scholarly journals The flavonoid 7,8-DHF fosters prenatal brain proliferation potency in a mouse model of Down syndrome

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fiorenza Stagni ◽  
Beatrice Uguagliati ◽  
Marco Emili ◽  
Andrea Giacomini ◽  
Renata Bartesaghi ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Intellectual Disability ◽  
Granule Cells ◽  
Neonatal Period ◽  
Hippocampal Neurogenesis ◽  
Chromosome 21 ◽  
Prenatal Treatment ◽  
Long Term Effects ◽  
Neonatal Treatment

AbstractNeurogenesis impairment is a key determinant of intellectual disability in Down syndrome (DS), a genetic pathology due to triplication of chromosome 21. Since neurogenesis ceases after birth, apart in the hippocampus and olfactory bulb, the only means to tackle the problem of neurogenesis impairment in DS at its root is to intervene during gestation. A few studies in DS mouse models show that this is possible, although the drugs used may raise caveats in terms of safety. We previously found that neonatal treatment with 7,8-dihydroxyflavone (7,8-DHF), a flavonoid present in plants, restores hippocampal neurogenesis in the Ts65Dn model of DS. The goal of the current study was to establish whether prenatal treatment with 7,8-DHF improves/restores overall brain proliferation potency. Pregnant Ts65Dn females received 7,8-DHF from embryonic day 10 until delivery. On postnatal day 2 (P2) the pups were injected with BrdU and were killed after either 2 h or 52–60 days (P52–60). Evaluation of the number of proliferating (BrdU+) cells in various forebrain neurogenic niches of P2 mice showed that in treated Ts65Dn mice proliferation potency was improved or even restored in most of the examined regions, including the hippocampus. Quantification of the surviving BrdU+ cells in the dentate gyrus of P52–60 mice showed no difference between treated and untreated Ts65Dn mice. At P52–60, however, treated Ts65Dn mice exhibited a larger number of granule cells in comparison with their untreated counterparts, although their number did not reach that of euploid mice. Results show that 7,8-DHF has a widespread impact on prenatal proliferation potency in Ts65Dn mice and exerts mild long-term effects. It remains to be established whether treatment extending into the neonatal period can lead to an improvement in brain development that is retained in adulthood.

scholarly journals Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome

2021 ◽  
Author(s):  
Veronique Brault ◽  
Thu Lan Nguyen ◽  
Javier Flores-Gutierrez ◽  
Marie-Christine Birling ◽  
Valerie Lalanne ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Intellectual Disability ◽  
Autism Spectrum ◽  
Conditional Knockout ◽  
Synaptic Proteins ◽  
Chromosome 21 ◽  
Gene Copy ◽  
Glutamatergic Neurons ◽  
The Impact

Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Mutation in the DYRK1A gene located on human chromosome 21 (Hsa21) leads to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles (MRD7). Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg(Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16Lipi-Zbtb21)1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key post-synaptic proteins implicated in mechanism leading to long-term enhanced synaptic plasticity. Altogether, our work gives important information to understand the action of DYRK1A inhibitors and have a better therapeutic approach.

scholarly journals Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome

PLoS Genetics ◽  
2021 ◽  
Vol 17 (9) ◽  
pp. e1009777
Author(s):  
Véronique Brault ◽  
Thu Lan Nguyen ◽  
Javier Flores-Gutiérrez ◽  
Giovanni Iacono ◽  
Marie-Christine Birling ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Intellectual Disability ◽  
Autism Spectrum ◽  
Conditional Knockout ◽  
Synaptic Proteins ◽  
Chromosome 21 ◽  
Gene Copy ◽  
Glutamatergic Neurons ◽  
The Impact

Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Loss-of-function mutations in the DYRK1A gene, located on human chromosome 21 (Hsa21,) lead to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles. Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg(Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16Lipi-Zbtb21)1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in postnatal glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key post-synaptic proteins implicated in mechanism leading to long-term enhanced synaptic plasticity. Altogether, our work gives important information to understand the action of DYRK1A inhibitors and have a better therapeutic approach.

scholarly journals Neuroinflammatory changes of the normal brain tissue in cured mice following combined radiation and anti-PD-1 blockade therapy for glioma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mariano Guardia Clausi ◽  
Alexander M. Stessin ◽  
Zirun Zhao ◽  
Stella E. Tsirka ◽  
Samuel Ryu
Keyword(s):  
Brain Tissue ◽  
Cranial Irradiation ◽  
Subcortical White Matter ◽  
Glioma Cell Line ◽  
Hippocampal Neurogenesis ◽  
Normal Brain ◽  
Long Term Effects ◽  
Normal Brain Tissue ◽  
Molecule Inhibitor

AbstractThe efficacy of combining radiation therapy with immune checkpoint inhibitor blockade to treat brain tumors is currently the subject of multiple investigations and holds significant therapeutic promise. However, the long-term effects of this combination therapy on the normal brain tissue are unknown. Here, we examined mice that were intracranially implanted with murine glioma cell line and became long-term survivors after treatment with a combination of 10 Gy cranial irradiation (RT) and anti-PD-1 checkpoint blockade (aPD-1). Post-mortem analysis of the cerebral hemisphere contralateral to tumor implantation showed complete abolishment of hippocampal neurogenesis, but neural stem cells were well preserved in subventricular zone. In addition, we observed a drastic reduction in the number of mature oligodendrocytes in the subcortical white matter. Importantly, this observation was evident specifically in the combined (RT + aPD-1) treatment group but not in the single treatment arm of either RT alone or aPD-1 alone. Elimination of microglia with a small molecule inhibitor of colony stimulated factor-1 receptor (PLX5622) prevented the loss of mature oligodendrocytes. These results identify for the first time a unique pattern of normal tissue changes in the brain secondary to combination treatment with radiotherapy and immunotherapy. The results also suggest a role for microglia as key mediators of the adverse treatment effect.

Long-term effects of repetitive pain in the neonatal period

2005 ◽  
pp. 197-210
Author(s):  
Kanwaljeet Anand ◽  
Adnan Bhutta ◽  
Richard Hall ◽  
Cynthia Rovnaghi ◽  
Elie Al-Chaer
Keyword(s):  
Neonatal Period ◽  
Long Term Effects

scholarly journals Long-Term Overconsumption of Sugar Starting at Adolescence Produces Persistent Hyperactivity and Neurocognitive Deficits in Adulthood

2021 ◽  
Vol 15 ◽  
Author(s):  
Kate Beecher ◽  
Ignatius Alvarez Cooper ◽  
Joshua Wang ◽  
Shaun B. Walters ◽  
Fatemeh Chehrehasa ◽  
...  
Keyword(s):  
Dietary Habits ◽  
Hippocampal Neurogenesis ◽  
Neurocognitive Deficits ◽  
Long Term Effects ◽  
Sugar Consumption ◽  
Food And Beverages ◽  
Increased Risk ◽  
Newborn Neurons ◽  
Dependent Learning

Sugar has become embedded in modern food and beverages. This has led to overconsumption of sugar in children, adolescents, and adults, with more than 60 countries consuming more than four times (>100 g/person/day) the WHO recommendations (25 g/person/day). Recent evidence suggests that obesity and impulsivity from poor dietary habits leads to further overconsumption of processed food and beverages. The long-term effects on cognitive processes and hyperactivity from sugar overconsumption, beginning at adolescence are not known. Using a well-validated mouse model of sugar consumption, we found that long-term sugar consumption, at a level that significantly augments weight gain, elicits an abnormal hyperlocomotor response to novelty and alters both episodic and spatial memory. Our results are similar to those reported in attention deficit and hyperactivity disorders. The deficits in hippocampal-dependent learning and memory were accompanied by altered hippocampal neurogenesis, with an overall decrease in the proliferation and differentiation of newborn neurons within the dentate gyrus. This suggests that long-term overconsumption of sugar, as that which occurs in the Western Diet might contribute to an increased risk of developing persistent hyperactivity and neurocognitive deficits in adulthood.

Short- and long-term effects of neonatal pharmacotherapy with epigallocatechin-3-gallate on hippocampal development in the Ts65Dn mouse model of Down syndrome

Neuroscience ◽  
2016 ◽  
Vol 333 ◽  
pp. 277-301 ◽  
Author(s):  
Fiorenza Stagni ◽  
Andrea Giacomini ◽  
Marco Emili ◽  
Stefania Trazzi ◽  
Sandra Guidi ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Mouse Model ◽  
Long Term Effects ◽  
Ts65dn Mouse ◽  
Short And Long Term ◽  
Hippocampal Development

What We Should Not Forget about Down Syndrome

Neurographics ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 149-165
Author(s):  
D.C. Fragoso ◽  
D.M. Nunes ◽  
A.C.M. Maia ◽  
L.A.L. Garcia ◽  
H.C.B.R. Alves ◽  
...  
Keyword(s):  
Down Syndrome ◽  
Intellectual Disability ◽  
Cognitive Decline ◽  
Early Recognition ◽  
Point Of View ◽  
Chromosome 21 ◽  
Age Related ◽  
Organ Systems ◽  
Notable Increase ◽  
Age Related Cognitive Decline

Down syndrome is the foremost common genetic cause of intellectual disability. The additional copy of chromosome 21 confers potential changes in virtually all organ systems, including the brain, neck structures, and spine. Neuroradiologists should be aware of the multitude of imaging findings in patients with Down syndrome to correctly identify and diagnose life-altering conditions associated with this syndrome. In particular, the high prevalence of age-related cognitive decline and dementia stands out more clearly in recent decades due to the notable increase in these individuals' survival. Although the early and timely diagnosis of cognitive decline in patients with varying degrees of intellectual disability has not been an easy task from the clinical point of view, anatomic and functional brain studies have shown an essential role because they allow the early recognition of abnormalities that precede the cognitive decline. Furthermore, the similarities and differences in neuropathologic, genetic, and imaging aspects in patients with Down syndrome have allowed extrapolation for a better understanding of the mechanisms linked to Alzheimer disease development.Learning Objective: To review and systematize the distinctive characteristics and abnormalities of the head and neck, vertebral column, and CNS present in Down syndrome

The Long-Term Effects of Relocation on People with an Intellectual Disability: Quality of Life, Behavior, and Environment

2000 ◽  
Vol 10 (2) ◽  
pp. 195-208 ◽  
Author(s):  
Brian Cooper ◽  
Cliff Picton
Keyword(s):  
Quality Of Life ◽  
Intellectual Disability ◽  
Challenging Behaviors ◽  
Positive Outcomes ◽  
Life Care ◽  
Long Term Effects ◽  
Social Work Research ◽  
Living Skills

This article reports on the long-term effects of relocation on a sample of 45 people with an intellectual disability who moved from an institution to the community and to other institutions. Data were gathered for 3 years after relocation. Results revealed that a move to supported community residences and to refurbished units within other institutions was associated with increased quality of life/care and, for interinstitutional movers, decreased challenging behaviors. Relocation did not lead to increased performance of independent community living skills, despite increased opportunities in the community. Where significant changes were identified they were modest and occurred within 6 months of relocation. It is concluded that positive outcomes result from community placement and interinstitutional relocation. The implications and limitations of this evidence for social work research and practice are discussed.

Neonatal immune challenge does not affect body weight regulation in rats

2007 ◽  
Vol 293 (2) ◽  
pp. R581-R589 ◽  
Author(s):  
Sarah J. Spencer ◽  
Abdeslam Mouihate ◽  
Michael A. Galic ◽  
Shaun L. Ellis ◽  
Quentin J. Pittman
Keyword(s):  
Body Weight ◽  
Immune System ◽  
Neonatal Period ◽  
Weight Regulation ◽  
Immune Challenge ◽  
Body Weight Regulation ◽  
Long Term Effects ◽  
Immune System Activation ◽  
System Activation

The perinatal environment plays a crucial role in programming many aspects of adult physiology. Myriad stressors during pregnancy, from maternal immune challenge to nutritional deficiency, can alter long-term body weight set points of the offspring. In light of the increasing concern over body weight issues, such as obesity and anorexia, in modern societies and accumulating evidence that developmental stressors have long-lasting effects on other aspects of physiology (e.g., fever, pain), we explored the role of immune system activation during neonatal development and its impact on body weight regulation in adulthood. Here we present a thorough evaluation of the effects of immune system activation (LPS, 100 μg/kg ip) at postnatal days 3, 7, or 14 on long-term body weight, adiposity, and body weight regulation after a further LPS injection (50 μg/kg ip) or fasting and basal and LPS-induced circulating levels of the appetite-regulating proinflammatory cytokine leptin. We show that neonatal exposure to LPS at various times during the neonatal period has no long-term effects on growth, body weight, or adiposity. We also observed no effects on body weight regulation in response to a short fasting period or a further exposure to LPS. Despite reductions in circulating leptin levels in response to LPS during the neonatal period, no long-term effects on leptin were seen. These results convincingly demonstrate that adult body weight and weight regulation are, unlike many other aspects of adult physiology, resistant to programming by a febrile-dose neonatal immune challenge.

Sign in / Sign up

Export Citation Format

Share Document