN THEIR LIFETIME, WITH HUGE COSTS FOR SOCIETY. NEUROBIOLOGICAL MECHANISMS OF DEPRESSION ARE STILL NOT WELL KNOWN, ALTHOUGH THERE IS CONSENSUS ABOUT INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS. ANTIDEPRESSANT MEDICATIONS ARE FREQUENTLY USED IN DEPRESSION, BUT AT LEAST 50% OF PATIENTS ARE POOR RESPONDERS, EVEN TO MORE RECENTLY DISCOVERED MEDICATIONS. FURTHERMORE, CLINICAL RESPONSE ONLY OCCURS FOLLOWING WEEKS TO MONTHS OF TREATMENT AND ONLY CHRONIC TREATMENT IS EFFECTIVE, SUGGESTING THAT ACTIONS BEYOND THE RAPIDLY OCCURRING EFFECT OF ENHANCING MONOAMINERGIC SYSTEMS, SUCH AS ADAPTATION OF THESE SYSTEMS, ARE RESPONSIBLE FOR THE EFFECTS OF ANTIDEPRESSANTS. RECENT STUDIES INDICATE THAT AN IMPAIRMENT OF SYNAPTIC PLASTICITY (NEUROGENESIS, AXON BRANCHING, DENDRITOGENESIS AND SYNAPTOGENESIS) IN SPECIFIC AREAS OF THE CNS, PARTICULARLY THE HIPPOCAMPUS, MAY BE A CORE FACTOR IN THE PATHOPHYSIOLOGY OF DEPRESSION. THE ABNORMAL NEURAL PLASTICITY MAY BE RELATED TO ALTERATIONS IN THE LEVELS OF NEUROTROPHIC FACTORS, NAMELY BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), WHICH PLAY A CENTRAL ROLE IN PLASTICITY. AS BDNF IS REPRESSED BY STRESS, EPIGENETIC REGULATION OF THE BDNF GENE MAY PLAY AN IMPORTANT ROLE IN DEPRESSION. THE HIPPOCAMPUS IS SMALLER IN DEPRESSED PATIENTS, ALTHOUGH IT IS UNCLEAR WHETHER SMALLER SIZE IS A CONSEQUENCE OF DEPRESSION OR A PRE-EXISTING, VULNERABILITY MARKER FOR DEPRESSION. ENVIRONMENTAL STRESSORS TRIGGERING ACTIVATION OF THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS CAUSE THE BRAIN TO BE EXPOSED TO CORTICOSTEROIDS, AFFECTING NEUROBEHAVIOURAL FUNCTIONS WITH A STRONG DOWNREGULATION OF HIPPOCAMPAL NEUROGENESIS, AND ARE A MAJOR RISK FACTOR FOR DEPRESSION. ANTIDEPRESSANT TREATMENT INCREASES BDNF LEVELS, STIMULATES NEUROGENESIS AND REVERSES THE INHIBITORY EFFECTS OF STRESS, BUT THIS EFFECT IS EVIDENT ONLY AFTER 3-4 WEEKS OF ADMINISTRATION, THE TIME COURSE FOR MATURATION OF NEW NEURONS. THE ABLATION OF HIPPOCAMPAL NEUROGENESIS BLOCKS THE BEHAVIOURAL EFFECTS OF ANTIDEPRESSANTS IN ANIMAL MODELS. THE ABOVE FINDINGS SUGGEST NEW POSSIBLE TARGETS FOR THE PHARMACOTHERAPY OF DEPRESSION SUCH AS NEUROTROPHIC FACTORS, THEIR RECEPTORS AND RELATED INTRACELLULAR SIGNALLING CASCADES; AGENTS COUNTERACTING THE EFFECTS OF STRESS ON HIPPOCAMPAL NEUROGENESIS (INCLUDING ANTAGONISTS OF CORTICOSTEROIDS, INFLAMMATORY CYTOKINES AND THEIR RECEPTORS); AND AGENTS FACILITATING THE ACTIVATION OF GENE EXPRESSION AND INCREASING THE TRANSCRIPTION OF NEUROTROPHINS IN THE BRAIN. 2011 13 4620 28 NEURO-IMMUNE DYSFUNCTION DURING BRAIN AGING: NEW INSIGHTS IN MICROGLIAL CELL REGULATION. MICROGLIA, THE RESIDENT IMMUNE CELLS OF THE BRAIN, ARE AT THE CENTER OF COMMUNICATION BETWEEN THE CENTRAL NERVOUS SYSTEM AND IMMUNE SYSTEM. WHILE THESE BRAIN-IMMUNE INTERACTIONS ARE BALANCED IN HEALTHY ADULTHOOD, THE ABILITY TO MAINTAIN HOMEOSTASIS DURING AGING IS IMPAIRED. MICROGLIA DEVELOP A LOSS OF INTEGRATED REGULATORY NETWORKS INCLUDING ABERRANT SIGNALING FROM OTHER BRAIN CELLS, IMMUNE SENSORS, AND EPIGENETIC MODIFIERS. THE LOW-GRADE CHRONIC NEUROINFLAMMATION ASSOCIATED WITH THIS DYSFUNCTIONAL ACTIVITY LIKELY CONTRIBUTES TO COGNITIVE DEFICITS AND SUSCEPTIBILITY TO AGE-RELATED PATHOLOGIES. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS RESPONSIBLE FOR NEURO-IMMUNE DYSREGULATION WITH AGE IS CRUCIAL FOR PROVIDING TARGETED THERAPEUTIC STRATEGIES TO SUPPORT BRAIN REPAIR AND HEALTHY AGING. 2016 14 5164 36 PRECLINICAL AND CLINICAL EVIDENCE OF DNA METHYLATION CHANGES IN RESPONSE TO TRAUMA AND CHRONIC STRESS. EXPOSURE TO CHRONIC STRESS, EITHER REPEATED SEVERE ACUTE OR MODERATE SUSTAINED STRESS, IS ONE OF THE STRONGEST RISK FACTORS FOR THE DEVELOPMENT OF PSYCHOPATHOLOGIES SUCH AS POST-TRAUMATIC STRESS DISORDER AND DEPRESSION. CHRONIC STRESS IS LINKED WITH SEVERAL LASTING BIOLOGICAL CONSEQUENCES, PARTICULARLY TO THE STRESS ENDOCRINE SYSTEM BUT ALSO AFFECTING INTERMEDIATE PHENOTYPES SUCH AS BRAIN STRUCTURE AND FUNCTION, IMMUNE FUNCTION, AND BEHAVIOR. ALTHOUGH GENETIC PREDISPOSITION CONFERS A PROPORTION OF THE RISK, THE MOST RELEVANT MOLECULAR MECHANISMS DETERMINING THOSE SUSCEPTIBLE AND RESILIENT TO THE EFFECTS OF STRESS AND TRAUMA MAY BE EPIGENETIC. EPIGENETICS REFERS TO THE MECHANISMS THAT REGULATE GENOMIC INFORMATION BY DYNAMICALLY CHANGING THE PATTERNS OF TRANSCRIPTION AND TRANSLATION OF GENES. MOUNTING EVIDENCE FROM PRECLINICAL RODENT AND CLINICAL POPULATION STUDIES STRONGLY SUPPORT THAT EPIGENETIC MODIFICATIONS CAN OCCUR IN RESPONSE TO TRAUMATIC AND CHRONIC STRESS. HERE, WE DISCUSS THIS LITERATURE EXAMINING STRESS-INDUCED EPIGENETIC CHANGES IN PRECLINICAL MODELS AND CLINICAL COHORTS OF STRESS AND TRAUMA OCCURRING EARLY IN LIFE OR IN ADULTHOOD. WE HIGHLIGHT THAT A COMPLEX RELATIONSHIP BETWEEN THE TIMING OF ENVIRONMENTAL STRESSORS AND GENETIC PREDISPOSITIONS LIKELY MEDIATE THE RESPONSE TO CHRONIC STRESS OVER TIME, AND THAT A BETTER UNDERSTANDING OF EPIGENETIC CHANGES IS NEEDED BY FURTHER INVESTIGATIONS IN LONGITUDINAL AND POSTMORTEM BRAIN CLINICAL COHORTS. 2017 15 679 23 BRAIN FOODS - THE ROLE OF DIET IN BRAIN PERFORMANCE AND HEALTH. THE PERFORMANCE OF THE HUMAN BRAIN IS BASED ON AN INTERPLAY BETWEEN THE INHERITED GENOTYPE AND EXTERNAL ENVIRONMENTAL FACTORS, INCLUDING DIET. FOOD AND NUTRITION, ESSENTIAL IN MAINTENANCE OF BRAIN PERFORMANCE, ALSO AID IN PREVENTION AND TREATMENT OF MENTAL DISORDERS. BOTH THE OVERALL COMPOSITION OF THE HUMAN DIET AND SPECIFIC DIETARY COMPONENTS HAVE BEEN SHOWN TO HAVE AN IMPACT ON BRAIN FUNCTION IN VARIOUS EXPERIMENTAL MODELS AND EPIDEMIOLOGICAL STUDIES. THIS NARRATIVE REVIEW PROVIDES AN OVERVIEW OF THE ROLE OF DIET IN 5 KEY AREAS OF BRAIN FUNCTION RELATED TO MENTAL HEALTH AND PERFORMANCE, INCLUDING: (1) BRAIN DEVELOPMENT, (2) SIGNALING NETWORKS AND NEUROTRANSMITTERS IN THE BRAIN, (3) COGNITION AND MEMORY, (4) THE BALANCE BETWEEN PROTEIN FORMATION AND DEGRADATION, AND (5) DETERIORATIVE EFFECTS DUE TO CHRONIC INFLAMMATORY PROCESSES. FINALLY, THE ROLE OF DIET IN EPIGENETIC REGULATION OF BRAIN PHYSIOLOGY IS DISCUSSED. 2021 16 5313 30 PSYCHOLOGICAL STRESS AS A MODULATOR OF FUNCTIONAL RECOVERY FOLLOWING SPINAL CORD INJURY. THERE IS STRONG EVIDENCE INDICATING THAT THE SOCIAL ENVIRONMENT TRIGGERS CHANGES TO THE PSYCHOLOGICAL STRESS RESPONSE AND GLUCOCORTICOID RECEPTOR FUNCTION. CONSIDERABLE LITERATURE LINKS THE SUBSEQUENT CHANGES IN STRESS RESILIENCY TO PHYSICAL HEALTH. HERE, CONVERGING EVIDENCE FOR THE MODULATORY ROLE OF CHRONIC PSYCHOLOGICAL STRESS IN THE RECOVERY PROCESS FOLLOWING SPINAL CORD INJURY (SCI) IS PRESENTED. DESPITE THE CONSIDERABLE ADVANCES IN SCI RESEARCH, WE ARE STILL UNABLE TO IDENTIFY THE CAUSES OF VARIABILITY IN PATIENTS' RECOVERY FOLLOWING INJURY. WE PROPOSE THAT INDIVIDUALS' PAST AND PRESENT LIFE EXPERIENCES (IN THE FORM OF STRESS EXPOSURE) MAY SIGNIFICANTLY MODULATE PATIENTS' OUTCOME POST-SCI. WE PROPOSE A THEORETICAL MODEL TO EXPLAIN THE NEGATIVE IMPACT OF CHRONIC PSYCHOLOGICAL STRESS ON PHYSICAL AND PSYCHOLOGICAL RECOVERY. THE STRESS EXPERIENCED IN LIFE PRIOR TO SCI AND ALSO AS A RESULT OF THE TRAUMATIC INJURY, COULD COMPROMISE GLUCOCORTICOID RECEPTOR SENSITIVITY AND FUNCTION, AND CONTRIBUTE TO HIGH LEVELS OF INFLAMMATION AND APOPTOSIS POST-SCI, DECREASING THE TISSUE REMAINING AT THE INJURY SITE AND UNDERMINING RECOVERY OF FUNCTION. BOTH STRESS-INDUCED GLUCOCORTICOID RESISTANCE AND STRESS-INDUCED EPIGENETIC CHANGES TO THE GLUCOCORTICOID RECEPTOR CAN MODULATE THE NUCLEAR FACTOR-KAPPA B REGULATED INFLAMMATORY PATHWAYS AND THE BCL-2 REGULATED APOPTOSIS PATHWAYS. THIS MODEL NOT ONLY CONTRIBUTES TO THE THEORETICAL UNDERSTANDING OF THE RECOVERY PROCESS FOLLOWING INJURY, BUT ALSO PROVIDES CONCRETE TESTABLE HYPOTHESES FOR FUTURE STUDIES. 2014 17 6400 29 THE ROLES OF CLASS I HISTONE DEACETYLASES (HDACS) IN MEMORY, LEARNING, AND EXECUTIVE COGNITIVE FUNCTIONS: A REVIEW. COORDINATED CHANGES IN GENE EXPRESSION ARE CRITICAL FOR SYNAPTIC PLASTICITY SUPPORTING LEARNING, MEMORY, AND OPTIMAL COGNITIVE TASK PERFORMANCE. THESE GENE EXPRESSION CHANGES ARE NOT ONLY MEDIATED BY SIGNALING PATHWAYS THAT ACTIVATE TRANSCRIPTION FACTORS, BUT ALSO BY CHROMATIN MODIFICATIONS THAT INFLUENCE THE ACCESSIBILITY OF THE TRANSCRIPTIONAL MACHINERY TO SPECIFIC GENOMIC REGIONS. DURING THE PAST DECADE, EVIDENCE ACCUMULATED THAT ALTERATIONS IN CHROMATIN-BASED EPIGENETIC REGULATION OF GENE EXPRESSION ARE LINKED TO COGNITIVE DYSFUNCTIONS IN THE AGEING OR NEURODEGENERATING BRAIN AS WELL AS TO COGNITIVE DYSFUNCTIONS RESULTING FROM CHRONIC STRESS EXPOSURE. THIS REVIEW SUMMARIZES THE RESULTS OF STUDIES THAT UNRAVELED A ROLE OF HISTONE MODIFYING ENZYMES AND HISTONE MODIFICATIONS IN NORMAL AND IMPAIRED LEARNING AND MEMORY, AND IN THE DISRUPTION OF EXECUTIVE COGNITIVE TASK PERFORMANCE. IT EMPHASIZES THE DIFFERENT ROLES OF SPECIFIC CLASS I HISTONE DEACETYLASES (HDACS) IN COGNITIVE PROCESSES GOVERNED BY THE HIPPOCAMPUS AND PREFRONTAL CORTEX AND DISCUSSES THE POTENTIAL THERAPEUTIC IMPLICATIONS OF TARGETING THEM TO HOLD THE PROGRESSION OF DISEASE-RELATED COGNITIVE DYSFUNCTIONS. 2017 18 2414 30 EPIGENETIC SIGNALING IN PSYCHIATRIC DISORDERS. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL ILLNESSES INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION. WHILE GENETIC FACTORS ARE IMPORTANT IN THE ETIOLOGY OF DISORDERS SUCH AS DEPRESSION AND ADDICTION, RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS CLEARLY INDICATE THE IMPORTANCE OF ADDITIONAL MECHANISMS. ENVIRONMENTAL FACTORS SUCH AS STRESS OR PRIOR DRUG EXPOSURE ARE KNOWN TO PLAY A ROLE IN THE ONSET OF THESE ILLNESSES. SUCH EXPOSURE TO ENVIRONMENTAL INSULTS INDUCES STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR, AND THESE MALADAPTATIONS APPEAR DISTINCT BETWEEN DEVELOPMENTAL AND ADULT EXPOSURES. INCREASING EVIDENCE INDICATES THAT THESE SUSTAINED ABNORMALITIES ARE MAINTAINED BY EPIGENETIC MODIFICATIONS IN SPECIFIC BRAIN REGIONS. INDEED, TRANSCRIPTIONAL DYSREGULATION AND ASSOCIATED ABERRANT EPIGENETIC REGULATION IS A UNIFYING THEME IN PSYCHIATRIC DISORDERS. ASPECTS OF DEPRESSION AND ADDICTION CAN BE MODELED IN ANIMALS BY INDUCING DISEASE-LIKE STATES THROUGH ENVIRONMENTAL MANIPULATIONS (E.G., CHRONIC STRESS, DRUG ADMINISTRATION). UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY IN ANIMAL MODELS REVEALS NEW INSIGHT INTO DISEASE MECHANISMS IN HUMANS. 2014 19 2386 24 EPIGENETIC REGULATORY MECHANISMS IN STRESS-INDUCED BEHAVIOR. STRESS RESPONSE IS CONSIDERED TO HAVE ADAPTIVE VALUE FOR ORGANISMS FACED WITH STRESSFUL CONDITION. CHRONIC STRESS HOWEVER ADVERSELY AFFECTS THE PHYSIOLOGY AND MAY LEAD TO NEUROPSYCHIATRIC DISORDERS. REPEATED STRESSFUL EVENTS IN ANIMAL MODELS HAVE BEEN SHOWN TO CAUSE LONG-LASTING CHANGES IN NEURAL CIRCUITRIES AT MOLECULAR, CELLULAR, AND PHYSIOLOGICAL LEVEL, LEADING TO DISORDERS OF MOOD AS WELL AS COGNITION. MOLECULAR STUDIES IN RECENT YEARS HAVE IMPLICATED DIVERSE EPIGENETIC MECHANISMS, INCLUDING HISTONE MODIFICATIONS, DNA METHYLATION, AND NONCODING RNAS, THAT UNDERLIE DYSREGULATION OF GENES IN THE AFFECTED NEURAL CIRCUITRIES IN CHRONIC STRESS-INDUCED PATHOPHYSIOLOGY. A REVIEW OF THE MYRIAD EPIGENETIC REGULATORY MECHANISMS ASSOCIATED WITH NEURAL AND BEHAVIORAL RESPONSES IN ANIMAL MODELS OF STRESS-INDUCED NEUROPSYCHIATRIC DISORDERS IS PRESENTED HERE. THE REVIEW ALSO DEALS WITH CLINICAL EVIDENCE OF THE EPIGENETIC DYSREGULATION OF GENES IN PSYCHIATRIC DISORDERS WHERE CHRONIC STRESS APPEARS TO UNDERLIE THE ETIOPATHOLOGY. 2014 20 6257 32 THE MOLECULAR BASIS OF TOLERANCE. TOLERANCE IS DEFINED AS THE DIMINISHED RESPONSE TO ALCOHOL OR OTHER DRUGS OVER THE COURSE OF REPEATED OR PROLONGED EXPOSURE. THIS MECHANISM ALLOWS PHYSIOLOGICAL PROCESSES TO ACHIEVE STABILITY IN A CONSTANTLY CHANGING ENVIRONMENT. THE ONSET OF TOLERANCE MAY OCCUR WITHIN MINUTES, DURING A SINGLE EXPOSURE TO ALCOHOL (I.E., ACUTE TOLERANCE), OR OVER LONGER TIMEFRAMES AND WITH PROLONGED EXPOSURE TO ALCOHOL (I.E., RAPID OR CHRONIC TOLERANCE). CHANGES IN TOLERANCE INDUCED BY ALCOHOL MAY AFFECT SEVERAL PROCESSES AT THE MOLECULAR, CELLULAR, OR BEHAVIORAL LEVEL. THESE EFFECTS OFTEN ARE INTERRELATED AND MAY BE DIFFICULT TO SEPARATE. THIS ARTICLE DESCRIBES CHANGES AT THE MOLECULAR LEVEL THAT ARE RELATED TO THE ONSET OF ACUTE, RAPID, OR CHRONIC TOLERANCE. IT FOCUSES ON NEURONAL MEMBRANE-BOUND CHANNELS AND THE FACTORS THAT AFFECT THEIR FUNCTION AND PRODUCTION, SUCH AS MODIFICATION OF PROTEIN SYNTHESIS AND ACTIVITY, INTERACTION WITH THE MEMBRANE LIPID MICROENVIRONMENT, EPIGENETIC EFFECTS ON CYTOPLASMIC REGULATION, AND GENE TRANSCRIPTION. ALSO CONSIDERED IS THE GENETICS OF TOLERANCE. 2008