June 2022
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10 Reads
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1 Citation
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June 2022
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10 Reads
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1 Citation
June 2022
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13 Reads
January 2022
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24 Reads
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2 Citations
SSRN Electronic Journal
Understanding cortical function requires studying multiple scales: molecular, cellular, circuit, and behavioral. We develop a multiscale, biophysically detailed model of mouse primary motor cortex (M1) with over 10,000 neurons and 30 million synapses. Neuron types, densities, spatial distributions, morphologies, biophysics, connectivity, and dendritic synapse locations are constrained by experimental data. The model includes long-range inputs from seven thalamic and cortical regions and noradrenergic inputs. Connectivity depends on cell class and cortical depth at sublaminar resolution. The model accurately predicts in vivo layer- and cell-type-specific responses (firing rates and LFP) associated with behavioral states (quiet wakefulness and movement) and experimental manipulations (noradrenaline receptor blockade and thalamus inactivation). We generate mechanistic hypotheses underlying the observed activity and analyzed low-dimensional population latent dynamics. This quantitative theoretical framework can be used to integrate and interpret M1 experimental data and sheds light on the cell-type-specific multiscale dynamics associated with several experimental conditions and behaviors.
April 2021
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183 Reads
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13 Citations
Frontiers in Cellular Neuroscience
Odor stimuli consist of thousands of possible molecules, each molecule with many different properties, each property a dimension of the stimulus. Processing these high dimensional stimuli would appear to require many stages in the brain to reach odor perception, yet, in mammals, after the sensory receptors this is accomplished through only two regions, the olfactory bulb and olfactory cortex. We take a first step toward a fundamental understanding by identifying the sequence of local operations carried out by microcircuits in the pathway. Parallel research provided strong evidence that processed odor information is spatial representations of odor molecules that constitute odor images in the olfactory bulb and odor objects in olfactory cortex. Paleontology provides a unique advantage with evolutionary insights providing evidence that the basic architecture of the olfactory pathway almost from the start ∼330 million years ago (mya) has included an overwhelming input from olfactory sensory neurons combined with a large olfactory bulb and olfactory cortex to process that input, driven by olfactory receptor gene duplications. We identify a sequence of over 20 microcircuits that are involved, and expand on results of research on several microcircuits that give the best insights thus far into the nature of the high dimensional processing.
April 2021
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136 Reads
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46 Citations
eLife
Sensory-guided limb control relies on communication across sensorimotor loops. For active touch with the hand, the longest loop is the transcortical continuation of ascending pathways, particularly the lemnisco-cortical and corticocortical pathways carrying tactile signals via the cuneate nucleus, ventral posterior lateral (VPL) thalamus, and primary somatosensory (S1) and motor (M1) cortices to reach corticospinal neurons and influence descending activity. We characterized excitatory connectivity along this pathway in the mouse. In the lemnisco-cortical leg, disynaptic cuneate→VPL→S1 connections excited mainly layer (L) 4 neurons. In the corticocortical leg, S1→M1 connections from L2/3 and L5A neurons mainly excited downstream L2/3 neurons, which excite corticospinal neurons. The findings provide a detailed new wiring diagram for the hand/forelimb-related transcortical circuit, delineating a basic but complex set of cell-type-specific feedforward excitatory connections that selectively and extensively engage diverse intratelencephalic projection neurons, thereby polysynaptically linking subcortical somatosensory input to cortical motor output to spinal cord.
July 2020
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37 Reads
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5 Citations
Journal of Neurophysiology
The first compartmental computer models of brain neurons using the Rall method predicted novel and unexpected dendrodendritic interactions between mitral and granule cells in the olfactory bulb. We review the models from a 50 year perspective on the work that has challenged, supported and extended the original proposal that these interactions mediate both lateral inhibition and oscillatory activity, essential steps in the neural basis of olfactory processing and perception. We highlight strategies behind the neurophysiological experiments and the Rall method that enhance the ability of detailed compartmental modeling to give counter intuitive predictions that lead to deeper insights into neural organization at the synaptic, circuit, and behavioral level. Extensions of the methods to mechanisms of neurogenesis and plasticity are exciting challenges for the future.
February 2020
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136 Reads
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24 Citations
NeuroImage
Odorants can reach olfactory receptor neurons (ORNs) by two routes: orthonasally, when volatiles enter the nasal cavity during inhalation/sniffing; and retronasally, when food volatiles released in the mouth pass into the nasal cavity during exhalation/eating. Previous work in humans has shown that orthonasal and retronasal delivery of the same odorant can evoke distinct perceptions and patterns of neural responses. Each delivery route is known to influence specific responses across the glomerular sheet of the dorsal parts of the olfactory bulb (OB), but spatial distributions across the entire glomerular sheet throughout the whole OB remain largely unexplored. We used functional MRI (fMRI) to measure and compare activations across the entire glomerular sheet in rat OB resulting from both orthonasal and retronasal stimulations of the same odors. We observed reproducible fMRI activation maps of the whole OB during both orthonasal and retronasal stimuli. However, retronasal stimuli required double the orthonasal odor concentration for similar response amplitudes in the OB. Regardless, both the magnitude and spatial extent of activity were larger during orthonasal versus retronasal stimuli for the same odor. Orthonasal and retronasal response patterns show overlap as well as some route-specific dominance. Orthonasal maps were dominant in dorsal-medial regions, whereas retronasal maps were dominant in caudal and lateral regions. These different whole OB encodings likely underlie differences in odor perception between these biologically important routes for odorants among mammals. These results establish the relationships between orthonasal and retronasal odor representations in the rat OB.
July 2019
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280 Reads
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8 Citations
Neuroinformatics
Knowledge discovery via an informatics resource is constrained by the completeness of the resource, both in terms of the amount of data it contains and in terms of the metadata that exists to describe the data. Increasing completeness in one of these categories risks reducing completeness in the other because manually curating metadata is time consuming and is restricted by familiarity with both the data and the metadata annotation scheme. The diverse interests of a research community may drive a resource to have hundreds of metadata tags with few examples for each making it challenging for humans or machine learning algorithms to learn how to assign metadata tags properly. We demonstrate with ModelDB, a computational neuroscience model discovery resource, that using manually-curated regular-expression based rules can overcome this challenge by parsing existing texts from data providers during user data entry to suggest metadata annotations and prompt them to suggest other related metadata annotations rather than leaving the task to a curator. In the ModelDB implementation, analyzing the abstract identified 6.4 metadata tags per abstract at 79% precision. Using the full-text produced higher recall with low precision (41%), and the title alone produced few (1.3) metadata annotations per entry; we thus recommend data providers use their abstract during upload. Grouping the possible metadata annotations into categories (e.g. cell type, biological topic) revealed that precision and recall for the different text sources varies by category. Given this proof-of-concept, other bioinformatics resources can likewise improve the quality of their metadata by adopting our approach of prompting data uploaders with relevant metadata at the minimal cost of formalizing rules for each potential metadata annotation.
March 2019
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483 Reads
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31 Citations
Frontiers in Neuroanatomy
Precision in neuron names is increasingly needed. We are entering a new era in which classical anatomical criteria are only the beginning toward defining the identity of a neuron as carried in its name. New criteria include patterns of gene expression, membrane properties of channels and receptors, pharmacology of neurotransmitters and neuropeptides, physiological properties of impulse firing, and state-dependent variations in expression of characteristic genes and proteins. These gene and functional properties are increasingly defining neuron types and subtypes. Clarity will therefore be enhanced by conveying as much as possible the genes and properties in the neuron name. Using a tested format of parent-child relations for the region and subregion for naming a neuron, we show how the format can be extended so that these additional properties can become an explicit part of a neuron’s identity and name, or archived in a linked properties database. Based on the mouse, examples are provided for neurons in several brain regions as proof of principle, with extension to the complexities of neuron names in the cerebral cortex. The format has dual advantages, of ensuring order in archiving the hundreds of neuron types across all brain regions, as well as facilitating investigation of a given neuron type or given gene or property in the context of all its properties. In particular, we show how the format is extensible to the variety of neuron types and subtypes being revealed by RNA-seq and optogenetics. As current research reveals increasingly complex properties, the proposed approach can facilitate a consensus that goes beyond traditional neuron types.
November 2018
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896 Reads
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1 Citation
Biophysical modeling of neuronal networks helps to integrate and interpret rapidly growing and disparate experimental datasets at multiple scales. The NetPyNE tool ( www.netpyne.org ) provides both programmatic and graphical interfaces to develop data-driven multiscale network models in NEURON. NetPyNE clearly separates model parameters from implementation code. Users provide specifications at a high level via a standardized declarative language, e.g., a connectivity rule, instead of tens of loops to create millions of cell-to-cell connections. Users can then generate the NEURON network, run efficiently parallelized simulations, optimize and explore network parameters through automated batch runs, and use built-in functions for visualization and analysis – connectivity matrices, voltage traces, raster plots, local field potentials, and information theoretic measures. NetPyNE also facilitates model sharing by exporting and importing using NeuroML and SONATA standardized formats. NetPyNE is already being used to teach computational neuroscience students and by modelers to investigate different brain regions and phenomena.
... These limitations highlight the need for more detailed and accurate modeling of neuronal dynamics, the integration of cortical influences and developmental changes, and continuous experimental validation to strengthen hypotheses and improve model accuracy. A crucial consideration is the presence of a corticothalamic pathway, where layer VI pyramidal neurons excitatorily project onto thalamic Rs. 22,25,26 In light of the described pattern completion process, this pathway could enable direct cortical influence on the reticular inhibition process in the relay layer. Phenomena such as perception, hallucinations, dreams, and consciousness 17 may, to some extent, find their roots in the processes simulated by our network. ...
August 2010
... However, examination of a newborn's fontanelles or an adult's brain either during open-skull surgery, or under phase-based-motion-amplified magnetic resonance imaging reveals a highly dynamic pulsatile organ [5] 1 . Indeed, as early as 1880, Mosso, studying adult patients with skull abnormalities, developed a technique known as plethysmography, with which he directly observed the brief cerebral-volume pulsations associated with cardiac and respiratory rhythms [6,7]. Furthermore, Mosso recorded sudden increases in slower-volume pulsations when his subjects engaged in mental activities, thereby paving the way for modern-day functional brain imaging-techniques (i.e., positron emission tomography and functional magnetic resonance imaging) that measure localized increases in blood flow known as functional hyperemia [8][9][10][11]. ...
September 2014
... The neuron doctrine is defined here as consisting in three parts (cf. Glickstein, 2014;Shepherd, 2016): First, there are particular types of cells found in the nervous system, called neurons. Second, neurons are connected but do not fuse together, that is, they remain individual cells. ...
October 2015
... • Hybrid approaches. [293] integrate predicted connectivity with simplified dynamics for some components and detailed biophysics for others. For example, corticospinal and corticostriatal cell model morphologies had 706 and 325 compartments, but excitatory and inhibitory neurons had 6 and 3 compartments (soma, axon, dendrite). ...
Reference:
NeuroAI for AI Safety
January 2022
SSRN Electronic Journal
... The OB has a very high ratio of INs to projection neurons (100:1) compared to any other brain structure (Shepherd et al., 2021). OB INs are small, often anaxonic, and modulate the activity of the OB projection neurons (Whitman and Greer, 2007a). ...
April 2021
Frontiers in Cellular Neuroscience
... However, an interaction between genotype and object distance during pull-back sessions was detected in total correct choices (F(4, 60) = 2.6, p = 0.04, Fig. 3d). Consistent with impaired sensitivity (e.g., reduced precision) for detecting object location, the pull-back curve Discrimination index wt (8) +/- (6) wt (10) +/- (10) wt (7) +/- a Novel object recognition texture (NOR-T) task structure in which mice are tasked to discriminate between visually identical objects having either 8 or 9 verticals ribs/cm. The light level in the arena is 85 lux. ...
April 2021
eLife
... The result appears to be a beautiful, orderly activation pattern for each odorant, comparable to a fingerprint for each odor molecule in the brain (Xu, Greer, & Shepherd, 2000). If olfaction operated similarly to the visual system, this bulbar topography would be expected to be maintained throughout further cortical processing (although, strictly speaking, not the entire striatum but its layer IV revealed such strong signal correspondence, the underlying topographic paradigm has been central Note. the bulb's extensive interneuron circuitry, which generates temporally highly differentiated signals via complicated inhibitory and excitatory networks, is omitted (Shepherd, Hines, Migliore, Chen, & Greer, 2020). to olfaction; Shepherd, 2012). ...
July 2020
Journal of Neurophysiology
... The inability to recognize the same object across different concentrations would clearly be disadvantageous, particularly for salient odors such as food. Natural interaction with food stuffs would enable an animal to associate a range of concentrations with the same object; consuming the food provides much weaker activation of the olfactory epithelium by retronasal olfaction (48). We therefore investigated whether natural 'passive' association of the odor with food was able to endow perceptual constancy for ethyl tiglate across the full range of concentrations we used. ...
February 2020
NeuroImage
... Over three-quarters of all neurons in the mammalian cortex are pyramidal cells (see Fig A in S1 Text), which have dendrites spanning the thickness of the cortex (several mm) and AIS lengths on the order of tens of mm [8][9][10][11]. The AIS requires a high density of voltage-gated sodium channels (Na V s) to prime and initiate action potentials (APs) [12][13][14]. In pyramidal cells, the AIS features two Na V subtypes, with an interesting spatial distribution: Na V 1.2 channels cluster near the soma (i.e. at the proximal AIS) while Na V 1.6 cluster toward the distal AIS [15][16][17]. ...
March 2019
Frontiers in Neuroanatomy
... [83] and NetPyNE (www.netpyne.org) [84], a Python package to facilitate the development of biological neuronal networks in the NEURON simulator. Upon publication, we will make the full source code available on github and ModelDB. ...
November 2018