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.
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.
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.
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.
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.
Martin Wallner, Anne Kerstin Lindemeyer, and Richard W. Olsen
GABAA receptors (GABAARs) are the main inhibitory neurotransmitter receptors and mediate rapid synaptic as well as slow extrasynaptic inhibitory neurotransmission. Structurally, GABAARs are ligand-gated ion channels formed by a total of 19 homologous subunits, each with four transmembrane domains assembled as pentamers, forming a GABA-gated Cl– channels. The major classical synaptic GABAAR subtypes are formed by 2α2β and a γ subunit, with six different possible α subunits, three different β subunits, and three γ subunits, with the most abundant subtype, α1β2γ2 receptors. More recently, highly GABA-sensitive extrasynaptic δ subunit-containing receptors that are persistently (tonically) activated by low ambient levels of GABA have entered the limelight. GABAARs are targets for sedative/hypnotic and anxiolytic drugs (e.g., benzodiazepines [BZs] and other BZ site ligands), as well as general anesthetics (e.g., etomidate, propofol, barbiturate, and neurosteroid anesthetics, and possibly volatile agents and long-chain alcohols), and also are important targets for alcohol actions.
The main function of brains is to generate adaptive behavior. Far from being the stereotypical, robot-like insect, the fruit fly Drosophila exhibits astounding flexibility and chooses different courses of actions even under identical external circumstances. Due to the power of genetics, we now are beginning to understand the neuronal mechanisms underlying this behavioral flexibility. Interestingly, the evidence from studies of disparate behaviors converges on common organizational principles common to many if not all behaviors, such as modified sensory processing, involvement of biogenic amines in network remodeling, ongoing activity, and modulation by feedback. Seemingly foreseeing these recent insights, the first research fields in Drosophila behavioral neurogenetics reflected this constant negotiation between internal and external demands on the animal as the common mechanism underlying adaptive behavioral choice in Drosophila.
Giedre Milinkeviciute and Karina S. Cramer
The auditory brainstem carries out sound localization functions that require an extraordinary degree of precision. While many of the specializations needed for these functions reside in auditory neurons, additional adaptations are made possible by the functions of glial cells. Astrocytes, once thought to have mainly a supporting role in nervous system function, are now known to participate in synaptic function. In the auditory brainstem, they contribute to development of specialized synapses and to mature synaptic function. Oligodendrocytes play critical roles in regulating timing in sound localization circuitry. Microglia enter the central nervous system early in development, and also have important functions in the auditory system’s response to injury. This chapter highlights the unique functions of these non-neuronal cells in the auditory system.
Alessio Masi, Maria Novella Romanelli, Guido Mannaioni, and Elisabetta Cerbai
Hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels are members of the voltage-gated K+ channels family, but with unique properties. In stark contrast to close relatives, HCN channels are permeable to both Na+ and K+, and they are activated by hyperpolarization. Activation by hyperpolarization is indeed a pretty funny feature, to the point that the physiologists who first characterized HCN current in heart muscle cells named it “funny current” or If. Since then, the funny current has also been recorded from several neuronal types in both the central and peripheral nervous systems, as well as from some non-excitable cells, becoming progressively less “funny” over the years. In fact, HCN current goes now by the more serious designation of “Ih,” for “hyperpolarization-activated.” Forty years after the first current recording, it is now established that HCN channels, by virtue of their special properties and a host of modulatory mechanisms, are profoundly involved in many critical aspects of neuronal function in physiological and pathological conditions.