1 578 109 BEHAVIOR, BDNF AND EPIGENETIC MECHANISMS IN RESPONSE TO SOCIAL ISOLATION AND SOCIAL SUPPORT IN MIDDLE AGED RATS EXPOSED TO CHRONIC STRESS. SOCIAL DEPRIVATION CAN BE STRESSFUL FOR GROUP-LIVING MAMMALS. ON THE OTHER HAND, AN AMAZING RESPONSE OF THESE ANIMALS TO STRESS IS SEEKING SOCIAL CONTACT TO GIVE AND RECEIVE JOINT PROTECTION IN THREATENING SITUATIONS. WE EXPLORED THE EFFECTS OF SOCIAL ISOLATION AND SOCIAL SUPPORT ON EPIGENETIC AND BEHAVIORAL RESPONSES TO CHRONIC STRESS. MORE SPECIFICALLY, WE INVESTIGATED THE BEHAVIORAL RESPONSES, CORTICOSTERONE LEVELS, BDNF GENE EXPRESSION, AND MARKERS OF HIPPOCAMPAL EPIGENETIC ALTERATIONS (LEVELS OF H3K9 ACETYLATION AND METHYLATION, H3K27 METHYLATION, HDAC5, DNMT1, AND DNMT3A GENE EXPRESSIONS) IN MIDDLE-AGED ADULT RATS MAINTAINED IN DIFFERENT HOUSING CONDITIONS (ISOLATION OR ACCOMPANIED HOUSING) AND EXPOSED TO THE CHRONIC UNPREDICTABLE STRESS PROTOCOL (CUS). ISOLATION WAS ASSOCIATED WITH DECREASED BASAL LEVELS OF CORTICOSTERONE, IMPAIRED LONG-TERM MEMORY, AND DECREASED EXPRESSION OF THE BDNF GENE, BESIDES ALTERING THE BALANCE OF H3K9 FROM ACETYLATION TO METHYLATION AND INCREASING THE DNMT1 GENE EXPRESSION. THE CUS PROTOCOL DECREASED H3K9 ACETYLATION, BESIDES INCREASING H3K27 METHYLATION AND DNMT1 GENE EXPRESSION, BUT HAD NO SIGNIFICANT EFFECTS ON MEMORY AND BDNF GENE EXPRESSION. INTERESTINGLY, THE EFFECTS OF CUS ON CORTICOSTERONE AND HDAC5 GENE EXPRESSION WERE SEEN ONLY IN ISOLATED ANIMALS, WHEREAS THE EFFECTS OF CUS ON DNMT1 GENE EXPRESSION WERE MORE PRONOUNCED IN ISOLATED THAN ACCOMPANIED ANIMALS. IN CONCLUSION, SOCIAL ISOLATION IN MIDDLE AGE SHOWED BROADER EFFECTS THAN CHRONIC UNPREDICTABLE STRESS ON BEHAVIORAL AND EPIGENETIC ALTERATIONS POTENTIALLY ASSOCIATED WITH DECREASED BDNF EXPRESSION. MOREOVER, SOCIAL SUPPORT PREVENTED THE ADVERSE EFFECTS OF CUS ON HPA AXIS FUNCTIONING, HDAC5, AND DNMT1 GENE EXPRESSIONS. 2023 2 5752 56 SOCIAL ISOLATION AND SOCIAL SUPPORT AT ADULTHOOD AFFECT EPIGENETIC MECHANISMS, BRAIN-DERIVED NEUROTROPHIC FACTOR LEVELS AND BEHAVIOR OF CHRONICALLY STRESSED RATS. EPIGENETIC MODULATION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) PROVIDES ONE POSSIBLE EXPLANATION FOR THE DYSFUNCTIONS INDUCED BY STRESS, SUCH AS PSYCHIATRIC DISORDERS AND COGNITIVE DECLINE. INTERESTINGLY, SOCIAL SUPPORT CAN BE PROTECTIVE AGAINST SOME OF THESE EFFECTS, BUT THE MECHANISMS OF SOCIAL BUFFERING ARE POORLY UNDERSTOOD. CONVERSELY, EARLY ISOLATION EXACERBATES THE RESPONSES TO STRESSORS, ALTHOUGH ITS EFFECTS IN ADULTHOOD REMAIN UNCLEAR. THIS STUDY INVESTIGATED THE EFFECTS OF SOCIAL ISOLATION AND SOCIAL BUFFERING ON HIPPOCAMPAL EPIGENETIC MECHANISMS, BDNF LEVELS AND BEHAVIORAL RESPONSES OF CHRONICALLY STRESSED YOUNG ADULT RATS. MALE WISTAR RATS (3 MONTHS) WERE ASSIGNED TO ACCOMPANIED (PAIRED) OR ISOLATED HOUSING. AFTER ONE-MONTH HALF OF EACH GROUP WAS SUBMITTED TO A CHRONIC UNPREDICTABLE STRESS (CUS) PROTOCOL FOR 18 DAYS. AMONG ACCOMPANIED ANIMALS, ONLY ONE WAS EXPOSED TO STRESS. BEHAVIORAL ANALYSIS ENCOMPASSED THE OPEN FIELD, PLUS MAZE AND INHIBITORY AVOIDANCE TASKS. HIPPOCAMPAL H3K9 AND H4K12 ACETYLATION, HDAC5 EXPRESSION AND BDNF LEVELS WERE EVALUATED. ISOLATED HOUSING INCREASED HDAC5 EXPRESSION, DECREASED H3K9 AND H4K12 ACETYLATION, REDUCED BDNF LEVELS, AND IMPAIRED LONG-TERM MEMORY. STRESS AFFECTED WEIGHT GAIN, INDUCED ANXIETY-LIKE BEHAVIOR AND DECREASED ACK9H3 LEVELS. INTERACTIONS BETWEEN HOUSING CONDITIONS AND SOCIAL STRESS WERE SEEN ONLY FOR HDAC5 EXPRESSION, WHICH SHOWED A FURTHER INCREASE IN THE ISOLATED + CUS GROUP BUT REMAINED CONSTANT IN ACCOMPANIED ANIMALS. IN CONCLUSION, SOCIAL ISOLATION AT ADULTHOOD INDUCED EPIGENETIC ALTERATIONS AND EXACERBATED THE EFFECTS OF CHRONIC STRESS ON HDAC5. NOTWITHSTANDING, SOCIAL SUPPORT COUNTERACTED THE ADVERSE EFFECTS OF STRESS ON HDAC5 EXPRESSION. 2019 3 3973 34 LONG-TERM BEHAVIORAL AND NEUROENDOCRINE ALTERATIONS FOLLOWING CHRONIC SOCIAL STRESS IN MICE: IMPLICATIONS FOR STRESS-RELATED DISORDERS. THE PERIOD OF ADOLESCENCE IS CHARACTERIZED BY A HIGH VULNERABILITY TO STRESS AND TRAUMA, WHICH MIGHT RESULT IN LONG-LASTING CONSEQUENCES AND AN INCREASED RISK TO DEVELOP PSYCHIATRIC DISORDERS. USING A RECENTLY DEVELOPED MOUSE MODEL FOR CHRONIC SOCIAL STRESS DURING ADOLESCENCE, WE STUDIED PERSISTENT NEUROENDOCRINE AND BEHAVIORAL EFFECTS OF CHRONIC SOCIAL STRESS OBTAINED 12 MONTHS AFTER CESSATION OF THE STRESSOR. AS A REFERENCE, WE INVESTIGATED IMMEDIATE EFFECTS OF CHRONIC STRESS EXPOSURE OBTAINED AT THE END OF THE CHRONIC STRESS PERIOD. IMMEDIATELY AFTER THE 7 WEEK CHRONIC STRESS PERIOD STRESSED ANIMALS SHOW SIGNIFICANTLY INCREASED ADRENAL WEIGHTS, DECREASED THYMUS WEIGHT, INCREASED BASAL CORTICOSTERONE SECRETION AND A FLATTENED CIRCADIAN RHYTHM. FURTHERMORE, STRESSED ANIMALS DISPLAY AN INCREASED ANXIETY-LIKE BEHAVIOR IN THE ELEVATED PLUS MAZE AND THE NOVELTY-INDUCED SUPPRESSION OF FEEDING TEST. HIPPOCAMPAL MINERALOCORTICOID RECEPTOR (MR) AND THE GLUCOCORTICOID RECEPTOR (GR) MRNA LEVELS WERE SIGNIFICANTLY DECREASED. TO INVESTIGATE PERSISTENT CONSEQUENCES OF THIS EARLY STRESSFUL EXPERIENCE, THE SAME PARAMETERS WERE ASSESSED IN AGED MICE 12 MONTHS AFTER THE CESSATION OF THE STRESSOR. INTERESTINGLY, WE STILL FOUND DIFFERENCES BETWEEN FORMERLY STRESSED AND CONTROL MICE IN IMPORTANT STRESS-RELATED PARAMETERS. MR EXPRESSION LEVELS WERE SIGNIFICANTLY LOWER IN STRESSED ANIMALS, SUGGESTING LASTING, POSSIBLY EPIGENETIC ALTERATIONS IN GENE EXPRESSION REGULATION. FURTHERMORE, WE OBSERVED LONG-TERM BEHAVIORAL ALTERATIONS IN ANIMALS STRESSED DURING ADOLESCENCE. THUS, WE COULD DEMONSTRATE THAT CHRONIC STRESS EXPOSURE DURING A CRUCIAL DEVELOPMENTAL TIME PERIOD RESULTS IN LONG-TERM, PERSISTENT EFFECTS ON PHYSIOLOGICAL AND BEHAVIORAL PARAMETERS THROUGHOUT LIFE, WHICH MAY CONTRIBUTE TO AN ENHANCED VULNERABILITY TO STRESS-INDUCED DISEASES. 2008 4 5019 35 PERSISTENT INFLAMMATORY PAIN IS LINKED WITH ANXIETY-LIKE BEHAVIORS, INCREASED BLOOD CORTICOSTERONE, AND REDUCED GLOBAL DNA METHYLATION IN THE RAT AMYGDALA. CHRONIC PAIN INCREASES THE RISK OF DEVELOPING ANXIETY, WITH LIMBIC AREAS BEING LIKELY NEUROLOGICAL SUBSTRATES. DESPITE HIGH CLINICAL RELEVANCE, LITTLE IS KNOWN ABOUT THE PRECISE BEHAVIORAL, HORMONAL, AND BRAIN NEUROPLASTIC CORRELATES OF ANXIETY IN THE CONTEXT OF PERSISTENT PAIN. PREVIOUS STUDIES HAVE SHOWN THAT DECREASED NOCICEPTIVE THRESHOLDS IN CHRONIC PAIN MODELS ARE PARALLELED BY ANXIETY-LIKE BEHAVIOR IN RATS, BUT THERE ARE CONFLICTING IDEAS REGARDING ITS EFFECTS ON THE STRESS RESPONSE AND CIRCULATING CORTICOSTERONE LEVELS. EVEN LESS IS KNOWN ABOUT THE MOLECULAR MECHANISMS THROUGH WHICH THE BRAIN ENCODES PAIN-RELATED ANXIETY. THIS STUDY EXAMINES HOW PERSISTENT INFLAMMATORY PAIN IN A RAT MODEL WOULD IMPACT ANXIETY-LIKE BEHAVIORS AND CORTICOSTERONE RELEASE, AND WHETHER THESE CHANGES WOULD BE REFLECTED IN LEVELS OF GLOBAL DNA METHYLATION IN BRAIN AREAS INVOLVED IN STRESS REGULATION. COMPLETE FREUND'S ADJUVANT (CFA) OR SALINE WAS ADMINISTERED IN THE RIGHT HINDPAW OF ADULT MALE WISTAR RATS. BEHAVIORAL TESTING INCLUDED THE MEASUREMENT OF NOCICEPTIVE THRESHOLDS (DIGITAL ANESTHESIOMETER), MOTOR FUNCTION (OPEN FIELD TEST), AND ANXIETY-LIKE BEHAVIORS (ELEVATED PLUS MAZE AND THE DARK-LIGHT BOX TEST). CORTICOSTERONE WAS MEASURED VIA RADIOIMMUNOASSAY. GLOBAL DNA METHYLATION (ENZYME IMMUNOASSAY) AS WELL AS DNMT3A LEVELS (WESTERN BLOTTING) WERE QUANTIFIED IN THE AMYGDALA, PREFRONTAL CORTEX, AND VENTRAL HIPPOCAMPUS. CFA ADMINISTRATION RESULTED IN PERSISTENT REDUCTION IN NOCICEPTIVE THRESHOLD IN THE ABSENCE OF LOCOMOTOR ABNORMALITIES. INCREASED ANXIETY-LIKE BEHAVIORS WERE OBSERVED IN THE ELEVATED PLUS MAZE AND WERE ACCOMPANIED BY INCREASED BLOOD CORTICOSTERONE LEVELS 10 DAYS AFTER PAIN INDUCTION. GLOBAL DNA METHYLATION WAS DECREASED IN THE AMYGDALA, WITH NO CHANGES IN DNMT3A ABUNDANCE IN ANY OF THE REGIONS EXAMINED. PERSISTENT INFLAMMATORY PAIN PROMOTES ANXIETY -LIKE BEHAVIORS, HPA AXIS ACTIVATION, AND EPIGENETIC REGULATION THROUGH DNA METHYLATION IN THE AMYGDALA. THESE FINDINGS DESCRIBE A MOLECULAR MECHANISM THAT LINKS PAIN AND STRESS IN A WELL-CHARACTERIZED RODENT MODEL. 2022 5 5207 29 PRENATAL STRESS INDUCES SPATIAL MEMORY DEFICITS AND EPIGENETIC CHANGES IN THE HIPPOCAMPUS INDICATIVE OF HETEROCHROMATIN FORMATION AND REDUCED GENE EXPRESSION. STRESS DURING PREGNANCY HAS A WIDE VARIETY OF NEGATIVE EFFECTS IN BOTH HUMAN [1] AND ANIMAL OFFSPRING [2]. THESE EFFECTS ARE ESPECIALLY APPARENT IN VARIOUS FORMS OF LEARNING AND MEMORY SUCH AS OBJECT RECOGNITION [3] AND SPATIAL MEMORY [4]. THE COGNITIVE EFFECTS OF PRENATAL STRESS (PNS) MAY BE MEDIATED THROUGH EPIGENETIC CHANGES SUCH AS HISTONE ACETYLATION AND DNA METHYLATION [5]. AS SUCH, THE PRESENT STUDY INVESTIGATED THE EFFECTS OF CHRONIC UNPREDICTABLE PNS ON MEMORY AND EPIGENETIC MEASURES IN ADULT OFFSPRING. MICE THAT UNDERWENT PNS EXHIBITED IMPAIRED SPATIAL MEMORY IN THE MORRIS WATER MAZE, AS WELL AS SEX-SPECIFIC CHANGES IN LEVELS OF DNA METHYLTRANSFERASE (DNMT) 1 PROTEIN, AND ACETYLATED HISTONE H3 (ACH3) IN THE HIPPOCAMPUS, AND SERUM CORTICOSTERONE. MALE MICE EXPOSED TO PNS EXHIBITED DECREASED HIPPOCAMPAL ACH3, WHEREAS FEMALE PNS MICE DISPLAYED A FURTHER REDUCTION IN ACH3, AS WELL AS HEIGHTENED HIPPOCAMPAL DNMT1 PROTEIN LEVELS AND CORTICOSTERONE LEVELS. THESE DATA SUGGEST THAT PNS MAY EPIGENETICALLY REDUCE TRANSCRIPTION IN THE HIPPOCAMPUS, PARTICULARLY IN FEMALES IN WHOM THIS EFFECT MAY BE RELATED TO INCREASED BASELINE STRESS HORMONE LEVELS, AND WHICH MAY UNDERLIE THE SEXUAL DIMORPHISM IN RATES OF MENTAL ILLNESS IN HUMANS. 2015 6 1614 35 DNA METHYLTRANSFERASE 3A IS INVOLVED IN THE SUSTAINED EFFECTS OF CHRONIC STRESS ON SYNAPTIC FUNCTIONS AND BEHAVIORS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS REGULATE ABERRANT GENE TRANSCRIPTION IN STRESS-ASSOCIATED MENTAL DISORDERS. HOWEVER, IT REMAINS TO BE ELUCIDATED ABOUT THE ROLE OF DNA METHYLATION AND ITS CATALYZING ENZYMES, DNA METHYLTRANSFERASES (DNMTS), IN THIS PROCESS. HERE, WE FOUND THAT MALE RATS EXPOSED TO CHRONIC (2-WEEK) UNPREDICTABLE STRESS EXHIBITED A SUBSTANTIAL REDUCTION OF DNMT3A AFTER STRESS CESSATION IN THE PREFRONTAL CORTEX (PFC), A KEY TARGET REGION OF STRESS. TREATMENT OF UNSTRESSED CONTROL RATS WITH DNMT INHIBITORS RECAPITULATED THE EFFECT OF CHRONIC UNPREDICTABLE STRESS ON DECREASED AMPAR EXPRESSION AND FUNCTION IN PFC. IN CONTRAST, OVEREXPRESSION OF DNMT3A IN PFC OF STRESSED ANIMALS PREVENTED THE LOSS OF GLUTAMATERGIC RESPONSES. MOREOVER, THE STRESS-INDUCED BEHAVIORAL ABNORMALITIES, INCLUDING THE IMPAIRED RECOGNITION MEMORY, HEIGHTENED AGGRESSION, AND HYPERLOCOMOTION, WERE PARTIALLY ATTENUATED BY DNMT3A EXPRESSION IN PFC OF STRESSED ANIMALS. FINALLY, WE FOUND THAT THERE WERE GENOME-WIDE DNA METHYLATION CHANGES AND TRANSCRIPTOME ALTERATIONS IN PFC OF STRESSED RATS, BOTH OF WHICH WERE ENRICHED AT SEVERAL NEURAL PATHWAYS, INCLUDING GLUTAMATERGIC SYNAPSE AND MICROTUBULE-ASSOCIATED PROTEIN KINASE SIGNALING. THESE RESULTS HAVE THEREFORE RECOGNIZED THE POTENTIAL ROLE OF DNA EPIGENETIC MODIFICATION IN STRESS-INDUCED DISTURBANCE OF SYNAPTIC FUNCTIONS AND COGNITIVE AND EMOTIONAL PROCESSES. 2021 7 1808 37 EFFECTS OF ADOLESCENT SOCIAL STRESS AND ANTIDEPRESSANT TREATMENT ON COGNITIVE INFLEXIBILITY AND BDNF EPIGENETIC MODIFICATIONS IN THE MPFC OF ADULT MICE. ADOLESCENT SOCIAL STRESS (ASS) CAN INCREASE SUSCEPTIBILITY TO DEPRESSION IN ADULTHOOD. HOWEVER, THE UNDERLYING PSYCHOLOGICAL AND NEURAL MECHANISMS REMAIN UNCLEAR. CORTICALLY MEDIATED COGNITIVE DYSFUNCTIONS ARE INCREASINGLY RECOGNIZED AS AN INDEPENDENT AND IMPORTANT RISK FACTOR OF DEPRESSION. USING SOCIAL DEFEAT STRESS, A CLASSICAL ANIMAL MODEL OF DEPRESSION, OUR PREVIOUS STUDIES FOUND THAT MICE SUBJECTED TO THIS FORM OF STRESS DURING EARLY ADOLESCENCE DISPLAYED COGNITIVE INFLEXIBILITY (CI) IN ADULTHOOD. THIS CHANGE WAS ACCOMPANIED BY A DOWN-REGULATION OF BDNF GENE EXPRESSION IN THE MEDIAL PREFRONTAL CORTEX (MPFC); THIS GENE ENCODES A KEY MOLECULE INVOLVED IN DEPRESSION AND ANTIDEPRESSANT ACTION. IN THE PRESENT PAPER, WE IDENTIFIED EPIGENETIC MODIFICATION OF BDNF AS A POSSIBLE MECHANISM UNDERLYING THE BEHAVIORAL AND MOLECULAR CHANGES. ASS INDUCED A SET OF DEPRESSIVE PHENOTYPES, INCLUDING INCREASED SOCIAL AVOIDANCE AND CI, AS WELL AS REDUCED LEVELS OF TOTAL BDNF AND ISOFORM IV BUT NOT ISOFORM I OR VI TRANSCRIPTS IN THE MPFC. IN PARALLEL WITH CHANGES IN BDNF GENE EXPRESSION, PREVIOUSLY STRESSED ADULT MICE SHOWED INCREASED LEVELS OF DIMETHYLATION OF HISTONE H3 AT LYSINE K9 (H3K9ME2) IMMEDIATELY DOWNSTREAM OF THE BDNF IV PROMOTER. ON THE OTHER HAND, NO DIFFERENCES WERE FOUND IN TRIMETHYLATION OF HISTONE H3 AT LYSINE K4 (H3K4ME3) OR IN ACETYLATION OF HISTONE H3 AT LYSINE K9 (H3K9AC) OR AT K4 (H3K4AC) IN THE BDNF IV PROMOTER. LIKEWISE, NO ALTERATIONS WERE FOUND IN DNA METHYLATION OF THE BDNF IV PROMOTER. ADDITIONALLY, TREATMENT WITH THE CHRONIC ANTIDEPRESSANT TRANYLCYPROMINE REVERSED BDNF EPIGENETIC CHANGES AND RELATED GENE TRANSCRIPTION WHILE ALSO REVERSING CI, BUT NOT SOCIAL AVOIDANCE, IN PREVIOUSLY STRESSED ADULT MICE. THESE RESULTS SUGGEST THAT EPIGENETIC CHANGES TO THE BDNF GENE IN THE MPFC AFTER ADOLESCENT SOCIAL ADVERSITY MAY BE INVOLVED IN THE REGULATION OF COGNITIVE DYSFUNCTION IN DEPRESSION AND ANTIDEPRESSANT ACTION IN ADULTHOOD. 2018 8 2740 21 EXPOSURE TO EARLY LIFE STRESS RESULTS IN EPIGENETIC CHANGES IN NEUROTROPHIC FACTOR GENE EXPRESSION IN A PARKINSONIAN RAT MODEL. EARLY LIFE ADVERSITY INCREASES THE RISK OF MENTAL DISORDERS LATER IN LIFE. CHRONIC EARLY LIFE STRESS MAY ALTER NEUROTROPHIC FACTOR GENE EXPRESSION INCLUDING THOSE FOR BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) AND GLIAL CELL DERIVED NEUROTROPHIC FACTOR (GDNF) THAT ARE IMPORTANT IN NEURONAL GROWTH, SURVIVAL, AND MAINTENANCE. MATERNAL SEPARATION WAS USED IN THIS STUDY TO MODEL EARLY LIFE STRESS. FOLLOWING UNILATERAL INJECTION OF A MILD DOSE OF 6-HYDROXYDOPAMINE (6-OHDA), WE MEASURED CORTICOSTERONE (CORT) IN THE BLOOD AND STRIATUM OF STRESSED AND NONSTRESSED RATS; WE ALSO MEASURED DNA METHYLATION AND BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM USING REAL TIME PCR. IN THE PRESENCE OF STRESS, WE FOUND THAT THERE WAS INCREASED CORTICOSTERONE CONCENTRATION IN BOTH BLOOD AND STRIATAL TISSUE. FURTHER TO THIS, WE FOUND HIGHER DNA METHYLATION AND DECREASED NEUROTROPHIC FACTOR GENE EXPRESSION. 6-OHDA LESION INCREASED NEUROTROPHIC FACTOR GENE EXPRESSION IN BOTH STRESSED AND NONSTRESSED RATS BUT THIS INCREASE WAS HIGHER IN THE NONSTRESSED RATS. OUR RESULTS SUGGEST THAT EXPOSURE TO EARLY POSTNATAL STRESS INCREASES CORTICOSTERONE CONCENTRATION WHICH LEADS TO INCREASED DNA METHYLATION. THIS EFFECT RESULTS IN DECREASED BDNF AND GDNF GENE EXPRESSION IN THE STRIATUM LEADING TO DECREASED PROTECTION AGAINST SUBSEQUENT INSULTS LATER IN LIFE. 2016 9 1790 27 EFFECT OF CHRONIC MILD STRESS ON HIPPOCAMPAL TRANSCRIPTOME IN MICE SELECTED FOR HIGH AND LOW STRESS-INDUCED ANALGESIA AND DISPLAYING DIFFERENT EMOTIONAL BEHAVIORS. THERE IS INCREASING EVIDENCE THAT MOOD DISORDERS MAY DERIVE FROM THE IMPACT OF ENVIRONMENTAL PRESSURE ON GENETICALLY SUSCEPTIBLE INDIVIDUALS. STRESS-INDUCED HIPPOCAMPAL PLASTICITY HAS BEEN IMPLICATED IN DEPRESSION. WE STUDIED HIPPOCAMPAL TRANSCRIPTOMES IN STRAINS OF MICE THAT DISPLAY HIGH (HA) AND LOW (LA) SWIM STRESS-INDUCED ANALGESIA AND THAT DIFFER IN EMOTIONAL BEHAVIORS AND RESPONSES TO DIFFERENT CLASSES OF ANTIDEPRESSANTS. CHRONIC MILD STRESS (CMS) AFFECTED EXPRESSION OF A NUMBER OF GENES COMMON FOR BOTH STRAINS. CMS ALSO PRODUCED STRAIN SPECIFIC CHANGES IN EXPRESSION SUGGESTING THAT HIPPOCAMPAL RESPONSES TO STRESS DEPEND ON GENOTYPE. CONSIDERABLY LARGER NUMBER OF GENES, BIOLOGICAL PROCESSES, MOLECULAR FUNCTIONS, BIOCHEMICAL PATHWAYS, AND GENE NETWORKS WERE AFFECTED BY CMS IN LA THAN IN HA MICE. THE RESULTS SUGGEST THAT POTENTIAL DRUG TARGETS AGAINST DETRIMENTAL EFFECTS OF STRESS INCLUDE GLUTAMATE TRANSPORTERS, AND CHOLINERGIC, CHOLECYSTOKININ (CCK), GLUCOCORTICOIDS, AND THYROID HORMONES RECEPTORS. FURTHERMORE, SOME BIOLOGICAL PROCESSES EVOKED BY STRESS AND DIFFERENT BETWEEN THE STRAINS, SUCH AS APOPTOSIS, NEUROGENESIS AND CHROMATIN MODIFICATIONS, MAY BE RESPONSIBLE FOR THE LONG-TERM, IRREVERSIBLE EFFECTS OF STRESS AND SUGGEST A ROLE FOR EPIGENETIC REGULATION OF MOOD RELATED STRESS RESPONSES. 2011 10 1698 31 DYNAMIC EFFECTS OF EARLY ADOLESCENT STRESS ON DEPRESSIVE-LIKE BEHAVIORS AND EXPRESSION OF CYTOKINES AND JMJD3 IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF RATS. AIMS: EXPRESSION OF INFLAMMATORY CYTOKINES IN THE BRAIN HAS BEEN REPORTED TO BE INVOLVED IN THE PATHOGENESIS OF AND SUSCEPTIBILITY TO DEPRESSION. JUMONJI DOMAIN-CONTAINING 3 (JMJD3), WHICH IS A HISTONE H3 LYSINE 27 (H3K27) DEMETHYLASE AND CAN REGULATE MICROGLIAL ACTIVATION, HAS BEEN REGARDED AS A CRUCIAL ELEMENT IN THE EXPRESSION OF INFLAMMATORY CYTOKINES. FURTHERMORE, RECENT STUDIES HIGHLIGHTED THE FACT THAT LIPOPOLYSACCHARIDES INDUCE DEPRESSIVE-LIKE BEHAVIORS AND HIGHER JMJD3 EXPRESSION AND LOWER H3K27ME3 EXPRESSION IN THE BRAIN. HOWEVER, WHETHER THE PROCESS OF JMJD3 MEDIATING INFLAMMATORY CYTOKINES WAS INVOLVED IN THE SUSCEPTIBILITY TO DEPRESSION DUE TO EARLY-LIFE STRESS REMAINED ELUSIVE. METHODS: RATS EXPOSED TO CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IN ADOLESCENCE WERE USED IN ORDER TO DETECT DYNAMIC ALTERATIONS IN DEPRESSIVE-LIKE BEHAVIORS AND EXPRESSION OF CYTOKINES, JMJD3, AND H3K27ME3 IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS. MOREOVER, MINOCYCLINE, AN INHIBITOR OF MICROGLIAL ACTIVATION, WAS EMPLOYED TO OBSERVE THE PROTECTIVE EFFECTS. RESULTS: OUR RESULTS SHOWED THAT CUMS DURING THE ADOLESCENT PERIOD INDUCED DEPRESSIVE-LIKE BEHAVIORS, OVER-EXPRESSION OF CYTOKINES, AND INCREASED JMJD3 AND DECREASED H3K27ME3 EXPRESSION IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF BOTH ADOLESCENT AND ADULT RATS. HOWEVER, MINOCYCLINE RELIEVED ALL THE ALTERATIONS. CONCLUSION: THE STUDY REVEALED THAT JMJD3 MIGHT BE INVOLVED IN THE SUSCEPTIBILITY TO DEPRESSIVE-LIKE BEHAVIORS BY MODULATING H3K27ME3 AND PRO-INFLAMMATORY CYTOKINE EXPRESSION IN THE PREFRONTAL CORTEX AND HIPPOCAMPUS OF RATS THAT HAD BEEN STRESSED DURING EARLY ADOLESCENCE. 2018 11 1753 33 EARLY LIFE STRESS TRIGGERS SUSTAINED CHANGES IN HISTONE DEACETYLASE EXPRESSION AND HISTONE H4 MODIFICATIONS THAT ALTER RESPONSIVENESS TO ADOLESCENT ANTIDEPRESSANT TREATMENT. EARLY LIFE STRESS CAN ELICIT LONG-LASTING CHANGES IN GENE EXPRESSION AND BEHAVIOR. RECENT STUDIES ON RODENTS SUGGEST THAT THESE LASTING EFFECTS DEPEND ON THE GENETIC BACKGROUND. WHETHER EPIGENETIC FACTORS ALSO PLAY A ROLE REMAINS TO BE INVESTIGATED. HERE WE EXPOSED THE STRESS-SUSCEPTIBLE MOUSE STRAIN BALB/C AND THE MORE RESILIENT STRAIN C57BL/6 TO A POWERFUL EARLY LIFE STRESS PARADIGM, INFANT MATERNAL SEPARATION. IN BALB/C MICE, INFANT MATERNAL SEPARATION LED TO DECREASED EXPRESSION OF MRNA ENCODING THE HISTONE DEACETYLASES (HDACS) 1, 3, 7, 8, AND 10 IN THE FOREBRAIN NEOCORTEX IN ADULTHOOD, AN EFFECT ACCOMPANIED BY INCREASED EXPRESSION OF ACETYLATED HISTONE H4 PROTEINS, ESPECIALLY ACETYLATED H4K12 PROTEIN. THESE CHANGES IN HDAC EXPRESSION AND HISTONE MODIFICATIONS WERE NOT DETECTED IN C57BL/6 MICE EXPOSED TO EARLY LIFE STRESS. MOREOVER, A REVERSAL OF THE H4K12 HYPERACETYLATION DETECTED IN INFANT MATERNALLY SEPARATED BALB/C MICE (ACHIEVED WITH CHRONIC ADOLESCENT TREATMENT WITH A LOW DOSE OF THEOPHYLLINE THAT ONLY ACTIVATES HDACS) WORSENED THE ABNORMAL EMOTIONAL PHENOTYPE RESULTING FROM THIS EARLY LIFE STRESS EXPOSURE. IN CONTRAST, FLUOXETINE, A DRUG WITH POTENT ANTIDEPRESSANT EFFICACY IN INFANT MATERNALLY SEPARATED BALB/C MICE, POTENTIATED ALL HISTONE MODIFICATIONS TRIGGERED BY EARLY LIFE STRESS. MOREOVER, IN NON-STRESSED BALB/C MICE, CO-ADMINISTRATION OF AN HDAC INHIBITOR AND FLUOXETINE, BUT NOT FLUOXETINE ALONE, ELICITED ANTIDEPRESSANT EFFECTS AND ALSO TRIGGERED CHANGES IN HISTONE H4 EXPRESSION THAT WERE SIMILAR TO THOSE PROVOKED BY FLUOXETINE TREATMENT OF MICE EXPOSED TO EARLY LIFE STRESS. THESE RESULTS SUGGEST THAT BALB/C MICE DEVELOP EPIGENETIC MODIFICATIONS AFTER EARLY LIFE STRESS EXPOSURE THAT, IN TERMS OF THE EMOTIVE PHENOTYPE, ARE OF ADAPTIVE NATURE, AND THAT ENHANCE THE EFFICACY OF ANTIDEPRESSANT DRUGS. 2012 12 2472 30 EPIGENETIC TRANSMISSION OF THE IMPACT OF EARLY STRESS ACROSS GENERATIONS. BACKGROUND: TRAUMATIC EXPERIENCES IN EARLY LIFE ARE RISK FACTORS FOR THE DEVELOPMENT OF BEHAVIORAL AND EMOTIONAL DISORDERS. SUCH DISORDERS CAN PERSIST THROUGH ADULTHOOD AND HAVE OFTEN BEEN REPORTED TO BE TRANSMITTED ACROSS GENERATIONS. METHODS: TO INVESTIGATE THE TRANSGENERATIONAL EFFECT OF EARLY STRESS, MICE WERE EXPOSED TO CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION FROM POSTNATAL DAY 1 TO 14. RESULTS: WE SHOW THAT CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION INDUCES DEPRESSIVE-LIKE BEHAVIORS AND ALTERS THE BEHAVIORAL RESPONSE TO AVERSIVE ENVIRONMENTS IN THE SEPARATED ANIMALS WHEN ADULT. MOST OF THE BEHAVIORAL ALTERATIONS ARE FURTHER EXPRESSED BY THE OFFSPRING OF MALES SUBJECTED TO MATERNAL SEPARATION, DESPITE THE FACT THAT THESE MALES ARE REARED NORMALLY. CHRONIC AND UNPREDICTABLE MATERNAL SEPARATION ALSO ALTERS THE PROFILE OF DNA METHYLATION IN THE PROMOTER OF SEVERAL CANDIDATE GENES IN THE GERMLINE OF THE SEPARATED MALES. COMPARABLE CHANGES IN DNA METHYLATION ARE ALSO PRESENT IN THE BRAIN OF THE OFFSPRING AND ARE ASSOCIATED WITH ALTERED GENE EXPRESSION. CONCLUSIONS: THESE FINDINGS HIGHLIGHT THE NEGATIVE IMPACT OF EARLY STRESS ON BEHAVIORAL RESPONSES ACROSS GENERATIONS AND ON THE REGULATION OF DNA METHYLATION IN THE GERMLINE. 2010 13 586 25 BEHAVIOURAL AND EPIGENETIC EFFECTS OF PATERNAL EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE ON OFFSPRING VULNERABILITY TO STRESS. CHRONIC CANNABINOID EXPOSURE DURING ADOLESCENCE IN MALE RATS INDUCES CHRONIC COGNITIVE AND EMOTIONAL IMPAIRMENTS. HOWEVER, THE IMPACT OF THIS FORM OF EXPOSURE ON OFFSPRING VULNERABILITY TO STRESS IS UNKNOWN. THE AIM OF THIS STUDY WAS TO EVALUATE THE BEHAVIOURAL AND EPIGENETIC EFFECTS OF STRESS IN THE OFFSPRING OF MALE RATS WHOSE FATHERS WERE EXPOSED TO CANNABINOIDS DURING ADOLESCENCE. MALE ADOLESCENT OFFSPRING OF WIN55,212-2 (1.2 MG/KG) TREATED RATS WERE EXPOSED DURING ONE WEEK TO VARIABLE STRESSORS AND SUBJECTED TO BEHAVIOURAL TESTS OF ANXIETY AND EPISODIC-LIKE MEMORY, FOLLOWED BY AN ASSESSMENT OF GLOBAL DNA METHYLATION AND EXPRESSION OF DNA METHYLTRANSFERASES ENZYMES DNMT1 AND DNMT3A MRNA IN THE PREFRONTAL CORTEX. STRESS EXPOSURE INDUCED A SIGNIFICANT ANXIOGENIC-LIKE EFFECT BUT DID NOT AFFECT THE EPISODIC-LIKE MEMORY IN THE OFFSPRING OF WIN55,212-2 EXPOSED FATHERS IN COMPARISON TO THE OFFSPRING OF NON-EXPOSED FATHERS. THESE BEHAVIOURAL CHANGES WERE SUBSEQUENT TO A SIGNIFICANT INCREASE IN GLOBAL DNA METHYLATION AND DNMT1 AND DNMTA3 TRANSCRIPTION IN THE PREFRONTAL CORTEX. THESE DATA SUGGEST THAT THE DELETERIOUS EFFECT OF CHRONIC EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE ARE NOT LIMITED TO THE EXPOSED INDIVIDUALS BUT MAY INCREASE THE VULNERABILITY TO STRESS-INDUCED ANXIETY IN THE OFFSPRING AND ALTER THEIR EPIGENETIC PROGRAMMING. 2019 14 5199 29 PRENATAL MATERNAL STRESS IS ASSOCIATED WITH INCREASED SENSITIVITY TO NEUROPATHIC PAIN AND SEX-SPECIFIC CHANGES IN SUPRASPINAL MRNA EXPRESSION OF EPIGENETIC- AND STRESS-RELATED GENES IN ADULTHOOD. EXPOSURE TO PRENATAL MATERNAL STRESS IMPACTS ADULT BEHAVIORAL OUTCOMES AND HAS BEEN SUGGESTED AS A RISK FACTOR FOR CHRONIC PAIN. HOWEVER, THE NEUROBIOLOGICAL MECHANISMS IMPLICATED ARE NOT WELL-CHARACTERIZED. IN THIS STUDY, WE ANALYZED THE EFFECT OF A PRENATAL MATERNAL STRESS ON THE DEVELOPMENT OF NEUROPATHIC PAIN-RELATED BEHAVIOURS AND GENE EXPRESSION IN THE FRONTAL CORTEX AND HIPPOCAMPUS IN ADULT OFFSPRING FOLLOWING CHRONIC CONSTRICTION INJURY OF THE SCIATIC NERVE IN MALE AND FEMALE CD1 MICE. NERVE INJURY-INDUCED MECHANICAL HYPERSENSITIVITY WAS AMPLIFIED IN BOTH MALE AND FEMALE PRENATALLY-STRESSED OFFSPRING, SUGGESTING THAT PRENATAL STRESS EXACERBATES PAIN AFTER INJURY. ANALYSIS OF MRNA EXPRESSION OF GENES RELATED TO EPIGENETIC REGULATION AND STRESS RESPONSES IN THE FRONTAL CORTEX AND HIPPOCAMPUS, BRAIN STRUCTURES IMPLICATED IN CHRONIC PAIN, SHOWED DISTINCT SEX AND REGION-SPECIFIC PATTERNS OF DYSREGULATION. IN GENERAL, MRNA EXPRESSION WAS MOST FREQUENTLY ALTERED IN THE MALE HIPPOCAMPUS AND EFFECTS OF PRENATAL STRESS WERE MORE PREVALENT THAN EFFECTS OF NERVE INJURY IN BOTH SUPRASPINAL AREAS. THESE FINDINGS DEMONSTRATE THE IMPACT OF PRENATAL STRESS ON BEHAVIORAL SENSITIVITY TO A PAINFUL INJURY. CHANGES IN THE EXPRESSION OF EPIGENETIC- AND STRESS-RELATED GENES SUGGEST A POSSIBLE MECHANISM BY WHICH THE EARLY LIFE STRESS BECOMES EMBEDDED IN THE CENTRAL NERVOUS SYSTEM. INCREASED UNDERSTANDING OF THE INTERACTIONS AMONG EARLY-LIFE STRESS, SEX, AND PAIN MAY LEAD TO THE IDENTIFICATION OF NOVEL THERAPEUTIC TARGETS AND EPIGENETIC DRUGS FOR THE TREATMENT OF CHRONIC PAIN DISORDERS. 2020 15 5206 35 PRENATAL STRESS INDUCES LONG-TERM BEHAVIORAL SEX-DEPENDENT CHANGES IN RATS OFFSPRING: THE ROLE OF THE HPA AXIS AND EPIGENETICS. PRECLINICAL GENETIC STUDIES HAVE RELATED STRESS EARLY EXPOSURES WITH CHANGES IN GENE REGULATORY MECHANISMS, INCLUDING EPIGENETIC ALTERATIONS, SUCH AS MODIFICATIONS OF DNA METHYLATION, HISTONE DEACETYLATION, AND HISTONES ACETYLATION. THIS STUDY EVALUATES THE EFFECTS OF PRENATAL STRESS ON THE BEHAVIOR, HYPOTHALAMUS-PITUITARY-ADRENAL (HPA)-AXIS, AND EPIGENETIC PARAMETERS IN STRESSED DAMS AND THEIR OFFSPRING. THE RATS WERE SUBJECTED TO A PROTOCOL OF CHRONIC UNPREDICTABLE MILD STRESS ON THE FOURTEENTH DAY OF PREGNANCY UNTIL THE BIRTH OF OFFSPRING. AFTER BIRTH, MATERNAL CARE WAS EVALUATED FOR SIX DAYS. FOLLOWING WEANING, THE LOCOMOTOR AND DEPRESSIVE-LIKE BEHAVIORS OF THE DAMS AND THEIR OFFSPRING (60 DAYS OLD) WERE ASSESSED. THE HPA AXIS PARAMETERS WERE EVALUATED IN SERUM FROM DAMS AND OFFSPRING, AND EPIGENETIC PARAMETERS (HISTONE ACETYLTRANSFERASE (HAT), HISTONE DEACETYLASE (HDAC), DNA METHYLTRANSFERASE (DNMT) ACTIVITIES, AND THE LEVELS OF HISTONE H3 ACETYLATED AT LYSINE RESIDUE 9 (H3K9AC) AND HISTONE 3 ACETYLATED AT LYSINE RESIDUE 14 (H3K14AC)) WERE ASSESSED IN DAMS' AND OFFSPRING' BRAINS. PRENATAL STRESS DID NOT SIGNIFICANTLY INFLUENCE MATERNAL CARE; HOWEVER, IT INDUCED MANIC BEHAVIOR IN FEMALE OFFSPRING. THESE BEHAVIORAL ALTERATIONS IN THE OFFSPRING WERE ACCOMPANIED BY HYPERACTIVITY OF THE HPA-AXIS, EPIGENETIC ADAPTATIONS IN THE ACTIVITY OF HDAC AND DNMT, AND ACETYLATION IN THE HISTONES H3K9 AND H3K14. IN ADDITION, THE PRENATAL STRESSED FEMALE OFFSPRING SHOWED INCREASED LEVELS OF ACTH COMPARED TO THEIR MALE COUNTERPART. OUR FINDINGS REINFORCE THE IMPACT OF PRENATAL STRESS ON BEHAVIOR, STRESS RESPONSE, AND EPIGENETIC PROFILE OF OFFSPRING. 2023 16 5467 34 RESILIENT PHENOTYPE IN CHRONIC MILD STRESS PARADIGM IS ASSOCIATED WITH ALTERED EXPRESSION LEVELS OF MIR-18A-5P AND SEROTONIN 5-HT(1A) RECEPTOR IN DORSAL PART OF THE HIPPOCAMPUS. DISTURBED SEROTONERGIC SIGNALING IN THE HIPPOCAMPUS OBSERVED IN MANY INDIVIDUALS VULNERABLE TO STRESS HAS BEEN SUGGESTED AS ONE OF THE PRIMARY FACTORS CONTRIBUTING TO THE DEVELOPMENT OF DEPRESSION. HOWEVER, LITTLE IS KNOWN ABOUT THE PHYSIOLOGY OF THE BRAIN IN THE RESILIENT PHENOTYPE. RESILIENT SUBJECTS MAINTAIN A POSITIVE MOOD AND PSYCHOLOGICAL BALANCE DESPITE BEING UNDER THE STRESS INFLUENCE. IN OUR STUDY, WE GENERATED STRESS-VULNERABLE AND RESILIENT RATS BY USING A CHRONIC MILD STRESS (CMS) PARADIGM. USING DIFFERENT MOLECULAR APPROACHES, WE REVEALED THAT RESILIENT ANIMALS EXHIBITED A SIGNIFICANTLY DECREASED EXPRESSION LEVEL OF MIR-18A-5P AND, IN THE SAME TIME, AN ELEVATED LEVEL OF 5-HT1AR IN DORSAL, BUT NOT VENTRAL, PART OF THE HIPPOCAMPUS. DESCRIBED BIOCHEMICAL CHANGES WERE NOT OBSERVED IN ANIMALS BEHAVIORALLY VULNERABLE TO STRESS. FURTHER, IN VITRO ANALYSIS SHOWED THAT MIR-18A-5P MAY BE A NEGATIVE EPIGENETIC REGULATOR OF 5-HT1AR SINCE THE TREATMENT OF ADULT HIPPOCAMPAL NEURONS WITH MIR-18A-5P MIMIC SIGNIFICANTLY LOWERED THE EXPRESSION LEVEL OF MRNA ENCODING 5-HT1AR. MOREOVER, BIOINFORMATIC ANALYSIS OF POTENTIAL TARGET GENES EXPRESSED IN THE HIPPOCAMPUS AND BEING REGULATED BY MIR-18A-5P SHOWED THAT THIS MICRORNA MAY REGULATE BIOLOGICAL PROCESSES, SUCH AS AXONOGENESIS, WHICH ARE IMPORTANT IN THE FUNCTIONING OF THE HIPPOCAMPUS IN BOTH RATS AND HUMANS. ALL THESE MOLECULAR FEATURES MAY CONTRIBUTE TO SEROTONERGIC HOMEOSTATIC BALANCE AT THE LEVEL OF SEROTONIN TURNOVER OBSERVED IN HIPPOCAMPI OF RESILIENT BUT NOT STRESS-VULNERABLE RATS. DELINEATION OF FURTHER MOLECULAR AND BIOCHEMICAL MARKERS UNDERLYING RESILIENCE TO STRESS MAY CONTRIBUTE TO THE DEVELOPMENT OF NEW ANTIDEPRESSANT STRATEGIES WHICH WILL RESTORE RESILIENT PHENOTYPE IN DEPRESSED PATIENTS. 2019 17 219 34 ACUTE IMMOBILIZATION STRESS FOLLOWING CONTEXTUAL FEAR CONDITIONING REDUCES FEAR MEMORY: TIMING IS ESSENTIAL. BACKGROUND: HISTONE ACETYLATION IS REGULATED IN RESPONSE TO STRESS AND PLAYS AN IMPORTANT ROLE IN LEARNING AND MEMORY. CHRONIC STRESS IS KNOWN TO DETERIORATE COGNITION, WHEREAS ACUTE STRESS FACILITATES MEMORY FORMATION. HOWEVER, WHETHER ACUTE STRESS FACILITATES MEMORY FORMATION WHEN IT IS APPLIED AFTER FEAR STIMULATION IS NOT YET KNOWN. THEREFORE, THIS STUDY AIMED TO INVESTIGATE THE EFFECT OF ACUTE STRESS APPLIED AFTER FEAR TRAINING ON MEMORY FORMATION, MRNA EXPRESSION OF BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF), EPIGENETIC REGULATION OF BDNF EXPRESSION, AND CORTICOSTERONE LEVEL IN MICE IN VIVO. METHODS: MICE WERE SUBJECTED TO ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 OR 90 MIN AFTER CONTEXTUAL FEAR CONDITIONING TRAINING, AND ACETYLATION OF HISTONE 3 AT LYSINE 14 (H3K14) AND LEVEL OF CORTICOSTERONE WERE MEASURED USING WESTERN BLOT ANALYSIS AND ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), RESPECTIVELY. A FREEZING BEHAVIOR TEST WAS PERFORMED 24 H AFTER TRAINING, AND MRNA EXPRESSION OF BDNF WAS MEASURED USING REAL-TIME POLYMERASE CHAIN REACTIONS. DIFFERENT GROUPS OF MICE WERE USED FOR EACH TEST. RESULTS: FREEZING BEHAVIOR SIGNIFICANTLY DECREASED WITH THE DOWN-REGULATION OF BDNF MRNA EXPRESSION CAUSED BY ACUTE IMMOBILIZATION STRESS AT 60 MIN AFTER FEAR CONDITIONING TRAINING OWING TO THE REDUCTION OF H3K14 ACETYLATION. HOWEVER, BDNF MRNA EXPRESSION AND H3K14 ACETYLATION WERE NOT REDUCED IN ANIMALS SUBJECTED TO IMMOBILIZATION STRESS AT 90 MIN AFTER THE TRAINING. FURTHER, THE CORTICOSTERONE LEVEL WAS SIGNIFICANTLY HIGH IN MICE SUBJECTED TO IMMOBILIZATION STRESS AT 60 MIN AFTER THE TRAINING. CONCLUSION: ACUTE IMMOBILIZATION STRESS FOR 30 MIN AT 60 MIN AFTER FEAR CONDITIONING TRAINING IMPAIRED MEMORY FORMATION AND REDUCED BDNF MRNA EXPRESSION AND H3K14 ACETYLATION IN THE HIPPOCAMPUS OF MICE OWING TO THE HIGH LEVEL OF CORTICOSTERONE. 2016 18 3462 31 HYPOTHALAMIC NR3C1 DNA METHYLATION IN RATS EXPOSED TO PRENATAL STRESS. BACKGROUND: HUMAN AND ANIMAL STUDIES HAVE INDICATED THAT MATERNAL PRENATAL STRESS (PS) HAS MOLECULAR AND BEHAVIORAL EFFECTS DURING PREGNANCY AND EARLY LIFE. THE PRESENT STUDY AIMED TO EVALUATE THE EPIGENETIC CHANGES OF THE NR3C1 GENE INVOLVED IN THE HPA AXIS IN THE HYPOTHALAMIC TISSUES OF RATS EXPOSED TO PS INDUCED BY CHRONIC UNPREDICTABLE MILD STRESS (CUMS). BEHAVIORAL AND MOLECULAR EFFECTS OF THESE CHANGES ON THE NEXT GENERATION WERE ALSO ASSESSED. METHODS AND RESULTS: CUMS PROTOCOL WAS USED TO GENERATE STRESS IN PREGNANT WISTAR RATS. TO DETERMINE THE EFFECTS OF STRESS ON ANHEDONIA AND MOVEMENT, SUCROSE PREFERENCE TEST, FORCED SWIMMING TEST, AND OPEN FIELD TEST WERE PERFORMED. FOLLOWING THESE BEHAVIORAL EXPERIMENTS, BISULFITE SEQUENCING PCR FOR DNA METHYLATION LEVELS OF THE NR3C1 GENE, RT-QPCR FOR MRNA LEVELS, AND WESTERN BLOT TECHNIQUES FOR PROTEIN ANALYSIS WERE USED IN THE HYPOTHALAMIC TISSUE OF SACRIFICED RATS. DEPRESSION-LIKE BEHAVIORS WERE EVIDENT IN THE BEHAVIORAL TESTS OF STRESS-EXPOSED MOTHERS AND PUPS. IN PS-EXPOSED PUPS, HYPOTHALAMIC NR3C1 PROMOTER METHYLATION WAS HIGHER, AND NR3C1 MRNA LEVELS AND NR3C1 PROTEIN LEVELS WERE LOWER COMPARED WITH CONTROLS, REGARDLESS OF SEX. CONCLUSION: OUR RESULTS CONFIRM THE RELATIONSHIP BETWEEN PS AND EPIGENETIC CHANGES OF HPA AXIS-RELATED GENES AND SHOW THAT NR3C1 GENE METHYLATION STATUS IN PUPS IS SENSITIVE TO PS DURING PREGNANCY. ENVIRONMENTAL MATERNAL STRESS MAY HAVE TRANSGENERATIONAL EFFECTS THAT ARE POTENTIALLY ASSOCIATED WITH ADVERSE OUTCOMES IN THE PUPS. 2022 19 5818 30 STRESS AND TRAUMA: BDNF CONTROL OF DENDRITIC-SPINE FORMATION AND REGRESSION. CHRONIC RESTRAINT STRESS LEADS TO INCREASES IN BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA AND PROTEIN IN SOME REGIONS OF THE BRAIN, E.G. THE BASAL LATERAL AMYGDALA (BLA) BUT DECREASES IN OTHER REGIONS SUCH AS THE CA3 REGION OF THE HIPPOCAMPUS AND DENDRITIC SPINE DENSITY INCREASES OR DECREASES IN LINE WITH THESE CHANGES IN BDNF. GIVEN THE POWERFUL INFLUENCE THAT BDNF HAS ON DENDRITIC SPINE GROWTH, THESE OBSERVATIONS SUGGEST THAT THE FUNDAMENTAL REASON FOR THE DIRECTION AND EXTENT OF CHANGES IN DENDRITIC SPINE DENSITY IN A PARTICULAR REGION OF THE BRAIN UNDER STRESS IS DUE TO THE CHANGES IN BDNF THERE. THE MOST LIKELY CAUSE OF THESE CHANGES IS PROVIDED BY THE STRESS INITIATED RELEASE OF STEROIDS, WHICH READILY ENTER NEURONS AND ALTER GENE EXPRESSION, FOR EXAMPLE THAT OF BDNF. OF PARTICULAR INTEREST IS HOW GLUCOCORTICOIDS AND MINERALOCORTICOIDS TEND TO HAVE OPPOSITE EFFECTS ON BDNF GENE EXPRESSION OFFERING THE POSSIBILITY THAT DIFFERENCES IN THE DISTRIBUTION OF THEIR RECEPTORS AND OF THEIR DOWNSTREAM EFFECTS MIGHT PROVIDE A BASIS FOR THE DIFFERENTIAL TRANSCRIPTION OF THE BDNF GENES. ALTERNATIVELY, DIFFERENCES IN THE EXTENT OF METHYLATION AND ACETYLATION IN THE EPIGENETIC CONTROL OF BDNF TRANSCRIPTION ARE POSSIBLE IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS. ALTHOUGH PRESENT EVIDENCE POINTS TO CHANGES IN BDNF TRANSCRIPTION BEING THE MAJOR CAUSAL AGENT FOR THE CHANGES IN SPINE DENSITY IN DIFFERENT PARTS OF THE BRAIN FOLLOWING STRESS, STEROIDS HAVE SIGNIFICANT EFFECTS ON DOWNSTREAM PATHWAYS FROM THE TRKB RECEPTOR ONCE IT IS ACTED UPON BY BDNF, INCLUDING THOSE THAT MODULATE THE DENSITY OF DENDRITIC SPINES. FINALLY, ALTHOUGH GLUCOCORTICOIDS PLAY A CANONICAL ROLE IN DETERMINING BDNF MODULATION OF DENDRITIC SPINES, RECENT STUDIES HAVE SHOWN A ROLE FOR CORTICOTROPHIN RELEASING FACTOR (CRF) IN THIS REGARD. THERE IS CONSIDERABLE IMPROVEMENT IN THE EXTENT OF CHANGES IN SPINE SIZE AND DENSITY IN RODENTS WITH FOREBRAIN SPECIFIC KNOCKOUT OF CRF RECEPTOR 1 (CRFR1) EVEN WHEN THE GLUCOCORTICOID PATHWAYS ARE LEFT INTACT. IT SEEMS THEN THAT CRF DOES HAVE A ROLE TO PLAY IN DETERMINING BDNF CONTROL OF DENDRITIC SPINES. 2014 20 3177 29 H3K9ME2 REGULATION OF BDNF EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX IS INVOLVED IN THE DEPRESSIVE-LIKE PHENOTYPE INDUCED BY MATERNAL SEPARATION IN MALE RATS. BACKGROUND: EARLY LIFE STRESS (ELS) INDUCES A DEPRESSIVE-LIKE PHENOTYPE AND INCREASES THE RISK OF DEPRESSION. BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) HAS BEEN CONFIRMED TO BE INVOLVED IN THE PATHOPHYSIOLOGY OF DEPRESSION. HOWEVER, THE MECHANISM BY WHICH ELS ALTERS THE EPIGENETIC REGULATION OF BDNF AND CHANGES SUSCEPTIBILITY TO DEPRESSION HAS NOT BEEN FULLY CLARIFIED. METHODS: THE PRESENT STUDY USED MATERNAL SEPARATION (MS) AND CHRONIC UNPREDICTED MILD STRESS (CUMS) TO ESTABLISH AN MS ANIMAL MODEL AND A DEPRESSIVE ANIMAL MODEL. WE ASSESSED DEPRESSIVE-LIKE BEHAVIOURS, INCLUDING ANHEDONIA, LOCOMOTOR ACTIVITY, ANXIETY-LIKE BEHAVIOUR, AND SPATIAL MEMORY, USING THE SUCROSE PREFERENCE TEST, THE OPEN FIELD TEST, THE ELEVATED PLUS MAZE TEST, AND THE MORRIS WATER MAZE TEST. WE ALSO INVESTIGATED BDNF AND H3K9ME2 EXPRESSION IN THE HIPPOCAMPUS AND MEDIAL PREFRONTAL CORTEX (MPFC) BY IMMUNOHISTOCHEMISTRY, WESTERN BLOTTING, AND QPCR ANALYSIS. ADDITIONALLY, WE USED UNC0642, A SMALL MOLECULE INHIBITOR OF HISTONE METHYLTRANSFERASE (G9A), AS AN INTERVENTION. RESULTS: THE RESULTS SHOWED THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIOURS IN RATS AND RESULTED IN INCREASED H3K9ME2 EXPRESSION AND DECREASED BDNF EXPRESSION IN THE HIPPOCAMPUS AND MPFC. MORE IMPORTANTLY, ADULT MS RATS EXPERIENCING CUMS HAD MORE SEVERE DEPRESSIVE BEHAVIOURS, HAD HIGHER EXPRESSION OF H3K9ME2 IN THE HIPPOCAMPUS AND MPFC, AND HAD LOWER EXPRESSION OF BDNF IN THE HIPPOCAMPUS AND MPFC. IN ADDITION, ADMINISTRATION OF THE G9A INHIBITOR REVERSED MOST OF THE CHANGES. CONCLUSIONS: OUR STUDY SUGGESTS THAT ELS CHANGED BDNF AND H3K9ME2 EXPRESSION IN THE RAT BRAIN, RESULTING IN A DEPRESSIVE-LIKE PHENOTYPE. 2021