Motor learning is an essential part of human behavior, but poorly understood in the context of walking control. Here, we discuss our recent work on locomotor adaptation, which is an error driven motor learning process used to alter spatiotemporal elements of walking. Locomotor adaptation can be induced using a split-belt treadmill that controls the speed of each leg independently. Practicing split-belt walking changes the coordination between the legs, resulting in storage of a new walking pattern. Here, we review findings from this experimental paradigm regarding the learning and generalization of locomotor adaptation. First, we discuss how split-belt walking adaptation develops slowly throughout childhood and adolescence. Second, we demonstrate that conscious effort to change the walking pattern during split-belt training can speed up adaptation but worsens retention. In contrast, distraction (i.e., performing a dual task) during training slows adaptation but improves retention. Finally, we show the walking pattern acquired on the split-belt treadmill generalizes to natural walking when vision is removed. This suggests that treadmill learning can be generalized to different contexts if visual cues specific to the treadmill are removed. These findings allow us to highlight the many future questions that will need to be answered in order to develop more rational methods of rehabilitation for walking deficits.
locomotion; motor learning; adaptation; generalization of learning; rehabilitation
Epidemiological studies show that adverse cardiovascular events peak in the morning (i.e., between 6 AM and noon) and that shift work is associated with cardiovascular disease, obesity, and diabetes. The endogenous circadian timing system modulates certain cardiovascular risk markers to be highest (e.g., cortisol, nonlinear dynamic heart rate control, and platelet activation) or to respond most unfavorably to stressors such as exercise (e.g., epinephrine, norepinephrine, and vagal cardiac modulation) at an internal body time corresponding to the time of day when adverse cardiovascular events most likely occur. This indicates that the circadian timing system and its interaction with external cardiovascular stressors (e.g., physical activity) could contribute to the morning peak in adverse cardiovascular events. Moreover, circadian misalignment and simulated night work have adverse effects on cardiovascular and metabolic function. This suggests that misalignment between the behavioral cycle and the circadian timing system in shift workers contributes to that population’s increased risk for cardiometabolic disease.
biological clock; circadian misalignment; glucose metabolism; heart; night work; shift work; suprachiasmatic nucleus
The cochlear implant (CI) is one of the great success stories of modern medicine. A high level of function is provided for most patients. However, some patients still do not achieve excellent or even good results using the present-day devices. Accumulating evidence is pointing to differences in the processing abilities of the “auditory brain” among patients as a principal contributor to this remaining and still large variability in outcomes. In this chapter, we describe a new approach to the design of CIs that takes these differences into account and thereby may improve outcomes for patients with compromised auditory brains.
cochlear implant; cochlear prosthesis; auditory prosthesis; brain–machine interface; brain plasticity; neural prostheses; hearing; deafness; central auditory processing; auditory cortex
After birth, there is striking biological and functional development of the brain’s fiber tracts as well as remodeling of cortical and subcortical structures. Behavioral development in children involves a complex and dynamic set of genetically guided processes by which neural structures interact constantly with the environment. This is a protracted process, beginning in the third week of gestation and continuing into early adulthood. Reviewed here are studies using structural imaging techniques, with a special focus on diffusion weighted imaging, describing age-related brain maturational changes in children and adolescents, as well as studies that link these changes to behavioral differences. Finally, we discuss evidence for effects on the brain of several factors that may play a role in mediating these brain–behavior associations in children, including genetic variation, behavioral interventions, and hormonal variation associated with puberty. At present longitudinal studies are few, and we do not yet know how variability in individual trajectories of biological development in specific neural systems map onto similar variability in behavioral trajectories.
MRI; DTI; brain development; cognitive development; individual differences; fiber tracts
A panic response is an adaptive response to deal with an imminent threat and consists of an integrated pattern of behavioral (aggression, fleeing or freezing) and increased cardiorespiratory and endocrine responses that are highly conserved across vertebrate species. In the 1920’s and 1940’s Philip Bard and Walter Hess respectively determined that the posterior regions of the hypothalamus are critical for a “fight-or-flight” reaction to deal with an imminent threat. Since the 1940’s it was determined that the posterior hypothalamic panic area was located dorsal (perifornical nucleus: PeF) and dorsomedial (dorsomedial hypothalamus: DMH) to the fornix. This area is also critical for regulating circadian rhythms and in 1998, a novel wake-promoting neuropeptide called orexin/hypocretin (ORX) was discovered and determined to be almost exclusively synthesized in the DMH/PeF and adjacent lateral hypothalamus. The most proximally emergent role of ORX is in regulation of wakefulness through interactions with efferent systems that mediate arousal and energy homeostasis. A hypoactive ORX system is also linked to narcolepsy. However, ORX’s role in more complex emotional responses is emerging in more recent studies where ORX is linked to depression and anxiety states. Here we review data that, demonstrates ORX’s ability to mobilize a coordinated adaptive panic/defence response (anxiety, cardiorespiratory and endocrine components), and summarize the evidence that supports a hyperactive ORX system being linked to pathological panic and anxiety states.
Neural prosthetic systems aim to help disabled patients suffering from a range of neurological injuries and disease by using neural activity from the brain to directly control assistive devices. This approach in effect bypasses the dysfunctional neural circuitry, such as an injured spinal cord. To do so, neural prostheses depend critically on a scientific understanding of the neural activity that drives them. We review here several recent studies aimed at understanding the neural processes in premotor cortex that precede arm movements and lead to the initiation of movement. These studies were motivated by hypotheses and predictions conceived of within a dynamical systems perspective. This perspective concentrates on describing the neural state using as few degrees of freedom as possible and on inferring the rules that govern the motion of that neural state. Although quite general, this perspective has led to a number of specific predictions that have been addressed experimentally. It is hoped that the resulting picture of the dynamical role of preparatory and movement-related neural activity will be particularly helpful to the development of neural prostheses, which can themselves be viewed as dynamical systems under the control of the larger dynamical system to which they are attached.
premotor cortex; motor cortex; motor preparation; state space; dynamical systems; singletrial analysis; neural prostheses; brain machine interface; brain computer interface
Breathing emerges through complex network interactions involving neurons distributed throughout the nervous system. The respiratory rhythm generating network is composed of micro networks functioning within larger networks to generate distinct rhythms and patterns that characterize breathing. The pre-Bötzinger complex, a rhythm generating network located within the ventrolateral medulla assumes a core function without which respiratory rhythm generation and breathing cease altogether. It contains subnetworks with distinct synaptic and intrinsic membrane properties that give rise to different types of respiratory rhythmic activities including eupneic, sigh, and gasping activities. While critical aspects of these rhythmic activities are preserved when isolated in in vitro preparations, the pre-Bötzinger complex functions in the behaving animal as part of a larger network that receives important inputs from areas such as the pons and parafacial nucleus. The respiratory network is also an integrator of modulatory and sensory inputs that imbue the network with the important ability to adapt to changes in the behavioral, metabolic, and developmental conditions of the organism. This review summarizes our current understanding of these interactions and relates the emerging concepts to insights gained in other rhythm generating networks.
Breathing; Respiratory rhythm generation; Pre-Botzinger complex and interactions
Neural activity in the lateral intraparietal area (LIP) has been associated with attention to a location in visual space, and with the intention to make saccadic eye movement. In this study we show that neurons in LIP respond to recently flashed task-irrelevant stimuli and saccade targets brought into the receptive field by a saccade, although they respond much to the same stimuli when they are stable in the environment. LIP neurons respond to the appearance of a flashed distractor even when a monkey is planning a memory-guided delayed saccade elsewhere. We then show that a monkey’s attention, as defined by an increase in contrast sensitivity, is pinned to the goal of a memory-guided saccade throughout the delay period, unless a distractor appears, in which case attention transiently moves to the site of the distractor and then returns to the goal of the saccade. LIP neurons respond to both the saccade goal and the distractor, and this activity correlates with the monkey’s locus of attention. In particular, the activity of LIP neurons predicts when attention migrates from the distractor back to the saccade goal. We suggest that the activity in LIP provides a salience map that is interpreted by the oculomotor system as a saccade goal when a saccade is appropriate, and simultaneously is used by the visual system to determine the locus of attention.
lateral intraparietal area; saccade; attention; contrast sensitivity; monkey
Of the several aquaporin (AQP) water channels expressed in the central nervous system, AQP4 is an attractive target for drug discovery. AQP4 is expressed in astroglia, most strongly at the blood–brain and brain–cerebrospinal fluid barriers. Phenotype analysis of AQP4 knockout mice indicates the involvement of AQP4 in three distinct processes: brain water balance, astroglial cell migration and neural signal transduction. By slowing water uptake into the brain, AQP4 knockout mice manifest reduced brain swelling and improved outcome in models of cytotoxic cerebral oedema such as water intoxication, focal ischaemia and meningitis. However, by slowing the clearance of excess water from brain, AQP4 knockout mice do worse in models of vasogenic oedema such as brain tumour, abscess and hydrocephalus. AQP4 deficient astroglial cells show greatly impaired migration in response to chemotactic stimuli, reducing glial scar formation, by a mechanism that we propose involves AQP4-facilitated water flux in lamellipodia of migrating cells. AQP4 knockout mice also manifest increased seizure threshold and duration, by a mechanism that may involve slowed K+ uptake from the extracellular space (ECS) following neuroexcitation, as well as ECS expansion. Notwithstanding challenges in drug delivery to the central nervous system and their multiplicity of actions, AQP4 inhibitors have potential utility in reducing cytotoxic brain swelling, increasing seizure threshold and reducing glial scar formation; enhancers of AQP4 expression have potential utility in reducing vasogenic brain swelling. AQP4 modulators may thus offer new therapeutic options for stroke, tumour, infection, hydrocephalus, epilepsy and traumatic brain and spinal cord injury.
AQP4; water transport; transgenic mouse; brain oedema; cell migration; epilepsy
Sleep, which is evolutionarily conserved across species, is a biological imperative that cannot be ignored or replaced. However, the percentage of habitually sleep-restricted adults has increased in recent decades. Extended work hours and commutes, shift work schedules, and television viewing are particularly potent social factors that influence sleep duration. Chronic partial sleep restriction, a product of these social expediencies, leads to the accumulation of sleep debt over time and consequently increases sleep propensity, decreases alertness, and impairs critical aspects of cognitive functioning. Significant interindividual variability in the neurobehavioral responses to sleep restriction exists—this variability is stable and phenotypic—suggesting a genetic basis. Identifying vulnerability to sleep loss is essential as many adults cannot accurately judge their level of impairment in response to sleep restriction. Indeed, the consequences of impaired performance and the lack of insight due to sleep loss can be catastrophic. In order to cope with the effects of social expediencies on biological imperatives, identification of biological (including genetic) and behavioral markers of sleep loss vulnerability as well as development of technological approaches for fatigue management are critical.
sleep deprivation; sleep duration; neurobehavioral functions; fatigue management; individual differences; genetics; biomarkers
Basic tendencies to detect and respond to significant events are present in the simplest single cell organisms, and persist throughout all invertebrates and vertebrates. Within vertebrates, the overall brain plan is highly conserved, though differences in size and complexity also exist. The forebrain differs the most between mammals and other vertebrates. The classic notion that the evolution of mammals led to radical changes such that new forebrain structures (limbic system and neocortex) were added has not held up, nor has the idea that so-called limbic areas are primarily involved in emotion. Modern efforts have focused on specific emotion systems, like the fear or defense system, rather than on the search for a general purpose emotion systems. Such studies have found that fear circuits are conserved in mammals, including humans. Animal work has been especially successful in determining how the brain detects and responds to danger. Caution should be exercised when attempting to discuss other aspects of emotion, namely subjective feelings, in animals since there are no scientific ways of verifying and measuring such states except in humans.
The nonhuman primate brain, the model system closest to the human brain, plays a critical role in our understanding of neural computation, cognition, and behavior. The continued quest to crack the neural codes in the monkey brain would be greatly enhanced with new tools and technologies that can rapidly and reversibly control the activities of desired cells at precise times during specific behavioral states. Recent advances in adapting optogenetic technologies to monkeys have enabled precise control of specific cells or brain regions at the millisecond timescale, allowing for the investigation of the causal role of these neural circuits in this model system. Validation of optogenetic technologies in monkeys also represents a critical preclinical step on the translational path of new generation cell-type-specific neural modulation therapies. Here, I discuss the current state of the application of optogenetics in the nonhuman primate model system, highlighting the available genetic, optical and electrical technologies, and their limitations and potentials.
monkey; genetic manipulation; optical; channelrhodopsin; archaerhodopsin; halorhodopsin; rat
The magnocellular neurons of the hypothalamic supraoptic nucleus (SON) are a major source of both systemic and central release of the neurohypophyseal peptides, oxytocin (OXT) and arginine–vasopressin (AVP). Both OXT and AVP are released from the somatodendritic compartment of magnocellular neurons and act within the SON to modulate the electrophysiological function of these cells. Cannabinoids (CBs) affect hormonal output and the SON may represent a neural substrate through which CBs exert specific physiological and behavioural effects. Dynamic modulation of synaptic inputs is a fundamental mechanism through which neuronal output is controlled. Dendritically released OXT acts on autoreceptors to generate endocannabinoids (eCBs) which modify both excitatory and inhibitory inputs to OXT neurons through actions on presynaptic CB receptors. As such, OXT and eCBs cooperate to shape the electrophysiological properties of magnocellular OXT neurons, regulating the physiological function of this nucleus. Further study of eCB signalling in the SON, including its interaction with AVP neurons, promises to extend our understanding of the synaptic regulation of SON physiological function.
PMID: 18655878 CAMSID: cams2631
hypothalamus; oxytocin; magnocellular neurons; retrograde messengers
The ability to silence, in a temporally precise fashion, the electrical activity of specific neurons embedded within intact brain tissue, is important for understanding the role that those neurons play in behaviors, brain disorders, and neural computations. “Optogenetic” silencers, genetically encoded molecules that, when expressed in targeted cells within neural networks, enable their electrical activity to be quieted in response to pulses of light, are enabling these kinds of causal circuit analyses studies. Two major classes of optogenetic silencer are in broad use in species ranging from worm to monkey: light-driven inward chloride pumps, or halorhodopsins, and light-driven outward proton pumps, such as archaerhodopsins and fungal light-driven proton pumps. Both classes of molecule, when expressed in neurons via viral or other transgenic means, enable the targeted neurons to be hyperpolarized by light. We here review the current status of these sets of molecules, and discuss how they are being discovered and engineered. We also discuss their expression properties, ionic properties, spectral characteristics, and kinetics. Such tools may not only find many uses in the quieting of electrical activity for basic science studies, but may also, in the future, find clinical uses for their ability to safely and transiently shut down cellular electrical activity in a precise fashion.
optogenetics; opsins; neural silencing; halorhodopsin; archaerhodopsin; channelrhodopsin; control; cell types; neural circuits; causality
Functional MRI (fMRI) studies performed during both waking rest and sleep show that the brain is continually active in distinct patterns that appear to reflect its underlying functional connectivity. In this review, potential sources that contribute to spontaneous fMRI activity will be discussed.
This chapter reviews the neurological phenotype of Down syndrome (DS) in early development, childhood, and aging. Neuroanatomic abnormalities in DS are manifested as aberrations in gross brain structure as well as characteristic microdysgenetic changes. As the result of these morphological abnormalities, brain circuitry is impaired. While an intellectual disability is ubiquitous in DS, there is a wide range of variation in cognitive performance and a growing understanding between aberrant brain circuitry and the cognitive phenotype. Hypotonia is most marked at birth, affecting gait and ligamentous laxity. Seizures are bimodal in presentation with infantile spasms common in infancy and generalized seizures associated with cognitive decline observed in later years. While all individuals have the characteristic neuropathology of Alzheimer's disease (AD) by age 40years, the prevalence of dementia is not universal. The tendency to develop AD is related, in part, to several genes on chromosome 21 that are overexpressed in DS. Intraneuronal accumulation of β-amyloid appears to trigger a cascade of neurodegeneration resulting in the neuropathological and clinical manifestations of dementia. Functional brain imaging has elucidated the temporal sequence of amyloid deposition and glucose metabolic rate in the development of dementia in DS. Mitochondrial abnormalities contribute to oxidative stress which is part of AD pathogenesis in DS as well as AD in the general population. A variety of medical comorbidities threaten cognitive performance including sleep apnea, abnormalities in thyroid metabolism, and behavioral disturbances. Mouse models for DS are providing a platform for the formulation of clinical trials with intervention targeted to synaptic plasticity, brain biochemistry, and morphological brain alterations.
Down syndrome; brain development; seizures; hypotonia; dementia; clinical trials
Fluorescent protein technology has evolved to include genetically-encoded biosensors that can monitor levels of ions, metabolites, and enzyme activities as well as protein conformation and even membrane voltage. They are well suited to live-cell microscopy and quantitative analysis, and they can be used in multiple imaging modes, including one or two-photon fluorescence intensity or lifetime microscopy. Although not nearly complete, there now exists a substantial set of genetically-encoded reporters that can be used to monitor many aspects of neuronal and glial biology, and these biosensors can be used to visualize synaptic transmission and activity-dependent signaling in vitro and in vivo. In this review we present an overview of design strategies for engineering biosensors, including sensor designs using circularly-permuted fluorescent proteins and using fluorescence resonance energy transfer (FRET) between fluorescent proteins. We also provide examples of indicators that sense small ions (e.g., pH, chloride, zinc), metabolites (e.g., glutamate, glucose, ATP, cAMP, lipid metabolites), signaling pathways (e.g., G protein coupled receptors, Rho GTPases), enzyme activities (e.g., protein kinase A, caspases), and reactive species. We focus on examples where these genetically-encoded indicators have been applied to brain-related studies and used with live-cell fluorescence microscopy.
Genetically-encoded; biosensor; fluorescent protein; circularly-permute; resonance energy transfer; FRET; live-cell microscopy
The tremendous shifts in the size, structure, and function of the brain during primate evolution are ultimately caused by changes at the genetic level. Understanding what these changes are and how they effect the phenotypic changes observed lies at the heart of understanding evolutionary change. This chapter focuses on understanding the genetic basis of primate brain evolution, considering the substrates and mechanisms through which genetic change occurs. It also discusses the implications that our current understandings and tools have for what we have already discovered and where our studies will head in the future. While genetic and genomic studies have identified many regions undergoing positive selection during primate evolution, the findings are certainly not exhaustive and functional relevance remains to be confirmed. Nevertheless, a strong foundation has been built upon which future studies will emerge.
Genetic evolution; molecular evolution; catarrhine; hominoid; hominin; FOXP2; microcephaly; opsin; olfaction; pleiotropy; gene regulation; divergence; polymorphism
Spinal cord injuries above mid-thoracic levels can lead to a potentially life-threatening hypertensive condition termed autonomic dysreflexia that is often triggered by distension of pelvic viscera (bladder or bowel). This syndrome is characterized by episodic hypertension due to sudden, massive discharge of sympathetic preganglionic neurons in the thoracolumbar spinal cord. This hypertension is usually accompanied by bradycardia, particularly if the injury is caudal to the 2nd to 4th thoracic spinal segments. The development of autonomic dysreflexia is correlated with aberrant sprouting of peptidergic afferent fibers into the spinal cord below the injury. In particular, sprouting of nerve growth factor-responsive afferent fibers has been shown to have a major influence on dysreflexia, perhaps by amplifying the activation of disinhibited sympathetic neurons. Using a model of noxious bowel distension after complete thoracic spinal transection at the 4th thoracic segment in rats, we selectively altered C-fiber sprouting, at specified spinal levels caudal to the injury, with microinjections of adenovirus encoding the growth-promoting nerve growth factor or the growth-inhibitory semaphorin 3A. This was followed by assessment of physiological responses to colorectal distension and subsequent histology. Additionally, anterograde tract tracers were injected into the lumbosacral region to compare the extent of labeled propriospinal rostral projections in uninjured cords to those incords after complete 4th thoracic transection. In summary, over-expression of chemorepulsive semaphorin 3A impeded C-fiber sprouting in lumbosacral segments and mitigated hypertensive autonomic dysreflexia, whereas the opposite results were obtained with nerve growth factor over-expression. Furthermore, compared to naïve rats there were significantly more labeled lumbosacral propriospinal projections rostrally after thoracic injury. Collectively, our findings suggest that distension of pelvic viscera increases the excitation of expanded afferent terminals in the disinhibited lumbosacral spinal cord. This, in turn, triggers excitation and sprouting of local propriospinal neurons to relay visceral sensory stimuli and amplify the activation of sympathetic preganglionic neurons in the thoracolumbar cord, to enhance transmission in the spinal viscero-sympathetic reflex pathway. These responses are manifested as autonomic dysreflexia.
nerve growth factor; semaphorin3A; sprouting; sympathetic; neurotrophin; propriospinal; gene therapy
Studies of adaptation to patterns of deterministic forces have revealed the ability of the motor control system to form and use predictive representations of the environment. These studies have also pointed out that adaptation to novel dynamics is aimed at preserving the trajectories of a controlled endpoint, either the hand of a subject or a transported object. We review some of these experiments and present more recent studies aimed at understanding how the motor system forms representations of the physical space in which actions take place. An extensive line of investigations in visual information processing has dealt with the issue of how the Euclidean properties of space are recovered from visual signals that do not appear to possess these properties. The same question is addressed here in the context of motor behavior and motor learning by observing how people remap hand gestures and body motions that control the state of an external device. We present some theoretical considerations and experimental evidence about the ability of the nervous system to create novel patterns of coordination that are consistent with the representation of extrapersonal space. We also discuss the perspective of endowing human–machine interfaces with learning algorithms that, combined with human learning, may facilitate the control of powered wheelchairs and other assistive devices.
motor learning; space; dimensionality reduction; human-machine interface; brain-computer interface.