1 1804 127 EFFECT OF RAT PARENTAL MORPHINE EXPOSURE ON PASSIVE AVOIDANCE MEMORY AND MORPHINE CONDITIONED PLACE PREFERENCE IN MALE OFFSPRING. DRUG ADDICTION IS A CHRONIC DISORDER RESULTED FROM COMPLEX INTERACTION OF GENETIC, ENVIRONMENTAL, AND DEVELOPMENTAL FACTORS. EPIGENETIC MECHANISMS PLAY AN IMPORTANT ROLE IN THE DEVELOPMENT AND MAINTENANCE OF ADDICTION AND ALSO MEMORY FORMATION IN THE BRAIN. WE HAVE EXAMINED PASSIVE AVOIDANCE MEMORY AND MORPHINE CONDITIONED PLACE PREFERENCE (CPP) IN THE OFFSPRING OF MALE AND/OR FEMALE RATS WITH A HISTORY OF ADULTHOOD MORPHINE CONSUMPTION. ADULT MALE AND FEMALE ANIMALS RECEIVED CHRONIC ORAL MORPHINE FOR 21DAYS AND THEN WERE MAINTAINED DRUG FREE FOR 10DAYS. AFTER THAT, THEY WERE LET TO MATE WITH EITHER AN ABSTINENT OR CONTROL RAT. MALE OFFSPRING'S MEMORY WAS EVALUATED BY STEP THROUGH TEST. BESIDES, REWARDING EFFECTS OF MORPHINE WERE CHECKED WITH CCP PARADIGM. OFFSPRING OF ABSTINENT ANIMALS SHOWED SIGNIFICANT MEMORY IMPAIRMENT COMPARED TO THE CONTROL GROUP WHICH WAS MORE PROMINENT IN THE OFFSPRING OF ABSTINENT FEMALES. CONDITIONING RESULTS SHOWED THAT ADMINISTRATION OF A HIGH DOSE OF MORPHINE (10MG/KG) THAT COULD SIGNIFICANTLY INDUCE CPP IN CONTROL RATS, WAS NOT ABLE TO INDUCE SIMILAR RESULTS IN THE OFFSPRING OF MORPHINE ABSTINENT PARENTS; AND CPP WAS MUCH MORE PROMINENT WHEN IT WAS INDUCED IN THE OFFSPRING OF MORPHINE EXPOSED FEMALES COMPARED TO THE PROGENY OF MORPHINE EXPOSED MALES. IT IS CONCLUDED THAT PARENTAL MORPHINE CONSUMPTION IN ADULTHOOD EVEN BEFORE MATING HAS DESTRUCTIVE EFFECTS ON MEMORY STATE OF THE MALE OFFSPRING AND ALSO LEADS TO TOLERANCE TO THE REWARDING EFFECTS OF MORPHINE. THESE EFFECTS ARE GREATER WHEN THE MORPHINE CONSUMER PARENT IS THE FEMALE ONE. 2018 2 6559 48 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 3 6551 59 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 4 586 30 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 5 4931 42 PATERNAL ALCOHOL EXPOSURE REDUCES ALCOHOL DRINKING AND INCREASES BEHAVIORAL SENSITIVITY TO ALCOHOL SELECTIVELY IN MALE OFFSPRING. ALCOHOL USE DISORDER (AUD) IS HERITABLE, BUT THE GENETIC BASIS FOR THIS DISEASE REMAINS POORLY UNDERSTOOD. ALTHOUGH NUMEROUS GENE VARIANTS HAVE BEEN ASSOCIATED WITH AUD, THESE VARIANTS ACCOUNT FOR ONLY A SMALL FRACTION OF THE TOTAL RISK. THE IDEA OF INHERITANCE OF ACQUIRED CHARACTERISTICS, I.E. "EPIGENETIC INHERITANCE," IS RE-EMERGING AS A PROVEN ADJUNCT TO TRADITIONAL MODES OF GENETIC INHERITANCE. WE HYPOTHESIZED THAT ALCOHOL DRINKING AND NEUROBIOLOGICAL SENSITIVITY TO ALCOHOL ARE INFLUENCED BY ANCESTRAL ALCOHOL EXPOSURE. TO TEST THIS HYPOTHESIS, WE EXPOSED MALE MICE TO CHRONIC VAPOR ETHANOL OR CONTROL CONDITIONS, MATED THEM TO ETHANOL-NAIVE FEMALES, AND TESTED ADULT OFFSPRING FOR ETHANOL DRINKING, ETHANOL-INDUCED BEHAVIORS, GENE EXPRESSION, AND DNA METHYLATION. WE FOUND THAT ETHANOL-SIRED MALE OFFSPRING HAD REDUCED ETHANOL PREFERENCE AND CONSUMPTION, ENHANCED SENSITIVITY TO THE ANXIOLYTIC AND MOTOR-ENHANCING EFFECTS OF ETHANOL, AND INCREASED BDNF EXPRESSION IN THE VENTRAL TEGMENTAL AREA (VTA) COMPARED TO CONTROL-SIRED MALE OFFSPRING. THERE WERE NO DIFFERENCES AMONG ETHANOL- AND CONTROL-SIRED FEMALE OFFSPRING ON THESE ASSAYS. ETHANOL EXPOSURE ALSO DECREASED DNA METHYLATION AT THE BDNFAEPROMOTER OF SIRE'S GERM CELLS AND HYPOMETHYLATION WAS MAINTAINED IN THE VTA OF BOTH MALE AND FEMALE ETHANOL-SIRED OFFSPRING. OUR FINDINGS SHOW THAT PATERNAL ALCOHOL EXPOSURE IS A PREVIOUSLY UNRECOGNIZED REGULATOR OF ALCOHOL DRINKING AND BEHAVIORAL SENSITIVITY TO ALCOHOL IN MALE, BUT NOT FEMALE, OFFSPRING. PATERNAL ALCOHOL EXPOSURE ALSO INDUCES EPIGENETIC ALTERATIONS (DNA HYPOMETHYLATION) AND GENE EXPRESSION CHANGES THAT PERSIST IN THE VTA OF OFFSPRING. THESE RESULTS PROVIDE NEW INSIGHT INTO THE INHERITANCE AND DEVELOPMENT OF ALCOHOL DRINKING BEHAVIORS. 2014 6 4937 39 PATERNAL MORPHINE EXPOSURE IN RATS REDUCES SOCIAL PLAY IN ADOLESCENT MALE PROGENY WITHOUT AFFECTING DRUG-TAKING BEHAVIOR IN JUVENILE MALES OR FEMALE OFFSPRING. THE ONGOING OPIOID ADDICTION CRISIS NECESSITATES THE IDENTIFICATION OF NOVEL RISK FACTORS TO IMPROVE PREVENTION AND TREATMENT OF OPIOID USE DISORDER. PARENTAL OPIOID EXPOSURE HAS RECENTLY EMERGED AS A POTENTIAL REGULATOR OF OFFSPRING VULNERABILITY TO OPIOID MISUSE, IN ADDITION TO HERITABLE GENETIC LIABILITY. AN UNDERSTUDIED ASPECT OF THIS "MISSING HERITABILITY" IS THE DEVELOPMENTAL PRESENTATION OF THESE CROSS-GENERATIONAL PHENOTYPES. THIS IS AN ESPECIALLY RELEVANT QUESTION IN THE CONTEXT OF INHERITED ADDICTION-RELATED PHENOTYPES, GIVEN THE PROMINENT ROLE OF DEVELOPMENTAL PROCESSES IN THE ETIOLOGY OF PSYCHIATRIC DISORDERS. PATERNAL MORPHINE SELF-ADMINISTRATION WAS PREVIOUSLY SHOWN TO ALTER THE SENSITIVITY TO THE REINFORCING AND ANTINOCICEPTIVE PROPERTIES OF OPIOIDS IN THE NEXT GENERATION. HERE, PHENOTYPING WAS EXPANDED TO INCLUDE THE ADOLESCENT PERIOD, WITH A FOCUS ON ENDOPHENOTYPES RELATED TO OPIOID USE DISORDERS AND PAIN. PATERNAL MORPHINE EXPOSURE DID NOT ALTER HEROIN OR COCAINE SELF-ADMINISTRATION IN MALE AND FEMALE JUVENILE PROGENY. FURTHER, BASELINE SENSORY REFLEXES RELATED TO PAIN WERE UNALTERED IN MORPHINE-SIRED ADOLESCENT RATS OF EITHER SEX. HOWEVER, MORPHINE-SIRED ADOLESCENT MALES EXHIBITED A REDUCTION IN SOCIAL PLAY BEHAVIOR. OUR FINDINGS SUGGEST THAT, IN MORPHINE-SIRED MALE OFFSPRING, PATERNAL OPIOID EXPOSURE DOES NOT AFFECT OPIOID INTAKE DURING ADOLESCENCE, SUGGESTING THAT THIS PHENOTYPE DOES NOT EMERGE UNTIL LATER IN LIFE. ALTERED SOCIAL BEHAVIORS IN MALE MORPHINE-SIRED ADOLESCENTS INDICATE THAT THE CHANGES IN DRUG-TAKING BEHAVIOR IN ADULTS SIRED BY MORPHINE-EXPOSED SIRES MAY BE DUE TO MORE COMPLEX FACTORS NOT YET FULLY ASSESSED. 2023 7 1418 39 DIFFERENCES IN DNA METHYLATION REPROGRAMMING UNDERLIE THE SEXUAL DIMORPHISM OF BEHAVIORAL DISORDER CAUSED BY PRENATAL STRESS IN RATS. PRENATAL STRESS (PS) CAN LEAD TO NEUROENDOCRINE AND EMOTIONAL DISORDERS LATER IN ADOLESCENCE. SEXUAL DIMORPHISM IN THESE NEURODEVELOPMENTAL OUTCOMES HAVE BEEN OBSERVED; HOWEVER, THE UNDERLYING MECHANISMS ARE NOT FULLY UNDERSTOOD. TO ADDRESS THIS ISSUE, WE INVESTIGATED WHETHER THERE ARE SEX DIFFERENCES IN EPIGENETIC REPROGRAMMING IN RATS EXPOSED TO PS. PREGNANT FEMALE RATS WERE SUBJECTED TO CHRONIC RESTRAINT STRESS FROM GESTATIONAL DAY (G)12 TO G18. FROM POSTNATAL DAY (P)38 TO P45, SUBGROUPS OF OFFSPRING INCLUDING BOTH MALES AND FEMALES WERE SUBJECTED TO BEHAVIORAL TESTING AND BRAIN TISSUE SPECIMENS WERE ANALYZED BY DNA PYROSEQUENCING, WESTERN BLOTTING, AND GOLGI STAINING TO ASSESS CHANGES IN METHYLATION PATTERN OF GLUCOCORTICOID RECEPTOR (GR) GENE, EXPRESSION OF DNA METHYLTRANSFERASE (DNMT) AND DNA DEMETHYLASE, AND DENDRITE MORPHOLOGY, RESPECTIVELY. THE DNA METHYLTRANSFERASE INHIBITOR DECITABINE WAS ADMINISTERED TO RATS PRIOR TO PS TO FURTHER EVALUATE THE ROLE OF METHYLATION IN THE SEXUALLY DIMORPHIC EFFECTS OF PS. THE RESULTS SHOWED THAT PS INCREASED ANXIETY-LIKE BEHAVIOR IN OFFSPRING, ESPECIALLY IN FEMALES, WHILE DEPRESSION-LIKE BEHAVIOR WAS INCREASED IN MALE OFFSPRING COMPARED TO CONTROL LITTERMATES. THE METHYLATION PATTERN IN THE PROMOTER REGION OF THE GR GENE DIFFERED BETWEEN MALES AND FEMALES. SEX-SPECIFIC CHANGES IN THE EXPRESSION OF DNMTS (DNMT1 AND DNMT3A) AND DNA DEMETHYLASE (TET METHYLCYTOSINE DIOXYGENASE 2) WERE ALSO OBSERVED. INTERESTINGLY, DECITABINE ALLEVIATED THE BEHAVIORAL DISORDER CAUSED BY PS AND RESTORED DENDRITE DENSITY AND MORPHOLOGY IN FEMALE BUT NOT MALE RATS. THESE FINDINGS SUGGEST THAT DIFFERENT CHANGE PATTERNS OF DNMT AND DEMETHYLASE IN THE TWO SEXES AFTER PS ARE RESPONSIBLE FOR THE SEXUALLY DIMORPHISM, WHICH COULD HAVE IMPLICATIONS FOR THE CLINICAL MANAGEMENT OF STRESS-RELATED DISORDERS. 2020 8 1823 35 EFFECTS OF EARLY-LIFE STRESS AND HDAC INHIBITION ON MATERNAL BEHAVIOR IN MICE. DESPITE THE WELL-ESTABLISHED FACT THAT MATERNAL CARE PLAYS A PIVOTAL ROLE IN THE OFFSPRING DEVELOPMENT, LITTLE IS KNOWN ABOUT THE EFFECTS OF DISRUPTION OF MATERNAL CARE EARLY IN LIFE ON THE DEVELOPMENT OF THIS BEHAVIOR IN THE OFFSPRING. USING BRIEF REPEATED MATERNAL SEPARATION (45 MIN/DAY ON POSTNATAL DAYS 3-6), WHICH REPRESENTS A MODEL OF EARLY LIFE STRESS, WE FOUND BEHAVIORAL CHANGES IN ADULT FEMALE MICE OFFSPRING. THE DECREASE IN HOME CAGE EXPLORATORY BEHAVIOR (BOTH PUP-DIRECTED AND NONPUP-DIRECTED) WAS REVEALED LATER IN ADULTHOOD WITHOUT CHANGES IN MATERNAL CARE LEVEL. MATERNAL SEPARATION COUPLED WITH PAIN EXPOSURE CAUSED BY SUBCUTANEOUS SALINE INJECTION PROCEDURE HAD A CUMULATIVE RESULTING EFFECT, WHICH WAS MANIFESTED IN THE DECREASED LEVEL OF NURSING ASSOCIATED WITH LICKING-GROOMING IN ADULT FEMALES. THE BEHAVIORAL CHANGES FOUND IN ADULT FEMALE OFFSPRING COULD BE TRIGGERED BY IDENTIFIED CHANGES IN THE BEHAVIOR OF THEIR MOTHERS, WHILE ALTERATIONS OF THE LEVEL OF HISTONE H3 ACETYLATION IN THE NEONATAL BRAIN WERE NOT DETECTED. HISTONE DEACETYLASE INHIBITOR SODIUM VALPROATE WAS USED IN ORDER TO STUDY THE POSSIBILITY OF PREVENTING THE EFFECTS OF EARLY LIFE STRESS THROUGH INVOLVEMENT OF EPIGENETIC MECHANISMS. DESPITE THE INCREASE IN THE LEVEL OF HISTONE H3 ACETYLATION IN THE NEONATAL BRAIN CAUSED BY VALPROATE, ITS BEHAVIORAL EFFECTS WERE BARELY DETECTABLE. THESE EFFECTS WERE REFLECTED IN PREVENTION OF THE REDUCTION OF NURSING ASSOCIATED WITH LICKING-GROOMING INDUCED BY MATERNAL SEPARATION, ACCOMPANIED BY PAIN EXPOSURE. THE DATA ARE DISCUSSED IN TERMS OF THE POSSIBLE APPLICATION TO THE STUDIES OF MECHANISMS UNDERLYING LONG-TERM EFFECTS OF HUMAN EARLY LIFE TRAUMA. (PSYCINFO DATABASE RECORD (C) 2019 APA, ALL RIGHTS RESERVED). 2019 9 5485 37 REVERSAL OF COCAINE-CONDITIONED PLACE PREFERENCE THROUGH METHYL SUPPLEMENTATION IN MICE: ALTERING GLOBAL DNA METHYLATION IN THE PREFRONTAL CORTEX. ANALYSIS OF GLOBAL METHYLATION IN CELLS HAS REVEALED CORRELATIONS BETWEEN OVERALL DNA METHYLATION STATUS AND SOME BIOLOGICAL STATES. RECENT STUDIES SUGGEST THAT EPIGENETIC REGULATION THROUGH DNA METHYLATION COULD BE RESPONSIBLE FOR NEUROADAPTATIONS INDUCED BY ADDICTIVE DRUGS. HOWEVER, THERE IS NO INVESTIGATION TO DETERMINE GLOBAL DNA METHYLATION STATUS FOLLOWING REPEATED EXPOSURE TO ADDICTIVE DRUGS. USING MICE CONDITIONED PLACE PREFERENCE (CPP) PROCEDURE, WE MEASURED GLOBAL DNA METHYLATION LEVEL IN THE NUCLEUS ACCUMBENS (NAC) AND THE PREFRONTAL CORTEX (PFC) ASSOCIATED WITH DRUG REWARDING EFFECTS. WE FOUND THAT COCAINE-, BUT NOT MORPHINE- OR FOOD-CPP TRAINING DECREASED GLOBAL DNA METHYLATION IN THE PFC. CHRONIC TREATMENT WITH METHIONINE, A METHYL DONOR, FOR 25 CONSECUTIVE DAYS PRIOR TO AND DURING CPP TRAINING INHIBITED THE ESTABLISHMENT OF COCAINE, BUT NOT MORPHINE OR FOOD CPP. WE ALSO FOUND THAT BOTH MRNA AND PROTEIN LEVEL OF DNMT (DNA METHYTRANSFERASE) 3B IN THE PFC WERE DOWNREGULATED FOLLOWING THE ESTABLISHMENT OF COCAINE CPP, AND THE DOWNREGULATION COULD BE REVERSED BY REPEATED ADMINISTRATION OF METHIONINE. OUR STUDY INDICATES A CRUCIAL ROLE OF GLOBAL PFC DNA HYPOMETHYLATION IN THE REWARDING EFFECTS OF COCAINE. REVERSAL OF GLOBAL DNA HYPOMETHYLATION COULD SIGNIFICANTLY ATTENUATE THE REWARDING EFFECTS INDUCED BY COCAINE. OUR RESULTS SUGGEST THAT METHIONINE MAY HAVE BECOME A POTENTIAL THERAPEUTIC TARGET TO TREAT COCAINE ADDICTION. 2012 10 1004 32 CHRONIC TREATMENT WITH HORMONAL CONTRACEPTIVES ALTERS HIPPOCAMPAL BDNF AND HISTONE H3 POST-TRANSLATIONAL MODIFICATIONS BUT NOT LEARNING AND MEMORY IN FEMALE RATS. HORMONAL CONTRACEPTIVES PREVENT OVULATION WITH SUBSEQUENT REDUCTION IN ENDOGENOUS LEVELS OF ESTRADIOL, PROGESTERONE AND ITS NEUROACTIVE METABOLITE ALLOPREGNANOLONE. THESE NEUROSTEROIDS MODULATE SEVERAL BRAIN FUNCTIONS, INCLUDING NEURONAL PLASTICITY, COGNITION AND MEMORY. WE HYPOTHESIZED THAT HORMONAL CONTRACEPTIVES MIGHT AFFECT SYNAPTIC PLASTICITY, LEARNING AND MEMORY, AS A CONSEQUENCE OF SUPPRESSED ENDOGENOUS HORMONES LEVELS. FEMALE RATS WERE ORALLY TREATED WITH A COMBINATION OF ETHINYL ESTRADIOL (EE, 0.020 MG) AND LEVONORGESTREL (LNG, 0.060 MG) ONCE DAILY FOR FOUR WEEKS. DECREASED HIPPOCAMPAL BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) LEVELS AND ALTERED HISTONE H3 POST-TRANSLATIONAL MODIFICATIONS (PTMS) WERE OBSERVED 14 DAYS AFTER DISCONTINUATION FROM CHRONIC EE-LNG TREATMENT. THESE EFFECTS WERE NOT ACCOMPANIED BY ALTERATIONS IN LONG-TERM PLASTICITY AT GLUTAMATERGIC SYNAPSES, RECOGNITION MEMORY IN THE NOVEL OBJECT AND NOVEL PLACE LOCATION TESTS, OR SPATIAL LEARNING, MEMORY, AND BEHAVIORAL FLEXIBILITY IN THE MORRIS WATER MAZE TEST. THUS, DECREASED BDNF CONTENT DOES NOT AFFECT SYNAPTIC PLASTICITY AND COGNITIVE PERFORMANCE; RATHER IT MIGHT BE RELEVANT FOR THE OCCURRENCE OF CERTAIN PSYCHIATRIC SYMPTOMS, REPORTED BY SOME WOMEN USING HORMONAL CONTRACEPTIVES. THESE RESULTS PROVIDE THE FIRST EVIDENCE OF HIPPOCAMPAL EPIGENETIC CHANGES INDUCED BY HORMONAL CONTRACEPTIVES AND COMPLEMENT PREVIOUS STUDIES ON THE NEUROBIOLOGICAL ACTIONS OF HORMONAL CONTRACEPTIVES; THE FINDING THAT EFFECTS OF CHRONIC EE-LNG TREATMENT ON BDNF CONTENT AND HISTONE PTMS ARE OBSERVED 14 DAYS AFTER DRUG DISCONTINUATION WARRANTS FURTHER INVESTIGATION TO BETTER UNDERSTAND THE IMPLICATIONS OF SUCH LONG-TERM CONSEQUENCES FOR WOMEN'S HEALTH. 2022 11 5199 37 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 12 2740 26 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 13 5645 32 SEX DEPENDENT ALTERATION OF EPIGENETIC MARKS AFTER CHRONIC MORPHINE TREATMENT IN MICE ORGANS. EPIGENETIC MARKS MAY BE ALSO AFFECTED BY SEVERAL FACTORS, SUCH AS AGE, LIFESTYLE, EARLY LIFE EXPERIENCES AND EXPOSURE TO CHEMICALS OR DRUGS, SUCH AS OPIOIDS. PREVIOUS STUDIES HAVE FOCUSED ON HOW MORPHINE EPIGENETICALLY REGULATES DIFFERENT REGIONS OF THE BRAIN THAT ARE IMPLICATED IN TOLERANCE, DEPENDENCE AND OTHER PSYCHIATRIC DISORDERS MORE RELATED TO THE PHYSIO-PATHOLOGICAL EFFECTS OF OPIOIDS. NEVERTHELESS, A SIGNIFICANT KNOWLEDGE GAP REMAINS REGARDING THE EFFECT OF CHRONIC TREATMENT ON OTHER ORGANS AND BIOLOGICAL SYSTEMS. THEREFORE, THE AIM OF THIS WORK IS TO INCREASE OUR KNOWLEDGE ABOUT THE IMPACT OF CHRONIC MORPHINE EXPOSURE ON DNA METHYLATION AND HISTONE MODIFICATION LEVELS IN EACH OF THE ORGANS OF MALE AND FEMALE MODEL MICE IN VIVO. OUR RESULTS REVEAL, FOR THE FIRST TIME, THAT CHRONIC MORPHINE TREATMENT INDUCED CHANGES IN DNA METHYLATION/HYDROXYMETHYLATION AND HISTONE MODIFICATION IN-VIVO AT THE SYSTEMIC LEVEL, REVEALING A POTENTIAL PHYSIOLOGICAL EFFECT ON THE REGULATION OF GENE EXPRESSION. NOTABLY, MORPHINE-INDUCED EPIGENETIC MODIFICATION OCCURS IN A SEX-DEPENDENT MANNER, REVEALING THE EXISTENCE OF DIFFERENT UNDERLYING MECHANISMS OF EPIGENETIC MODIFICATION IN MALE AND FEMALE MICE. 2021 14 4949 34 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 15 1808 31 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 16 4938 26 PATERNAL NICOTINE ENHANCES FEAR MEMORY, REDUCES NICOTINE ADMINISTRATION, AND ALTERS HIPPOCAMPAL GENETIC AND NEURAL FUNCTION IN OFFSPRING. NICOTINE USE REMAINS HIGHLY PREVALENT WITH TOBACCO AND E-CIGARETTE PRODUCTS CONSUMED WORLDWIDE. HOWEVER, INCREASING EVIDENCE OF TRANSGENERATIONAL EPIGENETIC INHERITANCE SUGGESTS THAT NICOTINE USE MAY ALTER BEHAVIOR AND NEUROBIOLOGY IN SUBSEQUENT GENERATIONS. WE TESTED THE EFFECTS OF CHRONIC PATERNAL NICOTINE EXPOSURE IN C57BL6/J MICE ON FEAR CONDITIONING IN F1 AND F2 OFFSPRING, AS WELL AS CONDITIONED FEAR EXTINCTION AND SPONTANEOUS RECOVERY, NICOTINE SELF-ADMINISTRATION, HIPPOCAMPAL CHOLINERGIC FUNCTIONING, RNA EXPRESSION, AND DNA METHYLATION IN F1 OFFSPRING. PATERNAL NICOTINE EXPOSURE WAS ASSOCIATED WITH ENHANCED CONTEXTUAL AND CUED FEAR CONDITIONING AND SPONTANEOUS RECOVERY OF EXTINGUISHED FEAR MEMORIES. FURTHER, NICOTINE REINFORCEMENT WAS REDUCED IN NICOTINE-SIRED MICE, AS ASSESSED IN A SELF-ADMINISTRATION PARADIGM. THESE BEHAVIORAL PHENOTYPES WERE COUPLED WITH ALTERED RESPONSE TO NICOTINE, UPREGULATED HIPPOCAMPAL NICOTINIC ACETYLCHOLINE RECEPTOR BINDING, REDUCED EVOKED HIPPOCAMPAL CHOLINERGIC CURRENTS, AND ALTERED METHYLATION AND EXPRESSION OF HIPPOCAMPAL GENES RELATED TO NEURAL DEVELOPMENT AND PLASTICITY. GENE EXPRESSION ANALYSIS SUGGESTS MULTIGENERATIONAL EFFECTS ON BROADER GENE NETWORKS POTENTIALLY INVOLVED IN NEUROPLASTICITY AND MENTAL DISORDERS. THE CHANGES IN FEAR CONDITIONING SIMILARLY SUGGEST PHENOTYPES ANALOGOUS TO ANXIETY DISORDERS SIMILAR TO POST-TRAUMATIC STRESS. 2021 17 2472 34 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 18 4939 40 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 19 5168 40 PRECONCEPTIONAL PATERNAL EXPOSURE TO A SINGLE TRAUMATIC EVENT AFFECTS POSTNATAL GROWTH OF FEMALE BUT NOT MALE OFFSPRING. ALTHOUGH PRECONCEPTIONAL AND PERICONCEPTIONAL MATERNAL STRESS IS A RECOGNIZED RISK FACTOR FOR OFFSPRING NEURODEVELOPMENTAL DISTURBANCES, LESS IS KNOWN ABOUT THE RELEVANCE OF PATERNAL EXPOSURES. THESE HAVE HITHERTO BEEN INVESTIGATED MAINLY WITH RESPECT TO SUBSTANCE-INDUCED IMPAIRMENT IN THE PROGENY. IN RECENT YEARS, EXPERIENTIAL INFLUENCES ON OFFSPRING HAVE COME INTO FOCUS THROUGH GROWING INSIGHT INTO EPIGENETIC MECHANISMS SUCH AS NONGENETIC MODES OF TRANSMISSION. THE EFFECT OF CHRONIC AND/OR EARLY MANIPULATIONS IN MALES HAS BEEN STUDIED BUT MUCH LESS IS KNOWN ABOUT THE POTENTIAL IMPACT OF SINGULAR MANIPULATIONS IN OLDER INDIVIDUALS. WE INVESTIGATED THE INFLUENCE OF A STRONG STRESSOR EXPOSURE, REMINISCENT OF A TRAUMATIC EVENT, IN ADULT MALE MICE ON OFFSPRING BEHAVIOR. MALE MICE, 6 WEEKS OF AGE, RECEIVED A STRONG FOOTSHOCK AND WERE MATED TO NAIVE FEMALES SEVERAL WEEKS LATER. MALE AND FEMALE OFFSPRING WERE INVESTIGATED IN A VARIETY OF TESTS FOR ANXIETY-LIKE AND DEPRESSION-LIKE BEHAVIORS. IN ADDITION, BODYWEIGHT DEVELOPMENT WAS ASSESSED. ALTHOUGH WE DID NOT OBSERVE ANY ALTERATIONS IN ANXIETY-LIKE AND DEPRESSIVE-LIKE BEHAVIORAL INDICES, WE RECORDED REDUCED BODYWEIGHT DEVELOPMENT IN THE FEMALE OFFSPRING. OUR DATA EMPHASIZE THE RELEVANCE OF SEX AS A (CO)DETERMINANT OF OUTCOMES IN THE WAKE OF PARENTAL MANIPULATIONS. THEY FURTHER SUGGEST THAT THE WINDOW OF VULNERABILITY FOR THE INDUCTION OF PATRILINEAR EFFECTS MIGHT BE WIDER THAN THAT CURRENTLY ASSUMED. 2013 20 6477 37 TOLUENE IMPAIRS LEARNING AND MEMORY, HAS ANTINOCICEPTIVE EFFECTS, AND MODIFIES HISTONE ACETYLATION IN THE DENTATE GYRUS OF ADOLESCENT AND ADULT RATS. TOLUENE MISUSE USUALLY INITIATES AT AN EARLY AGE WHEN THE CENTRAL NERVOUS SYSTEM IS STILL IMMATURE, CAUSING DELETERIOUS EFFECTS SUCH AS COGNITIVE IMPAIRMENT. EPIGENETIC REGULATORY MECHANISMS HAVE BEEN PROPOSED TO EXPLAIN LONG-TERM CHANGES INVOLVED NOT ONLY IN MEMORY, BUT ALSO IN TOLUENE'S ACTIONS. THE AIM OF THIS STUDY WAS TO EVALUATE THE EFFECTS OF ACUTE AND CHRONIC TOLUENE EXPOSURE ON LEARNING, MEMORY AND HISTONE ACETYLATION IN THE RAT HIPPOCAMPUS DURING TWO STAGES OF LIFE: ADOLESCENCE AND YOUNG ADULTHOOD. BECAUSE THE MEMORY TESTS USED IN THIS WORK INVOLVED OBJECT EXPLORATION AND THE PERCEPTION OF A NOXIOUS STIMULUS, GENERAL ACTIVITY AND NOCICEPTION TESTS WERE ALSO CONDUCTED. ACUTE AND CHRONIC TOLUENE INHALATION IMPAIRED LEARNING, SHORT-TERM AND LONG-TERM MEMORY IN AN OBJECT-RECOGNITION TEST AND IN AN INHIBITORY AVOIDANCE TASK IN BOTH GROUPS OF AGE. THIS EFFECT WAS CONCENTRATION-DEPENDENT AND OCCURRED EVEN AT LOW TOLUENE CONCENTRATIONS (1000, 2000 PPM) THAT WERE OTHERWISE NON-EFFECTIVE. ACUTE TOLUENE INHALATION PRODUCED ANTINOCICEPTION, AND TOLERANCE TO THIS EFFECT DEVELOPED AFTER CHRONIC EXPOSURE. HISTONE ACETYLATION IN THE DENTATE GYRUS SHOWED DIFFERENCES DEPENDING ON THE HISTONE, TREATMENT AND AGE: A SINGLE TOLUENE EXPOSURE INCREASED H4 ACETYLATION IN ADOLESCENTS AND YOUNG ADULT RATS, WHEREAS CHRONIC EXPOSURE DECREASED H3 ACETYLATION, BUT ONLY IN ADULTS. IN CONCLUSION, THIS WORK PROVIDES EVIDENCE OF TOLUENE-INDUCED IMPAIRMENT ON LEARNING, SHORT- AND LONG-TERM MEMORY IN ADOLESCENT AND YOUNG ADULT RATS, AND SHOWS THAT EVEN A SINGLE TOLUENE EXPOSURE CAN INDUCE EPIGENETIC MODIFICATIONS IN THE RAT HIPPOCAMPUS. 2012