Showing papers in "Frontiers in Neuroscience in 2015"
TL;DR: This paper presents a full-custom mixed-signal VLSI device with neuromorphic learning circuits that emulate the biophysics of real spiking neurons and dynamic synapses for exploring the properties of computational neuroscience models and for building brain-inspired computing systems.
Abstract: Implementing compact, low-power artificial neural processing systems with real-time on-line learning abilities is still an open challenge. In this paper we present a full-custom mixed-signal VLSI device with neuromorphic learning circuits that emulate the biophysics of real spiking neurons and dynamic synapses for exploring the properties of computational neuroscience models and for building brain-inspired computing systems. The proposed architecture allows the on-chip configuration of a wide range of network connectivities, including recurrent and deep networks with short-term and long-term plasticity. The device comprises 128 K analog synapse and 256 neuron circuits with biologically plausible dynamics and bi-stable spike-based plasticity mechanisms that endow it with on-line learning abilities. In addition to the analog circuits, the device comprises also asynchronous digital logic circuits for setting different synapse and neuron properties as well as different network configurations. This prototype device, fabricated using a 180 nm 1P6M CMOS process, occupies an area of 51.4 mm 2 , and consumes approximately 4 mW for typical experiments, for example involving attractor networks. Here we describe the details of the overall architecture and of the individual circuits and present experimental results that showcase its potential. By supporting a wide range of cortical-like computational modules comprising plasticity mechanisms, this device will enable the realization of intelligent autonomous systems with on-line learning capabilities.
607 citations
TL;DR: The ongoing advancements in microelectrode technology are introduced, with focus on achieving higher resolution and quality of recordings by means of monolithic integration with on-chip circuitry.
Abstract: Microelectrode arrays and microprobes have been widely utilized to measure neuronal activity, both in vitro and in vivo. The key advantage is the capability to record and stimulate neurons at multiple sites simultaneously. However, unlike the single-cell or single-channel resolution of intracellular recording, microelectrodes detect signals from all possible sources around the sensor. Here, we review the current understanding of microelectrode signals and the techniques for analyzing them. We introduce the ongoing advancements in microelectrode technology, with focus on achieving higher resolution and quality of recordings by means of monolithic integration with on-chip circuitry. We show how recent advanced microelectrode array measurement methods facilitate the understanding of single neurons as well as network function.
537 citations
TL;DR: The presence of a functional and classical lymphatic system in the central nervous system suggests that current dogmas regarding brain tolerance and the immune privilege of the brain should be revisited in autism, which intersect with observations of increased extra-axial CSF (EAF) in the autism population.
Abstract: Autism spectrum disorders (ASD) represent an apparent pandemic threat to child development with the current CDC data documenting ASD affecting over 2% of U.S. males of school age ([CDC] Developmental Disabilities Monitoring Network Surveillance Year 2010 Principal, 2014). ASD are likely a heterogeneous group of disorders with genetic and environmental causes resulting in similar phenotypes. Genetic contributions to autism are extremely heterogeneous and may involve synaptic formation and maturation. Thus, multiple genes involved in the formation, specification, and maintenance of synapses have been identified as risk factors for ASD development (Hahn et al., 2013). Also the rate of brain growth in the first 2 years of life may contribute to ASD. Although abnormally enlarged brain volumes and increased rates of brain growth during early childhood are observed only in a minority of ASD children, nevertheless there is evidence of abnormalities in posterior lobes and posterior brain networks during the first 2 years of life in ASD (Lainhart, 2015).
If the etiology of ASD is still mysterious, there is a growing consensus for the role of neuroinflammation in ASD pathogenesis (Fatemi et al., 2012), and the recent publication in Nature of the existence of the previously unknown meningeal lymphatic system, invites a closer evaluation of its potential significance to brain development (Louveau et al., 2015).
In 1983, Aarli speculated the fluid of the brain traveled along mysterious perivascular channels, and noted that immunological challenges could affect the integrity of the blood brain barrier (Aarli, 1983). It was then accepted that the exit pathway for immune cells trafficking through the CNS was via the arachnoid granulations. The new study in Nature provides us with a secondary pathway leading to deep cervical lymph nodes.
We concur with the comment (Louveau et al., 2015) that; “the presence of a functional and classical lymphatic system in the central nervous system suggests that current dogmas regarding brain tolerance and the immune privilege of the brain should be revisited.”
This feature is critically important with regard to the observations of immunological dysregulation in autism, which intersect with observations of increased extra-axial CSF (EAF) in the autism population. MRI scans were used (Shen et al., 2013) to evaluate the EAF of infants born into families with an existing autistic child. They were able to predict the future onset and severity of autism based on the findings of early and persistent increases in EAF. In a similar way, we were able to demonstrate increased EAF using transcranial ultrasonography and we too observed a correlation between increased severity of autistic symptoms and increased EAF scores (Bradstreet et al., 2014). The mechanisms responsible for such an increased EAF, however, remained unknown. The newly discovered meningeal lymphatic system might help explaining how immunological dysfunctions and peripheral chronic infection/inflammation may affect the meninges and, consequently, brain development.
Several evidences point to a connection between meninges and abnormal CNS development. Meningeal cells are involved in cortical development (Dragunow, 2013), and meningeal alterations in mice modeling ASD-like behaviors contribute to incorrect neurogenesis during development (Mercier et al., 2011). In 2012, Zarbalis et al. demonstrated that meningeal defects alter migration of cortical interneurons in a mouse model, thus further stressing the role of the meninges in the establishment of proper neuronal interconnections (Zarbalis et al., 2012).
The observations of increased EAF in the autism population with these new observations of a central lymphatic system connected to cervical lymph nodes, should direct more attention to the role of meningeal lymphatics in the pathogenesis of ASD. It further begs the question: “could inflammation-associated deficits in meningeal lymph drainage be the culprit for the observed increased EAF?”
Intersecting the increased EAF volume observations in ASD with the EAF drainage to deep cervical lymph nodes draws our attention to the pathogenetic potential of chronic infections leading to inflammation and subsequent deficit in lymphatic drainage.
Supporting the role of chronic infection/inflammation in ASD pathogenesis, multiple polyomaviral infections were observed to be significantly more common in the post-mortem brains of ASD individuals (Lintas et al., 2010) and ASD individuals show immune transcriptome alterations in the temporal cortex that seem to indicate immune dysregulation with consequent inflammation (Garbett et al., 2008). Piras et al. (2014) correlated anti-brain antibodies with specific deficits in ASD, thus reinforcing the notion that chronic inflammation is a common denominator that may lead to EAF increase because of impaired meningeal lymphatic drainage.
The existence of a classical lymphatic system in the CNS might also explain the nature of the lesions in the brains of autistic subjects, which we observed with ultrasonography and designated “cortical dysplasia” (Bradstreet et al., 2014). Inefficient drainage with focal accumulation of CSF in certain areas of the cortex might explain the hypoechogenic appearance of focal “patches,” which we consistently observed in autistic subjects. Accumulation of fluid that typically appears hypoechogenic in ultrasonography, might thus disrupt neuronal/glial networking by increasing the distance between cells and by increasing extracellular pressure on cells with consequent alteration of gene expression trough modification of the cytoskeleton (Knoll, 2010). Since Stoner et al. (2014) also observed “patches” of decreased transcription in autism related brain bank specimens, it is tempting to speculate that such alterations of gene expression may be associated with the accumulation of EAF and its effects on neuronal and glial function.
Finally, transcranial ultrasonography deserves more attention as a harmless and low-cost means of evaluating CSF fluid volumes and stratifying ASD children potentially at-risk for chronic CNS inflammatory disorders. Transcranial ultrasonography enables reproducible evaluation of EAF by measuring the distances between the arachnoid membrane and the cortical pia layer (subarachnoid space), and may thus help establishing the degree of meningeal lymphatic drainage deficit. Since the measures can be easily repeated, the technique could be used for monitoring the progression of the disease or for objectively assessing the efficacy of treatments.
In conclusion, the observation by Louveau et al. (2015) leads us to hypothesize that meningeal lymphatic drainage deficit due to peripheral chronic infection/inflammation may be responsible for increased EAF and cortical dysplasia in ASD individuals and, possibly, for some of the symptoms typical of the disorder.
527 citations
TL;DR: An overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration is provided.
Abstract: Together with aspartate, glutamate is the major excitatory neurotransmitter in the brain. Glutamate binds and activates both ligand-gated ion channels (ionotropic glutamate receptors) and a class of G-protein coupled receptors (metabotropic glutamate receptors). Although the intracellular glutamate concentration in the brain is in the millimolar range, the extracellular glutamate concentration is kept in the low micromolar range by the action of excitatory amino acid transporters that import glutamate and aspartate into astrocytes and neurons. Excess extracellular glutamate may lead to excitotoxicity in vitro and in vivo in acute insults like ischemic stroke via the overactivation of ionotropic glutamate receptors. In addition, chronic excitotoxicity has been hypothesized to play a role in numerous neurodegenerative diseases including amyotrophic lateral sclerosis, Alzheimer's disease and Huntington's disease. Based on this hypothesis, a good deal of effort has been devoted to develop and test drugs that either inhibit glutamate receptors or decrease extracellular glutamate. In this review, we provide an overview of the different pathways that are thought to lead to an over-activation of the glutamatergic system and glutamate toxicity in neurodegeneration. In addition, we summarize the available experimental evidence for glutamate toxicity in animal models of neurodegenerative diseases.
519 citations
TL;DR: How physiologically occurring hormonal transition periods in humans can be used to model how changes in sex hormones influence functional connectivity, neurotransmission and brain structure in vivo is discussed.
Abstract: Sex hormones have been implicated in neurite outgrowth, synaptogenesis, dendritic branching, myelination and other important mechanisms of neural plasticity. Here we review the evidence from animal experiments and human studies reporting interactions between sex hormones and the dominant neurotransmitters, such as serotonin, dopamine, GABA and glutamate. We provide an overview of accumulating data during physiological and pathological conditions and discuss currently conceptualized theories on how sex hormones potentially trigger neuroplasticity changes through these four neurochemical systems. Many brain regions have been demonstrated to express high densities for estrogen- and progesterone receptors, such as the amygdala, the hypothalamus, and the hippocampus. As the hippocampus is of particular relevance in the context of mediating structural plasticity in the adult brain, we put particular emphasis on what evidence could be gathered thus far that links differences in behavior, neurochemical patterns and hippocampal structure to a changing hormonal environment. Finally, we discuss how physiologically occurring hormonal transition periods in humans can be used to model how changes in sex hormones influence functional connectivity, neurotransmission and brain structure in vivo.
399 citations
TL;DR: A main emerging concept is that these two neural cell types have different and energetically adapted glyoxalase defense mechanisms which may serve as protective mechanism against methylglyoxal-induced cellular damage.
Abstract: Glucose is the main energy substrate for the brain. There is now extensive evidence indicating that the metabolic profile of neural cells with regard to glucose utilization and glycolysis rate is not homogenous, with a marked propensity for glycolytic glucose processing in astrocytes compared to neurons. Methylglyoxal, a highly reactive dicarbonyl compound, is inevitably formed as a by-product of glycolysis. Methylglyoxal is a major cell-permeant precursor of advanced glycation end-products (AGEs), which are associated with several pathologies including diabetes, aging and neurodegenerative diseases. In normal situations, cells are protected against methylglyoxal toxicity by different mechanisms and in particular the glyoxalase system, which represents the most important pathway for the detoxification of methylglyoxal. While the neurotoxic effects of methylglyoxal and AGEs are well characterized, our understanding the glyoxalase system in the brain is more scattered. Considering the high energy requirements (i.e., glucose) of the brain, one should expect that the cerebral glyoxalase system is adequately fitted to handle methylglyoxal toxicity. This review focuses on our actual knowledge on the cellular aspects of the glyoxalase system in brain cells, in particular with regard to its activity in astrocytes and neurons. A main emerging concept is that these two neural cell types have different and energetically adapted glyoxalase defense mechanisms which may serve as protective mechanism against methylglyoxal-induced cellular damage.
372 citations
TL;DR: In this article, the authors proposed a method for converting existing Computer Vision static image datasets into Neuromorphic Vision datasets using an actuated pan-tilt camera platform, which eliminates timing artifacts introduced by monitor updates when simulating motion on a computer monitor.
Abstract: Creating datasets for Neuromorphic Vision is a challenging task. A lack of available recordings from Neuromorphic Vision sensors means that data must typically be recorded specifically for dataset creation rather than collecting and labelling existing data. The task is further complicated by a desire to simultaneously provide traditional frame-based recordings to allow for direct comparison with traditional Computer Vision algorithms. Here we propose a method for converting existing Computer Vision static image datasets into Neuromorphic Vision datasets using an actuated pan-tilt camera platform. Moving the sensor rather than the scene or image is a more biologically realistic approach to sensing and eliminates timing artifacts introduced by monitor updates when simulating motion on a computer monitor. We present conversion of two popular image datasets (MNIST and Caltech101) which have played important roles in the development of Computer Vision, and we provide performance metrics on these datasets using spike-based recognition algorithms. This work contributes datasets for future use in the field, as well as results from spike-based algorithms against which future works can compare. Furthermore, by converting datasets already popular in Computer Vision, we enable more direct comparison with frame-based approaches.
351 citations
TL;DR: Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.
Abstract: High levels of pro-inflammatory substances such as cytokines have been described in the blood and cerebrospinal fluid of schizophrenia patients. Animal models of schizophrenia show that under certain conditions an immune disturbance during early life, such as an infection-triggered immune activation, might trigger lifelong increased immune reactivity. A large epidemiological study clearly demonstrated that severe infections and autoimmune disorders are risk factors for schizophrenia. Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, in a region related to the human leucocyte antigen (HLA) system and other immune functions. Another line of evidence demonstrates that chronic (dis)stress is associated with immune activation. The vulnerability-stress-inflammation model of schizophrenia includes the contribution of stress on the basis of increased genetic vulnerability for the pathogenesis of schizophrenia, because stress may increase pro-inflammatory cytokines and even contribute to a lasting pro-inflammatory state. Immune alterations influence the dopaminergic, serotonergic, noradrenergic, and glutamatergic neurotransmission. The activated immune system in turn activates the enzyme indoleamine 2,3-dioxygenase (IDO) of the tryptophan/kynurenine metabolism which influences the serotonergic and glutamatergic neurotransmission via neuroactive metabolites such as kynurenic acid. The described loss of central nervous system volume and the activation of microglia, both of which have been clearly demonstrated in neuroimaging studies of schizophrenia patients, match the assumption of a (low level) inflammatory neurotoxic process. Further support for the inflammatory hypothesis comes from the therapeutic benefit of anti-inflammatory medication. Metaanalyses have shown an advantageous effect of cyclo-oxygenase-2 inhibitors in early stages of schizophrenia. Moreover, intrinsic anti-inflammatory, and immunomodulatory effects of antipsychotic drugs are known since a long time. Anti-inflammatory effects of antipsychotics, therapeutic effects of anti-inflammtory compounds, genetic, biochemical, and immunological findings point to a major role of inflammation in schizophrenia.
324 citations
TL;DR: Mechanisms that cause stress-induced monocyte re-distribution in the brain and how dynamic interactions between microglia, endothelial cells, and brain macrophages lead to maladaptive behavioral responses are discussed.
Abstract: Psychological stressors cause physiological, immunological, and behavioral alterations in humans and rodents that can be maladaptive and negatively affect quality of life. Several lines of evidence indicate that psychological stress disrupts key functional interactions between the immune system and brain that ultimately affects mood and behavior. For example, activation of microglia, the resident innate immune cells of the brain, has been implicated as a key regulator of mood and behavior in the context of prolonged exposure to psychological stress. Emerging evidence implicates a novel neuroimmune circuit involving microglia activation and sympathetic outflow to the peripheral immune system that further reinforces stress-related behaviors by facilitating the recruitment of inflammatory monocytes to the brain. Evidence from various rodent models, including repeated social defeat (RSD), revealed that trafficking of monocytes to the brain promoted the establishment of anxiety-like behaviors following prolonged stress exposure. In addition, new evidence implicates monocyte trafficking from the spleen to the brain as key regulator of recurring anxiety following exposure to prolonged stress. The purpose of this review is to discuss mechanisms that cause stress-induced monocyte re-distribution in the brain and how dynamic interactions between microglia, endothelial cells, and brain macrophages lead to maladaptive behavioral responses.
319 citations
TL;DR: It is demonstrated that species-specific vocalizations in rhesus monkeys activate preferentially the auditory ventral stream, and in particular areas of the antero-lateral belt and parabelt.
Abstract: Using functional magnetic resonance imaging in awake behaving monkeys we investigated how species-specific vocalizations are represented in auditory and auditory-related regions of the macaque brain. We found clusters of active voxels along the ascending auditory pathway that responded to various types of complex sounds: inferior colliculus (IC), medial geniculate nucleus (MGN), auditory core, belt, and parabelt cortex, and other parts of the superior temporal gyrus (STG) and sulcus (STS). Regions sensitive to monkey calls were most prevalent in the anterior STG, but some clusters were also found in frontal and parietal cortex on the basis of comparisons between responses to calls and environmental sounds. Surprisingly, we found that spectrotemporal control sounds derived from the monkey calls (“scrambled calls”) also activated the parietal and frontal regions. Taken together, our results demonstrate that species-specific vocalizations in rhesus monkeys activate preferentially the auditory ventral stream, and in particular areas of the antero-lateral belt and parabelt.
304 citations
TL;DR: The SOS attempts to merge ecological models that define a repertoire of contextually relevant threat induced survival behaviors with contemporary approaches to human affective science, proposing a highly integrated nervous system that has evolved to increase the organism's chances of survival.
Abstract: We propose a Survival Optimization System (SOS) to account for the strategies that humans and other animals use to defend against recurring and novel threats. The SOS attempts to merge ecological models that define a repertoire of contextually relevant threat induced survival behaviors with contemporary approaches to human affective science. We first propose that the goal of the nervous system is to reduce surprise and optimize actions by (i) predicting the sensory landscape, through simulation of possible encounters with threat, selecting appropriate action by pre-encounter avoidance and (ii) prevention strategies in which the organism manufactures safe environments. When a potential threat is encountered the (iii) threat orienting system is engaged to determine whether the organism ignores the stimulus or switches into a process of (iv) assessment, where the organism monitors the stimulus, weighs the threat value, predicts the actions of the threat, searches for safety, and guides behavioral actions crucial to directed escape. When under imminent attack, (v) defensive systems evoke fast reflexive indirect escape behaviors (i.e. fight or flight). This cascade of responses to threat of increasing magnitude are underwritten by an interconnected neural architecture that extends from cortical and hippocampal circuits, to attention, action and threat systems including the amygdala, striatum, and hard-wired defensive systems in the midbrain. The SOS also includes a modulatory feature consisting of cognitive appraisal systems that flexibly guide perception, risk and action. Moreover, personal and vicarious threat encounters fine-tune avoidance behaviors via model-based learning, with higher organisms bridging data to reduce face-to-face encounters with predators. Our theory unifies the divergent field of human affective science, proposing the highly integrated, interconnected nervous systems are optimized to avoid ecological dangers.
TL;DR: Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment.
Abstract: Alzheimer's disease (AD) is the most common form of dementia affecting elderly people. AD is a multifaceted pathology characterized by accumulation of extracellular neuritic plaques, intracellular neurofibrillary tangles (NFTs) and neuronal loss mainly in the cortex and hippocampus. AD etiology appears to be linked to a multitude of mechanisms that have not been yet completely elucidated. For long time, it was considered that insulin signaling has only peripheral actions but now it is widely accepted that insulin has neuromodulatory actions in the brain. Insulin signaling is involved in numerous brain functions including cognition and memory that are impaired in AD. Recent studies suggest that AD may be linked to brain insulin resistance and patients with diabetes have an increased risk of developing AD compared to healthy individuals. Indeed insulin resistance, increased inflammation and impaired metabolism are key pathological features of both AD and diabetes. However, the precise mechanisms involved in the development of AD in patients with diabetes are not yet fully understood. In this review we will discuss the role played by aberrant brain insulin signaling in AD. In detail, we will focus on the role of insulin signaling in the deposition of neuritic plaques and intracellular NFTs. Considering that insulin mitigates beta-amyloid deposition and phosphorylation of tau, pharmacological strategies restoring brain insulin signaling, such as intranasal delivery of insulin, could have significant therapeutic potential in AD treatment.
TL;DR: A combination of different sized, visualizable dextrans and radiolabeled molecules currently seems to be the most appropriate approach for qualitative and quantitative assessment of barrier integrity.
Abstract: In recent years there has been a resurgence of interest in brain barriers and various roles their intrinsic mechanisms may play in neurological disorders. Such studies require suitable models and markers to demonstrate integrity and functional changes at the interfaces between blood, brain, and cerebrospinal fluid. Studies of brain barrier mechanisms and measurements of plasma volume using dyes have a long-standing history, dating back to the late nineteenth-century. Their use in blood-brain barrier studies continues in spite of their known serious limitations in in vivo applications. These were well known when first introduced, but seem to have been forgotten since. Understanding these limitations is important because Evans blue is still the most commonly used marker of brain barrier integrity and those using it seem oblivious to problems arising from its in vivo application. The introduction of HRP in the mid twentieth-century was an important advance because its reaction product can be visualized at the electron microscopical level, but it also has limitations. Advantages and disadvantages of these markers will be discussed together with a critical evaluation of alternative approaches. There is no single marker suitable for all purposes. A combination of different sized, visualizable dextrans and radiolabeled molecules currently seems to be the most appropriate approach for qualitative and quantitative assessment of barrier integrity.
TL;DR: It is proposed that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD, leading to impairments in these domains.
Abstract: The cerebellum is one of the most consistent sites of abnormality in autism spectrum disorder (ASD) and cerebellar damage is associated with an increased risk of ASD symptoms, suggesting that cerebellar dysfunction may play a crucial role in the etiology of ASD. The cerebellum forms multiple closed-loop circuits with cerebral cortical regions that underpin movement, language, and social processing. Through these circuits, cerebellar dysfunction could impact the core ASD symptoms of social and communication deficits and repetitive and stereotyped behaviors. The emerging topography of sensorimotor, cognitive, and affective subregions in the cerebellum provides a new framework for interpreting the significance of regional cerebellar findings in ASD and their relationship to broader cerebro-cerebellar circuits. Further, recent research supports the idea that the integrity of cerebro-cerebellar loops might be important for early cortical development; disruptions in specific cerebro-cerebellar loops in ASD might impede the specialization of cortical regions involved in motor control, language, and social interaction, leading to impairments in these domains. Consistent with this concept, structural, and functional differences in sensorimotor regions of the cerebellum and sensorimotor cerebro-cerebellar circuits are associated with deficits in motor control and increased repetitive and stereotyped behaviors in ASD. Further, communication and social impairments are associated with atypical activation and structure in cerebro-cerebellar loops underpinning language and social cognition. Finally, there is converging evidence from structural, functional, and connectivity neuroimaging studies that cerebellar right Crus I/II abnormalities are related to more severe ASD impairments in all domains. We propose that cerebellar abnormalities may disrupt optimization of both structure and function in specific cerebro-cerebellar circuits in ASD.
TL;DR: It is shown for the first time that continuously spoken speech can be decoded into the expressed words from intracranial electrocorticographic recordings, and this approach contributes to the current understanding of the neural basis of continuous speech production by identifying those cortical regions that hold substantial information about individual phones.
Abstract: It has long been speculated whether communication between humans and machines based on natural speech related cortical activity is possible. Over the past decade, studies have suggested that it is feasible to recognize isolated aspects of speech from neural signals, such as auditory features, phones or one of a few isolated words. However, until now it remained an unsolved challenge to decode continuously spoken speech from the neural substrate associated with speech and language processing. Here, we show for the first time that continuously spoken speech can be decoded into the expressed words from intracranial electrocorticographic (ECoG) recordings.Specifically, we implemented a system, which we call Brain-To-Text that models single phones, employs techniques from automatic speech recognition (ASR), and thereby transforms brain activity while speaking into the corresponding textual representation. Our results demonstrate that our system can achieve word error rates as low as 25% and phone error rates below 50%. Additionally, our approach contributes to the current understanding of the neural basis of continuous speech production by identifying those cortical regions that hold substantial information about individual phones. In conclusion, the Brain-To-Text system described in this paper represents an important step toward human-machine communication based on imagined speech.
TL;DR: Given the high rates of obesity in most developed nations, it is critical that the mechanisms by which maternal obesity programs offspring behavior are thoroughly characterized, which will be critical in the development of preventative strategies and therapeutic interventions.
Abstract: Recent evidence indicates that perinatal exposure to maternal obesity, metabolic disease, including diabetes and hypertension, and unhealthy maternal diet has a long-term impact on offspring behavior and physiology. During the past three decades, the prevalence of both obesity and neuropsychiatric disorders has rapidly increased. Epidemiologic studies provide evidence that maternal obesity and metabolic complications increase the risk of attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, anxiety, depression, schizophrenia, eating disorders (food addiction, anorexia nervosa, and bulimia nervosa), and impairments in cognition in offspring. Animal models of maternal high-fat diet (HFD) induced obesity also document persistent changes in offspring behavior and impairments in critical neural circuitry. Animals exposed to maternal obesity and HFD consumption display hyperactivity, impairments in social behavior, increased anxiety-like and depressive-like behaviors, substance addiction, food addiction, and diminished cognition. During development, these offspring are exposed to elevated levels of nutrients (fatty acids, glucose), hormones (leptin, insulin), and inflammatory factors (C-reactive protein, interleukin, and tumor necrosis factor). Such factors appear to permanently change neuroendocrine regulation and brain development in offspring. In addition, inflammation of the offspring brain during gestation impairs the development of neural pathways critical in the regulation of behavior, such as serotoninergic, dopaminergic, and melanocortinergic systems. Dysregulation of these circuits increases the risk of mental health disorders. Given the high rates of obesity in most developed nations, it is critical that the mechanisms by which maternal obesity programs offspring behavior are thoroughly characterized. Such knowledge will be critical in the development of preventative strategies and therapeutic interventions.
TL;DR: The proposition, analogous to the phosphocreatine shuttle, purports that pyruvate, NAD+, NADH, and La− are held uniformly near equilibrium throughout the cell cytosol due to the high activity of LDH.
Abstract: Through much of the history of metabolism, lactate (La-) has been considered merely a deadend waste product during periods of dysoxia. Congruently, the end product of glycolysis has been viewed dichotomously: pyruvate in the presence of adequate oxygenation, La- in the absence of adequate oxygenation. In contrast, given the near-equilibrium nature of the lactate dehydrogenase (LDH) reaction and that LDH has a much higher activity than the putative regulatory enzymes of the glycolytic and oxidative pathways, we contend that La- is always the end product of glycolysis. Cellular La- accumulation, as opposed to flux, is dependent on 1) the rate of glycolysis, 2) oxidative enzyme activity, 3) cellular O2 level, and 4) the net rate of La- transport into (influx) or out of (efflux) the cell. For intracellular metabolism, we reintroduce the Cytosol-to-Mitochondria Lactate Shuttle. Our proposition, analogous to the phosphocreatine shuttle, purports that pyruvate, NAD+, NADH, and La- are held uniformly near equilibrium throughout the cell cytosol due to the high activity of LDH. La- is always the end product of glycolysis and represents the primary diffusing species capable of spatially linking glycolysis to oxidative phosphorylation.
TL;DR: It is shown that memristive devices can be used to implement different learning rules whose properties emerge directly from device physics: real time or accelerated operation, deterministic or stochastic behavior, long term or short term plasticity.
Abstract: Memristive devices present a new device technology allowing for the realization of compact non-volatile memories. Some of them are already in the process of industrialization. Additionally, they exhibit complex multilevel and plastic behaviors, which make them good candidates for the implementation of artificial synapses in neuromorphic engineering. However, memristive effects rely on diverse physical mechanisms, and their plastic behaviors differ strongly from one technology to another. Here, we present measurements performed on different memristive devices and the opportunities that they provide. We show that they can be used to implement different learning rules whose properties emerge directly from device physics: real time or accelerated operation, deterministic or stochastic behavior, long term or short term plasticity. We then discuss how such devices might be integrated into a complete architecture. These results highlight that there is no unique way to exploit memristive devices in neuromorphic systems. Understanding and embracing device physics is the key for their optimal use.
TL;DR: Identifying the human correlate of the lamprey habenula-projecting globus pallidus may help in elucidating the mechanism of the antidepressant effects of glutamatergic drugs.
Abstract: The very first free-moving animals in the oceans over 540 million years ago must have been able to obtain food, territory, and shelter, as well as reproduce. Therefore, they would have needed regulatory mechanisms to induce movements enabling achievement of these prerequisites for survival. It can be useful to consider these mechanisms in primitive chordates, which represent our earliest ancestors, to develop hypotheses addressing how these essential parts of human behavior are regulated and relate to more sophisticated behavioral manifestations such as mood. An animal comparable to lampreys was the earliest known vertebrate with a modern forebrain consisting of old and new cortical parts. Lampreys have a separate dorsal pallium, the forerunner of the most recently developed part of the cerebral cortex. In addition, the lamprey extrapyramidal system (EPS), which regulates movement, is modern. However, in lampreys and their putative forerunners, the hagfishes, the striatum, which is the input part of this EPS, probably corresponds to the human centromedial amygdala, which in higher vertebrates is part of a system mediating fear and anxiety. Both animals have well-developed nuclear habenulae, which are involved in several critical behaviors; in lampreys this system regulates the reward system that reinforces appetitive-seeking behavior or the avoidance system that reinforces flight behavior resulting from negative inputs. Lampreys also have a distinct glutamatergic nucleus, the so-called habenula-projection globus pallidus, which receives input from glutamatergic and GABAergic signals and gives output to the lateral habenula. Via this route, this nucleus influences midbrain monoaminergic nuclei and regulates the food acquisition system. These various structures involved in motor regulation in the lampreys may be conserved in humans and include two complementary mechanisms for reward reinforcement and avoidance behaviors. The first system is associated with experiencing pleasure and the second with happiness. The activities of these mechanisms are regulated by a tract running via the habenula to the upper brainstem. Identifying the human correlate of the lamprey habenula-projecting globus pallidus may help in elucidating the mechanism of the antidepressant effects of glutamatergic drugs.
TL;DR: The potential role of immune aging, inflammation and metabolic derangement in neurological diseases is discussed and novel therapeutic strategies targeting age-linked inflammation may promote healthy brain aging and the treatment of neurodegenerative as well as neuropsychiatric disorders.
Abstract: As we age, the immune system undergoes a process of senescence accompanied by the increased production of proinflammatory cytokines, a chronic subclinical condition named as "inflammaging". Emerging evidence from human and experimental models suggest that immune senescence also affects the central nervous system and promotes neuronal dysfunction, especially within susceptible neuronal populations. In this review we discuss the potential role of immune aging, inflammation and metabolic derangement in neurological diseases. The discovery of novel therapeutic strategies targeting age-linked inflammation may promote healthy brain aging and the treatment of neurodegenerative as well as neuropsychiatric disorders.
TL;DR: These pleiotropic functions of ATP as a danger signal in brain damage prompt a therapeutic interest to multi-target different purinergic receptors to provide maximal opportunities for neuroprotection.
Abstract: ATP is released in an activity-dependent manner from different cell types in the brain, fulfilling different roles as a neurotransmitter, neuromodulator, astrocyte-to-neuron communication, propagating astrocytic responses and formatting microglia responses This involves the activation of different ATP P2 receptors (P2R) as well as adenosine receptors upon extracellular ATP catabolism by ecto-nucleotidases Notably, brain noxious stimuli trigger a sustained increase of extracellular ATP, which plays a key role as danger signal in the brain This involves a combined action of extracellular ATP in different cell types, namely increasing the susceptibility of neurons to damage, promoting astrogliosis and recruiting and formatting microglia to mount neuroinflammatory responses Such actions involve the activation of different receptors, as heralded by neuroprotective effects resulting from blockade mainly of P2X7R, P2Y1R and adenosine A2A receptors (A2AR), which hierarchy, cooperation and/or redundancy is still not resolved These pleiotropic functions of ATP as a danger signal in brain damage prompt a therapeutic interest to multi-target different purinergic receptors to provide maximal opportunities for neuroprotection
TL;DR: The objective of this review is to present an overview of the current literature discussing the link between HPA axis-derived glucocorticoids and increased oxidative stress, particularly focussing on the redox changes observed in the hippocampus following glucoc Corticoid exposure.
Abstract: Glucocorticoids released from the adrenal gland in response to stress-induced activation of the hypothalamic-pituitary-adrenal (HPA) axis induce activity in the cellular reduction-oxidation (redox) system. The redox system is a ubiquitous chemical mechanism allowing the transfer of electrons between donor/acceptors and target molecules during oxidative phosphorylation while simultaneously maintaining the overall cellular environment in a reduced state. The objective of this review is to present an overview of the current literature discussing the link between HPA axis-derived glucocorticoids and increased oxidative stress, particularly focussing on the redox changes observed in the hippocampus following glucocorticoid exposure.
TL;DR: Immunity cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair.
Abstract: The innate immune system plays a dualistic role in the evolution of ischemic brain damage and has also been implicated in ischemic tolerance produced by different conditioning stimuli. Early after ischemia, perivascular astrocytes release cytokines and activate metalloproteases (MMPs) that contribute to blood–brain barrier (BBB) disruption and vasogenic oedema; whereas at later stages, they provide extracellular glutamate uptake, BBB regeneration and neurotrophic factors release. Similarly, early activation of microglia contributes to ischemic brain injury via the production of inflammatory cytokines, including tumor necrosis factor (TNF) and interleukin (IL)-1, reactive oxygen and nitrogen species and proteases. Nevertheless, microglia also contributes to the resolution of inflammation, by releasing IL-10 and tumor growth factor (TGF)-beta, and to the late reparative processes by phagocytic activity and growth factors production. Indeed, after ischemia, microglia/macrophages differentiate towards several phenotypes: the M1 pro-inflammatory phenotype is classically activated via toll-like receptors or interferon-γ, whereas M2 phenotypes are alternatively activated by regulatory mediators, such as ILs 4, 10, 13 or TGF-beta. Thus, immune cells exert a dualistic role on the evolution of ischemic brain damage, since the classic phenotypes promote injury, whereas alternatively activated M2 macrophages or N2 neutrophils prompt tissue remodeling and repair. Moreover, a subdued activation of the immune system has been involved in ischemic tolerance, since different preconditioning stimuli act via modulation of inflammatory mediators, including toll-like receptors and cytokine signaling pathways. This further underscores that the immuno-modulatory approach for the treatment of ischemic stroke should be aimed at blocking the detrimental effects, while promoting the beneficial responses of the immune reaction.
TL;DR: Advances in research on idiopathic autism and three genetic forms of autism that highlight the key roles that the cerebellum plays in this spectrum of neurodevelopmental disorders are summarized.
Abstract: The cerebellum contains the largest number of neurons and synapses of any structure in the central nervous system. The concept that the cerebellum is solely involved in fine motor function has become outdated; substantial evidence has accumulated linking the cerebellum with higher cognitive functions including language. Cerebellar deficits have been implicated in autism for more than two decades. The computational power of the cerebellum is essential for many, if not most of the processes that are perturbed in autism including language and communication, social interactions, stereotyped behavior, motor activity and motor coordination, and higher cognitive functions. The link between autism and cerebellar dysfunction should not be surprising to those who study its cellular, physiological, and functional properties. Postmortem studies have revealed neuropathological abnormalities in cerebellar cellular architecture while studies on mouse lines with cell loss or mutations in single genes restricted to cerebellar Purkinje cells have also strongly implicated this brain structure in contributing to the autistic phenotype. This connection has been further substantiated by studies investigating brain damage in humans restricted to the cerebellum. In this review, we summarize advances in research on idiopathic autism and three genetic forms of autism that highlight the key roles that the cerebellum plays in this spectrum of neurodevelopmental disorders.
TL;DR: Morphological T1-weighted MRIs of 137 AD, 76 MCIc, 134 MCInc, and 162 healthy controls selected from the ADNI cohort, were used by an optimized machine learning algorithm, encouraging the application of computer-based diagnosis in clinical practice of AD.
Abstract: Determination of sensitive and specific markers of very early AD progression is intended to aid researchers and clinicians to develop new treatments and monitor their effectiveness, as well as to lessen the time and cost of clinical trials. Magnetic Resonance (MR)-related biomarkers have been recently identified by the use of machine learning methods for the in vivo differential diagnosis of AD. However, the vast majority of neuroimaging papers investigating this topic are focused on the difference between AD and patients with mild cognitive impairment (MCI), not considering the impact of MCI patients who will (MCIc) or not convert (MCInc) to AD. Morphological T1-weighted MRIs of 137 AD, 76 MCIc, 134 MCInc, and 162 healthy controls (CN) selected from the Alzheimer's disease neuroimaging initiative (ADNI) cohort, were used by an optimized machine learning algorithm. Voxels influencing the classification between these AD-related pre-clinical phases involved hippocampus, entorhinal cortex, basal ganglia, gyrus rectus, precuneus, and cerebellum, all critical regions known to be strongly involved in the pathophysiological mechanisms of AD. Classification accuracy was 76% AD vs. CN, 72% MCIc vs. CN, 66% MCIc vs. MCInc (nested 20-fold cross validation). Our data encourage the application of computer-based diagnosis in clinical practice of AD opening new prospective in the early management of AD patients.
TL;DR: The current hypothesis states that early in development this interface is functional and more specific than in the adult, with differences historically termed as “immaturity” actually correctly reflecting developmental specialization.
Abstract: Well-known as one of the main sources of cerebrospinal fluid (CSF), the choroid plexuses have been, and still remain, a relatively understudied tissue in neuroscience. The choroid plexus and CSF (along with the blood-brain barrier proper) are recognised to provide a robust protective effort for the brain: a physical barrier to impede entrance of toxic metabolites to the brain; a ‘biochemical’ barrier that facilitates removal of moieties that circumvent this physical barrier; and buoyant physical protection by CSF itself. In addition, the choroid plexus-CSF system has been shown to be integral for normal brain development, central nervous system (CNS) homeostasis, and repair after disease and trauma. It has been suggested to provide a stem-cell like repository for neuronal and astrocyte glial cell progenitors. By far, the most widely recognised choroid plexus role is as the site of the blood-CSF barrier, controller of the internal CNS microenvironment. Mechanisms involved combine structural diffusion restraint from tight junctions between plexus epithelial cells (physical barrier) and specific exchange mechanisms across the interface (enzymatic barrier). The current hypothesis states that early in development this interface is functional and more specific than in the adult, with differences historically termed as ‘immaturity’ actually correctly reflecting developmental specialisation. The advanced knowledge of the choroid plexus-CSF system proves itself imperative to understand a range of neurological diseases, from those caused by plexus or CSF drainage dysfunction (e.g. hydrocephalus) to more complicated late-stage diseases (e.g. Alzheimer’s) and failure of CNS regeneration. This review will focus on choroid plexus development, outlining how early specializations may be exploited clinically.
TL;DR: In this article, the authors provide converging evidence showing that obesity is associated with exacerbated neuroinflammation leading to dysfunction in vulnerable brain regions associated with mood regulation, learning, and memory such as the hippocampus.
Abstract: Obesity is associated with a high prevalence of mood disorders and cognitive dysfunctions in addition to being a significant risk factor for important health complications such as cardiovascular diseases and type 2 diabetes. Identifying the pathophysiological mechanisms underlying these health issues is a major public health challenge. Based on recent findings, from studies conducted on animal models of obesity, it has been proposed that inflammatory processes may participate in both the peripheral and brain disorders associated with the obesity condition including the development of emotional and cognitive alterations. This is supported by the fact that obesity is characterized by peripheral low-grade inflammation, originating from increased adipose tissue mass and/or dysbiosis (changes in gut microbiota environment), both of which contribute to increased susceptibility to immune-mediated diseases. In this review, we provide converging evidence showing that obesity is associated with exacerbated neuroinflammation leading to dysfunction in vulnerable brain regions associated with mood regulation, learning, and memory such as the hippocampus. These findings give new insights to the pathophysiological mechanisms contributing to the development of brain disorders in the context of obesity and provide valuable data for introducing new therapeutic strategies for the treatment of neuropsychiatric complications often reported in obese patients.
TL;DR: The aim of this review is to summarize current findings on noradrenergic dysfunction in AD, as well as to point out deficiencies in knowledge where more research is needed.
Abstract: The brain noradrenergic system supplies the neurotransmitter norepinephrine throughout the brain via widespread efferent projections, and plays a pivotal role in modulating cognitive activities in the cortex. Profound noradrenergic degeneration in Alzheimer's disease (AD) patients has been observed for decades, with recent research suggesting that the locus coeruleus (where noradrenergic neurons are mainly located) is a predominant site where AD-related pathology begins. Mounting evidence indicates that the loss of noradrenergic innervation greatly exacerbates AD pathogenesis and progression, although the precise roles of noradrenergic components in AD pathogenesis remain unclear. The aim of this review is to summarize current findings on noradrenergic dysfunction in AD, as well as to point out deficiencies in our knowledge where more research is needed.
TL;DR: A model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing, however, more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders.
Abstract: Oxytocin and vasopressin are pituitary neuropeptides that have been shown to affect social processes in mammals. There is growing interest in these molecules and their receptors as potential precipitants of, and/or treatments for, social deficits in neurodevelopmental disorders, including autism spectrum disorder. Numerous behavioral-genetic studies suggest that there is an association between these peptides and individual social abilities; however, an explanatory model that links hormonal activity at the receptor level to complex human behavior remains elusive. The following review summarizes the known associations between the oxytocin and vasopressin neuropeptide systems and social neurocircuits in the brain. Following a micro- to macro- level trajectory, current literature on the synthesis and secretion of these peptides, and the structure, function and distribution of their respective receptors is first surveyed. Next, current models regarding the mechanism of action of these peptides on microcircuitry and other neurotransmitter systems are discussed. Functional neuroimaging evidence on the acute effects of exogenous administration of these peptides on brain activity is then reviewed. Overall, a model in which the local neuromodulatory effects of pituitary neuropeptides on brainstem and basal forebrain regions strengthen signaling within social neurocircuits proves appealing. However, these findings are derived from animal models; more research is needed to clarify the relevance of these mechanisms to human behavior and treatment of social deficits in neuropsychiatric disorders.
TL;DR: The diversity of astrocytes is reviewed and knowledge about their production and migration is summarized to help clarify the process underlying glial development.
Abstract: Astrocytes are one of the most abundant cell types in the mammalian central nervous system, and are known to have a wide variety of physiological functions, including maintenance of neurons, formation of the blood brain barrier, and regulation of synapse functions. Although the migration and positioning of neurons has been extensively studied over the last several decades and many aspects have been uncovered, the process underlying glial development was largely unknown until recently due to the existence of multiple subtypes of glia and the sustained proliferative ability of these cells through adulthood. To overcome these difficulties, new gene transfer techniques and genetically modified mice were developed, and have been gradually revealing when and how astrocytes develop during corticogenesis. In this paper, we review the diversity of astrocytes and summarize our knowledge about their production and migration.