scholarly journals Inhibitory neurons exhibit high controlling ability in the cortical microconnectome

2021 ◽  
Vol 17 (4) ◽  
pp. e1008846
Author(s):  
Motoki Kajiwara ◽  
Ritsuki Nomura ◽  
Felix Goetze ◽  
Masanori Kawabata ◽  
Yoshikazu Isomura ◽  
...  
Keyword(s):  
Firing Rate ◽  
Brain Regions ◽  
Inhibitory Neurons ◽  
Connectivity Pattern ◽  
Disease States ◽  
Neuronal Interactions ◽  
Excitatory Neurons ◽  
The Brain ◽  
Random Connectivity

The brain is a network system in which excitatory and inhibitory neurons keep activity balanced in the highly non-random connectivity pattern of the microconnectome. It is well known that the relative percentage of inhibitory neurons is much smaller than excitatory neurons in the cortex. So, in general, how inhibitory neurons can keep the balance with the surrounding excitatory neurons is an important question. There is much accumulated knowledge about this fundamental question. This study quantitatively evaluated the relatively higher functional contribution of inhibitory neurons in terms of not only properties of individual neurons, such as firing rate, but also in terms of topological mechanisms and controlling ability on other excitatory neurons. We combined simultaneous electrical recording (~2.5 hours) of ~1000 neurons in vitro, and quantitative evaluation of neuronal interactions including excitatory-inhibitory categorization. This study accurately defined recording brain anatomical targets, such as brain regions and cortical layers, by inter-referring MRI and immunostaining recordings. The interaction networks enabled us to quantify topological influence of individual neurons, in terms of controlling ability to other neurons. Especially, the result indicated that highly influential inhibitory neurons show higher controlling ability of other neurons than excitatory neurons, and are relatively often distributed in deeper layers of the cortex. Furthermore, the neurons having high controlling ability are more effectively limited in number than central nodes of k-cores, and these neurons also participate in more clustered motifs. In summary, this study suggested that the high controlling ability of inhibitory neurons is a key mechanism to keep balance with a large number of other excitatory neurons beyond simple higher firing rate. Application of the selection method of limited important neurons would be also applicable for the ability to effectively and selectively stimulate E/I imbalanced disease states.

scholarly journals Inhibitory neurons are a Central Controlling regulator in the effective cortical microconnectome

2020 ◽  
Author(s):  
Motoki Kajiwara ◽  
Ritsuki Nomura ◽  
Felix Goetze ◽  
Tatsuya Akutsu ◽  
Masanori Shimono
Keyword(s):  
Firing Rate ◽  
Normal Distribution ◽  
Inhibitory Neurons ◽  
Connectivity Pattern ◽  
Disease States ◽  
Controlling System ◽  
Excitatory Neurons ◽  
Log Normal ◽  
Log Normal Distribution ◽  
The Brain

AbstractThe brain is a network system in which excitatory and inhibitory neurons keep the activity balanced in the highly non-uniform connectivity pattern of the microconnectome. It is well known that the relative percentage of inhibitory neurons is much smaller than excitatory neurons. So, in general, how the inhibitory neurons can keep the balance with the surrounding excitatory neurons is an important question.We observed effective networks, reflecting causal interactions, of ~1000 neurons in cortical acute slices. Surprisingly, we found that inhibitory neurons are not only located at more central positions than excitatory neurons but also have stronger controlling ability of other neurons than excitatory neurons. Besides, we found that the precedence in centrality and controlling ability of inhibitory neurons are well observed in deep cortical layers by comparing with distribution of neurons coloured by NeuN immunostaining data. Preceding the observation, we also found that inhibitory neurons show higher firing rate than excitatory neurons, and that their firing rate also closely obey a log-normal distribution as previously known about excitatory neurons. Additionally, their connectivity strengths also obeyed a log-normal distribution.In summary, within the network interaction of huge numbers of neurons, inhibitory neurons seem to produce a central controlling system that sustains the homeostatic behavior of the brain. A similar evaluation in different life stages and in disease states etc. will not only provide deeper understandings in the homeostasis of the brain, but also will provide a selective and effective way to stimulate individual neurons to modulate neuropsychiatry or neurodegeneration disease states.

scholarly journals Neurotoxic astrocytic glypican-4 drives APOE4-dependent tau pathology

2021 ◽  
Author(s):  
Sivaprakasam Ramamoorthy ◽  
Kirill Gorbachev ◽  
Ana Pereira
Keyword(s):  
Late Onset ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Brain Regions ◽  
Tau Proteins ◽  
Tau Pathology ◽  
Density Lipoprotein Receptor ◽  
Apoe Receptor ◽  
The Brain

Apolipoprotein E4 (APOE4) is the crucial genetic risk factor of late-onset Alzheimer disease (AD). Aggregation of tau proteins into insoluble filaments and their spreading across the brain regions are major drivers of neurodegeneration in tauopathies, including in AD. However, the exact mechanisms through which APOE4 induces tau pathology remains unknown. Here, we report that the astrocyte-secreted protein glypican-4 (GPC-4), a novel binding partner of APOE4, drives tau pathology. GPC-4 preferentially interacts with APOE4 in comparison to other APOE isoforms and post-mortem APOE4-carrying AD brains highly express GPC-4 in neurotoxic astrocytes. The astrocyte-secreted GPC-4 induced both tau accumulation and propagation in vitro. CRISPR/dCas9 mediated activation of GPC-4 in a tauopathy animal model robustly induced tau pathology. Further, APOE4-induced tau pathology was greatly diminished in the absence of GPC-4. We found that GPC-4 promoted the stabilization of the APOE receptor low-density lipoprotein receptor-related protein 1 (LRP1) on the cellular surface, which effectively facilitates endocytosis of tau protein. Together, our data comprehensively demonstrate that one of the key APOE4-induced tau pathologies is directly mediated by GPC-4.

scholarly journals Remote control of glucose-sensing neurons to analyze glucose metabolism

2018 ◽  
Vol 315 (3) ◽  
pp. E327-E339 ◽  
Author(s):  
Alexandra Alvarsson ◽  
Sarah A. Stanley
Keyword(s):  
Firing Rate ◽  
Brain Regions ◽  
Glucose Sensing ◽  
Neural Stimulation ◽  
Neural Activation ◽  
Glucose Levels ◽  
Disease States ◽  
Neural Populations ◽  
Synthetic Ligand ◽  
The Central Nervous System

The central nervous system relies on a continual supply of glucose, and must be able to detect glucose levels and regulate peripheral organ functions to ensure that its energy requirements are met. Specialized glucose-sensing neurons, first described half a century ago, use glucose as a signal and modulate their firing rates as glucose levels change. Glucose-excited neurons are activated by increasing glucose concentrations, while glucose-inhibited neurons increase their firing rate as glucose concentrations fall and decrease their firing rate as glucose concentrations rise. Glucose-sensing neurons are present in multiple brain regions and are highly expressed in hypothalamic regions, where they are involved in functions related to glucose homeostasis. However, the roles of glucose-sensing neurons in healthy and disease states remain poorly understood. Technologies that can rapidly and reversibly activate or inhibit defined neural populations provide invaluable tools to investigate how specific neural populations regulate metabolism and other physiological roles. Optogenetics has high temporal and spatial resolutions, requires implants for neural stimulation, and is suitable for modulating local neural populations. Chemogenetics, which requires injection of a synthetic ligand, can target both local and widespread populations. Radio- and magnetogenetics offer rapid neural activation in localized or widespread neural populations without the need for implants or injections. These tools will allow us to better understand glucose-sensing neurons and their metabolism-regulating circuits.

HORMONES MODULATE THE CONCENTRATION OF CYTOPLASMIC PROGESTIN RECEPTORS IN THE BRAIN OF MALE RING DOVES (STREPTOPELIA RISORIA)

1980 ◽  
Vol 86 (2) ◽  
pp. 251-261 ◽  
Author(s):  
J. BALTHAZART ◽  
J. D. BLAUSTEIN ◽  
M. F. CHENG ◽  
H. H. FEDER
Keyword(s):  
Testosterone Propionate ◽  
Brain Regions ◽  
Posterior Hypothalamus ◽  
Vitro Assay ◽  
Progestin Receptors ◽  
Streptopelia Risoria ◽  
Oestradiol Benzoate ◽  
Ring Doves ◽  
The Brain

A cytoplasmic progestin receptor has been characterized in the brain of castrated ring doves using an in-vitro assay that measures the binding of a synthetic progestin, [3H]17α,21-dimethyl-19-nor-pregna-4,9-diene-3,20-dione(promegestone; R5020). The affinity of the receptor was similar in both the hyperstriatum and the hypothalamus (Kd≃4 × 10−10 mol/l). Its concentration was higher in the anterior hypothalamus–preoptic area (63 ± 4 fmol/mg (s.e.m.) protein) than in other brain regions (posterior hypothalamus, 33 ± 5; hyperstriatum, 28 ± 3; midbrain, 17 ± 4 fmol/mg protein; n = 7). Progesterone and R5020 competed well for binding but oestradiol and 5β-dihydrotestosterone did not. Corticosterone and, to a lesser extent, testosterone and 5α-dihydrotestosterone competed for binding but much higher concentrations were required than for progestins. Injections of testosterone (200 pg testosterone propionate daily for 7 days) significantly increased the concentration of progestin receptors in the anterior and posterior hypothalamus without having any significant effect on other brain areas. Shorter treatment, lasting for 2 days, with testosterone propionate (200 μg daily), 5α-dihydrotestosterone (200 μg daily) or oestradiol benzoate (50 μg daily) did not always cause this increase but seven injections of oestradiol benzoate (50 pg daily for 7 days) were even more effective than seven injections of testosterone propionate (200 μg daily for 7 days). These data suggested that the sensitivity to progesterone of the brain of the bird changes as a consequence of increases in the level of testosterone in the circulation.

scholarly journals In vitro Modeling of Prion Strain Tropism

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 236
Author(s):  
Etienne Levavasseur ◽  
Nicolas Privat ◽  
Stéphane Haïk
Keyword(s):  
Protein Misfolding ◽  
Genetic Material ◽  
Brain Regions ◽  
Experimental Models ◽  
Neuronal Cultures ◽  
Infectious Agents ◽  
Prion Strain ◽  
Specific Targeting ◽  
The Brain

Prions are atypical infectious agents lacking genetic material. Yet, various strains have been isolated from animals and humans using experimental models. They are distinguished by the resulting pattern of disease, including the localization of PrPsc deposits and the spongiform changes they induce in the brain of affected individuals. In this paper, we discuss the emerging use of cellular and acellular models to decipher the mechanisms involved in the strain-specific targeting of distinct brain regions. Recent studies suggest that neuronal cultures, protein misfolding cyclic amplification, and combination of both approaches may be useful to explore this under-investigated but central domain of the prion field.

scholarly journals Amplification, not spreading limits rate of tau aggregate accumulation in Alzheimer’s disease

2020 ◽  
Author(s):  
Georg Meisl ◽  
Yukun Zuo ◽  
Kieren Allinson ◽  
Timothy Rittman ◽  
Sarah DeVos ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Regions ◽  
Replication Rate ◽  
Promising Strategy ◽  
Human Brains ◽  
The Brain ◽  
Tau Aggregate ◽  
Rate Of Accumulation

AbstractBoth the replication of protein aggregates and their spreading throughout the brain are implicated in the progression of Alzheimer’s disease (AD). However, the rates of these processes are unknown and the identity of the rate-determining process in humans has therefore remained elusive. By bringing together chemical kinetics with measurements of tau seeds and aggregates across brain regions, we are able to quantify their replication rate in human brains. Remarkably, we obtain comparable rates in several different datasets, with 5 different methods of tau quantification, from seed amplification assays in vitro to tau PET studies in living patients. Our results suggest that the overall rate of accumulation of tau in neocortical regions is limited not by spreading between brain regions but by local replication, which doubles the number of seeds every ~5 years. Thus, we propose that limiting local replication constitutes the most promising strategy to control tau accumulation during AD.

scholarly journals Effective connectivity inferred from fMRI transition dynamics during movie viewing points to a balanced reconfiguration of cortical interactions

2017 ◽  
Author(s):  
Matthieu Gilson ◽  
Gustavo Deco ◽  
Karl Friston ◽  
Patric Hagmann ◽  
Dante Mantini ◽  
...  
Keyword(s):  
Effective Connectivity ◽  
Functional Integration ◽  
Brain Regions ◽  
Connectivity Pattern ◽  
Model Parameters ◽  
Auditory Information ◽  
Brain Areas ◽  
Brain Hemispheres ◽  
Dynamic Coordination ◽  
The Brain

AbstractOur behavior entails a flexible and context-sensitive interplay between brain areas to integrate information according to goal-directed requirements. How-ever, the neural mechanisms governing the entrainment of functionally specialized brain areas remain poorly understood. In particular, the question arises whether observed changes in the regional activity for different cognitive conditions are explained by modifications of the inputs to the brain or its connectivity? We observe that transitions of fMRI activity between areas convey information about the tasks performed by 19 subjects, watching a movie versus a black screen (rest). We use a model-based framework that explains this spatiotemporal functional connectivity pattern by the local variability for 66 cortical regions and the network effective connectivity between them. We find that, among the estimated model parameters, movie viewing affects to a larger extent the local activity, which we interpret as extrinsic changes related to the increased stimulus load. However, detailed changes in the effective connectivity preserve a balance in the propagating activity and select specific pathways such that high-level brain regions integrate visual and auditory information, in particular boosting the communication between the two brain hemispheres. These findings speak to a dynamic coordination underlying the functional integration in the brain.

The Effect of Minor Doses of Olanzapine-Solid Lipid Nanoparticles on an Animal Model of Schizophrenia (Neurochemical and Behavioral Study) and the Side Effect

2019 ◽  
Vol 9 (4) ◽  
pp. 308-320
Author(s):  
Areeg Abd-Elrazek ◽  
Tayseer Elnawawy
Keyword(s):  
Solid Lipid Nanoparticles ◽  
In Vitro Release ◽  
Lipid Nanoparticles ◽  
Brain Regions ◽  
Free Form ◽  
High Dose ◽  
Solid Lipid ◽  
The Brain ◽  
Different Doses

Background and Objective:Olanzapine (OLZ) is an atypical psychotic agent; the poor bioavailability of olanzapine is the most important issue in its treatment. The present work was carried out to evaluate the oral form of olanzapine solid lipid nanoparticles (OLZ-SLN) to overcome its poor bioavailability and compare between the effect of different doses of OLZ and OLZ-SLN on ketamineinduced schizophrenic-like symptoms. The study was extended to evaluate the adverse effects of subchronic administration of these doses of OLZ and its SLN.Methods:OLZ-SLN was prepared by hot homogenization, particle size, zeta potential and in vitro release and entrapping efficiency studies were performed. In order to assess the effective dose in the treatment of schizophrenia, the effect of different doses of OLZ and OLZ-SLN on open field was assessed and passive avoidance tests were carried out. The test was performed to examine the effects of excitatory and inhibitory amino acids, as well as dopamine and serotonin levels in the brain regions.Results and Conclusion:The new oral formula showed high stability and sustained release. The administration of low and high dose of OLZ-SLN equivalent to (1/10 and 1/20 from the therapeutic dose before ketamine attenuated the behavioral abnormalities by blocking the effect of ketamine-induced increase in glutamate, dopamine and serotonin levels and enhanced apoptosis were studied in the brain areas. In addition, the sub-chronic treatment with OLZ-SLN showed no adverse effect while the treatment with OLZ free form did.

scholarly journals Brain Barriers and brain fluids research in 2020 and the fluids and barriers of the CNS thematic series on advances in in vitro modeling of the blood–brain barrier and neurovascular unit

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Richard F. Keep ◽  
Hazel C. Jones ◽  
Lester R. Drewes
Keyword(s):  
Blood Brain Barrier ◽  
Neurovascular Unit ◽  
Brain Barrier ◽  
In Vitro Modeling ◽  
Disease States ◽  
System Disease ◽  
Blood Brain ◽  
The Brain ◽  
Brain Barriers

AbstractThis editorial discusses advances in brain barrier and brain fluid research in 2020. Topics include: the cerebral endothelium and the neurovascular unit; the choroid plexus; the meninges; cerebrospinal fluid and the glymphatic system; disease states impacting the brain barriers and brain fluids; drug delivery to the brain. This editorial also highlights the recently completed Fluids Barriers CNS thematic series entitled, ‘Advances in in vitro modeling of the blood–brain barrier and neurovascular unit’. Such in vitro modeling is progressing rapidly.

scholarly journals Synaptic plasticity is predicted by spatiotemporal firing rate patterns and robust to in vivo-like variability

2021 ◽  
Author(s):  
Dan B Dorman ◽  
Kim T Blackwell
Keyword(s):  
Synaptic Plasticity ◽  
Firing Rate ◽  
Dendritic Tree ◽  
Spike Timing ◽  
Synaptic Activity ◽  
Data Driven ◽  
Synaptic Inputs ◽  
The Brain

Synaptic plasticity, the experience-induced change in connections between neurons, underlies learning and memory in the brain. Most of our understanding of synaptic plasticity derives from in vitro experiments with precisely repeated stimulus patterns; however, neurons exhibit significant variability in vivo during repeated experiences. Further, the spatial pattern of synaptic inputs to the dendritic tree influences synaptic plasticity, yet is not considered in most synaptic plasticity rules. Here, we address the sensitivity of plasticity to trial-to-trial variability and delineate how spatiotemporal synaptic input patterns produce plasticity with in vivo-like conditions using a data-driven computational model with a calcium-based plasticity rule. Using in vivo spike train recordings as inputs, we show that plasticity is strongly robust to trial-to-trial variability of spike timing, and derive general synaptic plasticity rules describing how spatiotemporal patterns of synaptic inputs control the magnitude and direction of plasticity. Specifically, a high temporal input firing rate to a synapse late in a trial correlated with neighboring synaptic activity produces potentiation, while an earlier, moderate firing rate that is negatively correlated with neighboring synaptic activity produces depression. Together, our results reveal that calcium dynamics can unify diverse plasticity rules and reveal how spatiotemporal firing rate patterns control synaptic plasticity.

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