Chronic pain is a debilitating and rather common health problem. The present shortage in analgesic drugs with a favorable spectrum but without remarkable side effects furthered the search for alternative therapeutic manipulations. Increasing evidence from both basic and clinical research on acupuncture, a main alternative therapy of traditional Chinese medicine, suggests that chronic pain is sensitive to acupuncture procedures. Clarification of the underlying mechanisms is a challenge of great theoretical and practical significance. The seminal hypothesis of Geoffrey Burnstock and the astounding findings of Maiken Nedergaard on the involvement of purinergic signaling in the beneficial effects of acupuncture fertilized the field and led to an intensification of research on acupurines. In this review, we will summarize the state-of-the-art situation and try to forecast how the field is likely to develop in the future.
The prefrontal cortex is the center of cognitive control. Processing in prefrontal cortical circuits enables us to direct attention to behaviorally relevant events; to memorize, structure, and categorize information; and to learn new concepts. The prefrontal cortex receives strong projections from midbrain neurons that use dopamine as a transmitter. In this article, we review the crucial role dopamine plays as a modulator of prefrontal cognitive functions, in the primate brain in particular. Following a summary of the anatomy and physiology of the midbrain dopamine system, we focus on recent studies that investigated dopaminergic effects in prefrontal cortex at the cellular level. We then discuss how unregulated prefrontal dopamine signaling could contribute to major disorders of cognition. The studies highlighted in this review demonstrate the powerful influence dopamine exerts on the mind.
Microglia, the resident innate immune cells in the brain, have long been understood to be crucial to maintenance in the nervous system, by clearing debris, monitoring for infiltration of infectious agents, and mediating the brain’s inflammatory and repair response to traumatic injury, stroke, or neurodegeneration. A wave of new research has shown that microglia are also active players in many basic processes in the healthy brain, including cell proliferation, synaptic connectivity, and physiology. Microglia, both in their capacity as phagocytic cells and via secretion of many neuroactive molecules, including cytokines and growth factors, play a central role in early brain development, including sexual differentiation of the brain. In this review, we present the vast roles microglia play in normal brain development and how perturbations in the normal neuroimmune environment during development may contribute to the etiology of brain-based disorders. There are notable differences between microglia and neuroimmune signaling in the male and female brain throughout the life span, and these differences may contribute to the vast differences in the incidence of neuropsychiatric and neurological disorders between males and females.
The axon initial segment (AIS) is a specialized axonal compartment that is involved in conversion of synaptic potentials into action potentials. Recent studies revealed that structural properties of the AIS, such as length and position relative to the soma, are differentiated in a cell-specific manner and shape signal processing of individual neurons. Moreover, these structural properties are not fixed but vary in response to prolonged changes of neuronal activity, which readjusts action potential threshold and compensates for the changes of activity, indicating that this structural plasticity of the AIS works as a homeostatic mechanism and contributes to maintain neuronal activity. Neuronal activity plays a crucial role in formation, maintenance, and refinement of neural circuits as well as in pathogenesis and/or pathophysiology of diseases. Thus, this plasticity should be a key to understand physiology and pathology of the brain.
Since the discovery of the segment polarity gene Hedgehog in Drosophila three decades ago, our knowledge of Hedgehog signaling pathway has considerably improved and paved the way to a wide field of investigations in the developing and adult central nervous system. Its peculiar transduction mechanism together with its implication in tissue patterning, neural stem cell biology, and neural tissue homeostasis make Hedgehog pathway of interest in a high number of normal or pathological contexts. Consistent with its role during brain development, misregulation of Hedgehog signaling is associated with congenital diseases and tumorigenic processes while its recruitment in damaged neural tissue may be part of the repairing process. This review focuses on the most recent data regarding the Hedgehog pathway in the developing and adult central nervous system and also its relevance as a therapeutic target in brain and spinal cord diseases.
Is it possible to understand the intentions of others by merely observing their movements? Current debate has been mainly focused on the role that mirror neurons and motor simulation may play in this process, with surprisingly little attention being devoted to how intentions are actually translated into movements. Here, we delineate an alternative approach to the problem of intention-from-movement understanding, which takes "action execution" rather than "action observation" as a starting point. We first consider whether and to what extent, during action execution, intentions shape movement kinematics. We then examine whether observers are sensitive to intention information conveyed by visual kinematics and can use this information to discriminate between different intentions. Finally, we consider the neural mechanisms that may contribute to intention-from-movement understanding. We argue that by reframing the relationship between intention and movement, this evidence opens new perspectives into the neurobiology of how we know other minds and predict others’ behavior.
In the CNS, astrocytes, oligodendrocytes and microglias are involved in not only development but also pathology such as spinal cord injury (SCI). Glial cells play dual roles (negative vs. positive effects) in these processes. After SCI, detrimental effects usually dominate and significantly retard functional recovery, and curbing these effects is critical for promoting neurological improvement. Bone marrow stromal cells (BMSCs) represent a new therapeutic approach for SCI by enabling improved sensory and motor functions in animal models. Although transdifferentiation to spinal neurons was poor, because of their pleiotropic nature, the protective effects of BMSCs are broad and are primarily mediated through modulation of transdifferentiation into host spinal glial components. Transplantation of BMSCs can positively alter the spinal microenvironment and enhance recovery. The objective of this review is to discuss these and other related mechanisms. Since BMSCs transplantation has been applied in other clinical fields, we hope to provide useful clues for the clinical application of BMSCs to treat the SCI in the near future.
Recognition that virtually every neuronal progenitor cell and neuron in the cerebral cortex is ciliated has triggered intense interest in neuronal cilia function. Here, we review recent studies that suggest the primary cilia of cortical progenitor cells are required for establishing and maintaining the organization within pools of proliferative cells. In addition, signaling via primary cilia differentially influence the migration and differentiation of excitatory and inhibitory neurons in the developing cortex. Specifically, the primary cilia of excitatory neurons appear to play a significant role in regulating the post-migratory differentiation of these neurons whereas cilia of inhibitory neurons appear to be required for the proper migration and positioning of those cells in cortex. Given the recently discovered functions of cilia in proliferation, neuronal migration, and differentiation, it is likely that further studies of cilia signaling will improve our understanding of how these basic developmental processes are regulated and may provide insight into how mutations in specific cilia genes linked to ciliopathies lead to the many neurological deficits associated with these diseases.
The processing of brain information relies on the organization of neuronal networks and circuits that in the end must provide the substrate for human cognition. However, the presence of highly complex and multirelay neuronal interactions has limited our ability to disentangle the assemblies of brain systems. The present review article focuses on the latest developments to understand the architecture of functional streams of the human brain at the large-scale level. Particularly, this article presents a comprehensive framework and recent findings about how the highly modular sensory cortex, such as the visual, somatosensory, auditory, as well as motor cortex areas, connects to more parallel-organized cortical hubs in the brain’s functional connectome.
The surprising discovery of bona fide synapses between neurons and oligodendrocytes precursor cells (OPCs) 15 years ago placed these progenitors as real partners of neurons in the CNS. The role of these synapses has not been established yet, but a main hypothesis is that neuron–OPC synaptic activity is a signaling pathway controlling OPC proliferation/differentiation, influencing the myelination process. However, new evidences describing non-synaptic mechanisms of communication between neurons and OPCs have revealed that neuron–OPC interactions are more complex than expected. The activation of extrasynaptic receptors by ambient neurotransmitter or local spillover and the ability of OPCs to sense neuronal activity through a potassium channel suggest that distinct modes of communication mediate different functions of OPCs in the CNS. This review discusses different mechanisms used by OPCs to interact with neurons and their potential roles during postnatal development and in brain disorders.
The global burden of cancer pain is enormous and opioids, despite their side effects, remain the primary therapeutic approach. The cause of cancer pain is unknown. Mechanisms driving cancer pain differ from those mechanisms responsible for inflammatory and neuropathic pain. The prevailing hypothesis put forward to explain cancer pain posits that cancers generate and secrete mediators which sensitize and activate primary afferent nociceptors in the cancer microenvironment. Moreover, cancers induce neurochemical reorganization of the spinal cord, which contributes to spontaneous activity and enhanced responsiveness. The purpose of this review, which covers clinical and preclinical studies, is to highlight those peripheral and central mechanisms responsible for cancer pain. The challenges facing neuroscientists and clinicians studying and ultimately treating cancer pain are discussed.
During the last 20 years, it has been well established that a finely tuned, continuous crosstalk between neurons and astrocytes not only critically modulates physiological brain functions but also underlies many neurological diseases. In particular, this novel way of interpreting brain activity is markedly influencing our current knowledge of epilepsy, prompting a re-evaluation of old findings and guiding novel experimentation. Here, we review recent studies that have unraveled novel and unique contributions of astrocytes to the generation and spread of convulsive and nonconvulsive seizures and epileptiform activity. The emerging scenario advocates an overall framework in which a dynamic and reciprocal interplay among astrocytic and neuronal ensembles is fundamental for a fuller understanding of epilepsy. In turn, this offers novel astrocytic targets for the development of those really novel chemical entities for the control of convulsive and nonconvulsive seizures that have been acknowledged as a key priority in the management of epilepsy.
People with incomplete spinal cord injury (SCI) frequently suffer motor disabilities due to spasticity and poor muscle control, even after conventional therapy. Abnormal spinal reflex activity often contributes to these problems. Operant conditioning of spinal reflexes, which can target plasticity to specific reflex pathways, can enhance recovery. In rats in which a right lateral column lesion had weakened right stance and produced an asymmetrical gait, up-conditioning of the right soleus H-reflex, which increased muscle spindle afferent excitation of soleus, strengthened right stance and eliminated the asymmetry. In people with hyperreflexia due to incomplete SCI, down-conditioning of the soleus H-reflex improved walking speed and symmetry. Furthermore, modulation of electromyographic activity during walking improved bilaterally, indicating that a protocol that targets plasticity to a specific pathway can trigger widespread plasticity that improves recovery far beyond that attributable to the change in the targeted pathway. These improvements were apparent to people in their daily lives. They reported walking faster and farther, and noted less spasticity and better balance. Operant conditioning protocols could be developed to modify other spinal reflexes or corticospinal connections; and could be combined with other therapies to enhance recovery in people with SCI or other neuromuscular disorders.
Neurons are exquisitely specialized for rapid electrical transmission of signals, but some properties of glial cells, which do not communicate with electrical impulses, are well suited for participating in complex cognitive functions requiring broad spatial integration and long-term temporal regulation. Astrocytes, microglia, and oligodendrocytes all have biological properties that could influence learning and cognition. Myelination by oligodendrocytes increases conduction velocity, affecting spike timing and oscillations in neuronal activity. Astrocytes can modulate synaptic transmission and may couple multiple neurons and synapses into functional assemblies. Microglia can remove synapses in an activity-dependent manner altering neural networks. Incorporating glia into a bicellular mechanism of nervous system function may help answer long-standing questions concerning the cellular mechanisms of learning and cognition.
Metaplasticity refers to the modification of plasticity induction (direction, magnitude, duration) by previous activity of the same postsynaptic neuron or neuronal network. In recent years evidence from animal studies has been accumulated that metaplasticity significantly contributes to network function and behavior. Here, we review the evidence for metaplasticity at the system level of the human cortex as investigated by non-invasive brain stimulation. These studies support the notion that metaplasticity is also operative in the human brain and is mostly homeostatic in nature, that is, keeping network activity within a physiological range. However, non-homeostatic metaplasticity has also been described, which can increase non-invasive brain stimulation–induced aftereffects on cortical excitability, or learning. Current evidence further suggests that aberrant metaplasticity may underlie some neurological and psychiatric diseases. Finally, first proof-of-principle studies show that the concept of metaplasticity can be harnessed for treatment of patients suffering from brain diseases.
The development of methods to follow the dynamics of synaptic molecules in living neurons has radically altered our view of the synapse, from that of a generally static structure to that of a dynamic molecular assembly at steady state. This view holds not only for relatively labile synaptic components, such as synaptic vesicles, cytoskeletal elements, and neurotransmitter receptors, but also for the numerous synaptic molecules known as scaffolding molecules, a generic name for a diverse class of molecules that organize synaptic function in time and space. Recent studies reveal that these molecules, which confer a degree of stability to synaptic assemblies over time scales of hours and days, are themselves subject to significant dynamics. Furthermore, these dynamics are probably not without effect; wherever studied, these seem to be associated with spontaneous changes in scaffold molecule content, synaptic size, and possibly synaptic function. This review describes the dynamics exhibited by synaptic scaffold molecules, their typical time scales, and the potential implications to our understanding of synaptic function.
Botulinum neurotoxin type A (BoNT/A) is a metalloprotease that produces a sustained yet transitory blockade of transmitter release from peripheral nerve terminals. Local delivery of this neurotoxin is successfully employed in clinical practice to reduce muscle hyperactivity such as in spasticity and dystonia, and to relieve pain with long-lasting therapeutic effects. However, not all BoNT/A effects can be explained by an action at peripheral nerve terminals. Indeed, it appears that BoNT/A is endowed with trafficking properties similar to the parental tetanus neurotoxin and thus be able to directly affect the CNS. In this review, we present and discuss novel compelling evidence for a direct central effect of BoNT/A in both dorsal and ventral horns of the animal and human spinal cord after peripheral injection of the neurotoxin, with important consequences on pain and motor control. This new knowledge is expected to radically change the approach to the use of BoNT/A in the future. As BoNT/A central action appears to also contribute to functional improvement, for instance in human spastic gait, the challenge will be to develop new subtypes or BoNT derivatives with deliberate, cell-specific central effects in order to fully exploit the spectrum of BoNT/A therapeutic activity.
Endocannabinoids (eCBs) are endogenous lipid mediators involved in a variety of physiological, pharmacological, and pathological processes. While activation of the eCB system primarily induces inhibitory effects on both GABAergic and glutamatergic synaptic transmission and plasticity through acting on presynaptically expressed CB1 receptors in the brain, accumulated information suggests that eCB signaling is also capable of facilitating or potentiating excitatory synaptic transmission in the hippocampus. Recent studies show that a long-lasting potentiation of excitatory synaptic transmission at Schaffer collateral (SC)-CA1 synapses is induced by spatiotemporally primed inputs, accompanying with a long-term depression of inhibitory synaptic transmission (I-LTD) in hippocampal CA1 pyramidal neurons. This input timing–dependent long-lasting synaptic potentiation at SC-CA1 synapses is mediated by 2-arachidonoylglycerol (2-AG) signaling triggered by activation of postsynaptic N-methyl-
Although brain plasticity is greatest in the first few years of life, the brain continues to be shaped by experience throughout adulthood. Advances in fMRI have enabled us to examine the plasticity of large-scale networks using blood oxygen level–dependent (BOLD) correlations measured at rest. Resting-state functional connectivity analysis makes it possible to measure task-independent changes in brain function and therefore could provide unique insights into experience-dependent brain plasticity in humans. Here, we evaluate the hypothesis that resting-state functional connectivity reflects the repeated history of co-activation between brain regions. To this end, we review resting-state fMRI studies in the sensory, motor, and cognitive learning literature. This body of research provides evidence that the brain’s resting-state functional architecture displays dynamic properties in young adulthood.
The rapid development of social media and social networking sites in human society within the past decade has brought about an increased focus on the value of social relationships and being connected with others. Research suggests that we pursue socially valued or rewarding outcomes—approval, acceptance, reciprocity—as a means toward learning about others and fulfilling social needs of forming meaningful relationships. Focusing largely on recent advances in the human neuroimaging literature, we review findings highlighting the neural circuitry and processes that underlie pursuit of valued rewarding outcomes across non-social and social domains. We additionally discuss emerging human neuroimaging evidence supporting the idea that social rewards provide a gateway to establishing relationships and forming social networks. Characterizing the link between social network, brain, and behavior can potentially identify contributing factors to maladaptive influences on decision making within social situations.
Gene therapy has strong potential for treating a variety of genetic disorders, as demonstrated in recent clinical trials. There is unfortunately no scarcity of disease targets, and the grand challenge in this field has instead been the development of safe and efficient gene delivery platforms. To date, approximately two thirds of the 1800 gene therapy clinical trials completed worldwide have used viral vectors. Among these, adeno-associated virus (AAV) has emerged as particularly promising because of its impressive safety profile and efficiency in transducing a wide range of cell types. Gene delivery to the CNS involves both considerable promise and unique challenges, and better AAV vectors are thus needed to translate CNS gene therapy approaches to the clinic. This review discusses strategies for vector design, potential routes of administration, immune responses, and clinical applications of AAV in the CNS.
Estradiol effects on memory depend on hormone levels and the interaction of different estrogen receptors within neural circuits. Estradiol induces gene transcription and rapid membrane signaling mediated by estrogen receptor-alpha (ERα), estrogen receptor-beta (ERβ), and a recently characterized G-protein coupled estrogen receptor, each with distinct distributions and ability to influence estradiol-dependent signaling. Investigations using receptor specific agonists suggest that all three receptors rapidly activate kinase-signaling and have complex dose-dependent influences on memory. Research employing receptor knockout mice demonstrate that ERα maintains transcription and memory as estradiol levels decline. This work indicates a regulatory role of ERβ in transcription and cognition, which depends on estradiol levels and the function of ERα. The regulatory role of ERβ is due in part to ERβ acting as a negative regulator of ERα-mediated transcription. Vector-mediated expression of estrogen receptors in the hippocampus provides an innovative research approach and suggests that memory depends on the relative expression of ERα and ERβ interacting with estradiol levels. Notably, the ability of estradiol to improve cognition declines with advanced age along with decreased expression of estrogen receptors. Thus, it will be important for future research to determine the mechanisms that regulate estrogen receptor expression during aging.
Addiction is characterized as a chronic relapsing disorder whereby addicted individuals persistently engage in drug seeking and use despite profound negative consequences. The results of studies using animal models of addiction and relapse indicate that drug seeking is mediated by alterations in cortico-accumbal plasticity induced by chronic drug exposure. Among the maladaptive responses to drug exposure are long-lasting alterations in the expression of proteins localized to accumbal astrocytes, which are responsible for maintaining glutamate homeostasis. These alterations engender an aberrant potentiation of glutamate transmission in the cortico-accumbens circuit that is linked to the reinstatement of drug seeking. Accordingly, pharmacological restoration of glutamate homeostasis functions as an efficient method of reversing drug-induced plasticity and inhibiting drug seeking in both rodents and humans.
In recent years, the importance of the cellular redox status for neural stem cell (NSC) homeostasis has become increasingly clear. Similarly, the transcription factor and tumor suppressor p53 has been implicated in the regulation of cell metabolism, in antioxidant response, and in stem cell quiescence and fate commitment. Here, we explore the known and putative functions of p53 in antioxidant response and metabolic control and examine how reactive oxygen species, p53, and related cellular signaling may regulate NSC homeostasis, quiescence, and differentiation. We also discuss the role that PI3K-Akt-mTOR signaling plays in NSC biology and oxidative signaling and how p53 contributes to the regulation of this signaling cascade. Finally, we invite reflection on the several unanswered questions of the role that p53 plays in NSC biology and metabolism, anticipating future directions.
Microglia are brain resident immune cells and their functions are implicated in both the normal and diseased brain. Microglia express a plethora of ion channels, including K+ channels, Na+ channels, TRP channels, Cl– channels, and proton channels. These ion channels play critical roles in microglial proliferation, migration, and production/release of cytokines, chemokines, and neurotoxic or neurotrophic substances. Among microglial ion channels, the voltage-gated proton channel HV1 is a recently cloned ion channel that rapidly removes protons from depolarized cytoplasm and is highly expressed in the immune system. However, the function of microglial HV1 in the brain is poorly understood. Recent studies showed that HV1 is selectively expressed in microglia but not neurons in the brain. At the cellular level, microglial HV1 regulates intracellular pH and aids in NADPH oxidase-dependent generation of reactive oxygen species. In a mouse model of middle cerebral artery occlusion, microglial HV1 contributes to neuronal cell death and ischemic brain damage. This review discusses the discovery, properties, regulation, and pathophysiology of microglial HV1 proton channel in the brain.
During the last two decades, many experiments have examined the ability of cell transplants to ameliorate the loss of function after spinal cord injuries, with the hope of developing interventions to benefit patients. Although many reports suggest positive effects, there is growing concern over the quality of the available preclinical data. It is therefore important to ask whether this worldwide investigative process is close to defining a cell transplant protocol that could be translated into human patients with a realistic chance of success. This review systematically examines the strength of the preclinical evidence and outlines mechanisms by which transplanted cells may mediate their effects in spinal cord injuries. First, we examined changes in voluntary movements in the forelimb associated with cell transplants after partial cervical lesions. Second, we examined the efficacy of transplanted cells to restore electrophysiological conduction across a complete thoracic lesion. We postulated that cell therapies found to be successful in both models could reasonably have potential to treat human patients. We conclude that although there are data to support a beneficial effect of cell transplantation, most reports provide only weak evidence because of deficits in experimental design. The mechanisms by which transplanted cells mediate their functional effects remain unclear.
Initially discovered as a potent neurite outgrowth inhibitor in the central nervous system (CNS), Nogo-A has emerged as a multifunctional protein. Involvement of this protein has been demonstrated in numerous developmental processes, ranging from cell migration, axon guidance and fasciculation, dendritic branching and CNS plasticity to oligodendrocyte differentiation and myelination. Although initially necessary and beneficial for shaping and later maintaining CNS structure and functionality, the growth restricting properties of Nogo-A can have negative effects on nervous system injury or disease. Hence, correlating with its various neurobiological roles, Nogo-A was implicated in a range of CNS disturbances, including trauma such as spinal cord injury or stroke, neurodegenerative diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis or multiple sclerosis, or in schizophrenia. In this review, we summarize the current state of knowledge for Nogo-A’s involvement in these nervous system diseases and perturbations and discuss the possible underlying mechanisms. Furthermore, we provide a comprehensive overview on molecular signaling pathways as well as structural properties identified for Nogo-A and point to open questions in the field.
Stroke is a common problem, and with an aging population, it is likely to become more so. Outcomes from stroke are wide ranging from death to complete recovery, but the majority result in severe motor impairments that affect quality of life and become a burden on health care systems, family, and friends. Therapeutically, removal of thromboses can greatly improve outcomes, but for many stroke sufferers, the only currently available therapy is rehabilitative training in which spared brain areas and fiber tracts are strengthened and trained to take over new functions. Experimental data in animals show that this is in part based on changes in the connectivity of the brain and spinal cord and on the growth of new nerve fiber branches, a process called structural plasticity. So, just how plastic is the brain after a stroke? In this review, we explore the factors that affect plasticity after strokes, such as age and the overall size and location of the lesion. We discuss the peri-infarct area as extensive research has shown that processes occurring there are likely to be involved mechanistically in plastic changes in cortical circuitry. Finally, we review promising interventions being tested preclinically and discuss those that have been translated into clinical research.
Cytoskeletal restructuring is essential for nearly all cellular processes in the developing brain. After cell fate determination, newborn cortical neurons must migrate to their final positions while establishing proper axon-dendrite polarity. Significant progress has recently been made towards understanding the cellular and molecular mechanisms underlying neuronal polarization in vivo. Collapsin response mediator protein 2 (CRMP2) has long been identified as a microtubule-binding protein that regulates neuronal polarity in vitro. Recent studies provide new insights into the roles of CRMP2 in neuronal migration and subsequent neuronal differentiation. Both the expression and activity of CRMP2 are tightly regulated during cortex development. CRMP2 is suggested to be important in the multipolar-bipolar transition in radial migration. The increasing number of known interaction partners indicates that CRMP2 has functions beyond cytoskeletal regulation, including axonal transport, vesicle trafficking, and neurotransmitter release. This review discusses the current knowledge about CRMP2 in the context of neuronal development and highlights a recent emerging theme regarding its potential therapeutic applications.
Physical exercise is known to exert various beneficial effects on brain function and bodily health throughout life. In biomedical research, these effects are widely studied by introducing running wheels into the cages of laboratory rodents. Yet, although rodents start to run in the wheels immediately, and perform wheel-running excessively on a voluntary basis, the biological significance of wheel-running is still not clear. Here, we review the current literature on wheel-running and discuss potentially negative side-effects that may give cause for concern. We particularly emphasize on analogies of wheel-running with stereotypic and addictive behavior to stimulate further research on this topic.
Immune activity in the CNS parenchyma under various acute and chronic neurodegenerative conditions has been often interpreted as a sign of pathological inflammation. The apparent resemblance of the local neuroinflammatory processes to autoimmune diseases, such as multiple sclerosis (MS), generated the view that, despite differences in etiology and pathology, neurodegenerative disorders with a local inflammatory component can benefit from systemic anti-inflammatory therapy. In addition, as CNS self-reactive T cells are associated with the etiology of MS, autoimmunity was assumed to solely reflect pathology, and therefore, was universally linked to autoimmune disease. Yet, it is becoming increasingly clear that CNS-specific T cells, along with circulating and local innate immune cells, can enhance CNS healing processes following non-infectious injuries, or any deviation from homeostasis, including chronic pathological conditions. Here, we discuss the theory of "protective autoimmunity," which describes the activity of an immune cell network encompassing effector and regulatory T cells with specificity for CNS antigens, in CNS maintenance and repair. Such an immune network, evoked in response to external and internal threats, functions in a tightly regulated way, ensuring restoration of the brain’s equilibrium and return to homeostasis.
The brain is limited in its capacity to process all sensory stimuli present in the physical world at any point in time and relies instead on the cognitive process of attention to focus neural resources according to the contingencies of the moment. Attention can be categorized into two distinct functions: bottom-up attention, referring to attentional guidance purely by externally driven factors to stimuli that are salient because of their inherent properties relative to the background; and top-down attention, referring to internal guidance of attention based on prior knowledge, willful plans, and current goals. Over the past few years, insights on the neural circuits and mechanisms of bottom-up and top-down attention have been gained through neurophysiological experiments. Attention affects the mean neuronal firing rate as well as its variability and correlation across neurons. Although distinct processes mediate the guidance of attention based on bottom-up and top-down factors, a common neural apparatus, the frontoparietal network, is essential in both types of attentional processes.
The natural complexity of the brain, its hierarchical structure, and the sophisticated topological architecture of the neurons organized in micronetworks and macronetworks are all factors contributing to the limits of the application of Euclidean geometry and linear dynamics to the neurosciences. The introduction of fractal geometry for the quantitative analysis and description of the geometric complexity of natural systems has been a major paradigm shift in the last decades. Nowadays, modern neurosciences admit the prevalence of fractal properties such as self-similarity in the brain at various levels of observation, from the microscale to the macroscale, in molecular, anatomic, functional, and pathological perspectives. Fractal geometry is a mathematical model that offers a universal language for the quantitative description of neurons and glial cells as well as the brain as a whole, with its complex three-dimensional structure, in all its physiopathological spectrums. For a holistic view of fractal geometry of the brain, we review here the basic concepts of fractal analysis and its main applications to the basic neurosciences.
It has been ascertained that the human brain is a complex system studied at multiple scales, from neurons and microcircuits to macronetworks. The brain is characterized by a hierarchical organization that gives rise to its highly topological and functional complexity. Over the last decades, fractal geometry has been shown as a universal tool for the analysis and quantification of the geometric complexity of natural objects, including the brain. The fractal dimension has been identified as a quantitative parameter for the evaluation of the roughness of neural structures, the estimation of time series, and the description of patterns, thus able to discriminate different states of the brain in its entire physiopathological spectrum. Fractal-based computational analyses have been applied to the neurosciences, particularly in the field of clinical neurosciences including neuroimaging and neuroradiology, neurology and neurosurgery, psychiatry and psychology, and neuro-oncology and neuropathology. After a review of the basic concepts of fractal analysis and its main applications to the basic neurosciences in part I of this series, here, we review the main applications of fractals to the clinical neurosciences for a holistic approach towards a fractal geometry model of the brain.
Astroglia are the homoeostatic cells of the central nervous system that control a normal function of synaptically connected neuronal networks and contribute to brain defense. Recent advances in comprehension of pathological potential of astroglia indicate that astrocytes are fundamental for most (if not all) neurological diseases. Neuropathological and neuroimaging studies demonstrate prominent astroglial atrophy and astroglial asthenia occurring in most of neuropsychiatric illnesses. In chronic diseases such as schizophrenia and major depression, decrease in astroglial numbers and functional capabilities are, arguably, fundamental for pathological developments being responsible for neurotransmitter disbalance and failures in connectivity within neural networks. In neurodegenerative diseases atrophic changes in astrocytes are complemented by astrogliosis triggered by specific lesions such as senile plaques or dying neurons, these two processes contributing to cognitive decline and ultimately neuronal death. It is therefore possible to hypothesize that neuropsychiatric diseases represent a chronic astrogliopathology, which compromises glial homeostatic and defensive capabilities, and the degree and the alacrity of gliodegenerative changes define the progression and outcome of these disorders.
The brain’s "reward circuit" has been widely implicated in the pathophysiology of mental illness. Although there has been significant progress in identifying the functional characteristics of individual nodes within the circuit and linking dysfunction of these brain areas to various forms of psychopathology, there remains a substantial gap in understanding how the nodes of the circuit interact with one another, and how the growing neurobiological knowledge may be applied to improve psychiatric patient care. In this article, we summarize what is currently known about the functions and interactions of two key nodes of this circuit—the ventral striatum and the ventromedial prefrontal/orbital frontal cortex—in relation to mental illness.
The 22q11 deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans and presents with a complex and variable psychiatric phenotype. Patients show cognitive impairment and have a higher probability of psychiatric disorders. As much as 30% of patients with 22q11DS suffer from schizophrenia, the strongest association between any mutation and the disease. Schizophrenia is a complex psychiatric disease that affects multiple brain regions, giving rise to a constellation of seemingly unrelated symptoms including hallucinations, social withdrawal, and memory deficits. Synaptic or neuronal malfunctions within certain physiological circuits appear to be at the core of these symptoms. Understanding disease at the synaptic level requires genetic model systems where intact neural circuits can be interrogated for functional deficits. Because of the overlap between 22q11DS and schizophrenia, models of 22q11DS may be key genetic tools for investigating both diseases. Here we discuss the advantages of using a synaptic function approach to studying mouse models of 22q11DS, review recent findings, and discuss them in the broader context of 22q11DS and schizophrenia.
An epileptic brain is permanently in a diseased state, but seizures occur rarely and without warning. Here we examine this paradox, common to paroxysmal diseases. We review the problem in the context of the prototypic acquired epilepsies of the medial temporal lobe. We ask how an epileptic temporal lobe differs from a healthy one and examine biological mechanisms that may explain the transition to seizure. Attempts to predict seizure timing from analyses of brain electrical activity suggest that the neurological processes involved may be initiated significantly before a seizure. Furthermore, whereas seizures are said to occur without warning, some patients say they know when a seizure is imminent. Several factors, including sleep deprivation, oscillations in hormonal levels, or withdrawal from drugs, increase the probability of a seizure. We ask whether these seizure precipitants might act through common neuronal mechanisms. Several precipitating factors seem to involve relief from a neurosteroid modulation of gamma-amino butyric acid receptor type A (GABAA) receptors. We propose tests of this hypothesis.
Since the discovery of short, regulatory microRNAs (miRNA) 20 years ago, the understanding of their impact on gene regulation has dramatically increased. Differentiation of cells requires comprehensive changes in regulatory networks at all levels of gene expression. Posttranscriptional regulation by miRNA leads to rapid modifications in the protein level of large gene networks, and it is therefore not surprising that miRNAs have been found to influence the fate of differentiating cells. Several recent studies have shown that overexpression of a single miRNA in different cellular contexts results in forced differentiation of nerve cells. Loss of this miRNA constrains neurogenesis and promotes gliogenesis. This miRNA, miR-124, is probably the most well-documented example of a miRNA that controls nerve cell fate determination. In this review we summarize the recent findings on miR-124, potential molecular mechanisms used by miR-124 to drive neuronal differentiation, and outline future directions.
On the face of it, memory, imagination, and prediction seem to be distinct cognitive functions. However, metacognitive, cognitive, neuropsychological, and neuroimaging evidence is emerging that they are not, suggesting intimate links in their underlying processes. Here, we explore these empirical findings and the evolving theoretical frameworks that seek to explain how a common neural system supports our recollection of times past, imagination, and our attempts to predict the future.
The idea of two separate attention networks in the human brain for the voluntary deployment of attention and the reorientation to unexpected events, respectively, has inspired an enormous amount of research over the past years. In this review, we will reconcile these theoretical ideas on the dorsal and ventral attentional system with recent empirical findings from human neuroimaging experiments and studies in stroke patients. We will highlight how novel methods—such as the analysis of effective connectivity or the combination of neurostimulation with functional magnetic resonance imaging—have contributed to our understanding of the functionality and interaction of the two systems. We conclude that neither of the two networks controls attentional processes in isolation and that the flexible interaction between both systems enables the dynamic control of attention in relation to top-down goals and bottom-up sensory stimulation. We discuss which brain regions potentially govern this interaction according to current task demands.
X-linked intellectual disability (XLID) affects 1% to 3% of the population. XLID subsumes several heterogeneous conditions, all of which are marked by cognitive impairment and reduced adaptive skills. XLID arises from mutations on the X chromosome; to date, 102 XLID genes have been identified. The proteins encoded by XLID genes are involved in higher brain functions, such as cognition, learning and memory, and their molecular role is the subject of intense investigation. Here, we review recent findings concerning a representative group of XLID proteins: the fragile X mental retardation protein; methyl-CpG-binding protein 2 and cyclin-dependent kinase-like 5 proteins, which are involved in Rett syndrome; the intracellular signaling molecules of the Rho guanosine triphosphatases family; and the class of cell adhesion molecules. We discuss how XLID gene mutations affect the structure and function of synapses.
Advances in cellular reprograming have shown that the delivery of specific transcription factors can result in the shift of one cell type to another. Brief forced expression of the four Yamanaka reprogramming factors (Klf4, Sox2, c-Myc, and Oct4) is able to convert many cell types into induced pluripotent stem cells, whereas some lineage specific transcription factors can convert cells from one type directly to another. Numerous strategies have already been developed for deriving neural cell types, with the hopes of better understanding/alleviating neurodegenerative disease. These cells facilitate drug discovery and constitute an autologous source of cells for brain repair, thus, avoiding rejection issues faced by allografts derived from embryonic stem cells. However, proper characterization of the various types of reprogrammed cells and an understanding of how these cells acquire neural fate is necessary before their translation into the clinic. Here, we review the progress, problems, and prospects with reprogrammed cell types with regards to neurodegenerative disease.
The idea that magnetic fields could be used therapeutically arose 2000 years ago. These therapeutic possibilities were expanded after the discovery of electromagnetic induction by the Englishman Michael Faraday and the American Joseph Henry. In 1896, Arsène d’Arsonval reported his experience with noninvasive brain magnetic stimulation to the scientific French community. In the second half of the 20th century, changing magnetic fields emerged as a noninvasive tool to study the nervous system and to modulate neural function. In 1985, Barker, Jalinous, and Freeston presented transcranial magnetic stimulation, a relatively focal and painless technique. Transcranial magnetic stimulation has been proposed as a clinical neurophysiology tool and as a potential adjuvant treatment for psychiatric and neurologic conditions. This article aims to contextualize the progress of use of magnetic fields in the history of neuroscience and medical sciences, until 1985.
Functional magnetic resonance imaging (fMRI) studies of recognition memory ubiquitously demonstrate retrieval-related activity in left lateral parietal cortex (LLPC) when contrasting studied ("old") items with unstudied ("new") items. Recent work demonstrates that there is considerable functional–anatomical heterogeneity in LLPC. One implication of this observation is that single- or dual-process models fall short of characterizing LLPC contributions to memory retrieval. Instead of considering LLPC as a single entity, functional accounts must be given for each of the distinct regions that show retrieval-related effects; we posit there are a minimum of four such regions and very likely more. Identification of these LLPC regions requires careful analysis to map the boundaries and the extent of the regions precisely. In addition, characterizing the functional responses as activations or deactivations relative to baseline will be crucial in understanding the underlying cognitive processes. Considering LLPC in both memory and "nonmemory" domains will also illuminate the contribution of these regions, because it is certainly unlikely they serve only the domain of memory retrieval.
The brain has an intrinsic capacity to compensate for structural damage through reorganizing of surviving networks. These processes are fundamental for recovery of function after many forms of brain injury, including stroke. Functional neuroimaging techniques have allowed the investigation of these processes in vivo. Here, we review key advances over the past two decades that have shed light on the neural mechanisms enabling recovery of motor function after stroke. We first provide an overview on invasive stroke models in non-human primates that provided insights into lesion-induced changes in the cortical representations of the upper limb. We then present key findings from neuroimaging studies in human stroke patients, which suggest that the role of contralesional motor hemisphere in supporting recovered function depends on factors such time since stroke, lesion location and anatomical region. More recently, research has been directed at understanding how surviving brain regions influence one another during movement. It appears that it is not only the corticospinal tract but also brainstem pathways and interhemispheric connections that affect cortical reorganization patterns and functional recovery. In summary, neuroimaging opens the way for greater understanding of the mechanisms of recovery and potentially improves our ability to deliver effective restorative therapy.
Changes in brain circuits occur within specific paradigms of action in the adult brain. These paradigms include changes in behavioral activity patterns, alterations in environmental experience, and direct brain injury. Each of these paradigms can produce axonal sprouting, dendritic morphology changes, and alterations in synaptic connectivity. Activity-, experience-, and injury-dependent plasticity alter neuronal network function and behavioral output, and in the case of brain injury, may produce neurological recovery. The molecular substrate for adult neuronal plasticity overlaps in these three paradigms in key signaling pathways. These common pathways for adult plasticity suggest common mechanisms for activity-, experience-, and injury-dependent plasticity. These common pathways may also interact to enhance or impede each other during adult recovery of function after injury. This review focuses on common molecular changes evoked during the process of adult neuronal plasticity, with a focus on neural repair in stroke.
Neuronal death and suppression of functional synaptic inputs are well-known regressive events characterizing PNS and CNS development. In the CNS, participation of activity in synapse elimination has been known ever since the pioneering studies of Hubel and Wiesel, but only recently has a Hebb-based mechanism of spike synchrony versus asynchrony received unequivocal experimental support in the visual system. At the neuromuscular junction (NMJ), where synapse elimination was discovered, the specific function of the "timing of activity" was addressed by only one group of studies and did not receive widespread attention. Here we critically review the latest NMJ investigation advocating an "activity-independent" mechanism for synapse elimination and contrast it with an equally recent study demonstrating a key role for spike timing. Finally, we highlight how the striking similarities between the two mentioned studies on spike timing (visual system and NMJ) establish conclusively its role in the development of the nervous system in general.
Sensory cortices can not only detect and analyze incoming sensory information but can also undergo plastic changes while learning behaviorally important sensory cues. This experience-dependent cortical plasticity is essential for shaping and modifying neuronal circuits to perform computations of multiple, previously unknown sensations, the adaptive process that is believed to underlie perceptual learning. Intensive efforts to identify the mechanisms of cortical plasticity have provided several important clues; however, the exact cellular sites and mechanisms within the intricate neuronal networks that underlie cortical plasticity have yet to be elucidated. In this review, we present several parallels between cortical plasticity in the auditory cortex and recently discovered mechanisms of synaptic plasticity gating at thalamocortical projections that provide the main input to sensory cortices. Striking similarities between the features and mechanisms of thalamocortical synaptic plasticity and those of experience-dependent cortical plasticity in the auditory cortex, especially in terms of regulation of an early critical period, point to thalamocortical projections as an important locus of plasticity in sensory cortices.
Metabotropic glutamate receptors (mGluRs) are found throughout thalamus and cortex and are clearly important to circuit behavior in both structures, and so considering only participation of ionotropic glutamate receptors (e.g., [R,S]-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and N-methyl-d-aspartate receptors [NMDA] receptors) in glutamatergic processing would be an unfortunate oversimplification. These mGluRs are found both postsynaptically, on target cells of glutamatergic afferents, and presynaptically, on various synaptic terminals themselves, and when activated, they produce prolonged effects lasting at least hundreds of msec to several sec and perhaps longer. Two main types exist: activation of group I mGluRs causes postsynaptic depolarization, and group II, hyperpolarization. Both types are implicated in synaptic plasticity, both short term and long term. Their evident importance in functioning of thalamus and cortex makes it critical to develop a better understanding of how these receptors are normally activated, especially because they also seem implicated in a wide range of neurological and cognitive pathologies.
The monitoring of intracranial pressure (ICP) is an important tool in medicine for its ability to portray the brain’s compliance status. The bedside monitor displays the ICP waveform and intermittent mean values to guide physicians in the management of patients, particularly those having sustained a traumatic brain injury. Researchers in the fields of engineering and physics have investigated various mathematical analysis techniques applicable to the waveform in order to extract additional diagnostic and prognostic information, although they largely remain limited to research applications. The purpose of this review is to present the current techniques used to monitor and interpret ICP and explore the potential of using advanced mathematical techniques to provide information about system perturbations from states of homeostasis. We discuss the limits of each proposed technique and we propose that nonlinear analysis could be a reliable approach to describe ICP signals over time, with the fractal dimension as a potential predictive clinically meaningful biomarker. Our goal is to stimulate translational research that can move modern analysis of ICP using these techniques into widespread practical use, and to investigate to the clinical utility of a tool capable of simplifying multiple variables obtained from various sensors.
In psychiatric disorders, the effect of genetic and environmental factors may converge on molecular pathways and brain circuits related to growth factor functioning. In this review, we describe how disturbances in fibroblast growth factors (FGFs) and their receptors influence behavior by affecting brain development. Recently, several studies reported associations of members of the FGF family with psychiatric disorders. FGFs are key candidates to modulate the impact of environmental factors, such as stress. Mutant mice for FGF receptor 1 show schizophrenia-like behaviors that are related to general loss of neurons and postnatal glia dysfunction. Mice lacking FGF2, a FGFR1 ligand, show similar reductions in brain volume and hyperactivity, as well as increased anxiety behaviors. FGFR2 and FGF17 are involved in the development of frontal brain regions and impairments in cognitive and social behaviors, respectively. Moreover, treatment with FGF2 was beneficial for depressive and cognitive measures in several animal studies and one human study. These findings indicate the importance of the FGF system with respect to developing novel etiology-directed treatments for psychopathology.
For the past decade, DISC1 has been studied as a promising lead to understand the biology underlying major mental illnesses, such as schizophrenia. Consequently, many review articles on DISC1 have been published. In this article, rather than repeating comprehensive overviews of research articles, we will introduce the utility of DISC1 in the study of cortical development in association with a wide range of developmental brain disorders. Cortical development involves cell autonomous and cell nonautonomous mechanisms as well as host responses to environmental factors, all of which involve DISC1 function. Thus, we will discuss the significance of DISC1 in forming an overall understanding of multiple mechanisms that orchestrate corticogenesis and can serve as therapeutic targets in diseases caused by abnormal cortical development.
Astrocytes are the most abundant cell type in the adult central nervous system (CNS), and their functional diversity in response to injury is now being appreciated. Astrocytes have long been considered the main player in the inhibition of CNS repair via the formation of the gliotic scar, but now it is accepted that astrocyte can play an important role in CNS repair and remyelination. Interest in the relationship between astrocytes and myelination focused initially on attempts to understand how the development of plaques of astroglial scar tissue in multiple sclerosis was related to the failure of these lesions to remyelinate. It is now considered that this is an end stage pathological response to injury, and that normally astrocytes play important roles in supporting the development and maintenance of CNS myelin. This review will focus on how this new understanding may be exploited to develop new strategies to enhance remyelination in multiple sclerosis and other diseases.
The brain is neither uniform nor composed of similar modules but is rather a mosaic of different and highly interconnected regions. Accordingly, knowledge of functional connectivity between brain regions is crucial to understanding perception, cognition, and behavior. Functional connectivity methods estimate similarities between activity recorded in different regions of the brain. They are often applied to resting state activity, thus providing measures that are by nature task independent. The spatial patterns revealed by functional connectivity are not only shaped by the underlying anatomical structure of the brain but also partially depend on the history of task-driven coactivations. Inter-subject differences in functional connectivity may, at least to some degree, underlie variability observed in task performance across healthy subjects and in behavioral impairments in neurological patients. In this respect, recent studies have demonstrated that behavioral deficits in patients with brain injury are not only due to local tissue damage but also due to altered functional connectivity among structurally intact regions connected to the damaged site. Studies based on functional connectivity have the potential to advance basic understanding of how brain lesions induce neuropsychological syndromes. Furthermore, they may eventually suggest improved rehabilitation strategies for patients with brain injury, through the design of individualized treatment and recovery protocols.
Electrical stimulation of the brain was one of the first experimental methods applied to understanding brain organization and function and it continues as a highly useful method both in research and clinical applications. Intracortical microstimulation (ICMS) involves applying electrical stimuli through a microelectrode suitable for recording the action potentials of single neurons. ICMS can be categorized into single-pulse stimulation; high-frequency, short-duration stimulation; and high-frequency, long-duration stimulation. For clinical and experimental reasons, considerable interest focuses on the mechanism of neural activation by electrical stimuli. In this article, we discuss recent results suggesting that action potentials evoked in cortical neurons by high-frequency electrical stimulation do not sum with the natural, behaviorally related background activity; rather, high-frequency stimulation eliminates and replaces natural activity. We refer to this as neural hijacking. We propose that a major component of the mechanism underlying neural hijacking is excitation of axons by ICMS and elimination of natural spikes by antidromic collision with stimulus-driven spikes evoked at high frequency. Evidence also supports neural hijacking as an important mechanism underlying the action of deep brain stimulation in the subthalamic nucleus and its therapeutic effect in treating Parkinson’s disease.
Multiple sclerosis (MS) is a chronic demyelinating disorder of unknown etiology, possibly caused by a virus or virus-triggered immunopathology. The virus might reactivate after years of latency and lyse oligodendrocytes, as in progressive multifocal leukoencephalopathy, or initiate immunopathological demyelination, as in animals infected with Theiler’s murine encephalomyelitis virus or coronaviruses. The argument for a viral cause of MS is supported by epidemiological analyses and studies of MS in identical twins, indicating that disease is acquired. However, the most important evidence is the presence of bands of oligoclonal IgG (OCBs) in MS brain and CSF that persist throughout the lifetime of the patient. OCBs are found almost exclusively in infectious CNS disorders, and antigenic targets of OCBs represent the agent that causes disease. Here, the authors review past attempts to identify an infectious agent in MS brain cells and discuss the promise of using recombinant antibodies generated from clonally expanded plasma cells in brain and CSF to identify disease-relevant antigens. They show how this strategy has been used successfully to analyze antigen specificity in subacute sclerosing panencephalitis, a chronic encephalitis caused by measles virus, and in neuromyelitis optica, a chronic autoimmune demyelinating disease produced by antibodies directed against the aquaporin-4 water channel.
Recent advances in chromatin biology have identified a role for epigenetic mechanisms in the regulation of neuronal gene expression changes, a necessary process for proper synaptic plasticity and memory formation. Experimental evidence for dynamic chromatin remodeling influencing gene transcription in postmitotic neurons grew from initial reports describing posttranslational modifications of histones, including phosphorylation and acetylation occurring in various brain regions during memory consolidation. An accumulation of recent studies, however, has also highlighted the importance of other epigenetic modifications, such as DNA methylation and histone methylation, as playing a role in memory formation. This present review examines learning-induced gene transcription by chromatin remodeling underlying long-lasting changes in neurons, with direct implications for the study of epigenetic mechanisms in long-term memory formation and behavior. Furthermore, the study of epigenetic gene regulation, in conjunction with transcription factor activation, can provide complementary lines of evidence to further understanding transcriptional mechanisms subserving memory storage.
Mutations in mitochondrial DNA cause a number of neurological diseases with defined neuropathology; however, mutations in this genome have also been found to be important in a number of more common neurodegenerative diseases. In this review, the authors discuss the importance of mitochondrial DNA mutations in a number of different diseases and speculate how such mutations could lead to cell loss. Increasing our understanding of how mitochondrial DNA mutations affect mitochondrial metabolism and subsequently result in neurodegenerative disease will prove vital to the development of targeted therapies and treatments.