1 3534 134 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 2 4642 45 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 6174 47 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 4 2598 33 EPIGENETICS OF THE DEPRESSED BRAIN: ROLE OF HISTONE ACETYLATION AND METHYLATION. MAJOR DEPRESSIVE DISORDER IS A CHRONIC, REMITTING SYNDROME INVOLVING WIDELY DISTRIBUTED CIRCUITS IN THE BRAIN. STABLE ALTERATIONS IN GENE EXPRESSION THAT CONTRIBUTE TO STRUCTURAL AND FUNCTIONAL CHANGES IN MULTIPLE BRAIN REGIONS ARE IMPLICATED IN THE HETEROGENEITY AND PATHOGENESIS OF THE ILLNESS. EPIGENETIC EVENTS THAT ALTER CHROMATIN STRUCTURE TO REGULATE PROGRAMS OF GENE EXPRESSION HAVE BEEN ASSOCIATED WITH DEPRESSION-RELATED BEHAVIOR, ANTIDEPRESSANT ACTION, AND RESISTANCE TO DEPRESSION OR 'RESILIENCE' IN ANIMAL MODELS, WITH INCREASING EVIDENCE FOR SIMILAR MECHANISMS OCCURRING IN POSTMORTEM BRAINS OF DEPRESSED HUMANS. IN THIS REVIEW, WE DISCUSS RECENT ADVANCES IN OUR UNDERSTANDING OF EPIGENETIC CONTRIBUTIONS TO DEPRESSION, IN PARTICULAR THE ROLE OF HISTONE ACETYLATION AND METHYLATION, WHICH ARE REVEALING NOVEL MECHANISTIC INSIGHT INTO THE SYNDROME THAT MAY AID IN THE DEVELOPMENT OF NOVEL TARGETS FOR DEPRESSION TREATMENT. 2013 5 4327 38 MICRORNAS MODULATE INTERACTIONS BETWEEN STRESS AND RISK FOR COCAINE ADDICTION. EXPOSURE TO STRESS INCREASES VULNERABILITY TO DRUG ABUSE, AS WELL AS RELAPSE LIABILITY IN ADDICTED INDIVIDUALS. CHRONIC DRUG USE ALTERS STRESS RESPONSE IN A MANNER THAT INCREASES DRUG SEEKING BEHAVIORS AND RELAPSE. DRUG EXPOSURE AND WITHDRAWAL HAVE BEEN SHOWN TO ALTER STRESS RESPONSES, AND CORTICOSTEROID MEDIATORS OF STRESS HAVE BEEN SHOWN TO IMPACT ADDICTION-RELATED BRAIN FUNCTION AND DRUG-SEEKING BEHAVIOR. DESPITE THE DOCUMENTED INTERPLAY BETWEEN STRESS AND SUBSTANCE ABUSE, THE MECHANISMS BY WHICH STRESS EXPOSURE AND DRUG SEEKING INTERACT REMAIN LARGELY UNKNOWN. RECENT STUDIES INDICATE THAT MICRORNAS (MIRNA) PLAY A SIGNIFICANT ROLE IN STRESS MODULATION AS WELL AS ADDICTION-RELATED PROCESSES INCLUDING NEUROGENESIS, SYNAPSE DEVELOPMENT, PLASTICITY, DRUG ACQUISITION, WITHDRAWAL AND RELAPSE. MIRNAS ARE SHORT NON-CODING RNAS THAT FUNCTION AS BIDIRECTIONAL EPIGENETIC MODULATORS OF GENE EXPRESSION THROUGH IMPERFECT SEQUENCE TARGETED DEGRADATION AND/OR TRANSLATIONAL REPRESSION OF MRNAS. THEY SERVE AS DYNAMIC REGULATORS OF CNS PHYSIOLOGY AND PATHOPHYSIOLOGY, AND FACILITATE RAPID AND LONG-LASTING CHANGES TO COMPLEX SYSTEMS AND BEHAVIORS. MIRNAS FUNCTION IN GLUCOCORTICOID SIGNALING AND THE MESOLIMBIC DOPAMINE REWARD SYSTEM, AS WELL AS MOOD DISORDERS RELATED TO DRUG WITHDRAWAL. THE LITERATURE SUGGESTS MIRNAS PLAY A PIVOTAL ROLE IN THE INTERACTION BETWEEN EXPOSURES TO STRESS, ADDICTION-RELATED PROCESSES, AND NEGATIVE AFFECTIVE STATES RESULTING FROM EXTENDED DRUG WITHDRAWAL. THIS MANUSCRIPT REVIEWS RECENT EVIDENCE FOR THE ROLE OF MIRNAS IN THE MODULATION OF STRESS AND COCAINE RESPONSES, AND DISCUSSES POTENTIAL MEDIATION OF THE INTERACTION OF THESE SYSTEMS BY MIRNAS. UNCOVERING THE MECHANISM BEHIND THE ASSOCIATION OF STRESS AND DRUG TAKING HAS THE POTENTIAL TO IMPACT THE TREATMENT OF DRUG ABUSE AND PREVENTION OF RELAPSE. FURTHER COMPREHENSION OF THESE COMPLEX INTERACTIONS MAY PROVIDE PROMISING NEW TARGETS FOR THE TREATMENT OF DRUG ADDICTION. 2016 6 4633 42 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 7 6414 46 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 8 4650 37 NEUROPLASTICITY IN ADDICTION: CELLULAR AND TRANSCRIPTIONAL PERSPECTIVES. DRUG ADDICTION IS A CHRONIC, RELAPSING BRAIN DISORDER WHICH CONSISTS OF COMPULSIVE PATTERNS OF DRUG-SEEKING AND TAKING THAT OCCURS AT THE EXPENSE OF OTHER ACTIVITIES. THE TRANSITION FROM CASUAL TO COMPULSIVE DRUG USE AND THE ENDURING PROPENSITY TO RELAPSE IS THOUGHT TO BE UNDERPINNED BY LONG-LASTING NEUROADAPTATIONS IN SPECIFIC BRAIN CIRCUITRY, ANALOGOUS TO THOSE THAT UNDERLIE LONG-TERM MEMORY FORMATION. RESEARCH SPANNING THE LAST TWO DECADES HAS MADE GREAT PROGRESS IN IDENTIFYING CELLULAR AND MOLECULAR MECHANISMS THAT CONTRIBUTE TO DRUG-INDUCED CHANGES IN PLASTICITY AND BEHAVIOR. ALTERATIONS IN SYNAPTIC TRANSMISSION WITHIN THE MESOCORTICOLIMBIC AND CORTICOSTRIATAL PATHWAYS, AND CHANGES IN THE TRANSCRIPTIONAL POTENTIAL OF CELLS BY EPIGENETIC MECHANISMS ARE TWO IMPORTANT MEANS BY WHICH DRUGS OF ABUSE CAN INDUCE LASTING CHANGES IN BEHAVIOR. IN THIS REVIEW WE PROVIDE A SUMMARY OF MORE RECENT RESEARCH THAT HAS FURTHERED OUR UNDERSTANDING OF DRUG-INDUCED NEUROPLASTIC CHANGES BOTH AT THE LEVEL OF THE SYNAPSE, AND ON A TRANSCRIPTIONAL LEVEL, AND HOW THESE CHANGES MAY RELATE TO THE HUMAN DISEASE OF ADDICTION. 2012 9 110 31 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 10 4206 38 METABOTROPIC GLUTAMATE 2/3 RECEPTORS AND EPIGENETIC MODIFICATIONS IN PSYCHOTIC DISORDERS: A REVIEW. SCHIZOPHRENIA AND BIPOLAR DISORDER ARE CHRONIC PSYCHIATRIC DISORDERS, BOTH CONSIDERED AS "MAJOR PSYCHOSIS"; THEY ARE THOUGHT TO SHARE SOME PATHOGENETIC FACTORS INVOLVING A DYSFUNCTIONAL GENE X ENVIRONMENT INTERACTION. ALTERATIONS IN THE GLUTAMATERGIC TRANSMISSION HAVE BEEN SUGGESTED TO BE INVOLVED IN THE PATHOGENESIS OF PSYCHOSIS. OUR GROUP DEVELOPED AN EPIGENETIC MODEL OF SCHIZOPHRENIA ORIGINATED BY PRENATAL RESTRAINT STRESS (PRS) PARADIGM IN MICE. PRS MICE DEVELOPED SOME BEHAVIORAL ALTERATIONS OBSERVED IN SCHIZOPHRENIC PATIENTS AND CLASSIC ANIMAL MODELS OF SCHIZOPHRENIA, I.E. DEFICITS IN SOCIAL INTERACTION, LOCOMOTOR ACTIVITY AND PREPULSE INHIBITION. THEY ALSO SHOWED SPECIFIC CHANGES IN PROMOTER DNA METHYLATION ACTIVITY OF GENES RELATED TO SCHIZOPHRENIA SUCH AS REELIN, BDNF AND GAD67, AND ALTERED EXPRESSION AND FUNCTION OF MGLU2/3 RECEPTORS IN THE FRONTAL CORTEX. INTERESTINGLY, BEHAVIORAL AND MOLECULAR ALTERATIONS WERE REVERSED BY TREATMENT WITH MGLU2/3 AGONISTS. BASED ON THESE FINDINGS, WE SPECULATE THAT PHARMACOLOGICAL MODULATION OF THESE RECEPTORS COULD HAVE A GREAT IMPACT ON EARLY PHASE TREATMENT OF PSYCHOSIS TOGETHER WITH THE POSSIBILITY TO MODULATE SPECIFIC EPIGENETIC KEY PROTEIN INVOLVED IN THE DEVELOPMENT OF PSYCHOSIS. IN THIS REVIEW, WE WILL DISCUSS IN MORE DETAILS THE SPECIFIC FEATURES OF THE PRS MICE AS A SUITABLE EPIGENETIC MODEL FOR MAJOR PSYCHOSIS. WE WILL THEN FOCUS ON KEY PROTEINS OF CHROMATIN REMODELING MACHINERY AS POTENTIAL TARGET FOR NEW PHARMACOLOGICAL TREATMENT THROUGH THE ACTIVATION OF METABOTROPIC GLUTAMATE RECEPTORS. 2016 11 1981 33 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 12 3313 37 HIPPOCAMPAL BDNF IN PHYSIOLOGICAL CONDITIONS AND SOCIAL ISOLATION. EXPOSURE OF AN ORGANISM TO CHRONIC PSYCHOSOCIAL STRESS MAY AFFECT BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION THAT HAS BEEN IMPLICATED IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS, SUCH AS DEPRESSION. GIVEN THAT DEPRESSION IN HUMANS HAS BEEN LINKED WITH SOCIAL STRESS, THE CHRONIC SOCIAL STRESS PARADIGMS FOR MODELING PSYCHIATRIC DISORDERS IN ANIMALS HAVE THUS BEEN DEVELOPED. CHRONIC SOCIAL ISOLATION IN ANIMAL MODELS GENERALLY CAUSES CHANGES IN HYPOTHALAMIC-PITUITARY-ADRENAL AXIS FUNCTIONING, ASSOCIATED WITH ANXIETY- AND DEPRESSIVE-LIKE BEHAVIORS. ALSO, THIS CHRONIC STRESS CAUSES DOWNREGULATION OF BDNF PROTEIN AND MRNA IN THE HIPPOCAMPUS, A STRESS-SENSITIVE BRAIN REGION CLOSELY RELATED TO THE PATHOPHYSIOLOGY OF DEPRESSION. IN THIS REVIEW, WE DISCUSS THE CURRENT KNOWLEDGE REGARDING THE STRUCTURE, FUNCTION, INTRACELLULAR SIGNALING, INTER-INDIVIDUAL DIFFERENCES AND EPIGENETIC REGULATION OF BDNF IN BOTH PHYSIOLOGICAL CONDITIONS AND DEPRESSION AND CHANGES IN CORTICOSTERONE LEVELS, AS A MARKER OF STRESS RESPONSE. SINCE BDNF LEVELS ARE AGE DEPENDENT IN HUMANS AND RODENTS, THIS REVIEW WILL ALSO HIGHLIGHT THE EFFECTS OF ADOLESCENT AND ADULT CHRONIC SOCIAL ISOLATION MODELS OF BOTH GENDERS ON THE BDNF EXPRESSION. 2017 13 2513 32 EPIGENETICS AND PSYCHOSTIMULANT ADDICTION. CHRONIC DRUG EXPOSURE ALTERS GENE EXPRESSION IN THE BRAIN AND PRODUCES LONG-TERM CHANGES IN NEURAL NETWORKS THAT UNDERLIE COMPULSIVE DRUG TAKING AND SEEKING. EXACTLY HOW DRUG-INDUCED CHANGES IN SYNAPTIC PLASTICITY AND SUBSEQUENT GENE EXPRESSION ARE TRANSLATED INTO PERSISTENT NEUROADAPTATIONS REMAINS UNCLEAR. EMERGING EVIDENCE SUGGESTS THAT COMPLEX DRUG-INDUCED NEUROADAPTATIONS IN THE BRAIN ARE MEDIATED BY HIGHLY SYNCHRONIZED AND DYNAMIC PATTERNS OF GENE REGULATION. RECENTLY, IT HAS BECOME CLEAR THAT EPIGENETIC MECHANISMS CONTRIBUTE TO DRUG-INDUCED STRUCTURAL, SYNAPTIC, AND BEHAVIORAL PLASTICITY BY REGULATING EXPRESSION OF GENE NETWORKS. HERE WE REVIEW HOW ALTERATIONS IN HISTONE MODIFICATIONS, DNA METHYLATION, AND MICRORNAS REGULATE GENE EXPRESSION AND CONTRIBUTE TO PSYCHOSTIMULANT ADDICTION WITH A FOCUS ON THE EPIGENETIC MECHANISMS THAT REGULATE BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION FOLLOWING CHRONIC COCAINE EXPOSURE. IDENTIFYING EPIGENETIC SIGNATURES THAT DEFINE PSYCHOSTIMULANT ADDICTION MAY LEAD TO NOVEL, EFFICACIOUS TREATMENTS FOR DRUG CRAVING AND RELAPSE. 2013 14 2011 40 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 15 6228 27 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 16 534 33 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 17 38 31 A COMMON ROLE FOR PSYCHOTROPIC MEDICATIONS: MEMORY IMPAIRMENT. THE PSYCHOPATHOLOGIC PROFILE OF MENTAL DISORDERS IS VERY DIVERSE AND PSYCHOTROPIC MEDICATIONS USED TO TREAT THEM DIFFER IN THEIR CHEMICAL STRUCTURE. NEVERTHELESS, THESE DRUGS SHARE THESE FOUR CHARACTERISTICS: DELAYED ONSET OF CLINICAL RESPONSE, NOT ONE OF THEM CAN BE SAID TO CURE, THERE IS A HIGH NUMBER OF NON-RESPONDERS, AND THE MECHANISM RESPONSIBLE FOR THEIR THERAPEUTIC ACTION IS NOT KNOWN. IT IS HYPOTHESIZED THAT THE ACTION OF PSYCHOTROPIC MEDICATIONS IS MEMORY IMPAIRMENT, UNDERSTANDING MEMORY AS THE TRACE LEFT IN THE NERVOUS SYSTEM NOT ONLY BY INDIVIDUAL EXPERIENCES BUT ALSO BY GENETIC AND EPIGENETIC PHENOMENA. IT IS SUGGESTED THAT IT WOULD BE BENEFICIAL TO TRANSLATE SOME RESEARCH STRATEGIES FROM THE NEUROBIOLOGY OF LEARNING AND MEMORY TO THE STUDY OF THE EFFECTS OF PSYCHOTROPIC MEDICATIONS. THE HYPOTHESIS IS BRIEFLY ASSESSED ACCORDING TO THE FOLLOWING THREE CRITERIA: (A). THE COMPARISON BETWEEN THE MOLECULAR EFFECTS OF PSYCHOTROPIC MEDICATIONS AND THE SO-CALLED MOLECULAR BIOLOGY OF LEARNING AND MEMORY, (B). THE EFFECTS OF THESE DRUGS, PREFERENTIALLY AFTER CHRONIC USE, ON MEMORY TESTS, AND (C). THE EFFECTS OF DRUGS THAT IMPAIR MEMORY ON TESTS USED FOR SCREENING PSYCHOTROPIC MEDICATIONS. FINALLY, SOME GENERAL SUGGESTIONS FOR FUTURE RESEARCH ARE POINTED OUT. 2003 18 2058 24 EPIGENETIC CONTROL OF GENE EXPRESSION IN THE ALCOHOLIC BRAIN. CHRONIC ALCOHOL EXPOSURE CAUSES WIDESPREAD CHANGES IN BRAIN GENE EXPRESSION IN HUMANS AND ANIMAL MODELS. MANY OF THESE CONTRIBUTE TO CELLULAR ADAPTATIONS THAT ULTIMATELY LEAD TO BEHAVIORAL TOLERANCE AND ALCOHOL DEPENDENCE. THERE IS AN EMERGING APPRECIATION FOR THE ROLE OF EPIGENETIC PROCESSES IN ALCOHOL-INDUCED CHANGES IN BRAIN GENE EXPRESSION AND BEHAVIOR. FOR EXAMPLE, CHRONIC ALCOHOL EXPOSURE PRODUCES CHANGES IN DNA AND HISTONE METHYLATION, HISTONE ACETYLATION, AND MICRORNA EXPRESSION THAT AFFECT EXPRESSION OF MULTIPLE GENES IN VARIOUS TYPES OF BRAIN CELLS (I.E., NEURONS AND GLIA) AND CONTRIBUTE TO BRAIN PATHOLOGY AND BRAIN PLASTICITY ASSOCIATED WITH ALCOHOL ABUSE AND DEPENDENCE. DRUGS TARGETING THE EPIGENETIC "MASTER REGULATORS" ARE EMERGING AS POTENTIAL THERAPEUTICS FOR NEURODEGENERATIVE DISORDERS AND DRUG ADDICTION. 2013 19 2092 27 EPIGENETIC EFFECT OF CHRONIC STRESS ON DOPAMINE SIGNALING AND DEPRESSION. BECAUSE OF THE COMPLEX CAUSAL FACTORS LEADING TO DEPRESSION, EPIGENETICS IS OF CONSIDERABLE INTEREST FOR THE UNDERSTANDING EFFECT OF STRESS IN DEPRESSION. DOPAMINE IS A KEY NEUROTRANSMITTER IMPORTANT IN MANY PHYSIOLOGICAL FUNCTIONS, INCLUDING MOTOR CONTROL, MOOD, AND THE REWARD PATHWAY. THESE FACTORS LEAD MANY DRUGS TO TARGET DOPAMINE RECEPTORS IN TREATING DEPRESSIVE DISORDERS. IN THIS REVIEW, WE TRY TO PORTRAY HOW CHRONIC STRESS AS AN EPIGENETIC FACTOR CHANGES THE GENE REGULATION PATTERN BY INTERRUPTING DOPAMINE SIGNALING MECHANISM. 2013 20 1252 34 CURRENT PERSPECTIVES ON THE NEUROBIOLOGY OF DRUG ADDICTION: A FOCUS ON GENETICS AND FACTORS REGULATING GENE EXPRESSION. DRUG ADDICTION IS A CHRONIC, RELAPSING DISORDER DEFINED BY CYCLIC PATTERNS OF COMPULSIVE DRUG SEEKING AND TAKING INTERSPERSED WITH EPISODES OF ABSTINENCE. WHILE GENETIC VARIABILITY MAY INCREASE THE RISK OF ADDICTIVE BEHAVIOURS IN AN INDIVIDUAL, EXPOSURE TO A DRUG RESULTS IN NEUROADAPTATIONS IN INTERCONNECTED BRAIN CIRCUITS WHICH, IN SUSCEPTIBLE INDIVIDUALS, ARE BELIEVED TO UNDERLIE THE TRANSITION TO, AND MAINTENANCE OF, AN ADDICTED STATE. THESE ADAPTATIONS CAN OCCUR AT THE CELLULAR, MOLECULAR, OR (EPI)GENETIC LEVEL AND ARE ASSOCIATED WITH SYNAPTIC PLASTICITY AND ALTERED GENE EXPRESSION, THE LATTER BEING MEDIATED VIA BOTH FACTORS AFFECTING TRANSLATION (EPIGENETICS) AND TRANSCRIPTION (NON CODING MICRORNAS) OF THE DNA OR RNA ITSELF. NEW ADVANCES USING TECHNIQUES SUCH AS OPTOGENETICS HAVE THE POTENTIAL TO INCREASE OUR UNDERSTANDING OF THE MICROCIRCUITRY MEDIATING ADDICTIVE BEHAVIOURS. HOWEVER, THE PROCESSES LEADING TO ADDICTION ARE COMPLEX AND MULTIFACTORIAL AND THUS WE FACE A MAJOR CONTEMPORARY CHALLENGE TO ELUCIDATE THE FACTORS IMPLICATED IN THE DEVELOPMENT AND MAINTENANCE OF AN ADDICTED STATE. 2012