scholarly journals Region-specific KCC2 rescue by rhIGF-1 and oxytocin in a mouse model of Rett syndrome

2021 ◽  
Author(s):  
Valentina Gigliucci ◽  
Jasper Teutsch ◽  
Marc Woodbury-Smith ◽  
Mirko Luoni ◽  
Marta Busnelli ◽  
...  
Keyword(s):  
Postnatal Development ◽  
Rett Syndrome ◽  
Brain Regions ◽  
Recombinant Human Insulin ◽  
Signaling Crosstalk ◽  
Early Postnatal Development ◽  
Neuronal Excitation ◽  
Adult Mice ◽  
Frontal Brain ◽  
Trial Outcomes

Rett syndrome (RTT) is characterized by dysfunction in neuronal excitation/inhibition (E/I) balance, potentially impacting seizure susceptibility via deficits in K+/Cl- cotransporter 2 (KCC2) function. Mice lacking the Methyl-CpG binding protein 2 (MeCP2) recapitulate many symptoms of RTT, and recombinant human insulin-like growth factor-1 (rhIGF-1) restores KCC2 expression and E/I balance in MeCP2 KO mice. However, clinical trial outcomes of rhIGF-1 in RTT have been variable, and increasing its therapeutic efficacy is highly desirable. To this end, the neuropeptide oxytocin (OXT) is promising, as it also critically modulates KCC2 function during early postnatal development. We measured basal KCC2 expression levels in MeCP2 KO mice and identified three key frontal brain regions showing KCC2 alterations in young adult mice but not in postnatal P10 animals. We thus hypothesized that deficits in IGF-1/OXT signaling crosstalk modulating KCC2 may occur in RTT during postnatal development. Consistently, we detected alterations of IGF-1 receptor (IGF-1R) and OXT receptor (OXTR) levels in those brain areas. rhIGF-1 and OXT treatments in KO mice rescued KCC2 expression in a region-specific and complementary manner. These results suggest that region-selective combinatorial pharmacotherapeutic strategies could be the most effective at normalizing E/I balance in key brain regions subtending the RTT pathophysiology.

scholarly journals Unexpected Deposition of Brown Fat in Mammary Gland During Postnatal Development

2002 ◽  
Vol 16 (11) ◽  
pp. 2618-2627 ◽  
Author(s):  
Valérie Gouon-Evans ◽  
Jeffrey W. Pollard
Keyword(s):  
Mammary Gland ◽  
Postnatal Development ◽  
Mammary Epithelial Cells ◽  
Uncoupling Protein ◽  
Systemic Effect ◽  
Brown Adipocyte ◽  
Uncoupling Protein 1 ◽  
Early Postnatal Development ◽  
Adult Mice ◽  
Brown Adipose

Abstract Mammary fat tissue is crucial for mammary ductal morphogenesis in both fetal and adult mice. There are two kinds of adipocytes, the energy-storing white and the energy-dissipating brown adipocyte. The precise identity of the types of adipocyte in the mammary gland has never been investigated but was always assumed to be only white fat. In this study, we show that both white and brown adipocytes are present in the postnatal mammary gland. The amount of brown adipose tissue (BAT) examined by histology and electron microscopy correlates with the transcript levels of uncoupling protein 1, which is a mitochondrial carrier expressed exclusively in BAT. Uncoupling protein 1 mRNAs are the highest during prepuberty, decrease upon puberty, and are finally undetectable in the adult mammary gland. The analysis of a BAT-depleted mouse model showed that depletion of mammary BAT in early postnatal development induces epithelial differentiation. Alveolar structures were formed along all ducts and were functional since they produced β-casein. However, mammary transplantation experiments indicated that a systemic effect was responsible for epithelium differentiation. Our data suggest that BAT negatively regulates the differentiation of mammary epithelial cells in a systemic manner during prepubertal ductal outgrowth.

scholarly journals Antagonism between brain regions relevant for cognitive control and emotional memory facilitates the generation of humorous ideas

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Florian Bitsch ◽  
Philipp Berger ◽  
Andreas Fink ◽  
Arne Nagels ◽  
Benjamin Straube ◽  
...  
Keyword(s):  
Cognitive Control ◽  
Positive Emotions ◽  
Emotional Memory ◽  
Brain Regions ◽  
Neural Mechanisms ◽  
Functional Magnetic Resonance ◽  
Frontal Brain ◽  
Successful Resolution ◽  
Neural Underpinnings ◽  
The Brain

AbstractThe ability to generate humor gives rise to positive emotions and thus facilitate the successful resolution of adversity. Although there is consensus that inhibitory processes might be related to broaden the way of thinking, the neural underpinnings of these mechanisms are largely unknown. Here, we use functional Magnetic Resonance Imaging, a humorous alternative uses task and a stroop task, to investigate the brain mechanisms underlying the emergence of humorous ideas in 24 subjects. Neuroimaging results indicate that greater cognitive control abilities are associated with increased activation in the amygdala, the hippocampus and the superior and medial frontal gyrus during the generation of humorous ideas. Examining the neural mechanisms more closely shows that the hypoactivation of frontal brain regions is associated with an hyperactivation in the amygdala and vice versa. This antagonistic connectivity is concurrently linked with an increased number of humorous ideas and enhanced amygdala responses during the task. Our data therefore suggests that a neural antagonism previously related to the emergence and regulation of negative affective responses, is linked with the generation of emotionally positive ideas and may represent an important neural pathway supporting mental health.

scholarly journals Impact of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behaviors and BDNF mRNA expression in the adult Sprague–Dawley rats exposed to glutathione deficit during early postnatal development of the brain

2021 ◽  
Author(s):  
Marta A. Lech ◽  
Kinga Kamińska ◽  
Monika Leśkiewicz ◽  
Elżbieta Lorenc-Koci ◽  
Zofia Rogóż
Keyword(s):  
Mrna Expression ◽  
Postnatal Development ◽  
Repeated Treatment ◽  
Sprague Dawley ◽  
Biochemical Tests ◽  
Bdnf Mrna ◽  
Adult Rats ◽  
Behavioral Deficits ◽  
Glutathione Synthesis ◽  
Early Postnatal Development

Abstract Background Preclinical and clinical studies have indicated that impaired endogenous synthesis of glutathione during early postnatal development plays a significant role in the pathophysiology of schizophrenia. Moreover, some studies have suggested that antidepressants are able to increase the activity of atypical antipsychotics which may efficiently improve the treatment of negative and cognitive symptoms of schizophrenia. Methods In the present study, we investigated the influence of repeated co-treatment with escitalopram and aripiprazole on the schizophrenia-like behavior and BDNF mRNA expression in adult rats exposed to glutathione deficit during early postnatal development. Male pups between the postnatal days p5–p16 were treated with the inhibitor of glutathione synthesis, BSO (L-buthionine-(S,R)-sulfoximine) and the dopamine uptake inhibitor, GBR 12,909 alone or in combination. Escitalopram and aripiprazole were given repeatedly for 21 days before the tests. On p90–92 rats were evaluated in the behavioral and biochemical tests. Results BSO given alone and together with GBR 12,909 induced deficits in the studied behavioral tests and decreased the expression of BDNF mRNA. Repeated aripiprazole administration at a higher dose reversed these behavioral deficits. Co-treatment with aripiprazole and an ineffective dose of escitalopram also abolished the behavioral deficits in the studied tests. Conclusion The obtained data indicated that the inhibition of glutathione synthesis in early postnatal development induced long-term deficits corresponding to schizophrenia-like behavior and decreased the BDNF mRNA expression in adult rats, and these behavioral deficits were reversed by repeated treatment with a higher dose of aripiprazole and also by co-treatment with aripiprazole and ineffective dose of escitalopram.

scholarly journals Glutathione Deficiency during Early Postnatal Development Causes Schizophrenia-Like Symptoms and a Reduction in BDNF Levels in the Cortex and Hippocampus of Adult Sprague–Dawley Rats

2021 ◽  
Vol 22 (12) ◽  
pp. 6171
Author(s):  
Marta Anna Lech ◽  
Monika Leśkiewicz ◽  
Kinga Kamińska ◽  
Zofia Rogóż ◽  
Elżbieta Lorenc-Koci
Keyword(s):  
Postnatal Development ◽  
Time Course ◽  
Postnatal Life ◽  
Positive Symptoms ◽  
Gbr 12909 ◽  
Sprague Dawley ◽  
Bdnf Mrna ◽  
Synthesis Inhibitor ◽  
Early Postnatal Development ◽  
Middle Adolescence

Growing body of evidence points to dysregulation of redox status in the brain as an important factor in the pathogenesis of schizophrenia. The aim of our study was to evaluate the effects of l-buthionine-(S,R)-sulfoximine (BSO), a glutathione (GSH) synthesis inhibitor, and 1-[2-Bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride (GBR 12909), a dopamine reuptake inhibitor, given alone or in combination, to Sprague–Dawley pups during early postnatal development (p5–p16), on the time course of the onset of schizophrenia-like behaviors, and on the expression of brain-derived neurotrophic factor (BDNF) mRNA and its protein in the prefrontal cortex (PFC) and hippocampus (HIP) during adulthood. BSO administered alone decreased the levels of BDNF mRNA and its protein both in the PFC and HIP. Treatment with the combination of BSO + GBR 12909 also decreased BDNF mRNA and its protein in the PFC, but in the HIP, only the level of BDNF protein was decreased. Schizophrenia-like behaviors in rats were assessed at three time points of adolescence (p30, p42–p44, p60–p62) and in early adulthood (p90–p92) using the social interaction test, novel object recognition test, and open field test. Social and cognitive deficits first appeared in the middle adolescence stage and continued to occur into adulthood, both in rats treated with BSO alone or with the BSO + GBR 12909 combination. Behavior corresponding to positive symptoms in humans occurred in the middle adolescence period, only in rats treated with BSO + GBR 12909. Only in the latter group, amphetamine exacerbated the existing positive symptoms in adulthood. Our data show that rats receiving the BSO + GBR 12909 combination in the early postnatal life reproduced virtually all symptoms observed in patients with schizophrenia and, therefore, can be considered a valuable neurodevelopmental model of this disease.

scholarly journals STABILITY OF DNA IN PURKINJE CELL NUCLEI OF THE MOUSE

1974 ◽  
Vol 63 (2) ◽  
pp. 665-674 ◽  
Author(s):  
V. Mareš ◽  
B. Schultze ◽  
W. Maurer
Keyword(s):  
Young Adult ◽  
Purkinje Cell ◽  
Nuclear Dna ◽  
Brain Regions ◽  
Nuclear Volume ◽  
High Dose ◽  
Prenatal Period ◽  
Cell Nuclei ◽  
Grain Number ◽  
Adult Mice

Neurons of the mouse were labeled with [3H]thymidine during their prenatal period of proliferation. The 3H activity of the Purkinje cell nuclei was then studied autoradiographically 8, 25, 55, and 90 days after birth. The measured grain number per nucleus decreased by about 14% between the 8th and 25th postnatal days and then remained constant up to 90 days. There was no significant decrease of the 3H activity of the Purkinje cell nuclei after correction of the measured grain number per nucleus for increasing nuclear volume of the growing Purkinje cells and for the influence of [3H]ß self-absorption in the material of the sections. Injection of a high dose of [3H]thymidine into young adult mice did not result in 3H labeling of either Purkinje or other neurons in other brain regions. The results agree with the concept of metabolic stability of nuclear DNA. "Metabolic" DNA could not be observed in these experiments.

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