scholarly journals Placental endocrine function shapes cerebellar development and social behavior

2021 ◽  
Author(s):  
Claire-Marie Vacher ◽  
Helene Lacaille ◽  
Jiaqi J. O’Reilly ◽  
Jacquelyn Salzbank ◽  
Dana Bakalar ◽  
...  
Keyword(s):  
Single Injection ◽  
Hormone Replacement ◽  
Brain Regions ◽  
Late Gestation ◽  
Endocrine Function ◽  
Cerebellar White Matter ◽  
Gene Encoding ◽  
Gaba A ◽  
Placental Function ◽  
Placental Hormone

AbstractCompromised placental function or premature loss has been linked to diverse neurodevelopmental disorders. Here we show that placenta allopregnanolone (ALLO), a progesterone-derived GABA-A receptor (GABAAR) modulator, reduction alters neurodevelopment in a sex-linked manner. A new conditional mouse model, in which the gene encoding ALLO’s synthetic enzyme (akr1c14) is specifically deleted in trophoblasts, directly demonstrated that placental ALLO insufficiency led to cerebellar white matter abnormalities that correlated with autistic-like behavior only in male offspring. A single injection of ALLO or muscimol, a GABAAR agonist, during late gestation abolished these alterations. Comparison of male and female human preterm infant cerebellum also showed sex-linked myelination marker alteration, suggesting similarities between mouse placental ALLO insufficiency and human preterm brain development. This study reveals a new role for a placental hormone in shaping brain regions and behaviors in a sex-linked manner. Placental hormone replacement might offer novel therapeutic opportunities to prevent later neurobehavioral disorders.

scholarly journals Placental neurosteroids shape cerebellar development and social behaviour

2019 ◽  
Author(s):  
Claire-Marie Vacher ◽  
Jiaqi J. O’Reilly ◽  
Jacquelyn Salzbank ◽  
Helene Lacaille ◽  
Dana Bakalar ◽  
...  
Keyword(s):  
Brain Structures ◽  
Autism Spectrum ◽  
Late Gestation ◽  
Strong Positive Correlation ◽  
Repetitive Behaviour ◽  
Gene Encoding ◽  
Gaba A ◽  
Positive Modulator ◽  
Placental Hormone ◽  
Male Specific

ABSTRACTCompromised placental function or premature loss has been linked to diverse neurodevelopmental disorders 1,2. The placenta is the first functional foetal endocrine organ, but the direct impact of placental hormone loss on foetal brain in late gestation has not been empirically tested. Allopregnanolone (ALLO) is a non-glucocorticoid, progesterone derivative that acts as a positive modulator of GABA-A receptor activity3 with the potential to alter critical GABA-mediated developmental processes 4,5. To directly test the role of placental ALLO, we generated a novel mouse model in which the gene encoding the synthetic enzyme for ALLO (Akr1c14) is specifically deleted in trophoblasts using a tissue-specific Cre-Lox strategy. ALLO concentrations are significantly decreased in late gestation in placenta and brain when placental Akr1c14 is removed, indicating placenta as the primary gestational ALLO source. We now demonstrate that targeted placental ALLO loss leads to permanent changes in brain development in a sex- and regionally-specific manner. Placental ALLO insufficiency led to male-specific cerebellar white matter (WM) abnormalities characterized by excess myelination with increased myelin protein expression, similar to changes reported in boys with autism spectrum disorders (ASD)6,7. Behavioural testing of these mice revealed increased repetitive behaviour and sociability deficits, two hallmarks of ASD, only in male offspring with placental ALLO insufficiency. Notably, a strong positive correlation was seen between the cerebellar contents of myelin basic protein (MBP) and the severity of ASD-like behaviours. A single injection of ALLO during gestation was sufficient to rescue both cerebellar MBP levels and aberrant behaviours. This study reveals a new role for a placental hormone in shaping specific brain structures and behaviours, and suggests that identifying placental hormone insufficiency or preterm loss may offer novel therapeutic opportunities to prevent later neurobehavioural disorders.

Cortical Thinning Associated with Age and CSF Biomarkers in Early Parkinson’s Disease Is Modified by the SNCA rs356181 Polymorphism

2018 ◽  
Vol 18 (5-6) ◽  
pp. 233-238
Author(s):  
Frederic Sampedro ◽  
Juan Marín-Lahoz ◽  
Saul Martínez-Horta ◽  
Javier Pagonabarraga ◽  
Jaime Kulisevsky
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Cognitive Decline ◽  
De Novo ◽  
Brain Regions ◽  
Cortical Atrophy ◽  
Csf Biomarkers ◽  
Gene Encoding ◽  
Cortical Thinning ◽  
Age Related

The role of cerebrospinal fluid (CSF) biomarkers such as CSF α-synuclein and CSF tau in predicting cognitive decline in Parkinson’s disease (PD) continues to be inconsistent. Here, using a cohort of de novo PD patients with preserved cognition from the Parkinson’s Progression Markers Initiative (PPMI), we show that the SNCA rs356181 single nucleotide polymorphism (SNP) modulates the effect of these CSF biomarkers on cortical thinning. Depending on this SNP’s genotype, cortical atrophy was associated with either higher or lower CSF biomarker levels. Additionally, this SNP modified age-related atrophy. Importantly, the integrity of the brain regions where this phenomenon was observed correlated with cognitive measures. These results suggest that this genetic variation of the gene encoding the α-synuclein protein, known to be involved in the development of PD, also interferes in its subsequent neurodegeneration. Overall, our findings could shed light on the so far incongruent association of common CSF biomarkers with cognitive decline in PD.

Genomic analysis of neuroendocrine development of fetal brain-pituitary-adrenal axis in late gestation

2006 ◽  
Vol 24 (3) ◽  
pp. 218-224 ◽  
Author(s):  
Maureen Keller-Wood ◽  
Melanie J. Powers ◽  
Jason A. Gersting ◽  
Nyima Ali ◽  
Charles E. Wood
Keyword(s):  
Brain Stem ◽  
Hpa Axis ◽  
Fetal Brain ◽  
Genomic Analysis ◽  
Brain Regions ◽  
Late Gestation ◽  
Fetal Sheep ◽  
Genomic Expression ◽  
Feedback Sensitivity ◽  
Critical Components

The present study was performed to identify the changes in genomic expression of critical components of the hypothalamus-pituitary-adrenal (HPA) axis in the second half of gestation in fetal sheep. We isolated mRNA from pituitary, hypothalamus, hippocampus, and brain stem in fetal sheep at 80, 100, 120, 130, and 145 days of gestation and 1 and 7 days after delivery ( n = 4–5/group). Using real-time RT-PCR, we measured mRNA expression levels of glucocorticoid receptor (GR), mineralocorticoid receptor (MR), serum- and glucocorticoid-induced kinase-1 (sgk1), proopiomelanocortin (POMC), CRF, and arginine vasopressin (AVP). Both MR and GR were highly expressed in pituitary and hippocampus; in all tissues GR was more highly expressed than MR. AVP was more highly expressed than CRF in hypothalamus. MR, GR, and sgk1 expression were increased postnatally in brain stem, and sgk1 expression was increased postnatally in hypothalamus. GR expression was reduced in pituitary in term fetuses compared with younger ages. Hypothalamic CRF expression was increased at the end of gestation compared with younger ages, and AVP expression was increased in newborn lambs. Pituitary POMC was increased at 100 days of gestation compared with 80 days; hypothalamic POMC was increased at 120 days. Overall, the results demonstrate the expression of both MR and GR in brain regions important for control of the HPA axis. Decreases in expression of GR in pituitary at the end of gestation might contribute to the decreased corticosteroid negative feedback sensitivity at term in this species.

THE ROLE OF THE PITUITARY GLAND IN IMPLANTATION IN THE MOUSE: DELAY OF IMPLANTATION BY HYPOPHYSECTOMY AND NEURODEPRESSIVE DRUGS

1969 ◽  
Vol 43 (2) ◽  
pp. 225-235 ◽  
Author(s):  
B. M. BINDON
Keyword(s):  
Pituitary Gland ◽  
Early Pregnancy ◽  
Single Injection ◽  
Hormone Replacement ◽  
Oestrous Cycle ◽  
The Other ◽  
Optimum Conditions ◽  
Delayed Implantation ◽  
Long Acting

SUMMARY The optimum conditions for delay of implantation by hypophysectomy and neurodepressive agents are described. Hypophysectomy on day 1 without hormone replacement was followed by retarded development and subsequent degeneration of zygotes. Viability of blastocysts was maintained under these conditions by a single injection of a long-acting progestagen on day 1. Hypophysectomy at intervals beginning late on day 3 indicated that implantation is initiated by pituitary activity in the several hours around midnight of this day. In animals induced to ovulate and copulate by exogenous gonadotrophin injections, the corresponding time of pituitary activity was delayed by approximately 8 hr. This delay could not be explained solely on the basis of altered times of ovulation. It is evident that the events of early pregnancy do not follow the normal physiological pattern under these conditions, and caution should be exercised in utilizing such animals. Of five neurodepressive agents examined, only trifluoperazine effectively delayed implantation. The effect of this substance injected at various times on day 3 of pregnancy suggests that implantation in the mouse is initiated by neurally regulated pituitary activity between 16.00 and 24.00 hr. on this day. Comparison with the mechanism of ovulation indicates that ovulation and implantation are regulated by separate hypothalamic-pituitary events, one peculiar to the oestrous cycle, the other to early pregnancy.

Effects of pentylenetetrazol on GABA-A/benzodiazepine/picrotoxinin receptor complexes in rat brain regions

1986 ◽  
Vol 11 (5) ◽  
pp. 637-646 ◽  
Author(s):  
Masatoshi Ito ◽  
Ted H. Chiu ◽  
Howard C. Rosenberg
Keyword(s):  
Rat Brain ◽  
Brain Regions ◽  
Gaba A ◽  
Receptor Complexes ◽  
Rat Brain Regions

scholarly journals The zebrafishspiel-ohne-grenzen(spg) gene encodes the POU domain protein Pou2 related to mammalianOct4and is essential for formation of the midbrain and hindbrain, and for pre-gastrula morphogenesis

Development ◽  
2002 ◽  
Vol 129 (4) ◽  
pp. 905-916 ◽  
Author(s):  
Shawn Burgess ◽  
Gerlinde Reim ◽  
Wenbiao Chen ◽  
Nancy Hopkins ◽  
Michael Brand
Keyword(s):  
Insertional Mutagenesis ◽  
Inner Cell Mass ◽  
Insertion Site ◽  
Cell Mass ◽  
Brain Regions ◽  
Chemical Mutagenesis ◽  
Gene Encoding ◽  
Specific Expression ◽  
Pou Domain ◽  
Similar Phenotype

In early embryonic development, the brain is divided into three main regions along the anteroposterior axis: the forebrain, midbrain and hindbrain. Through retroviral insertional mutagenesis and chemical mutagenesis experiments in zebrafish, we have isolated mutations that cause abnormal hindbrain organization and a failure of the midbrain-hindbrain boundary (MHB) to form, a region that acts as an organizer for the adjacent brain regions. The mutations fail to complement the spiel-ohne-grenzen (spg) mutation, which causes a similar phenotype, but for which the affected gene is unknown. We show through genetic mapping, cloning of the proviral insertion site and allele sequencing that spg mutations disrupt pou2, a gene encoding the Pou2 transcription factor. Based on chromosomal synteny, phylogenetic sequence comparison, and expression and functional data, we suggest that pou2 is the zebrafish ortholog of mouse Oct3/Oct4 and human POU5F1. For the mammalian genes, a function in brain development has so far not been described. In the absence of functional pou2, expression of markers for the midbrain, MHB and the hindbrain primordium (pax2.1, wnt1, krox20) are severely reduced, correlating with the neuroectoderm-specific expression phase of pou2. Injection of pou2 mRNA restores these defects in spg mutant embryos, but does not activate these markers ectopically, demonstrating a permissive role for pou2. Injections of pou2-morpholinos phenocopy the spg phenotype at low concentration, further proving that spg encodes pou2. Two observations suggest that pou2 has an additional earlier function: higher pou2-morpholino concentrations specifically cause a pre-gastrula arrest of cell division and morphogenesis, and expression of pou2 mRNA itself is reduced in spg-homozygous embryos at this stage. These experiments suggest two roles for pou2. Initially, Pou2 functions during early proliferation and morphogenesis of the blastomeres, similar to Oct3/4 in mammals during formation of the inner cell mass. During zebrafish brain formation, Pou2 then functions a second time to activate gene expression in the midbrain and hindbrain primordium, which is reflected at later stages in the specific lack in spg embryos of the MHB and associated defects in the mid- and hindbrain.

scholarly journals GABA, A Primary Metabolite Controlled by the Gac/Rsm Regulatory Pathway, Favors a Planktonic Over a Biofilm Lifestyle in Pseudomonas protegens CHA0

2018 ◽  
Vol 31 (2) ◽  
pp. 274-282 ◽  
Author(s):  
Kasumi Takeuchi
Keyword(s):  
Signal Transduction Pathway ◽  
Succinic Semialdehyde ◽  
Gene Encoding ◽  
Primary Metabolite ◽  
Succinic Semialdehyde Dehydrogenase ◽  
Gaba A ◽  
Semialdehyde Dehydrogenase ◽  
Niche Adaptation ◽  
In The Wild

In Pseudomonas protegens CHA0 and other fluorescent pseudomonads, the Gac/Rsm signal transduction pathway is crucial for the expression of secondary metabolism and the biological control of fungi, nematodes, and insects. Based on the findings of a previous metabolomic study, the role of intracellular γ-aminobutyrate (GABA) as a potential signal in the Gac/Rsm pathway was investigated herein. The function and regulation of a gabDT (c01870-c01880) gene cluster in strain CHA0 were described. The gabT gene encoded GABA transaminase (GABAT) and enabled the growth of the bacterium on GABA, whereas the upstream gabD gene (annotated as a gene encoding succinic semialdehyde dehydrogenase) had an unknown function. A gacA mutant exhibited low GABAT activity, leading to the markedly greater intracellular accumulation of GABA than in the wild type. In the gacA mutant, the RsmA and RsmE proteins caused translational gabD repression, with concomitant gabT repression. Due to very low GABAT activity, the gabT mutant accumulated GABA to high levels. This trait promoted a planktonic lifestyle, reduced biofilm formation, and favored root colonization without exhibiting the highly pleiotropic gacA phenotypes. These results suggest an important role of GABA in the Gac/Rsm-regulated niche adaptation of strain CHA0 to plant roots.

Primary hypophysitis: a single-center experience in 16 cases

2004 ◽  
Vol 101 (2) ◽  
pp. 262-271 ◽  
Author(s):  
Gilberto K. K. Leung ◽  
Maria-Beatriz S. Lopes ◽  
Michael O. Thorner ◽  
Mary Lee Vance ◽  
Edward R. Laws
Keyword(s):  
Transsphenoidal Surgery ◽  
Hormone Replacement ◽  
Endocrine Function ◽  
Treatment Modalities ◽  
Visual Field Defects ◽  
Cerebrospinal Fluid Leakage ◽  
Equal Distribution ◽  
Content Type ◽  
Primary Hypophysitis ◽  
Fine Print

Object. The authors review their experience in the treatment of 16 patients with primary hypophysitis. Methods. A retrospective study was undertaken to review cases of primary hypophysitis. The mean age of the patients was 47 years and there was an equal distribution of sexes. Recent pregnancy and underlying autoimmunity were noted in 50% of the patients. Two patients had undergone previous transsphenoidal operations at other centers, one for prolactinoma and another for hypophysitis. Headache, anterior pituitary deficiency, and suprasellar mass lesions were the most common presenting features. The initial presumptive diagnosis was pituitary adenoma in six patients (37.5%) and inflammatory hypophysitis in 10 (62.5%). Five patients received initial medical therapy for hypophysitis; although three (60%) responded satisfactorily, two (40%) did not and later underwent surgery. Altogether 13 patients (81.2%) underwent transsphenoidal surgery. The histological diagnoses were lymphocytic hypophysitis in 10 (76.9%) and granulomatous hypophysitis in three (23.1%) of the surgically treated patients. A coexistent Rathke cleft cyst was noted in one patient. There was no death in this series. One patient experienced postoperative cerebrospinal fluid leakage and meningitis. One patient had bilateral internal carotid artery occlusion secondary to inflammatory involvement of the cavernous sinuses and arteritis. This patient recovered and is capable of independent functional activities. Conclusions. All surgical patients experienced improvement in their headache and/or visual field defects and none had visual deterioration. None of the patients experienced any improvement in endocrine function and all required long-term hormone replacement. Transsphenoidal surgery was a safe and effective treatment especially for visual and pressure symptoms. A postoperative recurrence developed in two patients (15.4%) and the treatment modalities included steroid therapy, repeated surgery, and radiosurgery.

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