Effects of developmental manganese, stress, and the combination of both on monoamines, growth, and corticosterone.
ABSTRACT: Developmental exposure to manganese (Mn) or stress can each be detrimental to brain development. Here, Sprague-Dawley rats were exposed to two housing conditions and Mn from postnatal day (P)4-28. Within each litter two males and 2 females were assigned to the following groups: 0 (vehicle), 50, or 100 mg/kg Mn by oral gavage every other day. Half the litters were reared in cages with standard bedding and half with no bedding. One pair/group in each litter had an acute shallow water stressor before tissue collection (i.e., standing in shallow water). Separate litters were assessed at P11, 19, or 29. Mn-treated rats raised in standard cages showed no change in baseline corticosterone but following acute stress increased more than controls on P19; no Mn effects were seen on P11 or P29. Mn increased neostriatal dopamine in females at P19 and norepinephrine at P11 and P29. Mn increased hippocampal dopamine at P11 and P29 and 5-HT at P29 regardless of housing or sex. Mn had no effect on hypothalamic dopamine, but increased norepinephrine in males at P29 and 5-HT in males at all ages irrespective of rearing condition. Barren reared rats showed no or opposite effects of Mn, i.e., barren rearing + Mn attenuated corticosterone increases to acute stress. Barren rearing also altered the Mn-induced changes in dopamine and norepinephrine in the neostriatum, but not in the hippocampus. Barren rearing caused a Mn-associated increase in hypothalamic dopamine at P19 and P29 not seen in standard reared Mn-treated groups. Developmental Mn alters monoamines and corticosterone as a function of age, stress (acute and chronic), and sex.
Project description:Despite restrictions, exposure to lead (Pb) continues. Moreover, exposure varies and is often higher in lower socioeconomic status (SES) families and remains a significant risk to cognitive development. Stress is another risk factor. Lower SES may be a proxy for stress in humans. When stress and Pb co-occur, risk may be increased. A few previous experiments have combined Pb with intermittent or acute stress but not with chronic stress. To determine if chronic developmental stress affects outcome in combination with Pb, we tested such effects on growth, organ weight, brain monoamines, and response to an acute stressor. Sprague Dawley rats were gavaged with Pb acetate (1 or 10 mg/kg) or vehicle every other day from postnatal day (P)4-29 and reared in standard or barren cages. Subsets were analyzed at different ages (P11, 19, 29). Chronic stress did not alter blood Pb levels but altered HPA axis response during early development whereas Pb did not. Pb treatment and rearing each altered organ-to-body weight ratios, most notably of thymus weights. Both Pb and rearing resulted in age- and region-dependent changes in serotonin and norepinephrine levels and in dopamine and serotonin turnover. The model introduced here may be useful for investigating the interaction of Pb and chronic developmental stress.
Project description:Neonatal exposure to methamphetamine (MA) and developmental chronic stress significantly alter neurodevelopmental profiles that show a variety of long-term physiological and behavioral effects. In the current experiment, Sprague-Dawley rats were exposed to one of two housing conditions along with MA. Rats were given 0 (saline), 5, or 7.5 mg/kg MA, four times per day from postnatal day (P)11 to 15 or P11 to 20. Half of the litters were reared in cages with standard bedding and half with no bedding. Separate litters were assessed at P15 or P20 for organ weights (adrenals, spleen, thymus); corticosterone; and monoamine assessments (dopamine, serotonin, norepinephrine) and their metabolites within the neostriatum, hippocampus, and prefrontal cortex. Findings show neonatal MA altered monoamines, corticosterone, and organ characteristics alone, and as a function of developmental age and stress compared with controls. These alterations may in part be responsible for MA and early life stress-induced long-term learning and memory deficits.
Project description:BACKGROUND:African grey parrots (Psittacus erithacus) are kept as pets and are frequently hand-reared. It has been observed that hand-reared African grey parrots may develop behavioral disorders such as feather damaging behavior (FDB). It is well known that chronic stress is involved in behavioral disorders in captive parrots. The main glucocorticoid in birds is corticosterone; its quantification provides information about adrenocortical activity and is considered to be a reliable indicator of stress levels in birds. We analyzed the differences in the excretion of corticosterone metabolites (CM) in the droppings of African grey parrots characterized by: 1. different rearing histories (parent rearing vs. hand rearing); and 2. the presence or absence of FDB in hand-reared parrots. METHODS:A total of 82 African grey parrots that were kept in captivity were considered. According to breeding methods, three groups of birds were defined: 1. The parent-reared (PR) parrots included birds kept in pairs (n = 30 pairs) with a conspecific partner of the opposite sex. All of these birds were healthy and never showed FDB signs; 2. The healthy hand-reared parrots (H-HR) included pet parrots individually kept, that were hand-reared and did not display any sign of FDB (n = 11, 7 males and 4 females); 3. The FDB hand-reared parrot (FDB-HR) included pet parrots individually kept, that were hand-reared and displayed FDB (n = 11, 7 males and 4 females). Droppings were collected in the morning over three alternating days in autumn 2014 and spring 2015. The CM were determined using a multi-species corticosterone enzyme immunoassay kit. Split-plot repeated-measure ANOVA was used to examine any differences using group, season and group × season as the main factors. RESULTS:Different quantities of CM in droppings were found for the three groups. The mean CM value was 587 ng/g in the PR parrots, 494 ng/g in the H-HR parrots and 1,744 ng/g in the FDB-HR parrots, irrespective of the season. The excretion of CM in FDB-HR was significantly higher than in PR or H-HR parrots. CM in droppings were not influenced by the season (autumn vs. spring); furthermore, the interaction between group and sampling season was not significant. Limited to the H-HR and FDB-HR groups, a trend in the significance of the difference in the mean CM excreted by male and female birds was observed, with the levels excreted by males being higher than those excreted by females. When the effect of age was considered (in the two separate groups), there was a statistically significant positive correlation only for H-HR. CONCLUSIONS:The highest amount of CM excretion was found in FDB-HR parrots, and a positive correlation between age and CM excretion was found in H-HR. Given that the CM excretion of both PR and H-HR parrots was similar in our study, future research is recommended to investigate the specific aspects of hand-rearing to improve parrot welfare.
Project description:Psoralea corylifolia L., (P. corylifolia), which is used for treating vitiligo in clinic, shows inhibitory and activating effects on tyrosinase, a rate-limiting enzyme of melanogenesis. This study aimed to determine the active ingredients in the ethenal extracts of P. corylifolia on tyrosinase activity. The spectrum-effect relationship and knock-out method were established to predict the active compounds. Their structures were then identified with the high resolution mass spectra. A high performance liquid chromatography method was established to obtain the specific chromatograms. Tyrosinase activity in vitro was assayed by the method of oxidation rate of levodopa. Partial least squares method was used to test the spectrum-effect relationships. Chromatographic peaks P2, P4, P9, P10, P11, P13, P21, P26, P28, and P30 were positively related to the activating effects on tyrosinase activity in PE, whereas chromatographic peaks P1, P3, P6, P14, P16, P19, P22, and P29 were negatively related to the activating effects on tyrosinase in the P. corylifolia (PEs). When the sample concentration was 0.5 g·mL-1, equal to the amount of raw medicinal herbs, the target components were daidzein (P2), psoralen (P5), neobavaisoflavone (P13), and psoralidin (P20), which were consistent with the results of spectrum-effect relationships.
Project description:The hypothesis that outdoor exposure might protect against myopia has generated much interest, although available data find only modest clinical efficacy. We tested the effect of outdoor rearing on form-deprivation myopia in chicks, a myopia model markedly inhibited by high-intensity indoor laboratory lighting.Unilaterally goggled cohorts of White Leghorn chicks were maintained in a species-appropriate, outdoor rural setting during daylight hours to the extent permitted by weather. Control chicks were reared indoors with incandescent lighting. Besides ocular refraction and ultrasound, we determined dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) content in retina and vitreous and measured mRNA expression levels of selected clock and circadian rhythm-related genes in the retina/RPE.Myopia developed in the goggled eyes of all cohorts. Whereas outdoor rearing lessened myopia by 44% at 4 days, a protective effect was no longer evident at 11 days. Outdoor rearing had no consistent effect on retinal or vitreous content of dopamine or DOPAC. Conforming to prior data on form-deprivation myopia, retina and vitreous levels of DOPAC were reduced in goggled eyes. Compared with contralateral eyes, the retinal expression of clock and circadian rhythm-related genes was modestly altered in myopic eyes of chicks reared indoors or outdoors.Outdoor rearing of chicks induces only a partial decrease of goggle-induced myopia that is not maintained, without evidence that retinal dopamine metabolism accounts for the partial myopia inhibition under these outdoor conditions. Although modest, alterations in retinal gene expression suggest that studying circadian signals might be informative for understanding refractive mechanisms.
Project description:Enrichments during pullet rearing may improve adaptation and welfare of hens as they move from indoor rearing to a free-range system. Individual variation in outdoor ranging may also affect welfare. This study assessed the effects of rearing enrichments and an imposed environmental stressor on hen welfare and egg quality along with the association of welfare with ranging. Hy-Line Brown® chicks (n = 1,386) were reared indoors until 16 weeks with 3 enrichment treatments including a "control" group with standard floor litter, a "novelty" group that received novel objects that were changed weekly, and a "structural" group with H-shaped perching structures. Pullets were then moved to a free-range system with three replicates of each rearing treatment. Daily ranging was individually tracked from 25 to 64 weeks via radiofrequency identification technology. Individual hen welfare assessments were performed at 25, 33, 43, 56, and 64 weeks and correlated with ranging time prior to these dates. At 44 weeks, the range area was reduced by 80% for 11 days to induce stress. Changes in ranging behavior, albumen corticosterone concentrations and egg quality were evaluated. GLMMs showed significant interactions between hen age and rearing treatment for live weight, number of comb wounds, plumage coverage, and toenail length (all P ? 0.003), with the enriched hens showing more consistent live weight at the later ages, fewer comb wounds at 33 weeks, and better plumage coverage at the later ages, whereas the structural hens had shorter toenails as age increased. Plumage coverage showed a positive relationship with range use across most age points (P < 0.0001). Hens reduced ranging time following the imposed stressor but increased their number of visits with the lowest increase by the structural hens (P = 0.03). Significant interactions between rearing treatment and stressor for albumen corticosterone concentrations showed the structural hens decreased concentrations immediately post-stress, but the control and novelty groups increased (P < 0.006). The stressor increased or decreased values of most egg quality parameters across all rearing groups (all P ? 0.02). Overall, provision of rearing enrichments and greater range use may have positive impacts on hen welfare.
Project description:The differential susceptibility hypothesis proposes that individuals who are more susceptible to the negative effects of adverse rearing conditions may also benefit more from enriched environments. Evidence derived from human experiments suggests the lower efficacy dopamine receptor D4 (DRD4) 7-repeat as a main factor in exhibiting these for better and for worse characteristics. However, human studies lack the genetic and environmental control offered by animal experiments, complicating assessment of causal relations. To study differential susceptibility in an animal model, we exposed Drd4+/- mice and control litter mates to a limited nesting/bedding (LN), standard nesting (SN) or communal nesting (CN) rearing environment from postnatal day (P) 2-14. Puberty onset was examined from P24 to P36 and adult females were assessed on maternal care towards their own offspring. In both males and females, LN reared mice showed a delay in puberty onset that was partly mediated by a reduction in body weight at weaning, irrespective of Drd4 genotype. During adulthood, LN reared females exhibited characteristics of poor maternal care, whereas dams reared in CN environments showed lower rates of unpredictability towards their own offspring. Differential susceptibility was observed only for licking/grooming levels of female offspring towards their litter; LN reared Drd4+/- mice exhibited the lowest and CN reared Drd4+/- mice the highest levels of licking/grooming. These results indicate that both genetic and early-environmental factors play an important role in shaping maternal care of the offspring for better and for worse.
Project description:The neurobiological basis of early life stress (ELS) impact on vulnerability to alcohol use disorder is not fully understood. The effect of ELS, adult ethanol consumption and single housing, on expression of stress and DNA methylation regulatory genes as well as blood corticosterone levels was investigated in the hypothalamus and pituitary of adult out-bred Wistar rats subjected to different rearing conditions. A prolonged maternal separation (MS) of 360 min (MS360) was used to study the effect of ELS, and a short MS of 15 min (MS15) was used as a control. Voluntary ethanol drinking was assessed using a two-bottle free choice paradigm to simulate human episodic drinking. The effects of single housing and ethanol were assessed in conventional animal facility rearing (AFR) conditions. Single housing in adulthood was associated with lower Crhr1 and higher Pomc expression in the pituitary, whereas ethanol drinking was associated with higher expression of Crh in the hypothalamus and Crhr1 in the pituitary, accompanied by lower corticosterone levels. As compared to controls with similar early life handling, rats exposed to ELS displayed lower expression of Pomc in the hypothalamus, and higher Dnmt1 expression in the pituitary. Voluntary ethanol drinking resulted in lower Fkbp5 expression in the pituitary and higher Crh expression in the hypothalamus, independently of rearing conditions. In rats exposed to ELS, water and ethanol drinking was associated with higher and lower corticosterone levels, respectively. The use of conventionally reared rats as control group yielded more significant results than the use of rats exposed to short MS. Positive correlations, restricted to the hypothalamus and ELS group, were observed between the expression of the hypothalamus-pituitary-adrenal receptor and the methylation-related genes. Promoter DNA methylation and expression of respective genes did not correlate suggesting that other loci are involved in transcriptional regulation. Concluding, single housing is a confounding factor to be considered in voluntary ethanol drinking paradigms. ELS and ethanol drinking in adulthood exert independent effects on hypothalamic and pituitary related genes, however, in a manner dependent on the control group used.
Project description:The reduced movement repertoire of Parkinson's disease (PD) is mainly due to degeneration of nigrostriatal dopamine neurons. Restoration of dopamine transmission by levodopa (L-DOPA) relieves motor symptoms of PD but often causes disabling dyskinesias. Subchronic L-DOPA increases levels of adaptor protein p11 (S100A10) in dopaminoceptive neurons of the striatum. Using experimental mouse models of Parkinsonism, we report here that global p11 knockout (KO) mice develop fewer jaw tremors in response to tacrine. Following L-DOPA, global p11KO mice show reduced therapeutic responses on rotational motor sensitization, but also develop less dyskinetic side effects. Studies using conditional p11KO mice reveal that distinct cell populations mediate these therapeutic and side effects. Selective deletion of p11 in cholinergic acetyltransferase (ChAT) neurons reduces tacrine-induced tremor. Mice lacking p11 in dopamine D2R-containing neurons have a reduced response to L-DOPA on the therapeutic parameters, but develop dyskinetic side effects. In contrast, mice lacking p11 in dopamine D1R-containing neurons exhibit tremor and rotational responses toward L-DOPA, but develop less dyskinesia. Moreover, coadministration of rapamycin with L-DOPA counteracts L-DOPA-induced dyskinesias in wild-type mice, but not in mice lacking p11 in D1R-containing neurons. 6-OHDA lesioning causes an increase of evoked striatal glutamate release in wild type, but not in global p11KO mice, indicating that altered glutamate neurotransmission could contribute to the reduced L-DOPA responsivity. These data demonstrate that p11 located in ChAT or D2R-containing neurons is involved in regulating therapeutic actions in experimental PD, whereas p11 in D1R-containing neurons underlies the development of L-DOPA-induced dyskinesias.
Project description:Manganese (manganese ion; referred to as Mn) is essential for neuronal function, yet it is toxic at high concentrations. Environmental and occupational exposure to high concentrations of Mn causes manganism, a well-defined movement disorder in humans, with symptoms resembling Parkinson's disease (PD). However, manganism is distinct from PD and the neural basis of its pathology is poorly understood. To address this issue, we generated a zebrafish model of manganism by incubating larvae in rearing medium containing Mn. We find that Mn-treated zebrafish larvae exhibit specific postural and locomotor defects. Larvae begin to float on their sides, show a curved spine and swim in circles. We discovered that treatment with Mn causes postural defects by interfering with mechanotransduction at the neuromasts. Furthermore, we find that the circling locomotion could be caused by long-duration bursting in the motor neurons, which can lead to long-duration tail bends in the Mn-treated larvae. Mn-treated larvae also exhibited fewer startle movements. Additionally, we show that the intensity of tyrosine hydroxylase immunoreactivity is reversibly reduced after Mn-treatment. This led us to propose that reduced dopamine neuromodulation drives the changes in startle movements. To test this, when we supplied an external source of dopamine to Mn-treated larvae, the larvae exhibited a normal number of startle swims. Taken together, these results indicate that Mn interferes with neuronal function at the sensory, motor and modulatory levels, and open avenues for therapeutically targeted studies on the zebrafish model of manganism.