scholarly journals Synaptojanin1 deficiency upregulates basal level autophagosome formation in astrocytes

2021 ◽  
Author(s):  
Ping-Yue Pan ◽  
Justin Zhu ◽  
Asma Rizvi ◽  
Xinyu Zhu ◽  
Hikari Tanaka ◽  
...  
Keyword(s):  
Brain Regions ◽  
Mammalian Brain ◽  
Missense Mutations ◽  
Autophagosome Formation ◽  
Vesicle Recycling ◽  
Lipid Phosphatase ◽  
Cultured Astrocytes ◽  
Energy Sensing ◽  
Lc3 Puncta ◽  
First Time

Macroautophagy (hereafter, autophagy) dysregulation is implicated in multiple neurological disorders. While the autophagy pathways are heavily investigated in heterologous cells and neurons, how autophagy is regulated in the astrocyte, the most abundant cell type in the mammalian brain, is less understood. Here we report that Synaptojanin1 (Synj1), a neuron enriched lipid phosphatase, is expressed in low levels in astrocytes and represses autophagy at the basal level. Synj1 is encoded by the Synj1 gene, whose missense mutations are linked to Parkinsonism with seizure. While the best-known role of Synj1 is to facilitate synaptic vesicle recycling, recent studies suggest that Synj1 also regulates autophagy. Our previous study using the Synj1 haploinsufficient (Synj1+/-) mouse demonstrated that Synj1 deficiency was associated with an age-dependent autophagy impairment in multiple brain regions. We now use cultured astrocytes from Synj1 deficient mice to investigate its role in astrocyte autophagy. We demonstrate that Synj1 deficient astrocytes exhibit increased LC3 puncta, which is more pronounced when lysosomal acidification is blocked. The increased autophagosome formation is accompanied by reduced autophagy substrate, p62, but an insensitivity to starvation induced autophagy clearance. Moreover, we show, for the first time, that the Parkinsonism associated R839C mutation impacts astrocyte autophagy. The profound impact of this mutation on Synj1s phosphatase functions results in elevated basal level autophagosome formation and clearance that mimics Synj1 deletion. We find that energy sensing molecules, including mTOR and AMPK, are altered in Synj1 deficient astrocytes, which may contribute to the enhanced basal level autophagy.

scholarly journals An architectonic type principle in the development of laminar patterns of cortico-cortical connections

2021 ◽  
Author(s):  
Sarah F. Beul ◽  
Alexandros Goulas ◽  
Claus C. Hilgetag
Keyword(s):  
Structural Connectivity ◽  
Macaque Monkey ◽  
Brain Regions ◽  
Adult Brain ◽  
Mammalian Brain ◽  
Cortical Connections ◽  
Cortical Projections ◽  
Structural Connections ◽  
High Degree ◽  
The Brain

AbstractStructural connections between cortical areas form an intricate network with a high degree of specificity. Many aspects of this complex network organization in the adult mammalian cortex are captured by an architectonic type principle, which relates structural connections to the architectonic differentiation of brain regions. In particular, the laminar patterns of projection origins are a prominent feature of structural connections that varies in a graded manner with the relative architectonic differentiation of connected areas in the adult brain. Here we show that the architectonic type principle is already apparent for the laminar origins of cortico-cortical projections in the immature cortex of the macaque monkey. We find that prenatal and neonatal laminar patterns correlate with cortical architectonic differentiation, and that the relation of laminar patterns to architectonic differences between connected areas is not substantially altered by the complete loss of visual input. Moreover, we find that the degree of change in laminar patterns that projections undergo during development varies in proportion to the relative architectonic differentiation of the connected areas. Hence, it appears that initial biases in laminar projection patterns become progressively strengthened by later developmental processes. These findings suggest that early neurogenetic processes during the formation of the brain are sufficient to establish the characteristic laminar projection patterns. This conclusion is in line with previously suggested mechanistic explanations underlying the emergence of the architectonic type principle and provides further constraints for exploring the fundamental factors that shape structural connectivity in the mammalian brain.

scholarly journals Screening Assay for Small-Molecule Inhibitors of Synaptojanin 1, a Synaptic Phosphoinositide Phosphatase

2013 ◽  
Vol 19 (4) ◽  
pp. 585-594 ◽  
Author(s):  
Laura Beth J. McIntire ◽  
Kyu-In Lee ◽  
Belle Chang-Ileto ◽  
Gilbert Di Paolo ◽  
Tae-Wan Kim
Keyword(s):  
Amyloid Β ◽  
Receptor Trafficking ◽  
Water Soluble ◽  
Amyloid Β Peptide ◽  
Screening Assay ◽  
Vesicle Recycling ◽  
Lipid Phosphatase ◽  
Phosphoinositide Phosphatase ◽  
Synaptojanin 1 ◽  
Behavioral Impairments

Elevation of amyloid β-peptide (Aβ) is critically associated with Alzheimer disease (AD) pathogenesis. Aβ-induced synaptic abnormalities, including altered receptor trafficking and synapse loss, have been linked to cognitive deficits in AD. Recent work implicates a lipid critical for neuronal function, phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], in Aβ-induced synaptic and behavioral impairments. Synaptojanin 1 (Synj1), a lipid phosphatase mediating the breakdown of PI(4,5)P2, has been shown to play a role in synaptic vesicle recycling and receptor trafficking in neurons. Heterozygous deletion of Synj1 protected neurons from Aβ-induced synaptic loss and restored learning and memory in a mouse model of AD. Thus, inhibition of Synj1 may ameliorate Aβ-associated impairments, suggesting Synj1 as a potential therapeutic target. To this end, we developed a screening assay for Synj1 based on detection of inorganic phosphate liberation from a water-soluble, short-chain PI(4,5)P2. The assay displayed saturable kinetics and detected Synj1’s substrate preference for PI(4,5)P2 over PI(3,4,5)P3. The assay will enable identification of novel Synj1 inhibitors that have potential utility as chemical probes to dissect the cellular role of Synj1 as well as potential to prevent or reverse AD-associated synaptic abnormalities.

scholarly journals Taste quality representation in the human brain

2019 ◽  
Author(s):  
Jason A. Avery ◽  
Alexander G. Liu ◽  
John E. Ingeholm ◽  
Cameron D. Riddell ◽  
Stephen J. Gotts ◽  
...  
Keyword(s):  
Human Brain ◽  
Cortical Neurons ◽  
Brain Regions ◽  
Taste Quality ◽  
7 Tesla ◽  
Mammalian Brain ◽  
High Magnetic Field Strength ◽  
Magnetic Resonance Imaging Mri ◽  
Spatial Locations ◽  
Univariate Analyses

SUMMARYIn the mammalian brain, the insula is the primary cortical substrate involved in the perception of taste. Recent imaging studies in rodents have identified a gustotopic organization in the insula, whereby distinct insula regions are selectively responsive to one of the five basic tastes. However, numerous studies in monkeys have reported that gustatory cortical neurons are broadly-tuned to multiple tastes, and tastes are not represented in discrete spatial locations. Neuroimaging studies in humans have thus far been unable to discern between these two models, though this may be due to the relatively low spatial resolution employed in taste studies to date. In the present study, we examined the spatial representation of taste within the human brain using ultra-high resolution functional magnetic resonance imaging (MRI) at high magnetic field strength (7-Tesla). During scanning, participants tasted sweet, salty, sour and tasteless liquids, delivered via a custom-built MRI-compatible tastant-delivery system. Our univariate analyses revealed that all tastes (vs. tasteless) activated primary taste cortex within the bilateral dorsal mid-insula, but no brain region exhibited a consistent preference for any individual taste. However, our multivariate searchlight analyses were able to reliably decode the identity of distinct tastes within those mid-insula regions, as well as brain regions involved in affect and reward, such as the striatum, orbitofrontal cortex, and amygdala. These results suggest that taste quality is not represented topographically, but by a combinatorial spatial code, both within primary taste cortex as well as regions involved in processing the hedonic and aversive properties of taste.

scholarly journals A Three-Pool Model Dissecting Readily Releasable Pool Replenishment at the Calyx of Held

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Jun Guo ◽  
Jian-long Ge ◽  
Mei Hao ◽  
Zhi-cheng Sun ◽  
Xin-sheng Wu ◽  
...  
Keyword(s):  
Time Course ◽  
Current View ◽  
Vesicle Recycling ◽  
Releasable Pool ◽  
Readily Releasable Pool ◽  
Central Synapse ◽  
Pool Model ◽  
Underlying Mechanisms ◽  
First Time ◽  
Intense Stimulation

Abstract Although vesicle replenishment is critical in maintaining exo-endocytosis recycling, the underlying mechanisms are not well understood. Previous studies have shown that both rapid and slow endocytosis recycle into a very large recycling pool instead of within the readily releasable pool (RRP) and the time course of RRP replenishment is slowed down by more intense stimulation. This finding contradicts the calcium/calmodulin-dependence of RRP replenishment. Here we address this issue and report a three-pool model for RRP replenishment at a central synapse. Both rapid and slow endocytosis provide vesicles to a large reserve pool (RP) ~42.3 times the RRP size. When moving from the RP to the RRP, vesicles entered an intermediate pool (IP) ~2.7 times the RRP size with slow RP-IP kinetics and fast IP-RRP kinetics, which was responsible for the well-established slow and rapid components of RRP replenishment. Depletion of the IP caused the slower RRP replenishment observed after intense stimulation. These results establish, for the first time, a realistic cycling model with all parameters measured, revealing the contribution of each cycling step in synaptic transmission. The results call for modification of the current view of the vesicle recycling steps and their roles.

scholarly journals Acute stress enhances adult rat hippocampal neurogenesis and activation of newborn neurons via secreted astrocytic FGF2

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Elizabeth D Kirby ◽  
Sandra E Muroy ◽  
Wayne G Sun ◽  
David Covarrubias ◽  
Megan J Leong ◽  
...  
Keyword(s):  
Basolateral Amygdala ◽  
Acute Stress ◽  
Memory Function ◽  
Brain Regions ◽  
Hippocampal Neurogenesis ◽  
Mammalian Brain ◽  
Stress Hormone ◽  
Adult Rat ◽  
Neural Stem Progenitor Cells ◽  
Newborn Neurons

Stress is a potent modulator of the mammalian brain. The highly conserved stress hormone response influences many brain regions, particularly the hippocampus, a region important for memory function. The effect of acute stress on the unique population of adult neural stem/progenitor cells (NPCs) that resides in the adult hippocampus is unclear. We found that acute stress increased hippocampal cell proliferation and astrocytic fibroblast growth factor 2 (FGF2) expression. The effect of acute stress occurred independent of basolateral amygdala neural input and was mimicked by treating isolated NPCs with conditioned media from corticosterone-treated primary astrocytes. Neutralization of FGF2 revealed that astrocyte-secreted FGF2 mediated stress-hormone-induced NPC proliferation. 2 weeks, but not 2 days, after acute stress, rats also showed enhanced fear extinction memory coincident with enhanced activation of newborn neurons. Our findings suggest a beneficial role for brief stress on the hippocampus and improve understanding of the adaptive capacity of the brain.

scholarly journals Optogenetic spatial and temporal control of cortical circuits on a columnar scale

2016 ◽  
Vol 115 (2) ◽  
pp. 1043-1062 ◽  
Author(s):  
Arani Roy ◽  
Jason J. Osik ◽  
Neil J. Ritter ◽  
Shen Wang ◽  
James T. Shaw ◽  
...  
Keyword(s):  
Visual Stimulation ◽  
Liquid Crystal Display ◽  
Brain Regions ◽  
Cortical Activation ◽  
Mammalian Brain ◽  
Optogenetic Stimulation ◽  
Brain Surface ◽  
Stimulation System ◽  
Circuit Function ◽  
Stimulation Of

Many circuits in the mammalian brain are organized in a topographic or columnar manner. These circuits could be activated—in ways that reveal circuit function or restore function after disease—by an artificial stimulation system that is capable of independently driving local groups of neurons. Here we present a simple custom microscope called ProjectorScope 1 that incorporates off-the-shelf parts and a liquid crystal display (LCD) projector to stimulate surface brain regions that express channelrhodopsin-2 (ChR2). In principle, local optogenetic stimulation of the brain surface with optical projection systems might not produce local activation of a highly interconnected network like the cortex, because of potential stimulation of axons of passage or extended dendritic trees. However, here we demonstrate that the combination of virally mediated ChR2 expression levels and the light intensity of ProjectorScope 1 is capable of producing local spatial activation with a resolution of ∼200–300 μm. We use the system to examine the role of cortical activity in the experience-dependent emergence of motion selectivity in immature ferret visual cortex. We find that optogenetic cortical activation alone—without visual stimulation—is sufficient to produce increases in motion selectivity, suggesting the presence of a sharpening mechanism that does not require precise spatiotemporal activation of the visual system. These results demonstrate that optogenetic stimulation can sculpt the developing brain.

A porcine brain-wide RNA editing landscape

2020 ◽  
Author(s):  
Jinrong Huang ◽  
Lin Lin ◽  
Zhanying Dong ◽  
Ling Yang ◽  
Tianyu Zheng ◽  
...  
Keyword(s):  
Rna Editing ◽  
Repetitive Sequences ◽  
Brain Regions ◽  
Mammalian Brain ◽  
Protein Coding ◽  
Porcine Brain ◽  
Coding Regions ◽  
Pig Brain ◽  
Genome Wide ◽  
A Genome

Abstract Adenosine-to-inosine (A-to-I) RNA editing, catalyzed by ADAR enzymes, is an essential post-transcriptional modification. Although hundreds of thousands of RNA editing sites have been reported in mammals, brain-wide analysis of the RNA editing in the mammalian brain remains rare. Here, a genome-wide RNA editing investigation is performed in 119 samples, representing 30 anatomically defined subregions in the pig brain. We identify a total of 682,037 A-to-I RNA editing sites of which 97% are not identified before. Within the pig brain, cerebellum and olfactory bulb are regions with most edited transcripts. The editing level of sites residing in protein-coding regions are similar across brain regions, whereas region-distinct editing is observed in repetitive sequences. Highly edited conserved recoding events in pig and human brain are found in neurotransmitter receptors, demonstrating the evolutionary importance of RNA editing in neurotransmission functions. The porcine brain-wide RNA landscape provides a rich resource to better understand the evolutionally importance of post-transcriptional RNA editing.

Mesozoic mammals and early mammalian brain diversity

2003 ◽  
Vol 26 (5) ◽  
pp. 556-557 ◽  
Author(s):  
Emmanuel Gilissen ◽  
Thierry Smith
Keyword(s):  
Middle Ear ◽  
Brain Regions ◽  
Mammalian Brain ◽  
Fossil Remains ◽  
Ear Ossicles ◽  
Mesozoic Mammals ◽  
Brain Expansion ◽  
The Relationship ◽  
The Brain

Fossil remains witness the relationship between the appearance of the middle ear and the expansion of the brain in early mammals. Nevertheless, the lack of detachment of ear ossicles in the mammaliaform Morganucodon, despite brain enlargement, points to other factors that triggered brain expansion in early mammals. Moreover, brain expansion in some early mammalian groups seems to have favored brain regions other than the cortex.

scholarly journals Imaging Subthreshold Voltage Oscillation With Cellular Resolution in the Inferior Olive in vitro

2020 ◽  
Vol 14 ◽  
Author(s):  
Kevin Dorgans ◽  
Bernd Kuhn ◽  
Marylka Yoe Uusisaari
Keyword(s):  
Inferior Olive ◽  
Brain Slices ◽  
Brain Regions ◽  
Mammalian Brain ◽  
Wide Field ◽  
Voltage Imaging ◽  
Subthreshold Oscillations ◽  
Cellular Resolution

Voltage imaging with cellular resolution in mammalian brain slices is still a challenging task. Here, we describe and validate a method for delivery of the voltage-sensitive dye ANNINE-6plus (A6+) into tissue for voltage imaging that results in higher signal-to-noise ratio (SNR) than conventional bath application methods. The not fully dissolved dye was injected into the inferior olive (IO) 0, 1, or 7 days prior to acute slice preparation using stereotactic surgery. We find that the voltage imaging improves after an extended incubation period in vivo in terms of labeled volume, homogeneous neuropil labeling with saliently labeled somata, and SNR. Preparing acute slices 7 days after the dye injection, the SNR is high enough to allow single-trial recording of IO subthreshold oscillations using wide-field (network-level) as well as high-magnification (single-cell level) voltage imaging with a CMOS camera. This method is easily adaptable to other brain regions where genetically-encoded voltage sensors are prohibitively difficult to use and where an ultrafast, pure electrochromic sensor, like A6+, is required. Due to the long-lasting staining demonstrated here, the method can be combined, for example, with deep-brain imaging using implantable GRIN lenses.

Does the preoptic anterior hypothalamus receive thermoafferent information?

1998 ◽  
Vol 274 (1) ◽  
pp. R9-R18 ◽  
Author(s):  
Nancy J. Berner ◽  
H. Craig Heller
Keyword(s):  
Brain Regions ◽  
Anterior Hypothalamus ◽  
Mammalian Brain ◽  
Eeg Activity ◽  
Arousal State ◽  
Firing Rates ◽  
State Changes ◽  
Unanesthetized Animals ◽  
Peripheral Temperature ◽  
State Selectivity

The preoptic anterior hypothalamus (POAH) is considered the thermointegrative center of the mammalian brain. Studies on anesthetized and unanesthetized animals have demonstrated neurons in the POAH that respond to changes in both POAH temperature (TPOAH) and skin temperature (Ts). In these studies, however, electroencephalographic (EEG) activity was not monitored. Recent work has revealed the potential for arousal state selectivity of neurons combined with thermal influences on arousal state to create the appearance that cells are thermosensitive or thermoresponsive when in fact they may not be responding directly to temperature or to thermoafferent input. It is therefore necessary to reexamine the influence of central and peripheral temperature on POAH cells. In the present study, 66 POAH cells were recorded from urethan-anesthetized rats while EEG, TPOAH, and Ts were monitored. Seventy-five percent (41 of 55) of the cells were EEG state responsive; 22% (6 of 27) were TPOAH sensitive; and 33% (19 of 58) appeared to be Tsresponsive. However, when EEG state changes were taken into account, none of the cells that appeared to be Ts responsive were responding to Ts within any uniform EEG state. All changes in their firing rates were associated with EEG state changes. This study raises a question as to whether or not peripheral temperature information is integrated in the POAH. Consideration should be given to the possibility that Ts information is integrated lower in the neuroaxis. Monitoring EEG is essential in studies attempting to characterize the integrative properties of POAH neurons of anesthetized or unanesthetized animals. This caveat applies not just to thermoregulatory studies but to investigations of other integrative functions of the hypothalamus and many other brain regions as well.

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