Neuroscience

Hearing loss generally occurs in the auditory periphery but leads to changes in the central auditory system. Noise-induced hearing loss (NIHL) and age-related hearing loss (ARHL) affect neurons in the ventral cochlear nucleus (VCN) at both the cellular and systems levels. In response to a decrease in auditory nerve activity associated with hearing loss, the large synaptic endings of the auditory nerve, the endbulbs of Held, undergo simplification of their structure and the volume of the postsynaptic bushy neurons decreases. A major functional change shared by NIHL and ARHL is the development of asynchronous transmitter release at endbulb synapses during periods of high afferent firing. Compensatory adjustements in transmitter release, including changes in release probability and quantal content, have also been reported. The excitability of the bushy cells undergoes subtle changes in the long-term, although short-term, reversible changes in excitability may also occur. These changes are not consistently observed across all models of hearing loss, suggesting that the time course of hearing loss, and potential developmental effects, may influence endbulb transmission in multiple ways. NIHL can alter the representation of the loudness of tonal stimuli by VCN neurons and is accompanied by changes in spontaneous activity in VCN neurons. However, little is known about the representation of more complex stimuli. The relationship between mechanistic changes in VCN neurons with noise-induced or age-related hearing loss, the accompanying change in sensory coding, and the reversibility of changes with the reintroduction of auditory nerve activity are areas that deserve further thoughtful exploration.

As arguably the third most common malady of industrialized populations, age-related hearing loss is associated with social isolation and depression in a subset of the population that will approach 25% by 2050. Development of behavioral or pharmacotherapeutic approaches to prevent or delay the onset of age-related hearing loss and mitigate the impact of hearing loss of speech understanding requires a better understanding of age-related changes that occur in the central auditory processor. This chapter critically reviews and discusses changes that occur in the auditory brainstem and thalamus with increased age. It briefly discusses age-related cellular changes that occur de novo within the central auditory system versus deafferentation plasticity and animal models of aging. Subsections discuss the cochlear nucleus, superior olivary complex, inferior colliculus, and the medial geniculate body with an emphasis on age-related changes in neurotransmission and how these changes could underpin the observed loss of precise temporal processing with increased age.

Behaviors of invertebrates can be modified by associative learning in a similar manner to those of vertebrates. Two simple forms of associative learning, Pavlovian and operant conditioning, allow animals to establish a predictive relationship between two events. Here we summarize five decades of studies of behavioral, cellular, and subcellular changes that are induced by these two learning paradigms in different invertebrate animal models. A comparative description of circuitry, neuronal elements, and properties that contribute to these conditioning procedures will be drawn to decipher common and distinguishing features of the learning processes. We will illustrate that similar circuits, synaptic and neuronal membrane plasticity, and similar molecular sites of detection of association are implicated in both forms of conditioning. However, evidence will also suggest that passively responding and endogenous dynamic properties of central networks and/or their constituent neurons might differentially contribute to Pavlovian and operant learning.

The auditory brainstem implant (ABI) is a surgically implanted device to electrically stimulate auditory neurons in the cochlear nucleus complex of the brainstem in humans to restore hearing sensations. The ABI is similar in function to a cochlear implant, but overall outcomes are poorer. However, recent applications of the ABI to new patient populations and improvements in surgical technique have led to significant improvements in outcomes. While the ABI provides hearing benefits to patients, the outcomes challenge our understanding of how the brain processes neural patterns of auditory information. The neural pattern of activation produced by an ABI is highly unnatural, yet some patients achieve high levels of speech understanding. Based on a meta-analysis of ABI surgeries and outcomes, a theory is proposed of a specialized sub-system of the cochlear nucleus that is critical for speech understanding.

Hearing in invertebrates has evolved independently as an adaptation to avoid predators or to mediate intraspecific communication. Although many invertebrate groups are able to respond to sound stimuli, insects are the only group in which hearing is widely used. Therefore, we will focus here on the auditory systems of some well-known insect models. Appearance of the ability to perceive sound in insects is presumably a quite recent event in evolution. As a result of independent evolution, diverse types of hearing organs are evolved in insects. Here we will introduce basic features of insect ears and the mechanisms through which sound stimuli are converted into neuronal electric signals. We will also summarize our current understanding of neural processing of auditory information, including tonotopy, sound localization, and pattern recognition.

A number of clinical studies indicated an association between autoantibodies and neuropathic pain. This is supported by the observation that immunotherapies that reduce antibody levels alleviate pain in patients and suggests that autoantibodies are not a byproduct of pathology but instead important drivers of neuropathic pain. These autoantibodies can target both neuronal and nonneuronal antigens within the sensory nervous system. Possible pathogenic mechanisms include nerve damage and inflammation as well as disruption of ion channel function. Whether autoantibodies are truly causal to neuropathic pain and exactly what their prevalence is in such pain conditions are important questions that are being addressed with the use of passive transfer in preclinical models and the screening of patient sera. Such studies support the idea that autoantibodies are a mechanism to cause neuropathic pain and provide insight into the molecular components regulating pain sensitivity in a pathological setting. Therefore, this work not only will be applicable to the treatment of patients with autoantibody-mediated pain, but also will facilitate the development of therapies to treat neuropathic pain in the more general context.

This chapter summarizes what is known about the organization of the axons that make up the white matter of the auditory brainstem. The sources of the axons in each of the major fiber bundles (the dorsal and intermediate acoustic striae, the ventral acoustic stria or trapezoid body, and the lateral lemniscus) are reviewed, and, where information is available, the organization of specific groups of axons within the fiber bundles is described. The chapter collects the extensive but scattered information about axon trajectories into one place, both to provide a summary of what is known and also to indicate important gaps in our knowledge. The emphasis is almost entirely on the routes followed by groups of axons over the relatively long distances between structures and on the organization of specific types of axons within the fiber bundles; information about the termination patterns of the axons can be obtained from the references cited and throughout the chapter. Because knowledge about axon trajectories has considerable practical value (as, for example, in designing and interpreting both anatomical and physiological studies), the most useful information is species specific. Fortunately, at least at our current level of understanding, the components and relative positions of the major fiber bundles are remarkably similar across species (undoubtedly reflecting a common mammalian developmental plan).

The encoding of speech and music in the auditory brainstem is available at the human scalp via the auditory-evoked frequency following response. The FFR, primarily reflecting activity in the inferior colliculus, may be evoked by speech or music stimulation and represents the combined activity of sensorimotor, cognitive, and reward centers in the brain. Its response properties, like the inferior colliculus itself, are influenced by long-term experience with sound. The transparency, individual-level reliability, and ability to gauge neural plasticity provide the researcher and clinician a powerful probe of auditory processing in the human brainstem. With it, we have learned a great deal about how mechanisms of decline, deprivation, and enrichment affect the processing of complex signals such as music and speech in the human brainstem.

Pain is a common and feared complication for many cancer patients. Cancer pain covers numerous pain syndromes; since the treatment is complex, it is essential to assess each individual patient with cancer pain thoroughly. Cancer pain includes not only elements of inflammatory and neuropathic pain, but also, importantly, cancer-specific elements. Starting with the clinical aspects of cancer pain and the current knowledge from in vivo models, this chapter provides an overview of the neurobiology known to drive cancer-induced bone pain as it evolves through the complex interplay between primary afferents, tumor cells, and bone cells. There continue to be many uncertainties and unknown mechanisms involved in cancer pain, and an effort to discover novel therapeutic targets should be emphasized as cancer pain poses an increasing clinical and socioeconomic burden.

Nociceptive primary afferents detect stimuli that are normally perceived as painful, and these afferents form synapses in the dorsal horn of the spinal cord and the spinal trigeminal nucleus. Here they are involved in highly complex neuronal circuits involving projection neurons belonging to the anterolateral tract (ALT) and interneurons, which modulate the incoming sensory information. The ALT neurons convey somatosensory information to a variety of brain regions that are involved in the various aspects of the pain experience. A spinothalamic-cortical pathway provides input to several regions of the cerebral cortex, including the first and second somatosensory areas (S1, S2), the insula and the cingluate cortex. These regions are thought be responsible for the sensory-discriminative aspects of pain (S1), pain-related learning (S2), the autonomic and motivational responses (insula), and the negative affect (cingulate). Another ascending system, The spinoparabrachial-limbic pathway targets a variety of brain regions, including the amygdala, and is likely involved in the affective component of pain. A descending system that includes the limbic system, the periaqueductal gray matter of the midbrain, the locus coeruleus, and the rostral ventral medulla, can suppress pain, and this operates partly through the monoamine transmitters noradrenaline and serotonin which are released in the spinal and trigeminal dorsal horn.

The inferior colliculus is an important auditory relay center that undergoes fundamental changes following hearing loss, whether noise induced (NIHL) or age related (ARHL). These changes may contribute to the induction or maintenance of phenomena such as tinnitus (phantom auditory sensations) and hyperacusis (increased sensitivity to sound). Here, we outline changes that can occur in the inferior colliculus following damage to the periphery and/or as a result of the ageing process, both immediate and long-term, and attempt to disentangle which changes relate to either tinnitus or hyperacusis, as opposed to solely hearing loss. Understanding these changes is ultimately important to reversing the underlying pathology and treating these conditions.

Pain is not a simple phenomenon and, beyond its conscious perception, involves circuitry that allows the brain to provide an affective context for nociception, which can influence mood and memory. In the past decade, neurobiological techniques have been developed that allow investigators to elucidate the importance of particular groups of neurons in different aspects of the pain response, something that may have important translational implications for the development of novel therapies. Chemo- and optogenetics represent two of the most important technical advances of recent times for gaining understanding of physiological circuitry underlying complex behaviors. The use of these techniques for teasing out the role of neurons and glia in nociceptive pathways is a rapidly growing area of research. The major findings of studies focused on understanding circuitry involved in different aspects of nociception and pain are highlighted. In addition, attention is drawn to the possibility of modification of chemo- and optogenetic techniques for use as potential therapies for treatment of chronic pain disorders in human patients.

Reception of chemicals via olfaction and gustation are prerequisites to find, distinguish, and recognize food and mates and to avoid dangers. Several receptor gene superfamilies are employed in arthropod chemosensation: inverse 7-transmembrane (7-TM) gustatory and olfactory receptors (GRs, ORs), 3-TM ionotropic glutamate-related receptors (IRs), receptor-guanylyl cyclases, transient receptor potential ion channels, and epithelial sodium channels. Some of these receptor gene families have ancient origins and expanded in several taxa, producing very large, variant gene families adapted to the respectively relevant odor ligands in species-specific environments. Biochemical and electrophysiological studies in situ as well as molecular genetics found evidence for G-protein-dependent signal transduction cascades for ORs, GRs, and IRs, suggesting that signal amplification is paramount for chemical senses. In contrast, heterologous expression studies argued for primarily ionotropic transduction as a prerequisite to interstimulus intervals in the range of microseconds.

Pain may be induced by activation of various ion channels expressed in primary afferent neurons. These channels function as molecular sensors that detect noxious chemical, temperature, or tactile stimuli and transduce them into nociceptor electrical signals. Transient receptor potential channels are good examples because they are activated by chemicals, heat, cold, and acid in nociceptors. Anion channels were little studied in nociception because of the notion that anion channels might induce hyperpolarization of nociceptors on opening. In contrast, opening of Cl^- channels in dorsal root ganglion (DRG) neurons depolarizes sensory neurons, resulting in excitation of nociceptors, thereby inducing pain. Anoctamin 1(ANO1)/TMEM16A is a Ca²⁺-activated Cl^- channel expressed mainly in small DRG neurons, suggesting a nociception role. ANO1 is a heat sensor that detects heat over 44°C. Ano1-deficient mice elicit less nocifensive behaviors to hot temperatures. In addition, mechanical allodynia and hyperalgesia induced by inflammation or nerve injury are alleviated in Ano1 ^-/- mice. More important, Ano1 transcripts are increased in chronic pain models. Bestrophin 1 (Best1) is another Ca²⁺-activated Cl^- channel expressed in nociceptors. Best1 is increased in axotomized DRG neurons. The role of Best1 in nociception is not clear. GABA_A receptors are in the central process of DRG neurons; GABA depolarizes the primary afferents. This depolarization consists of primary afferent depolarization essential for inhibiting nociceptive input to second-order neurons in the spinal cord, regulating pain signals to the brain. Thus, although Cl^- channels in nociceptors are not as numerous as TRP channels, their role in nociception is distinct and significant.

Important cnidarian contributions to our understanding of nervous system evolution may be found in the arrangement of conducting systems and their interactions. We see multiple, diffuse systems that interact to produce specific behaviors, the compression of conducting systems into compact directional or bidirectional conduction systems, and accumulation of multiple compressed conducting systems into integrating structures like nerve rings. We even see ganglion-like rhopalia that contain bilateral and directional conducting pathways. We now know that this compression and specificity of connections is controlled by conserved sets of genetic commands similar to those found in bilateral animals, and likely in common ancestors. This gradation in centralization is only limited in a directed pathway by the unique radial symmetry of cnidarians. Based on the compression of cnidarian conducting systems into integrating centers (nerve rings and rhopalia), the primary hurdle to cephalization is body symmetry. Medusoid cnidarians possess multiple “brains” connected by conducting systems that, by necessity, are nonpolarized.

Plasticity in neuronal circuits is essential for optimizing connections as animals develop and for adapting to injuries and aging, but it can also distort the processing, as well as compromise the conveyance of ongoing sensory information. This chapter summarizes evidence from electrophysiological studies in slices and in vivo that shows how remarkably robust signaling is in principal cells of the ventral cochlear nucleus. Even in the face of short-term plasticity, these neurons signal rapidly and with temporal precision. They can relay ongoing acoustic information from the cochlea to the brain largely independently of sounds to which they were exposed previously.

Tinnitus most commonly begins with alterations of input from the ear resulting from cochlear trauma or overstimulation of the ear. Because the cochlear nucleus is the first processing center in the brain receiving cochlear input, it is the first brainstem station to adjust to this modified input from the cochlea. Research published over the last 30 years demonstrates changes in neural circuitry and activity in the cochlear nucleus that are associated with and may be the origin of the signals that give rise to tinnitus percepts at the cortical level. This chapter summarizes what is known about these disturbances and their relationships to tinnitus. It also summarizes the mechanisms that trigger tinnitus-related disturbances and the anatomical, chemical, neurophysiological, and biophysical defects that underlie them. It concludes by highlighting some major controversies that research findings have generated and discussing the clinical implications the findings have for the future treatment of tinnitus.

This article reviews the status of research on locomotion in segmented worms. It focuses on three major groups (leeches, earthworms, and nereid polychaetes) that have attracted the most research attention. All three groups show two types of locomotion: crawling (moving over a solid substrate) and swimming (moving through a liquid). The adults of all three groups form a hydroskeleton by controlling the pressure within the segments, and they locomote by controlling the shapes of the individual segments in coordinated spatial and temporal patterns. Many annelid larvae use cilia to move through water. Four aspects of the locomotory patterns are considered: the kinematics (the movement patterns), biomechanics (how muscle contractions produce movement), the neuronal basis of the movement patterns, and efforts to produce robots that move like annelid worms.

This chapter will consider the control of posture and walking in decapod crustaceans (crabs, lobsters, rock lobsters, and crayfish). The walking system of crustaceans is composed of five pairs of appendages, each with seven articulated segments. While crabs sideways walking relies on stereotyped trailing and leading leg movements, forward/backward walking in lobsters and crayfish is achieved by different movements in the different legs, depending on their orientation versus body axis. Largely independent neural networks, localized in each of the 10 hemi-segmental thoracic ganglia, control each leg during locomotion. Each of these networks is modularly organized, with a specific central pattern generator (CPG) controlling each joint. Although coordinating interneurons have been described, inter-joint and inter-leg coordination is largely maintained by sensory feedback. Recently, the key role of proprioceptive signals in motor command processing has been addressed thanks to hybrid system experiments and modelling.

This article discusses legged locomotion in insects. It describes the basic patterns of coordinated movement both within each leg and among the various legs. The nervous system controls these actions through groups of joint pattern generators coupled through interneurons and interjoint reflexes in a range of insect species. These local control systems within the thoracic ganglia rely on leg proprioceptors that monitor joint movement and cuticular strain interacting with central pattern generation interneurons. The local control systems can change quantitatively and qualitatively as needed to generate turns or more forceful movements. In dealing with substantial obstacles or changes in navigational movements, more profound changes are required. These rely on sensory information processed in the brain that projects to the multimodal sensorimotor neuropils collectively referred to as the central complex. The central complex affects descending commands that alter local control circuits to accomplish appropriate redirected movements.