Mortality and ventilatory effects of central serotonin deficiency during postnatal development depend on age but not sex.
Ontology highlight
ABSTRACT:
SUBMITTER: Mouradian GC
PROVIDER: S-EPMC8259800 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Although the trophic actions of serotonin (5-HT) are well established, only few developmental defects have been reported in mouse strains with constitutive hyposerotonergia. We analyzed postnatal growth and cortical development in three different mutant mouse strains with constitutive reductions in central 5-HT levels. We compared two previously published mouse strains with severe (-95%) depletions of 5-HT, the tryptophan hydroxylase (Tph) 2(-/-) mouse line and VMAT2(sert-cre) mice, with a new strain, in which VMAT2 deletion is driven by Pet1 (VMAT2(pet1-cre)) in 5-HT raphe neurons leading to partial (-75%) reduction in brain 5-HT levels. We find that normal embryonic growth and postnatal growth retardation are common features of all these mouse strains. Postnatal growth retardation varied from mild to severe according to the extent of the brain 5-HT reduction and gender. Normal growth was reinstated in VMAT2(sert-cre) mice by reconstituting central 5-HT stores. Growth abnormalities could not be linked to altered food intake or temperature control. Morphological study of the cerebral cortex over postnatal development showed a delayed maturation of the upper cortical layers in the VMAT2(sert-cre) and Tph2(-/-) mice, but not in the VMAT2(pet1-cre) mice. No changes in layer-specific gene expression or morphological alterations of barrel cortex development were found. Overall, these observations sustain the notion that central 5-HT signaling is required for the preweaning growth spurt of mouse pups. Brain development appeared to be immune to severe central 5-HT depletion for its overall growth during prenatal life, whereas reduced brain growth and delayed cortical maturation development occurred during postnatal life. Reduced developmental 5-HT signaling during postnatal development might modulate the function and fine structure of neural circuits in ways that affect adult behavior.
| S-EPMC3547491 | biostudies-literature
Project description:The transcription factor Lmx1b is essential for the differentiation and survival of central serotonergic (5-HTergic) neurons during embryonic development. However, the role of Lmx1b in adult 5-HTergic neurons is unknown. We used an inducible Cre-LoxP system to selectively inactivate Lmx1b expression in the raphe nuclei of adult mice. Pet1-CreER(T2) mice were generated and crossed with Lmx1b(flox/flox) mice to obtain Pet1-CreER(T2); Lmx1b(flox/flox) mice (which termed as Lmx1b iCKO). After administration of tamoxifen, the level of 5-HT in the brain of Lmx1b iCKO mice was reduced to 60% of that in control mice, and the expression of tryptophan hydroxylase 2 (Tph2), serotonin transporter (Sert) and vesicular monoamine transporter 2 (Vmat2) was greatly down-regulated. On the other hand, the expression of dopamine and norepinephrine as well as aromatic L-amino acid decarboxylase (Aadc) and Pet1 was unchanged. Our results reveal that Lmx1b is required for the biosynthesis of 5-HT in adult mouse brain, and it may be involved in maintaining normal functions of central 5-HTergic neurons by regulating the expression of Tph2, Sert and Vmat2.
| S-EPMC3016403 | biostudies-literature
Project description:In laboratory strains of zebrafish, sex determination occurs in the absence of a typical sex chromosome and it is not known what regulates the proportion of animals that develop as males or females. Many sex determination and gonad differentiation genes that act downstream of a sex chromosome are well conserved among vertebrates, but studies that test their contribution to this process have mostly been limited to mammalian models. In mammals, WNT4 is a signaling ligand that is essential for ovary and Müllerian duct development, where it antagonizes the male-promoting FGF9 signal. Wnt4 is well conserved across all vertebrates, but it is not known if Wnt4 plays a role in sex determination and/or the differentiation of sex organs in nonmammalian vertebrates. This question is especially interesting in teleosts, such as zebrafish, because they lack an Fgf9 ortholog. Here we show that wnt4a is the ortholog of mammalian Wnt4, and that wnt4b was present in the last common ancestor of humans and zebrafish, but was lost in mammals. We show that wnt4a loss-of-function mutants develop predominantly as males and conclude that wnt4a activity promotes female sex determination and/or differentiation in zebrafish. Additionally, both male and female wnt4a mutants are sterile due to defects in reproductive duct development. Together these results strongly argue that Wnt4a is a conserved regulator of female sex determination and reproductive duct development in mammalian and nonmammalian vertebrates.
| S-EPMC6325708 | biostudies-other
Project description:Deficiency of arginase is associated with hyperargininemia, and prominent features include spastic diplegia/tetraplegia, clonus, and hyperreflexia; loss of ambulation, intellectual disability and progressive neurological decline are other signs. To gain greater insight into the unique neuromotor features, we performed gene expression profiling of the motor cortex of a murine model of the disorder. Coexpression network analysis suggested an abnormality with myelination, which was supported by limited existing human data. Utilizing electron microscopy, marked dysmyelination was detected in 2-week-old homozygous Arg1-KO mice. The corticospinal tract was found to be adversely affected, supporting dysmyelination as the cause of the unique neuromotor features and implicating oligodendrocyte impairment in a deficiency of hepatic Arg1. Following neonatal hepatic gene therapy to express Arg1, the subcortical white matter, pyramidal tract, and corticospinal tract all showed a remarkable recovery in terms of myelinated axon density and ultrastructural integrity with active wrapping of axons by nearby oligodendrocyte processes. These findings support the following conclusions: arginase deficiency is a leukodystrophy affecting the brain and spinal cord while sparing the peripheral nervous system, and neonatal AAV hepatic gene therapy can rescue the defects associated with myelinated axons, strongly implicating the functional recovery of oligodendrocytes after restoration of hepatic arginase activity.
| S-EPMC6777909 | biostudies-literature
Project description:BackgroundThe angiotensin II receptor subtype 2 (AT2 receptor) is ubiquitously and highly expressed in early postnatal life. However, its role in postnatal cardiac development remained unclear.Methodology/principal findingsHearts from 1, 7, 14 and 56 days old wild-type (WT) and AT2 receptor-deficient (KO) mice were extracted for histomorphometrical analysis as well as analysis of cardiac signaling and gene expression. Furthermore, heart and body weights of examined animals were recorded and echocardiographic analysis of cardiac function as well as telemetric blood pressure measurements were performed. Moreover, gene expression, sarcomere shortening and calcium transients were examined in ventricular cardiomyocytes isolated from both genotypes. KO mice exhibited an accelerated body weight gain and a reduced heart to body weight ratio as compared to WT mice in the postnatal period. However, in adult KO mice the heart to body weight ratio was significantly increased most likely due to elevated systemic blood pressure. At postnatal day 7 ventricular capillarization index and the density of ?-smooth muscle cell actin-positive blood vessels were higher in KO mice as compared to WT mice but normalized during adolescence. Echocardiographic assessment of cardiac systolic function at postnatal day 7 revealed decreased contractility of KO hearts in response to beta-adrenergic stimulation. Moreover, cardiomyocytes from KO mice showed a decreased sarcomere shortening and an increased peak Ca(2+) transient in response to isoprenaline when stimulated concomitantly with angiotensin II.ConclusionThe AT2 receptor affects postnatal cardiac growth possibly via reducing body weight gain and systemic blood pressure. Moreover, it moderately attenuates postnatal vascularization of the heart and modulates the beta adrenergic response of the neonatal heart. These AT2 receptor-mediated effects may be implicated in the physiological maturation process of the heart.
| S-EPMC3483305 | biostudies-literature
Project description:Women exhibit a nearly twofold increased risk of developing depression and anxiety disorders when compared to men, a fact that has been hypothesized to result in part from increased stress susceptibility. Here, we used the tryptophan hydroxylase-2 R439H knock-in mouse (Tph2KI) and the chronic unpredictable mild stress (CMS) model to examine sex differences in response to congenital 5-HT deficiency and chronic stress. Our results demonstrate that female mice, but not 5-HT-deficient animals, exhibit significantly increased susceptibility to CMS-induced despair-like behavior in the forced swim test. In addition, female 5-HT-deficient mice exhibit anhedonia-like behavior in the sucrose preference test, whereas male 5-HT-deficient animals do not, suggesting that females exhibit increased sensitivity to at least some of the effects of congenital 5-HT deficiency. Although CMS did not reduce cell proliferation in the hippocampus, low levels of brain 5-HT were associated with increased hippocampal cell proliferation, an effect that was predominantly observed in females. Overall, these results highlight the importance of interactions between psychiatric disease risk factors such as sex, chronic stress and congenital 5-HT deficiency in the development of aberrant emotional behavior.
| S-EPMC3918518 | biostudies-literature
Project description:Canavan disease (CD) is a neurodegenerative disease, caused by a deficiency in the enzyme aspartoacylase (ASPA). This enzyme has been localized to oligodendrocytes; however, it is still undefined how ASPA deficiency affects oligodendrocyte development. In normal mice the pattern of ASPA expression coincides with oligodendrocyte maturation. Therefore, postnatal oligodendrocyte maturation was analyzed in ASPA-deficient mice (CD mice). Early in development, CD mice brains showed decreased expression of neural cell markers that was later compensated. In addition, the levels of myelin proteins were decreased along with abnormal myelination in CD mice compared to wild-type (WT). These defects were associated with increased global levels of acetylated histone H3, decreased chromatin compaction and increased GFAP protein, a marker for astrogliosis. Together, these findings strongly suggest that, early in postnatal development, ASPA deficiency affects oligodendrocyte maturation and myelination.
| S-EPMC2964840 | biostudies-literature
Project description:Leptin modulates energy metabolism and lung development. We hypothesize that the effects of leptin on postnatal lung development are volume dependent from 2 to 10 wk of age and are independent of hypometabolism associated with leptin deficiency. To test the hypotheses, effects of leptin deficiency on lung maturation were characterized in age groups of C57BL/6J mice with varying Lep(ob) genotypes. Quasi-static pressure-volume curves and respiratory impedance measurements were performed to profile differences in respiratory system mechanics. Morphometric analysis was conducted to estimate alveolar size and number. Oxygen consumption was measured to assess metabolic rate. Lung volume at 40-cmH(2)O airway pressure (V(40)) increased with age in each genotypic group, and V(40) was significantly (P < 0.05) lower in leptin-deficient (ob/ob) mice beginning at 2 wk. Differences were amplified through 7 wk of age relative to wild-type (+/+) mice. Morphometric analysis showed that alveolar surface area was lower in ob/ob compared with +/+ and heterozygote (ob/+) mice beginning at 2 wk. Unlike the other genotypic groups, alveolar size did not increase with age in ob/ob mice. In another experiment, ob/ob at 4 wk received leptin replacement (5 microg.g(-1) x day(-1)) for 8 days, and expression levels of the Col1a1, Col3a1, Col6a3, Mmp2, Tieg1, and Stat1 genes were significantly increased concomitantly with elevated V(40). Leptin-induced increases in V(40) corresponded with enlarged alveolar size and surface area. Gene expression suggested a remodeling event of lung parenchyma after exogenous leptin replacement. These data support the hypothesis that leptin is critical to postnatal lung remodeling, particularly related to increased V(40) and enlarged alveolar surface area.
| S-EPMC2494837 | biostudies-literature
Project description:Early life stimuli during critical developmental time frames have been linked to increased risk for neurodevelopmental disorders later in life. The serotonergic system of the brain is implicated in mood disorders and is impacted by the duration of daylight, or photoperiod. Here we sought to investigate sensitive periods of prenatal and postnatal development for photoperiodic programming of DRN serotonin neurons, midbrain serotonin and metabolite levels along with affective behaviors in adolescence (P30) or adulthood (P50). To address these questions we restricted the interval of exposure to prenatal development (E0-P0) for Long summer-like photoperiods (LD 16:8), or Short winter-like photoperiods (LD 8:16) with postnatal development and maturation then occurring under the opposing photoperiod. Prenatal exposure alone to Long photoperiods was sufficient to fully program increased excitability of DRN serotonin neurons into adolescence and adulthood, similar to maintained exposure to Long photoperiods throughout development. Interestingly, Long photoperiod exposure can elevate serotonin and its' corresponding metabolite levels along with reducing affective behavior, which appear to have both pre and postnatal origins. Thus, exposure to Long photoperiods prenatally programs increased DRN serotonin neuronal excitability, but this step is insufficient to program serotonin signaling and affective behavior. Continuing influence of Long photoperiods during postnatal development then modulates serotonergic content and has protective effects for depressive-like behavior. Photoperiodic programing of serotonin function in mice appears to be a sequential process with programing of neuronal excitability as a first step occurring prenatally, while programing of circuit level serotonin signaling and behavior extends into the postnatal period.
| S-EPMC6517556 | biostudies-literature
Project description:There is a need for rigorous positron emission tomography (PET) and endocrine methods to address inconsistencies in the literature regarding age, sex, and reproductive hormone effects on central serotonin (5HT) 1A and 2A receptor binding potential (BP). Healthy subjects (n=71), aged 20-80 years, underwent 5HT1A and 2A receptor imaging using consecutive 90-min PET acquisitions with [(11)C]WAY100635 and [(18)F]altanserin. Logan graphical analysis was used to derive BP using atrophy-corrected distribution volume (V(T)) in prefrontal, mesiotemporal, occipital cortices, and raphe nucleus (5HT1A only). We used multivariate linear regression modeling to examine BP relationships with age, age(2), sex, and hormone concentrations, with post hoc regional significance set at p<0.008. There were small postsynaptic 5HT1A receptor BP increases with age and estradiol concentration in women (p=0.004-0.005) and a tendency for small 5HT1A receptor BP declines with age and free androgen index in men (p=0.05-0.06). Raphe 5HT1A receptor BP decreased 4.5% per decade of age (p=0.05), primarily in men. There was a trend for 15% receptor reductions in prefrontal cortical regions in women relative to men (post hoc p=0.03-0.10). The significant decline in 5HT2A receptor BP relative to age (8% per decade; p<0.001) was not related to sex or hormone concentrations. In conclusion, endocrine standardization minimized confounding introduced by endogenous hormonal fluctuations and reproductive stage and permitted us to detect small effects of sex, age, and endogenous sex steroid exposures upon 5HT1A binding. Reduced prefrontal cortical 5HT1A receptor BP in women vs men, but increased 5HT1A receptor BP with aging in women, may partially explain the increased susceptibility to affective disorders in women during their reproductive years that is mitigated in later life. 5HT1A receptor decreases with age in men might contribute to the known increased risk for suicide in men over age 75 years. Low hormone concentrations in adults <50 years of age may be associated with more extreme 5HT1A receptor BP values, but remains to be studied further. The 5HT2A receptor declines with age were not related to sex or hormone concentrations in this sample. Additional study in clinical populations is needed to further examine the affective role of sex-hormone-serotonin receptor relationships.
| S-EPMC3230496 | biostudies-literature