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Kathleen E. Cullen
As we go about our everyday activities, our brain computes accurate estimates of both our motion relative to the world, and of our orientation relative to gravity. Essential to this computation is the information provided by the vestibular system; it detects the rotational velocity and linear acceleration of our heads relative to space, making a fundamental contribution to our perception of self-motion and spatial orientation. Additionally, in everyday life, our perception of self-motion depends on the integration of both vestibular and nonvestibular cues, including visual and proprioceptive information. Furthermore, the integration of motor-related information is also required for perceptual stability, so that the brain can distinguish whether the experienced sensory inflow was a result of active self-motion through the world or if instead self-motion that was externally generated. To date, understanding how the brain encodes and integrates sensory cues with motor signals for the perception of self-motion during natural behaviors remains a major goal in neuroscience. Recent experiments have (i) provided new insights into the neural code used to represent sensory information in vestibular pathways, (ii) established that vestibular pathways are inherently multimodal at the earliest stages of processing, and (iii) revealed that self-motion information processing is adjusted to meet the needs of specific tasks. Our current level of understanding of how the brain integrates sensory information and motor-related signals to encode self-motion and ensure perceptual stability during everyday activities is reviewed.
Asymmetry of bilateral visual and auditory sensors has functional advantages for depth visual perception and localization of auditory signals, respectively. In order to detect the spatial distribution of an odor, bilateral olfactory organs may compare side differences of odor intensity and timing by using a simultaneous sampling mechanism; alternatively, they may use a sequential sampling mechanism to compare spatial and temporal input detected by one or several chemosensors. Extensive research on strategies and mechanisms necessary for odor source localization has been focused mainly on invertebrates. Several recent studies in mammals such as moles, rodents, and humans suggest that there is an evolutionary advantage in using stereo olfaction for successful navigation towards an odor source. Smelling in stereo or a three-dimensional olfactory space may significantly reduce the time to locate an odor source; this quality provides instantaneous information for both foraging and predator avoidance. However, since mammals are capable of finding odor sources and tracking odor trails with one sensor side blocked, they may use an intriguing temporal mechanism to compare odor concentration from sniff to sniff. A particular focus of this article is attributed to differences between insects and mammals regarding the use of unilateral versus bilateral chemosensors for odor source localization.
John D. Medaglia and Danielle S. Bassett
Network analyses in nervous system disorders involve constructing and analyzing anatomical and functional brain networks from neuroimaging data to describe and predict the clinical syndromes that result from neuropathology. A network view of neurological disease and clinical syndromes facilitates accurate quantitative characterizations and mathematical models of complex nervous system disorders with relatively simple tools drawn from the field of graph theory. Networks are predominantly constructed from in vivo data acquired using physiological and neuroimaging techniques at the macroscale of nervous system organization. Studies support the emerging view that neuropsychiatric and neurological disorders result from pathological processes that disrupt the brain’s economically wired small-world organization. The lens of network science offers theoretical insight into progressive neurodegeneration, neuropsychological dysfunction, and potential anatomical targets for interventions ranging from pharmacological agents to brain stimulation.
Jonathan M. Beckel and William C. de Groat
Functions of the lower urinary tract to store and periodically eliminate urine are regulated by a complex neural control system in the brain and lumbosacral spinal cord that coordinates the activity of smooth and striated muscles of the bladder and urethral outlet via a combination of voluntary and reflex mechanisms. Many neural circuits controlling the lower urinary tract exhibit switch-like patterns of activity that turn on and off in an all-or-none manner. During urine storage, spinal sympathetic and somatic reflexes are active to maintain a quiescent bladder and a closed outlet. During micturition, these spinal storage reflexes are suppressed by input from the brain, while parasympathetic pathways in the brain are activated to produce a bladder contraction and relaxation of the urethra. The major component of the micturition switching circuit is a spinobulbospinal parasympathetic pathway that consists of essential relay circuitry in the periaqueductal gray and pontine micturition center. These circuits in the rostral brain stem are, in turn, regulated by inputs from the forebrain that mediate voluntary control of micturition. Thus neural control of micturition is organized as a hierarchical system in which spinal storage reflexes and supraspinal voiding reflexes are regulated voluntarily by higher centers in the brain. In young children the voluntary mechanisms are undeveloped and voiding is purely reflex. Voluntary control emerges during maturation of the nervous system and depends on learned behavior. Diseases or injuries of the nervous system in adults cause re-emergence of involuntary micturition, leading to urinary incontinence.
Justin D. Lieber and Sliman J. Bensmaia
The ability to identify tactile objects depends in part on the perception of their surface microstructure and material properties. Texture perception can, on a first approximation, be described by a number of nameable perceptual axes, such as rough/smooth, hard/soft, sticky/slippery, and warm/cool, which exist within a complex perceptual space. The perception of texture relies on two different neural streams of information: Coarser features, measured in millimeters, are primarily encoded by spatial patterns of activity across one population of tactile nerve fibers, while finer features, down to the micron level, are encoded by finely timed temporal patterns within two other populations of afferents. These two streams of information ascend the somatosensory neuraxis and are eventually combined and further elaborated in the cortex to yield a high-dimensional representation that accounts for our exquisite and stable perception of texture.
Understanding the principles by which sensory systems represent natural stimuli is one of the holy grails of neuroscience. In the auditory system, the study of the coding of natural sounds has a particular prominence. Indeed, the relationships between neural responses to simple stimuli (usually pure tone bursts)—often used to characterize auditory neurons—and complex sounds (in particular natural sounds) may be complex. Many different classes of natural sounds have been used to study the auditory system. Sound families that researchers have used to good effect in this endeavor include human speech, species-specific vocalizations, an “acoustic biotope” selected in one way or another, and sets of artificial sounds that mimic important features of natural sounds.
Peripheral and brainstem representations of natural sounds are relatively well understood. The properties of the peripheral auditory system play a dominant role, and further processing occurs mostly within the frequency channels determined by these properties. At the level of the inferior colliculus, the highest brainstem station, representational complexity increases substantially due to the convergence of multiple processing streams. Undoubtedly, the most explored part of the auditory system, in term of responses to natural sounds, is the primary auditory cortex. In spite of over 50 years of research, there is still no commonly accepted view of the nature of the population code for natural sounds in the auditory cortex. Neurons in the auditory cortex are believed by some to be primarily linear spectro-temporal filters, by others to respond to conjunctions of important sound features, or even to encode perceptual concepts such as “auditory objects.” Whatever the exact mechanism is, many studies consistently report a substantial increase in the variability of the response patterns of cortical neurons to natural sounds. The generation of such variation may be the main contribution of auditory cortex to the coding of natural sounds.
Ruth I. Wood and Kathryn G. Wallin-Miller
Anabolic-androgenic steroids (AAS) are both performance-enhancing substances and drugs of abuse. Although AAS are banned in competitive sports, they are widely used by both elite and rank-and-file athletes. All AAS are derived from testosterone, the principle endogenous androgen produced by the testes of adult men. While AAS increase muscular strength and athletic performance, they also have serious consequences for health and behavior. AAS are implicated in maladaptive behavioral and cognitive changes such as increased risk-taking and altered decision-making. However, effects of AAS on cognition are not well understood. Studies of human AAS users are limited by an inability to control for pre-existing psychopathology and behavioral differences. Furthermore, in order to understand AAS effects on behavior, it is important to discover how AAS impact the brain. Animal models of AAS abuse parallel human studies to uncover effects on cognition, decision-making, and underlying neurobiological mechanisms. In operant discounting tests, rats treated with chronic high-dose testosterone are less sensitive to effort, punishment, and delay but are more sensitive to uncertainty. Likewise, they demonstrate impaired cognitive flexibility when tested for set-shifting and reversal learning. It appears that AAS induce many of these cognitive changes via effects on the mesocorticolimbic dopamine system, particularly through the dopamine D1- and D2-like receptors in subnuclei of the nucleus accumbens. AAS also have rewarding effects mediated by similar neural circuits. In preclinical studies, animals will voluntarily self-administer AAS. Human users may develop dependence. These findings highlight the vulnerability of brain circuits controlling cognition and reward to androgens at high doses.
Judith M. Ford, Holly K. Hamilton, and Alison Boos
Auditory verbal hallucinations (AVH), also referred to as “hearing voices,” are vivid perceptions of speech that occur in the absence of any corresponding external stimulus but seem very real to the voice hearer. They are experienced by the majority of people with schizophrenia, less frequently in other psychiatric and neurological conditions, and are relatively rare in the general population. Because antipsychotic medications are not always successful in reducing the severity or frequency of AVH, a better understanding is needed of their neurobiological basis, which may ultimately lead to more precise treatment targets.
What voices say and how the voices sound, or their phenomenology, varies widely within and across groups of people who hear them. In help-seeking populations, such as people with schizophrenia, the voices tend to be threatening and menacing, typically spoken in a non-self-voice, often commenting and sometimes commanding the voice hearers to do things they would not otherwise do. In psychotic populations, voices differ from normal inner speech by being unbidden and unintended, co-opting the voice hearer’s attention. In healthy voice-hearing populations, voices are not typically distressing nor disabling, and are sometimes comforting and reassuring. Regardless of content and valence, voices tend to activate some speech and language areas of the brain. Efforts to silence these brain areas with neurostimulation have had mixed success in reducing the frequency and salience of voices. Progress with this treatment approach would likely benefit from more precise anatomical targets and more precisely dosed neurostimulation.
Neural mechanisms that may underpin the experience of voices are being actively investigated and include mechanisms enabling context-based predictions and distinctions between experiences coming from self and other. Both these mechanisms can be studied in non-human animal “models” and both can provide new anatomical targets for neurostimulation.
Divine C. Nwafor, Allison L. Brichacek, Sreeparna Chakraborty, Catheryne A. Gambill, Stanley A. Benkovic, and Candice M. Brown
The blood-brain barrier (BBB) is a dynamic structural interface between the brain and periphery that plays a critical function in maintaining cerebral homeostasis. Over the past two decades, technological advances have improved our understanding of the neuroimmune and neuroendocrine mechanisms that regulate a healthy BBB. The combination of biological sex, sex steroids, age, coupled with innate and adaptive immune components orchestrates the crosstalk between the BBB and the periphery. Likewise, the BBB also serves as a nexus within the hypothalamic-pituitary-adrenal (HPA) and gut-brain-microbiota axes. Compromised BBB integrity permits the entry of bioactive molecules, immune cells, microbes, and other components that migrate into the brain parenchyma and compromise neuronal function. A paramount understanding of the mechanisms that determine the bidirectional crosstalk between the BBB and immune and endocrine pathways has become increasingly important for implementation of therapeutic strategies to treat a number of neurological disorders that are significantly impacted by the BBB. Examples of these disorders include multiple sclerosis, Alzheimer’s disease, stroke, epilepsy, and traumatic brain injury.
Ashlyn Swift-Gallant and S. Marc Breedlove
While prenatal sex hormones guide the development of sex-typical reproductive structures, they also act on the developing brain, resulting in sex differences in brain and behavior in animal models. Stemming from this literature is the prominent hypothesis that prenatal neuroendocrine factors underlie sex differences in human sexual orientation, to explain why most males have a preference for female sexual partners (gynephilia), whereas most females display a preference for male sexual partners (androphilia). Convergent evidence from experiments of nature and indirect markers of prenatal hormones strongly support a role for prenatal androgens in same-same sexual orientations in women, although this finding is specific to a subset of lesbians who are also gender nonconforming (“butch”). More gender-conforming lesbians (“femmes”) do not show evidence of increased prenatal androgens. The literature has been more mixed for male sexual orientation: some report evidence of low prenatal androgen exposure, while others report evidence of high androgen levels and many other studies find no support for a role of prenatal androgen exposure in the development of androphilia in males. Recent evidence suggests there may be subgroups of gay men who owe their sexual orientation to distinct biodevelopmental mechanisms, which could account for these mixed findings. Although this research is young, it is similar to findings from lesbian populations, because gay men who are more gender nonconforming, and report a preference for receptive anal sex, differ on markers of prenatal development from gay men who are more gender conforming and report a preference for insertive anal sex. This chapter concludes with future research avenues including assessing whether multiple biodevelopmental pathways underlie sexual orientation and whether neuroendocrine factors and other biological mechanisms (e.g., immunology, genetics) interact to promote a same-sex sexual orientation.
Lily Yan, Laura Smale, and Antonio A. Nunez
Circadian rhythms are endogenous daily rhythms evident in behavior and physiology. In mammals, these rhythms are controlled by a hierarchical network of oscillators showing a coherent circadian coordination or coupling. The hypothalamic suprachiasmatic nucleus (SCN) sits on top of the hierarchy and coordinates the phase of oscillators in other brain regions and in peripheral organs, including endocrine glands. The phase of the SCN oscillator, in reference to the daily light-dark cycle, is identical across mammalian species regardless of whether they are most active during the day or night, that is, diurnal or nocturnal. However, the extra-SCN or peripheral oscillators are out of phase and are often reversed by 180° across diurnal and nocturnal mammals. In the endocrine system, with the notable exception of the pattern of pineal melatonin secretion, which features elevated levels at night regardless of the activity profile of the species, most endocrine rhythms show a 180° reversal when diurnal and nocturnal species are compared. There is also evidence of differences between nocturnal and diurnal species with respect to their rhythms in sensitivity or responsiveness to hormonal stimulation. One of the major unanswered questions in the field of comparative endocrinology relates to the mechanism responsible for the differential coupling in diurnal and nocturnal mammals of extra-SCN oscillators and overt circadian rhythms with the SCN oscillator and the light dark cycle. Viable hypotheses include species-specific switches from excitation to inhibition at key nodes between the SCN and its targets, the presence of extra-SCN signals that converge on SCN targets and reverse the outcome of SCN signals, and changes in oscillatory parameters between the oscillator of the SCN and those outside the SCN resulting in an anti-phase coupling among key oscillators.
Allison E. Gaffey and Brandy S. Martinez
There are two main branches of the human stress response. The autonomic nervous system acts rapidly and is often referred to as our fight or flight response. The slow-acting arm of the stress response refers to the hypothalamic-pituitary-adrenal (HPA) axis, which triggers a hormone cascade resulting in the release of various hormones including cortisol. Healthy functioning of the HPA axis is tightly regulated by negative feedback, the endogenous self-regulatory mechanism of the system that terminates cortisol production. Alterations in HPA axis functioning are characterized by both hypo- and hypersecretion of cortisol in response to psychological stress and are typically associated with negative physical health outcomes as well as clinical pathology. What remains poorly understood is how HPA activity changes with age and the pathways through which these changes occur.
In addition to changes associated with the normative aging process, age-related changes in cortisol may also be driven by the cumulative effects of stress experienced across the life span (e.g., traumatic stress); stressors unique to later life (e.g., caring for an ailing loved one); or health problems. Although research examining how the HPA axis might change with age is inconsistent, there appears to be reasonable evidence to suggest that: (1) both stress-induced and diurnal cortisol output may increase with age, potentially beginning with changes in the cortisol awakening response, (2) variability in cortisol production increases with age, (3) diurnal (i.e., daily) cortisol rhythms are preserved in later life, and (4) age-related differences in cortisol may be more distinct in men than in women. However, it remains unknown whether these changes in older adults’ physiology reflect maladaptive functioning of the HPA axis or interact with other health concerns to negatively affect overall psychophysiological health. Further research is needed to disentangle the interplay between aging and HPA axis functioning to better understand what alterations are associated with the normative aging process, when they occur, and how they influence longevity.
Elisabetta Tolla, Jonathan H. Pérez, Ian C. Dunn, Simone L. Meddle, and Tyler J. Stevenson
Neuroendocrine mechanisms control the seasonal reproduction in birds and mammals. Seasonal reproduction is ubiquitous across vertebrate and invertebrate species, and its timing is extremely crucial in order to maximize offspring survival. The hypothalamus is the key brain region that integrates environmental cues. An endogenous circannual timer with oscillations that approximate one year is also localized in the hypothalamus. Successful timing of reproduction involves the combination of endogenous internal timers that are entrained by local environmental cues. Photoperiod, or the annual change in day length, is the primary cue most temperate animals use to predict future environmental conditions. Birds are able to detect light through photoreceptors located in the medio-basal hypothalamus. These photoreceptors are localized in neuroendocrine regions and regulate the key reproductive neuropeptide gonadotropin-releasing hormone (GnRH). In mammals, retinal photoreceptors transduce light information the suprachiasmatic nucleus in the hypothalamus, which then modulates the nocturnal duration of melatonin. Melatonin in mammals is crucial, as it regulates the neuroendocrine release of GnRH and downstream transitions across seasonal reproductive states. The tanycyte cells lining the third ventricle (3rdV) of the hypothalamus are the critical node for the integration of internal (i.e., circannual timing) and external (e.g., photoperiod) information necessary for the regulation of seasonal reproduction.
Gretchen N. Neigh, Mandakh Bekhbat, and Sydney A. Rowson
Bidirectional interactions between the immune system and central nervous system have been acknowledged for centuries. Over the past 100 years, pioneering studies in both animal models and humans have delineated the behavioral consequences of neuroimmune activation, including the different facets of sickness behavior. Rodent studies have uncovered multiple neural pathways and mechanisms that mediate anorexia, fever, sleep alterations, and social withdrawal following immune activation. Furthermore, work conducted in human patients receiving interferon treatment has elucidated some of the mechanisms underlying immune-induced behavioral changes such as malaise, depressive symptoms, and cognitive deficits.
These findings have provided the foundation for development of treatment interventions for conditions in which dysfunction of immune-brain interactions leads to behavioral pathology. Rodent models of neuroimmune activation frequently utilize endotoxins and cytokines to directly stimulate the immune system. In the absence of pathogen-induced inflammation, a variety of environmental stressors, including psychosocial stressors, also lead to neuroimmune alterations and concurrent behavioral changes. These behavioral alterations can be assessed using a battery of behavioral paradigms while distinguishing acute sickness behavior from the type of behavioral outcome being assessed. Animal studies have also been useful in delineating the role of microglia, the neuroendocrine system, neurotransmitters, and neurotrophins in mediating the behavioral implications of altered neuroimmune activity. Furthermore, the timing and duration of neuroimmune challenge as well as the sex of the organism can impact the behavioral manifestations of altered neuroimmune activity. Finally, neuroimmune modulation through pharmacological or psychosocial approaches has potential for modulating behavior.
Much progress has been made in unraveling the mechanisms that underlie the transition from acute to chronic pain. Traditional beliefs are being replaced by novel, more powerful concepts that consider the mutual interplay of neuronal and non-neuronal cells in the nervous system during the pathogenesis of chronic pain. The new focus is on the role of neuroinflammation for neuroplasticity in nociceptive pathways and for the generation, amplification, and mislocation of pain. The latest insights are reviewed here and provide a basis for understanding the interdependence of chronic pain and its comorbidities. The new concepts will guide the search for future therapies to prevent and reverse chronic pain.
Long-term changes in the properties and functions of nerve cells, including changes in synaptic strength, membrane excitability, and the effects of inhibitory neurotransmitters, can result from a wide variety of conditions. In the nociceptive system, painful stimuli, peripheral inflammation, nerve injuries, the use of or withdrawal from opioids—all can lead to enhanced pain sensitivity, to the generation of pain, and/or to the spread of pain to unaffected sites of the body. Non-neuronal cells, especially microglia and astrocytes, contribute to changes in nociceptive processing. Recent studies revealed not only that glial cells support neuroplasticity but also that their activation can trigger long-term changes in the nociceptive system.
Kenway Louie and Paul W. Glimcher
A core question in systems and computational neuroscience is how the brain represents information. Identifying principles of information coding in neural circuits is critical to understanding brain organization and function in sensory, motor, and cognitive neuroscience. This provides a conceptual bridge between the underlying biophysical mechanisms and the ultimate behavioral goals of the organism. Central to this framework is the question of computation: what are the relevant representations of input and output, and what algorithms govern the input-output transformation? Remarkably, evidence suggests that certain canonical computations exist across different circuits, brain regions, and species. Such computations are implemented by different biophysical and network mechanisms, indicating that the unifying target of conservation is the algorithmic form of information processing rather than the specific biological implementation.
A prime candidate to serve as a canonical computation is divisive normalization, which scales the activity of a given neuron by the activity of a larger neuronal pool. This nonlinear transformation introduces an intrinsic contextual modulation into information coding, such that the selective response of a neuron to features of the input is scaled by other input characteristics. This contextual modulation allows the normalization model to capture a wide array of neural and behavioral phenomena not captured by simpler linear models of information processing. The generality and flexibility of the normalization model arises from the normalization pool, which allows different inputs to directly drive and suppress a given neuron, effectively separating information that drives excitation and contextual modulation. Originally proposed to describe responses in early visual cortex, normalization has been widely documented in different brain regions, hierarchical levels, and modalities of sensory processing; furthermore, recent work shows that the normalization extends to cognitive processes such as attention, multisensory integration, and decision making. This ubiquity reinforces the canonical nature of the normalization computation and highlights the importance of an algorithmic framework in linking biological mechanism and behavior.
Caleigh Guoynes and Catherine Marler
How hormones and neuromodulators initiate and maintain paternal care is important for understanding the evolution of paternal care and the plasticity of the social brain. The focus here is on mammalian paternal behavior in rodents, non-human primates and humans. Only 5% of mammalian species express paternal care, and many of those species likely evolved the behavior convergently. This means that there is a high degree of variability in how hormones and neuromodulators shape paternal care across species. Important factors to consider include social experience (alloparental care, mating, pair bonding, raising a previous litter), types of care expressed (offspring protection, providing and sharing food, socio-cognitive development), and timing of hormonal changes (after mating, during gestation, after contact with offspring). The presence or absence of infanticide towards offspring prior to mating may also be a contributor, especially in rodents. Taking these important factors into account, we have found some general trends across species. (1) Testosterone and progesterone tend to be negatively correlated with paternal care but promote offspring defense in some species. The most evidence for a positive association between paternal care and testosterone have appeared in rodents. (2) Prolactin, oxytocin, corticosterone, and cortisol tend to be positively correlated. (3) Estradiol and vasopressin are likely nuclei specific—with some areas having a positive correlation with paternal care and others having a negative association. Some mechanisms appear to be coopted from females and others appear to have evolved independently. Overall, the neuroendocrine system seems especially important for mediating environmental influences on paternal behavior.
Color perception in macaque monkeys and humans depends on the visually evoked activity in three cone photoreceptors and on neuronal post-processing of cone signals. Neuronal post-processing of cone signals occurs in two stages in the pathway from retina to the primary visual cortex. The first stage, in in P (midget) ganglion cells in the retina, is a single-opponent subtractive comparison of the cone signals. The single-opponent computation is then sent to neurons in the Parvocellular layers of the Lateral Geniculate Nucleus (LGN), the main visual nucleus of the thalamus. The second stage of processing of color-related signals is in the primary visual cortex, V1, where multiple comparisons of the single-opponent signals are made. The diversity of neuronal interactions in V1cortex causes the cortical color cells to be subdivided into classes of single-opponent cells and double-opponent cells. Double-opponent cells have visual properties that can be used to explain most of the phenomenology of color perception of surface colors; they respond best to color edges and spatial patterns of color. Single opponent cells, in retina, LGN, and V1, respond to color modulation over their receptive fields and respond best to color modulation over a large area in the visual field.
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.
William Rodemer, Jianli Hu, and Michael E. Selzer
Human spinal cord injury (SCI) results in long-lasting disabilities due to the failure of damaged neurons to regenerate. The barriers to axon regeneration in mammalian central nervous system (CNS) are so great, and the anatomy so complex that incremental changes in regeneration brought about by pharmacological or molecular manipulations can be difficult to demonstrate. By contrast, lampreys recover functionally after a complete spinal cord transection (TX), based on regeneration of severed axons, even though lampreys share the basic organization of the mammalian CNS, including many of the same molecular barriers to regeneration. And because the regeneration is incomplete, it can be studied by manipulations designed to either inhibit or enhance it. In the face of reduced descending input, recovery of swimming and other locomotor functions must be accompanied by compensatory remodeling throughout the CNS, as would be required for functional recovery in mammals. For such studies, lampreys have significant advantages. They have several large, identified reticulospinal (RS) neurons, whose regenerative abilities have been individually quantified. Other large neurons and axons are visible in the spinal cord and can be impaled with microelectrodes under direct microscopic vision. The central pattern generator for locomotion is exceptionally well-defined, and is subject to significant neuromodulation. Finally, the lamprey genome has been sequenced, so that molecular homologs of human genes can be identified and cloned. Because of these advantages, the lamprey spinal cord has been a fertile source of information about the biology of axon regeneration in the vertebrate CNS, and has the potential to serve as a test bed for the investigation of novel therapeutic approaches to SCI and other CNS injuries.