Invertebrate Neuroscience

Nociception is a protective mechanism that mediates behavioral responses to a range of potentially damaging stimuli, including noxious temperature, chemicals, and mechanical stimulation. Nociceptive mechanisms are found throughout metazoans. Noxious stimuli are transduced by specialized, high-threshold peripheral nociceptors, which fire action potentials to elicit adaptive behavioral responses. Nociception is essential for survival and provides a mechanism for sensory perception of noxious stimuli, which alerts the organism to potential environmental dangers. When coupled with pain sensation and complex behavioral responses, this mechanism protects the organism from incipient damage. Moreover, acute and chronic pain may manifest as altered nociception in neuropathic pain states. Elucidating the neural bases of nociception is therefore important for identifying and implementing novel strategies for the treatment of neuropathic pain, as well as uncovering the mechanistic bases by which the nervous system integrates information to produce specific behaviors in response to a range of noxious stimuli. Invertebrate organisms, such as Drosophila melanogaster and Caenorhabditis elegans, have emerged as powerful, genetically tractable platforms for exploring these questions. Here, we concisely review the current state of knowledge regarding the cells, molecules, neural circuits, and behaviors associated with invertebrate nociception in the fruit fly and nematode worm.

New techniques for recording the activity of many neurons simultaneously have given insights into how neuronal circuits make the decision to perform one of many possible behaviors. A long-standing hypothesis for how behavioral choices are made in any animal is that “command neurons” are responsible for selecting individual behaviors, and that these same neurons inhibit the command neurons that elicit other behaviors. In fact, this mechanism has turned out to be just one of several ways that such decision-making is accomplished. In particular, for some behavioral choices, the circuits appear to overlap, sometimes extensively, to perform two or more behaviors. Making decisions using such “multifunctional neurons” has been proposed for large neural networks, but this strategy appears to be used in relatively small nervous systems, too. These simpler nervous systems can serve as useful test systems to test hypotheses about how the dynamics of networks of neurons can be used to select among different behaviors, similar to the mechanisms used by leeches deciding to swim, shorten, crawl, or feed.

The medicinal leech (Hirudo verbana) is an annelid (segmented worm) and one of the classic model systems in neuroscience. It has been used in research for over 50 years and was one of the first animals in which intracellular recordings of mechanosensory neurons were carried out. Remarkably, the leech has three main classes of mechanosensory neurons that exhibit many of the same properties found in vertebrates. The most sensitive of these neurons are the touch cells, which are rapidly adapting neurons that detect low-intensity mechanical stimuli. Next are the pressure cells, which are slow-adapting sensory neurons that respond to higher intensity, sustained mechanostimulation. Finally, there are nociceptive neurons, which have the highest threshold and respond to potentially damaging mechanostimuli, such as a pinch. As observed in mammals, the leech has separate mechanosensitive and polymodal nociceptors, the latter responding to mechanical, thermal, and chemical stimuli. The cell bodies for all three types of mechanosensitive neurons are found in the central nervous system where they are arranged as bilateral pairs. Each neuron extends processes to the skin where they form discrete receptive fields. In the touch and pressure cells, these receptive fields are arranged along the dorsal-ventral axis. For the mechano-only and polymodal nociceptive neurons, the peripheral receptive fields overlap with the mechano-only nociceptor, which also innervates the gut. The leech also has a type of mechanosensitive cell located in the periphery that responds to vibrations in the water and is used, in part, to detect potential prey nearby. In the central nervous system, the touch, pressure, and nociceptive cells all form synaptic connections with a variety of motor neurons, interneurons, and even each other, using glutamate as the neurotransmitter. Synaptic transmission by these cells can be modulated by a variety of activity-dependent processes as well as the influence of neuromodulatory transmitters, such as serotonin. The output of these sensory neurons can also be modulated by conduction block, a process in which action potentials fail to propagate to all the synaptic release sites, decreasing synaptic output. Activity in these sensory neurons leads to the initiation of a number of different motor behaviors involved in locomotion, such as swimming and crawling, as well as behaviors designed to recoil from aversive/noxious stimuli, such as local bending and shortening. In the case of local bending, the leech is able to bend in the appropriate direction away from the offending stimuli. It does so through a combination of which mechanosensory cell receptive fields have been activated and the relative activation of multiple sensory cells decoded by a layer of downstream interneurons.

The octopus, with its eight long and flexible arms, is an excellent example of the independent evolution of highly efficient motor behavior in a soft-bodied animal. Studies will be summarized to show that the amazing behavioral motor abilities of the octopus are achieved through a special embodied organization of its flexible body, unusual morphology, and a unique central and peripheral distribution of its extremely large nervous system. This special embodied organization of brain–body–environment reciprocal interactions makes it possible to overcome the difficulties involved in generation and control of movement in an animal, which unlike vertebrates and arthropods lacks rigid skeletal appendages.

Visual camouflage change is a hallmark of octopus, squid, and cuttlefish and serves as their primary defense against predators. They can change their total body appearance in less than a second due to one principal feature: every aspect of this sensorimotor system is neurally refined for speed. Cephalopods live in visually complex environments such as coral reefs and kelp forests and use their visual perception of backgrounds to rapidly decide which camouflage pattern to deploy. Counterintuitively, cuttlefish have evolved a small number of pattern designs to achieve camouflage: Uniform, Mottle, and Disruptive, each with variation. The expression of these body patterns is based on several fundamental scene features. In cuttlefish, there appear to be several “visual assessment shortcuts” that enable camouflage patterning change in as little as 125 milliseconds. Neural control of the dynamic body patterning of cephalopods appears to be organized hierarchically via a set of lobes within the brain, including the optic lobes, the lateral basal lobes, and the anterior/posterior chromatophore lobes. The motor output of the central nervous system (CNS) in terms of the skin patterns that are produced is under sophisticated neural control of chromatophores, iridophores, and three-dimensional skin papillae. Moreover, arm postures and skin papillae are also regulated visually for additional aspects of concealment. This coloration system, often referred to as rapid neural polyphenism, is unique in the animal kingdom and can be explained and interpreted in the context of sensory and behavioral ecology.

The crustacean stomatogastric nervous system contains a set of distinct but interacting rhythmic motor circuits that control movements of the foregut. When isolated, these circuits produce activity patterns that are almost perfect replicas of their behavior in vivo. The ease with which distinct circuit neurons are identified, recorded, and manipulated has provided considerable insight into the general principles of how motor circuits operate and are controlled at the cellular level. The small number of relatively large neurons has facilitated several technical advances in neuroscience research and allowed the identification of one of the earliest circuit connectomes. This enabled, for the first time, studies of circuit dynamics using the relationships between all component neurons of a nervous center. A major discovery was that circuits are not dedicated to producing a single neuronal activity pattern, and that the involved neurons are not committed to particular circuits. This flexibility results predominantly from the ability of neuromodulators to change the cellular and synaptic properties of circuit neurons. The relatively unique access to, and detailed documentation of, identified circuit, sensory, and descending pathways has also started new avenues into examining how individual modulatory neurons and transmitters affect their target cells. Groundbreaking experimental and modeling work has further demonstrated that the intrinsic properties of neurons depend on their recent history of activation and that neurons and circuits counterbalance destabilizing influences by compensatory homeostatic regulation of ionic conductances. The stomatogastric microcircuits continue to provide key insight into neural circuit operation in numerically larger and less accessible systems.

The predatory stomatopod crustaceans, or mantis shrimp, are among the most attractive and dynamic creatures living in the sea. Their special features include their powerful raptorial appendages, used to kill, stun, or disable other animals (whether predators, prey, or competitors), and their highly specialized compound eyes. Mantis shrimp vision is unlike that of any other animal and has several unique features. Their compound eyes are optically triple, each having three separate regions that produce overlapping visual fields viewing certain regions of space. They have the most diverse set of spectral classes of receptors ever described in animals, with as many as 16 types in a single compound eye. These receptors are based on a highly duplicated set of opsin molecules paired with strongly absorbing photostable filters in some photoreceptor types. The receptor set includes six ultraviolet types, all spectrally distinct, many themselves tuned by photostable filters. There are as many as eight types of polarization receptors of up to three spectral classes (including an ultraviolet class). In some species, two sets of these receptors analyze circularly polarized light, another unique capability. Stomatopod eyes move independently, each capable of visual field stabilization, image foveation and tracking, or scanning of image features. Stomatopods are known to recognize colors and polarization features and evidently use these in predation and communication. Altogether, mantis shrimps have perhaps the most unusual vision of any animal.

Urochordates are chordate siblings that comprise the following marine invertebrates: the sessile Ascidiaceae, or sea squirts; planktonic Larvacea; and the pelagic salps, doliolids, and pyrosomes (collectively the Thaliacea), each more beautiful than the next. Tadpole larvae of ascidians and adult larvaceans both have a body plan that is chordate, with a notochord and dorsal, tubular nervous system that forms from a neural plate. Thalaciacea have a ganglion developed from a tubular structure, which has been compared to the vertebrate mes-metencephalic region, and while salps have well developed eyes, other anterior brain components are absent, and the connections within their central nervous system, as well as the neurobiology of other Thaliacea are all little reported. The ascidian tadpole larva is extensively reported, especially in the model species Ciona intestinalis, as is the caudal nerve cord in the larvacean Oikopleura dioica. Chordate features that share proposed homology with vertebrate features include ciliary photoreceptors that hyperpolarize to light, descending decussating motor pathways that resemble Mauthner cell pathways, coronet cells in the ascidian larva and saccus vasculosus of fishes, the neural canal’s Reissner’s fiber; secondary mechanoreceptors that resemble hair cells; and ascidian bipolar cells that are like dorsal root ganglion cells.

The emergence and diversification of bilateral animals are among the most important transitions in the history of life on our planet. A proper understanding of the evolutionary process will derive from answering such key questions as, how did complex body plans arise in evolutionary time, and how are complex body plans “encoded” in the genome? the first step is focusing on the earliest stages in bilaterian evolution, probing the most elusive organization of the genomes and microscopic anatomy in basally branching taxa, which are currently assembled in a clade named Xenacoelomorpha. This enigmatic phylum is composed of three major taxa: acoel flatworms, nemertodermatids, and xenoturbellids. Interestingly, the constituent species of this clade have an enormously varied set of morphologies; not just the obvious external features but also their tissues present a high degree of constructional variation. This interesting diversity of morphologies (a clear example being the nervous system, with animals showing different degrees of compaction) provides a unique system in which to address outstanding questions regarding the parallel evolution of genomes and the many morphological characters encoded by them. A systematic exploration of the anatomy of members of these three taxa, employing immunohistochemistry, in situ hybridization, and high-throughput transmission electron microscopy, will provide the reference framework necessary to understand the changing roles of genes and gene networks during the evolution of xenacoelomorph morphologies and, in particular, of their nervous systems.