This Research Topic is part of a series: <a href="https://www.frontiersin.org/research-topics/38333/horizons-in-neural-circuits-volume-ii">Horizons in Neural Circuits</a>. This series showcases high-impact, authoritative and reader-friendly review articles covering the most topical research at the forefront of neural circuits. All contributing authors were nominated by the Chief Editors of the Journal in recognition of their prominence and influence in their respective fields. The cutting-edge work presented in this article collection highlights the diversity of research performed across the entire breadth of the field, and reflects on the latest advances in basic and translational research. Contributions to the collection are by invitation only. New articles will be added to this collection as they are published.

Harvard University

McGill University

Frontiers in Neural Circuits

Horizons in Neural Circuits

Adaptive neuronal circuit function requires a continual adjustment of synaptic network parameters known as “neuromodulation.” This process is now understood to be based primarily on the binding of myriad secreted “modulatory” ligands such as dopamine, serotonin and the neuropeptides to G protein-coupled receptors (GPCRs) that, in turn, regulate the function of the ion channels that establish synaptic weights and membrane excitability. Many of the basic molecular mechanisms of neuromodulation are now known, but the organization of neuromodulation at a network level is still an enigma. New single-cell RNA sequencing data and transcriptomic neurotaxonomies now offer bright new lights to shine on this critical “dark matter” of neuroscience. Here we leverage these advances to explore the cell-type-specific expression of genes encoding GPCRs, modulatory ligands, ion channels and intervening signal transduction molecules in mouse hippocampus area CA1, with the goal of revealing broad outlines of this well-studied brain structure’s neuromodulatory network architecture.

Adaptive neuronal circuit function requires a continual adjustment of synaptic network parameters known as &#x201c;neuromodulation.&#x201d; This process is now understood to be based primarily on the binding of myriad secreted &#x201c;modulatory&#x201d; ligands such as dopamine, serotonin and the neuropeptides to G protein-coupled receptors (GPCRs) that, in turn, regulate the function of the ion channels that establish synaptic weights and membrane excitability. Many of the basic molecular mechanisms of neuromodulation are now known, but the organization of neuromodulation at a network level is still an enigma. New single-cell RNA sequencing data and transcriptomic neurotaxonomies now offer bright new lights to shine on this critical &#x201c;dark matter&#x201d; of neuroscience. Here we leverage these advances to explore the cell-type-specific expression of genes encoding GPCRs, modulatory ligands, ion channels and intervening signal transduction molecules in mouse hippocampus area CA1, with the goal of revealing broad outlines of this well-studied brain structure&#x2019;s neuromodulatory network architecture.

A Molecular Landscape of Mouse Hippocampal Neuromodulation

Traditionally, functional representations in early visual areas are conceived as retinotopic maps preserving ego-centric spatial location information while ensuring that other stimulus features are uniformly represented for all locations in space. Recent results challenge this framework of relatively independent encoding of location and features in the early visual system, emphasizing location-dependent feature sensitivities that reflect specialization of cortical circuits for different locations in visual space. Here we review the evidence for such location-specific encoding including: (1) systematic variation of functional properties within conventional retinotopic maps in the cortex; (2) novel periodic retinotopic transforms that dramatically illustrate the tight linkage of feature sensitivity, spatial location, and cortical circuitry; and (3) retinotopic biases in cortical areas, and groups of areas, that have been defined by their functional specializations. We propose that location-dependent feature sensitivity is a fundamental organizing principle of the visual system that achieves efficient representation of positional regularities in visual experience, and reflects the evolutionary selection of sensory and motor circuits to optimally represent behaviorally relevant information. Future studies are necessary to discover mechanisms underlying joint encoding of location and functional information, how this relates to behavior, emerges during development, and varies across species.

Traditionally, functional representations in early visual areas are conceived as retinotopic maps preserving ego-centric spatial location information while ensuring that other stimulus features are uniformly represented for all locations in space. Recent results challenge this framework of relatively independent encoding of location and features in the early visual system, emphasizing location-dependent feature sensitivities that reflect specialization of cortical circuits for different locations in visual space. Here we review the evidence for such location-specific encoding including: (1) systematic variation of functional properties within conventional retinotopic maps in the cortex; (2) novel periodic retinotopic transforms that dramatically illustrate the tight linkage of feature sensitivity, spatial location, and cortical circuitry; and (3) retinotopic biases in cortical areas, and groups of areas, that have been defined by their functional specializations. We propose that location-dependent feature sensitivity is a fundamental organizing principle of the visual system that achieves efficient representation of positional regularities in visual experience, and reflects the evolutionary selection of sensory and motor circuits to optimally represent behaviorally relevant information. Future studies are necessary to discover mechanisms underlying joint encoding of location and functional information, how this relates to behavior, emerges during development, and varies across species.

What and Where: Location-Dependent Feature Sensitivity as a Canonical Organizing Principle of the Visual System

Müller glia of the retina share many features with astroglia located throughout the brain including maintenance of homeostasis, modulation of neurotransmitter spillover, and robust response to injury. Here we present the molecular factors and signaling events that govern Müller glial specification, patterning, and differentiation. Next, we discuss the various roles of Müller glia in retinal development, which include maintaining retinal organization and integrity as well as promoting neuronal survival, synaptogenesis, and phagocytosis of debris. Finally, we review the mechanisms by which Müller glia integrate into retinal circuits and actively participate in neuronal signaling during development.

M&#xfc;ller glia of the retina share many features with astroglia located throughout the brain including maintenance of homeostasis, modulation of neurotransmitter spillover, and robust response to injury. Here we present the molecular factors and signaling events that govern M&#xfc;ller glial specification, patterning, and differentiation. Next, we discuss the various roles of M&#xfc;ller glia in retinal development, which include maintaining retinal organization and integrity as well as promoting neuronal survival, synaptogenesis, and phagocytosis of debris. Finally, we review the mechanisms by which M&#xfc;ller glia integrate into retinal circuits and actively participate in neuronal signaling during development.

Müller Glia in Retinal Development: From Specification to Circuit Integration

Visual experience is mediated through a relay of finely-tuned neural circuits extending from the retina, to retinorecipient nuclei in the midbrain and thalamus, to the cortex which work together to translate light information entering our eyes into a complex and dynamic spatio-temporal representation of the world. While the experience-dependent developmental refinement and mature function of neurons in each major stage of the vertebrate visual system have been extensively characterized, the contributions of the glial cells populating each region are comparatively understudied despite important findings demonstrating that they mediate crucial processes related to the development, function, and plasticity of the system. In this article we review the mechanisms for neuron-glia communication throughout the vertebrate visual system, as well as functional roles attributed to astrocytes and microglia in visual system development and processing. We will also discuss important aspects of glial function that remain unclear, integrating the knowns and unknowns about glia in the visual system to advance new hypotheses to guide future experimental work.

Visual experience is mediated through a relay of finely-tuned neural circuits extending from the retina, to retinorecipient nuclei in the midbrain and thalamus, to the cortex which work together to translate light information entering our eyes into a complex and dynamic spatio-temporal representation of the world. While the experience-dependent developmental refinement and mature function of neurons in each major stage of the vertebrate visual system have been extensively characterized, the contributions of the glial cells populating each region are comparatively understudied despite important findings demonstrating that they mediate crucial processes related to the development, function, and plasticity of the system. In this article we review the mechanisms for neuron-glia communication throughout the vertebrate visual system, as well as functional roles attributed to astrocytes and microglia in visual system development and processing. We will also discuss important aspects of glial function that remain unclear, integrating the knowns and unknowns about glia in the visual system to advance new hypotheses to guide future experimental work.

Glia Regulate the Development, Function, and Plasticity of the Visual System From Retina to Cortex

Stimulus-selective response plasticity (SRP) is a robust and lasting modification of primary visual cortex (V1) that occurs in response to exposure to novel visual stimuli. It is readily observed as a pronounced increase in the magnitude of visual evoked potentials (VEPs) recorded in response to phase-reversing grating stimuli in neocortical layer 4. The expression of SRP at the individual neuron level is equally robust, but the qualities vary depending on the neuronal type and how activity is measured. This form of plasticity is highly selective for stimulus features such as stimulus orientation, spatial frequency, and contrast. Several key insights into the significance and underlying mechanisms of SRP have recently been made. First, it occurs concomitantly and shares core mechanisms with behavioral habituation, indicating that SRP reflects the formation of long-term familiarity that can support recognition of innocuous stimuli. Second, SRP does not manifest within a recording session but only emerges after an off-line period of several hours that includes sleep. Third, SRP requires not only canonical molecular mechanisms of Hebbian synaptic plasticity within V1, but also the opposing engagement of two key subclasses of cortical inhibitory neuron: the parvalbumin- and somatostatin-expressing GABAergic interneurons. Fourth, pronounced shifts in the power of cortical oscillations from high frequency (gamma) to low frequency (alpha/beta) oscillations provide respective readouts of the engagement of these inhibitory neuronal subtypes following familiarization. In this article we will discuss the implications of these findings and the outstanding questions that remain to gain a deeper understanding of this striking form of experience-dependent plasticity.

Stimulus-selective response plasticity (SRP) is a robust and lasting modification of primary visual cortex (V1) that occurs in response to exposure to novel visual stimuli. It is readily observed as a pronounced increase in the magnitude of visual evoked potentials (VEPs) recorded in response to phase-reversing grating stimuli in neocortical layer 4. The expression of SRP at the individual neuron level is equally robust, but the qualities vary depending on the neuronal type and how activity is measured. This form of plasticity is highly selective for stimulus features such as stimulus orientation, spatial frequency, and contrast. Several key insights into the significance and underlying mechanisms of SRP have recently been made. First, it occurs concomitantly and shares core mechanisms with behavioral habituation, indicating that SRP reflects the formation of long-term familiarity that can support recognition of innocuous stimuli. Second, SRP does not manifest within a recording session but only emerges after an off-line period of several hours that includes sleep. Third, SRP requires not only canonical molecular mechanisms of Hebbian synaptic plasticity within V1, but also the opposing engagement of two key subclasses of cortical inhibitory neuron: the parvalbumin- and somatostatin-expressing GABAergic interneurons. Fourth, pronounced shifts in the power of cortical oscillations from high frequency (gamma) to low frequency (alpha/beta) oscillations provide respective readouts of the engagement of these inhibitory neuronal subtypes following familiarization. In this article we will discuss the implications of these findings and the outstanding questions that remain to gain a deeper understanding of this striking form of experience-dependent plasticity.

Stimulus-Selective Response Plasticity in Primary Visual Cortex: Progress and Puzzles

One of the most salient features defining modern humans is our remarkable cognitive capacity, which is unrivaled by any other species. Although we still lack a complete understanding of how the human brain gives rise to these unique abilities, the past several decades have witnessed significant progress in uncovering some of the genetic, cellular, and molecular mechanisms shaping the development and function of the human brain. These features include an expansion of brain size and in particular cortical expansion, distinct physiological properties of human neurons, and modified synaptic development. Together they specify the human brain as a large primate brain with a unique underlying neuronal circuit architecture. Here, we review some of the known human-specific features of neuronal connectivity, and we outline how novel insights into the human genome led to the identification of human-specific genetic modifiers that played a role in the evolution of human brain development and function. Novel experimental paradigms are starting to provide a framework for understanding how the emergence of these human-specific genomic innovations shaped the structure and function of neuronal circuits in the human brain.

One of the most salient features defining modern humans is our remarkable cognitive capacity, which is unrivaled by any other species. Although we still lack a complete understanding of how the human brain gives rise to these unique abilities, the past several decades have witnessed significant progress in uncovering some of the genetic, cellular, and molecular mechanisms shaping the development and function of the human brain. These features include an expansion of brain size and in particular cortical expansion, distinct physiological properties of human neurons, and modified synaptic development. Together they specify the human brain as a large primate brain with a unique underlying neuronal circuit architecture. Here, we review some of the known human-specific features of neuronal connectivity, and we outline how novel insights into the human genome led to the identification of human-specific genetic modifiers that played a role in the evolution of human brain development and function. Novel experimental paradigms are starting to provide a framework for understanding how the emergence of these human-specific genomic innovations shaped the structure and function of neuronal circuits in the human brain.

Genetic Mechanisms Underlying the Evolution of Connectivity in the Human Cortex

Astrocytes are non-neuronal cells that regulate synapses, neuronal circuits, and behavior. Astrocytes ensheath neuronal synapses to form the tripartite synapse where astrocytes influence synapse formation, function, and plasticity. Beyond the synapse, recent research has revealed that astrocyte influences on the nervous system extend to the modulation of neuronal circuitry and behavior. Here we review recent findings on the active role of astrocytes in behavioral modulation with a focus on in vivo studies, primarily in mice. Using tools to acutely manipulate astrocytes, such as optogenetics or chemogenetics, studies reviewed here have demonstrated a causal role for astrocytes in sleep, memory, sensorimotor behaviors, feeding, fear, anxiety, and cognitive processes like attention and behavioral flexibility. Current tools and future directions for astrocyte-specific manipulation, including methods for probing astrocyte heterogeneity, are discussed. Understanding the contribution of astrocytes to neuronal circuit activity and organismal behavior will be critical toward understanding how nervous system function gives rise to behavior.

Astrocytes are non-neuronal cells that regulate synapses, neuronal circuits, and behavior. Astrocytes ensheath neuronal synapses to form the tripartite synapse where astrocytes influence synapse formation, function, and plasticity. Beyond the synapse, recent research has revealed that astrocyte influences on the nervous system extend to the modulation of neuronal circuitry and behavior. Here we review recent findings on the active role of astrocytes in behavioral modulation with a focus on in vivo studies, primarily in mice. Using tools to acutely manipulate astrocytes, such as optogenetics or chemogenetics, studies reviewed here have demonstrated a causal role for astrocytes in sleep, memory, sensorimotor behaviors, feeding, fear, anxiety, and cognitive processes like attention and behavioral flexibility. Current tools and future directions for astrocyte-specific manipulation, including methods for probing astrocyte heterogeneity, are discussed. Understanding the contribution of astrocytes to neuronal circuit activity and organismal behavior will be critical toward understanding how nervous system function gives rise to behavior.

From Synapses to Circuits, Astrocytes Regulate Behavior

Research on endocannabinoid signaling has greatly advanced our understanding of how the excitability of neural circuits is controlled in health and disease. In general, endocannabinoid signaling at excitatory synapses suppresses excitability by inhibiting glutamate release, while that at inhibitory synapses promotes excitability by inhibiting GABA release, although there are some exceptions in genetically epileptic animal models. In the epileptic brain, the physiological distributions of endocannabinoid signaling molecules are disrupted during epileptogenesis, contributing to the occurrence of spontaneous seizures. However, it is still unknown how endocannabinoid signaling changes during seizures and how the redistribution of endocannabinoid signaling molecules proceeds during epileptogenesis. Recent development of cannabinoid sensors has enabled us to investigate endocannabinoid signaling in much greater spatial and temporal details than before. Application of cannabinoid sensors to epilepsy research has elucidated activity-dependent changes in endocannabinoid signaling during seizures. Furthermore, recent endocannabinoid research has paved the way for the clinical use of cannabidiol for the treatment of refractory epilepsy, such as Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Cannabidiol significantly reduces seizures and is considered to have comparable tolerability to conventional antiepileptic drugs. In this article, we introduce recent advances in research on the roles of endocannabinoid signaling in epileptic seizures and discuss future directions.

Research on endocannabinoid signaling has greatly advanced our understanding of how the excitability of neural circuits is controlled in health and disease. In general, endocannabinoid signaling at excitatory synapses suppresses excitability by inhibiting glutamate release, while that at inhibitory synapses promotes excitability by inhibiting GABA release, although there are some exceptions in genetically epileptic animal models. In the epileptic brain, the physiological distributions of endocannabinoid signaling molecules are disrupted during epileptogenesis, contributing to the occurrence of spontaneous seizures. However, it is still unknown how endocannabinoid signaling changes during seizures and how the redistribution of endocannabinoid signaling molecules proceeds during epileptogenesis. Recent development of cannabinoid sensors has enabled us to investigate endocannabinoid signaling in much greater spatial and temporal details than before. Application of cannabinoid sensors to epilepsy research has elucidated activity-dependent changes in endocannabinoid signaling during seizures. Furthermore, recent endocannabinoid research has paved the way for the clinical use of cannabidiol for the treatment of refractory epilepsy, such as Dravet syndrome, Lennox-Gastaut syndrome and tuberous sclerosis complex. Cannabidiol significantly reduces seizures and is considered to have comparable tolerability to conventional antiepileptic drugs. In this article, we introduce recent advances in research on the roles of endocannabinoid signaling in epileptic seizures and discuss future directions.