Calcium signaling in neuronal development

The development of the nervous system involves the generation of a stunningly diverse array of neuronal subtypes that enable complex information processing and behavioral outputs. Deciphering how the nervous system acquires and interprets information and orchestrates behaviors will be greatly enhanced by the identification of distinct neuronal circuits and by an understanding of how these circuits are formed, changed, and/or maintained over time. Addressing these challenging questions depends in part on the ability to accurately identify and characterize the unique neuronal subtypes that comprise individual circuits. Distinguishing characteristics of neuronal subgroups include but are not limited to neurotransmitter phenotype, dendritic morphology, the identity of synaptic partners, and the expression of constellations of subgroup-specific proteins, including ion channel subtypes.     

Motor program selection in simple model systems

In recent years, studies of molluscan and crustacean feeding circuits have greatly expanded our knowledge of how the nervous system selects specific behaviors. Increasing use of neurobehavioral studies, and examination of the roles of identified command-like or influential neurons have narrowed the gap between knowledge of circuit connectivity and understanding of the normal behavioral functions of these circuits.     

Behavioral plasticity in C. elegans: paradigms,circuits, genes

Life in the soil is an intellectual and practical challenge that the nematode Caenorhabditis elegans masters by utilizing 302 neurons. The nervous system assembled by these 302 neurons is capable of executing a variety of behaviors, some of respectable complexity. The simplicity of the nervous system, its thoroughly characterized structure, several sets of well-defined behaviors, and its genetic amenability combined with its isogenic background make C. elegans an attractive model organism to study the genetics of behavior. This review describes several behavioral plasticity paradigms in C. elegans and their underlying neuronal circuits and then goes on to review the forward genetic analysis that has been undertaken to identify genes involved in the execution of these behaviors. Lastly, the review outlines how reverse genetics and genomic approaches can guide the analysis of the role of genes in behavior and why and how they will complement the forward genetic analysis of behavior.     

Modulation of circuits underlying rhythmic behaviors

Summary What have we learned about behavior from neuromodulatory studies of the crustacean stomatogastric system? The emphasis of this paper has been on the analysis of one single class of behaviors (rhythmic) in terms of microcircuitry (synaptic connections between identified neurons). But in the general case, all behaviors result from the generation of spatio-temporal patterns by the central nervous system. How individual nerve cells interact with each other to produce such patterns is of fundamental interest. We know from work on simple networks that it is possible to link the circuitry of the nervous system with behavior in a precise way, and that instead of a large number of dedicated circuits, behaviors can be altered by chemically adjusting the functional properties of the neuronal elements. One circuit can be configured to perform a variety of different behaviors by activating neurons which contain neuromodulatory substances or in response to neurohormones circulating in the hemolymph. At present we know only a few of the ways neuromodulatory neurons are triggered to release their contents onto the neurons making up CPGs.The findings described here raise many questions. What are the parameters which control the distribution of neuromodulatory substances throughout the nervous system? What happens when more than one neuromodulator is present? At the cellular level, what mechanisms are involved in transforming each neuron from one functional state to another, and then how does the entire constellation of changes give rise to a new output? It is important to answer such questions in reduced networks, because there are presently no techniques available to answer them in the more complex networks of the brain. While there is no question that modulatory activity occurs in the brain, whether or not the principles which have been discovered by using simple invertebrate circuits scale up to vertebrate circuits remains an intriguing question.     

The evolution of neuronal circuits underlying species-specific behavior.

The nervous system is evolutionarily conservative compared to the peripheral appendages that it controls. However, species-specific behaviors may have arisen from very small changes in neuronal circuits. In particular, changes in neuromodulatory systems may allow multifunctional circuits to produce different sets of behaviors in closely related species. Recently, it was demonstrated that even species differences in complex social behavior may be attributed to a change in the promoter region of a single gene regulating a neuromodulatory action.     

Developmental regulation of axon branching in the vertebrate nervous system

During nervous system development, axons generate branches to connect with multiple synaptic targets. As with axon growth and guidance, axon branching is tightly controlled in order to establish functional neural circuits, yet the mechanisms that regulate this important process are less well understood. Here, we review recent advances in the study of several common branching processes in the vertebrate nervous system. By focusing on each step in these processes we illustrate how different types of branching are regulated by extracellular cues and neural activity, and highlight some common principles that underlie the establishment of complex neural circuits in vertebrate development.     

Smelling on the fly: sensory cues and strategies for olfactory navigation in Drosophila

Navigating toward (or away from) a remote odor source is a challenging problem that requires integrating olfactory information with visual and mechanosensory cues. Drosophila melanogaster is a useful organism for studying the neural mechanisms of these navigation behaviors. There are a wealth of genetic tools in this organism, as well as a history of inventive behavioral experiments. There is also a large and growing literature in Drosophila on the neural coding of olfactory, visual, and mechanosensory stimuli. Here we review recent progress in understanding how these stimulus modalities are encoded in the Drosophila nervous system. We also discuss what strategies a fly might use to navigate in a natural olfactory landscape while making use of all these sources of sensory information. We emphasize that Drosophila are likely to switch between multiple strategies for olfactory navigation, depending on the availability of various sensory cues. Finally, we highlight future research directions that will be important in understanding the neural circuits that underlie these behaviors.     

Motor inactivity in hibernating frogs: Linking plasticity that stabilizes neuronal function to behavior in the natural environment

All animals must generate reliable neuronal activity to produce adaptive behaviors in an ever‐changing environment. Neural systems are thought to achieve this goal, in part, through cellular and synaptic plasticity mechanisms that stabilize electrophysiological functions. Despite strong evidence for a role in regulating neuronal properties, these plasticity mechanisms have been difficult to link to natural behaviors in animals. In this review, I discuss how animals that inhabit extreme environments can address this challenge. As an example, I highlight recent work from frogs that stop breathing for several months during hibernation and, in response, use classic mechanisms of stabilizing plasticity to support respiratory motor output shortly after emergence. Furthermore, I describe problems for neuronal stability that may benefit from the study of hibernators: how circuits with variable modes of output control stabilizing mechanisms over long time scales and why some neural systems mount robust compensatory responses and others do not. By continuing to appreciate how diverse animal groups overcome challenges in the natural environment, we will broaden our view of the role that plasticity mechanisms play in stabilizing the nervous system.     

Circuits for self-motion estimation and walking control in Drosophila

The brain's evolution and operation are inextricably linked to animal movement, and critical functions, such as motor control, spatial perception, and navigation, rely on precise knowledge of body movement. Such internal estimates of self-motion emerge from the integration of mechanosensory and visual feedback with motor-related signals. Thus, this internal representation likely depends on the activity of circuits distributed across the central nervous system. However, the circuits responsible for self-motion estimation, and the exact mechanisms by which motor-sensory coordination occurs within these circuits remain poorly understood. Recent technological advances have positioned Drosophila melanogaster as an advantageous model for investigating the emergence, maintenance, and utilization of self-motion representations during naturalistic walking behaviors. In this review, I will illustrate how the adult fly is providing insights into the fundamental problems of self-motion computations and walking control, which have relevance for all animals.     

Genetic basis of male sexual behavior

Male sexual behavior is increasingly the focus of genetic study in a variety of animals. Genetic analysis in the soil roundworm Caenorhabditis elegans and the fruit fly Drosophila melanogaster has lead to identification of genes and circuits that govern behaviors ranging from motivation and mate-searching to courtship and copulation. Some worm and fly genes have counterparts with related functions in higher animals and many more such correspondences can be expected. Analysis of mutations in mammals can potentially lead to insights into such issues as monogamous versus promiscuous sexual behavior and sexual orientation. Genetic analysis of sexual behavior has implications for understanding how the nervous system generates and controls a complex behavior. It can also help us to gain an appreciation of how behavior is encoded by genes and their regulatory sequences.     

Neural circuit flexibility in a small sensorimotor system

Neuronal circuits underlying rhythmic behaviors (central pattern generators: CPGs) can generate rhythmic motor output without sensory input. However, sensory input is pivotal for generating behaviorally relevant CPG output. Here we discuss recent work in the decapod crustacean stomatogastric nervous system (STNS) identifying cellular and synaptic mechanisms whereby sensory inputs select particular motor outputs from CPG circuits. This includes several examples in which sensory neurons regulate the impact of descending projection neurons on CPG circuits. This level of analysis is possible in the STNS due to the relatively unique access to identified circuit, projection, and sensory neurons. These studies are also revealing additional degrees of freedom in sensorimotor integration that underlie the extensive flexibility intrinsic to rhythmic motor systems.     

Spikes alone do not behavior make: why neuroscience needs biomechanics

Neural circuits do not function in isolation; they interact with the physical world, accepting sensory inputs and producing outputs via muscles. Since both these pathways are constrained by physics, the activity of neural circuits can only be understood by considering biomechanics of muscles, bodies, and the exterior world. We discuss how animal bodies have natural stable motions that require relatively little activation or control from the nervous system. The nervous system can substantially alter these motions, by subtly changing mechanical properties such as body or leg stiffness. Mechanics can also provide robustness to perturbations without sensory reflexes. By considering a complete neuromechanical system, neuroscientists and biomechanicians together can provide a more integrated view of neural circuitry and behavior.     

Caenorhabditis elegans glutamate transporters influence synaptic function and behavior at sites distant from the synapse

To ensure precise neurotransmission and prevent neurotoxic accumulation, l-glutamate (Glu), the major excitatory neurotransmitter in the brain, is cleared from the synapse by glutamate transporters (GluTs). The molecular components of Glu synapses are highly conserved between Caenorhabditis elegans and mammals, yet the absence of synaptic insulation in C. elegans raises fundamental questions about Glu clearance strategies in the nematode nervous system. To gain insight into how Glu clearance is accomplished and how GluTs impact neurotransmission, we probed expression and function of all 6 GluTs found in the C. elegans genome. Disruption of each GluT impacts multiple Glu-dependent behaviors, with GluT combinations commonly increasing the severity of behavioral deficits. Interestingly, the sole GluT that we find expressed in neurons is localized predominantly in presynaptic neurons, in contrast to the postsynaptic concentration of neuronal GluTs typical in mammals. Moreover, 3 of the 6 GluT genes appear strongly expressed on the capillary excretory canal cell, where they affect Glu-dependent behaviors from positions distal to glutamatergic circuits. Indeed, our focused study of GLT-3, one of the distally expressed GluTs, shows that despite this distance, GLT-3 function can balance the activity mediated by synaptic release and synaptic receptors. The effects of distal GluTs on glutamatergic circuits support that Glu diffusion outside the vicinity of the synapse is a critical factor in C. elegans neurotransmission. Together with the presynaptic localization of neuronal GluTs, these observations suggest an unusual strategy for Glu clearance in C. elegans.     

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.     

Modulation of Neural Circuits in Crustacea

Recent research has shown that neuromodulators play importantroles in shaping simple behaviors. They act at many differentsites within the animal in a coordinated fashion, modulatingthe motor circuits in the central nervous system, altering motoneuronexcitability, and modulating muscle response to motoneuron input.Within the central circuits that co-ordinate simple movements,neuromodulators play a dramatic sculpting role, changing thecells that participate in the circuit, altering their intrinsicproperties, and affecting the strength of synaptic interactionsthat form the "wiring diagram" of the circuit. As a result,they are able to shape a family of related circuits out of asingle anatomically identified network, each driving a uniquevariant on the basic motor theme. Examples of these actionsfrom the Crustacea are described in this paper, focussing onthe modulation of posture in the lobster, and on modulationof rhythmic motor programs for stomach movements in the stomatogastricganglion of lobsters and crabs.     

Sensory processing by neural circuits in Caenorhabditis elegans

The anatomical and developmental constancy of Caenorhabditis elegans belies the complexity of its numerically small nervous system. Indeed, there is an increased appreciation of C. elegans as an organism to study systems level questions. Many recent studies focus on the circuits that control locomotion, egg-laying, and male mating behaviors and their modulation by multiple sensory stimuli.     

Learning in sensorimotor circuits

The study of plasticity in the central nervous system is a major and very dynamic neuroscience research field with enormous clinical potential. Considerable advances in this field have been made during the past 10 years. It now appears that most circuits in the brain and spinal cord show plasticity and that they can be modified by experience. Knowledge of the mechanisms of plasticity in the nervous system is therefore essential for the understanding of how the nervous system is wired during development and how it adapts in response to changes in the body and environment. Recent findings indicate that functional sensorimotor modules probe the sensory signals from the body that are generated as a consequence of module specific activity and use this sensory feedback to calibrate the strength in its input-output connections. This experience-dependent signal adapts the circuitry in the sensorimotor module to the body anatomy and biomechanics.     

Maturation of an insect nervous system: Constancy in the face of change

Growth and refinement of nervous system function occurs during postembryonic development in both invertebrates and vertebrates. Here we focus on one example, the cereal sensory system of orthopteran insects. Comparative studies on the different cereal systems have demonstrated that maturation in insects is a dynamic process during which extensive morphological and functional changes of the peripheral nervous system are matched to the CNS. The cerci are paired abdominal appendages that are covered with hair sensilla. During the molting cycles, the sensilla grow in size and gradually modify their transduction properties. In addition, new sensilla are formed and their synapses intercalate into the already functioning neuronal circuits in the terminal abdominal ganglion. In spite of the peripheral changes, the response properties of the first-order interneurons remain constant, as do the behaviors controlled by this circuit. The accommodation of the changes is based primarily on a continual rearrangement of the synaptic circuitry.     

Signaling mechanisms underlying dendrite formation

During development, the nervous system is confronted with a problem of enormous complexity; to progress from a large number of 'disconnected' neurons to a network of neuronal circuitry that is able to dynamically process sensory information and generate an appropriate output. To form these circuits, growing axons must make synapses with targets, usually the dendrites of postsynaptic neurons. Although a significant amount is known about the signals that regulate and guide developing axons, we are only now starting to understand how environmental cues like growth factors and activity regulate the formation and maintenance of dendrites in the developing and mature nervous system.