scholarly journals Topoisomerase IIIβ Deficiency Induces Neuro-Behavioral Changes and Brain Connectivity Alterations in Mice

2021 ◽  
Vol 22 (23) ◽  
pp. 12806
Author(s):  
Faiz Ur Rahman ◽  
You-Rim Kim ◽  
Eun-Kyeung Kim ◽  
Hae-rim Kim ◽  
Sang-Mi Cho ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
Brain Connectivity ◽  
Brain Regions ◽  
Normal Brain ◽  
Dna And Rna ◽  
Positron Emission ◽  
Normal Brain Function ◽  
Ct Analysis ◽  
The Central Nervous System ◽  
And Behavior

Topoisomerase IIIβ (Top3β), the only dual-activity topoisomerase in mammals that can change topology of both DNA and RNA, is known to be associated with neurodevelopment and mental dysfunction in humans. However, there is no report showing clear associations of Top3β with neuropsychiatric phenotypes in mice. Here, we investigated the effect of Top3β on neuro-behavior using newly generated Top3β deficient (Top3β−/−) mice. We found that Top3β−/− mice showed decreased anxiety and depression-like behaviors. The lack of Top3β was also associated with changes in circadian rhythm. In addition, a clear expression of Top3β was demonstrated in the central nervous system of mice. Positron emission tomography/computed tomography (PET/CT) analysis revealed significantly altered connectivity between many brain regions in Top3β−/− mice, including the connectivity between the olfactory bulb and the cerebellum, the connectivity between the amygdala and the olfactory bulb, and the connectivity between the globus pallidus and the optic nerve. These connectivity alterations in brain regions are known to be linked to neurodevelopmental as well as psychiatric and behavioral disorders in humans. Therefore, we conclude that Top3β is essential for normal brain function and behavior in mice and that Top3β could be an interesting target to study neuropsychiatric disorders in humans.

The somatic error hypothesis of anxiety

2018 ◽  
Author(s):  
Sahib S. Khalsa ◽  
Justin S. Feinstein
Keyword(s):  
Central Nervous System ◽  
Physiological State ◽  
Brain Regions ◽  
Novel Therapies ◽  
Body State ◽  
Long Term Changes ◽  
The Central Nervous System ◽  
And Behavior ◽  
The Brain

A regulatory battle for control ensues in the central nervous system following a mismatch between the current physiological state of an organism as mapped in viscerosensory brain regions and the predicted body state as computed in visceromotor control regions. The discrepancy between the predicted and current body state (i.e. the “somatic error”) signals a need for corrective action, motivating changes in both cognition and behavior. This chapter argues that anxiety disorders are fundamentally driven by somatic errors that fail to be adaptively regulated, leaving the organism in a state of dissonance where the predicted body state is perpetually out of line with the current body state. Repeated failures to quell somatic error can result in long-term changes to interoceptive circuitry within the brain. This chapter explores the neuropsychiatric sequelae that can emerge following chronic allostatic dysregulation of somatic errors and discusses novel therapies that might help to correct this dysregulation.

scholarly journals Impaired endothelium-mediated cerebrovascular reactivity promotes anxiety and respiration disorders in mice

2020 ◽  
Vol 117 (3) ◽  
pp. 1753-1761 ◽  
Author(s):  
Jan Wenzel ◽  
Cathrin E. Hansen ◽  
Carla Bettoni ◽  
Miriam A. Vogt ◽  
Beate Lembrich ◽  
...  
Keyword(s):  
Vascular Diseases ◽  
Major Product ◽  
Cerebrovascular Reactivity ◽  
Vascular Pathology ◽  
Normal Brain ◽  
Strong Impact ◽  
Vasoactive Factors ◽  
Normal Brain Function ◽  
The Central Nervous System ◽  
Functional Relevance

Carbon dioxide (CO2), the major product of metabolism, has a strong impact on cerebral blood vessels, a phenomenon known as cerebrovascular reactivity. Several vascular risk factors such as hypertension or diabetes dampen this response, making cerebrovascular reactivity a useful diagnostic marker for incipient vascular pathology, but its functional relevance, if any, is still unclear. Here, we found that GPR4, an endothelial H+ receptor, and endothelial Gαq/11 proteins mediate the CO2/H+ effect on cerebrovascular reactivity in mice. CO2/H+ leads to constriction of vessels in the brainstem area that controls respiration. The consequential washout of CO2, if cerebrovascular reactivity is impaired, reduces respiration. In contrast, CO2 dilates vessels in other brain areas such as the amygdala. Hence, an impaired cerebrovascular reactivity amplifies the CO2 effect on anxiety. Even at atmospheric CO2 concentrations, impaired cerebrovascular reactivity caused longer apneic episodes and more anxiety, indicating that cerebrovascular reactivity is essential for normal brain function. The site-specific reactivity of vessels to CO2 is reflected by regional differences in their gene expression and the release of vasoactive factors from endothelial cells. Our data suggest the central nervous system (CNS) endothelium as a target to treat respiratory and affective disorders associated with vascular diseases.

scholarly journals Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

2020 ◽  
Author(s):  
R. Chittajallu ◽  
K. Auville ◽  
V. Mahadevan ◽  
M. Lai ◽  
S. Hunt ◽  
...  
Keyword(s):  
Cognitive Processing ◽  
Intrinsic Excitability ◽  
Inhibitory Influence ◽  
Essential Property ◽  
Normal Brain ◽  
Cellular Mechanisms ◽  
Normal Brain Function ◽  
Circuit Function ◽  
And Behavior ◽  
Activity Dependent

ABSTRACTThe ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance to human circuit function. In this study, we focus on neurogliaform cells, a specialized form of neuron that possess physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms relevant for human cognitive processing and behavior.

scholarly journals The Effect of Nimodipine on the Evolution of Human Cerebral Infarction Studied by PET

1989 ◽  
Vol 9 (4) ◽  
pp. 523-534 ◽  
Author(s):  
A. M. Hakim ◽  
A. C. Evans ◽  
L. Berger ◽  
H. Kuwabara ◽  
K. Worsley ◽  
...  
Keyword(s):  
Cerebral Blood Volume ◽  
Statistical Significance ◽  
Treated Group ◽  
Brain Regions ◽  
Normal Brain ◽  
Oxygen Extraction Ratio ◽  
Perfusion Measurement ◽  
Positron Emission ◽  
The Difference ◽  
Cortical Regions

Fourteen patients were studied by positron emission tomography (PET) within 48 h of onset of a hemispheric ischemic stroke and again 7 days later. After the first set of PET scans, the patients were randomized to receive either nimodipine (n = 7) or a carrier solution (n = 7) by intravenous infusion. The infusions were maintained until the end of the second PET studies. CBF, cerebral blood volume (CBV), oxygen extraction ratio (OER), CMRO2, and CMRglc were measured each time. These metabolic and perfusion measurements were performed by standard methods. A surface map of each metabolic and perfusion measurement in the cortical mantle was generated by interpolating between the available slices. The various surface maps representing the physiological characteristics determined in the same or subsequent studies were aligned so that all data sets could be analyzed identically using an array of square regions of interest (ROIs). The functional status of each ROI was recorded at the two intervals following the cerebrovascular accident to characterize the evolution of the infarct, penumbra, and normal brain regions. We presumed the ischemic penumbra to be cortical regions in the proximity of the infarct and perfused at CBF values between 12 and 18 ml/100 g/min on the first PET scan, while densely ischemic regions had CBF of <12 nl/100 g/min and normally perfused brain >18 ml/100 g/min. In the densely ischemic zone, CBF increased more in the nimodipine-treated group than in the carrier group. As well, in this region nimodipine reversed the decline in CMRO2 noted in the carrier group, the difference in the changes being significant. In the penumbra zone, comparable trends were noted in OER and CMRO2 but the difference in the changes between the two groups did not reach statistical significance. Changes in CMRglc and CBV were comparable between the two groups in both cortical regions.

scholarly journals No Longer Underappreciated: The Emerging Concept of Astrocyte Heterogeneity in Neuroscience

2020 ◽  
Vol 10 (3) ◽  
pp. 168 ◽  
Author(s):  
Francisco Pestana ◽  
Gabriela Edwards-Faret ◽  
T. Grant Belgard ◽  
Araks Martirosyan ◽  
Matthew G. Holt
Keyword(s):  
Brain Function ◽  
Synapse Formation ◽  
Normal Brain ◽  
Barrier Formation ◽  
Astrocyte Heterogeneity ◽  
Normal Brain Function ◽  
The Central Nervous System ◽  
And Function ◽  
And Control

Astrocytes are ubiquitous in the central nervous system (CNS). These cells possess thousands of individual processes, which extend out into the neuropil, interacting with neurons, other glia and blood vessels. Paralleling the wide diversity of their interactions, astrocytes have been reported to play key roles in supporting CNS structure, metabolism, blood-brain-barrier formation and control of vascular blood flow, axon guidance, synapse formation and modulation of synaptic transmission. Traditionally, astrocytes have been studied as a homogenous group of cells. However, recent studies have uncovered a surprising degree of heterogeneity in their development and function, in both the healthy and diseased brain. A better understanding of astrocyte heterogeneity is urgently needed to understand normal brain function, as well as the role of astrocytes in response to injury and disease.

scholarly journals Blood-Based Bioenergetic Profiling Reflects Differences in Brain Bioenergetics and Metabolism

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Daniel J. Tyrrell ◽  
Manish S. Bharadwaj ◽  
Matthew J. Jorgensen ◽  
Thomas C. Register ◽  
Carol Shively ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Fdg Pet ◽  
Nonhuman Primates ◽  
Brain Mitochondria ◽  
Brain Regions ◽  
Respiratory Capacity ◽  
Mitochondrial Alterations ◽  
Positron Emission ◽  
The Central Nervous System ◽  
Direct Measures

Blood-based bioenergetic profiling provides a minimally invasive assessment of mitochondrial health shown to be related to key features of aging. Previous studies show that blood cells recapitulate mitochondrial alterations in the central nervous system under pathological conditions, including the development of Alzheimer’s disease. In this study of nonhuman primates, we focus on mitochondrial function and bioenergetic capacity assessed by the respirometric profiling of monocytes, platelets, and frontal cortex mitochondria. Our data indicate that differences in the maximal respiratory capacity of brain mitochondria are reflected by CD14+ monocyte maximal respiratory capacity and platelet and monocyte bioenergetic health index. A subset of nonhuman primates also underwent [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) imaging to assess brain glucose metabolism. Our results indicate that platelet respiratory capacity positively correlates to measures of glucose metabolism in multiple brain regions. Altogether, the results of this study provide early evidence that blood-based bioenergetic profiling is related to brain mitochondrial metabolism. While these measures cannot substitute for direct measures of brain metabolism, provided by measures such as FDG-PET, they may have utility as a metabolic biomarker and screening tool to identify individuals exhibiting systemic bioenergetic decline who may therefore be at risk for the development of neurodegenerative diseases.

Neurological emergencies

2020 ◽  
pp. 125-150
Keyword(s):  
Nervous System ◽  
Early Interventions ◽  
Normal Brain ◽  
Acute Management ◽  
Raised Intracranial Pressure ◽  
Neurological Emergencies ◽  
Normal Brain Function ◽  
The Central Nervous System ◽  
The Individual ◽  
And Control

Neurological emergencies following any injury involving the central or peripheral nervous system can have a devastating outcome for the individual. Speedy diagnosis to enable early interventions is paramount to reducing morbidity and mortality. Acute management relies on practitioners understanding the importance of basic physiological principles of maintenance of normal brain function and the effects this can have on ensuring perfusion of the central nervous system and control of raised intracranial pressure.

scholarly journals Dysfunction of grey matter NG2 glial cells affects neuronal plasticity and behavior

2021 ◽  
Author(s):  
Aline Timmermann ◽  
Ronald Jabs ◽  
Anne Boehlen ◽  
Catia Domingos ◽  
Magdalena Skubal ◽  
...  
Keyword(s):  
Synaptic Input ◽  
Grey Matter ◽  
Distinct Type ◽  
Long Term Potentiation ◽  
Normal Brain ◽  
Targeted Deletion ◽  
Term Potentiation ◽  
Normal Brain Function ◽  
Physiological Impact ◽  
And Behavior

NG2 glia represent a distinct type of macroglial cells in the CNS and are unique among glia because they receive synaptic input from neurons. They are abundantly present in white and grey matter. While the majority of white matter NG2 glia differentiates into oligodendrocytes, the physiological impact of grey matter NG2 glia and their synaptic input are ill defined yet. Here we asked whether dysfunctional NG2 glia affect neuronal signaling and behavior. We generated mice with inducible deletion of the K+ channel Kir4.1 in NG2 glia and performed comparative electrophysiological, immunohistochemical, molecular and behavioral analyses. Focussing on the hippocampus, we found that loss of the Kir4.1 potentiated synaptic depolarizations of NG2 glia and enhanced the expression of myelin basic protein. Notably, while mice with targeted deletion of the K+ channel in NG2 glia showed impaired long term potentiation at CA3-CA1 synapses, they demonstrated improved spatial memory as revealed by testing new object location recognition. Our data demonstrate that proper NG2 glia function is critical for normal brain function and behavior.

scholarly journals Deep Neural Networks Carve the Brain at its Joints

2020 ◽  
Author(s):  
Maxwell A. Bertolero ◽  
Danielle S. Bassett
Keyword(s):  
Neural Networks ◽  
Deep Neural Networks ◽  
Linear Models ◽  
Brain Connectivity ◽  
Network Models ◽  
Brain Regions ◽  
Linear Functions ◽  
Complex Relationships ◽  
And Behavior ◽  
The Brain

AbstractHow an individual’s unique brain connectivity determines that individual’s cognition, behavior, and risk for pathology is a fundamental question in basic and clinical neuroscience. In seeking answers, many have turned to machine learning, with some noting the particular promise of deep neural networks in modelling complex non-linear functions. However, it is not clear that complex functions actually exist between brain connectivity and behavior, and thus if deep neural networks necessarily outperform simpler linear models, or if their results would be interpretable. Here we show that, across 52 subject measures of cognition and behavior, deep neural networks fit to each brain region’s connectivity outperform linear regression, particularly for the brain’s connector hubs—regions with diverse brain connectivity—whereas the two approaches perform similarly when fit to brain systems. Critically, averaging deep neural network predictions across brain regions results in the most accurate predictions, demonstrating the ability of deep neural networks to easily model the various functions that exists between regional brain connectivity and behavior, carving the brain at its joints. Finally, we shine light into the black box of deep neural networks using multislice network models. We determined that the relationship between connector hubs and behavior is best captured by modular deep neural networks. Our results demonstrate that both simple and complex relationships exist between brain connectivity and behavior, and that deep neural networks can fit both. Moreover, deep neural networks are particularly powerful when they are first fit to the various functions of a system independently and then combined. Finally, deep neural networks are interpretable when their architectures are structurally characterized using multislice network models.

scholarly journals Activity-dependent tuning of intrinsic excitability in mouse and human neurogliaform cells

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Ramesh Chittajallu ◽  
Kurt Auville ◽  
Vivek Mahadevan ◽  
Mandy Lai ◽  
Steven Hunt ◽  
...  
Keyword(s):  
Cognitive Processing ◽  
Intrinsic Excitability ◽  
Inhibitory Influence ◽  
Essential Property ◽  
Normal Brain ◽  
Cellular Mechanisms ◽  
Normal Brain Function ◽  
Circuit Function ◽  
And Behavior ◽  
Activity Dependent

The ability to modulate the efficacy of synaptic communication between neurons constitutes an essential property critical for normal brain function. Animal models have proved invaluable in revealing a wealth of diverse cellular mechanisms underlying varied plasticity modes. However, to what extent these processes are mirrored in humans is largely uncharted thus questioning their relevance in human circuit function. In this study, we focus on neurogliaform cells, that possess specialized physiological features enabling them to impart a widespread inhibitory influence on neural activity. We demonstrate that this prominent neuronal subtype, embedded in both mouse and human neural circuits, undergo remarkably similar activity-dependent modulation manifesting as epochs of enhanced intrinsic excitability. In principle, these evolutionary conserved plasticity routes likely tune the extent of neurogliaform cell mediated inhibition thus constituting canonical circuit mechanisms underlying human cognitive processing and behavior.

Sign in / Sign up

Export Citation Format

Share Document