Publications by authors named "Edward M Callaway"

115 Publications

Monosynaptic Projections to Excitatory and Inhibitory preBötzinger Complex Neurons.

Front Neuroanat 2020 4;14:58. Epub 2020 Sep 4.

Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.

The key driver of breathing rhythm is the preBötzinger Complex (preBötC) whose activity is modulated by various functional inputs, e.g., volitional, physiological, and emotional. While the preBötC is highly interconnected with other regions of the breathing central pattern generator (bCPG) in the brainstem, there is no data about the direct projections to either excitatory and inhibitory preBötC subpopulations from other elements of the bCPG or from suprapontine regions. Using modified rabies tracing, we identified neurons throughout the brain that send monosynaptic projections to identified excitatory and inhibitory preBötC neurons in mice. Within the brainstem, neurons from sites in the bCPG, including the contralateral preBötC, Bötzinger Complex, the nucleus of the solitary tract (NTS), parafacial region (pF /pF ), and parabrachial nuclei (PB), send direct projections to both excitatory and inhibitory preBötC neurons. Suprapontine inputs to the excitatory and inhibitory preBötC neurons include the superior colliculus, red nucleus, amygdala, hypothalamus, and cortex; these projections represent potential direct pathways for volitional, emotional, and physiological control of breathing.
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http://dx.doi.org/10.3389/fnana.2020.00058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7507425PMC
September 2020

The Mind of a Mouse.

Cell 2020 Sep;182(6):1372-1376

Neuroscience Department, Washington University School of Medicine, St. Louis, MO, USA.

Large scientific projects in genomics and astronomy are influential not because they answer any single question but because they enable investigation of continuously arising new questions from the same data-rich sources. Advances in automated mapping of the brain's synaptic connections (connectomics) suggest that the complicated circuits underlying brain function are ripe for analysis. We discuss benefits of mapping a mouse brain at the level of synapses.
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http://dx.doi.org/10.1016/j.cell.2020.08.010DOI Listing
September 2020

Context-dependent and dynamic functional influence of corticothalamic pathways to first- and higher-order visual thalamus.

Proc Natl Acad Sci U S A 2020 06 27;117(23):13066-13077. Epub 2020 May 27.

Systems Neurobiology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037;

Layer 6 (L6) is the sole purveyor of corticothalamic (CT) feedback to first-order thalamus and also sends projections to higher-order thalamus, yet how it engages the full corticothalamic circuit to contribute to sensory processing in an awake animal remains unknown. We sought to elucidate the functional impact of L6CT projections from the primary visual cortex to the dorsolateral geniculate nucleus (first-order) and pulvinar (higher-order) using optogenetics and extracellular electrophysiology in awake mice. While sustained L6CT photostimulation suppresses activity in both visual thalamic nuclei in vivo, moderate-frequency (10 Hz) stimulation powerfully facilitates thalamic spiking. We show that each stimulation paradigm differentially influences the balance between monosynaptic excitatory and disynaptic inhibitory corticothalamic pathways to the dorsolateral geniculate nucleus and pulvinar, as well as the prevalence of burst versus tonic firing. Altogether, our results support a model in which L6CTs modulate first- and higher-order thalamus through parallel excitatory and inhibitory pathways that are highly dynamic and context-dependent.
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http://dx.doi.org/10.1073/pnas.2002080117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293611PMC
June 2020

Extraction of Distinct Neuronal Cell Types from within a Genetically Continuous Population.

Neuron 2020 07 11;107(2):274-282.e6. Epub 2020 May 11.

Systems Neurobiology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address:

Single-cell transcriptomics of neocortical neurons have revealed more than 100 clusters corresponding to putative cell types. For inhibitory and subcortical projection neurons (SCPNs), there is a strong concordance between clusters and anatomical descriptions of cell types. In contrast, cortico-cortical projection neurons (CCPNs) separate into surprisingly few transcriptomic clusters, despite their diverse anatomical projection types. We used projection-dependent single-cell transcriptomic analyses and monosynaptic rabies tracing to compare mouse primary visual cortex CCPNs projecting to different higher visual areas. We find that layer 2/3 CCPNs with different anatomical projections differ systematically in their gene expressions, despite forming only a single genetic cluster. Furthermore, these neurons receive feedback selectively from the same areas to which they project. These findings demonstrate that gene-expression analysis in isolation is insufficient to identify neuron types and have important implications for understanding the functional role of cortical feedback circuits.
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http://dx.doi.org/10.1016/j.neuron.2020.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381365PMC
July 2020

Sources of off-target expression from recombinase-dependent AAV vectors and mitigation with cross-over insensitive ATG-out vectors.

Proc Natl Acad Sci U S A 2019 Dec 16. Epub 2019 Dec 16.

Systems Neurobiology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92039;

In combination with transgenic mouse lines expressing Cre or Flp recombinases in defined cell types, recombinase-dependent adeno-associated viruses (AAVs) have become the tool of choice for localized cell-type-targeted gene expression. Unfortunately, applications of this technique when expressing highly sensitive transgenes are impeded by off-target, or "leak" expression, from recombinase-dependent AAVs. We investigated this phenomenon and find that leak expression is mediated by both infrequent transcription from the inverted transgene in recombinant-dependent AAV designs and recombination events during bacterial AAV plasmid production. Recombination in bacteria is mediated by homology across the antiparallel recombinase-specific recognition sites present in recombinase-dependent designs. To address both of these issues we designed an AAV vector that uses mutant "cross-over insensitive" recognition sites combined with an "ATG-out" design. We show that these CIAO (cross-over insensitive ATG-out) vectors virtually eliminate leak expression. CIAO vectors provide reliable and targeted transgene expression and are extremely useful for recombinase-dependent expression of highly sensitive transgenes.
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http://dx.doi.org/10.1073/pnas.1915974116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936690PMC
December 2019

Mapping Brain-Wide Afferent Inputs of Parvalbumin-Expressing GABAergic Neurons in Barrel Cortex Reveals Local and Long-Range Circuit Motifs.

Cell Rep 2019 09;28(13):3450-3461.e8

Institute for Neuroanatomy, University Medical Center Göttingen, Georg-August-University Göttingen, 37075 Göttingen, Germany. Electronic address:

Parvalbumin (PV)-expressing GABAergic neurons are the largest class of inhibitory neocortical cells. We visualize brain-wide, monosynaptic inputs to PV neurons in mouse barrel cortex. We develop intersectional rabies virus tracing to specifically target GABAergic PV cells and exclude a small fraction of excitatory PV cells from our starter population. Local inputs are mainly from layer (L) IV and excitatory cells. A small number of inhibitory inputs originate from LI neurons, which connect to LII/III PV neurons. Long-range inputs originate mainly from other sensory cortices and the thalamus. In visual cortex, most transsynaptically labeled neurons are located in LIV, which contains a molecularly mixed population of projection neurons with putative functional similarity to LIII neurons. This study expands our knowledge of the brain-wide circuits in which PV neurons are embedded and introduces intersectional rabies virus tracing as an applicable tool to dissect the circuitry of more clearly defined cell types.
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http://dx.doi.org/10.1016/j.celrep.2019.08.064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6897332PMC
September 2019

A systematic topographical relationship between mouse lateral posterior thalamic neurons and their visual cortical projection targets.

J Comp Neurol 2020 01 12;528(1):95-107. Epub 2019 Jul 12.

The Salk Institute for Biological Studies, La Jolla, California.

Higher-order visual thalamus communicates broadly and bi-directionally with primary and extrastriate cortical areas in various mammals. In primates, the pulvinar is a topographically and functionally organized thalamic nucleus that is largely dedicated to visual processing. Still, a more granular connectivity map is needed to understand the role of thalamocortical loops in visually guided behavior. Similarly, the secondary visual thalamic nucleus in mice (the lateral posterior nucleus, LP) has extensive connections with cortex. To resolve the precise connectivity of these circuits, we first mapped mouse visual cortical areas using intrinsic signal optical imaging and then injected fluorescently tagged retrograde tracers (cholera toxin subunit B) into retinotopically-matched locations in various combinations of seven different visual areas. We find that LP neurons representing matched regions in visual space but projecting to different extrastriate areas are found in different topographically organized zones, with few double-labeled cells (~4-6%). In addition, V1 and extrastriate visual areas received input from the ventrolateral part of the laterodorsal nucleus of the thalamus (LDVL). These observations indicate that the thalamus provides topographically organized circuits to each mouse visual area and raise new questions about the contributions from LP and LDVL to cortical activity.
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http://dx.doi.org/10.1002/cne.24737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6842098PMC
January 2020

Color and orientation are jointly coded and spatially organized in primate primary visual cortex.

Science 2019 06;364(6447):1275-1279

The Salk Institute for Biological Studies, La Jolla, CA 92037, USA.

Previous studies support the textbook model that shape and color are extracted by distinct neurons in primate primary visual cortex (V1). However, rigorous testing of this model requires sampling a larger stimulus space than previously possible. We used stable GCaMP6f expression and two-photon calcium imaging to probe a very large spatial and chromatic visual stimulus space and map functional microarchitecture of thousands of neurons with single-cell resolution. Notable proportions of V1 neurons strongly preferred equiluminant color over achromatic stimuli and were also orientation selective, indicating that orientation and color in V1 are mutually processed by overlapping circuits. Single neurons could precisely and unambiguously code for both color and orientation. Further analyses revealed systematic spatial relationships between color tuning, orientation selectivity, and cytochrome oxidase histology.
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http://dx.doi.org/10.1126/science.aaw5868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6689325PMC
June 2019

Local and Global Influences of Visual Spatial Selection and Locomotion in Mouse Primary Visual Cortex.

Curr Biol 2019 05 2;29(10):1592-1605.e5. Epub 2019 May 2.

Systems Neurobiology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; Neurosciences Graduate Program, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

Sensory selection and movement locally and globally modulate neural responses in seemingly similar ways. For example, locomotion enhances visual responses in mouse primary visual cortex (V1), resembling the effects of spatial attention on primate visual cortical activity. However, interactions between these local and global mechanisms and the resulting effects on perceptual behavior remain largely unknown. Here, we describe a novel mouse visual spatial selection task in which animals either monitor one of two locations for a contrast change ("selective mice") or monitor both ("non-selective mice") and can run at will. Selective mice perform well only when their selected stimulus changes, giving rise to local electrophysiological changes in the corresponding hemisphere of V1 including decreased noise correlations and increased visual information. Non-selective mice perform well when either stimulus changes, giving rise to global changes across both hemispheres of V1. During locomotion, selective mice have worse behavioral performance, increased noise correlations in V1, and decreased visual information, while non-selective mice have decreased noise correlations in V1 but no change in performance or visual information. Our findings demonstrate that mice can locally or globally enhance visual information, but the interaction of the global effect of locomotion with local selection impairs behavioral performance. Moving forward, this mouse model will facilitate future studies of local and global sensory modulatory mechanisms and their effects on behavior.
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http://dx.doi.org/10.1016/j.cub.2019.03.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6529288PMC
May 2019

Higher-Order Thalamic Circuits Channel Parallel Streams of Visual Information in Mice.

Neuron 2019 04 5;102(2):477-492.e5. Epub 2019 Mar 5.

Allen Institute for Brain Science, 615 Westlake Avenue, Seattle, WA 98109, USA.

Higher-order thalamic nuclei, such as the visual pulvinar, play essential roles in cortical function by connecting functionally related cortical and subcortical brain regions. A coherent framework describing pulvinar function remains elusive because of its anatomical complexity and involvement in diverse cognitive processes. We combined large-scale anatomical circuit mapping with high-density electrophysiological recordings to dissect a homolog of the pulvinar in mice, the lateral posterior thalamic nucleus (LP). We define three broad LP subregions based on correspondence between connectivity and functional properties. These subregions form corticothalamic loops biased toward ventral or dorsal stream cortical areas and contain separate representations of visual space. Silencing the visual cortex or superior colliculus revealed that they drive visual tuning properties in separate LP subregions. Thus, by specifying the driving input sources, functional properties, and downstream targets of LP circuits, our data provide a roadmap for understanding the mechanisms of higher-order thalamic function in vision.
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http://dx.doi.org/10.1016/j.neuron.2019.02.010DOI Listing
April 2019

Intersectional monosynaptic tracing for dissecting subtype-specific organization of GABAergic interneuron inputs.

Nat Neurosci 2019 03 28;22(3):492-502. Epub 2019 Jan 28.

Development and Function of Inhibitory Neural Circuits, Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA.

Functionally and anatomically distinct cortical substructures, such as areas or layers, contain different principal neuron (PN) subtypes that generate output signals representing particular information. Various types of cortical inhibitory interneurons (INs) differentially but coordinately regulate PN activity. Despite a potential determinant for functional specialization of PN subtypes, the spatial organization of IN subtypes that innervate defined PN subtypes remains unknown. Here we develop a genetic strategy combining a recombinase-based intersectional labeling method and rabies viral monosynaptic tracing, which enables subtype-specific visualization of cortical IN ensembles sending inputs to defined PN subtypes. Our approach reveals not only cardinal but also underrepresented connections between broad, non-overlapping IN subtypes and PNs. Furthermore, we demonstrate that distinct PN subtypes defined by areal or laminar positions display different organization of input IN subtypes. Our genetic strategy will facilitate understanding of the wiring and developmental principles of cortical inhibitory circuits at unparalleled levels.
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http://dx.doi.org/10.1038/s41593-018-0322-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6387655PMC
March 2019

Centrifugal Inputs to the Main Olfactory Bulb Revealed Through Whole Brain Circuit-Mapping.

Front Neuroanat 2018 7;12:115. Epub 2019 Jan 7.

Crick-Jacobs Center for Theoretical and Computational Biology, Salk Institute for Biological Studies, La Jolla, CA, United States.

Neuronal activity in sensory regions can be modulated by attention, behavioral state, motor output, learning, and memory. This is often done through direct feedback or centrifugal projections originating from higher processing areas. Though, functionally important, the identity and organization of these feedback connections remain poorly characterized. Using a retrograde monosynaptic g-deleted rabies virus and whole-brain reconstructions, we identified the organization of feedback projecting neurons to the main olfactory bulb of the mouse. In addition to previously described projections from regions such as the Anterior Olfactory Nucleus (AON) and the piriform cortex, we characterized direct projections from pyramidal cells in the ventral CA1 region of hippocampus and the entorhinal cortex to the granule cell layer (GCL) of the main olfactory bulb (MOB). These data suggest that areas involved in stress, anxiety, learning and memory are all tethered to olfactory coding, two synapses away from where chemical compounds are first detected. Consequently, we hypothesize that understanding olfactory perception, even at the earliest stages, may require studying memory and behavior in addition to studying the physiochemical features of odors.
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http://dx.doi.org/10.3389/fnana.2018.00115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6330333PMC
January 2019

Genetic Dissection of Neural Circuits: A Decade of Progress.

Neuron 2018 04;98(2):256-281

Howard Hughes Medical Institute, Janelia Research Campus, Ashburn, VA 20147, USA.

Tremendous progress has been made since Neuron published our Primer on genetic dissection of neural circuits 10 years ago. Since then, cell-type-specific anatomical, neurophysiological, and perturbation studies have been carried out in a multitude of invertebrate and vertebrate organisms, linking neurons and circuits to behavioral functions. New methods allow systematic classification of cell types and provide genetic access to diverse neuronal types for studies of connectivity and neural coding during behavior. Here we evaluate key advances over the past decade and discuss future directions.
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http://dx.doi.org/10.1016/j.neuron.2018.03.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5912347PMC
April 2018

Brain technology: Neurons recorded en masse.

Nature 2017 11;551(7679):172-173

the Systems Neurobiology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037, USA.

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http://dx.doi.org/10.1038/551172aDOI Listing
November 2017

Automated identification of mouse visual areas with intrinsic signal imaging.

Nat Protoc 2017 Jan 1;12(1):32-43. Epub 2016 Dec 1.

Salk Institute for Biological Studies, La Jolla, California, USA.

Intrinsic signal optical imaging (ISI) is a rapid and noninvasive method for observing brain activity in vivo over a large area of the cortex. Here we describe our protocol for mapping retinotopy to identify mouse visual cortical areas using ISI. First, surgery is performed to attach a head frame to the mouse skull (∼1 h). The next day, intrinsic activity across the visual cortex is recorded during the presentation of a full-field drifting bar in the horizontal and vertical directions (∼2 h). Horizontal and vertical retinotopic maps are generated by analyzing the response of each pixel during the period of the stimulus. Last, an algorithm uses these retinotopic maps to compute the visual field sign and coverage, and automatically construct visual borders without human input. Compared with conventional retinotopic mapping with episodic presentation of adjacent stimuli, a continuous, periodic stimulus is more resistant to biological artifacts. Furthermore, unlike manual hand-drawn approaches, we present a method for automatically segmenting visual areas, even in the small mouse cortex. This relatively simple procedure and accompanying open-source code can be implemented with minimal surgical and computational experience, and is useful to any laboratory wishing to target visual cortical areas in this increasingly valuable model system.
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http://dx.doi.org/10.1038/nprot.2016.158DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381647PMC
January 2017

In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration.

Nature 2016 12 16;540(7631):144-149. Epub 2016 Nov 16.

Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 N. Torrey Pines Rd, La Jolla, California 92037, USA.

Targeted genome editing via engineered nucleases is an exciting area of biomedical research and holds potential for clinical applications. Despite rapid advances in the field, in vivo targeted transgene integration is still infeasible because current tools are inefficient, especially for non-dividing cells, which compose most adult tissues. This poses a barrier for uncovering fundamental biological principles and developing treatments for a broad range of genetic disorders. Based on clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) technology, here we devise a homology-independent targeted integration (HITI) strategy, which allows for robust DNA knock-in in both dividing and non-dividing cells in vitro and, more importantly, in vivo (for example, in neurons of postnatal mammals). As a proof of concept of its therapeutic potential, we demonstrate the efficacy of HITI in improving visual function using a rat model of the retinal degeneration condition retinitis pigmentosa. The HITI method presented here establishes new avenues for basic research and targeted gene therapies.
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http://dx.doi.org/10.1038/nature20565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5331785PMC
December 2016

A viral strategy for targeting and manipulating interneurons across vertebrate species.

Nat Neurosci 2016 12 31;19(12):1743-1749. Epub 2016 Oct 31.

NYU Neuroscience Institute, New York University Langone Medical Center, New York, New York, USA.

A fundamental impediment to understanding the brain is the availability of inexpensive and robust methods for targeting and manipulating specific neuronal populations. The need to overcome this barrier is pressing because there are considerable anatomical, physiological, cognitive and behavioral differences between mice and higher mammalian species in which it is difficult to specifically target and manipulate genetically defined functional cell types. In particular, it is unclear the degree to which insights from mouse models can shed light on the neural mechanisms that mediate cognitive functions in higher species, including humans. Here we describe a novel recombinant adeno-associated virus that restricts gene expression to GABAergic interneurons within the telencephalon. We demonstrate that the viral expression is specific and robust, allowing for morphological visualization, activity monitoring and functional manipulation of interneurons in both mice and non-genetically tractable species, thus opening the possibility to study GABAergic function in virtually any vertebrate species.
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http://dx.doi.org/10.1038/nn.4430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348112PMC
December 2016

Distinct Hippocampal Pathways Mediate Dissociable Roles of Context in Memory Retrieval.

Cell 2016 11 20;167(4):961-972.e16. Epub 2016 Oct 20.

Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, 4058 Basel, Switzerland; University of Basel, 4003 Basel, Switzerland. Electronic address:

Memories about sensory experiences are tightly linked to the context in which they were formed. Memory contextualization is fundamental for the selection of appropriate behavioral reactions needed for survival, yet the underlying neuronal circuits are poorly understood. By combining trans-synaptic viral tracing and optogenetic manipulation, we found that the ventral hippocampus (vHC) and the amygdala, two key brain structures encoding context and emotional experiences, interact via multiple parallel pathways. A projection from the vHC to the basal amygdala mediates fear behavior elicited by a conditioned context, whereas a parallel projection from a distinct subset of vHC neurons onto midbrain-projecting neurons in the central amygdala is necessary for context-dependent retrieval of cued fear memories. Our findings demonstrate that two fundamentally distinct roles of context in fear memory retrieval are processed by distinct vHC output pathways, thereby allowing for the formation of robust contextual fear memories while preserving context-dependent behavioral flexibility.
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http://dx.doi.org/10.1016/j.cell.2016.09.051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5382990PMC
November 2016

Distributed and Mixed Information in Monosynaptic Inputs to Dopamine Neurons.

Neuron 2016 Sep 8;91(6):1374-1389. Epub 2016 Sep 8.

Department of Molecular and Cellular Biology, Center for Brain Science, Harvard University, Cambridge, MA 02138, USA. Electronic address:

Dopamine neurons encode the difference between actual and predicted reward, or reward prediction error (RPE). Although many models have been proposed to account for this computation, it has been difficult to test these models experimentally. Here we established an awake electrophysiological recording system, combined with rabies virus and optogenetic cell-type identification, to characterize the firing patterns of monosynaptic inputs to dopamine neurons while mice performed classical conditioning tasks. We found that each variable required to compute RPE, including actual and predicted reward, was distributed in input neurons in multiple brain areas. Further, many input neurons across brain areas signaled combinations of these variables. These results demonstrate that even simple arithmetic computations such as RPE are not localized in specific brain areas but, rather, distributed across multiple nodes in a brain-wide network. Our systematic method to examine both activity and connectivity revealed unexpected redundancy for a simple computation in the brain.
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http://dx.doi.org/10.1016/j.neuron.2016.08.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5033723PMC
September 2016

Comment on "Principles of connectivity among morphologically defined cell types in adult neocortex".

Science 2016 09;353(6304):1108

Kavli institute of Brain Science, Columbia University, Department of Biological Sciences, West 120 Street, New York, NY 10027, USA.

Jiang et al (Research Article, 27 November 2015, aac9462) describe detailed experiments that substantially add to the knowledge of cortical microcircuitry and are unique in the number of connections reported and the quality of interneuron reconstruction. The work appeals to experts and laypersons because of the notion that it unveils new principles and provides a complete description of cortical circuits. We provide a counterbalance to the authors' claims to give those less familiar with the minutiae of cortical circuits a better sense of the contributions and the limitations of this study.
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http://dx.doi.org/10.1126/science.aaf5663DOI Listing
September 2016

Genetic-Based Dissection Unveils the Inputs and Outputs of Striatal Patch and Matrix Compartments.

Neuron 2016 Sep 25;91(5):1069-1084. Epub 2016 Aug 25.

Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address:

The striatum contains neurochemically defined compartments termed patches and matrix. Previous studies suggest patches preferentially receive limbic inputs and project to dopamine neurons in substantia nigra pars compacta (SNc), whereas matrix neurons receive sensorimotor inputs and do not innervate SNc. Using BAC-Cre transgenic mice with viral tracing techniques, we mapped brain-wide differences in the input-output organization of the patch/matrix. Findings reveal a displaced population of striatal patch neurons termed "exo-patch," which reside in matrix zones but have neurochemistry, connectivity, and electrophysiological characteristics resembling patch neurons. Contrary to previous studies, results show patch/exo-patch and matrix neurons receive both limbic and sensorimotor information. A novel inhibitory projection from bed nucleus of the stria terminalis to patch/exo-patch neurons was revealed. Projections to SNc were found to originate from patch/exo-patch and matrix neurons. These findings redefine patch/matrix beyond traditional neurochemical topography and reveal new principles about their input-output connectivity, providing a foundation for future functional studies.
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http://dx.doi.org/10.1016/j.neuron.2016.07.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017922PMC
September 2016

Efficient Receptive Field Tiling in Primate V1.

Neuron 2016 Aug 4;91(4):893-904. Epub 2016 Aug 4.

Systems Neurobiology Laboratories, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. Electronic address:

The primary visual cortex (V1) encodes a diverse set of visual features, including orientation, ocular dominance (OD), and spatial frequency (SF), whose joint organization must be precisely structured to optimize coverage within the retinotopic map. Prior experiments have only identified efficient coverage based on orthogonal maps. Here we used two-photon calcium imaging to reveal an alternative arrangement for OD and SF maps in macaque V1; their gradients run parallel but with unique spatial periods, whereby low-SF regions coincide with monocular regions. Next we mapped receptive fields and found surprisingly precise micro-retinotopy that yields a smaller point-image and requires more efficient inter-map geometry, thus underscoring the significance of map relationships. While smooth retinotopy is constraining, studies suggest that it improves both wiring economy and the V1 population code read downstream. Altogether, these data indicate that connectivity within V1 is finely tuned and precise at the level of individual neurons.
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http://dx.doi.org/10.1016/j.neuron.2016.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5384649PMC
August 2016

Diverse Representations of Olfactory Information in Centrifugal Feedback Projections.

J Neurosci 2016 07;36(28):7535-45

Crick-Jacobs Center for Theoretical and Computational Biology, Computational Neurobiology Laboratory, Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, California 92037.

Unlabelled: Although feedback or centrifugal projections from higher processing centers of the brain to peripheral regions have long been known to play essential functional roles, the anatomical organization of these connections remains largely unknown. Using a virus-based retrograde labeling strategy and 3D whole-brain reconstruction methods, we mapped the spatial organization of centrifugal projections from two olfactory cortical areas, the anterior olfactory nucleus (AON) and the piriform cortex, to the granule cell layer of the main olfactory bulb in the mouse. Both regions are major recipients of information from the bulb and are the largest sources of feedback to the bulb, collectively constituting circuits essential for olfactory coding and olfactory behavior. We found that, although ipsilateral inputs from the AON were uniformly distributed, feedback from the contralateral AON had a strong ventral bias. In addition, we observed that centrifugally projecting neurons were spatially clustered in the piriform cortex, in contrast to the distributed feedforward axonal inputs that these cells receive from the principal neurons of the bulb. Therefore, information carried from the bulb to higher processing structures by anatomically stereotypic projections is likely relayed back to the bulb by organizationally distinct feedback projections that may reflect different coding strategies and therefore different functional roles.

Significance Statement: Principles of anatomical organization, sometimes instantiated as "maps" in the mammalian brain, have provided key insights into the structure and function of circuits in sensory systems. Generally, these characterizations focus on projections from early sensory processing areas to higher processing structures despite considerable evidence that feedback or centrifugal projections often constitute major conduits of information flow. Our results identify structure in the organization of centrifugal feedback projections to the olfactory bulb that is fundamentally different from the organization of feedforward circuits. Our study suggests that understanding computations performed in the olfactory bulb, and more generally in the olfactory system, requires understanding interactions between feedforward and feedback "maps" both structurally and functionally.
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http://dx.doi.org/10.1523/JNEUROSCI.3358-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4945671PMC
July 2016

Afferent Inputs to Neurotransmitter-Defined Cell Types in the Ventral Tegmental Area.

Cell Rep 2016 06 9;15(12):2796-808. Epub 2016 Jun 9.

Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA. Electronic address:

The ventral tegmental area (VTA) plays a central role in the neural circuit control of behavioral reinforcement. Though considered a dopaminergic nucleus, the VTA contains substantial heterogeneity in neurotransmitter type, containing also GABA and glutamate neurons. Here, we used a combinatorial viral approach to transsynaptically label afferents to defined VTA dopamine, GABA, or glutamate neurons. Surprisingly, we find that these populations received qualitatively similar inputs, with dominant and comparable projections from the lateral hypothalamus, raphe, and ventral pallidum. However, notable differences were observed, with striatal regions and globus pallidus providing a greater share of input to VTA dopamine neurons, cortical input preferentially on to glutamate neurons, and GABA neurons receiving proportionally more input from the lateral habenula and laterodorsal tegmental nucleus. By comparing inputs to each of the transmitter-defined VTA cell types, this study sheds important light on the systems-level organization of diverse inputs to VTA.
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http://dx.doi.org/10.1016/j.celrep.2016.05.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917450PMC
June 2016

Improved Monosynaptic Neural Circuit Tracing Using Engineered Rabies Virus Glycoproteins.

Cell Rep 2016 Apr 14;15(4):692-699. Epub 2016 Apr 14.

Systems Neurobiology Laboratories, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address:

Monosynaptic rabies virus tracing is a unique and powerful tool used to identify neurons making direct presynaptic connections onto neurons of interest across the entire nervous system. Current methods utilize complementation of glycoprotein gene-deleted rabies of the SAD B19 strain with its glycoprotein, B19G, to mediate retrograde transsynaptic spread across a single synaptic step. In most conditions, this method labels only a fraction of input neurons and would thus benefit from improved efficiency of transsynaptic spread. Here, we report newly engineered glycoprotein variants to improve transsynaptic efficiency. Among them, oG (optimized glycoprotein) is a codon-optimized version of a chimeric glycoprotein consisting of the transmembrane/cytoplasmic domain of B19G and the extracellular domain of rabies Pasteur virus strain glycoprotein. We demonstrate that oG increases the tracing efficiency for long-distance input neurons up to 20-fold compared to B19G. oG-mediated rabies tracing will therefore allow identification and study of more complete monosynaptic input neural networks.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063660PMC
http://dx.doi.org/10.1016/j.celrep.2016.03.067DOI Listing
April 2016

Brain-Wide Maps of Synaptic Input to Cortical Interneurons.

J Neurosci 2016 Apr;36(14):4000-9

Systems Neurobiology Laboratories, Salk Institute for Biological Studies, La Jolla, California 92037,

Unlabelled: Cortical inhibition is mediated by diverse inhibitory neuron types that can each play distinct roles in information processing by virtue of differences in their input sources, intrinsic properties, and innervation targets. Previous studies in brain slices have demonstrated considerable cell-type specificity in laminar sources of local inputs. In contrast, little is known about possible differences in distant inputs to different cortical interneuron types. We used the monosynaptic rabies virus system, in conjunction with mice expressing Cre recombinase in either parvalbumin-positive, somatostatin-positive (SST+), or vasoactive intestinal peptide-positive (VIP+) neurons, to map the brain-wide input to the three major nonoverlapping classes of interneurons in mouse somatosensory cortex. We discovered that all three classes of interneurons received considerable input from known cortical and thalamic input sources, as well as from probable cholinergic cells in the basal nucleus of Meynert. Despite their common input sources, these classes differed in the proportion of long-distance cortical inputs originating from deep versus superficial layers. Similar to their laminar differences in local input, VIP+ neurons received inputs predominantly from deep layers while SST+ neurons received mostly superficial inputs. These classes also differed in the amount of input they received. Cortical and thalamic inputs were greatest onto VIP+ interneurons and smallest onto SST+ neurons.

Significance Statement: These results indicate that all three major interneuron classes in the barrel cortex integrate both feedforward and feedback information from throughout the brain to modulate the activity of the local cortical circuit. However, differences in laminar sources and magnitude of distant cortical input suggest differential contributions from cortical areas. More input to vasoactive intestinal peptide-positive (VIP+) neurons than to somatostatin-positive (SST+) neurons suggests that disinhibition of the cortex via VIP+ cells, which inhibit SST+ cells, might be a general feature of long-distance corticocortical and thalamocortical circuits.
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http://dx.doi.org/10.1523/JNEUROSCI.3967-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821911PMC
April 2016