Potential of Multiscale Astrocyte Imaging for Revealing Mechanisms Underlying Neurodevelopmental Disorders

Astrocytes provide trophic and metabolic support to neurons and modulate circuit formation during development. In addition, astrocytes help maintain neuronal homeostasis through neurovascular coupling, blood–brain barrier maintenance, clearance of metabolites and nonfunctional proteins via the glymphatic system, extracellular potassium buffering, and regulation of synaptic activity. Thus, astrocyte dysfunction may contribute to a myriad of neurological disorders. Indeed, astrocyte dysfunction during development has been implicated in Rett disease, Alexander’s disease, epilepsy, and autism, among other disorders. Numerous disease model mice have been established to investigate these diseases, but important preclinical findings on etiology and pathophysiology have not translated into clinical interventions. A multidisciplinary approach is required to elucidate the mechanism of these diseases because astrocyte dysfunction can result in altered neuronal connectivity, morphology, and activity. Recent progress in neuroimaging techniques has enabled noninvasive investigations of brain structure and function at multiple spatiotemporal scales, and these technologies are expected to facilitate the translation of preclinical findings to clinical studies and ultimately to clinical trials. Here, we review recent progress on astrocyte contributions to neurodevelopmental and neuropsychiatric disorders revealed using novel imaging techniques, from microscopy scale to mesoscopic scale.

Download Full-text

Everything you wanted to know about neuroimaging and psychiatry, but were afraid to ask

BJPsych Advances ◽

10.1192/apt.bp.114.013763 ◽

2015 ◽

Vol 21 (4) ◽

pp. 251-260 ◽

Cited By ~ 4

Author(s):

Cristina Martinelli ◽

Sukhwinder S. Shergill

Keyword(s):

Clinical Practice ◽

Psychiatric Disorder ◽

Mental Disorder ◽

Brain Structure ◽

Imaging Techniques ◽

Structure And Function ◽

Everyday Clinical Practice ◽

Brain Structure And Function ◽

And Function ◽

The Brain

SummaryRecent years have seen a dramatic increase in the advances and applications of medical imaging techniques. Tools with familiar acronyms such as MRI, EEG/MEG and PET/SPECT have provided invaluable information not only about the brain structure and function associated with psychiatric disorders, but increasingly about the mechanisms underpinning these disorders. This evolving understanding of the specific pathophysiology of mental disorder paves the way for improvement in the diagnosis, treatment and prognosis of the disorders managed in everyday clinical practice. This article gives an overview of the main neuroimaging approaches, contemporary applications of this technology to psychiatric disorder and signposts to the exciting possibilities for the future.

Download Full-text

The Effects of Leptin Replacement on Neural Plasticity

Neural Plasticity ◽

10.1155/2016/8528934 ◽

2016 ◽

Vol 2016 ◽

pp. 1-8 ◽

Cited By ~ 15

Author(s):

Gilberto J. Paz-Filho

Keyword(s):

Neural Plasticity ◽

Observational Studies ◽

Neuronal Development ◽

Neuronal Morphology ◽

Synaptic Activity ◽

Hypothalamic Amenorrhea ◽

Glutamate Receptor Trafficking ◽

Brain Structure And Function ◽

And Function

Leptin, an adipokine synthesized and secreted mainly by the adipose tissue, has multiple effects on the regulation of food intake, energy expenditure, and metabolism. Its recently-approved analogue, metreleptin, has been evaluated in clinical trials for the treatment of patients with leptin deficiency due to mutations in the leptin gene, lipodystrophy syndromes, and hypothalamic amenorrhea. In such patients, leptin replacement therapy has led to changes in brain structure and function in intra- and extrahypothalamic areas, including the hippocampus. Furthermore, in one of those patients, improvements in neurocognitive development have been observed. In addition to this evidence linking leptin to neural plasticity and function, observational studies evaluating leptin-sufficient humans have also demonstrated direct correlation between blood leptin levels and brain volume and inverse associations between circulating leptin and risk for the development of dementia. This review summarizes the evidence in the literature on the role of leptin in neural plasticity (in leptin-deficient and in leptin-sufficient individuals) and its effects on synaptic activity, glutamate receptor trafficking, neuronal morphology, neuronal development and survival, and microglial function.

Download Full-text

Brain structure and function in gender dysphoria

Endocrine Abstracts ◽

10.1530/endoabs.56.s30.3 ◽

2018 ◽

Author(s):

Julie Bakker

Keyword(s):

Brain Structure ◽

Gender Dysphoria ◽

Structure And Function ◽

Brain Structure And Function ◽

And Function

Download Full-text

The ENIGMA Brain Injury Working Group: Approach, Challenges, and Potential Benefits

10.31234/osf.io/t96xb ◽

2019 ◽

Cited By ~ 7

Author(s):

Elisabeth A. Wilde ◽

Emily L. Dennis ◽

David F Tate

Keyword(s):

Brain Injury ◽

Working Group ◽

Meta Analysis ◽

Special Issue ◽

Group Approach ◽

Challenges And Opportunities ◽

Brain Structure And Function ◽

Potential Benefits ◽

And Function ◽

Neuroimaging Genetics

The Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium brings together researchers from around the world to try to identify the genetic underpinnings of brain structure and function, along with robust, generalizable effects of neurological and psychiatric disorders. The recently-formed ENIGMA Brain Injury working group includes 8 subgroups, based largely on injury mechanism and patient population. This introduction to the special issue summarizes the history, organization, and objectives of ENIGMA Brain Injury, and includes a discussion of strategies, challenges, opportunities and goals common across 6 of the subgroups under the umbrella of ENIGMA Brain Injury. The following articles in this special issue, including 6 articles from different subgroups, will detail the challenges and opportunities specific to each subgroup.

Download Full-text

Targeting Pin1 for Modulation of Cell Motility and Cancer Therapy

Biomedicines ◽

10.3390/biomedicines9040359 ◽

2021 ◽

Vol 9 (4) ◽

pp. 359

Author(s):

Hsiang-Hao Chuang ◽

Yen-Yi Zhen ◽

Yu-Chen Tsai ◽

Cheng-Hao Chuang ◽

Ming-Shyan Huang ◽

...

Keyword(s):

Cancer Therapy ◽

Tumor Suppressors ◽

Protein Conformation ◽

Genome Stability ◽

Recent Progress ◽

Multiple Roles ◽

Cancer Development ◽

Cancer Hallmarks ◽

Underlying Mechanisms ◽

And Function

Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (Pin1) specifically binds and isomerizes the phosphorylated serine/threonine-proline (pSer/Thr-Pro) motif, which leads to changes in protein conformation and function. Pin1 is widely overexpressed in cancers and plays an important role in tumorigenesis. Mounting evidence has revealed that targeting Pin1 is a potential therapeutic approach for various cancers by inhibiting cell proliferation, reducing metastasis, and maintaining genome stability. In this review, we summarize the underlying mechanisms of Pin1-mediated upregulation of oncogenes and downregulation of tumor suppressors in cancer development. Furthermore, we also discuss the multiple roles of Pin1 in cancer hallmarks and examine Pin1 as a desirable pharmaceutical target for cancer therapy. We also summarize the recent progress of Pin1-targeted small-molecule compounds for anticancer activity.

Download Full-text

Restoration of Noradrenergic Function in Parkinson’s Disease Model Mice

ASN NEURO ◽

10.1177/17590914211009730 ◽

2021 ◽

Vol 13 ◽

pp. 175909142110097

Author(s):

Kui Cui ◽

Fan Yang ◽

Turan Tufan ◽

Muhammad U. Raza ◽

Yanqiang Zhan ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Transcription Factors ◽

Disease Model ◽

Neuronal Loss ◽

Mrna Levels ◽

Gene Therapies ◽

Protein Levels ◽

Dopaminergic Systems ◽

And Function

Dysfunction of the central noradrenergic and dopaminergic systems is the primary neurobiological characteristic of Parkinson’s disease (PD). Importantly, neuronal loss in the locus coeruleus (LC) that occurs in early stages of PD may accelerate progressive loss of dopaminergic neurons. Therefore, restoring the activity and function of the deficient noradrenergic system may be an important therapeutic strategy for early PD. In the present study, the lentiviral constructions of transcription factors Phox2a/2b, Hand2 and Gata3, either alone or in combination, were microinjected into the LC region of the PD model VMAT2 Lo mice at 12 and 18 month age. Biochemical analysis showed that microinjection of lentiviral expression cassettes into the LC significantly increased mRNA levels of Phox2a, and Phox2b, which were accompanied by parallel increases of mRNA and proteins of dopamine β-hydroxylase (DBH) and tyrosine hydroxylase (TH) in the LC. Furthermore, there was considerable enhancement of DBH protein levels in the frontal cortex and hippocampus, as well as enhanced TH protein levels in the striatum and substantia nigra. Moreover, these manipulations profoundly increased norepinephrine and dopamine concentrations in the striatum, which was followed by a remarkable improvement of the spatial memory and locomotor behavior. These results reveal that over-expression of these transcription factors in the LC improves noradrenergic and dopaminergic activities and functions in this rodent model of PD. It provides the necessary groundwork for the development of gene therapies of PD, and expands our understanding of the link between the LC-norepinephrine and dopamine systems during the progression of PD.

Download Full-text

The long noncoding RNA Synage regulates synapse stability and neuronal function in the cerebellum

Cell Death and Differentiation ◽

10.1038/s41418-021-00774-3 ◽

2021 ◽

Author(s):

Fei Wang ◽

Qianqian Wang ◽

Baowei Liu ◽

Lisheng Mei ◽

Sisi Ma ◽

...

Keyword(s):

Noncoding Rna ◽

Cerebellar Atrophy ◽

Synaptic Activity ◽

Motor Dysfunction ◽

Cerebellar Development ◽

Full Spectrum ◽

Density Reduction ◽

Adult Mice ◽

Synapse Density ◽

And Function

AbstractThe brain is known to express many long noncoding RNAs (lncRNAs); however, whether and how these lncRNAs function in modulating synaptic stability remains unclear. Here, we report a cerebellum highly expressed lncRNA, Synage, regulating synaptic stability via at least two mechanisms. One is through the function of Synage as a sponge for the microRNA miR-325-3p, to regulate expression of the known cerebellar synapse organizer Cbln1. The other function is to serve as a scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complex in PF-PC synapses. Although somewhat divergent in its mature mRNA sequence, the locus encoding Synage is positioned adjacent to the Cbln1 loci in mouse, rhesus macaque, and human, and Synage is highly expressed in the cerebella of all three species. Synage deletion causes a full-spectrum cerebellar ablation phenotype that proceeds from cerebellar atrophy, through neuron loss, on to synapse density reduction, synaptic vesicle loss, and finally to a reduction in synaptic activity during cerebellar development; these deficits are accompanied by motor dysfunction in adult mice, which can be rescued by AAV-mediated Synage overexpression from birth. Thus, our study demonstrates roles for the lncRNA Synage in regulating synaptic stability and function during cerebellar development.

Download Full-text