The modulatory influence of sex hormones on acute pain, chronic pain disorders, and pain management has been reported for over seven decades. The effect of hormones on pain is clearly evidenced by the multitude of chronic pain disorders that are more common in women, such as headache and migraine, temporomandibular joint disorder, irritable bowel syndrome, chronic pelvic pain, fibromyalgia, rheumatoid arthritis, and osteoarthritis. Several of these pain disorders also fluctuate in pain intensity over the menstrual cycle, including headache and migraine and temporomandibular joint disorder. The sex steroid hormones (estrogen, progesterone, and testosterone) as well as some peptide hormones (prolactin, oxytocin, and vasopressin) have been linked to pain by both clinical and preclinical research. Progesterone and testosterone are widely accepted as having protective effects against pain, while the literature on estrogen reports both exacerbation and attenuation of pain. Prolactin is reported to trigger pain, while oxytocin and vasopressin have analgesic properties in both sexes. Only in the last two decades have neuroscientists begun to unravel the complex anatomical and molecular mechanisms underlying the direct effects of sex hormones and mechanisms have been reported in both the central and peripheral nervous systems. Mechanisms include directly or indirectly targeting receptors and ion channels on sensory neurons, activating pain excitatory or pain inhibitory centers in the brain, and reducing inflammatory mediators. Despite recent progress, there remains significant controversy and challenges in the field and the seemingly pleiotropic role estrogen plays on pain remains ambiguous. Current knowledge of the effects of sex hormones on pain has led to the burgeoning of gender-based medicine, and gaining further insight will lead to much needed improvement in pain management in women.
Dayna L. Averitt, Rebecca S. Hornung, and Anne Z. Murphy
Kristina A. Kigerl and Phillip G. Popovich
Spinal cord injury (SCI) disrupts the autonomic nervous system (ANS) and impairs communication with organ systems throughout the body, resulting in chronic multi-organ pathology and dysfunction. This dysautonomia contributes to the pronounced immunosuppression and gastrointestinal dysfunction seen after SCI. All of these factors likely contribute to the development of gut dysbiosis after SCI—an imbalance in the composition of the gut microbiota that can impact the development and progression of numerous pathological conditions, including SCI. The gut microbiota are the community of microbes (bacteria, viruses, fungi) that live in the GI tract and are critical for nutrient absorption, digestion, and immune system development. These microbes also communicate with the CNS through modulation of the immune system, production of neuroactive metabolites and neurotransmitters, and activation of the vagus nerve. After SCI, gut dysbiosis develops and persists for more than one year from the time of injury. In experimental models of SCI, gut dysbiosis is correlated with changes in inflammation and functional recovery. Moreover, probiotic treatment can improve locomotor recovery and immune function in the gut-associated lymphoid tissue (GALT). Since different types of bacteria produce different metabolites with unique physiological and pathological effects throughout the body, it may be possible to predict the prevalence or severity of post-injury immune dysfunction and other related comorbidities (e.g., metabolic disease, fatigue, anxiety) using microbiome sequencing data. As research identifies microbial-derived small molecules and the genes responsible for their production, it is likely that it will become feasible to manipulate these molecules to affect human biology and disease.
Peter Wenner and Pernille Bülow
Homeostatic plasticity refers to a collection of mechanisms that function to homeostatically maintain some feature of neural function. The field began with the view that homeostatic plasticity exists predominantly for the maintenance of spike rate. However, it has become clear that multiple features undergo some form of homeostatic control, including network activity, burst rate, or synaptic strength. There are several different forms of homeostatic plasticity, which are typically triggered following perturbations in activity levels. Homeostatic intrinsic plasticity (HIP) appears to compensate for the perturbation with changes in membrane excitability (voltage-gated conductances); synaptic scaling is thought to be a multiplicative increase or decrease of synaptic strengths throughout the cell following an activity perturbation; presynaptic homeostatic plasticity is a change in probability of release following a perturbation to postsynaptic receptor activity. Each form of homeostatic plasticity can be different in terms of the mechanisms that are engaged, the feature that is homeostatically regulated, the trigger that initiates the compensation, and the signaling cascades that mediate these processes. Homeostatic plasticity is often described in development, but can extend into maturity and has been described in vitro and in vivo.
Kaitlin Farrell, Megan R. Detloff, and John D. Houle
Spinal cord injury has instantaneous, destructive effects on bodily functions, as readily demonstrated by muscle paralysis and non-responsiveness to sensory stimulation. This primary response has underlying features at molecular, cellular, tissue and organ levels which will, in a relatively brief time, initiate a secondary cascade of events that exacerbates the extent of the primary focus of damage. Interestingly, the initial extent of motor and sensory loss often is followed by limited, but significant spontaneous functional recovery. Recovery may be due to intrinsic central pattern generators such as for locomotion, the uncovering of dormant anatomical and physiological pathways such as the crossed phrenic for respiration, or to the sprouting of undamaged axons within the spinal cord to establish new connections around or across the injury site. Together the responses to injury and spontaneous efforts for repair represent plastic changes in the central nervous system (CNS) that may result in meaningful functional outcomes, though aberrant sprouting is a possible negative consequence of neuroplasticity that lends caution to the desire for extensive but uncontrolled sprouting.
D. Grahame Hardie and A. Mark Evans
AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that monitors the levels of AMP and ADP relative to ATP. If increases in AMP:ATP and/or ADP:ATP ratios are detected (indicating a reduction in cellular energy status), AMPK is activated by the canonical mechanism involving both allosteric activation and enhanced net phosphorylation at Thr172 on the catalytic subunit. Once activated, AMPK phosphorylates dozens of downstream targets, thus switching on catabolic pathways that generate ATP and switching off anabolic pathways and other energy-consuming processes. AMPK can also be activated by non-canonical mechanisms, triggered either by glucose starvation by a mechanism independent of changes in adenine nucleotides, or by increases in intracellular Ca 2 + in response to hormones, mediated by the alternate upstream kinase CaMKK2. AMPK is expressed in almost all eukaryotic cells, including neurons, as heterotrimeric complexes comprising a catalytic α subunit and regulatory β and γ subunits. The α subunits contain the kinase domain and regulatory regions that interact with the other two subunits. The β subunits contain a domain that, with the small lobe of the kinase domain on the α subunit, forms the “ADaM” site that binds synthetic drugs that are potent allosteric activators of AMPK, while the γ subunits contain the binding sites for the classical regulatory nucleotides, AMP, ADP, and ATP. Although much undoubtedly remains to be discovered about the roles of AMPK in the nervous system, emerging evidence has confirmed the proposal that, in addition to its universal functions in regulating energy balance at the cellular level, AMPK also has cell- and circuit-specific roles at the whole-body level, particularly in energy homeostasis. These roles are mediated by phosphorylation of neural-specific targets such as ion channels, distinct from the targets by which AMPK regulates general, cell-autonomous energy balance. Examples of these cell- and circuit-specific functions discussed in this review include roles in the hypothalamus in balancing energy intake (feeding) and energy expenditure (thermogenesis), and its role in the brainstem, where it supports the hypoxic ventilatory response (breathing), increasing the supply of oxygen to the tissues during systemic hypoxia.
Jeremy C. Borniger and Luis de Lecea
The hypocretins (also known as orexins) are selectively expressed in a subset of lateral hypothalamic neurons. Since the reports of their discovery in 1998, they have been intensely investigated in relation to their role in sleep/wake transitions, feeding, reward, drug abuse, and motivated behavior. This research has cemented their role as a subcortical relay optimized to tune arousal in response to various salient stimuli. This article reviews their discovery, physiological modulation, circuitry, and integrative functionality contributing to vigilance state transitions and stability. Specific emphasis is placed on humoral and neural inputs regulating hcrt neural function and new evidence for an autoimmune basis of the sleep disorder narcolepsy. Future directions for this field involve dissection of the heterogeneity of this neural population using single-cell transcriptomics, optogenetic, and chemogenetics, as well as monitoring population and single cell activity. Computational models of the hypocretin network, using the “flip-flop” or “integrator neuron” frameworks, provide a fundamental understanding of how this neural population influences brain-wide activity and behavior.
Jimena Perez-Sanchez and Yves De Koninck
One of the most remarkable properties of neural circuits is the ability to restructure their synaptic connections throughout life. This synaptic plasticity allows neurons to structurally reorganize and adapt their function in response to experience. Among the multiple mechanisms that can modulate this property is synaptic inhibition by gamma-Aminobutyric acid (GABA) and/or glycine ionotropic receptors, which allow the flow of chloride and bicarbonate ions through the membrane. Neurons rely upon tight regulation of intracellular chloride for efficient inhibition through these receptors. The maintenance of chloride gradients is important not only to determine the strength of synaptic inhibition but also to determine its nature. Indeed, this inhibition can be hyperpolarizing or depolarizing, or with no outright change in the membrane potential. Despite the fact that membrane depolarization is commonly associated with excitation, depolarizing GABA/glycine can also produce inhibition, thereby highlighting the dual action of these neurotransmitters. Several considerations must be taken into account in order to allow depolarizing GABA/glycine responses to be excitatory. On the other hand, chloride homeostasis is never steady-state and even small changes of chloride across the membrane can impact the strength of inhibition. This dynamic effect has a direct impact on neuronal excitability and makes its regulation by changes in chloride gradients a highly tunable mechanism. Furthermore, increased excitability may also open a window for system refinement changes, such as synaptic plasticity. Indeed, the regulation of chloride homeostasis may underlie periods of enhanced plasticity, such as during early development. Finally, disruption of chloride gradients arises as a hub for pathology, which is evidenced in multiple disorders in the central nervous system.
Simona Candiani and Mario Pestarino
The central and peripheral nervous systems of amphioxus adults and larvae are characterized by morphofunctional features relevant to understanding the origins and evolutionary history of the vertebrate CNS. Classical neuroanatomical studies are mainly on adult amphioxus, but there has been a recent focus, both by TEM and molecular methods, on the larval CNS. The latter is small and remarkably simple, and new data on the localization of glutamatergic, GABAergic/glycinergic, cholinergic, dopaminergic, and serotonergic neurons within the larval CNS are now available. In consequence, it has been possible begin the process of identifying specific neuronal circuits, including those involved in controlling larval locomotion. This is especially useful for the insights it provides into the organization of comparable circuits in the midbrain and hindbrain of vertebrates. A much better understanding of basic chordate CNS organization will eventually be possible when further experimental data will emerge.
Norio Miyamoto and Hiroshi Wada
Hemichordates are marine invertebrates consisting of two distinct groups: the solitary enteropneusts and the colonial pterobranchs. Hemichordates are phylogenetically a sister group to echinoderm composing Ambulacraria. The adult morphology of hemichordates shares some features with chordates. For that reason, hemichordates have been considered key organisms to understand the evolution of deuterostomes and the origin of the chordate body plan. The nervous system of hemichordates is also important in the discussion of the origin of centralized nervous systems. However, unlike other deuterostomes, such as echinoderms and chordates, information on the nervous system of hemichordates is limited. Recent improvements in the accessibility of embryos, development of functional tools, and genomic resources from several model organisms have provided essential information on the nervous system organization and neurogenesis in hemichordates. The comparison of the nervous system between hemichordates and other bilaterians helps to elucidate the origin of the chordate central nervous system. Extant hemichordates are divided into two groups: enteropneusts and pterobranchs. The nervous system of adult enteropneusts consists of nerve cords and the basiepidermal nerve net. The two nerve cords run along the dorsal and ventral midlines. The dorsal nerve cord forms a tubular structure in the collar region. The two nerve cords are connected through the prebranchial nerve ring. The larval nervous system of enteropneusts develops along the ciliary band and there is a ganglion at the anterior end of the body called the apical ganglion. A pair of pigmented eyespots is situated at the lateral side of the apical ganglion. The adult nervous system of pterobranchs is basiepidermal and there are several condensations of plexuses. The most prominent one is the brain, located at the base of the tentaculated arms. From the brain, small fibers radiate and enter tentaculated arms to form a tentacle nerve in each. There is a basiepidermal nerve cord in the ventral midline of the trunk.
Synaptic connections in the brain can change their strength in response to patterned activity. This ability of synapses is defined as synaptic plasticity. Long lasting forms of synaptic plasticity, long-term potentiation (LTP), and long-term depression (LTD), are thought to mediate the storage of information about stimuli or features of stimuli in a neural circuit. Since its discovery in the early 1970s, synaptic plasticity became a central subject of neuroscience, and many studies centered on understanding its mechanisms, as well as its functional implications.