scholarly journals Opposing Roles of apolipoprotein E in aging and neurodegeneration

2019 ◽  
Vol 2 (1) ◽  
pp. e201900325 ◽  
Author(s):  
Eloise Hudry ◽  
Jacob Klickstein ◽  
Claudia Cannavo ◽  
Rosemary Jackson ◽  
Alona Muzikansky ◽  
...  
Keyword(s):  
Apolipoprotein E ◽  
Calcium Imaging ◽  
Brain Function ◽  
Neural Circuits ◽  
Evoked Responses ◽  
Neuronal Responses ◽  
Neuronal Function ◽  
Two Photon ◽  
Synapse Loss

Apolipoprotein E (APOE) effects on brain function remain controversial. Removal of APOE not only impairs cognitive functions but also reduces neuritic amyloid plaques in mouse models of Alzheimer’s disease (AD). Can APOE simultaneously protect and impair neural circuits? Here, we dissociated the role of APOE in AD versus aging to determine its effects on neuronal function and synaptic integrity. Using two-photon calcium imaging in awake mice to record visually evoked responses, we found that genetic removal of APOE improved neuronal responses in adult APP/PSEN1 mice (8–10 mo). These animals also exhibited fewer neuritic plaques with less surrounding synapse loss, fewer neuritic dystrophies, and reactive glia. Surprisingly, the lack of APOE in aged mice (18–20 mo), even in the absence of amyloid, disrupted visually evoked responses. These results suggest a dissociation in APOE’s role in AD versus aging: APOE may be neurotoxic during early stages of amyloid deposition, although being neuroprotective in latter stages of aging.

scholarly journals Seizures start as silent microseizures by neuronal ensembles

2018 ◽  
Author(s):  
Michael Wenzel ◽  
Jordan P. Hamm ◽  
Darcy S. Peterka ◽  
Rafael MD Yuste
Keyword(s):  
Calcium Imaging ◽  
Travelling Wave ◽  
Inhibitory Neurons ◽  
Neural Activation ◽  
Calcium Dynamics ◽  
Neuronal Ensembles ◽  
Two Photon ◽  
Step Model

AbstractUnderstanding seizure formation and spread remains a critical goal of epilepsy research. While many studies have documented seizure spread, it remains mysterious how they start. We used fast in-vivo two-photon calcium imaging to reconstruct, at cellular resolution, the dynamics of focal cortical seizures as they emerge in epileptic foci (intrafocal), and subsequently propagate (extrafocal). We find that seizures start as intrafocal coactivation of small numbers of neurons (ensembles), which are electrographically silent. These silent “microseizures” expand saltatorily until they break into neighboring cortex, where they progress smoothly and first become detectable by LFP. Surprisingly, we find spatially heterogeneous calcium dynamics of local PV interneuron sub-populations, which rules out a simple role of inhibitory neurons during seizures. We propose a two-step model for the circuit mechanisms of focal seizures, where neuronal ensembles first generate a silent microseizure, followed by widespread neural activation in a travelling wave, which is then detected electrophysiologically.

scholarly journals RNAi-Mediated Reverse Genetic Screen Identified Drosophila Chaperones Regulating Eye and Neuromuscular Junction Morphology

2017 ◽  
Vol 7 (7) ◽  
pp. 2023-2038 ◽  
Author(s):  
Sandeep Raut ◽  
Bhagaban Mallik ◽  
Arpan Parichha ◽  
Valsakumar Amrutha ◽  
Chandan Sahi ◽  
...  
Keyword(s):  
Molecular Chaperones ◽  
Bioinformatics Analysis ◽  
Reverse Genetic ◽  
Unfolded Proteins ◽  
Neuronal Function ◽  
Synapse Loss ◽  
Functional Relevance ◽  
Reverse Genetic Screen ◽  
Behavioral Assays

Abstract Accumulation of toxic proteins in neurons has been linked with the onset of neurodegenerative diseases, which in many cases are characterized by altered neuronal function and synapse loss. Molecular chaperones help protein folding and the resolubilization of unfolded proteins, thereby reducing the protein aggregation stress. While most of the chaperones are expressed in neurons, their functional relevance remains largely unknown. Here, using bioinformatics analysis, we identified 95 Drosophila chaperones and classified them into seven different classes. Ubiquitous actin5C-Gal4-mediated RNAi knockdown revealed that ∼50% of the chaperones are essential in Drosophila. Knocking down these genes in eyes revealed that ∼30% of the essential chaperones are crucial for eye development. Using neuron-specific knockdown, immunocytochemistry, and robust behavioral assays, we identified a new set of chaperones that play critical roles in the regulation of Drosophila NMJ structural organization. Together, our data present the first classification and comprehensive analysis of Drosophila chaperones. Our screen identified a new set of chaperones that regulate eye and NMJ morphogenesis. The outcome of the screen reported here provides a useful resource for further elucidating the role of individual chaperones in Drosophila eye morphogenesis and synaptic development.

scholarly journals Long-term stability of cortical ensembles

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Jesús Pérez-Ortega ◽  
Tzitzitlini Alejandre-García ◽  
Rafael Yuste
Keyword(s):  
Calcium Imaging ◽  
Pyramidal Neurons ◽  
Evoked Responses ◽  
Single Session ◽  
Long Term Stability ◽  
Neuronal Ensembles ◽  
Two Photon ◽  
Layer 2 ◽  
Over Time

Neuronal ensembles, coactive groups of neurons found in spontaneous and evoked cortical activity, are causally related to memories and perception, but it still unknown how stable or flexible they are over time. We used two-photon multiplane calcium imaging to track over weeks the activity of the same pyramidal neurons in layer 2/3 of the visual cortex from awake mice and recorded their spontaneous and visually evoked responses. Less than half of the neurons were commonly active across any two imaging sessions. These 'common neurons' formed stable ensembles lasting weeks, but some ensembles were also transient and appeared only in one single session. Stable ensembles preserved ~68 % of their neurons up to 46 days, our longest imaged period, and these 'core' cells had stronger functional connectivity. Our results demonstrate that neuronal ensembles can last for weeks and could, in principle, serve as a substrate for long-lasting representation of perceptual states or memories.

scholarly journals A standardized behavioral event equally impacts the activity of cortical visual areas and layers

2020 ◽  
Author(s):  
Mahdi Ramadan ◽  
Eric Kenji Lee ◽  
Shiella Caldejon ◽  
India Kato ◽  
Kate Roll ◽  
...  
Keyword(s):  
Visual Cortex ◽  
Motor Behavior ◽  
Sensory Information ◽  
Response Patterns ◽  
Neuronal Responses ◽  
Two Photon ◽  
Visual Areas ◽  
Cortical Visual Areas ◽  
Behavioral Event

AbstractMultiple recent studies have shown that motor activity greatly impacts the activity of primary sensory areas like V1. Yet, the role of this motor related activity in sensory processing is still unclear. Here we further dissect how these behavior relevant signals are broadcast to different layers and areas of visual cortex. To do so, we leveraged a standardized motor behavior fidget event in behavioral videos of passively viewing mice. A large two-photon Ca2+ imaging database of neuronal responses uncovered four neural response types during fidgets that are surprisingly consistent in their proportion and response patterns across all visual areas and layers of the visual cortex. Indeed, the layer and area identity could not be decoded above chance level based only on neuronal recordings. The broad availability of standardized behavior signals could be a key component in how the cortex selects, learns and binds local sensory information with relevant motor outputs.

scholarly journals Modeling Neuronal Diseases in Zebrafish in the Era of CRISPR

2020 ◽  
Vol 18 (2) ◽  
pp. 136-152
Author(s):  
Angeles Edith Espino-Saldaña ◽  
Roberto Rodríguez-Ortiz ◽  
Elizabeth Pereida-Jaramillo ◽  
Ataúlfo Martínez-Torres
Keyword(s):  
Brain Function ◽  
Rapid Development ◽  
Living Organism ◽  
Human Diseases ◽  
Brain Diseases ◽  
Neuronal Function ◽  
Brain Organization ◽  
Crispr System ◽  
Technology Applications

Background: Danio rerio is a powerful experimental model for studies in genetics and development. Recently, CRISPR technology has been applied in this species to mimic various human diseases, including those affecting the nervous system. Zebrafish offer multiple experimental advantages: external embryogenesis, rapid development, transparent embryos, short life cycle, and basic neurobiological processes shared with humans. This animal model, together with the CRISPR system, emerging imaging technologies, and novel behavioral approaches, lay the basis for a prominent future in neuropathology and will undoubtedly accelerate our understanding of brain function and its disorders. Objective: Gather relevant findings from studies that have used CRISPR technologies in zebrafish to explore basic neuronal function and model human diseases. Method: We systematically reviewed the most recent literature about CRISPR technology applications for understanding brain function and neurological disorders in D. rerio. We highlighted the key role of CRISPR in driving forward our understanding of particular topics in neuroscience. Results: We show specific advances in neurobiology when the CRISPR system has been applied in zebrafish and describe how CRISPR is accelerating our understanding of brain organization. Conclusion: Today, CRISPR is the preferred method to modify genomes of practically any living organism. Despite the rapid development of CRISPR technologies to generate disease models in zebrafish, more efforts are needed to efficiently combine different disciplines to find the etiology and treatments for many brain diseases.

scholarly journals Synaptic Loss in Alzheimer's Disease: Mechanistic Insights Provided by Two-Photon in vivo Imaging of Transgenic Mouse Models

2020 ◽  
Vol 14 ◽  
Author(s):  
Jaichandar Subramanian ◽  
Julie C. Savage ◽  
Marie-Ève Tremblay
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Synaptic Loss ◽  
Two Photon ◽  
Synapse Loss ◽  
Disease Mutations ◽  
The Brain

Synapse loss is the strongest correlate for cognitive decline in Alzheimer's disease. The mechanisms underlying synapse loss have been extensively investigated using mouse models expressing genes with human familial Alzheimer's disease mutations. In this review, we summarize how multiphoton in vivo imaging has improved our understanding of synapse loss mechanisms associated with excessive amyloid in the living animal brain. We also discuss evidence obtained from these imaging studies for the role of cell-intrinsic calcium dyshomeostasis and cell-extrinsic activities of microglia, which are the immune cells of the brain, in mediating synapse loss.

scholarly journals Curvature-processing domains in primate V4

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Rendong Tang ◽  
Qianling Song ◽  
Ying Li ◽  
Rui Zhang ◽  
Xingya Cai ◽  
...  
Keyword(s):  
Calcium Imaging ◽  
Visual Object ◽  
Visual Object Recognition ◽  
Intrinsic Signal ◽  
Two Photon ◽  
Contour Shape ◽  
Wide Range ◽  
Shape Tuning ◽  
Common Shape

Neurons in primate V4 exhibit various types of selectivity for contour shapes, including curves, angles, and simple shapes. How are these neurons organized in V4 remains unclear. Using intrinsic signal optical imaging and two-photon calcium imaging, we observed submillimeter functional domains in V4 that contained neurons preferring curved contours over rectilinear ones. These curvature domains had similar sizes and response amplitudes as orientation domains but tended to separate from these regions. Within the curvature domains, neurons that preferred circles or curve orientations clustered further into finer scale subdomains. Nevertheless, individual neurons also had a wide range of contour selectivity, and neighboring neurons exhibited a substantial diversity in shape tuning besides their common shape preferences. In strong contrast to V4, V1 and V2 did not have such contour-shape-related domains. These findings highlight the importance and complexity of curvature processing in visual object recognition and the key functional role of V4 in this process.

scholarly journals Three-dimensional Two-Photon Optogenetics and Imaging of Neural Circuits in vivo

2017 ◽  
Author(s):  
Weijian Yang ◽  
Luis Carrillo-Reid ◽  
Yuki Bando ◽  
Darcy S. Peterka ◽  
Rafael Yuste
Keyword(s):  
Visual Cortex ◽  
Neural Activity ◽  
Calcium Imaging ◽  
Pyramidal Neurons ◽  
Neural Circuits ◽  
Three Dimensional ◽  
Two Photon ◽  
Cellular Resolution ◽  
Photon Excitation

We demonstrate a holographic system for simultaneous three-dimensional (3D) two-photon stimulation and imaging of neural activity in the mouse neocortex in vivo with cellular resolution. Dual two-photon excitation paths are implemented with independent 3D targeting for calcium imaging and precision optogenetics. We validate the usefulness of the microscope by photoactivating local pools of interneurons in awake mice visual cortex in 3D, which suppress the nearby pyramidal neurons’ response to visual stimuli.

scholarly journals Long-range population dynamics of anatomically defined neocortical networks

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Jerry L Chen ◽  
Fabian F Voigt ◽  
Mitra Javadzadeh ◽  
Roland Krueppel ◽  
Fritjof Helmchen
Keyword(s):  
Population Dynamics ◽  
Long Range ◽  
Calcium Imaging ◽  
Brain Function ◽  
Motor Behavior ◽  
Mammalian Brain ◽  
Projection Neurons ◽  
Motor Behaviors ◽  
Two Photon ◽  
Sensory Cortices

The coordination of activity across neocortical areas is essential for mammalian brain function. Understanding this process requires simultaneous functional measurements across the cortex. In order to dissociate direct cortico-cortical interactions from other sources of neuronal correlations, it is furthermore desirable to target cross-areal recordings to neuronal subpopulations that anatomically project between areas. Here, we combined anatomical tracers with a novel multi-area two-photon microscope to perform simultaneous calcium imaging across mouse primary (S1) and secondary (S2) somatosensory whisker cortex during texture discrimination behavior, specifically identifying feedforward and feedback neurons. We find that coordination of S1-S2 activity increases during motor behaviors such as goal-directed whisking and licking. This effect was not specific to identified feedforward and feedback neurons. However, these mutually projecting neurons especially participated in inter-areal coordination when motor behavior was paired with whisker-texture touches, suggesting that direct S1-S2 interactions are sensory-dependent. Our results demonstrate specific functional coordination of anatomically-identified projection neurons across sensory cortices.

A thalamocortical top-down circuit for associative memory

Science ◽  
2020 ◽  
Vol 370 (6518) ◽  
pp. 844-848 ◽  
Author(s):  
M. Belén Pardi ◽  
Johanna Vogenstahl ◽  
Tamas Dalmay ◽  
Teresa Spanò ◽  
De-Lin Pu ◽  
...  
Keyword(s):  
Calcium Imaging ◽  
Presynaptic Inhibition ◽  
Higher Order ◽  
Top Down ◽  
Strong Connection ◽  
Two Photon ◽  
Related Information ◽  
Cell Recording

The sensory neocortex is a critical substrate for memory. Despite its strong connection with the thalamus, the role of direct thalamocortical communication in memory remains elusive. We performed chronic in vivo two-photon calcium imaging of thalamic synapses in mouse auditory cortex layer 1, a major locus of cortical associations. Combined with optogenetics, viral tracing, whole-cell recording, and computational modeling, we find that the higher-order thalamus is required for associative learning and transmits memory-related information that closely correlates with acquired behavioral relevance. In turn, these signals are tightly and dynamically controlled by local presynaptic inhibition. Our results not only identify the higher-order thalamus as a highly plastic source of cortical top-down information but also reveal a level of computational flexibility in layer 1 that goes far beyond hard-wired connectivity.

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