121-140 of 185 Results

Article

Octopus Motor Control  

Nir Nesher, Guy Levy, Letizia Zullo, and Benyamin Hochner

The octopus, with its eight long and flexible arms, is an excellent example of the independent evolution of highly efficient motor behavior in a soft-bodied animal. Studies will be summarized to show that the amazing behavioral motor abilities of the octopus are achieved through a special embodied organization of its flexible body, unusual morphology, and a unique central and peripheral distribution of its extremely large nervous system. This special embodied organization of brain–body–environment reciprocal interactions makes it possible to overcome the difficulties involved in generation and control of movement in an animal, which unlike vertebrates and arthropods lacks rigid skeletal appendages.

Article

Olfactory Perception  

Daniel W. Wesson, Sang Eun Ryu, and Hillary L. Cansler

The perception of odors exerts powerful influences on moods, decisions, and actions. Indeed, odor perception is a major driving force underlying some of the most important human behaviors. How is it that the simple inhalation of airborne molecules can exert such strong effects on complex aspects of human functions? Certainly, just like in the case of vision and audition, the perception of odors is dictated by the ability to transduce environmental information into an electrical “code” for the brain to use. However, the use of that information, including whether or not the information is used at all, is governed strongly by many emotional and cognitive factors, including learning and experiences, as well as states of arousal and attention. Understanding the manners whereby these factors regulate both the perception of odors and how an individual responds to those percepts are paramount for appreciating the orchestration of behavior.

Article

The Ouroboros of Inflammatory Signaling to the Brain for the Control of Neuroendocrine Function  

Georgia E. Hodes

In the late 20th century, the discovery that the immune system and central nervous system were not autonomous revolutionized exploration of the mechanisms by which stress contributes to immune disorders and immune regulation contributes to mental illness. There is increasing evidence of stress as integrated across the brain and body. The immune system acts in concert with the peripheral nervous system to shape the brain’s perception of the environment. The brain in turn communicates with the endocrine and immune systems to guide their responses to that environment. Examining the groundwork of mechanisms governing communication between the body and brain will hopefully provide a better understanding of the ontogeny and symptomology of some mood disorders.

Article

Pain and Its Modulation  

Asaf Keller

Sensory perceptions are inherently subjective, being influenced by factors such as expectation, attention, affect, and past experiences. Nowhere is this more commonly experienced than with the perception of pain, whose perceived intensity and emotional impact can fluctuate rapidly. The perception of pain in response to the same nociceptive signal can also vary substantially between individuals. Pain is not only a sensory experience. It also involves profound affective and cognitive dimensions, reflecting the activation of and interactions among multiple brain regions. The modulation of pain perception by such interactions has been most extensively characterized in the context of the “descending pain modulatory system.” This system includes a variety of pathways that directly or indirectly modulate the activity of neurons in the spinal dorsal horn, the second-order neurons that receive inputs directly from nociceptors. Less understood are the interactions among brain regions that modulate the affective and cognitive aspects of pain perception. Emerging data suggest that certain pain conditions result from dysfunction in pain modulation, suggesting that targeting these dysfunctions might have therapeutic value. Some therapies that are thought to target pain modulation pathways—such as cognitive behavior therapy, mindfulness-based stress reduction, and placebo analgesia—are safer and less expensive than pharmacologic or surgical approaches, further emphasizing the importance of understanding these modulatory mechanisms. Understanding the mechanisms through which pain modulation functions may also illuminate fundamental mechanisms of perception and consciousness.

Article

Paternal Behavior from a Neuroendocrine Perspective  

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.

Article

Phantom Limbs and Brain Plasticity in Amputees  

Tamar Makin and London Plasticity Lab

Phantom sensations are experienced by almost every person who has lost their hand in adulthood. This mysterious phenomenon spans the full range of bodily sensations, including the sense of touch, temperature, movement, and even the sense of wetness. For a majority of upper-limb amputees, these sensations will also be at times unpleasant, painful, and for some even excruciating to the point of debilitating, causing a serious clinical problem, termed phantom limb pain (PLP). Considering the sensory organs (the receptors in the skin, muscle or tendon) are physically missing, in order to understand the origins of phantom sensations and pain the potential causes must be studied at the level of the nervous system, and the brain in particular. This raises the question of what happens to a fully developed part of the brain that becomes functionally redundant (e.g. the sensorimotor hand area after arm amputation). Relatedly, what happens to the brain representation of a body part that becomes overused (e.g. the intact hand, on which most amputees heavily rely for completing daily tasks)? Classical studies in animals show that the brain territory in primary somatosensory cortex (S1) that was “freed up” due to input loss (hereafter deprivation) becomes activated by other body part representations, those neighboring the deprived cortex. If neural resources in the deprived hand area get redistributed to facilitate the representation of other body parts following amputation, how does this process relate to persistent phantom sensation arising from the amputated hand? Subsequent work in humans, mostly with noninvasive neuroimaging and brain stimulation techniques, have expanded on the initial observations of cortical remapping in two important ways. First, research with humans allows us to study the perceptual consequence of remapping, particularly with regards to phantom sensations and pain. Second, by considering the various compensatory strategies amputees adopt in order to account for their disability, including overuse of their intact hand and learning to use an artificial limb, use-dependent plasticity can also be studied in amputees, as well as its relationship to deprivation-triggered plasticity. Both of these topics are of great clinical value, as these could inform clinicians how to treat PLP, and how to facilitate rehabilitation and prosthesis usage in particular. Moreover, research in humans provides new insight into the role of remapping and persistent representation in facilitating (or hindering) the realization of emerging technologies for artificial limb devices, with special emphasis on the role of embodiment. Together, this research affords a more comprehensive outlook at the functional consequences of cortical remapping in amputees’ primary sensorimotor cortex.

Article

Physiology of Color Vision in Primates  

Robert Shapley

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.

Article

Plastic Changes After Spinal Cord Injury  

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.

Article

Plasticity in the Micturition Circuit During Development and Following Spinal Cord Injury  

Harrison W. Hsiang and Margaret A. Vizzard

The micturition reflex relies on complex neural signaling to enable the coordination of the lower urinary tract. In neonates, this reflex is organized in the lumbosacral spinal cord and responds automatically to distension of the bladder or, in animals, to stimulation of the perigenital region by the mother. During development, competitive reorganization by supraspinal inputs places the reflex under conscious control and gives rise to the mature micturition reflex. Traumatic injury to the spinal cord that interrupts supraspinal inputs to the lumbosacral spinal cord can result in reversion to an automatic, spinal micturition reflex accompanied by lower urinary tract dysfunction such as neurogenic detrusor overactivity and detrusor–sphincter dyssynergia. This is accompanied by a number of changes in the anatomy and function of the lower urinary tract; various signaling pathways, including neurotrophins and neuropeptides; and reorganization of spinal circuitry. Evidence suggests that, following spinal cord injury, the bladder hypertrophies and urothelial and external urethral sphincter function are altered, giving rise to phasic spontaneous behavior and reduced bladder outlet bursting during voiding, respectively. Sensitization of Aδ-fiber afferents and “awakening” of C-fibers in the lumbosacral micturition pathway contribute to the emergence of a spinal micturition reflex and subsequent lower urinary tract dysfunction, with substantial evidence indicating a primary role for altered neurotrophin and neuropeptide signaling.

Article

Plasticity in the Regenerating Nervous System of the Lamprey, a “Simple” Vertebrate  

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.

Article

Plasticity of Information Processing in the Auditory System  

Andrew J. King

Information processing in the auditory system shows considerable adaptive plasticity across different timescales. This ranges from very rapid changes in neuronal response properties—on the order of hundreds of milliseconds when the statistics of sounds vary or seconds to minutes when their behavioral relevance is altered—to more gradual changes that are shaped by experience and learning. Many aspects of auditory processing and perception are sculpted by sensory experience during sensitive or critical periods of development. This developmental plasticity underpins the acquisition of language and musical skills, matches neural representations in the brain to the statistics of the acoustic environment, and enables the neural circuits underlying the ability to localize sound to be calibrated by the acoustic consequences of growth-related changes in the anatomy of the body. Although the length of these critical periods depends on the aspect of auditory processing under consideration, varies across species and brain level, and may be extended by experience and other factors, it is generally accepted that the potential for plasticity declines with age. Nevertheless, a substantial degree of plasticity is exhibited in adulthood. This is important for the acquisition of new perceptual skills; facilitates improvements in the detection or discrimination of fine differences in sound properties; and enables the brain to compensate for changes in inputs, including those resulting from hearing loss. In contrast to the plasticity that shapes the developing brain, perceptual learning normally requires the sound attribute in question to be behaviorally relevant and is driven by practice or training on specific tasks. Progress has recently been made in identifying the brain circuits involved and the role of neuromodulators in controlling plasticity, and an understanding of plasticity in the central auditory system is playing an increasingly important role in the treatment of hearing disorders.

Article

Plasticity of Stepping Rhythms in the Intact and Injured Mammalian Spinal Cord  

Serge Rossignol

The spinal cord is a prime example of how the central nervous system has evolved to execute and retain movements adapted to the environment. This results from the evolution of inborn intrinsic spinal circuits modified continuously by repetitive interactions with the outside world, as well as by developing internal needs or goals. This article emphasizes the underlying neuroplastic spinal mechanisms through observations of normal animal adaptive locomotor behavior in different imposed conditions. It further explores the motor spinal capabilities after various types of lesions to the spinal cord and the potential mechanisms underlying the spinal changes occurring after these lesions, leading to recovery of function. Together, these observations strengthen the idea of the immense potential of the motor rehabilitation approach in humans with spinal cord injury since extrinsic interventions (training, pharmacology, and electrical stimulation) can modulate and optimize remnant motor functions after injury.

Article

Postnatal Neurogenesis in the Olfactory Bulb  

Aleksandra Polosukhina and Pierre-Marie Lledo

This is an advance summary of a forthcoming article in the Oxford Research Encyclopedia of Neuroscience. Please check back later for the full article. In adult mammals, the olfactory bulb and the hippocampus are the regions in the brain that undergo continuous neurogenesis (production and recruitment of newborn neurons). While the other regions of the brain still retain a certain degree of plasticity after birth, they no longer can integrate new neurons. In rodents, thousands of adult-born neurons integrate into the bulb each day, and this process has been found to contribute not only to sensory function, but also to olfactory memory. This was a surprising finding, since historically the adult-brain has been viewed as a static organ. Understanding the process of regeneration of mature neurons in the brain has great potential for therapeutic applications. Consequently, this process of adult-neurogenesis has received widespread attention from clinicians and scientists. Neuroblasts bound for the olfactory bulb are produced in the subventricular zone of the lateral ventricle. Once they reach the olfactory bulb, they mostly develop into inhibitory interneurons called granule cells. Just after one month, about half of the adult-born neurons are eliminated, and the other half fully integrate and function in the olfactory bulb. These cells not only process information from the sensory neurons in the bulb, but also receive massive innervation from various regions of the brain, including the olfactory cortex, locus coeruleus, the horizontal limb of diagonal band of Broca, and the dorsal raphe nucleus. The sensory (bottom-up) and cortical (top-down) activity has been found to play a vital role in the adult-born granule cell survival. Though the exact purpose of these newborn neurons has not been identified, some emerging functions include maintenance of olfactory bulb circuitry, modulating sensory information, modulating olfactory learning, and memory.

Article

Predictive Coding Theories of Cortical Function  

Linxing Preston Jiang and Rajesh P.N. Rao

Predictive coding is a unifying framework for understanding perception, action, and neocortical organization. In predictive coding, different areas of the neocortex implement a hierarchical generative model of the world that is learned from sensory inputs. Cortical circuits are hypothesized to perform Bayesian inference based on this generative model. Specifically, the Rao–Ballard hierarchical predictive coding model assumes that the top-down feedback connections from higher to lower order cortical areas convey predictions of lower-level activities. The bottom-up, feedforward connections in turn convey the errors between top-down predictions and actual activities. These errors are used to correct current estimates of the state of the world and generate new predictions. Through the objective of minimizing prediction errors, predictive coding provides a functional explanation for a wide range of neural responses and many aspects of brain organization.

Article

The Processing of Hydrodynamic Stimuli With the Fish Lateral Line System  

Joachim Mogdans

All fish have a mechanosensory lateral line system for the detection of hydrodynamic stimuli. It is thus not surprising that the lateral line system is involved in numerous behaviors, including obstacle avoidance, localization of predators and prey, social communication, and orientation in laminar and turbulent flows. The sensory units of the lateral line system are the neuromasts, which occur freestanding on the skin (superficial neuromasts) and within subdermal canals (canal neuromasts). The canals are in contact with the surrounding water through a series of canal pores. Neuromasts consist of a patch of sensory hair cells covered by a gelatinous cupula. Water flow causes cupula motion, which in turn leads to a change in the hair cells’ receptor potentials and a subsequent change in the firing rate of the innervating afferent nerve fibers. These fibers encode velocity, direction, and vorticity of water motions by means of spike trains. They project predominantly to lateral line neurons in the brainstem for further processing of the received hydrodynamic signals. From the brainstem, lateral line information is transferred to the cerebellum and to midbrain and forebrain nuclei, where lateral line information is integrated with information from other sensory modalities to create a three-dimensional image of the hydrodynamic world surrounding the animal. For fish to determine spatial location and identity of a wave source as well as direction and velocity of water movements, the lateral line system must analyze the various types of hydrodynamic stimuli that fish are exposed to in their natural habitat. Natural hydrodynamic stimuli include oscillatory water motions generated by stationary vibratory sources, such as by small crustaceans; complex water motions produced by animate or inanimate moving objects, such as by swimming fish; bulk water flow in rivers and streams; and water flow containing vortices generated at the edges of objects in a water flow. To uncover the mechanisms that underlie the coding of hydrodynamic information by the lateral line system, neurophysiological experiments have been performed at the level of the primary afferent nerve fibers, but also in the central nervous system, predominantly in the brainstem and midbrain, using sinusoidally vibrating spheres, moving objects, vortex rings, bulk water flow, and Kármán vortex streets as wave sources. Unravelling these mechanisms is fundamental to understanding how the fish brain uses hydrodynamic information to adequately guide behavior.

Article

Prolactin: Regulation and Actions  

Robert S. Bridges

Prolactin (PRL) is a protein hormone with a molecular weight of approximately 23 KD, although variants in size exist. It binds to receptor dimers on the cytoplasmic surface of its target cells and acts primarily through the activation of the STAT5 pathway, which in turn alters gene activity. Pituitary prolactin, while being the main, but not only, source of PRL, is primarily under inhibitory control by hypothalamic dopaminergic neurons. Release of dopamine (DA) into the hypothalamo-hypophyseal portal system binds on DA D2 receptors on PRL-producing lactotrophs within the anterior pituitary gland. Prolactin’s functions include the regulation of behaviors that include maternal care, anxiety, and feeding as well as lactogenesis, hepatic bile formation, immune function, corpora lutea function, and more generally cell proliferation and differentiation. Dysfunctional conditions related to prolactin’s actions include its role in erectile dysfunction and male infertility, mood disorders such as depression during the postpartum period, possible roles in breast and hepatic cancer, prostate hyperplasia, galactorrhea, obesity, immune function, and diabetes. Future studies will further elucidate both the underlying mechanisms of prolactin action together with prolactin’s involvement in these clinical disorders.

Article

Rapid Adaptive Camouflage in Cephalopods  

Chuan-Chin Chiao and Roger T. Hanlon

Visual camouflage change is a hallmark of octopus, squid, and cuttlefish and serves as their primary defense against predators. They can change their total body appearance in less than a second due to one principal feature: every aspect of this sensorimotor system is neurally refined for speed. Cephalopods live in visually complex environments such as coral reefs and kelp forests and use their visual perception of backgrounds to rapidly decide which camouflage pattern to deploy. Counterintuitively, cuttlefish have evolved a small number of pattern designs to achieve camouflage: Uniform, Mottle, and Disruptive, each with variation. The expression of these body patterns is based on several fundamental scene features. In cuttlefish, there appear to be several “visual assessment shortcuts” that enable camouflage patterning change in as little as 125 milliseconds. Neural control of the dynamic body patterning of cephalopods appears to be organized hierarchically via a set of lobes within the brain, including the optic lobes, the lateral basal lobes, and the anterior/posterior chromatophore lobes. The motor output of the central nervous system (CNS) in terms of the skin patterns that are produced is under sophisticated neural control of chromatophores, iridophores, and three-dimensional skin papillae. Moreover, arm postures and skin papillae are also regulated visually for additional aspects of concealment. This coloration system, often referred to as rapid neural polyphenism, is unique in the animal kingdom and can be explained and interpreted in the context of sensory and behavioral ecology.

Article

Raptor Vision  

Mindaugas Mitkus, Simon Potier, Graham R. Martin, Olivier Duriez, and Almut Kelber

Diurnal raptors (birds of the orders Accipitriformes and Falconiformes), renowned for their extraordinarily sharp eyesight, have fascinated humans for centuries. The high visual acuity in some raptor species is possible due to their large eyes, both in relative and absolute terms, and a high density of cone photoreceptors. Some large raptors, such as wedge-tailed eagles and the Old World vultures, have visual acuities twice as high as humans and six times as high as ostriches—the animals with the largest terrestrial eyes. The raptor retina has rods, double cones, and four spectral types of single cones. The highest density of single cones occurs in one or two specialized retinal regions: the foveae, where, at least in some species, rods and double cones are absent. The deep central fovea allows for the highest acuity in the lateral visual field that is probably used for detecting prey from a large distance. Pursuit-hunting raptors have a second, shallower, temporal fovea that allows for sharp vision in the frontal field of view. Scavenging carrion eaters do not possess a temporal fovea that may indicate different needs in foraging behavior. Moreover, pursuit-hunting and scavenging raptors also differ in configuration of visual fields, with a more extensive field of view in scavengers. The eyes of diurnal raptors, unlike those of most other birds, are not very sensitive to ultraviolet light, which is strongly absorbed by their cornea and lens. As a result of the low density of rods, and the narrow and densely packed single cones in the central fovea, the visual performance of diurnal raptors drops dramatically as light levels decrease. These and other visual properties underpin prey detection and pursuit and show how these birds’ vision is adapted to make them successful diurnal predators.

Article

Regulating Systems in Neuroimmunology  

William H. Walker II and A. Courtney DeVries

Neuroimmunology is the study of the interaction between the immune system and nervous system during development, homeostasis, and disease states. Descriptions of neuroinflammatory diseases dates back centuries. However, in depth scientific investigation in the field began in the late 19th century and continues into the 21st century. Contrary to prior dogma in the field of neuroimmunology, there is immense reciprocal crosstalk between the brain and the immune system throughout development, homeostasis, and disease states. Proper neuroimmune functioning is necessary for optimal health, as the neuroimmune system regulates vital processes including neuronal signaling, synapse pruning, and clearance of debris and pathogens within the central nervous system. Perturbations in optimal neuroimmune functioning can have detrimental consequences for the host and underlie a myriad of physical, cognitive, and behavioral abnormalities. As such, the field of neuroimmunology is still relatively young and dynamic and represents an area of active research and discovery.

Article

Regulation of Chloride Gradients and Neural Plasticity  

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.