Ruili Xie, Tessa-Jonne F. Ropp, Michael R. Kasten, and Paul B. Manis
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.
John M. Dawes and David L. Bennett
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.
Andrew J. Todd and Fan Wang
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.
Changes in the Inferior Colliculus Associated with Hearing Loss: Noise-Induced Hearing Loss, Age-Related Hearing Loss, Tinnitus and Hyperacusis
Alan R. Palmer and Joel I. Berger
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.
Sascha R.A. Alles, Anne-Marie Malfait, and Richard J. Miller
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.
Donata Oertel, Xiao-Jie Cao, and Alberto Recio-Spinoso
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.
J.A. Kaltenbach and D.A. Godfrey
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.
Taesun Eom, Ilham A. Muslimov, Anna Iacoangeli, and Henri Tiedge
This chapter reviews current developments in the area of translational control in neurons. It focuses on the activity-dependent translational modulation by neuronal regulatory RNAs, including underlying interactions with eukaryotic initiation factors (eIFs), and on the role of such modulation in locally controlled protein synthesis in synapto-dendritic domains. It highlights the role of dendritic RNA targeting as a key prerequisite of local translation at the synapse and discusses the significance of these mechanisms in the expression of higher brain functions, including learning, memory, and cognition. The chapter concludes with discussion of anticipated future work to continue to elucidate these mechanisms and provide advances in the area of translational regulation in neurons and our understanding of how translational dysregulation contributes to neurological and cognitive disorders.
Brett R. Schofield and Nichole L. Beebe
Descending auditory pathways originate from multiple levels of the auditory system and use a variety of neurotransmitters, including glutamate, GABA, glycine, acetylcholine, and dopamine. Targets of descending projections include cells that project to higher or lower centers, setting up circuit loops and chains that provide top-down modulation of many ascending and descending circuits in the auditory system. Descending pathways from the auditory cortex can evoke plasticity in subcortical centers. Such plasticity relies, at least in part, on brainstem cholinergic systems that are closely tied to descending cortical projections. Finally, the ventral nucleus of the trapezoid body, a component of the superior olivary complex, is a major target of descending projections from the cortex and midbrain. Through its complement of different neurotransmitter phenotypes, and its wide array of projections, the ventral nucleus of the trapezoid body is positioned to serve as a hub in the descending auditory system.
Paul Albert Fuchs
Cochlear afferents differ in form and function. The great majority are type I, large diameter, myelinated neurons that contact a single inner hair cell to transmit acoustic information. Each inner hair cell is presynaptic to a pool of 10–30 type I afferents, among which spontaneous activity and acoustic threshold vary widely. Variation in the number, voltage-gating, and density of L-type calcium channels at each presynaptic active zone (ribbon) may dictate this functional diversity. Despite contacting large numbers of outer hair cells, the scarce, unmyelinated type II afferents are acoustically insensitive, and only weakly depolarized by outer hair cell transmitter release. However, type II afferents respond strongly to adenosine triphosphate released by cochlear tissue damage, providing a biological basis for painful hearing (noxacusis).
Hanns Ulrich Zeilhofer and Robert Ganley
The spinal dorsal horn and its equivalent structure in the brainstem constitute the first sites of synaptic integration in the pain pathway. A huge body of literature exists on alterations in spinal nociceptive signal processing that contribute to the generation of exaggerated pain states and hence to what is generally known as “central sensitization.” Such mechanisms include changes in synaptic efficacy or neuronal excitability, which can be evoked by intense nociceptive stimulation or by inflammatory or neuropathic insults. Some of these changes cause alterations in the functional organization of dorsal horn sensory circuits, leading to abnormal pathological pain sensations. This chapter reviews the present state of this knowledge. It does not cover the contributions of astrocytes and microglia in detail as their functions are the subject of a separate chapter.
Edward C. Emery and Patrik Ernfors
Primary sensory neurons of the dorsal root ganglion (DRG) respond and relay sensations that are felt, such as those for touch, pain, temperature, itch, and more. The ability to discriminate between the various types of stimuli is reflected by the existence of specialized DRG neurons tuned to respond to specific stimuli. Because of this, a comprehensive classification of DRG neurons is critical for determining exactly how somatosensation works and for providing insights into cell types involved during chronic pain. Here, we review the recent advances in unbiased classification of molecular types of DRG neurons in the perspective of known functions as well as predicted functions based on gene expression profiles. The data show that sensory neurons are organized in a basal structure of three cold-sensitive neuron types, five mechano-heat sensitive nociceptor types, four A-Low threshold mechanoreceptor types, five itch-mechano-heat–sensitive nociceptor types and a single C–low-threshold mechanoreceptor type with a strong relation between molecular neuron types and functional types. As a general feature, each neuron type displays a unique and predicable response profile; at the same time, most neuron types convey multiple modalities and intensities. Therefore, sensation is likely determined by the summation of ensembles of active primary afferent types. The new classification scheme will be instructive in determining the exact cellular and molecular mechanisms underlying somatosensation, facilitating the development of rational strategies to identify causes for chronic pain.
Chelcie F. Heaney and Kimberly F. Raab-Graham
Major depressive disorder is a debilitating disorder with a lifetime prevalence of 17% in the adult population. By reverse engineering how antidepressants work at the cellular level, significant progress has been made within the last decade regarding the underlying etiology of depression. Unexpectedly, dysregulation of protein synthesis pathways is at the core of depression. Activation of one or more mRNA translation, initiation, or elongation pathways (including mammalian target of rapamycin [mTOR] kinase, extracellular regulated kinase, and eukaryotic elongation factor 2) is central to symptomatic relief. In preclinical models of stress and/or depression, co-administration of antidepressants and pharmacological inhibitors of these pathways block hallmark characteristics of antidepressant efficacy, including upregulation of key synaptic proteins, increased dendritic and spine complexity, and antidepressant-like behaviors. In this chapter, we review studies demonstrating altered translational pathways in animal models, treated and untreated patients, with a focus on mTOR-regulated protein synthesis.
Currently there is no effective cure or intervention available for Alzheimer’s disease (AD), a devastating neurodegenerative disease and the most common form of dementia. It is urgent to understand the basic cellular/molecular signaling mechanisms underlying AD pathophysiology to identify novel therapeutic targets and diagnostic biomarkers. Many studies indicate impaired synaptic function as a key and early event in AD pathogenesis. Mounting evidence suggests that dysregulations in mRNA translation (protein synthesis) may contribute to the development of synaptic dysfunction and cognitive defects in neurodegenerative diseases including AD. Protein synthesis happens in three phases (initiation, elongation, and termination) and is tightly controlled through regulation of multiple signaling pathways in response to various stimuli. Integral protein synthesis is indispensable for memory formation and maintenance of synaptic plasticity. Interruption of protein synthesis homeostasis can lead to impairments in cognition and synaptic plasticity. This chapter reviews recent studies supporting the idea that impaired protein synthesis is an important mechanism underlying AD-associated cognitive deficits and synaptic failure. It focuses on three signaling cascades controlling protein synthesis: eukaryotic initiation factor 2α (eIF2α), the mammalian target of rapamycin complex 1 (mTORC1), and eukaryotic elongation factor 2 (eEF2). Findings from human and animal studies demonstrating an association between dysregulation of these pathways and AD pathophysiology are summarized and discussed.
Chloe Alexandre, Alban Latremoliere, and Patrick H. Finan
With the advent of modern lifestyles, there has been a significant extension of daily activities, mostly at the cost of sleep. Lack of sleep affects many biological systems, including various cognitive functions, the immune system, metabolism, and pain. Both sleep and pain are complex neurological processes that encompass many dynamic components. As a result, defining the precise interactions between these two systems represents a challenge, especially for chronic paradigms. This chapter describes how sleep is measured and how it can be experimentally altered in humans and animal models, and, in turn, how sleep disturbances, either acute or chronic, can affect different aspects of pain. Possible mechanisms involved are discussed, including an increase in inflammatory processes, a loss of nociceptive inhibitory pathways, and a defect in the cognitive processing of noxious inputs.
Ana Belén Elgoyhen, Carolina Wedemeyer, and Mariano N. Di Guilmi
The auditory system consists of ascending and descending neuronal pathways. The best studied is the ascending pathway, whereby sounds that are transduced in the cochlea into electrical signals are sent to the brain via the auditory nerve. Before reaching the auditory cortex, auditory ascending information has several central relays: the cochlear nucleus and superior olivary complex in the brainstem, the lateral lemniscal nuclei and inferior colliculus in the midbrain, and the medial geniculate body in the thalamus. The function(s) of the descending corticofugal pathway is less well understood. It plays important roles in shaping or even creating the response properties of central auditory neurons and in the plasticity of the auditory system, such as reorganizing cochleotopic and computational maps. Corticofugal projections are present at different relays of the auditory system. This review focuses on the physiology and plasticity of the medial efferent olivocochlear system.
Gregory D. Clemenson, Fred H. Gage, and Craig E.L. Stark
This chapter reviews the literature on environmental enrichment and specifically discusses its influence on the hippocampus of the brain. In animal models, the term “environmental enrichment” is used to describe a well-defined manipulation in which animals are exposed to a larger and more stimulating environment. This experience has been shown to have a powerful and positive impact on hippocampal cognition and neuroplasticity in animals. In humans, however, the translation of environmental enrichment is less clear. Despite the fact that humans live considerably more enriching lives compared to laboratory animals, studies have shown that training and expertise (such as exercise and spatial exploration) can lead to both functional and structural changes in the human brain. This chapter is a comprehensive review of environmental enrichment, drawing parallels between animal models and humans to present a more complete understanding of environmental enrichment.
Leonard K. Kaczmarek
All neurons express a subset of over seventy genes encoding potassium channel subunits. These channels have been studied in auditory neurons, particularly in the medial nucleus of the trapezoid body. The amplitude and kinetics of various channels in these neurons can be modified by the auditory environment. It has been suggested that such modulation is an adaptation of neuronal firing patterns to specific patterns of auditory inputs. Alternatively, such modulation may allow a group of neurons, all expressing the same set of channels, to represent a variety of responses to the same pattern of incoming stimuli. Such diversity would ensure that a small number of genetically identical neurons could capture and encode many aspects of complex sound, including rapid changes in timing and amplitude. This review covers the modulation of ion channels in the medial nucleus of the trapezoid body and how it may maximize the extraction of auditory information.All neurons express a subset of over seventy genes encoding potassium channel subunits. These channels have been studied in auditory neurons, particularly in the medial nucleus of the trapezoid body. The amplitude and kinetics of various channels in these neurons can be modified by the auditory environment. It has been suggested that such modulation is an adaptation of neuronal firing patterns to specific patterns of auditory inputs. Alternatively, such modulation may allow a group of neurons, all expressing the same set of channels, to represent a variety of responses to the same pattern of incoming stimuli. Such diversity would ensure that a small number of genetically identical neurons could capture and encode many aspects of complex sound, including rapid changes in timing and amplitude. This review covers the modulation of ion channels in the medial nucleus of the trapezoid body and how it may maximize the extraction of auditory information.
Monica C. Lannom and Stephanie Ceman
New protein synthesis is critical for learning and memory. The discovery of ribosomes at synapses indicated the potential for local protein synthesis in response to stimulation. miRNAs play a key role in this process as evidenced by their role in normal neuronal development and function and in neurological disease. miRNA production is regulated and once bound by AGO2, the ensuing RISC complex is able to bind mRNAs and direct their translation suppression and degradation. However, other RNA binding proteins, including FMRP and MOV10, regulate AGO2 association with the miRNA recognition element (MRE) in target mRNAs. AGO2 itself is regulated by post-translational modifications, and neuronal activity controls post-translational modifications of FMRP and MOV10 that lead to their regulation and degradation. In addition, RNA localization at the synapse is a critical regulated event that depends on both cis sequences in the mRNA and the identity of the bound RNA binding proteins.