Circuit Neuroscience Research Articles

The Budding Neuroscience of Ant Social Behavior.

Ant physiology has been fashioned by 100 million years of social evolution. Ants perform many sophisticated social and collective behaviors yet possess nervous systems similar in schematic and scale to that of the fruit fly Drosophila melanogaster, a popular solitary model organism. Ants are thus attractive complementary subjects to investigate adaptations pertaining to complex social behaviors that are absent in flies. Despite research interest in ant behavior and the neurobiological foundations of sociality more broadly, our understanding of the ant nervous system is incomplete. Recent technical advances have enabled cutting-edge investigations of the nervous system in a fashion that is less dependent on model choice, opening the door for mechanistic social insect neuroscience. In this review, we revisit important aspects of what is known about the ant nervous system and behavior, and we look forward to how functional circuit neuroscience in ants will help us understand what distinguishes solitary animals from highly social ones.

The Emerging Role of Brain Mitochondria in Fear and Anxiety.

The functional complexity of brain circuits underlies the broad spectrum of behaviors, cognitive functions, and their associated disorders. Mitochondria, traditionally known for their role in cellular energy metabolism, are increasingly recognized as central to brain function and behavior. This review examines how mitochondria are pivotal in linking cellular energy processes with the functioning of neural circuits that govern fear and anxiety. Following an introductory section in which we summarize current knowledge about fear and anxiety neural circuits, we provide a brief summary of mitochondria fundamental roles (e.g., from energy production and calcium buffering to their involvement in reactive oxygen species (ROS) generation, mitochondrial dynamics, and signaling), particularly emphasizing their contribution to synaptic plasticity, neurodevelopment, and stress response mechanisms. The review's core focuses on the current state of knowledge regarding how mitochondrial function and dysfunction impact the neural substrates of fear and anxiety. Furthermore, we explore the implications of mitochondrial alterations in the context of posttraumatic stress disorder (PTSD) and anxiety disorders, underscoring the potential of mitochondrial pathways as new therapeutic targets. Integrating insights from genetic, biochemical, neurobiological, behavioral, and clinical studies, we propose a model in which mitochondrial function is critical for regulating the neural circuits that underpin fear and anxiety behaviors, highlighting how mitochondrial dysfunction can lead to their pathological manifestations. This integration emphasizes the potential for developing novel treatments targeting the biological roots of fear, anxiety, and related disorders. By merging mitochondrial biology with behavioral and circuit neuroscience, we enrich our neurobiological understanding of fear and anxiety, uncovering promising avenues for therapeutic intervention.

The cerebellum

The cerebellum, that stripey 'little brain', sits at the back of your head, under your visual cortex, and contains more than half of the neurons in your entire nervous system. The cerebellum is highly conserved across vertebrates, and its evolutionary expansion has tended to proceed in concert with expansion of cerebral cortex. The crystalline neuronal architecture of the cerebellar cortex was first described by Cajal a century ago, and its functional connectivity was elucidated in exquisite anatomical and physiological detail by the mid-20th century. The ability to clearly identify molecularly distinct cerebellar cell types that constitute discrete circuit elements is perhaps unparalleled among brain areas, even within the context of modern circuit neuroscience. Although traditionally thought of as primarily a motor structure, the cerebellum is highly interconnected with diverse brain areas and, as I will explain in this Primer, is well-poised to influence a wide range of motor and cognitive functions.

Combining long-term circuit mapping and network transcriptomics with SiR-N2c.

An exciting frontier in circuit neuroscience lies at the intersection between neural network mapping and single-cell genomics. Monosynaptic rabies viruses provide a promising platform for the merger of circuit mapping methods with -omics approaches. However, three key limitations have hindered the extraction of physiologically meaningful gene expression profiles from rabies-mapped circuits: inherent viral cytotoxicity, high viral immunogenicity and virus-induced alteration of cellular transcriptional regulation. These factors alter the transcriptional and translational profiles of infected neurons and their neighboring cells. To overcome these limitations we applied a self-inactivating genomic modification to the less immunogenic rabies strain, CVS-N2c, to generate a self-inactivating CVS-N2c rabies virus (SiR-N2c). SiR-N2c not only eliminates undesired cytotoxic effects but also substantially reduces gene expression alterations in infected neurons and dampens the recruitment of innate and acquired immune responses, thus enabling open-ended interventions on neural networks and their genetic characterization using single-cell genomic approaches.

Hypocretins (orexins): The ultimate translational neuropeptides.

The hypocretins (Hcrts), also known as orexins, are two neuropeptides produced exclusively in the lateral hypothalamus. They act on two specific receptors that are widely distributed across the brain and involved in a myriad of neurophysiological functions that include sleep, arousal, feeding, reward, fear, anxiety and cognition. Hcrt cell loss in humans leads to narcolepsy with cataplexy (narcolepsy type 1), a disorder characterized by intrusions of sleep into wakefulness, demonstrating that the Hcrt system is nonredundant and essential for sleep/wake stability. The causal link between Hcrts and arousal/wakefulness stabilisation has led to the development of a new class of drugs, Hcrt receptor antagonists to treat insomnia, based on the assumption that blocking orexin-induced arousal will facilitate sleep. This has been clinically validated: currently, two Hcrt receptor antagonists are approved to treat insomnia (suvorexant and lemborexant), with a New Drug Application recently submitted to the US Food and Drug Administration for a third drug (daridorexant). Other therapeutic applications under investigation include reduction of cravings in substance-use disorders and prevention of neurodegenerative disorders such as Alzheimer's disease, given the apparent bidirectional relationship between poor sleep and worsening of the disease. Circuit neuroscience findings suggest that the Hcrt system is a hub that integrates diverse inputs modulating arousal (e.g., circadian rhythms, metabolic status, positive and negative emotions) and conveys this information to multiple output regions. This neuronal architecture explains the wealth of physiological functions associated with Hcrts and highlights the potential of the Hcrt system as a therapeutic target for a number of disorders. We discuss present and future possible applications of drugs targeting the Hcrt system for the treatment of circuit-related neuropsychiatric and neurodegenerative conditions.

A low-cost open-source 5-choice operant box system optimized for electrophysiology and optophysiology in mice

Operant boxes enable the application of complex behavioural paradigms to support circuit neuroscience and drug discovery research. However, commercial operant box systems are expensive and often not optimised for combining behaviour with neurophysiology. Here we introduce a fully open-source Python-based operant-box system in a 5-choice design (pyOS-5) that enables assessment of multiple cognitive and affective functions. It is optimized for fast turn-over between animals, and for testing of tethered mice for simultaneous physiological recordings or optogenetic manipulation. For reward delivery, we developed peristaltic and syringe pumps based on a stepper motor and 3D-printed parts. Tasks are specified using a Python-based syntax implemented on custom-designed printed circuit boards that are commercially available at low cost. We developed an open-source graphical user interface (GUI) and task definition scripts to conduct assays assessing operant learning, attention, impulsivity, working memory, or cognitive flexibility, alleviating the need for programming skills of the end user. All behavioural events are recorded with millisecond resolution, and TTL-outputs and -inputs allow straightforward integration with physiological recordings and closed-loop manipulations. This combination of features realizes a cost-effective, nose-poke-based operant box system that allows reliable circuit-neuroscience experiments investigating correlates of cognition and emotion in large cohorts of subjects.

Enhancing scientific dissemination in neuroscience via preprint peer-review: "Peer Community In Circuit Neuroscience"

The dissemination of scientific results and new technologies in biomedical science is rapidly evolving from an exclusive and fee-oriented publishing system towards more open, free and independent strategies for sharing knowledge. In this context, preprint servers such as bioRxiv answer a very real scientific need by enabling the rapid, free and easy dissemination of findings, regardless of whether these are novel, replicated, or even showcasing negative results. Currently, thousands of manuscripts are being shared via bioRxiv each month, and neuroscience is the largest and fastest growing subject category. However, commenting on bioRxiv is declining and no structured scientific validation such as peer-review is currently available. The Peer Community In (PCI) platform addresses this unmet need by facilitating the rigorous evaluation and validation of preprints, and PCI Circuit Neuroscience (PCI C Neuro) aims to develop and extend this tool for the neuroscience community. Here we discuss PCI C Neuro’s mission, how it works, and why it is an essential initiative in this new era of open science.

Expanding the Optogenetics Toolkit by Topological Inversion of Rhodopsins

Targeted manipulation of activity in specific populations of neurons is important for investigating the neural circuit basis of behavior. Optogenetic approaches using light-sensitive microbial rhodopsins have permitted manipulations to reach a level of temporal precision that is enabling functional circuit dissection. As demand for more precise perturbations to serve specific experimental goals increases, a palette of opsins with diverse selectivity, kinetics, and spectral properties will be needed. Here, we introduce a novel approach of "topological engineering"-inversion of opsins in the plasma membrane-and demonstrate that it can produce variants with unique functional properties of interest for circuit neuroscience. In one striking example, inversion of a Channelrhodopsin variant converted it from a potent activator into a fast-acting inhibitor that operates as a cation pump. Our findings argue that membrane topology provides a useful orthogonal dimension of protein engineering that immediately permits as much as a doubling of the available toolkit.

Assessing Individual Neuronal Activity Across the Intact Brain: Using Hybridization Chain Reaction (HCR) to Detect Arc mRNA Localized to the Nucleus in Volumes of Cleared Brain Tissue.

Arc (activity-regulated cytoskeleton-associated protein) is an immediate early gene that may be used to label recently active neurons. Arc is transcribed following neuronal activity, and its mRNA is then rapidly transported to dendrites. This feature allows nuclear-localized Arc mRNA to define ensembles of recently active neurons in systems or circuit neuroscience. However, typical in situ hybridization techniques severely constrain the thickness of the tissue specimen (typically 20-µm brain slices). Here, we describe a protocol for visualizing intranuclear Arc mRNA in large (4 × 4 × 3 mm) volumes of intact mouse brain tissue. We combined a tissue clearing protocol (iDISCO+) with an advanced in situ hybridization technique (hybridization chain reaction [HCR]) to detect nuclear-localized Arc mRNA in whole, intact brain regions without the need for brain sectioning or reconstruction. We successfully applied this protocol to image ensembles of neurons of the basolateral amygdala in mice that are active following the recall of a conditioned fear memory. © 2018 by John Wiley & Sons, Inc.

The Mind Bending Quest for Cognitive Enhancers.

Adequate cognitive functioning is essential for daily activities. When there is an insult to the brain, cognitive abilities can suffer, which, in turn, produce substantial medical and functional impairment. Advances in neurobiology, circuit neuroscience, and clinical assessment technology are converging in a manner that holds promise for the development of new pharmacological agents for cognitive enhancement in neuropsychiatric disease.

3D object retrieval in an atlas of neuronal structures

Circuit neuroscience tries to solve one of the most challenging questions in biology: How does the brain work? An important step toward an answer to this question is to gather detailed knowledge about the neuronal circuits of the model organism Drosophila melanogaster. Geometric representations of neuronal objects of the Drosophila are acquired using molecular genetic methods, confocal microscopy, nonrigid registration and segmentation. These objects are integrated into a constantly growing common atlas. The comparison of new segmented neuronal objects to already known neuronal structures is a frequent task, which evolves with a growing amount of data into a bottleneck of the knowledge discovery process. Thus, the exploration of the atlas by means of domain specific similarity measures becomes a pressing need. To enable similarity based retrieval of neuronal objects, we defined together with domain experts tailored dissimilarity measures for each of the three typical neuronal structures cell body, projection, and arborization. Moreover, we defined the neuron enhanced similarity for projections and arborizations. According to domain experts, the developed system has big advantages for all tasks, which involve extensive data exploration.

Circuit neuroscience: the road ahead

OPINION article Front. Neurosci., 01 August 2008 Volume 2 - 2008 | https://doi.org/10.3389/neuro.01.017.2008