1 1548 197 DNA METHYLATION IN THE DEVELOPING HIPPOCAMPUS AND AMYGDALA OF ANXIETY-PRONE VERSUS RISK-TAKING RATS. ALL ORGANISMS EXHIBIT A WIDE RANGE OF EMOTIONAL BEHAVIORS AND INTERACT WITH THE ENVIRONMENT IN DIFFERENT WAYS. SOME INDIVIDUALS MAY BE MORE QUIET AND SHY WHEREAS OTHERS ARE MORE OUTGOING AND ADVENTUROUS. THESE TEMPERAMENTAL AND PERSONALITY DIFFERENCES CAN PREDISPOSE INDIVIDUALS TO CERTAIN PSYCHOPATHOLOGIES WHICH MAY BE INFLUENCED BY GENETIC VULNERABILITY AND/OR EARLY LIFE EXPERIENCES. RODENT MODELS CAN BE USED TO RECAPITULATE EMOTIONAL REACTIVITY DIFFERENCES, AND THESE MODELS CAN, IN TURN, BE USED TO EXAMINE POTENTIAL NEUROBIOLOGICAL UNDERPINNINGS OF THESE TRAITS. THE PRESENT STUDY UTILIZES TWO STRAINS OF RATS THAT WERE SELECTIVELY BRED FOR DIFFERENCES IN NOVELTY SEEKING. HIGH NOVELTY-RESPONDING (BHR) RATS ARE VERY ACTIVE IN RESPONSE TO NOVELTY, EXHIBIT EXAGGERATED RISK-TAKING, AGGRESSION, IMPULSIVITY, AND SHOW INCREASED BEHAVIORAL RESPONSE TO COCAINE. LOW NOVELTY-RESPONDING (BLR) RATS SHOW INCREASED ANXIETY, DEPRESSIVE BEHAVIOR AND VULNERABILITY TO CHRONIC STRESS. ONE WAY IN WHICH THE BHR VERSUS BLR BEHAVIORAL PHENOTYPES MAY DIFFER IS THROUGH EPIGENETIC MODIFICATION OF DNA. DNA CAN BE MODIFIED THROUGH PROCESSES SUCH AS ACETYLATION OR METHYLATION TO EITHER ENHANCE OR SUBDUE GENE EXPRESSION. THIS STUDY EXAMINES PUTATIVE DIFFERENCES IN METHYLATION LEVELS IN THE HIPPOCAMPUS AND AMYGDALA OF DEVELOPING BHR-BLR RATS. PREVIOUS RESEARCH OBSERVED WIDESPREAD GENE EXPRESSION DIFFERENCES IN THE BLR DEVELOPING HIPPOCAMPUS, AND THE CURRENT STUDY AIMS TO BEGIN TO EXAMINE POTENTIAL EPIGENETIC FACTORS THAT MAY CONTRIBUTE TO THOSE GENE DIFFERENCES. THE AMYGDALA WAS CHOSEN BECAUSE IT IS INVOLVED IN EMOTIONAL PROCESSES, IN PART THROUGH ITS CONNECTIONS WITH THE HIPPOCAMPUS. THEREFORE, THE PRESENT STUDY USED IN SITU HYBRIDIZATION TO ASSESS THE EXPRESSION OF DNA METHYLTRANSFERASE-1 (DNMT1) MRNA IN THE HIPPOCAMPUS, AMYGDALA AND SEVERAL OTHER BRAIN AREAS OF BHR AND BLR PUPS AT THREE DEVELOPMENTAL TIME POINTS: POSTNATAL DAYS (P) 7, 14, AND 21. WE FOCUSED ON THE FIRST 3 POSTNATAL WEEKS, IN PART TO PARALLEL OUR EARLY MICROARRAY GENE EXPRESSION WORK, AND BECAUSE THIS REPRESENTS A CRITICAL PERIOD OF BRAIN DEVELOPMENT, WHICH SHAPES INDIVIDUALS' LIFELONG EMOTIONAL AND STRESS REACTIVITY. WE FOUND SIGNIFICANT DIFFERENCES IN DENTATE GYRUS AND CA3 REGIONS OF THE HIPPOCAMPUS AT P7 WITH NO DIFFERENCES SEEN AT P14 OR P21. INTERESTINGLY, WE ALSO FOUND SIGNIFICANT BHR-BLR DNMT1 DIFFERENCES AT P7 WITHIN THE LATERAL, BASOLATERAL AND MEDIAL NUCLEI OF THE AMYGDALA, WITH NO DIFFERENCE AT P14 AND P21, SUGGESTING THAT THE FIRST POSTNATAL WEEK IS A CRITICAL PERIOD FOR DNA METHYLATION DURING BRAIN DEVELOPMENT. 2012 2 5873 47 SWEET SUCCESS, BITTER DEFEAT: A TASTE PHENOTYPE PREDICTS SOCIAL STATUS IN SELECTIVELY BRED RATS. FOR SOCIAL OMNIVORES SUCH AS RATS AND HUMANS, TASTE IS FAR MORE THAN A CHEMICAL SENSE ACTIVATED BY FOOD. BY VIRTUE OF EVOLUTIONARY AND EPIGENETIC ELABORATION, TASTE IS ASSOCIATED WITH NEGATIVE AFFECT, STRESS VULNERABILITY, RESPONSES TO PSYCHOACTIVE SUBSTANCES, PAIN, AND SOCIAL JUDGMENT. A CRUCIAL GAP IN THIS LITERATURE, WHICH SPANS BEHAVIOR GENETICS, AFFECTIVE AND SOCIAL NEUROSCIENCE, AND EMBODIED COGNITION, CONCERNS LINKS BETWEEN TASTE AND SOCIAL BEHAVIOR IN RATS. HERE WE SHOW THAT RATS SELECTIVELY BRED FOR LOW SACCHARIN INTAKE ARE SUBORDINATE TO HIGH-SACCHARIN-CONSUMING RATS WHEN THEY COMPETE IN WEIGHT-MATCHED DYADS FOR FOOD, A TASK USED TO MODEL DEPRESSION. STATISTICAL AND EXPERIMENTAL CONTROLS SUGGEST THAT DIFFERENTIAL RESOURCE UTILIZATION WITHIN DYADS IS NOT AN ARTIFACT OF INDIVIDUAL-LEVEL PROCESSES SUCH AS APPARATUS HABITUATION OR INGESTIVE MOTIVATION. TAIL SKIN TEMPERATURE MEASUREMENTS SHOWED THAT LOS RATS DISPLAY LARGER HYPERTHERMIC RESPONSES TO SOCIAL INTERACTION AFTER STATUS IS ESTABLISHED, EVIDENCE LINKING TASTE, SOCIAL STRESS, AUTONOMIC REACTIVITY, AND DEPRESSION-LIKE SYMPTOMS. BASED ON REGRESSION USING EARLY- AND LATE-COMPETITION PREDICTORS TO PREDICT DYADIC DISPARITY IN FINAL COMPETITION SCORES, WE TENTATIVELY SUGGEST THAT HIS RATS EMERGE AS DOMINANT BOTH BECAUSE OF AN "EARLY SURGE" ON THEIR PART AND BECAUSE LOS ACQUIESCE LATER. THESE FINDINGS SHOULD INVIGORATE THE COMPARATIVE STUDY OF INDIVIDUAL DIFFERENCES IN SOCIAL STATUS AND ITS RELATIONSHIP TO MENTAL AND PHYSICAL HEALTH. 2012 3 4924 37 PARENTAL HYPOXIC EXPOSURE CONFERS OFFSPRING HYPOXIA RESISTANCE IN ZEBRAFISH (DANIO RERIO). PARENTAL INFLUENCES ARE A POTENTIALLY IMPORTANT COMPONENT OF TRANSGENERATIONAL TRANSFER OF PHENOTYPE IN VERTEBRATES. THIS STUDY EXAMINED HOW CHRONIC HYPOXIC EXPOSURE ON ADULT ZEBRAFISH (DANIO RERIO) AFFECTED THE PHENOTYPE OF THEIR OFFSPRING. SEPARATE ADULT POPULATIONS WERE EXPOSED TO HYPOXIA (13.1 KPA O(2)) OR NORMOXIA (21.1 KPA O(2)) FOR PERIODS RANGING FROM 1 TO 12 WEEKS. ADULTS WERE THEN RETURNED TO NORMOXIA AND BRED WITHIN EXPERIMENTAL GROUPS. ADULT FECUNDITY AND EGG CHARACTERISTICS (VOLUME OF EGG, YOLK AND PERIVITELLINE FLUID) WERE ASSESSED. SUBSEQUENTLY, LARVAL BODY LENGTH, TIME TO LOSS OF EQUILIBRIUM IN SEVERE HYPOXIA (~4 KPA O(2)), AND CRITICAL THERMAL MINIMA (CT(MIN)) AND MAXIMA (CT(MAX)) WERE MEASURED AT 6, 9, 12, 15, 18, 21 AND 60 DAYS POST-FERTILIZATION (D.P.F.). ADULT FECUNDITY WAS DEPRESSED BY HYPOXIC EXPOSURE. EGG COMPONENT VOLUMES WERE ALSO DEPRESSED IN ADULTS EXPOSED TO 1-2 WEEKS OF HYPOXIA, BUT RETURNED TO CONTROL LEVELS FOLLOWING LONGER HYPOXIC EXPOSURE. ADULT HYPOXIC EXPOSURES OF >1 WEEK RESULTED IN LONGER BODY LENGTHS IN THEIR LARVAL OFFSPRING. TIME TO LOSS OF EQUILIBRIUM IN SEVERE HYPOXIA (I.E. HYPOXIC RESISTANCE) IN CONTROL LARVAE DECREASED FROM 6 TO 12 D.P.F., REMAINING CONSTANT THEREAFTER. NOTABLY, HYPOXIC RESISTANCE FROM 6 TO 18 D.P.F. WAS ~15% LOWER IN LARVAE WHOSE PARENTS WERE EXPOSED TO JUST 1 WEEK OF CHRONIC HYPOXIA, BUT RESISTANCE WAS SIGNIFICANTLY INCREASED BY ~24-30% IN 6-18 D.P.F. LARVAE FROM ADULTS EXPOSED TO 2, 3 OR 4 WEEKS OF HYPOXIA. CT(MIN) (~10-12 DEGREES C) AND CT(MAX) (~39.5 DEGREES C) WERE UNCHANGED BY PARENTAL HYPOXIC EXPOSURE. THIS STUDY DEMONSTRATES THAT PARENTAL HYPOXIC EXPOSURE IN ADULT ZEBRAFISH HAS PROFOUND EPIGENETIC EFFECTS ON THE MORPHOLOGICAL AND PHYSIOLOGICAL PHENOTYPE OF THEIR OFFSPRING. 2012 4 4949 36 PATERNAL TRANSMISSION OF STRESS-INDUCED PATHOLOGIES. BACKGROUND: THERE HAS BEEN RECENT INTEREST IN THE POSSIBILITY THAT EPIGENETIC MECHANISMS MIGHT CONTRIBUTE TO THE TRANSGENERATIONAL TRANSMISSION OF STRESS-INDUCED VULNERABILITY. HERE, WE FOCUSED ON POSSIBLE PATERNAL TRANSMISSION WITH THE SOCIAL DEFEAT STRESS PARADIGM. METHODS: ADULT MALE MICE EXPOSED TO CHRONIC SOCIAL DEFEAT STRESS OR CONTROL NONDEFEATED MICE WERE BRED WITH NORMAL FEMALE MICE, AND THEIR OFFSPRING WERE ASSESSED BEHAVIORALLY FOR DEPRESSIVE- AND ANXIETY-LIKE MEASURES. PLASMA LEVELS OF CORTICOSTERONE AND VASCULAR ENDOTHELIAL GROWTH FACTOR WERE ALSO ASSAYED. TO DIRECTLY ASSESS THE ROLE OF EPIGENETIC MECHANISMS, WE USED IN VITRO FERTILIZATION (IVF); BEHAVIORAL ASSESSMENTS WERE CONDUCTED ON OFFSPRING OF MICE FROM IVF-CONTROL AND IVF-DEFEATED FATHERS. RESULTS: WE SHOW THAT BOTH MALE AND FEMALE OFFSPRING FROM DEFEATED FATHERS EXHIBIT INCREASED MEASURES OF SEVERAL DEPRESSION- AND ANXIETY-LIKE BEHAVIORS. THE MALE OFFSPRING OF DEFEATED FATHERS ALSO DISPLAY INCREASED BASELINE PLASMA LEVELS OF CORTICOSTERONE AND DECREASED LEVELS OF VASCULAR ENDOTHELIAL GROWTH FACTOR. HOWEVER, MOST OF THESE BEHAVIORAL CHANGES WERE NOT OBSERVED WHEN OFFSPRING WERE GENERATED THROUGH IVF. CONCLUSIONS: THESE RESULTS SUGGEST THAT, ALTHOUGH BEHAVIORAL ADAPTATIONS THAT OCCUR AFTER CHRONIC SOCIAL DEFEAT STRESS CAN BE TRANSMITTED FROM THE FATHER TO HIS MALE AND FEMALE F1 PROGENY, ONLY VERY SUBTLE CHANGES MIGHT BE TRANSMITTED EPIGENETICALLY UNDER THE CONDITIONS TESTED. 2011 5 611 43 BIDIRECTIONAL RESCUE OF EXTREME GENETIC PREDISPOSITIONS TO ANXIETY: IMPACT OF CRH RECEPTOR 1 AS EPIGENETIC PLASTICITY GENE IN THE AMYGDALA. THE CONTINUUM OF PHYSIOLOGICAL ANXIETY UP TO PSYCHOPATHOLOGY IS NOT MERELY DEPENDENT ON GENES, BUT IS ORCHESTRATED BY THE INTERPLAY OF GENETIC PREDISPOSITION, GENE X ENVIRONMENT AND EPIGENETIC INTERACTIONS. ACCORDINGLY, INBORN ANXIETY IS CONSIDERED A POLYGENIC, MULTIFACTORIAL TRAIT, LIKELY TO BE SHAPED BY ENVIRONMENTALLY DRIVEN PLASTICITY AT THE GENOMIC LEVEL. WE HERE TOOK ADVANTAGE OF THE EXTREME GENETIC PREDISPOSITION OF THE SELECTIVELY BRED HIGH (HAB) AND LOW ANXIETY (LAB) MOUSE MODEL EXHIBITING HIGH VS LOW ANXIETY-RELATED BEHAVIOR AND TESTED WHETHER AND HOW BENEFICIAL (ENRICHED ENVIRONMENT) VS DETRIMENTAL (CHRONIC MILD STRESS) ENVIRONMENTAL MANIPULATIONS ARE CAPABLE OF RESCUING PHENOTYPES FROM BOTH ENDS OF THE ANXIETY CONTINUUM. WE PROVIDE EVIDENCE THAT (I) EVEN INBORN AND SEEMINGLY RIGID BEHAVIORAL AND NEUROENDOCRINE PHENOTYPES CAN BIDIRECTIONALLY BE RESCUED BY APPROPRIATE ENVIRONMENTAL STIMULI, (II) CORTICOTROPIN-RELEASING HORMONE RECEPTOR 1 (CRHR1), CRITICALLY INVOLVED IN TRAIT ANXIETY, SHOWS BIDIRECTIONAL ALTERATIONS IN ITS EXPRESSION IN THE BASOLATERAL AMYGDALA (BLA) UPON ENVIRONMENTAL STIMULATION, (III) THESE ALTERATIONS ARE LINKED TO AN INCREASED METHYLATION STATUS OF ITS PROMOTER AND, FINALLY, (IV) BINDING OF THE TRANSCRIPTION FACTOR YIN YANG 1 (YY1) TO THE CRHR1 PROMOTER CONTRIBUTES TO ITS GENE EXPRESSION IN A METHYLATION-SENSITIVE MANNER. THUS, CRHR1 IN THE BLA IS CRITICALLY INVOLVED AS PLASTICITY GENE IN THE BIDIRECTIONAL EPIGENETIC RESCUE OF EXTREMES IN TRAIT ANXIETY. 2014 6 5465 61 RESILIENCE TO STRESS: LESSONS FROM RODENTS ABOUT NATURE VERSUS NURTURE. INDIVIDUAL DIFFERENCES IN HUMAN TEMPERAMENT INFLUENCE HOW WE RESPOND TO STRESS AND CAN CONFER VULNERABILITY (OR RESILIENCE) TO EMOTIONAL DISORDERS. FOR EXAMPLE, HIGH LEVELS OF BEHAVIORAL INHIBITION IN CHILDREN PREDICT INCREASED RISK OF MOOD AND ANXIETY DISORDERS IN LATER LIFE. THE BIOLOGICAL UNDERPINNINGS OF TEMPERAMENT ARE UNKNOWN, ALTHOUGH IMPROVED UNDERSTANDING CAN OFFER INSIGHT INTO THE PATHOGENESIS OF EMOTIONAL DISORDERS. OUR LABORATORY HAS USED A RAT MODEL OF TEMPERAMENTAL DIFFERENCES TO STUDY NEURODEVELOPMENTAL FACTORS THAT LEAD TO A HIGHLY INHIBITED, STRESS VULNERABLE PHENOTYPE. SELECTIVE BREEDING FOR HIGH VERSUS LOW BEHAVIORAL RESPONSE TO NOVELTY CREATED TWO RAT STRAINS THAT EXHIBIT DRAMATIC BEHAVIOR DIFFERENCES OVER MULTIPLE DOMAINS RELEVANT TO EMOTIONAL DISORDERS. LOW NOVELTY RESPONDER (BLR) RATS EXHIBIT HIGH LEVELS OF BEHAVIORAL INHIBITION, PASSIVE STRESS COPING, ANHEDONIA, DECREASED SOCIABILITY AND VULNERABILITY TO CHRONIC STRESS COMPARED TO HIGH NOVELTY RESPONDERS (BHRS). ON THE OTHER HAND, BHRS EXHIBIT HIGH LEVELS OF BEHAVIORAL DIS-INHIBITION, ACTIVE COPING, AND AGGRESSION. THIS REVIEW ARTICLE SUMMARIZES OUR WORK WITH THE BHR/BLR MODEL SHOWING THE DEVELOPMENTAL EMERGENCE OF THE BHR/BLR PHENOTYPES, THE ROLE THE ENVIRONMENT PLAYS IN SHAPING IT, AND THE INVOLVEMENT OF EPIGENETIC PROCESSES SUCH AS DNA METHYLATION THAT MEDIATE DIFFERENCES IN EMOTIONALITY AND STRESS REACTIVITY. 2022 7 879 33 CHRONIC CHEMOGENETIC STIMULATION OF THE NUCLEUS ACCUMBENS PRODUCES LASTING REDUCTIONS IN BINGE DRINKING AND AMELIORATES ALCOHOL-RELATED MORPHOLOGICAL AND TRANSCRIPTIONAL CHANGES. BINGE DRINKING IS A DANGEROUS PATTERN OF BEHAVIOR. WE TESTED WHETHER CHRONICALLY MANIPULATING NUCLEUS ACCUMBENS (NAC) ACTIVITY (VIA CLOZAPINE-N-OXIDE (CNO) AND DESIGNER RECEPTORS EXCLUSIVELY ACTIVATED BY DESIGNER DRUGS (DREADD)) COULD PRODUCE LASTING EFFECTS ON ETHANOL BINGE-LIKE DRINKING IN MICE SELECTIVELY BRED TO DRINK TO INTOXICATION. WE FOUND CHRONICALLY INCREASING NAC ACTIVITY (4 WEEKS, VIA CNO AND THE EXCITATORY DREADD, HM3DQ) DECREASED BINGE-LIKE DRINKING, BUT DID NOT OBSERVE CNO-INDUCED CHANGES IN DRINKING WITH THE INHIBITORY DREADD, HM4DI. THE CNO/HM3DQ-INDUCED REDUCTION IN ETHANOL DRINKING PERSISTED FOR AT LEAST ONE WEEK, SUGGESTING ADAPTIVE NEUROPLASTICITY VIA TRANSCRIPTIONAL AND EPIGENETIC MECHANISMS. THEREFORE, WE DEFINED THIS PLASTICITY AT THE MORPHOLOGICAL AND TRANSCRIPTOMIC LEVELS. WE FOUND THAT CHRONIC BINGE DRINKING (6 WEEKS) ALTERED NEURONAL MORPHOLOGY IN THE NAC, AN EFFECT THAT WAS AMELIORATED WITH CNO/HM3DQ. MOREOVER, WE DETECTED SIGNIFICANT CHANGES IN EXPRESSION OF SEVERAL PLASTICITY-RELATED GENES WITH BINGE DRINKING THAT WERE AMELIORATED WITH CNO TREATMENT (E.G., HDAC4). LASTLY, WE FOUND THAT LMK235, AN HDAC4/5 INHIBITOR, REDUCED BINGE-LIKE DRINKING. THUS, WE WERE ABLE TO TARGET SPECIFIC MOLECULAR PATHWAYS USING PHARMACOLOGY TO MIMIC THE BEHAVIORAL EFFECTS OF DREADDS. 2020 8 1005 51 CHRONIC VARIABLE PHYSICAL STRESS DURING THE PERIPUBERTAL-JUVENILE PERIOD CAUSES DIFFERENTIAL DEPRESSIVE AND ANXIOGENIC EFFECTS IN THE NOVELTY-SEEKING PHENOTYPE: FUNCTIONAL IMPLICATIONS FOR HIPPOCAMPAL AND AMYGDALAR BRAIN-DERIVED NEUROTROPHIC FACTOR AND THE MOSSY FIBRE PLASTICITY. EXPERIMENTALLY NAIVE RATS SHOW VARIANCE IN THEIR LOCOMOTOR REACTIVITY TO NOVELTY, SOME DISPLAYING HIGHER (HR) WHILE OTHERS DISPLAYING LOWER (LR) REACTIVITY, ASSOCIATED WITH VULNERABILITY TO STRESS. WE EMPLOYED A CHRONIC VARIABLE PHYSICAL STRESS REGIMEN INCORPORATING INTERMITTENT AND RANDOM EXPOSURES OF PHYSICAL STRESSORS OR CONTROL HANDLING DURING THE PERIPUBERTAL-JUVENILE PERIOD TO ASSESS INTERACTIONS BETWEEN STRESS AND THE LRHR PHENOTYPE IN DEPRESSIVE- AND ANXIETY-LIKE BEHAVIORS ON THE FORCED SWIM AND SOCIAL INTERACTION TESTS, RESPECTIVELY. A DECREASE IN IMMOBILITY IN THE FORCED SWIM TEST ALONG WITH A DECREASE IN SOCIAL CONTACT IN THE SOCIAL INTERACTION TEST WERE OBSERVED IN THE JUVENILE HRS, COUPLED WITH INCREASES IN BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) MRNA IN THE HIPPOCAMPUS AND IN THE BASOLATERAL AMYGDALA WITH CHRONIC VARIABLE PHYSICAL STRESS. IN CONTRAST, AN INCREASE IN IMMOBILITY IN THE FORCED SWIM TEST AND A DECREASE IN SOCIAL CONTACT WAS OBSERVED IN THE LR COUNTERPARTS COUPLED WITH AN INCREASE IN THE BDNF MRNA IN THE BASOLATERAL AMYGDALA FOLLOWING CHRONIC VARIABLE PHYSICAL STRESS. FURTHERMORE, CHRONIC PHYSICAL STRESS LED TO INCREASED H3 AND H4 ACETYLATION AT THE P2 AND P4 PROMOTERS OF THE HIPPOCAMPAL BDNF GENE IN THE HR RATS THAT IS ASSOCIATED WITH INCREASED SUPRAPYRAMIDAL MOSSY FIBRE (SP-MF) TERMINAL FIELD VOLUME. IN CONTRAST, CHRONIC VARIABLE PHYSICAL STRESS LED TO DECREASED H4 ACETYLATION AT THE P4 PROMOTER, ASSOCIATED WITH DECREASED SP-MF VOLUME IN THE LR RATS. THESE FINDINGS SHOW DISSOCIATION IN DEPRESSIVE- AND ANXIETY-LIKE BEHAVIORS FOLLOWING CHRONIC VARIABLE PHYSICAL STRESS IN THE JUVENILE HR ANIMALS THAT MAY BE MEDIATED BY INCREASED LEVELS OF BDNF IN THE HIPPOCAMPUS AND IN THE AMYGDALA, RESPECTIVELY. MOREOVER, CHRONIC VARIABLE PHYSICAL STRESS DURING THE PERIPUBERTAL-JUVENILE PERIOD RESULTS IN OPPOSITE EFFECTS IN DEPRESSIVE-LIKE BEHAVIOR IN THE LRHR RATS BY WAY OF INDUCING DIFFERENTIAL EPIGENETIC REGULATION OF THE HIPPOCAMPAL BDNF GENE THAT, IN TURN, MAY MEDIATE MOSSY FIBRE SPROUTING. 2011 9 4939 38 PATERNAL NICOTINE EXPOSURE IN RATS PRODUCES LONG-LASTING NEUROBEHAVIORAL EFFECTS IN THE OFFSPRING. STUDIES OF INTERGENERATIONAL EFFECTS OF PARENTAL CHEMICAL EXPOSURE HAVE PRINCIPALLY FOCUSED ON MATERNAL EXPOSURE, PARTICULARLY FOR STUDIES OF ADVERSE NEUROBEHAVIORAL CONSEQUENCES ON THE OFFSPRING. MATERNAL NICOTINE EXPOSURE HAS LONG BEEN KNOWN TO CAUSE ADVERSE NEUROBEHAVIORAL EFFECTS ON THE OFFSPRING. HOWEVER, PATERNAL TOXICANT EXPOSURE HAS ALSO BEEN FOUND TO CAUSE NEUROBEHAVIORAL TOXICITY IN THEIR OFFSPRING. RECENT WORK SUGGESTS THAT PATERNAL NICOTINE EXPOSURE CAN HAVE EPIGENETIC EFFECTS, ALTHOUGH IT REMAINS UNCLEAR WHETHER SUCH CHANGES LEAD TO NEUROBEHAVIORAL EFFECTS. IN THE CURRENT STUDY, WE INVESTIGATED THE EFFECTS OF PATERNAL NICOTINE EXPOSURE ON NEUROBEHAVIORAL DEVELOPMENT OF THEIR OFFSPRING. MALE SPRAGUE-DAWLEY RATS WERE EXPOSED TO 0 OR 2 MG/KG/DAY NICOTINE (SC) FOR 56 CONSECUTIVE DAYS WITH TWO CONSECUTIVE 2ML4 OSMOTIC MINIPUMPS. FOLLOWING TREATMENT, THESE MALES WERE MATED WITH DRUG-NAIVE FEMALE RATS. OFFSPRING OF BOTH SEXES WERE TESTED IN A BEHAVIORAL BATTERY TO ASSESS LOCOMOTION, EMOTIONAL FUNCTION AND COGNITION. PATERNAL NICOTINE EXPOSURE DID NOT IMPACT OFFSPRING VIABILITY, HEALTH OR GROWTH. HOWEVER, BEHAVIORAL FUNCTION OF THE OFFSPRING WAS SIGNIFICANTLY ALTERED BY PATERNAL NICOTINE EXPOSURE. MALE OFFSPRING WITH PATERNAL NICOTINE EXPOSURE EXHIBITED LOCOMOTOR HYPERACTIVITY IN THE FIGURE-8 APPARATUS WHEN TESTED DURING ADOLESCENCE. WHEN RETESTED IN ADULTHOOD AND REGARDLESS OF SEX, OFFSPRING OF THE NICOTINE EXPOSED FATHER SHOWED SIGNIFICANTLY REDUCED HABITUATION OF LOCOMOTOR ACTIVITY OVER THE COURSE OF THE SESSION. COMPARED TO CONTROLS, FEMALE OFFSPRING OF NICOTINE-EXPOSED FATHERS SHOWED SIGNIFICANTLY REDUCED RESPONSE LATENCY IN THE RADIAL ARM MAZE TEST. IN ADDITION TO LOCOMOTOR HYPERACTIVITY, THE OFFSPRING OF NICOTINE-EXPOSED FATHERS ALSO SHOWED SIGNIFICANTLY DIMINISHED HABITUATION IN THE NOVEL OBJECT RECOGNITION TEST. THESE RESULTS INDICATE THAT CHRONIC PATERNAL NICOTINE EXPOSURE CAN IMPACT THE BEHAVIOR OF OFFSPRING, PRODUCING LOCOMOTOR HYPERACTIVITY AND IMPAIRED HABITUATION. 2019 10 1803 22 EFFECT OF PROLONGED EMOTIONAL AND PAIN STRESS ON THE CONTENT OF METHYLCYTOSINE-BINDING PROTEIN MECP2 IN NUCLEI OF HIPPOCAMPAL NEURONS IN RATS WITH DIFFERENT EXCITABILITY OF THE NERVOUS SYSTEM. IN RATS WITH LOW EXCITABILITY THRESHOLD OF THE NERVOUS SYSTEM DEMONSTRATING SIGNIFICANT AND PERSISTENT BEHAVIORAL DISORDERS UNDER STRESS CONDITIONS, THE CONTENT OF METHYLCYTOSINE-BINDING PROTEIN MECP2 IN NEURONAL NUCLEI OF HIPPOCAMPAL FIELD CA3 DECREASED OVER 2 WEEKS AFTER LONG-TERM EMOTIONAL AND PAIN STRESS. IT WAS HYPOTHESIZED THAT PROTEIN MECP2 TRIGGERS EPIGENETIC CHANGES IN DNA THAT UNDERLIE "STRESS MEMORY". 2006 11 6551 49 TRANSGENERATIONAL BLUNTING OF MORPHINE-INDUCED CORTICOSTERONE SECRETION IS ASSOCIATED WITH DYSREGULATED GENE EXPRESSION IN MALE OFFSPRING. A NUMBER OF PARENTAL EXPERIENCES, EVEN WHEN OCCURRING PRIOR TO CONCEPTION, HAVE BEEN SHOWN TO INDUCE TRANSGENERATIONAL EFFECTS BEYOND THE FIRST GENERATION. IN THE CASE OF EXPOSURE TO DRUGS OF ABUSE, STUDIES IN RODENTS SUGGEST THAT OFFSPRING DEMONSTRATE SIGNIFICANT DIFFERENCES IN HOW THEY RESPOND TO THE DRUG TO WHICH THEIR PARENT WAS EXPOSED. WE HAVE PREVIOUSLY OBSERVED SIGNIFICANT ALTERATIONS IN MORPHINE ANALGESIA, CONDITIONED PLACE PREFERENCE AND SELF-ADMINISTRATION IN THE OFFSPRING OF FEMALES EXPOSED TO MORPHINE DURING ADOLESCENT DEVELOPMENT. IN ADDITION TO EFFECTS ON PAIN PERCEPTION AND REWARD, MORPHINE ALSO MODULATES THE HYPOTHALAMIC PITUITARY ADRENAL (HPA) AXIS. THE PURPOSE OF THE CURRENT STUDY WAS TO DETERMINE WHETHER FEMALE ADOLESCENT MORPHINE EXPOSURE RESULTS IN TRANSGENERATIONAL EFFECTS ON REGULATION OF THE HPA AXIS BY MORPHINE IN FUTURE GENERATIONS. ADOLESCENT MORPHINE WAS ADMINISTERED TO FEMALE SPRAGUE DAWLEY RATS USING A 10 DAY, ESCALATING DOSE REGIMEN OF MORPHINE (5-25 MG/KG; FROM 30 TO 39 DAYS OF AGE). CONTROL ANIMALS RECEIVED SALINE. BOTH SALINE AND MORPHINE EXPOSED FEMALES (SAL-F0 AND MOR-F0, RESPECTIVELY) WERE MATED WITH DRUG NAIVE MALES BEGINNING AT LEAST 3 WEEKS AFTER THE FINAL INJECTION. PLASMA CORTICOSTERONE LEVELS WERE MEASURED IN MALE AND FEMALE OFFSPRING (F1) DURING ADULTHOOD FOLLOWING 0, 0.1, OR 10 MG/KG MORPHINE. IN ADDITION, EXPRESSION OF CORTICOTROPIN RELEASING HORMONE (CRH) AND MU OPIOID RECEPTOR (OPRM1) IN THE PARAVENTRICULAR NUCLEUS (PVN) WERE MEASURED USING QUANTITATIVE PCR. MOR-F1 MALES, BUT NOT FEMALES, HAD BLUNTED MORPHINE-INDUCED CORTICOSTERONE SECRETION. THIS EFFECT WAS SPECIFIC TO OFFSPRING FROM FEMALES EXPOSED TO MORPHINE DURING ADOLESCENCE AS THOSE EXPOSED DURING ADULTHOOD PRODUCED OFFSPRING IN WHICH THE EFFECT WAS ABSENT. IN ADDITION, MOR-F1 MALES HAD SIGNIFICANTLY LOWER LEVELS OF PVN CRH FOLLOWING SALINE. THESE EFFECTS WERE NOT DRIVEN BY PVN OPRM1 IN THE F1 MALES AS THERE WERE NO DIFFERENCES BASED ON MATERNAL ADOLESCENT EXPOSURE. TO DETERMINE THE PERSISTENCE OF THE BLUNTED MORPHINE-INDUCED CORTICOSTERONE EFFECT, SAL-F2 AND MOR-F2 MALES WERE EXAMINED. BLUNTED MORPHINE-INDUCED CORTICOSTERONE SECRETION EXTENDED INTO THE MOR-F2 GENERATION, AS WELL AS EFFECTS ON CRH. IN ADDITION, THERE WAS ADDITIONAL DYSREGULATION OFOPRM1 EXPRESSION IN THE PVN IN MOR-F2 COMPARED WITH SAL-F2 MALES. THESE FINDINGS SUGGEST THAT SEX-SPECIFIC ALTERATIONS IN OPIOID-MEDIATED REGULATION OF THE HPA AXIS ARE TRANSGENERATIONALLY TRANSMITTED FOR AT LEAST TWO GENERATIONS FOLLOWING FEMALE ADOLESCENT MORPHINE EXPOSURE. THESE EFFECTS MAY PLAY A ROLE IN THE PREVIOUSLY OBSERVED CHANGES IN MORPHINE ANALGESIA AND REWARD-RELATED BEHAVIORS OBSERVED IN THIS PHENOTYPE. IN ADDITION, ALTERATIONS IN HPA FUNCTIONING SUCH AS THESE MAY PLAY A BROAD ROLE IN TRANSGENERATIONAL EPIGENETIC TRANSMISSION. 2018 12 4944 30 PATERNAL PRECONCEPTION ETHANOL EXPOSURE BLUNTS HYPOTHALAMIC-PITUITARY-ADRENAL AXIS RESPONSIVITY AND STRESS-INDUCED EXCESSIVE FLUID INTAKE IN MALE MICE. A GROWING NUMBER OF ENVIRONMENTAL INSULTS HAVE BEEN SHOWN TO INDUCE EPIGENETIC EFFECTS THAT PERSIST ACROSS GENERATIONS. FOR INSTANCE, PATERNAL PRECONCEPTION EXPOSURES TO ETHANOL OR STRESS HAVE INDEPENDENTLY BEEN SHOWN TO EXERT SUCH INTERGENERATIONAL EFFECTS. SINCE ETHANOL EXPOSURE IS A PHYSIOLOGICAL STRESSOR THAT ACTIVATES THE HYPOTHALAMIC-PITUITARY-ADRENAL (HPA) AXIS, WE HYPOTHESIZED THAT PATERNAL ETHANOL EXPOSURE WOULD IMPACT STRESS RESPONSIVITY OF OFFSPRING. ADULT MALE MICE WERE EXPOSED TO CHRONIC INTERMITTENT VAPOR ETHANOL OR CONTROL CONDITIONS FOR 5 WEEKS BEFORE BEING MATED WITH ETHANOL-NAIVE FEMALES TO PRODUCE ETHANOL (E)- AND CONTROL (C)-SIRED OFFSPRING. ADULT MALE AND FEMALE OFFSPRING WERE TESTED FOR PLASMA CORTICOSTERONE (CORT) LEVELS FOLLOWING ACUTE RESTRAINT STRESS AND THE MALE OFFSPRING WERE FURTHER EXAMINED FOR STRESS-EVOKED 2-BOTTLE CHOICE ETHANOL-DRINKING. PATERNAL ETHANOL EXPOSURE BLUNTED PLASMA CORT LEVELS FOLLOWING ACUTE RESTRAINT STRESS SELECTIVELY IN MALE OFFSPRING; FEMALES WERE UNAFFECTED. IN A STRESS-EVOKED ETHANOL-DRINKING ASSAY, THERE WAS NO EFFECT OF STRESS ON ETHANOL CONSUMPTION. HOWEVER, C-SIRED MALES EXHIBITED INCREASED TOTAL FLUID INTAKE (POLYDIPSIA) IN RESPONSE TO STRESS WHILE E-SIRED MALES WERE RESISTANT TO THIS STRESS-INDUCED PHENOTYPE. TAKEN TOGETHER, THESE DATA SUGGEST THAT PATERNAL ETHANOL EXPOSURE IMPARTS STRESS HYPORESPONSIVITY TO MALE OFFSPRING. 2016 13 6108 39 THE ENRICHED ENVIRONMENT AMELIORATES CHRONIC UNPREDICTABLE MILD STRESS-INDUCED DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE IMPAIRMENT BY ACTIVATING THE SIRT1/MIR-134 SIGNALING PATHWAY IN HIPPOCAMPUS. BACKGROUND: CHRONIC UNPREDICTABLE MILD STRESS (CUMS) IS AN IMPORTANT RISK FACTOR FOR DEPRESSION AND COGNITIVE DEFICITS IN HUMANS. ENRICHED ENVIRONMENT (EE) SHOWED A BENEFICIAL EFFECT ON DEPRESSION AND COGNITION BY ENHANCING BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) EXPRESSION AND SYNAPTIC PLASTICITY. HOWEVER, IT IS STILL NOT CLEARLY UNDERSTOOD WHETHER AN EPIGENETIC MECHANISM IS INVOLVED IN THE BDNF MODULATION AND SYNAPTIC PLASTICITY THAT OCCURS AFTER EE TREATMENT FOR THE DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS ELICITED BY CUMS. IN THIS STUDY, WE INVESTIGATED THE POSSIBLE MECHANISM OF THE NEUROPROTECTIVE EFFECT OF EE. METHODS: ALL RATS WERE EXPOSED TO THE 5-WEEK CUMS PROCEDURE EXCEPT THE CONTROL GROUP. AFTER CUMS PROCEDURE, SOME RATS WERE STEREOTAXICALLY INJECTED WITH SIRT1 PHARMACOLOGIC INHIBITOR EX527 OR SIRT1 KNOCKING DOWN LENTIVIRUS (SH-SIRT1) IN THE HIPPOCAMPUS FOLLOWED BY EE TREATMENT FOR 3 WEEKS. OTHER RATS WERE DIRECTLY SUBJECTED TO EE TREATMENT WITHOUT STEREOTAXIC INJECTION. BEHAVIORAL TESTS WERE USED TO APPRAISE DEPRESSION AND COGNITION AFTER EE TREATMENT. THEN EPIGENETIC MOLECULES, SYNAPTIC PROTEINS, DENDRITIC SPINE DENSITY AND BRANCHES, AND SYNAPTIC MORPHOLOGY OF THE DORSAL HIPPOCAMPUS WERE DETERMINED. RESULTS: WE FOUND THAT CUMS INDUCED DEPRESSIVE-LIKE BEHAVIORS INCLUDING DECREASED SUCROSE PREFERENCE RATIO, PROLONGED IMMOBILITY AND REDUCED LOCOMOTOR AND EXPLORATORY ACTIVITY; COGNITIVE DEFICITS INCLUDING SPATIAL LEARNING AND MEMORY IMPAIRMENT; REDUCED DENDRITIC SPINE DENSITY AND NUMBER OF BRANCHES; THINNED POSTSYNAPTIC DENSITY; DOWNREGULATED SIRT1/MICRORNA-134 PATHWAY, DECREASED BDNF AND SYNAPTIC PROTEINS INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95) EXPRESSION IN THE HIPPOCAMPUS. HOWEVER, THE CUMS-INDUCED DEPRESSIVE-LIKE BEHAVIORS, COGNITIVE DEFICITS, DENDRITIC SPINE DENSITY AND BRANCH NUMBER REDUCTION, POSTSYNAPTIC DENSITY THINNING, SIRT1/MICRORNA-134 PATHWAY DOWNREGULATION, BDNF AND SYNAPTIC PROTEINS REDUCTION, INCLUDING SYNAPTOPHYSIN (SYN) AND POSTSYNAPTIC DENSITY PROTEIN 95 (PSD95), WERE REVERSED BY EE TREATMENT. HOWEVER, DEPRESSIVE-LIKE BEHAVIORS AND COGNITIVE DEFICITS WERE OBSERVED AGAIN IN RATS SUBJECTED TO STEREOTAXIC INJECTION WITH EX527 OR SH-SIRT1. FURTHERMORE, THIS STUDY ALSO FOUND THAT SIRT1/MICRORNA-134 REGULATES THE DOWNSTREAM MOLECULES BDNF, AND THE SYNAPTIC PROTEINS SYN AND PSD95 IN PRIMARY CULTURED HIPPOCAMPAL NEURONS. CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE FOR THE NEUROPROTECTIVE ROLE OF EE ON DEPRESSION AND COGNITIVE DEFICITS BY ACTIVATING THE SIRT1/MICRORNA-134 PATHWAY, WHICH ACCOUNTS FOR THE REGULATION OF SYNAPTIC PROTEINS, INCLUDING BDNF, PSD95 AND SYN, DENDRITIC REMODELING AND ULTRASTRUCTURE CHANGES OF SYNAPSES IN THE HIPPOCAMPUS. 2019 14 5651 36 SEX DIFFERENCES IN THE EPIGENETIC REGULATION OF CHRONIC VISCERAL PAIN FOLLOWING UNPREDICTABLE EARLY LIFE STRESS. BACKGROUND: WE PREVIOUSLY REPORTED THAT EARLY LIFE STRESS (ELS) DYSREGULATED GLUCOCORTICOID RECEPTOR (GR) AND CORTICOTROPHIN-RELEASING HORMONE (CRH) EXPRESSION IN THE CENTRAL NUCLEUS OF THE AMYGDALA (CEA). EPIGENETIC MODIFICATIONS SERVE AS MEMORIES OF ADVERSE EVENTS THAT OCCURRED DURING EARLY LIFE. THEREFORE, WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS ALTER GR AND CRH EXPRESSION IN THE CEA AND UNDERLIE CHRONIC VISCERAL PAIN AFTER ELS. METHODS: NEONATAL RATS WERE EXPOSED TO UNPREDICTABLE, PREDICTABLE ELS, OR ODOR ONLY (NO STRESS CONTROL) FROM POSTNATAL DAYS 8 TO 12. IN ADULTHOOD, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR WESTERN BLOT OR CHIP-QPCR TO STUDY HISTONE MODIFICATIONS AT THE GR AND CRH PROMOTERS. FEMALE ADULT RATS UNDERWENT STEREOTAXIC IMPLANTATION OF INDWELLING CANNULAS FOR MICROINJECTIONS OF GARCINOL (HAT INHIBITOR) INTO THE CEA. AFTER 7 DAYS OF MICROINJECTIONS, VISCERAL SENSITIVITY WAS ASSESSED OR THE CEA WAS ISOLATED FOR CHIP-QPCR ASSAYS. RESULTS: UNPREDICTABLE ELS INCREASED VISCERAL SENSITIVITY IN ADULT FEMALE RATS, BUT NOT IN MALE COUNTERPARTS. ELS INCREASED HISTONE 3 LYSINE 9 (H3K9) ACETYLATION IN THE CEA AND H3K9 ACETYLATION LEVELS AT THE GR PROMOTER IN THE CEA OF ADULT FEMALE RATS. AFTER UNPREDICTABLE ELS, H3K9 ACETYLATION WAS INCREASED AND GR BINDING WAS DECREASED AT THE CRH PROMOTER. ADMINISTRATION OF GARCINOL IN THE CEA OF ADULT FEMALES, THAT UNDERWENT UNPREDICTABLE ELS, NORMALIZED H3K9 ACETYLATION AND RESTORED GR BINDING AT THE CRH PROMOTER. CONCLUSION: DYSREGULATED HISTONE ACETYLATION AND GR BINDING AT THE CRH PROMOTER IN THE CEA ARE AN IMPORTANT MECHANISM FOR "MEMORIZING" ELS EVENTS MEDIATING VISCERAL PAIN IN ADULTHOOD. 2020 15 73 36 A MULTI-GENERATIONAL STUDY ON LOW-DOSE BPA EXPOSURE IN WISTAR RATS: EFFECTS ON MATERNAL BEHAVIOR, FLAVOR INTAKE AND DEVELOPMENT. BISPHENOL A (BPA) IS A COMMON ENDOCRINE DISRUPTOR FOUND AS AN ENVIRONMENTAL AND FOOD CONTAMINANT. IT EXERTS BOTH DEVELOPMENTAL AND BEHAVIORAL EFFECTS, MAINLY WHEN EXPOSURE OCCURS IN EARLY LIFE. THE AIM OF THIS STUDY WAS TO DETERMINE THE MULTI-GENERATIONAL EFFECTS OF CHRONIC, HUMAN-RELEVANT LOW-DOSE EXPOSURE TO BPA ON DEVELOPMENT, MATERNAL BEHAVIOR AND FLAVOR PREFERENCE IN WISTAR RATS. BPA WAS ORALLY ADMINISTERED AT A DAILY DOSE OF 5 MUG/KG BODY WEIGHT TO F0 PREGNANT DAMS FROM THE FIRST DAY OF GESTATION (GD 1) UNTIL THE LAST DAY OF LACTATION (LD 21), AND THEN TO F1 OFFSPRING FROM WEANING (PND 21) TO ADULTHOOD (PND 100). F2 OFFSPRING WERE NOT EXPOSED. DEVELOPMENT AND CLINICAL SIGNS OF TOXICITY WERE ASSESSED DAILY. MATERNAL BEHAVIOR WAS EVALUATED BY OBSERVING NURSING AND PUP-CARING ACTIONS, AS WELL AS "NON-MATERNAL" BEHAVIORS IN F0 AND F1 DAMS FROM PARTURITION UNTIL LD 8. THE FLAVOR PREFERENCES OF F1 AND F2 OFFSPRING WERE EVALUATED BASED ON THE INTAKE OF SWEET, SALT AND FAT SOLUTIONS USING THE TWO-BOTTLE CHOICE TEST ON PND 21-34 AND PND 86-99. BPA EXPOSURE: 1) DECREASED MATERNAL BEHAVIOR IN F1 DAMS, 2) CAUSED DEVELOPMENTAL DEFECTS IN BOTH F1 AND F2 OFFSPRING, WITH A NOTICEABLE DECREASE IN ANOGENITAL DISTANCE IN MALE RATS, AND 3) DID NOT AFFECT FLAVORED SOLUTION INTAKE IN F1, BUT INDUCED CHANGES IN SWEET PREFERENCE IN F2 JUVENILES AND IN SALT AND FAT SOLUTION INTAKES IN F2 ADULTS, AND 4) INDUCED A BODY WEIGHT INCREASE IN THE F2 GENERATION ONLY, WHEREAS FOOD INTAKE AND WATER CONSUMPTION DID NOT CHANGE. TAKEN AS A WHOLE, OUR FINDINGS SHOWED THAT BOTH GESTATIONAL (F0) AND LIFELONG (F1) EXPOSURES TO A HUMAN-RELEVANT DOSE OF BPA COULD INDUCE MULTI-GENERATIONAL EFFECTS ON BOTH DEVELOPMENT AND BEHAVIOR. THESE RESULTS SUGGEST POSSIBLE SELECTIVE NEUROENDOCRINE DEFECTS AND/OR EPIGENETIC CHANGES CAUSED BY BPA EXPOSURE. 2014 16 1740 38 EARLY ENRICHED ENVIRONMENT PREVENTS EPIGENETIC P11 GENE CHANGES INDUCED BY ADULTHOOD STRESS IN MICE. POSITIVE EXPERIENCES IN EARLY LIFE MAY IMPROVE THE CAPACITY TO COPE WITH ADULTHOOD STRESS THROUGH EPIGENETIC MODIFICATION. WE INVESTIGATED WHETHER AN ENRICHED ENVIRONMENT (EE) IN THE POSTNATAL PERIOD AFFECTED EPIGENETIC CHANGES IN THE P11 GENE INDUCED BY CHRONIC UNPREDICTABLE STRESS (CUS) IN ADULT C57BL/6J MICE. EE WAS INTRODUCED FOR 5 WEEKS DURING POSTNATAL DAYS 21-55. AFTER EE, THE MICE WERE SUBJECTED TO CUS FOR 4 WEEKS. EE PREVENTED DEPRESSION-LIKE BEHAVIOR INDUCED BY ADULT CUS. EE PREVENTED A DECREASE IN P11 MRNA AND HISTONE H3 ACETYLATION INDUCED BY CUS, WITH CHANGES IN THE EXPRESSION OF HISTONE DEACETYLASE 5. MOREOVER, EE PREVENTED CHANGES IN TRIMETHYLATION OF HISTONE H3 LYSINE 4 (H3K4) AND H3K27 INDUCED BY CUS. FURTHERMORE, EE HAD POSITIVE EFFECTS ON BEHAVIOR AND EPIGENETIC ALTERATIONS IN ADULT MICE WITHOUT CUS. THESE RESULTS SUGGEST THAT ONE OF THE UNDERLYING MECHANISMS OF EARLY-LIFE EE MAY INVOLVE EPIGENETIC MODIFICATION OF THE HIPPOCAMPAL P11 GENE PROMOTER. 2021 17 4930 42 PATERNAL ALCOHOL EXPOSURE REDUCES ACQUISITION OF OPERANT ALCOHOL SELF-ADMINISTRATION AND AFFECTS BDNF DNA METHYLATION IN MALE AND FEMALE OFFSPRING. FAMILIAL TRANSMISSION OF ALCOHOL USE DISORDER REFLECTS GENETIC AND ENVIRONMENTAL FACTORS. PATERNAL ALCOHOL EXPOSURE MAY AFFECT RODENT OFFSPRING VIA EPIGENETIC MODIFICATIONS TRANSMITTED THROUGH THE MALE GERM LINE. WHILE SUCH EXPOSURE ALTERS ALCOHOL SENSITIVITY IN MOUSE OFFSPRING, NO STUDIES EXAMINED IF IT IMPACTS THE DEVELOPMENT OF OPERANT ALCOHOL SELF-ADMINISTRATION IN RATS. WE EXPOSED MALE (SIRES) WISTAR RATS TO CHRONIC INTERMITTENT ETHANOL IN VAPOUR CHAMBERS (16 H/DAY; 5 DAYS/WEEK) OR TO AIR FOR 6 WEEKS. EIGHT WEEKS LATER, RATS WERE MATED WITH ALCOHOL-NAIVE FEMALES. ADULT ALCOHOL- AND CONTROL-SIRED F1 OFFSPRING WERE ASSESSED IN ACQUISITION OF ALCOHOL SELF-ADMINISTRATION IN WHICH INCREASING ALCOHOL CONCENTRATIONS (2.5%, 5% AND 10%, V/V) WERE DELIVERED AFTER ONE LEVER PRESS (FIXED RATIO 1 OR FR1). PRIOR TO ALCOHOL SESSIONS, RATS WERE TRAINED TO LEVER PRESS FOR FOOD DELIVERY UNDER AN FR1 SCHEDULE OF REINFORCEMENT. DNA METHYLATION LEVELS OF THE BRAIN DERIVED NEUROTROPHIC FACTOR (BDNF) GENE WERE MEASURED IN SPERM, NUCLEUS ACCUMBENS (NAC) AND MEDIAL PREFRONTAL CORTEX (MPFC) IN SIRES AND IN OFFSPRING. ALCOHOL-EXPOSED SIRES HAD LOWER BDNF DNA METHYLATION LEVELS IN NAC AND GREATER METHYLATION LEVELS IN MPFC. ALTHOUGH THIS PATTERN WAS NOT RECAPITULATED IN OFFSPRING, ALCOHOL-SIRED OFFSPRING OF BOTH SEXES DID SHOW ABERRANT BDNF DNA METHYLATION PATTERNS COMPARED TO CONTROL-SIRED OFFSPRING. ALCOHOL-SIRED OFFSPRING SELF-ADMINISTERED LESS ALCOHOL (5% AND 10%) WITH NO GROUP DIFFERENCES IN FOOD RESPONDING. RESULTS INDICATE THAT PATERNAL ALCOHOL EXPOSURE PRIOR TO CONCEPTION PROTECTS AGAINST ALCOHOL'S INITIAL REINFORCING EFFECTS BUT THE PATTERN OF DYSREGULATED BDNF METHYLATION IN REWARD-RELATED CIRCUITRY DID NOT MIMIC CHANGES SEEN IN SIRES. 2022 18 69 30 A MEDIAL PREFRONTAL CORTEX-NUCLEUS ACUMENS CORTICOTROPIN-RELEASING FACTOR CIRCUITRY FOR NEUROPATHIC PAIN-INCREASED SUSCEPTIBILITY TO OPIOID REWARD. RECENT STUDIES HAVE SHOWN THAT PERSISTENT PAIN FACILITATES THE RESPONSE TO MORPHINE REWARD. HOWEVER, THE CIRCUIT MECHANISM UNDERLYING THIS PROCESS REMAINS AMBIGUOUS. IN THIS STUDY, USING CHRONIC CONSTRICTION INJURY (CCI) OF THE SCIATIC NERVE IN MICE, WE FOUND THAT PERSISTENT NEUROPATHIC PAIN REDUCED THE MINIMUM NUMBER OF MORPHINE CONDITIONING SESSIONS REQUIRED TO INDUCE CONDITIONED PLACE PREFERENCE (CPP) BEHAVIOR. THIS DOSE OF MORPHINE HAD NO EFFECT ON THE PAIN THRESHOLD. IN THE MEDIAL PREFRONTAL CORTEX (MPFC), WHICH IS INVOLVED IN BOTH PAIN AND EMOTION PROCESSING, CORTICOTROPIN-RELEASING FACTOR (CRF) EXPRESSING NEURONAL ACTIVITY WAS INCREASED IN CCI MICE. CHEMOGENETIC INHIBITION OF MPFC CRF NEURONS REVERSED CCI-INDUCED MORPHINE CPP FACILITATION. FURTHERMORE, THE NUCLEUS ACUMENS (NAC) RECEIVED MPFC CRF FUNCTIONAL PROJECTIONS THAT EXERTED EXCITATORY EFFECTS ON NAC NEURONS. OPTOGENETIC INHIBITION OF MPCF NEURONAL TERMINALS OR LOCAL INFUSION OF THE CRF RECEPTOR 1 (CRFR1) ANTAGONIST IN THE NAC RESTORED THE EFFECTS OF NEUROPATHIC PAIN ON MORPHINE-INDUCED CPP BEHAVIOR, BUT NOT IN NORMAL MICE. ON A MOLECULAR LEVEL, IN CCI MICE, CRFR1 PROTEIN EXPRESSION WAS INCREASED IN THE NAC BY A HISTONE DIMETHYLTRANSFERASE G9A-MEDIATED EPIGENETIC MECHANISM. LOCAL G9A KNOCKDOWN INCREASED THE EXPRESSION OF CRFR1 AND MIMICKED CCI-INDUCED HYPERSENSITIVITY TO ACQUIRING MORPHINE CPP. TAKEN TOGETHER, THESE FINDINGS DEMONSTRATE A PREVIOUSLY UNKNOWN AND SPECIFIC MPFC CRF ENGAGEMENT OF NAC NEURONAL CIRCUITS, THE SENSITIZATION OF WHICH FACILITATES BEHAVIORAL RESPONSES TO MORPHINE REWARD IN NEUROPATHIC PAIN STATES VIA CRFR1S. 2018 19 5752 43 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 20 6559 32 TRANSGENERATIONAL INFLUENCE OF PARENTAL MORPHINE EXPOSURE ON PAIN PERCEPTION, ANXIETY-LIKE BEHAVIOR AND PASSIVE AVOIDANCE MEMORY AMONG MALE AND FEMALE OFFSPRING OF WISTAR RATS. ACCUMULATING EVIDENCE SUGGESTS THAT EPIGENETIC MECHANISMS PLAY AN IMPORTANT ROLE IN THE FORMATION AND MAINTENANCE OF MEMORY WITHIN THE BRAIN. MOREOVER, THE EFFECT OF PARENTAL DRUG-EXPOSURE BEFORE GESTATION ON BEHAVIORAL STATE OF OFFSPRING HAS BEEN LITTLE STUDIED. THE MAIN OBJECTIVE OF THE CURRENT STUDY IS TO EVALUATE THE EFFECT OF PARENTAL MORPHINE EXPOSURE ON AVOIDANCE MEMORY, MORPHINE PREFERENCE AND ANXIETY-LIKE BEHAVIOR OF OFFSPRING. THE TOTAL OF 32 MALES AND 32 FEMALES WERE USED FOR MATING. THE ANIMALS WERE TREATED WITH MORPHINE. THE OFFSPRING ACCORDING TO THEIR PARENTAL MORPHINE TREATMENT WAS DIVIDED INTO FOUR GROUPS (N=16) INCLUDING PATERNALLY TREATED, MATERNALLY TREATED, BOTH OF PARENTS TREATED AND NAIVE ANIMALS. THE PAIN PERCEPTION, ANXIETY-LIKE BEHAVIOR, AND AVOIDANCE MEMORY WERE EVALUATED IN THE OFFSPRING. IN THE CURRENT STUDY, THE TOTAL OF 256 OFFSPRING WAS USED FOR THE EXPERIMENTS (4 TASKS X 4 GROUPS OF OFFSPRING X 8 FEMALE OFFSPRING X 8 MALE OFFSPRING). THE FINDING REVEALED THAT THE AVOIDANCE MEMORY AND VISCERAL PAIN WERE REDUCED SIGNIFICANTLY IN MALE AND FEMALE OFFSPRING WITH AT LEAST ONE MORPHINE-TREATED PARENT. MOREOVER, ANXIETY-LIKE BEHAVIOR WAS REDUCED SIGNIFICANTLY IN THE MALE OFFSPRING WITH AT LEAST ONE MORPHINE-TREATED PARENT. WHILE ANXIETY-LIKE BEHAVIOR WAS INCREASED SIGNIFICANTLY IN FEMALE OFFSPRING THAT WERE TREATED BY MORPHINE EITHER MATERNALLY OR BOTH OF PARENTS. THE DATA REVEALED THAT THE ENDOGENOUS OPIOID SYSTEM MAY BE ALTERED IN THE OFFSPRING OF MORPHINE-TREATED PARENT(S), AND EPIGENETIC ROLE COULD BE IMPORTANT. HOWEVER, ANALYSIS OF VARIANCE SIGNIFIED THE IMPORTANT ROLE OF MATERNAL INHERITANCE. 2019