1  2742 131 EXPOSURE TO THE PLASTICIZER, DI-(2-ETHYLHEXYL) PHTHALATE DURING JUVENILE PERIOD EXACERBATES AUTISM-LIKE BEHAVIOR IN ADULT BTBR T + TF/J MICE DUE TO DNA HYPOMETHYLATION AND ENHANCED INFLAMMATION IN BRAIN AND SYSTEMIC IMMUNE CELLS. EPIGENETIC MODIFICATIONS ARE KNOWN TO PLAY A CRUCIAL ROLE IN THE BEHAVIORAL MODIFICATIONS THROUGH REGULATION OF GENE EXPRESSION. ENVIRONMENTAL FACTORS ARE KNOWN TO REGULATE GENETIC TRANSCRIPTION THROUGH DNA METHYLATION WHICH IS ONE OF THE MECHANISMS OF EPIGENETIC MODIFICATION. DI-2-ETHYLHEXYL PHTHALATE (DEHP) IS ONE OF THE MOST ABUNDANT PHTHALATE PLASTICIZERS IN DAY-TO-DAY PRODUCTS. PRENATAL/POSTNATAL DEHP ADMINISTRATION HAS BEEN REPORTED TO CAUSE INFLAMMATION AS WELL AS BEHAVIORAL DYSREGULATION, HOWEVER IT IS NOT KNOWN IF EXPOSURE TO DEHP DURING JUVENILE STAGE AFFECTS PERIPHERAL/NEURONAL INFLAMMATION AND AUTISM-LIKE SYMPTOMS IN BTBR MICE AT ADULTHOOD. THIS STUDY INVESTIGATED EFFECT OF DEHP EXPOSURE DURING JUVENILE PERIOD ON DNA METHYLATION (GLOBAL DNA METHYLATION/DNMT1 EXPRESSION) AND INFLAMMATION (IL-17A, IL-6, MCP-1, TNF-ALPHA) IN CD4 + T CELLS/CD11C + DCS AND CORTEX, AND AUTISM-LIKE SYMPTOMS (THREE-CHAMBERED SOCIABILITY TEST, SELF-GROOMING AND MARBLE BURYING TEST) IN ASOCIAL BTBR AND SOCIAL C57 MICE AT ADULTHOOD. OUR DATA REVEAL THAT BTBR MICE EXPOSED TO DEHP DURING JUVENILE PERIOD HAVE HYPOMETHYLATED DNA/DNMT1 EXPRESSION IN CD11C + DCS AND CORTEX AS COMPARED TO VEHICLE-EXPOSED BTBR MICE. IT WAS ASSOCIATED WITH UPREGULATED INFLAMMATION IN PERIPHERY [PLASMA IL-6/IL-17A, CD11C + DCS (IL-6/MCP-1/TNF-ALPHA), AND CD4+ T CELLS (IL-17A)] AND CORTEX (IL-6, MCP-1, TNF-ALPHA), AND AGGRAVATION IN AUTISM-LIKE SYMPTOMS IN DEHP-TREATED BTBR MICE. THESE DATA PROPOSE THAT EXPOSURE OF DEHP DURING JUVENILE PERIOD MAY AFFECT AUTISM-LIKE BEHAVIOR AND INFLAMMATION IN BTBR MICE AT ADULTHOOD THROUGH EPIGENETIC REGULATION. THEREFORE, UNDERLYING GENETIC PREDISPOSITION MAY PLAY A CRUCIAL ROLE IN WORSENING OF AUTISTIC SYMPTOMS IN ASD SUBJECTS IN ADULTHOOD IF THEY ARE EXPOSED TO ENVIRONMENTAL POLLUTANTS SUCH AS DEHP DURING JUVENILE PERIOD.	2021	
                                                                                                                                                                                                              
2   998  27 CHRONIC SUBCONVULSIVE ACTIVITY DURING EARLY POSTNATAL LIFE PRODUCES AUTISTIC BEHAVIOR IN THE ABSENCE OF NEUROTOXICITY IN THE JUVENILE WEANLING PERIOD. THE DIAGNOSIS OF AUTISM SPECTRUM DISORDER (ASD) VARIES FROM VERY MILD TO SEVERE SOCIAL AND COGNITIVE IMPAIRMENTS. WE HYPOTHESIZED THAT EPIGENETIC SUBCONVULSIVE ACTIVITY IN EARLY POSTNATAL LIFE MAY CONTRIBUTE TO THE DEVELOPMENT OF AUTISTIC BEHAVIOR IN A SEX-RELATED MANNER. LOW DOSES OF KAINIC ACID (KA) (25-100 MUG) WERE ADMINISTERED TO RAT PUPS FOR 15 DAYS BEGINNING ON POSTNATAL (P) DAY 6 TO CHRONICALLY ELEVATE NEURONAL ACTIVITY. A BATTERY OF CLASSICAL AND NOVEL BEHAVIORAL TESTS WAS USED, AND SEX DIFFERENCES WERE OBSERVED. OUR NOVEL OPEN HANDLING TEST REVEALED THAT ASD MALES NOSE POKED MORE OFTEN AND ASD FEMALES CLIMBED AND ESCAPED MORE FREQUENTLY WITH AGE. IN THE SOCIAL INTERACTION TEST, ASD MALES WERE LESS SOCIAL THAN ASD FEMALES WHO WERE MORE ANXIOUS IN HANDLING AND ELEVATED PLUS MAZE (EPM) TASKS. TO EVALUATE GROUP DYNAMICS, SIBLING AND NON-SIBLING CONTROL AND EXPERIMENTAL ANIMALS EXPLORED 3 DIFFERENT SHAPED NOVEL SOCIAL ENVIRONMENTS. CONTROL PUPS HUDDLED QUICKLY AND MORE FREQUENTLY IN ALL ENVIRONMENTS WHETHER THEY SOCIALIZED WITH LITTERMATES OR NON-SIBLINGS COMPARED TO ASD GROUPS. NON-SIBLING ASD PUPS WERE ERRATIC AND HUDDLED IN SMALLER GROUPS. IN THE OBJECT RECOGNITION TEST, ONLY ASD MALES SPENT LESS TIME WITH THE NOVEL OBJECT COMPARED TO CONTROL PUPS. DATA SUGGEST THAT CHRONIC SUBCONVULSIVE ACTIVITY IN EARLY POSTNATAL LIFE LEADS TO AN ASD PHENOTYPE IN THE ABSENCE OF CELL DEATH. MALES WERE MORE SUSCEPTIBLE TO DEVELOPING ASOCIAL BEHAVIORS AND COGNITIVE PATHOLOGIES, WHEREAS FEMALES WERE PRONE TO HIGHER LEVELS OF HYPERACTIVITY AND ANXIETY, VALIDATING OUR POSTNATAL ASD MODEL APPARENT IN THE PRE-JUVENILE PERIOD.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
3  4857  32 OPTOGENETIC STIMULATION OF THE ANTERIOR CINGULATE CORTEX AMELIORATES AUTISTIC-LIKE BEHAVIORS IN RATS INDUCED BY NEONATAL ISOLATION, CAUDATE PUTAMEN AS A SITE FOR ALTERATION. EPIGENETIC AGENTS, SUCH AS NEONATAL ISOLATION DURING NEURODEVELOPMENTAL PERIOD OF LIFE, CAN CHANGE VARIOUS REGIONS OF THE BRAIN. IT MAY FURTHER INDUCE PSYCHOLOGICAL DISORDERS SUCH AS AUTISTIC-LIKE PHENOMENA. THIS STUDY INDICATED THE ROLE OF CHRONIC INCREASED ANTERIOR CINGULATE CORTEX (ACC) OUTPUT ON ALTERATION OF CAUDATE PUTAMEN (CPU) AS A MAIN BEHAVIOR REGULATOR REGION OF THE BRAIN IN ADULT MATERNAL DEPRIVED (MD) RATS. FOR MAKING AN ANIMAL MODEL, NEONATES WERE ISOLATED FROM THEIR MOTHERS IN POSTNATAL DAYS (PND 1-10, 3 H/DAY). SUBSEQUENTLY, THEY BILATERALLY RECEIVED PLENTI-CAMKIIA-HCHR2 (H134R)-MCHERRY-WPRE VIRUS IN ACC AREA VIA STEREOTAXIC SURGERY IN PND50. AFTER 22 DAYS, THESE REGIONS WERE EXPOSED TO BLUE LASER (473 NM) FOR SIX CONSECUTIVE DAYS (15 MIN/DAY). THEN, BEHAVIORAL DEFICITS WERE TESTED AND WERE COMPARED WITH CONTROL GROUP IN THE FOLLOWING DAY. ANIMALS WERE IMMEDIATELY KILLED AND THEIR BRAINS WERE PREPARED FOR TISSUE PROCESSING. RESULTS SHOWED THAT NEONATAL ISOLATION INDUCES AUTISTIC-LIKE BEHAVIORS AND LEADS TO OVEREXPRESSION OF NMDAR1 AND NOX2-GP91(PHOX) PROTEINS AND ELEVATION OF CATALASE ACTIVITY IN THE CPU REGIONS OF THE ADULT OFFSPRING COMPARED WITH CONTROL GROUP. CHRONIC OPTOGENETIC STIMULATION OF ACC NEURONS CONTAINING (CHR2+) LED TO SIGNIFICANT REDUCTION IN THE APPEARANCE OF STEREOTYPICAL BEHAVIOR AND ALIEN-PHOBIA IN MD RATS. THE AMOUNT OF NMDAR1 AND NOX2-GP91(PHOX) EXPRESSION AND THE CATALASE ACTIVITY IN CPU WERE REDUCED AFTER THIS TREATMENT. THEREFORE, AUTISTIC-LIKE BEHAVIOR SEEMS TO BE RELATED WITH ELEVATION OF NMDAR1 AND NOX2-GP91(PHOX) PROTEIN LEVELS THAT ENHANCE THE EFFECT OF GLUTAMATERGIC PROJECTION ON CPU REGIONS. OPTOGENETIC TREATMENT ALSO COULD AMELIORATE BEHAVIORAL DEFICITS BY MODULATING THESE PROTEIN DENSITIES.	2019	
                                                                                                                                                                                                                                                                                                                                                   
4   168  23 ABNORMAL TRANSMETHYLATION/TRANSSULFURATION METABOLISM AND DNA HYPOMETHYLATION AMONG PARENTS OF CHILDREN WITH AUTISM. AN INTEGRATED METABOLIC PROFILE REFLECTS THE COMBINED INFLUENCE OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS THAT AFFECT THE CANDIDATE PATHWAY OF INTEREST. RECENT EVIDENCE SUGGESTS THAT SOME AUTISTIC CHILDREN MAY HAVE REDUCED DETOXIFICATION CAPACITY AND MAY BE UNDER CHRONIC OXIDATIVE STRESS. BASED ON REPORTS OF ABNORMAL METHIONINE AND GLUTATHIONE METABOLISM IN AUTISTIC CHILDREN, IT WAS OF INTEREST TO EXAMINE THE SAME METABOLIC PROFILE IN THE PARENTS. THE RESULTS INDICATED THAT PARENTS SHARE SIMILAR METABOLIC DEFICITS IN METHYLATION CAPACITY AND GLUTATHIONE-DEPENDENT ANTIOXIDANT/DETOXIFICATION CAPACITY OBSERVED IN MANY AUTISTIC CHILDREN. STUDIES ARE UNDERWAY TO DETERMINE WHETHER THE ABNORMAL PROFILE IN PARENTS REFLECTS LINKED GENETIC POLYMORPHISMS IN THESE PATHWAYS OR WHETHER IT SIMPLY REFLECTS THE CHRONIC STRESS OF COPING WITH AN AUTISTIC CHILD.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
5  6300  33 THE PUTATIVE ROLE OF ENVIRONMENTAL ALUMINIUM IN THE DEVELOPMENT OF CHRONIC NEUROPATHOLOGY IN ADULTS AND CHILDREN. HOW STRONG IS THE EVIDENCE AND WHAT COULD BE THE MECHANISMS INVOLVED? THE CONCEPTUALISATION OF AUTISTIC SPECTRUM DISORDER AND ALZHEIMER'S DISEASE HAS UNDERGONE SOMETHING OF A PARADIGM SHIFT IN RECENT YEARS AND RATHER THAN BEING VIEWED AS SINGLE ILLNESSES WITH A UNITARY PATHOGENESIS AND PATHOPHYSIOLOGY THEY ARE INCREASINGLY CONSIDERED TO BE HETEROGENEOUS SYNDROMES WITH A COMPLEX MULTIFACTORIAL AETIOPATHOGENESIS, INVOLVING A HIGHLY COMPLEX AND DIVERSE COMBINATION OF GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS. ONE SUCH ENVIRONMENTAL FACTOR IMPLICATED AS A POTENTIAL CAUSE IN BOTH SYNDROMES IS ALUMINIUM, AS AN ELEMENT OR AS PART OF A SALT, RECEIVED, FOR EXAMPLE, IN ORAL FORM OR AS AN ADJUVANT. SUCH ADMINISTRATION HAS THE POTENTIAL TO INDUCE PATHOLOGY VIA SEVERAL ROUTES SUCH AS PROVOKING DYSFUNCTION AND/OR ACTIVATION OF GLIAL CELLS WHICH PLAY AN INDISPENSABLE ROLE IN THE REGULATION OF CENTRAL NERVOUS SYSTEM HOMEOSTASIS AND NEURODEVELOPMENT. OTHER ROUTES INCLUDE THE GENERATION OF OXIDATIVE STRESS, DEPLETION OF REDUCED GLUTATHIONE, DIRECT AND INDIRECT REDUCTIONS IN MITOCHONDRIAL PERFORMANCE AND INTEGRITY, AND INCREASING THE PRODUCTION OF PROINFLAMMATORY CYTOKINES IN BOTH THE BRAIN AND PERIPHERALLY. THE MECHANISMS WHEREBY ENVIRONMENTAL ALUMINIUM COULD CONTRIBUTE TO THE DEVELOPMENT OF THE HIGHLY SPECIFIC PATTERN OF NEUROPATHOLOGY SEEN IN ALZHEIMER'S DISEASE ARE DESCRIBED. ALSO DETAILED ARE SEVERAL MECHANISMS WHEREBY SIGNIFICANT QUANTITIES OF ALUMINIUM INTRODUCED VIA IMMUNISATION COULD PRODUCE CHRONIC NEUROPATHOLOGY IN GENETICALLY SUSCEPTIBLE CHILDREN. ACCORDINGLY, IT IS RECOMMENDED THAT THE USE OF ALUMINIUM SALTS IN IMMUNISATIONS SHOULD BE DISCONTINUED AND THAT ADULTS SHOULD TAKE STEPS TO MINIMISE THEIR EXPOSURE TO ENVIRONMENTAL ALUMINIUM.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                       
6  4068  23 MATERNAL ANDROGEN EXCESS AND OBESITY INDUCE SEXUALLY DIMORPHIC ANXIETY-LIKE BEHAVIOR IN THE OFFSPRING. MATERNAL POLYCYSTIC OVARY SYNDROME (PCOS), A CONDITION ASSOCIATED WITH HYPERANDROGENISM, IS SUGGESTED TO INCREASE ANXIETY-LIKE BEHAVIOR IN THE OFFSPRING. BECAUSE PCOS IS CLOSELY LINKED TO OBESITY, WE INVESTIGATED THE IMPACT OF AN ADVERSE HORMONAL OR METABOLIC MATERNAL ENVIRONMENT AND OFFSPRING OBESITY ON ANXIETY IN THE OFFSPRING. THE OBESE PCOS PHENOTYPE WAS INDUCED BY CHRONIC HIGH-FAT-HIGH-SUCROSE (HFHS) CONSUMPTION TOGETHER WITH PRENATAL DIHYDROTESTOSTERONE EXPOSURE IN MOUSE DAMS. ANXIETY-LIKE BEHAVIOR WAS ASSESSED IN ADULT OFFSPRING WITH THE ELEVATED-PLUS MAZE AND OPEN-FIELD TESTS. THE INFLUENCE OF MATERNAL ANDROGENS AND MATERNAL AND OFFSPRING DIET ON GENES IMPLICATED IN ANXIETY WERE ANALYZED IN THE AMYGDALA AND HYPOTHALAMUS WITH REAL-TIME PCR ( N = 47). INDEPENDENT OF DIET, FEMALE OFFSPRING EXPOSED TO MATERNAL ANDROGENS WERE MORE ANXIOUS AND DISPLAYED UP-REGULATION OF ADRENOCEPTOR ALPHA 1B IN THE AMYGDALA AND UP-REGULATION OF HYPOTHALAMIC CORTICOTROPIN-RELEASING HORMONE ( CRH). BY CONTRAST, MALE OFFSPRING EXPOSED TO A HFHS MATERNAL DIET HAD INCREASED ANXIETY-LIKE BEHAVIOR AND SHOWED UP-REGULATION OF EPIGENETIC MARKERS IN THE AMYGDALA AND UP-REGULATION OF HYPOTHALAMIC CRH. OVERALL, THERE WERE SUBSTANTIAL SEX DIFFERENCES IN GENE EXPRESSION IN THE BRAIN. THESE FINDINGS PROVIDE NOVEL INSIGHT INTO HOW MATERNAL ANDROGENS AND OBESITY EXERT SEX-SPECIFIC EFFECTS ON BEHAVIOR AND GENE EXPRESSION IN THE OFFSPRING OF A PCOS MOUSE MODEL.-MANTI, M., FORNES, R., QI, X., FOLMERZ, E., LINDEN HIRSCHBERG, A., DE CASTRO BARBOSA, T., MALIQUEO, M., BENRICK, A., STENER-VICTORIN, E. MATERNAL ANDROGEN EXCESS AND OBESITY INDUCE SEXUALLY DIMORPHIC ANXIETY-LIKE BEHAVIOR IN THE OFFSPRING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
7  5178  21 PREGNANCY AS A FUNDAMENTAL DETERMINANT OF CHILD HEALTH: A REVIEW. PURPOSE OF REVIEW: MATERNAL CONDITIONS AND EXPOSURES DURING PREGNANCY INCLUDING OVER- AND UNDERNUTRITION ARE ASSOCIATED WITH POOR CHILDBIRTH OUTCOMES, GROWTH, DEVELOPMENT AND CHRONIC CHILDHOOD DISEASES. WE EXAMINED CONTEMPORARY PREGNANCY-RELATED DETERMINANTS OF CHILD HEALTH. RECENT FINDINGS: WHILE MATERNAL UNDERNUTRITION REMAINS A MAJOR CONTRIBUTOR TO LOW BIRTH WEIGHT, MATERNAL OBESITY AFFECTS FOETAL GROWTH, BIRTH WEIGHT, SURVIVAL AND IS ASSOCIATED WITH CHILDHOOD OBESITY, ASTHMA AND AUTISTIC SPECTRUM DISORDERS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC CHANGES, THE PRENATAL MICROBIOME AND MATERNAL IMMUNE ACTIVATION (MIA), A NEUROINFLAMMATORY PROCESS INDUCED BY DIET AND OTHER EXPOSURES CAUSE FOETAL PROGRAMMING RESULTING IN THESE CHRONIC CHILDHOOD DISEASES. MATERNAL DIET IS POTENTIALLY A MODIFIABLE RISK FACTOR FOR CONTROLLING LOW BIRTH WEIGHT, OBESITY AND CHRONIC DISEASE IN CHILDHOOD. FURTHER STUDIES ARE WARRANTED TO REFINE GUIDANCE ON DIETARY RESTRICTION AND PHYSICAL ACTIVITY DURING PREGNANCY AND DETERMINE HOW MIA AND PRENATAL MICROBIOTA CAN BE APPLIED TO CONTROL CHILDHOOD DISEASES ARISING FROM PROGRAMMING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8  4939  30 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	
                                                                                                                                                                      
9   267  27 AFFECTIVE AND COGNITIVE BEHAVIOR IN THE ALPHA-GALACTOSIDASE A DEFICIENT MOUSE MODEL OF FABRY DISEASE. FABRY DISEASE IS AN X-LINKED INHERITED LYSOSOMAL STORAGE DISORDER WITH INTRACELLULAR ACCUMULATION OF GLOBOTRIAOSYLCERAMIDE (GB3) DUE TO ALPHA-GALACTOSIDASE A (ALPHA-GAL A) DEFICIENCY. FABRY PATIENTS FREQUENTLY REPORT OF ANXIETY, DEPRESSION, AND IMPAIRED COGNITIVE FUNCTION. WE CHARACTERIZED AFFECTIVE AND COGNITIVE PHENOTYPE OF MALE MICE WITH ALPHA-GAL A DEFICIENCY (FABRY KO) AND COMPARED RESULTS WITH THOSE OF AGE-MATCHED MALE WILDTYPE (WT) LITTERMATES. YOUNG (3 MONTHS) AND OLD (>/= 18 MONTHS) MICE WERE TESTED IN THE NAIVE STATE AND AFTER I.PL. INJECTION OF COMPLETE FREUND;S ADJUVANT (CFA) AS AN INFLAMMATORY PAIN MODEL. WE USED THE ELEVATED PLUS MAZE (EPM), THE LIGHT-DARK BOX (LDB) AND THE OPEN FIELD TEST (OF) TO INVESTIGATE ANXIETY-LIKE BEHAVIOR. THE FORCED SWIM TEST (FST) AND MORRIS WATER MAZE (MWM) WERE APPLIED TO ASSESS DEPRESSIVE-LIKE AND LEARNING BEHAVIOR. THE EPM TEST REVEALED NO INTERGROUP DIFFERENCE FOR ANXIETY-LIKE BEHAVIOR IN NAIVE YOUNG AND OLD FABRY KO MICE COMPARED TO WT LITTERMATES, EXCEPT FOR LONGER TIME SPENT IN OPEN ARMS OF THE EPM FOR YOUNG WT MICE COMPARED TO YOUNG FABRY KO MICE (P<0.05). AFTER CFA INJECTION, YOUNG FABRY KO MICE SHOWED INCREASED ANXIETY-LIKE BEHAVIOR COMPARED TO YOUNG WT LITTERMATES (P<0.05) AND NAIVE YOUNG FABRY KO MICE (P<0.05) IN THE EPM AS REFLECTED BY SHORTER TIME SPENT IN EPM OPEN ARMS. THERE WERE NO RELEVANT DIFFERENCES IN THE LDB AND THE OF TEST, EXCEPT FOR LONGER TIME SPENT IN THE CENTER ZONE OF THE OF BY YOUNG WT MICE COMPARED TO YOUNG FABRY KO MICE (P<0.05). COMPLEMENTARY TO THIS, DEPRESSION-LIKE AND LEARNING BEHAVIOR WERE NOT DIFFERENT BETWEEN GENOTYPES AND AGE-GROUPS, EXCEPT FOR THE EXPECTEDLY LOWER MEMORY PERFORMANCE IN OLDER AGE-GROUPS COMPARED TO YOUNG MICE. OUR RESULTS INDICATE THAT GENETIC INFLUENCES ON AFFECTIVE AND COGNITIVE SYMPTOMS IN FD MAY BE OF SUBORDINATE RELEVANCE, DRAWING ATTENTION TO POTENTIAL INFLUENCES OF ENVIRONMENTAL AND EPIGENETIC FACTORS.	2017	
                                                                                                                                                                                                                                                 
10  1821  27 EFFECTS OF CHRONIC SOCIAL DEFEAT ON BEHAVIORAL AND NEURAL CORRELATES OF SOCIALITY: VASOPRESSIN, OXYTOCIN AND THE VASOPRESSINERGIC V1B RECEPTOR. CHRONIC SOCIAL STRESS IN RODENTS PRODUCES BEHAVIORAL AND NEUROENDOCRINE PATTERNS ANALOGOUS TO SYMPTOMS ASSOCIATED WITH PSYCHOPATHOLOGIES IN HUMANS. CHRONIC SOCIAL DEFEAT IN MICE HAS BEEN USED TO STUDY THE GENETIC AND EPIGENETIC PRECURSORS OF STRESS-RELATED SOCIAL DISORDERS. THE NEUROPEPTIDES ARGININE VASOPRESSIN (AVP) AND OXYTOCIN (OT) ARE RELEASED IN CENTRAL TARGETS TO MODULATE ANTI- AND PRO-SOCIAL BEHAVIORS, RESPECTIVELY. AVP BINDS TO V1A AND V1B RECEPTORS (V1BRS) IN DISCRETE BRAIN REGIONS RELATED TO ANXIETY, DEPRESSION AND AFFILIATIVE BEHAVIORS. RECENT EVIDENCE SUGGESTS THAT V1BRS ARE INVOLVED IN STRESS AND ANXIETY AND MAY BE AN ATTRACTIVE TARGET FOR THE TREATMENT OF ASSOCIATED DISORDERS. IN THE PRESENT SERIES OF EXPERIMENTS, WE AIMED TO EVALUATE THE EFFECTS OF CHRONIC SOCIAL DEFEAT STRESS ON: 1) ANXIETY-RELATED BEHAVIORS IN A SOCIAL INVESTIGATION PARADIGM AND THEIR POTENTIAL MODULATION BY AN ACUTE DOSE OF SSR149415, A V1BR ANTAGONIST; 2) AVP AND FOS PROTEIN LEVELS IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS (PVN) AND; 3) AVP- AND OT-RECEPTOR (OTR) MRNA LEVELS IN BRAIN REGIONS ASSOCIATED WITH SOCIALITY. WHEN COMPARED TO UNDEFEATED ANIMALS, SOCIALLY DEFEATED MICE EXHIBITED AN ANXIOGENIC BEHAVIORAL PROFILE TOWARDS A NOVEL MALE CONSPECIFIC, WITH SSR149415 PARTLY ATTENUATING THESE EFFECTS. HISTOCHEMISTRY USING IMMUNOFLUORESCENCE SHOWED DEFEAT PRODUCED SIGNIFICANT ELEVATIONS OF FOS AND DOUBLE LABELING OF AVP AND FOS PROTEINS IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS (PVN). SSR149415 ATTENUATED THE EFFECTS OF DEFEAT ON FOS AND AVP/FOS DOUBLE LABELING, CONSISTENT WITH AN ANXIOLYTIC EFFECT. DEFEATED MICE SHOWED ELEVATED LEVELS OF OTR MRNA LEVELS IN THE LATERAL SEPTUM (LS) IN ADDITION TO INCREASED V1BR AND OTR MRNA IN THE MEDIAL AMYGDALA (MEA). WE SUGGEST THE INVOLVEMENT OF V1BRS AND OTRS IN A CIRCUIT INVOLVING THE PVN, MEA AND LS IN THE EFFECTS OF DEFEAT ON SOCIALITY. SSR149415 ATTENUATED ANXIOGENESIS IN THE SOCIAL INVESTIGATION MODEL AND BOTH FOS AND AVP/FOS LABELING, SUGGESTING V1BRS ARE AN ATTRACTIVE TARGET FOR THE TREATMENT OF ANXIETY IN GENERAL AND DISORDERS OF SOCIALITY IN PARTICULAR.	2011	

11   905  32 CHRONIC EXPOSURE TO CANNABINOIDS DURING ADOLESCENCE CAUSES LONG-LASTING BEHAVIORAL DEFICITS IN ADULT MICE. REGULAR USE OF MARIJUANA DURING ADOLESCENCE ENHANCES THE RISK OF LONG-LASTING NEUROBIOLOGICAL CHANGES IN ADULTHOOD. THE PRESENT STUDY WAS AIMED AT ASSESSING THE EFFECT OF LONG-TERM ADMINISTRATION OF THE SYNTHETIC CANNABINOID WIN55212.2 DURING ADOLESCENCE IN YOUNG ADULT MICE. ADOLESCENT MICE AGED 5 WEEKS WERE SUBJECTED DAILY TO THE PHARMACOLOGICAL ACTION OF WIN55212.2 FOR 3 WEEKS AND WERE THEN LEFT UNDISTURBED IN THEIR HOME CAGE FOR A 5-WEEK PERIOD AND FINALLY EVALUATED BY BEHAVIORAL TESTING. MICE THAT RECEIVED THE DRUG DURING ADOLESCENCE SHOWED MEMORY IMPAIRMENT IN THE MORRIS WATER MAZE, AS WELL AS A DOSE-DEPENDENT MEMORY IMPAIRMENT IN FEAR CONDITIONING. IN ADDITION, THE ADMINISTRATION OF 3 MG/KG WIN55212.2 IN ADOLESCENCE INCREASED ADULT HIPPOCAMPAL AEA LEVELS AND PROMOTED DNA HYPERMETHYLATION AT THE INTRAGENIC REGION OF THE INTRACELLULAR SIGNALING MODULATOR RGS7, WHICH WAS ACCOMPANIED BY A LOWER RATE OF MRNA TRANSCRIPTION OF THIS GENE, SUGGESTING A POTENTIAL CAUSAL RELATION. ALTHOUGH THE CONCRETE MECHANISMS UNDERLYING THE BEHAVIORAL OBSERVATIONS REMAIN TO BE ELUCIDATED, WE DEMONSTRATE THAT LONG-TERM ADMINISTRATION OF 3 MG/KG OF WIN DURING ADOLESCENCE LEADS TO INCREASED ENDOCANNABINOID LEVELS AND ALTERED RGS7 EXPRESSION IN ADULTHOOD AND ESTABLISH A POTENTIAL LINK TO EPIGENETIC CHANGES.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12   369  23 AN ANDROGEN-DEPENDENT SEXUAL DIMORPHISM VISIBLE AT PUBERTY IN THE RAT HYPOTHALAMUS. MORPHOLOGICAL STUDIES IN RODENTS HAVE WELL DOCUMENTED THE MASCULINIZATION OF THE PERINATAL BRAIN BY ESTRADIOL DERIVED FROM AROMATIZED TESTOSTERONE, AND THE RESULTING IRREVERSIBLE QUANTITATIVE SEX-DIFFERENCES GENERATED IN CELL NUMBERS OR EXPRESSION OF CHEMICAL PHENOTYPES. HERE, USING IMMUNOHISTOCHEMISTRY, WE EXPLORED HOW THIS APPLIES TO THE POSTNATAL DEVELOPMENT AND MASCULINIZATION OF THE NEUROKININ B (NKB)-CONTAINING SYSTEM OF THE ARCUATE NUCLEUS/MEDIAN EMINENCE COMPLEX (ARC/ME). IN ADULT RATS, NKB-IMMUNOREACTIVE NEURONS EXHIBIT AN UNUSUAL, QUALITATIVE SEXUAL DIMORPHISM OF THEIR VENTRAL AXONAL PROJECTIONS: TO THE NEUROPIL IN FEMALES, TO CAPILLARY VESSELS IN MALES. IN ADULTS, THERE WAS NO SEX-DIFFERENCE IN THE NUMBERS OF NKB-IMMUNOREACTIVE PERIKARYA OR CAPILLARY VESSELS IN THE ARC/ME, SUGGESTING THAT THIS SEXUAL DIMORPHISM CANNOT BE EXPLAINED BY THE EXISTENCE OF SUPERNUMERARY STRUCTURES. AT BIRTH (DAY 0) THE NKB SYSTEM WAS IMMATURE IN BOTH SEXES, AND WHILE ITS ADULT FEATURES EMERGED PROGRESSIVELY UNTIL PUBERTY IN FEMALES, THEY DID NOT DEVELOP BEFORE PUBERTY (DAY 40) IN MALES, REVEALING A SEXUAL DIMORPHISM ONLY LATE POSTNATALLY. WHEN MALES WERE ORCHIDECTOMIZED AT DAY 30, THE MASCULINE DISTRIBUTION OF NKB-IMMUNOREACTIVE AXONS EXPECTED AT DAY 40 WAS NOT SEEN, WHILE IT WAS APPARENT AFTER CHRONIC TREATMENT WITH TESTOSTERONE OR DIHYDROTESTOSTERONE, SUGGESTING A TESTICULAR MASCULINIZING ACTION VIA ANDROGEN RECEPTORS AT PUBERTY. MOREOVER IN THESE PREPUBERTAL-ORCHIDECTOMIZED MALES, THE DISTRIBUTION OF NKB-IMMUNOREACTIVE AXONS WAS SURPRISINGLY FEMINIZED BY CHRONIC ESTRADIOL ALONE, SUGGESTING THAT NKB NEURONS ARE NOT IRREVERSIBLY PROGRAMMED BEFORE PUBERTY. LAST, IN ADULT FEMALES, THE DISTRIBUTION OF NKB-IMMUNOREACTIVE AXONS WAS FEMININE 30 DAYS AFTER OVARIECTOMY, AND IT WAS MASCULINIZED AFTER CONCURRENT CHRONIC DIHYDROTESTOSTERONE, SUGGESTING THAT NKB NEURONS REMAIN RESPONSIVE TO ANDROGENS LATE IN REPRODUCTIVE LIFE. THUS, THE SEXUAL DIFFERENTIATION OF THE HYPOTHALAMUS PROCEEDS WELL BEYOND THE PERINATAL PERIOD AND INCLUDES THE EPIGENETIC ACTION OF NON-AROMATIZABLE ANDROGENS UPON SUBSETS OF NEURONS THAT HAVE RETAINED BIPOTENT FEATURES.	2007	
                                       
13  1004  26 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	
                                                                                                                                                                                                                                                                                                                                                                                                        
14  1774  25 EARLY-LIFE STRESS: FROM NEUROENDOCRINE MECHANISMS TO STRESS-RELATED DISORDERS. STRESS EXPOSURE IS HIGHLY PREVALENT IN THE GENERAL POPULATION; HOWEVER, THE EXPERIENCE OF STRESS DURING VULNERABLE PERIODS OF DEVELOPMENT HAS SUBSTANTIAL AND PERMANENT EFFECTS ON BRAIN STRUCTURE AND FUNCTION AND PHYSICAL HEALTH IN ADULTHOOD. STRESS, THE STATE OF THREATENED HOMEOSTASIS, IS GENERALLY ASSOCIATED WITH A TIME-LIMITED ACTIVATION OF THE STRESS SYSTEM, I.E., THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS AND THE AROUSAL/SYMPATHETIC NERVOUS SYSTEM, TAILORED TO THE STRESSFUL STIMULUS ALSO KNOWN AS THE STRESSOR. ON THE OTHER HAND, CHRONIC STRESS MAY BE ASSOCIATED WITH LINGERING HYPER- OR HYPOSECRETION OF MEDIATORS OF THE STRESS SYSTEM. THIS CHRONIC CONDITION IS CALLED DYSHOMEOSTASIS, ALLOSTASIS, OR CACOSTASIS AND IS ASSOCIATED WITH INCREASED MENTAL AND PHYSICAL MORBIDITY IN THE LONG TERM. STRESSFUL OR TRAUMATIC EXPERIENCES DURING FETAL LIFE, EARLY CHILDHOOD, AND ADOLESCENCE HAVE BEEN RELATED TO PERSISTENT NEUROENDOCRINE AND EPIGENETIC CHANGES. FURTHER, BRAIN STRUCTURES INVOLVED IN THE STRESS RESPONSE, SUCH AS THOSE OF THE STRESS SYSTEM, THE HIPPOCAMPUS, AND THE AMYGDALA, MAY BE PROGRAMMED EARLY ON FOR A LIFE OF ADVERSITY.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15  1804  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
16  4938  30 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  5201  26 PRENATAL MORPHINE EXPOSURE INCREASES GAMMA OSCILLATION AND THETA COHERENCE IN THE RAT REWARD SYSTEM. PREVIOUS STUDIES HAVE FOUND THAT PRENATAL MORPHINE (PNM) EXPOSURE LEADS TO BOTH INCREASED AND DECREASED RISK OF SUBSTANCE ABUSE IN OFFSPRING. UNDERSTANDING MORE ABOUT THE NEUROBIOLOGICAL CHANGES AFTER THE PNM EXPOSURE WOULD HELP TO UNDERSTAND MORE ABOUT THIS ISSUE. SIGNALING FROM DOPAMINE NEURONS OF THE VENTRAL TEGMENTAL AREA (VTA) IN THE MESOACCUMBAL AND MESOCORTICAL PATHWAYS PLAYS A VITAL ROLE IN DRUG DEPENDENCY. TO PROVIDE FURTHER KNOWLEDGE ABOUT THE EFFECTS OF PNM ON DRUG SEEKING BEHAVIOR AND THE DOPAMINE SYSTEM. WE RECORDED LOCAL FIELD POTENTIALS (LFP) SIMULTANEOUSLY IN THE VTA, NAC (NUCLEUS ACCUMBENS), BLA (BASOLATERAL AMYGDALA) AND MPFC (MEDIAL PREFRONTAL CORTEX) IN MALE ADULT RATS PRENATALLY TREATED WITH SALINE OR MORPHINE. MORPHINE (10 MG/KG) INDUCED CONDITIONED PLACE PREFERENCE (CPP) ESTABLISHMENT, EXTINCTION AND PRIMING WERE TESTED TO INVESTIGATE THE EFFECTS OF PNM ON ADDICTIVE-LIKE BEHAVIOR. IN ADDITION, THE EXPRESSION OF NUCLEAR HISTONE DEACETYLASES (HDAC4, HDAC5), WHICH PLAYS ESSENTIAL EPIGENETIC ROLES IN NEUROPLASTICITY AFTER DRUG USE WERE ALSO TESTED IN VTA AND NAC. THE RESULTS SHOWED THAT PNM DID NOT CHANGE THE ACQUISITION OF MORPHINE CPP IN MALE RATS, BUT IMPAIRED CPP EXTINCTION AND MORPHINE (5 MG/KG) - PRIMED REINSTATEMENT OF CPP AFTER EXTINCTION. PNM INCREASED THE LOW GAMMA (30-60 HZ) AND HIGH (60-90 HZ) GAMMA LFP POWERS IN NAC AND BLA. PNM ALSO LEADS TO INCREASED THETA (4-9 HZ) COHERENCE BETWEEN VTA AND NAC, AND INCREASED HDAC5 EXPRESSION IN VTA. AFTER CHRONIC MORPHINE ADMINISTRATION, COHERENCE BETWEEN VTA-NAC, MPFC-NAC AND MPFC-BLA INCREASED SIGNIFICANTLY IN PNS RATS, BUT NO CHANGES WERE FIND IN PNM RATS, INDICATING IMPAIRED PLASTICITY IN BRAIN CIRCUITS. ALL THESE RESULTS SUGGEST THAT PNM EXPOSURE INCREASED REWARD PROCESSING IN ADULT MALE RATS, BUT IMPAIRED MORPHINE CPP EXTINCTION AND REINSTATEMENT, WHICH RELATE TO DECREASES NETWORK PLASTICITY AND INCREASED HDAC5 EXPRESSION IN THE REWARD SYSTEM.	2022	
                                                                                                                                                                                                                                       
18  5819  24 STRESS CHANGES AMPHETAMINE RESPONSE, D2 RECEPTOR EXPRESSION AND EPIGENETIC REGULATION IN LOW-ANXIETY RATS. THE AIM OF THIS STUDY WAS TO ASSESS THE INFLUENCE OF CHRONIC RESTRAINT STRESS ON AMPHETAMINE (AMPH)-RELATED APPETITIVE 50-KHZ ULTRASONIC VOCALISATIONS (USVS) IN RATS DIFFERING IN FREEZING DURATION IN A CONTEXTUAL FEAR TEST (CFT), I.E. HR (HIGH-ANXIETY RESPONSIVE) AND LR (LOW-ANXIETY RESPONSIVE) RATS. THE LR AND THE HR RATS, PREVIOUSLY EXPOSED TO AN AMPH BINGE EXPERIENCE, DIFFERED IN SENSITIVITY TO AMPH'S REWARDING EFFECTS, MEASURED AS APPETITIVE VOCALISATIONS. MOREOVER, CHRONIC RESTRAINT STRESS ATTENUATED AMPH-RELATED APPETITIVE VOCALISATIONS IN THE LR RATS BUT HAD NO INFLUENCE ON THE HR RATS' BEHAVIOUR. TO SPECIFY, THE RESTRAINT LR RATS VOCALISED APPETITIVELY LESS IN THE AMPH-ASSOCIATED CONTEXT AND AFTER AN AMPH CHALLENGE THAN THE CONTROL LR RATS. THIS PHENOMENON WAS ASSOCIATED WITH A DECREASE IN THE MRNA LEVEL FOR D2 DOPAMINE RECEPTOR IN THE AMYGDALA AND ITS PROTEIN EXPRESSION IN THE BASAL AMYGDALA (BA) AND OPPOSITE CHANGES IN THE NUCLEUS ACCUMBENS (NAC) - AN INCREASE IN THE MRNA LEVEL FOR D2 DOPAMINE RECEPTOR AND ITS PROTEIN EXPRESSION IN THE NAC SHELL, COMPARED TO CONTROL CONDITIONS. MOREOVER, WE OBSERVED THAT CHRONIC RESTRAINT STRESS INFLUENCED EPIGENETIC REGULATION IN THE LR AND THE HR RATS DIFFERENTLY. THE CONTRASTING CHANGES WERE OBSERVED IN THE DENTATE GYRUS (DG) OF THE HIPPOCAMPUS - THE LR RATS PRESENTED A DECREASE, BUT THE HR RATS SHOWED AN INCREASE IN H3K9 TRIMETHYLATION. THE RESTRAINT LR RATS ALSO SHOWED HIGHER MIR-494 AND MIR-34C LEVELS IN THE NAC THAN THE CONTROL LR GROUP. OUR STUDY PROVIDES BEHAVIOURAL AND BIOCHEMICAL DATA CONCERNING THE ROLE OF DIFFERENCES IN FEAR-CONDITIONED RESPONSE IN STRESS VULNERABILITY AND AMPH-ASSOCIATED APPETITIVE BEHAVIOUR. THE LR RATS WERE LESS SENSITIVE TO THE REWARDING EFFECTS OF AMPH WHEN PREVIOUSLY EXPOSED TO CHRONIC STRESS THAT WAS ACCOMPANIED BY CHANGES IN D2 DOPAMINE RECEPTOR EXPRESSION AND EPIGENETIC REGULATION IN MESOLIMBIC AREAS.	2019	
                                                                                                                                                                                                                                                                    
19  4086  23 MATERNAL OBESITY DISRUPTS THE METHIONINE CYCLE IN BABOON PREGNANCY. MATERNAL INTAKE OF DIETARY METHYL-MICRONUTRIENTS (E.G. FOLATE, CHOLINE, BETAINE AND VITAMIN B-12) DURING PREGNANCY IS ESSENTIAL FOR NORMAL MATERNAL AND FETAL METHIONINE METABOLISM, AND IS CRITICAL FOR IMPORTANT METABOLIC PROCESSES INCLUDING THOSE INVOLVED IN DEVELOPMENTAL PROGRAMMING. MATERNAL OBESITY AND NUTRIENT EXCESS DURING PREGNANCY INFLUENCE DEVELOPMENTAL PROGRAMMING POTENTIALLY PREDISPOSING ADULT OFFSPRING TO A VARIETY OF CHRONIC HEALTH PROBLEMS. IN THE PRESENT STUDY, WE HYPOTHESIZED THAT MATERNAL OBESITY WOULD DYSREGULATE THE MATERNAL AND FETAL METHIONINE CYCLE. TO TEST THIS HYPOTHESIS, WE DEVELOPED A NULLIPAROUS BABOON OBESITY MODEL FED A HIGH FAT, HIGH ENERGY DIET (HF-HED) PRIOR TO AND DURING GESTATION, AND EXAMINED METHIONINE CYCLE BIOMARKERS (E.G., CIRCULATING CONCENTRATIONS OF HOMOCYSTEINE, METHIONINE, CHOLINE, BETAINE, KEY AMINO ACIDS, FOLATE, AND VITAMIN B-12). ANIMALS WERE GROUP HOUSED ALLOWING FULL PHYSICAL ACTIVITY AND SOCIAL INTERACTION. MATERNAL PREPREGNANCY PERCENT BODY FAT WAS 5% IN CONTROLS AND 19% IN HF-HED MOTHERS, WHILE FETAL WEIGHT WAS 16% LOWER IN OFFSPRING OF HF-HED MOTHERS AT TERM. MATERNAL AND FETAL HOMOCYSTEINE WERE HIGHER, WHILE MATERNAL AND FETAL VITAMIN B-12 AND BETAINE WERE LOWER IN THE HF-HED GROUP. ELEVATIONS IN CIRCULATING MATERNAL FOLATE WERE EVIDENT IN THE HF-HED GROUP INDICATING IMPAIRED FOLATE METABOLISM (METHYL-TRAP) AS A CONSEQUENCE OF MATERNAL VITAMIN B-12 DEPLETION. FINALLY, FETAL METHIONINE, GLYCINE, SERINE, AND TAURINE WERE LOWER IN THE HF-HED FETUSES. THESE DATA SHOW THAT MATERNAL OBESITY DISTURBS THE METHIONINE CYCLE IN PRIMATE PREGNANCY, PROVIDING A MECHANISM FOR THE EPIGENETIC CHANGES OBSERVED AMONG OBESE PREGNANT WOMEN AND SUGGESTING DIAGNOSTIC AND THERAPEUTIC OPPORTUNITIES IN HUMAN PREGNANCIES COMPLICATED BY OBESITY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                             
20   580  34 BEHAVIORAL AND NEUROBIOLOGICAL EFFECTS OF PRENATAL STRESS EXPOSURE IN MALE AND FEMALE APPSWE/PS1DE9 MICE. EPIDEMIOLOGICAL EVIDENCE IMPLIES A ROLE FOR CHRONIC STRESS AND STRESS-RELATED DISORDERS IN THE ETIOPATHOGENESIS OF SPORADIC ALZHEIMER'S DISEASE (AD). ALTHOUGH CHRONIC STRESS EXPOSURE DURING VARIOUS STAGES OF LIFE HAS BEEN SHOWN TO EXACERBATE AD-RELATED COGNITIVE DEFICITS AND NEUROPATHOLOGY IN AD MOUSE MODELS, THE ROLE OF STRESS EXPOSURE DURING THE PRENATAL PERIOD ON AD DEVELOPMENT AND PROGRESSION REMAINED TO BE INVESTIGATED. THE PRESENT STUDY THEREFORE EXPLORED THE EFFECTS OF PRENATAL MATERNAL STRESS (PMS) IN BOTH MALE AND FEMALE APPSWE/PS1DE9 MOUSE OFFSPRING IN TERMS OF COGNITION, AFFECT, AND AD-RELATED NEUROPATHOLOGY. AS PRENATAL PERTURBATIONS ARE LIKELY TO MEDIATE THEIR EFFECTS VIA ALTERATIONS IN EPIGENETIC REGULATION, CHANGES IN HIPPOCAMPAL DNA METHYLTRANSFERASE 3A, 5-METHYLCYTOSINE AND 5-HYDROXYMETHYLCYTOSINE LEVELS WERE ASSESSED AS UNDERLYING MECHANISMS. REPETITIVE RESTRAINT STRESS DURING THE FIRST WEEK OF GESTATION EXERTED A SEX-DEPENDENT EFFECT, WITH MALE PMS MICE SHOWING SPATIAL MEMORY DEFICITS AND A BLUNTED HYPOTHALAMUS-PITUITARY-ADRENAL AXIS RESPONSE, WHILE FEMALE PMS MICE SHOWED IMPROVED SPATIAL MEMORY PERFORMANCE, INCREASED DEPRESSIVE-LIKE BEHAVIOR, AS WELL AS A DECREASE IN HIPPOCAMPAL PLAQUE LOAD. IN ADDITION, SEX DIFFERENCES WERE OBSERVED AMONG APPSWE/PS1DE9 MICE, INDEPENDENT OF PMS (I.E., FEMALE MICE SHOWED IMPAIRED SPATIAL MEMORY PERFORMANCE, HIGHER HIPPOCAMPAL PLAQUE LOAD, ALTERED AMYLOID PRECURSOR PROTEIN PROCESSING IN THE CA3 AND LOWER DNA METHYLTRANSFERASE 3A IMMUNOREACTIVITY IN THE DENTATE GYRUS WHEN COMPARED WITH MALE MICE OF THE SAME AGE). IN CONCLUSION, PMS EXPOSURE IMPACTS ON THE BEHAVIORAL PHENOTYPE AND NEUROPATHOLOGY OF APPSWE/PS1DE9 MICE. MOREOVER, GIVEN THE REMARKABLE SEX DIFFERENCES OBSERVED, ONE SHOULD NOT OVERLOOK THE IMPACT OF SEX-SPECIFIC RESPONSES TO ENVIRONMENTAL EXPOSURES WHEN INVESTIGATING GENE-ENVIRONMENT INTERACTIONS IN AD.	2013