1 4328 100 MICRORNAS, STEM CELLS IN BIPOLAR DISORDER, AND LITHIUM THERAPEUTIC APPROACH. BIPOLAR DISORDER (BD) IS A SEVERE, CHRONIC, AND DISABLING NEUROPSYCHIATRIC DISORDER CHARACTERIZED BY RECURRENT MOOD DISTURBANCES (MANIA/HYPOMANIA AND DEPRESSION, WITH OR WITHOUT MIXED FEATURES) AND A CONSTELLATION OF COGNITIVE, PSYCHOMOTOR, AUTONOMIC, AND ENDOCRINE ABNORMALITIES. THE ETIOLOGY OF BD IS MULTIFACTORIAL, INCLUDING BOTH BIOLOGICAL AND EPIGENETIC FACTORS. RECENTLY, MICRORNAS (MIRNAS), A CLASS OF EPIGENETIC REGULATORS OF GENE EXPRESSION PLAYING A CENTRAL ROLE IN BRAIN DEVELOPMENT AND PLASTICITY, HAVE BEEN RELATED TO SEVERAL NEUROPSYCHIATRIC DISORDERS, INCLUDING BD. MOREOVER, AN ALTERATION IN THE NUMBER/DISTRIBUTION AND DIFFERENTIATION POTENTIAL OF NEURAL STEM CELLS HAS ALSO BEEN DESCRIBED, SIGNIFICANTLY AFFECTING BRAIN HOMEOSTASIS AND NEUROPLASTICITY. THIS REVIEW AIMED TO EVALUATE THE MOST RELIABLE SCIENTIFIC EVIDENCE ON MIRNAS AS BIOMARKERS FOR THE DIAGNOSIS OF BD AND ASSESS THEIR IMPLICATIONS IN RESPONSE TO MOOD STABILIZERS, SUCH AS LITHIUM. NEURAL STEM CELL DISTRIBUTION, REGULATION, AND DYSFUNCTION IN THE ETIOLOGY OF BD ARE ALSO DISSECTED. 2022 2 2534 39 EPIGENETICS IN BIPOLAR DISORDER: A CRITICAL REVIEW OF THE LITERATURE. INTRODUCTION: BIPOLAR DISORDER (BD) IS A CHRONIC, DISABLING DISEASE CHARACTERISED BY ALTERNATE MOOD EPISODES, SWITCHING THROUGH DEPRESSIVE AND MANIC/HYPOMANIC PHASES. MOOD STABILIZERS, IN PARTICULAR LITHIUM SALTS, CONSTITUTE THE CORNERSTONE OF THE TREATMENT IN THE ACUTE PHASE AS WELL AS FOR THE PREVENTION OF RECURRENCES. THE PATHOPHYSIOLOGY OF BD AND THE MECHANISMS OF ACTION OF MOOD STABILIZERS REMAIN LARGELY UNKNOWN BUT SEVERAL PIECES OF EVIDENCE POINT TO GENE X ENVIRONMENT INTERACTIONS. EPIGENETICS, DEFINED AS THE REGULATION OF GENE EXPRESSION WITHOUT GENETIC CHANGES, COULD BE THE MOLECULAR SUBSTRATE OF THESE INTERACTIONS. IN THIS LITERATURE REVIEW, WE SUMMARIZE THE MAIN EPIGENETIC FINDINGS ASSOCIATED WITH BD AND RESPONSE TO MOOD STABILIZERS. METHODS: WE SEARCHED PUBMED, AND EMBASE DATABASES AND CLASSIFIED THE ARTICLES DEPENDING ON THE EPIGENETIC MECHANISMS (DNA METHYLATION, HISTONE MODIFICATIONS AND NON-CODING RNAS). RESULTS: WE PRESENT THE DIFFERENT EPIGENETIC MODIFICATIONS ASSOCIATED WITH BD OR WITH MOOD-STABILIZERS. THE MAJOR REPORTED MECHANISMS WERE DNA METHYLATION, HISTONE METHYLATION AND ACETYLATION, AND NON-CODING RNAS. OVERALL, THE ASSESSMENTS ARE POORLY HARMONIZED AND THE RESULTS ARE MORE LIMITED THAN IN OTHER PSYCHIATRIC DISORDERS (E.G. SCHIZOPHRENIA). HOWEVER, THE NATURE OF BD AND ITS TREATMENT OFFER EXCELLENT OPPORTUNITIES FOR EPIGENETIC RESEARCH: CLEAR IMPACT OF ENVIRONMENTAL FACTORS, CLINICAL VARIATION BETWEEN MANIC OR DEPRESSIVE EPISODES RESULTING IN POSSIBLE IDENTIFICATION OF STATE AND TRAITS BIOMARKERS, DOCUMENTED IMPACT OF MOOD-STABILIZERS ON THE EPIGENOME. CONCLUSION: EPIGENETIC IS A GROWING AND PROMISING FIELD IN BD THAT MAY SHED LIGHT ON ITS PATHOPHYSIOLOGY OR BE USEFUL AS BIOMARKERS OF RESPONSE TO MOOD-STABILIZER. 2021 3 4623 31 NEUROBIOLOGY OF BIPOLAR DISORDERS: A REVIEW OF GENETIC COMPONENTS, SIGNALING PATHWAYS, BIOCHEMICAL CHANGES, AND NEUROIMAGING FINDINGS. BIPOLAR DISORDER (BD) IS A CHRONIC MENTAL ILLNESS CHARACTERIZED BY CHANGES IN MOOD THAT ALTERNATE BETWEEN MANIA AND HYPOMANIA OR BETWEEN DEPRESSION AND MIXED STATES, OFTEN ASSOCIATED WITH FUNCTIONAL IMPAIRMENT. ALTHOUGH EFFECTIVE PHARMACOLOGICAL AND NON-PHARMACOLOGICAL TREATMENTS ARE AVAILABLE, SEVERAL PATIENTS WITH BD REMAIN SYMPTOMATIC. THE ADVANCE IN THE UNDERSTANDING OF THE NEUROBIOLOGY UNDERLYING BD COULD HELP IN THE IDENTIFICATION OF NEW THERAPEUTIC TARGETS AS WELL AS BIOMARKERS FOR EARLY DETECTION, PROGNOSIS, AND RESPONSE TO TREATMENT IN BD. IN THIS REVIEW, WE DISCUSS GENETIC, EPIGENETIC, MOLECULAR, PHYSIOLOGICAL AND NEUROIMAGING FINDINGS ASSOCIATED WITH THE NEUROBIOLOGY OF BD. DESPITE THE ADVANCES IN THE PATHOPHYSIOLOGICAL KNOWLEDGE OF BD, THE DIAGNOSIS AND MANAGEMENT OF THE DISEASE ARE STILL ESSENTIALLY CLINICAL. GIVEN THE COMPLEXITY OF THE BRAIN AND THE CLOSE RELATIONSHIP BETWEEN ENVIRONMENTAL EXPOSURE AND BRAIN FUNCTION, INITIATIVES THAT INCORPORATE GENETIC, EPIGENETIC, MOLECULAR, PHYSIOLOGICAL, CLINICAL, ENVIRONMENTAL DATA, AND BRAIN IMAGING ARE NECESSARY TO PRODUCE INFORMATION THAT CAN BE TRANSLATED INTO PREVENTION AND BETTER OUTCOMES FOR PATIENTS WITH BD. 2020 4 2963 22 GENETIC AND EPIGENETIC MECHANISMS LINKING PAIN AND PSYCHIATRIC DISORDERS. THE NEUROPHYSIOLOGICAL LINK BETWEEN NEUROPATHIC PAIN AND DEPRESSION REMAINS UNKNOWN DESPITE EVIDENT HIGH COMORBIDITY OF THESE TWO DISORDERS. HOWEVER, THERE IS CONVINCING EVIDENCE THAT GENOTYPE PLAYS A ROLE IN BOTH PAIN AND DEPRESSION. USING VARIOUS TYPES OF GENETIC ANALYSIS - POPULATION GENETICS, CYTOGENETICS AND MOLECULAR TECHNOLOGIES - SPECIFIC GENES HAVE BEEN IMPLICATED IN MEDIATING ALMOST ALL ASPECTS OF NOCICEPTION AND MOOD DISORDERS. THE CURRENT REVIEW ATTEMPTS TO IDENTIFY SPECIFIC GENES AND EPIGENETIC MECHANISMS COMMON TO BOTH DISORDERS. IT IS CONCLUDED THAT EXTERNAL AND INTERNAL FACTORS (INFLAMMATION, STRESS, GENDER, ETC.) THAT CONTRIBUTE TO THE PATHOLOGIES MAY DO SO THROUGH EPIGENETIC MECHANISMS THAT MAY AFFECT EXPRESSION OF THESE PARTICULAR GENES. THE POSSIBLE INVOLVEMENT OF EPIGENETIC REGULATION IN PAIN AND PSYCHIATRIC DISORDERS SUGGESTS THAT TREATMENTS TARGETING EPIGENETIC MECHANISMS THAT MEDIATE ADVERSE LIFE EVENTS SHOULD BE CONSIDERED. 2015 5 4321 33 MICRORNAS IN MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD) IS A SEVERE AND CHRONIC PSYCHIATRIC DISORDER WITH A HIGH PREVALENCE IN THE POPULATION. ALTHOUGH OUR UNDERSTANDING OF ITS PATHOPHYSIOLOGICAL MECHANISMS HAS SIGNIFICANTLY INCREASED OVER THE YEARS, AVAILABLE TREATMENTS STILL PRESENT SEVERAL LIMITATIONS AND ARE NOT EFFECTIVE TO ALL MDD PATIENTS. EPIGENETIC MECHANISMS HAVE RECENTLY BEEN SUGGESTED TO PLAY KEY ROLES IN MDD PATHOGENESIS AND TREATMENT, INCLUDING THE EFFECTS OF SMALL NONCODING RNAS KNOWN AS MICRORNAS (MIRNAS). MIRNAS CAN MODULATE GENE EXPRESSION POSTTRANSCRIPTIONALLY BY INTERFERING WITH THE STABILITY AND TRANSLATION OF MESSENGER RNA MOLECULES AND ARE ALSO KNOWN TO CROSS-TALK WITH OTHER EPIGENETIC MECHANISMS. IN THIS REVIEW, WE WILL SUMMARIZE AND DISCUSS RECENT FINDINGS OF ALTERATIONS IN MIRNAS IN TISSUES OF PATIENTS WITH MDD AND EVIDENCE OF TREATMENT-INDUCED EFFECTS IN THESE MOLECULES. 2019 6 4370 39 MIRNAS AND THEIR ROLE IN THE CORRELATION BETWEEN SCHIZOPHRENIA AND CANCER (REVIEW). SCHIZOPHRENIA (SZ) AND CANCER (CA) HAVE A BROAD SPECTRUM OF CLINICAL PHENOTYPES AND A COMPLEX BIOLOGICAL BACKGROUND, IMPLICATING A LARGE NUMBER OF GENETIC AND EPIGENETIC FACTORS. SZ IS A CHRONIC NEURODEVELOPMENTAL DISORDER SIGNIFIED BY AN INCREASE IN THE EXPRESSION OF APOPTOTIC MOLECULAR SIGNALS, WHEREAS CA IS CONVERSELY CHARACTERIZED BY AN INCREASE IN APPROPRIATE MOLECULAR SIGNALING THAT STIMULATES UNCONTROLLED CELL PROLIFERATION. THE RATHER LOW RISK OF DEVELOPING CA IN PATIENTS SUFFERING FROM SZ IS A HYPOTHESIS THAT IS STILL UNDER DEBATE. RECENT EVIDENCE HAS INDICATED THAT MICRORNAS (MIRNAS OR MIRS), A LARGE GROUP OF SMALL NON?CODING OLIGONOUCLEOTIDES, MAY PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF CA AND MAJOR PSYCHIATRIC DISORDERS, SUCH AS SZ, BIPOLAR DISORDER, AUTISM SPECTRUM DISORDERS, SUICIDALITY AND DEPRESSION, THROUGH THEIR INTERFERENCE WITH THE EXPRESSION OF MULTIPLE GENES. FOR INSTANCE, THE POSSIBLE ROLE OF LET?7, MIR?98 AND MIR?183 AS BIOMARKERS FOR CA AND SZ WAS INVESTIGATED IN OUR PREVIOUS RESEARCH STUDIES. THEREFORE, FURTHER INVESTIGATIONS ON THE EXPRESSION PROFILES OF THESE REGULATORY, SMALL RNA MOLECULES AND THE MOLECULAR PATHWAYS THROUGH WHICH THEY EXERT THEIR CONTROL MAY PROVIDE A PLAUSIBLE EXPLANATION AS TO WHETHER THERE IS A CORRELATION BETWEEN PSYCHIATRIC DISORDERS AND LOW RISK OF DEVELOPING CA. 2016 7 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 8 2231 31 EPIGENETIC MODIFICATIONS OF MAJOR DEPRESSIVE DISORDER. MAJOR DEPRESSIVE DISORDER (MDD) IS A CHRONIC DISEASE WHOSE NEUROLOGICAL BASIS AND PATHOPHYSIOLOGY REMAIN POORLY UNDERSTOOD. INITIALLY, IT WAS PROPOSED THAT GENETIC VARIATIONS WERE RESPONSIBLE FOR THE DEVELOPMENT OF THIS DISEASE. NEVERTHELESS, SEVERAL STUDIES WITHIN THE LAST DECADE HAVE PROVIDED EVIDENCE SUGGESTING THAT ENVIRONMENTAL FACTORS PLAY AN IMPORTANT ROLE IN MDD PATHOPHYSIOLOGY. ALTERATIONS IN EPIGENETICS MECHANISM, SUCH AS DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA EXPRESSION COULD FAVOR MDD ADVANCE IN RESPONSE TO STRESSFUL EXPERIENCES AND ENVIRONMENTAL FACTORS. THE AIM OF THIS REVIEW IS TO DESCRIBE GENETIC ALTERATIONS, AND PARTICULARLY ALTERED EPIGENETIC MECHANISMS, THAT COULD BE DETERMINANTS FOR MDD PROGRESS, AND HOW THESE ALTERATIONS MAY ARISE AS USEFUL SCREENING, DIAGNOSIS AND TREATMENT MONITORING BIOMARKERS OF DEPRESSIVE DISORDERS. 2016 9 4323 34 MICRORNAS IN PSYCHOLOGICAL STRESS REACTIONS AND THEIR USE AS STRESS-ASSOCIATED BIOMARKERS, ESPECIALLY IN HUMAN SALIVA. MICRORNAS (MIRNAS) PLAY A CENTRAL ROLE IN THE REGULATION OF MANY CELLULAR PROCESSES INCLUDING PHYSIOLOGICAL AND PSYCHOLOGICAL STRESS REACTION PATHWAYS. PSYCHOLOGICAL STRESS IS AN IMPORTANT FACTOR FOR THE GENESIS AND MAINTENANCE OF MANY DISEASES. SEVERAL MIRNAS HAVE ALREADY BEEN DESCRIBED TO BE INVOLVED IN ITS REGULATION. THE PRESENCE OF MIRNAS IN ALL BODY FLUIDS IMPLIES A WIDESPREAD ROLE IN COMMUNICATION THROUGHOUT THE WHOLE ORGANISM AND TOGETHER WITH THEIR STABILITY MAKES THEM FORMIDABLE CANDIDATES AS BIOMARKERS. ALTERATIONS OF STRESS-ASSOCIATED MIRNA EXPRESSION LEVELS HAVE BEEN FOUND IN THE BRAIN AND WHOLE BLOOD OF HUMANS AND ANIMALS. IN THIS PAPER, WE REVIEW THE PARTICIPATION OF MIRNAS IN STRESS-REACTIVE PROCESSES AS WELL AS THEIR USABILITY AS SALIVARY BIOMARKERS OF SUCH PROCESSES. IN CONCLUSION, WE SUGGEST THAT SALIVARY MIRNAS MAY BE USEFUL AS NONINVASIVE BIOMARKERS TO ASSESS EPIGENETIC REGULATION PROCESSES OF CHRONIC OR ACUTE PSYCHOLOGICAL STRESS REACTIONS. 2017 10 1329 30 DEPRESSION ASSOCIATED WITH DIABETES: FROM PATHOPHYSIOLOGY TO TREATMENT. DIABETES IS A CHRONIC AND PROGRESSIVE SYNDROME COMMONLY ASSOCIATED WITH SEVERAL NEUROPSYCHIATRIC COMORBITIES, OF WHICH DEPRESSION IS THE MOST STUDIED. THE PREVALENCE OF DEPRESSION IS ABOUT TWO OR THREE TIMES HIGHER IN DIABETIC PATIENTS COMPARED TO THE GENERAL POPULATION. IT IS BELIEVED THAT THE DIABETES - DEPRESSION RELATION MAY BE BIDIRECTIONAL, I.E., THE DEPRESSION CAN LEAD TO DIABETES AND CONVERSELY DIABETES COULD FACILITATE THE EMERGENCE OF DEPRESSION. DEPRESSION IS ONE OF THE MOST NEGLECTED SYMPTOMS IN DIABETIC PATIENTS AND IS DIRECTLY LINKED WITH LOWERING OF QUALITY OF LIFE. THE TREATMENT OF DEPRESSION IN THESE PATIENTS IS STILL QUITE INEFFECTIVE AND IN MANY CASES TREATMENTREFRACTORY. FURTHERMORE, SOME OF THE FIRST CHOICE DRUGS USED TO TREAT THE DEPRESSION AFFECT THE BLOOD GLUCOSE CONTROL, AGGRAVATING THE HYPERGLYCEMIC STATE. THESE ISSUES UNDERSCORE THE URGENCY IN STUDIES SEARCHING FOR NEW PHARMACOLOGICAL TARGETS FOR THE TREATMENT OF DEPRESSION ASSOCIATED WITH DIABETES. FOR THIS, A BETTER UNDERSTANDING OF THE PATHOPHYSIOLOGY THAT RELATES THIS COMORBIDITY BECOMES CRITICAL. IN THIS RESPECT, THIS REVIEW WILL FOCUS ON SOME HYPOTHESES THAT HAVE BEEN PROPOSED TO EXPLAIN THE MECHANISMS UNDERLYING DEPRESSION ASSOCIATED WITH DIABETES, HIGHLIGHTING THE TREATMENT OPTIONS CURRENTLY AVAILABLE AND THEIR LIMITATIONS. AMONG THESE HYPOTHESES, WE WILL POINT OUT THE HYPERGLYCEMIA AS A PRIMARY METABOLIC CAUSE OF THE DEPRESSION DEVELOPMENT, THE INVOLVEMENT OF THE DYSREGULATION OF HYPOTHALAMIC PITUITARY-ADRENAL (HPA) AXIS AND OF NEUROTRANSMITTER SYSTEMS, SPECIALLY MONOAMINERGIC SYSTEM. BESIDES, THE ROLE OF OXIDATIVE STRESS, NEUROINFLAMMATION AND CELL DEATH, ESPECIALLY IN HIPPOCAMPUS AND PREFRONTAL CORTEX, BRAIN AREAS IMPORTANT FOR THE MEDIATION AND MODULATION OF EMOTIONAL BEHAVIOR WILL ALSO BE DISCUSSED. FINALLY, WE WILL BRING UP THE INFLUENCE OF THE EPIGENETIC REGULATION WITH RESPECT TO NEUROPSYCHIATRIC DISORDERS. 2016 11 1736 25 EARLY DETECTION AND PREVENTION OF SCHIZOPHRENIC PSYCHOSIS-A REVIEW. PSYCHOTIC DISORDERS OFTEN RUN A CHRONIC COURSE AND ARE ASSOCIATED WITH A CONSIDERABLE EMOTIONAL AND SOCIAL IMPACT FOR PATIENTS AND THEIR RELATIVES. THEREFORE, EARLY RECOGNITION, COMBINED WITH THE POSSIBILITY OF PREVENTIVE INTERVENTION, IS URGENTLY WARRANTED SINCE THE DURATION OF UNTREATED PSYCHOSIS (DUP) SIGNIFICANTLY DETERMINES THE FURTHER COURSE OF THE DISEASE. IN ADDITION TO ESTABLISHED DIAGNOSTIC TOOLS, NEUROBIOLOGICAL FACTORS IN THE DEVELOPMENT OF SCHIZOPHRENIC PSYCHOSES ARE INCREASINGLY BEING INVESTIGATED. IT IS SHOWN THAT NUMEROUS MOLECULAR ALTERATIONS ALREADY EXIST BEFORE THE CLINICAL ONSET OF THE DISEASE. AS SCHIZOPHRENIC PSYCHOSES ARE NOT ELICITED BY A SINGLE MUTATION IN THE DEOXYRIBONUCLEIC ACID (DNA) SEQUENCE, EPIGENETICS LIKELY CONSTITUTE THE MISSING LINK BETWEEN ENVIRONMENTAL INFLUENCES AND DISEASE DEVELOPMENT AND COULD POTENTIALLY SERVE AS A BIOMARKER. THE RESULTS FROM TRANSCRIPTOMIC AND PROTEOMIC STUDIES POINT TO A DYSREGULATED IMMUNE SYSTEM, LIKELY EVOKED BY EPIGENETIC ALTERATIONS. DESPITE THE INCREASING KNOWLEDGE OF THE NEUROBIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF PSYCHOTIC DISORDERS, FURTHER RESEARCH EFFORTS WITH LARGE POPULATION-BASED STUDY DESIGNS ARE NEEDED TO IDENTIFY SUITABLE BIOMARKERS. IN CONCLUSION, A COMBINATION OF BLOOD EXAMINATIONS, FUNCTIONAL IMAGING TECHNIQUES, ELECTROENCEPHALOGRAPHY (EEG) INVESTIGATIONS AND POLYGENIC RISK SCORES SHOULD BE CONSIDERED AS THE BASIS FOR PREDICTING HOW SUBJECTS WILL TRANSITION INTO MANIFEST PSYCHOSIS. 2021 12 6260 22 THE MOLECULAR NEUROBIOLOGY OF CHRONIC PAIN-INDUCED DEPRESSION. THE INCREASING NUMBER OF INDIVIDUALS WITH COMORBIDITIES POSES AN URGENT NEED TO IMPROVE THE MANAGEMENT OF PATIENTS WITH MULTIPLE CO-EXISTING DISEASES. AMONG THESE COMORBIDITIES, CHRONIC PAIN AND MOOD DISORDERS, TWO LONG-LASTING DISABLING CONDITIONS THAT SIGNIFICANTLY REDUCE THE QUALITY OF LIFE, COULD BE CITED FIRST. THE RECENT DEVELOPMENT OF ANIMAL MODELS ACCELERATED THE STUDIES FOCUSING ON THE UNDERLYING MECHANISMS OF THE CHRONIC PAIN AND DEPRESSION/ANXIETY COMORBIDITY. THIS REVIEW PROVIDES AN OVERVIEW OF CLINICAL AND PRE-CLINICAL STUDIES PERFORMED OVER THE PAST TWO DECADES ADDRESSING THE MOLECULAR ASPECTS OF THE COMORBID RELATIONSHIP OF CHRONIC PAIN AND DEPRESSION. WE THUS FOCUSED ON THE STUDIES THAT INVESTIGATED THE MOLECULAR CHARACTERISTICS OF THE COMORBID RELATIONSHIP BETWEEN CHRONIC PAIN AND MOOD DISORDERS, ESPECIALLY MAJOR DEPRESSIVE DISORDERS, FROM THE GENETIC AND EPIGENETIC POINT OF VIEW TO KEY NEUROMODULATORS WHICH HAVE BEEN SHOWN TO PLAY AN IMPORTANT ROLE IN THIS COMORBIDITY. 2019 13 6324 29 THE ROLE OF ALPHA-SYNUCLEIN IN THE PATHOPHYSIOLOGY OF ALCOHOLISM. ALCOHOLISM HAS COMPLEX ETIOLOGY AND THERE IS EVIDENCE FOR BOTH GENETIC AND ENVIRONMENTAL FACTORS IN ITS PATHOPHYSIOLOGY. CHRONIC, LONG-TERM ALCOHOL ABUSE AND ALCOHOL DEPENDENCE ARE ASSOCIATED WITH NEURONAL LOSS WITH THE PREFRONTAL CORTEX BEING PARTICULARLY SUSCEPTIBLE TO NEUROTOXIC DAMAGE. THIS BRAIN REGION IS INVOLVED IN THE DEVELOPMENT AND PERSISTENCE OF ALCOHOL ADDICTION AND NEUROTOXIC DAMAGE IS LIKELY TO EXACERBATE THE REINFORCING EFFECTS OF ALCOHOL AND MAY HINDER TREATMENT. UNDERSTANDING THE MECHANISM OF ALCOHOL'S NEUROTOXIC EFFECTS ON THE BRAIN AND THE GENETIC RISK FACTORS ASSOCIATED WITH ALCOHOL ABUSE ARE THE FOCUS OF CURRENT RESEARCH. BECAUSE OF ITS WELL-ESTABLISHED ROLE IN NEURODEGENERATIVE AND NEUROPSYCHOLOGICAL DISORDERS, AND ITS EMERGING ROLE IN THE PATHOPHYSIOLOGY OF ADDICTION, HERE WE REVIEW THE GENETIC AND EPIGENETIC FACTORS INVOLVED IN REGULATING ALPHA-SYNUCLEIN EXPRESSION AND ITS POTENTIAL ROLE IN THE PATHOPHYSIOLOGY OF CHRONIC ALCOHOL ABUSE. ELUCIDATION OF THE MECHANISMS OF ALPHA-SYNUCLEIN REGULATION MAY PROVE BENEFICIAL IN UNDERSTANDING THE ROLE OF THIS KEY SYNAPTIC PROTEIN IN DISEASE AND ITS POTENTIAL FOR THERAPEUTIC MODULATION IN THE TREATMENT OF SUBSTANCE USE DISORDERS AS WELL AS OTHER NEURODEGENERATIVE DISEASES. 2013 14 4313 41 MICRORNAS AS CANDIDATES FOR BIPOLAR DISORDER BIOMARKERS. BIPOLAR DISORDER (BD) IS A COMMON, RECURRING PSYCHIATRIC ILLNESS WITH UNKNOWN PATHOGENESIS. MUCH LIKE OTHER PSYCHIATRIC DISEASES, BD SUFFERS FROM THE CHRONIC LACK OF RELIABLE BIOMARKERS AND INNOVATIVE PHARMACOLOGICAL INTERVENTIONS. BETTER CHARACTERIZATION OF CLINICAL PROFILES, EXPERIMENTAL MEDICINE, GENOMIC DATA MINING, AND THE UTILIZATION OF EXPERIMENTAL MODELS, INCLUDING STEM CELL AND GENETICALLY MODIFIED MICE, ARE SUGGESTED WAYS FORWARD. ENVIRONMENT, INCLUDING EARLY CHILDHOOD EXPERIENCES, HAS BEEN DOCUMENTED TO MODULATE THE RISK FOR THE DEVELOPMENT OF PSYCHIATRIC DISORDERS VIA EPIGENETIC MECHANISMS. KEY EPIGENETIC REGULATORS, MICRORNAS (MIRNAS, MIRS), GOVERN NORMAL NEURONAL FUNCTIONING AND SHOW ALTERED EXPRESSION IN DIVERSE BRAIN PATHOLOGIES. WE OBSERVED SIGNIFICANT ALTERATIONS OF EXOSOMAL MIR-29C LEVELS IN PREFRONTAL CORTEX (BRODMANN AREA 9, BA9) OF BD PATIENTS. WE ALSO DEMONSTRATED THAT EXOSOMES EXTRACTED FROM THE ANTERIOR CINGULATE CORTEX (BA24), A CRUCIAL AREA FOR MODULATING EMOTIONAL EXPRESSION AND AFFECT, HAVE INCREASED LEVELS OF MIR-149 IN BD PATIENTS COMPARED TO CONTROLS. BECAUSE MIR-149 HAS BEEN SHOWN TO INHIBIT GLIAL PROLIFERATION, WE HYPOTHESIZED THAT INCREASED MIR-149 EXPRESSION IN BA24-DERIVED EXOSOMES MAY BE CONSISTENT WITH THE PREVIOUSLY REPORTED REDUCED GLIAL CELL NUMBERS IN BA24 OF PATIENTS DIAGNOSED WITH FAMILIAL BD. QPCR ANALYSIS OF LASER-MICRODISSECTED NEURONAL AND GLIAL CELLS FROM BA24 CORTICAL SAMPLES OF BD PATIENTS VERIFIED THAT THE GLIAL, BUT NOT NEURONAL, POPULATION EXHIBITS SIGNIFICANTLY INCREASED MIR-149 EXPRESSION. THESE FINDINGS SUPPORT NEURON-GLIA INTERACTION AS A POSSIBLE TARGET MECHANISM IN BD, IMPLICATED BY OTHERS IN NEUROIMAGING, POSTMORTEM, AND IN VIVO STUDIES OF THE PATHOLOGICAL CHANGES MEDIATED BY GLIAL CELLS. 2021 15 641 34 BIOMARKERS OF MAJOR DEPRESSIVE DISORDER: KNOWING IS HALF THE BATTLE. MAJOR DEPRESSIVE DISORDER (MDD) IS A HETEROGENEOUS DISEASE WHICH IS WHY THERE ARE CURRENTLY NO SPECIFIC METHODS TO ACCURATELY TEST THE SEVERITY, ENDOPHENOTYPE OR THERAPY RESPONSE. THIS LACK OF PROGRESS IS PARTLY ATTRIBUTED TO THE COM-PLEXITY AND VARIABILITY OF DEPRESSION, IN ASSOCIATION WITH ANALYTICAL VARIABILITY OF CLINICAL LITERATURE AND THE WIDE NUMBER OF THEORETICALLY COMPLEX BIOMARKERS. THE LITERATURE ACCESSIBLE, INDICATES THAT MARKERS INVOLVED IN INFLAMMATORY, NEURO-TROPHIC AND METABOLIC PROCESSES AND COMPONENTS OF NEUROTRANSMITTERS AND NEUROENDOCRINE SYSTEMS ARE RATHER STRONG INDICATORS TO BE CONSIDERED CLINICALLY AND CAN BE MEASURED THROUGH GENETIC AND EPIGENETIC, TRANSCRIPTOMIC AND PROTEOMIC, METABOLOMICS AND NEUROIMAGING ASSESSMENTS. PROMISING BIOLOGIC SYSTEMS/MARKERS FOUND WERE I.E., GROWTH BIOMARKERS, ENDOCRINE MARKERS, OXIDANT STRESS MARKERS, PROTEOMIC AND CHRONIC INFLAMMATORY MARKERS, ARE DISCUSSED IN THIS REVIEW. SEVERAL LINES OF EVIDENCE SUGGEST THAT A PORTION OF MDD IS A DOPAMINE AGONIST-RESPONSIVE SUBTYPE. THIS REVIEW ANALYZES CONCISE REPORTS ON THE PATHOPHYSIOLOGICAL BIOMARKERS OF MDD AND THERAPEUTIC REACTIONS VIA PERIPHERAL DEVELOPMENTAL FACTORS, INFLAMMATIVE CYTOKINES, ENDOCRINE FACTORS AND METABOLIC MARKERS. VARIOUS LITERATURES ALSO SUPPORT THAT ENDOCRINE AND METABOLISM CHANGES ARE ASSOCIATED WITH MDD. ACCUMULATING EVIDENCE SUGGESTS THAT AT LEAST A PORTION OF MDD PATIENTS SHOW CHARACTERISTICS PATHOLOGICAL CHANGES REGARDING DIFFERENT CLINICAL PATHOLOGICAL BIOMARKERS. BY THIS REVIEW WE SUM UP ALL THE DIFFERENT BIOMARKERS PLAYING AN IMPORTANT ROLE IN THE DETECTION OR TREATMENT OF THE DIFFERENT PATIENTS SUFFERING FROM MDD. THE REVIEW ALSO GIVES AN OVERVIEW OF DIFFERENT BIOMARKER'S PLAYING A POTENTIAL ROLE IN MODULATING EFFECT OF MDD. 2021 16 4277 32 MICROGLIA SEQUELAE: BRAIN SIGNATURE OF INNATE IMMUNITY IN SCHIZOPHRENIA. SCHIZOPHRENIA IS A PSYCHIATRIC DISORDER WITH SIGNIFICANT IMPACT ON INDIVIDUALS AND SOCIETY. THE CURRENT PHARMACOLOGIC TREATMENT, WHICH PRINCIPALLY ALLEVIATES PSYCHOSIS, IS FOCUSED ON NEUROTRANSMITTERS MODULATION, RELYING ON DRUGS WITH SEVERE SIDE EFFECTS AND INEFFECTIVENESS IN A SIGNIFICANT PERCENTAGE OF CASES. THEREFORE, AND DUE TO DIFFICULTIES INHERENT TO DIAGNOSIS AND TREATMENT, IT IS VITAL TO REASSESS ALTERNATIVE CELLULAR AND MOLECULAR DRUG TARGETS. DISTINCT RISK FACTORS - GENETIC, DEVELOPMENTAL, EPIGENETIC, AND ENVIRONMENTAL - HAVE BEEN ASSOCIATED WITH DISEASE ONSET AND PROGRESSION, GIVING RISE TO THE PROPOSAL OF DIFFERENT PATHOPHYSIOLOGICAL MECHANISMS AND PUTATIVE PHARMACOLOGICAL TARGETS. IMMUNITY IS INVOLVED AND, PARTICULARLY MICROGLIA - INNATE IMMUNE CELLS OF THE CENTRAL NERVOUS SYSTEM, CRITICALLY INVOLVED IN BRAIN DEVELOPMENT - HAVE CAPTURED ATTENTION AS CELLULAR PLAYERS. MICROGLIA UNDERGO MARKED MORPHOLOGIC AND FUNCTIONAL ALTERATIONS IN THE HUMAN DISEASE, AS WELL AS IN ANIMAL MODELS OF SCHIZOPHRENIA, AS REPORTED IN SEVERAL ORIGINAL PAPERS. WE CLUSTER THE MAIN FINDINGS OF CLINICAL STUDIES BY GROUPS OF PATIENTS: (1) AT ULTRA-HIGH RISK OF PSYCHOSIS, (2) WITH A FIRST EPISODE OF PSYCHOSIS OR RECENT-ONSET SCHIZOPHRENIA, AND (3) WITH CHRONIC SCHIZOPHRENIA; IN TRANSLATIONAL STUDIES, WE HIGHLIGHT THE TIME WINDOW OF APPEARANCE OF PARTICULAR MICROGLIA ALTERATIONS IN THE MOST WELL STUDIED ANIMAL MODEL IN THE FIELD (MATERNAL IMMUNE ACTIVATION). THE ORGANIZATION OF CLINICAL AND TRANSLATIONAL FINDINGS BASED ON SCHIZOPHRENIA-ASSOCIATED MICROGLIA CHANGES IN DIFFERENT PHASES OF THE DISEASE COURSE MAY HELP DEFINING A TEMPORAL PATTERN OF MICROGLIA CHANGES AND MAY DRIVE THE DESIGN OF NOVEL THERAPEUTIC STRATEGIES. 2022 17 6866 32 [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 18 6846 29 [MIGRAINE: IGNITION OF THE BRAIN]. ALTHOUGH OUR KNOWLEDGE OF WHICH SYSTEMS ARE ACTIVATED DURING MIGRAINE IS REASONABLY COMPLETE, WHY THE SYSTEM IS ACTIVATED REMAINS UNKNOWN. INCORPORATING THE FINDINGS OBTAINED IN STUDIES ON PAIN IN GENERAL HAS ALLOWED A MORE INTEGRATED MODEL TO BE GENERATED. ACCORDING TO THIS NEW MODEL, THERE IS AN ANATOMICAL SUBSTRATE CONSISTING IN A COMPLEX FRAMEWORK OF PAIN THAT IS MADE UP NOT ONLY OF THE TRIGEMINOVASCULAR SYSTEM (END PATHWAY) BUT OF A NUMBER OF NETWORKS THAT ARE IN TURN CONNECTED TO ONE ANOTHER, LIKE THE NEUROLIMBIC, THE ASCENDING AND DESCENDING MODULATORY SYSTEM. THIS COMPLEX NETWORK IS RESPONSIBLE FOR MODULATING AND CONVEYING NOCICEPTIVE SIGNALS. IN PATIENTS WITH MIGRAINE, HYPEREXCITABILITY OF THIS FRAMEWORK IS CONDITIONED BY GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC CHANGES ARE CHEMICAL MODIFICATIONS AFFECTING CHROMATIN, WHICH MODULATES THE ACTIVITY OF GENES WITHOUT MODIFYING THE DNA SEQUENCE, AND WHICH ARE CAPABLE OF MODULATING THE EXPRESSION OF GENES INVOLVED IN A NUMBER OF DIFFERENT ASPECTS, SUCH AS PLASTICITY, SYSTEM EXCITABILITY, MEMORY OF PAIN OR MOODS. IN TURN, THE PRESENCE OF EXTERNAL FACTORS (SUCH AS ENVIRONMENTAL CHANGES OR ALCOHOL) AND INTERNAL FACTORS (SUCH AS HORMONES OR SLEEP DISORDERS) CONTRIBUTE TO ACTIVATE THIS LOADED ANATOMICAL SUBSTRATE, RESULTING IN THE ATTACK OF MIGRAINE. 2013 19 2415 28 EPIGENETIC SIGNALING IN PSYCHIATRIC DISORDERS: STRESS AND DEPRESSION. PSYCHIATRIC DISORDERS ARE COMPLEX MULTIFACTORIAL DISORDERS INVOLVING CHRONIC ALTERATIONS IN NEURAL CIRCUIT STRUCTURE AND FUNCTION. WHILE GENETIC FACTORS PLAY A ROLE IN THE ETIOLOGY OF DISORDERS SUCH AS DEPRESSION, ADDICTION, AND SCHIZOPHRENIA, RELATIVELY HIGH RATES OF DISCORDANCE AMONG IDENTICAL TWINS CLEARLY POINT TO THE IMPORTANCE OF ADDITIONAL FACTORS. ENVIRONMENTAL FACTORS, SUCH AS STRESS, PLAY A MAJOR ROLE IN THE PSYCHIATRIC DISORDERS BY INDUCING STABLE CHANGES IN GENE EXPRESSION, NEURAL CIRCUIT FUNCTION, AND ULTIMATELY BEHAVIOR. INSULTS AT THE DEVELOPMENTAL STAGE AND IN ADULTHOOD APPEAR TO INDUCE DISTINCT MALADAPTATIONS. 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 CAN BE MODELED IN ANIMALS BY INDUCING DISEASE-LIKE STATES THROUGH ENVIRONMENTAL MANIPULATIONS, AND THESE STUDIES CAN PROVIDE A MORE GENERAL UNDERSTANDING OF EPIGENETIC MECHANISMS IN PSYCHIATRIC DISORDERS. UNDERSTANDING HOW ENVIRONMENTAL FACTORS RECRUIT THE EPIGENETIC MACHINERY IN ANIMAL MODELS IS PROVIDING NEW INSIGHTS INTO DISEASE MECHANISMS IN HUMANS. 2014 20 2288 37 EPIGENETIC REGULATION IN MAJOR DEPRESSION AND OTHER STRESS-RELATED DISORDERS: MOLECULAR MECHANISMS, CLINICAL RELEVANCE AND THERAPEUTIC POTENTIAL. MAJOR DEPRESSIVE DISORDER (MDD) IS A CHRONIC, GENERALLY EPISODIC AND DEBILITATING DISEASE THAT AFFECTS AN ESTIMATED 300 MILLION PEOPLE WORLDWIDE, BUT ITS PATHOGENESIS IS POORLY UNDERSTOOD. THE HERITABILITY ESTIMATE OF MDD IS 30-40%, SUGGESTING THAT GENETICS ALONE DO NOT ACCOUNT FOR MOST OF THE RISK OF MAJOR DEPRESSION. ANOTHER FACTOR KNOWN TO ASSOCIATE WITH MDD INVOLVES ENVIRONMENTAL STRESSORS SUCH AS CHILDHOOD ADVERSITY AND RECENT LIFE STRESS. RECENT STUDIES HAVE EMERGED TO SHOW THAT THE BIOLOGICAL IMPACT OF ENVIRONMENTAL FACTORS IN MDD AND OTHER STRESS-RELATED DISORDERS IS MEDIATED BY A VARIETY OF EPIGENETIC MODIFICATIONS. THESE EPIGENETIC MODIFICATION ALTERATIONS CONTRIBUTE TO ABNORMAL NEUROENDOCRINE RESPONSES, NEUROPLASTICITY IMPAIRMENT, NEUROTRANSMISSION AND NEUROGLIA DYSFUNCTION, WHICH ARE INVOLVED IN THE PATHOPHYSIOLOGY OF MDD. FURTHERMORE, EPIGENETIC MARKS HAVE BEEN ASSOCIATED WITH THE DIAGNOSIS AND TREATMENT OF MDD. THE EVALUATION OF EPIGENETIC MODIFICATIONS HOLDS PROMISE FOR FURTHER UNDERSTANDING OF THE HETEROGENEOUS ETIOLOGY AND COMPLEX PHENOTYPES OF MDD, AND MAY IDENTIFY NEW THERAPEUTIC TARGETS. HERE, WE REVIEW PRECLINICAL AND CLINICAL EPIGENETIC FINDINGS, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, NONCODING RNA, RNA MODIFICATION, AND CHROMATIN REMODELING FACTOR IN MDD. IN ADDITION, WE ELABORATE ON THE CONTRIBUTION OF THESE EPIGENETIC MECHANISMS TO THE PATHOLOGICAL TRAIT VARIABILITY IN DEPRESSION AND DISCUSS HOW SUCH MECHANISMS CAN BE EXPLOITED FOR THERAPEUTIC PURPOSES. 2023