Associative and sensorimotor cortico‐basal ganglia circuit roles in effects of abused drugs

The mammalian forebrain is characterized by the presence of several parallel cortico‐basal ganglia circuits that shape the learning and control of actions. Among these are the associative, limbic and sensorimotor circuits. The function of all of these circuits has now been implicated in responses to drugs of abuse, as well as drug seeking and drug taking. While the limbic circuit has been most widely examined, key roles for the other two circuits in control of goal‐directed and habitual instrumental actions related to drugs of abuse have been shown. In this review we describe the three circuits and effects of acute and chronic drug exposure on circuit physiology. Our main emphasis is on drug actions in dorsal striatal components of the associative and sensorimotor circuits. We then review key findings that have implicated these circuits in drug seeking and taking behaviors, as well as drug use disorders. Finally, we consider different models describing how the three cortico‐basal ganglia circuits become involved in drug‐related behaviors. This topic has implications for drug use disorders and addiction, as treatments that target the balance between the different circuits may be useful for reducing excessive substance use.     

Microcircuits in visual cortex

The microcircuitry of the neocortex is bewildering in its anatomical detail, but seen through the filters of physiology, some simple circuits have been suggested. Intensive investigations of the cortical representation of orientation, however, show how difficult it is to achieve any consensus on what the circuits are, how they develop, and how they work. New developments in modeling allied with powerful experimental tools are changing this. Experimental work combining optical imaging with anatomy and physiology has revealed a rich local cortical circuitry. Whereas older models of cortical circuits have concentrated on simple 'feedforward' circuits, newer theoretical work has explored more the role of the recurrent cortical circuits, which are more realistic representations of the actual circuits and are computationally richer.     

Emergence of complex behaviour from simple circuit structures

The set of (feedback) circuits of a complex system is the machinery that allows the system to be aware of the levels of its crucial constituents. Circuits can be identified without ambiguity from the elements of the Jacobian matrix of the system. There are two types of circuits: positive if they comprise an even number of negative interactions, negative if this number is odd. The two types of circuits play deeply different roles: negative circuits are required for homeostasis, with or without oscillations, positive circuits are required for multistationarity, and hence, in biology, for differentiation and memory. In non-linear systems, a circuit can positive or negative (an 'ambiguous circuit', depending on the location in phase space. Full circuits are those circuits (or unions of disjoint circuits) that imply all the variables of the system. There is a tight relation between circuits and steady states. Each full circuit, if isolated, generates steady state(s) whose nature (eigenvalues) is determined by the structure of the circuit. Multistationarity requires the presence of at least two full circuits of opposite Eisenfeld signs, or else, an ambiguous circuit. We show how a significant part of the dynamical behaviour of a system can be predicted by a mere examination of its Jacobian matrix. We also show how extremely complex dynamics can be generated by such simple logical structures as a single (full and ambiguous) circuit.     

Assembly of motor circuits in the spinal cord: driven to function by genetic and experience-dependent mechanisms

Motor circuits in the spinal cord integrate information from various sensory and descending pathways to control appropriate motor behavior. Recent work has revealed that target-derived retrograde signaling mechanisms act to influence sequential assembly of motor circuits through combinatorial action of genetic and experience-driven programs. These parallel activities imprint somatotopic information at the level of the spinal cord in precisely interconnected circuits and equip animals with motor circuits capable of reacting to changing demands throughout life.     

Invertebrate central pattern generator circuits

There are now a reasonable number of invertebrate central pattern generator (CPG) circuits described in sufficient detail that a mechanistic explanation of how they work is possible. These small circuits represent the best-understood neural circuits with which to investigate how cell-to-cell synaptic connections and individual channel conductances combine to generate rhythmic and patterned output. In this review, some of the main lessons that have appeared from this analysis are discussed and concrete examples of circuits ranging from single phase to multiple phase patterns are described. While it is clear that the cellular components of any CPG are basically the same, the topology of the circuits have evolved independently to meet the particular motor requirements of each individual organism and only a few general principles of circuit operation have emerged. The principal usefulness of small systems in relation to the brain is to demonstrate in detail how cellular infrastructure can be used to generate rhythmicity and form specialized patterns in a way that may suggest how similar processes might occur in more complex systems. But some of the problems and challenges associated with applying data from invertebrate preparations to the brain are also discussed. Finally, I discuss why it is useful to have well-defined circuits with which to examine various computational models that can be validated experimentally and possibly applied to brain circuits when the details of such circuits become available.     

Inspiring song: The role of respiratory circuitry in the evolution of vertebrate vocal behavior

Vocalization is a common means of communication across vertebrates, but the evolutionary origins of the neural circuits controlling these behaviors are not clear. Peripheral mechanisms of sound production vary widely: fish produce sounds with a swimbladder or pectoral fins; amphibians, reptiles, and mammalians vocalize using a larynx; birds vocalize with a syrinx. Despite the diversity of vocal effectors across taxa, there are many similarities in the neural circuits underlying the control of these organs. Do similarities in vocal circuit structure and function indicate that vocal behaviors first arose in a single common ancestor, or have similar neural circuits arisen independently multiple times during evolution? In this review, we describe the hindbrain circuits that are involved in vocal production across vertebrates. Given that vocalization depends on respiration in most tetrapods, it is not surprising that vocal and respiratory hindbrain circuits across distantly related species are anatomically intermingled and functionally linked. Such vocal‐respiratory circuit integration supports the hypothesis that vocal evolution involved the expansion and functional diversification of breathing circuits. Recent phylogenetic analyses, however, suggest vocal behaviors arose independently in all major tetrapod clades, indicating that similarities in vocal control circuits are the result of repeated co‐options of respiratory circuits in each lineage. It is currently unknown whether vocal circuits across taxa are made up of homologous neurons, or whether vocal neurons in each lineage arose from developmentally and evolutionarily distinct progenitors. Integrative comparative studies of vocal neurons across brain regions and taxa will be required to distinguish between these two scenarios.     

Using imaging and genetics in zebrafish to study developing spinal circuits in vivo

Imaging and molecular approaches are perfectly suited to young, transparent zebrafish (Danio rerio), where they have allowed novel functional studies of neural circuits and their links to behavior. Here, we review cutting-edge optical and genetic techniques used to dissect neural circuits in vivo and discuss their application to future studies of developing spinal circuits using living zebrafish. We anticipate that these experiments will reveal general principles governing the assembly of neural circuits that control movements.     

The cortex as a central pattern generator

Vertebrate spinal cord and brainstem central pattern generator (CPG) circuits share profound similarities with neocortical circuits. CPGs can produce meaningful functional output in the absence of sensory inputs. Neocortical circuits could be considered analogous to CPGs as they have rich spontaneous dynamics that, similar to CPGs, are powerfully modulated or engaged by sensory inputs, but can also generate output in their absence. We find compelling evidence for this argument at the anatomical, biophysical, developmental, dynamic and pathological levels of analysis. Although it is possible that cortical circuits are particularly plastic types of CPG ('learning CPGs'), we argue that present knowledge about CPGs is likely to foretell the basic principles of the organization and dynamic function of cortical circuits.     

A spectrum of modularity in multi‐functional gene circuits

A major challenge in systems biology is to understand the relationship between a circuit's structure and its function, but how is this relationship affected if the circuit must perform multiple distinct functions within the same organism? In particular, to what extent do multi‐functional circuits contain modules which reflect the different functions? Here, we computationally survey a range of bi‐functional circuits which show no simple structural modularity: They can switch between two qualitatively distinct functions, while both functions depend on all genes of the circuit. Our analysis reveals two distinct classes: hybrid circuits which overlay two simpler mono‐functional sub‐circuits within their circuitry, and emergent circuits, which do not. In this second class, the bi‐functionality emerges from more complex designs which are not fully decomposable into distinct modules and are consequently less intuitive to predict or understand. These non‐intuitive emergent circuits are just as robust as their hybrid counterparts, and we therefore suggest that the common bias toward studying modular systems may hinder our understanding of real biological circuits.     

Development of larval motor circuits in Drosophila

How are functional neural circuits formed during development? Despite recent advances in our understanding of the development of individual neurons, little is known about how complex circuits are assembled to generate specific behaviors. Here, we describe the ways in which Drosophila motor circuits serve as an excellent model system to tackle this problem. We first summarize what has been learned during the past decades on the connectivity and development of component neurons, in particular motor neurons and sensory feedback neurons. We then review recent progress in our understanding of the development of the circuits as well as studies that apply optogenetics and other innovative techniques to dissect the circuit diagram. New approaches using Drosophila as a model system are now making it possible to search for developmental rules that regulate the construction of neural circuits.     

New insights from small rhythmic circuits

Small rhythmic circuits, such as those found in invertebrates, have provided fundamental insights into how circuit dynamics depend on individual neuronal and synaptic properties. Degenerate circuits are those with different network parameters and similar behavior. New work on degenerate circuits and their modulation illustrates some of the rules that help maintain stable and robust circuit function despite environmental perturbations. Advances in neuropeptide isolation and identification provide enhanced understanding of the neuromodulation of circuits for behavior. The advent of molecular studies of mRNA expression provides new insight into animal-to-animal variability and the homeostatic regulation of excitability in neurons and networks.     

Constraint and Contingency in Multifunctional Gene Regulatory Circuits

Gene regulatory circuits drive the development, physiology, and behavior of organisms from bacteria to humans. The phenotypes or functions of such circuits are embodied in the gene expression patterns they form. Regulatory circuits are typically multifunctional, forming distinct gene expression patterns in different embryonic stages, tissues, or physiological states. Any one circuit with a single function can be realized by many different regulatory genotypes. Multifunctionality presumably constrains this number, but we do not know to what extent. We here exhaustively characterize a genotype space harboring millions of model regulatory circuits and all their possible functions. As a circuit''s number of functions increases, the number of genotypes with a given number of functions decreases exponentially but can remain very large for a modest number of functions. However, the sets of circuits that can form any one set of functions becomes increasingly fragmented. As a result, historical contingency becomes widespread in circuits with many functions. Whether a circuit can acquire an additional function in the course of its evolution becomes increasingly dependent on the function it already has. Circuits with many functions also become increasingly brittle and sensitive to mutation. These observations are generic properties of a broad class of circuits and independent of any one circuit genotype or phenotype.     

合成基因线路规模化设计面临的挑战

随着合成基因线路规模的增加,传统的合成基因线路设计思路的瓶颈逐渐凸显,许多之前被忽略的因素对大规模基因线路的性能可能造成显著影响,这对合成基因线路的设计带来了新的挑战。本文重点梳理了基因表达噪声和竞争效应两方面对基因线路性能的影响,阐释了二者间的紧密联系,并基于理性设计的思路,从模拟-数字运算设计、网络拓扑设计、基因线路中的信息传递理论和动态信号等方面,归纳总结了解决这些问题的潜在方案,并展望了规模化合成基因线路理性设计的未来发展方向。     

Imaging in systems biology

Most systems biology approaches involve determining the structure of biological circuits using genomewide "-omic" analyses. Yet imaging offers the unique advantage of watching biological circuits function over time at single-cell resolution in the intact animal. Here, we discuss the power of integrating imaging tools with more conventional -omic approaches to analyze the biological circuits of microorganisms, plants, and animals.     

Prominent Inhibitory Projections Guide Sensorimotor Computation: An Invertebrate Perspective

From single‐cell organisms to complex neural networks, all evolved to provide control solutions to generate context‐ and goal‐specific actions. Neural circuits performing sensorimotor computation to drive navigation employ inhibitory control as a gating mechanism as they hierarchically transform (multi)sensory information into motor actions. Here, the focus is on this literature to critically discuss the proposition that prominent inhibitory projections form sensorimotor circuits. After reviewing the neural circuits of navigation across various invertebrate species, it is argued that with increased neural circuit complexity and the emergence of parallel computations, inhibitory circuits acquire new functions. The contribution of inhibitory neurotransmission for navigation goes beyond shaping the communication that drives motor neurons, and instead includes encoding of emergent sensorimotor representations. A mechanistic understanding of the neural circuits performing sensorimotor computations in invertebrates will unravel the minimum circuit requirements driving adaptive navigation.     

Dream contents and failing memories

Mentation during sleep states is thought to originate in an activation of brain circuits that encode inherited and experiential memories. Spontaneous degradation of the strengths of synapses occurs in all brain circuits because of "turnover" of molecules essential for synaptic function. In circuits employed frequently during waking, synaptic strengths are refreshed and maintained in their dedicated or functional ranges largely through use, by virtue of activity-dependent synaptic plasticity. In circuits employed infrequently during waking, synaptic strengths are refreshed largely during sleep, by circuit activations induced by spontaneous, self-generated, largely low-frequency brain waves, also by virtue of activity-dependent synaptic plasticity. The outputs of circuits activated during sleep do not necessarily rise to the level of 'unconscious' awareness. Such an absence of awareness of the outputs of individual circuits, that is, an absence of dreaming, is proposed to be the primitive condition in animals that sleep. On the other hand, temporal binding of these outputs is accompanied by the thoughts and perceptions of dreams, which is proposed to be the advanced condition. Linking or serial ordering of otherwise 'static' thoughts and perceptions gives rise to continuous, often narrative and veridical, dreams. In all cases, dream contents are derived from the memories--not necessarily veridical--encoded in the reinforced circuitry. In the absence of synaptic strength refreshments during sleep, synaptic strengths in infrequently used circuits would weaken and the circuits would become incompetent, with their encoded memories degraded or lost. Maintenance of synaptic strengths in infrequently used circuitry during sleep apparently does not always achieve perfection. Weakened synapses begin to occur in circuits in appreciable numbers in children after the age of about 5 years. When these 'incompetent' circuits (with weakened synapses) are activated during sleep, there are minimal influences on dream contents, namely, distortions that make some objects, such as animals, faces, and scenes, unrecognizable. As weakened synapses increase in numbers with age, the numbers of distorted objects in dreams also increase. In adults, people in as many as 80% of dreams may be unrecognizable. Besides the normal weakening of synaptic strengths, some synapses become defective, in consequence of deleterious, adventitious, exogenous influences, for example, radiation. As these faulty synapses accumulate in old memories, activation of circuits incorporating them during sleep leads to dreams with incoherent, bizarre, or impossible contents. The infrequent activation of such old, incompetent circuits in some waking conditions leads to false memories, delusions, or hallucinations.     

Brain estrogen signaling effects acute modulation of acoustic communication behaviors: A working hypothesis

Although estrogens are widely considered circulating “sex steroid hormones” typically associated with female reproduction, recent evidence suggests that estrogens can act as local modulators of brain circuits in both males and females. The functional implications of this newly characterized estrogen signaling system have begun to emerge. This essay summarizes evidence in support of the hypothesis that the rapid production of estrogens in brain circuits can drive acute changes in both the production and perception of acoustic communication behaviors. These studies have revealed two fundamental neurobiological concepts: (1) estrogens can be locally produced in brain circuits, independent of levels in nearby circuits and in the circulation and (2) estrogens can have very rapid effects within these brain circuits to modulate social vocalizations, acoustic processing, and sensorimotor integration. This vertebrate‐wide span of research, including vocalizing fishes, amphibians, and birds, emphasizes the importance of comparative model systems in understanding principles of neurobiology.     

Synthetic genetic circuits for programmable biological functionalities

Living organisms evolve complex genetic networks to interact with the environment. Due to the rapid development of synthetic biology, various modularized genetic parts and units have been identified from these networks. They have been employed to construct synthetic genetic circuits, including toggle switches, oscillators, feedback loops and Boolean logic gates. Building on these circuits, complex genetic machines with capabilities in programmable decision-making could be created. Consequently, these accomplishments have led to novel applications, such as dynamic and autonomous modulation of metabolic networks, directed evolution of biological units, remote and targeted diagnostics and therapies, as well as biological containment methods to prevent release of engineered microorganisms and genetic materials. Herein, we outline the principles in genetic circuit design that have initiated a new chapter in transforming concepts to realistic applications. The features of modularized building blocks and circuit architecture that facilitate realization of circuits for a variety of novel applications are discussed. Furthermore, recent advances and challenges in employing genetic circuits to impart microorganisms with distinct and programmable functionalities are highlighted. We envision that this review gives new insights into the design of synthetic genetic circuits and offers a guideline for the implementation of different circuits in various aspects of biotechnology and bioengineering.     

Implementation Considerations,Not Topological Differences,Are the Main Determinants of Noise Suppression Properties in Feedback and Incoherent Feedforward Circuits

Biological systems use a variety of mechanisms to deal with the uncertain nature of their external and internal environments. Two of the most common motifs employed for this purpose are the incoherent feedforward (IFF) and feedback (FB) topologies. Many theoretical and experimental studies suggest that these circuits play very different roles in providing robustness to uncertainty in the cellular environment. Here, we use a control theoretic approach to analyze two common FB and IFF architectures that make use of an intermediary species to achieve regulation. We show the equivalence of both circuits topologies in suppressing static cell-to-cell variations. While both circuits can suppress variations due to input noise, they are ineffective in suppressing inherent chemical reaction stochasticity. Indeed, these circuits realize comparable improvements limited to a modest 25% variance reduction in best case scenarios. Such limitations are attributed to the use of intermediary species in regulation, and as such, they persist even for circuit architectures that combine both IFF and FB features. Intriguingly, while the FB circuits are better suited in dealing with dynamic input variability, the most significant difference between the two topologies lies not in the structural features of the circuits, but in their practical implementation considerations.     

Beyond the connectome: how neuromodulators shape neural circuits

Powerful ultrastructural tools are providing new insights into neuronal circuits, revealing a wealth of anatomically-defined synaptic connections. These wiring diagrams are incomplete, however, because functional connectivity is actively shaped by neuromodulators that modify neuronal dynamics, excitability, and synaptic function. Studies of defined neural circuits in crustaceans, C. elegans, Drosophila, and the vertebrate retina have revealed the ability of modulators and sensory context to reconfigure information processing by changing the composition and activity of functional circuits. Each ultrastructural connectivity map encodes multiple circuits, some of which are active and some of which are latent at any given time.