Inferring cortical function in the mouse visual system through large-scale systems neuroscience

The scientific mission of the Project MindScope is to understand neocortex, the part of the mammalian brain that gives rise to perception, memory, intelligence, and consciousness. We seek to quantitatively evaluate the hypothesis that neocortex is a relatively homogeneous tissue, with smaller functional modules that perform a common computational function replicated across regions. We here focus on the mouse as a mammalian model organism with genetics, physiology, and behavior that can be readily studied and manipulated in the laboratory. We seek to describe the operation of cortical circuitry at the computational level by comprehensively cataloging and characterizing its cellular building blocks along with their dynamics and their cell type-specific connectivities. The project is also building large-scale experimental platforms (i.e., brain observatories) to record the activity of large populations of cortical neurons in behaving mice subject to visual stimuli. A primary goal is to understand the series of operations from visual input in the retina to behavior by observing and modeling the physical transformations of signals in the corticothalamic system. We here focus on the contribution that computer modeling and theory make to this long-term effort.

Download Full-text

Amyloid conformers of the FXR1 protein prevent mRNA degradation in cortical neurons

10.1101/544650 ◽

2019 ◽

Author(s):

J.V. Sopova ◽

E. I Koshel ◽

T.A. Belashova ◽

S.P. Zadorsky ◽

A.V. Sergeeva ◽

...

Keyword(s):

Cortical Neurons ◽

Large Scale ◽

Amyloid Fibrils ◽

Mammalian Species ◽

Rnase A ◽

Mammalian Brain ◽

Polarization Microscopy ◽

Proteomic Approach ◽

Functional Amyloids

AbstractFunctional amyloids regulate vital processes in a variety of organisms from bacteria to higher eukaryotes. The development of methods enabling large-scale screening for amyloids opens up opportunity for systemic analysis of the prevalence of amyloids in nature. Using an original proteomic approach, we identified several proteins forming amyloid-like detergent-resistant aggregates in the rat brain. One of them is the FXR1 protein, which is known to regulate memory and emotions (1, 2). We demonstrated that in brain FXR1 forms amyloid oligomers and insoluble detergent-resistant aggregates that strongly colocalize with amyloid-specific dye Thioflavin S and bind mRNA molecules. Moreover, we demonstrated that mRNAs colocalized with FXR1 amyloid particles are completely resistant to treatment with RNAse A. Taking into consideration that the members of ribonuclease A superfamily function in neurons (3) we can conclude that amyloid conformers of FXR1 control RNA stability in brain. Thus, in contrast to pathological amyloids that cause neurodegeneration, FXR1 is the functional amyloid in forebrain. We showed that amyloid properties of FXR1 depend on its N-terminal part from 1 to 379 amino acids. This fragment forms amyloid fibrils in vitro that bind Congo red and manifest apple-green birefringence when assayed by polarization microscopy. The amyloid-forming region of FXR1 is highly conserved in mammals. These data suggest that the ability of amyloid conformers of FXR1 to protect mRNAs is characteristic of different mammalian species, including humans.Significance StatementAmyloids are highly ordered cross-β sheet protein fibrils associated with many neurodegenerative diseases including Alzheimer’s disease. However, some amyloid proteins regulate vital processes. We identified a set of proteins that form amyloid-like aggregates in the brain of healthy rats. One of them - the FXR1 protein is known to regulate memory and emotions. FXR1 forms amyloid fibrils that bind RNA molecules and prevent their degradation in brain cortex neurons. Amyloid-forming sequence of FXR1 is highly conserved across mammals including human. Discovery of functional amyloids in mammalian brain shows that strategy aimed at the development of universal anti-amyloid drugs is unpromising. Such potential drugs should prevent or suppress formation of pathological aggregates of a certain protein, but not affect functional amyloids.

Download Full-text

Multi-plane Imaging of Neural Activity From the Mammalian Brain Using a Fast-switching Liquid Crystal Spatial Light Modulator

10.1101/506618 ◽

2018 ◽

Cited By ~ 2

Author(s):

Rui Liu ◽

Neil Ball ◽

James Brockill ◽

Leonard Kuan ◽

Daniel Millman ◽

...

Keyword(s):

Liquid Crystal ◽

Neural Activity ◽

Spatial Light Modulator ◽

Large Scale ◽

Striate Cortex ◽

Mammalian Brain ◽

Light Modulator ◽

Fast Switching ◽

Large Populations ◽

Two Photon Fluorescence

We report a novel two-photon fluorescence microscope based on a fast-switching liquid crystal spatial light modulator and a pair of galvo-resonant scanners for large-scale recording of neural activity from the mammalian brain. The utilized imaging technique is capable of monitoring large populations of neurons spread across different layers of the neocortex in awake and behaving mice. During each imaging session, all visual stimulus driven somatic activity could be recorded in the same behavior state. We observed heterogeneous response to different types of visual stimuli from ~ 3,300 excitatory neurons reaching from layer II/III to V of the striate cortex.

Download Full-text

Circuit mechanisms for the chemical modulation of cortex-wide network interactions and behavioral variability

Science Advances ◽

10.1126/sciadv.abf5620 ◽

2021 ◽

Vol 7 (29) ◽

pp. eabf5620

Author(s):

Thomas Pfeffer ◽

Adrian Ponce-Alvarez ◽

Konstantinos Tsetsos ◽

Thomas Meindertsma ◽

Christoffer Julius Gahnström ◽

...

Keyword(s):

Cortical Neurons ◽

Large Scale ◽

Choice Behavior ◽

Circuit Modeling ◽

Behavioral Variability ◽

Double Dissociation ◽

Cortical Areas ◽

Cortical Circuit ◽

Chemical Modulation ◽

And Behavior

Influential theories postulate distinct roles of catecholamines and acetylcholine in cognition and behavior. However, previous physiological work reported similar effects of these neuromodulators on the response properties (specifically, the gain) of individual cortical neurons. Here, we show a double dissociation between the effects of catecholamines and acetylcholine at the level of large-scale interactions between cortical areas in humans. A pharmacological boost of catecholamine levels increased cortex-wide interactions during a visual task, but not rest. An acetylcholine boost decreased interactions during rest, but not task. Cortical circuit modeling explained this dissociation by differential changes in two circuit properties: the local excitation-inhibition balance (more strongly increased by catecholamines) and intracortical transmission (more strongly reduced by acetylcholine). The inferred catecholaminergic mechanism also predicted noisier decision-making, which we confirmed for both perceptual and value-based choice behavior. Our work highlights specific circuit mechanisms for shaping cortical network interactions and behavioral variability by key neuromodulatory systems.

Download Full-text

GABA—from Inhibition to Cognition: Emerging Concepts

The Neuroscientist ◽

10.1177/1073858417734530 ◽

2017 ◽

Vol 24 (5) ◽

pp. 501-515 ◽

Cited By ~ 18

Author(s):

T. Schmidt-Wilcke ◽

E. Fuchs ◽

K. Funke ◽

A. Vlachos ◽

F. Müller-Dahlhaus ◽

...

Keyword(s):

Cortical Neurons ◽

Brain Regions ◽

Mammalian Brain ◽

Resonance Spectroscopy ◽

Inhibitory Neurotransmitter ◽

Electrophysiological Properties ◽

Potential Strategy ◽

The One ◽

And Behavior

Neural functioning and plasticity can be studied on different levels of organization and complexity ranging from the molecular and synaptic level to neural circuitry of whole brain networks. Across neuroscience different methods are being applied to better understand the role of various neurotransmitter systems in the evolution of perception and cognition. GABA is the main inhibitory neurotransmitter in the adult mammalian brain and, depending on the brain region, up to 25% of the total number of cortical neurons are GABAergic interneurons. At the one end of the spectrum, GABAergic neurons have been accurately described with regard to cell morphological, molecular, and electrophysiological properties; at the other end researchers try to link GABA concentrations in specific brain regions to human behavior using magnetic resonance spectroscopy. One of the main challenges of modern neuroscience currently is to integrate knowledge from highly specialized subfields at distinct biological scales into a coherent picture that bridges the gap between molecules and behavior. In the current review, recent findings from different fields of GABA research are summarized delineating a potential strategy to develop a more holistic picture of the function and role of GABA.

Download Full-text

A Guide to Emerging Technologies for Large-Scale and Whole-Brain Optical Imaging of Neuronal Activity

Annual Review of Neuroscience ◽

10.1146/annurev-neuro-072116-031458 ◽

2018 ◽

Vol 41 (1) ◽

pp. 431-452 ◽

Cited By ~ 33

Author(s):

Siegfried Weisenburger ◽

Alipasha Vaziri

Keyword(s):

High Speed ◽

Large Scale ◽

Mammalian Brain ◽

Large Area ◽

The Past ◽

Hybrid Approaches ◽

Large Populations ◽

Temporal And Spatial ◽

The Brain ◽

Neuroscience Community

The mammalian brain is a densely interconnected network that consists of millions to billions of neurons. Decoding how information is represented and processed by this neural circuitry requires the ability to capture and manipulate the dynamics of large populations at high speed and high resolution over a large area of the brain. Although the use of optical approaches by the neuroscience community has rapidly increased over the past two decades, most microscopy approaches are unable to record the activity of all neurons comprising a functional network across the mammalian brain at relevant temporal and spatial resolutions. In this review, we survey the recent development in optical technologies for Ca2+imaging in this regard and provide an overview of the strengths and limitations of each modality and its potential for scalability. We provide guidance from the perspective of a biological user driven by the typical biological applications and sample conditions. We also discuss the potential for future advances and synergies that could be obtained through hybrid approaches or other modalities.

Download Full-text

A Population Density Approach That Facilitates Large-Scale Modeling of Neural Networks: Extension to Slow Inhibitory Synapses

Neural Computation ◽

10.1162/089976601300014448 ◽

2001 ◽

Vol 13 (3) ◽

pp. 511-546 ◽

Cited By ~ 41

Author(s):

Duane Q. Nykamp ◽

Daniel Tranchina

Keyword(s):

Cortical Neurons ◽

Large Scale ◽

The State ◽

Inhibitory Synapses ◽

One Dimensional ◽

Scale Modeling ◽

Transmembrane Voltage ◽

Large Populations ◽

Inhibitory Conductance ◽

Synaptic Conductances

A previously developed method for efficiently simulating complex networks of integrate-and-fire neurons was specialized to the case in which the neurons have fast unitary postsynaptic conductances. However, inhibitory synaptic conductances are often slower than excitatory ones for cortical neurons, and this difference can have a profound effect on network dynamics that cannot be captured with neurons that have only fast synapses. We thus extend the model to include slow inhibitory synapses. In this model, neurons are grouped into large populations of similar neurons. For each population, we calculate the evolution of a probability density function (PDF), which describes the distribution of neurons over state-space. The population firing rate is given by the flux of probability across the threshold voltage for firing an action potential. In the case of fast synaptic conductances, the PDF was one-dimensional, as the state of a neuron was completely determined by its transmembrane voltage. An exact extension to slow inhibitory synapses increases the dimension of the PDF to two or three, as the state of a neuron now includes the state of its inhibitory synaptic conductance. However, by assuming that the expected value of a neuron's inhibitory conductance is independent of its voltage, we derive a reduction to a one-dimensional PDF and avoid increasing the computational complexity of the problem. We demonstrate that although this assumption is not strictly valid, the results of the reduced model are surprisingly accurate.

Download Full-text

How Cortical Circuits Implement Cortical Computations: Mouse Visual Cortex as a Model

Annual Review of Neuroscience ◽

10.1146/annurev-neuro-102320-085825 ◽

2021 ◽

Vol 44 (1) ◽

Author(s):

Cristopher M. Niell ◽

Massimo Scanziani

Keyword(s):

Visual Cortex ◽

Cortical Neurons ◽

Model Organism ◽

Annual Review ◽

Publication Date ◽

Cortical Circuits ◽

Cortical Function ◽

Mouse Visual Cortex ◽

The Brain ◽

Insight Into

The mouse, as a model organism to study the brain, gives us unprecedented experimental access to the mammalian cerebral cortex. By determining the cortex's cellular composition, revealing the interaction between its different components, and systematically perturbing these components, we are obtaining mechanistic insight into some of the most basic properties of cortical function. In this review, we describe recent advances in our understanding of how circuits of cortical neurons implement computations, as revealed by the study of mouse primary visual cortex. Further, we discuss how studying the mouse has broadened our understanding of the range of computations performed by visual cortex. Finally, we address how future approaches will fulfill the promise of the mouse in elucidating fundamental operations of cortex. Expected final online publication date for the Annual Review of Neuroscience, Volume 44 is July 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Download Full-text

Rapid purification and metabolomic profiling of synaptic vesicles from mammalian brain

10.1101/2020.06.05.136093 ◽

2020 ◽

Cited By ~ 1

Author(s):

Lynne Chantranupong ◽

Jessica L. Saulnier ◽

Wengang Wang ◽

Drew R. Jones ◽

Michael E. Pacold ◽

...

Keyword(s):

Cortical Neurons ◽

Synaptic Vesicles ◽

Brain Regions ◽

Mammalian Brain ◽

Metabolomic Profiling ◽

Polar Metabolites ◽

A Cell ◽

Cell Type Specific ◽

Rapid Purification ◽

Activity Dependent

AbstractNeurons communicate by the activity-dependent release of small-molecule neurotransmitters packaged into synaptic vesicles (SVs). Although many molecules have been identified as neurotransmitters, technical limitations have precluded a full metabolomic analysis of synaptic vesicle content. Here, we present a workflow to rapidly isolate SVs and to interrogate their metabolic contents at a high-resolution using mass spectrometry. We validated the enrichment of glutamate in SVs of primary cortical neurons using targeted polar metabolomics. Unbiased and extensive global profiling of SVs isolated from these neurons revealed that the only detectable polar metabolites they contain are the established neurotransmitters glutamate and GABA. Finally, we adapted the approach to enable quick capture of SVs directly from brain tissue and determined the neurotransmitter profiles of diverse brain regions in a cell-type specific manner. The speed, robustness, and precision of this method to interrogate SV contents will facilitate novel insights into the chemical basis of neurotransmission.

Download Full-text

Rapid purification and metabolomic profiling of synaptic vesicles from mammalian brain

eLife ◽

10.7554/elife.59699 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Lynne Chantranupong ◽

Jessica L Saulnier ◽

Wengang Wang ◽

Drew R Jones ◽

Michael E Pacold ◽

...

Keyword(s):

Cortical Neurons ◽

Synaptic Vesicles ◽

Brain Regions ◽

Mammalian Brain ◽

Metabolomic Profiling ◽

Polar Metabolites ◽

A Cell ◽

Cell Type Specific ◽

Rapid Purification ◽

Activity Dependent

Neurons communicate by the activity-dependent release of small-molecule neurotransmitters packaged into synaptic vesicles (SVs). Although many molecules have been identified as neurotransmitters, technical limitations have precluded a full metabolomic analysis of SV content. Here, we present a workflow to rapidly isolate SVs and to interrogate their metabolic contents at high-resolution using mass spectrometry. We validated the enrichment of glutamate in SVs of primary cortical neurons using targeted polar metabolomics. Unbiased and extensive global profiling of SVs isolated from these neurons revealed that the only detectable polar metabolites they contain are the established neurotransmitters glutamate and GABA. In addition, we adapted the approach to enable quick capture of SVs directly from brain tissue and determined the neurotransmitter profiles of diverse brain regions in a cell-type-specific manner. The speed, robustness, and precision of this method to interrogate SV contents will facilitate novel insights into the chemical basis of neurotransmission.

Download Full-text

Dendritic calcium signals in rhesus macaque motor cortex drive an optical brain-computer interface

10.1101/780486 ◽

2019 ◽

Cited By ~ 2

Author(s):

Eric M. Trautmann ◽

Daniel J. O’Shea ◽

Xulu Sun ◽

James H. Marshel ◽

Ailey Crow ◽

...

Keyword(s):

Motor Cortex ◽

Rhesus Macaque ◽

Cortical Neurons ◽

Imaging System ◽

Movement Direction ◽

Cortical Function ◽

Calcium Signals ◽

Two Photon ◽

Large Populations ◽

Motor Cortical

AbstractCalcium imaging has rapidly developed into a powerful tool for recording from large populations of neurons in vivo. Imaging in rhesus macaque motor cortex can enable the discovery of new principles of motor cortical function and can inform the design of next generation brain-computer interfaces (BCIs). Surface two-photon (2P) imaging, however, cannot presently access somatic calcium signals of neurons from all layers of macaque motor cortex due to photon scattering. Here, we demonstrate an implant and imaging system capable of chronic, motion-stabilized two-photon (2P) imaging of calcium signals from in macaques engaged in a motor task. By imaging apical dendrites, some of which originated from deep layer 5 neurons, as as well as superficial cell bodies, we achieved optical access to large populations of deep and superficial cortical neurons across dorsal premotor (PMd) and gyral primary motor (M1) cortices. Dendritic signals from individual neurons displayed tuning for different directions of arm movement, which was stable across many weeks. Combining several technical advances, we developed an optical BCI (oBCI) driven by these dendritic signals and successfully decoded movement direction online. By fusing 2P functional imaging with CLARITY volumetric imaging, we verify that an imaged dendrite, which contributed to oBCI decoding, originated from a putative Betz cell in motor cortical layer 5. This approach establishes new opportunities for studying motor control and designing BCIs.

Download Full-text