Showing papers in "Nature Neuroscience in 2005"
TL;DR: In this paper, the authors adapted the naturally occurring algal protein Channelrhodopsin-2, a rapidly gated light-sensitive cation channel, by using lentiviral gene delivery in combination with high-speed optical switching to photostimulate mammalian neurons.
Abstract: Temporally precise, noninvasive control of activity in well-defined neuronal populations is a long-sought goal of systems neuroscience. We adapted for this purpose the naturally occurring algal protein Channelrhodopsin-2, a rapidly gated light-sensitive cation channel, by using lentiviral gene delivery in combination with high-speed optical switching to photostimulate mammalian neurons. We demonstrate reliable, millisecond-timescale control of neuronal spiking, as well as control of excitatory and inhibitory synaptic transmission. This technology allows the use of light to alter neural processing at the level of single spikes and synaptic events, yielding a widely applicable tool for neuroscientists and biomedical engineers.
4,411 citations
TL;DR: It is hypothesized that the change from voluntary drug use to more habitual and compulsive drug use represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behavior as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation.
Abstract: Drug addiction is increasingly viewed as the endpoint of a series of transitions from initial drug use--when a drug is voluntarily taken because it has reinforcing, often hedonic, effects--through loss of control over this behavior, such that it becomes habitual and ultimately compulsive. Here we discuss evidence that these transitions depend on interactions between pavlovian and instrumental learning processes. We hypothesize that the change from voluntary drug use to more habitual and compulsive drug use represents a transition at the neural level from prefrontal cortical to striatal control over drug seeking and drug taking behavior as well as a progression from ventral to more dorsal domains of the striatum, involving its dopaminergic innervation. These neural transitions may themselves depend on the neuroplasticity in both cortical and striatal structures that is induced by chronic self-administration of drugs.
3,439 citations
TL;DR: Extracellular ATP regulates microglial branch dynamics in the intact brain, and its release from the damaged tissue and surrounding astrocytes mediates a rapid microglia response towards injury.
Abstract: Parenchymal microglia are the principal immune cells of the brain. Time-lapse two-photon imaging of GFP-labeled microglia demonstrates that the fine termini of microglial processes are highly dynamic in the intact mouse cortex. Upon traumatic brain injury, microglial processes rapidly and autonomously converge on the site of injury without cell body movement, establishing a potential barrier between the healthy and injured tissue. This rapid chemotactic response can be mimicked by local injection of ATP and can be inhibited by the ATP-hydrolyzing enzyme apyrase or by blockers of G protein-coupled purinergic receptors and connexin channels, which are highly expressed in astrocytes. The baseline motility of microglial processes is also reduced significantly in the presence of apyrase and connexin channel inhibitors. Thus, extracellular ATP regulates microglial branch dynamics in the intact brain, and its release from the damaged tissue and surrounding astrocytes mediates a rapid microglial response towards injury.
3,251 citations
TL;DR: This work considers dual-action choice systems from a normative perspective, and suggests a Bayesian principle of arbitration between them according to uncertainty, so each controller is deployed when it should be most accurate.
Abstract: A broad range of neural and behavioral data suggests that the brain contains multiple systems for behavioral choice, including one associated with prefrontal cortex and another with dorsolateral striatum. However, such a surfeit of control raises an additional choice problem: how to arbitrate between the systems when they disagree. Here, we consider dual-action choice systems from a normative perspective, using the computational theory of reinforcement learning. We identify a key trade-off pitting computational simplicity against the flexible and statistically efficient use of experience. The trade-off is realized in a competition between the dorsolateral striatal and prefrontal systems. We suggest a Bayesian principle of arbitration between them according to uncertainty, so each controller is deployed when it should be most accurate. This provides a unifying account of a wealth of experimental evidence about the factors favoring dominance by either system.
2,171 citations
TL;DR: Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala, and relative uncoupling of this circuit.
Abstract: Carriers of the short allele of a functional 5¢ promoter polymorphism of the serotonin transporter gene have increased anxietyrelated temperamental traits, increased amygdala reactivity and elevated risk of depression. Here, we used multimodal neuroimaging in a large sample of healthy human subjects to elucidate neural mechanisms underlying this complex genetic association. Morphometrical analyses showed reduced gray matter volume in short-allele carriers in limbic regions critical for processing of negative emotion, particularly perigenual cingulate and amygdala. Functional analysis of those regions during perceptual processing of fearful stimuli demonstrated tight coupling as a feedback circuit implicated in the extinction of negative affect. Short-allele carriers showed relative uncoupling of this circuit. Furthermore, the magnitude of coupling inversely predicted almost 30% of variation in temperamental anxiety. These genotype-related alterations in anatomy and function of an amygdalacingulate feedback circuit critical for emotion regulation implicate a developmental, systems-level mechanism underlying normal emotional reactivity and genetic susceptibility for depression. Depression is among the four leading causes of disability and disease burden throughout the world and is associated with serious medical conditions and mortality across the lifespan 1,2 . The importance of serotonergic neurotransmission for the pathogenesis of depression is suggested clinically by the efficacy of serotonin re-uptake inhibitors (SSRIs), the first-line treatment of depression and most related anxiety disorders 1 and by induction of depression by tryptophan depletion in susceptible individuals 2 . Post-mortem and in vivo studies of the serotonin transporter (5-HTT) and receptors support a role for this neurotransmitter system in depression and anxiety disorders 1 . Further
1,928 citations
TL;DR: It is argued that addicted people become unable to make drug-use choices on the basis of long-term outcome, and a neural framework is proposed that explains this myopia for future consequences.
Abstract: Here I argue that addicted people become unable to make drug-use choices on the basis of long-term outcome, and I propose a neural framework that explains this myopia for future consequences. I suggest that addiction is the product of an imbalance between two separate, but interacting, neural systems that control decision making: an impulsive, amygdala system for signaling pain or pleasure of immediate prospects, and a reflective, prefrontal cortex system for signaling pain or pleasure of future prospects. After an individual learns social rules, the reflective system controls the impulsive system via several mechanisms. However, this control is not absolute; hyperactivity within the impulsive system can override the reflective system. I propose that drugs can trigger bottom-up, involuntary signals originating from the amygdala that modulate, bias or even hijack the goal-driven cognitive resources that are needed for the normal operation of the reflective system and for exercising the willpower to resist drugs.
1,906 citations
TL;DR: It is found that ensemble fMRI signals in early visual areas could reliably predict on individual trials which of eight stimulus orientations the subject was seeing, when subjects had to attend to one of two overlapping orthogonal gratings.
Abstract: The potential for human neuroimaging to read out the detailed contents of a person's mental state has yet to be fully explored. We investigated whether the perception of edge orientation, a fundamental visual feature, can be decoded from human brain activity measured with functional magnetic resonance imaging (fMRI). Using statistical algorithms to classify brain states, we found that ensemble fMRI signals in early visual areas could reliably predict on individual trials which of eight stimulus orientations the subject was seeing. Moreover, when subjects had to attend to one of two overlapping orthogonal gratings, feature-based attention strongly biased ensemble activity toward the attended orientation. These results demonstrate that fMRI activity patterns in early visual areas, including primary visual cortex (V1), contain detailed orientation information that can reliably predict subjective perception. Our approach provides a framework for the readout of fine-tuned representations in the human brain and their subjective contents.
1,843 citations
TL;DR: The biochemical isolation of discrete amyloid-β moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.
Abstract: A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the amyloid-β protein interferes with cognitive function. Soluble oligomeric forms of amyloid-β, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Although β-amyloidosis has long been hypothesized to affect cognition, the abnormally folded protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete amyloid-β moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.
1,719 citations
TL;DR: Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.
Abstract: The central melanocortin system is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis. This collection of circuits is unique in having the capability of sensing signals from a staggering array of hormones, nutrients and afferent neural inputs. It is likely to be involved in integrating long-term adipostatic signals from leptin and insulin, primarily received by the hypothalamus, with acute signals regulating hunger and satiety, primarily received by the brainstem. The system is also unique from a regulatory point of view in that it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.
1,453 citations
TL;DR: It is found that application of amyloid-β promoted endocytosis of NMDA receptors in cortical neurons, indicating a new mechanism by which amyloids-β can cause synaptic dysfunction and contribute to Alzheimer disease pathology.
Abstract: Amyloid-beta peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-beta reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-beta promoted endocytosis of NMDA receptors in cortical neurons. In addition, neurons from a genetic mouse model of Alzheimer disease expressed reduced amounts of surface NMDA receptors. Reducing amyloid-beta by treating neurons with a gamma-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-beta application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-beta-dependent endocytosis of NMDA receptors required the alpha-7 nicotinic receptor, protein phosphatase 2B (PP2B) and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis. These data indicate a new mechanism by which amyloid-beta can cause synaptic dysfunction and contribute to Alzheimer disease pathology.
1,442 citations
TL;DR: Variation in eye fixation within autistic individuals was strongly and positively associated with amygdala activation across both studies, suggesting a heightened emotional response associated with gaze fixation in autism.
Abstract: Diminished gaze fixation is one of the core features of autism and has been proposed to be associated with abnormalities in the neural circuitry of affect. We tested this hypothesis in two separate studies using eye tracking while measuring functional brain activity during facial discrimination tasks in individuals with autism and in typically developing individuals. Activation in the fusiform gyrus and amygdala was strongly and positively correlated with the time spent fixating the eyes in the autistic group in both studies, suggesting that diminished gaze fixation may account for the fusiform hypoactivation to faces commonly reported in autism. In addition, variation in eye fixation within autistic individuals was strongly and positively associated with amygdala activation across both studies, suggesting a heightened emotional response associated with gaze fixation in autism.
TL;DR: A major goal for future research is to determine whether common underpinnings of addiction can be exploited for the development of more effective treatments for a wide range of addictive disorders.
Abstract: Drugs of abuse have very different acute mechanisms of action but converge on the brain's reward pathways by producing a series of common functional effects after both acute and chronic administration. Some similar actions occur for natural rewards as well. Researchers are making progress in understanding the molecular and cellular basis of these common effects. A major goal for future research is to determine whether such common underpinnings of addiction can be exploited for the development of more effective treatments for a wide range of addictive disorders.
TL;DR: To the degree that drugs and food activate common reward circuitry in the brain, drugs offer powerful tools for understanding the neural circuitry that mediates food-motivated habits and how this circuitry may be hijacked to cause appetitive behaviors to go awry.
Abstract: To the degree that drugs and food activate common reward circuitry in the brain, drugs offer powerful tools for understanding the neural circuitry that mediates food-motivated habits and how this circuitry may be hijacked to cause appetitive behaviors to go awry.
TL;DR: Positive correlations between practicing and fiber tract organization in different regions for each age period are found, and long-term training within critical developmental periods may induce regionally specific plasticity in myelinating tracts.
Abstract: Using diffusion tensor imaging, we investigated effects of piano practicing in childhood, adolescence and adulthood on white matter, and found positive correlations between practicing and fiber tract organization in different regions for each age period. For childhood, practicing correlations were extensive and included the pyramidal tract, which was more structured in pianists than in non-musicians. Long-term training within critical developmental periods may thus induce regionally specific plasticity in myelinating tracts.
TL;DR: The authors showed that, in response to high conflict, cognitive control mechanisms enhance performance by transiently amplifying cortical responses to task-relevant information rather than by inhibiting responses to the task-irrelevant information.
Abstract: A prominent model of how the brain regulates attention proposes that the anterior cingulate cortex monitors the occurrence of conflict between incompatible response tendencies and signals this information to a cognitive control system in dorsolateral prefrontal cortex. Cognitive control is thought to resolve conflict through the attentional biasing of perceptual processing, emphasizing task-relevant stimulus information. It is not known, however, whether conflict resolution is mediated by amplifying neural representations of task-relevant information, inhibiting representations of task-irrelevant information, or both. Here we manipulated trial-by-trial levels of conflict and control during a Stroop task using face stimuli, while recording hemodynamic responses from human visual cortex specialized for face processing. We show that, in response to high conflict, cognitive control mechanisms enhance performance by transiently amplifying cortical responses to task-relevant information rather than by inhibiting responses to task-irrelevant information. These results implicate attentional target-feature amplification as the primary mechanism for conflict resolution through cognitive control.
TL;DR: This work focuses on recent approaches to the study of genetic variation in personality and physiological traits, and their influence on and interaction with addictive diseases.
Abstract: Genetic variation may partially underlie complex personality and physiological traits--such as impulsivity, risk taking and stress responsivity--as well as a substantial proportion of vulnerability to addictive diseases. Furthermore, personality and physiological traits themselves may differentially affect the various stages of addiction, defined chronologically as initiation of drug use, regular drug use, addiction/dependence and potentially relapse. Here we focus on recent approaches to the study of genetic variation in these personality and physiological traits, and their influence on and interaction with addictive diseases.
TL;DR: A phonological regularity of English indefinite articles is exploited in combination with event-related brain potential recordings from the human scalp to show that readers' brains can pre-activate individual words in a graded fashion to a degree that can be estimated from the probability that each word is given as a continuation for a sentence fragment offline.
Abstract: Despite the numerous examples of anticipatory cognitive processes at micro and macro levels in many animal species, the idea that anticipation of specific words plays an integral role in real-time language processing has been contentious. Here we exploited a phonological regularity of English indefinite articles ('an' precedes nouns beginning with vowel sounds, whereas 'a' precedes nouns beginning with consonant sounds) in combination with event-related brain potential recordings from the human scalp to show that readers' brains can pre-activate individual words in a graded fashion to a degree that can be estimated from the probability that each word is given as a continuation for a sentence fragment offline. These findings are evidence that readers use the words in a sentence (as cues to their world knowledge) to estimate relative likelihoods for upcoming words.
TL;DR: It is argued that drug addiction also involves a 'dark side'—a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of anti-reward systems.
Abstract: Drug seeking is associated with activation of reward neural circuitry. Here we argue that drug addiction also involves a ‘dark side’—a decrease in the function of normal reward-related neurocircuitry and persistent recruitment of anti-reward systems. Understanding the neuroplasticity of the dark side of this circuitry is the key to understanding vulnerability to addiction. Drug addiction has been conceptualized as a progression from impulsive to compulsive behavior, ending in chronic, relapsing drug taking. Patients with impulse control disorders experience an increasing sense of tension or arousal before committing an impulsive act; pleasure, gratification or relief at the time of committing the act; and then regret, selfreproach or guilt after the act 1 . In contrast, patients with compulsive disorders experience anxiety and stress before committing a compulsive repetitive behavior, then relief from the stress by performing the behavior 1 . In addiction, drug-taking behavior progresses from impulsivity to compulsivity in a three-stage cycle: binge/intoxication, withdrawal/negative affect and preoccupation/anticipation 2 . In the impulsive stage, the drive for the drug-taking behavior is positive reinforcement, in which stimuli increase the probability of the response. As individuals move to the compulsive stage, the drive transitions to negative reinforcement, in which removal of the aversive state increases the probability of the response. Different theoretical perspectives from experimental psychology (positive and negative reinforcement framework), social psychology (self-regulation failure framework) and neurobiology (counteradaptive and sensitization framework) can be superimposed on the stages of the addiction cycle 2 . These stages are thought to feed into each other, becoming more intense and ultimately leading to the pathological state known as addiction. Our thesis is that addiction involves a longterm, persistent plasticity in the activity of neural circuits mediating two different motivational systems: decreased function of brain reward systems driven by natural rewards, and recruitment of anti-reward systems that drive aversive states. The concept of anti-reward is based on the hypothesis that there are brain systems in place to limit reward (see footnote in ref. 2), an ‘opponent process’ concept that is a general feature of biological systems 3 . From a neurobiological perspective, progression through the three stages of the addiction cycle induces plasticity in neural circuitry that drives compulsive drug taking, narrowing the behavioral repertoire to drug seeking. Animal models have been developed that have face validity (resembles the human condition) and some construct validity (possesses explanatory power) for all three stages of the addiction cycle and the transition to drug addiction. Acute selfadministration of drugs (intravenous and oral) has construct validity for drug intoxication and elements of drug binges in humans. Self-stimulation and place conditioning (learning to avoid a location previously paired with an aversive stimulus or state) are sensitive measures of ‘motivational’ withdrawal. Cue-induced or
TL;DR: It is found that the infralimbic and prelimbic regions of the ventral medial prefrontal cortex (mPFCv) in rats detect whether a stressor is under the organism's control and implies that the presence of control inhibits stress-induced neural activity in brainstem nuclei, in contrast to the prevalent view that such activity is induced by a lack of control.
Abstract: The degree of behavioral control that an organism has over a stressor is a potent modulator of the stressor's impact; uncontrollable stressors produce numerous outcomes that do not occur if the stressor is controllable. Research on controllability has focused on brainstem nuclei such as the dorsal raphe nucleus (DRN). Here we find that the infralimbic and prelimbic regions of the ventral medial prefrontal cortex (mPFCv) in rats detect whether a stressor is under the organism's control. When a stressor is controllable, stress-induced activation of the DRN is inhibited by the mPFCv, and the behavioral sequelae of uncontrollable stress are blocked. This suggests a new function for the mPFCv and implies that the presence of control inhibits stress-induced neural activity in brainstem nuclei, in contrast to the prevalent view that such activity is induced by a lack of control.
TL;DR: It is shown that even at conventional resolutions it is possible to use fMRI to obtain a direct measure of orientation-selective processing in V1 and to successfully predict which one of two oriented stimuli a participant was viewing, even when masking rendered that stimulus invisible.
Abstract: Humans can experience aftereffects from oriented stimuli that are not consciously perceived, suggesting that such stimuli receive cortical processing. Determining the physiological substrate of such effects has proven elusive owing to the low spatial resolution of conventional human neuroimaging techniques compared to the size of orientation columns in visual cortex. Here we show that even at conventional resolutions it is possible to use fMRI to obtain a direct measure of orientation-selective processing in V1. We found that many parts of V1 show subtle but reproducible biases to oriented stimuli, and that we could accumulate this information across the whole of V1 using multivariate pattern recognition. Using this information, we could then successfully predict which one of two oriented stimuli a participant was viewing, even when masking rendered that stimulus invisible. Our findings show that conventional fMRI can be used to reveal feature-selective processing in human cortex, even for invisible stimuli.
TL;DR: In this article, the impact of normal aging on top-down modulation, a cognitive control mechanism that supports both attention and memory by the suppression and enhancement of sensory processing in accordance with task goals, was assessed.
Abstract: In this study, we assess the impact of normal aging on top-down modulation, a cognitive control mechanism that supports both attention and memory by the suppression and enhancement of sensory processing in accordance with task goals. Using fMRI (functional magnetic resonance imaging), we show that healthy older adults demonstrated a prominent deficit in the suppression of cortical activity associated with task-irrelevant representations, whereas enhancement of task-relevant activity was preserved. Moreover, this suppression-specific attention deficit correlated with impaired working memory performance.
TL;DR: It is suggested that the transition toward access to consciousness relates to the optional triggering of a late wave of activation that spreads through a distributed network of cortical association areas.
Abstract: In the phenomenon of attentional blink, identical visual stimuli are sometimes fully perceived and sometimes not detected at all. This phenomenon thus provides an optimal situation to study the fate of stimuli not consciously perceived and the differences between conscious and nonconscious processing. We correlated behavioral visibility ratings and recordings of event-related potentials to study the temporal dynamics of access to consciousness. Intact early potentials (P1 and N1) were evoked by unseen words, suggesting that these brain events are not the primary correlates of conscious perception. However, we observed a rapid divergence around 270 ms, after which several brain events were evoked solely by seen words. Thus, we suggest that the transition toward access to consciousness relates to the optional triggering of a late wave of activation that spreads through a distributed network of cortical association areas.
TL;DR: It is shown that spatial attention deficits in neglect after right frontal damage correlate with abnormal activation of structurally intact dorsal and ventral parietal regions that mediate related attentional operations in the normal brain.
Abstract: The syndrome of spatial neglect is typically associated with focal injury to the temporoparietal or ventral frontal cortex. This syndrome shows spontaneous partial recovery, but the neural basis of both spatial neglect and its recovery is largely unknown. We show that spatial attention deficits in neglect (rightward bias and reorienting) after right frontal damage correlate with abnormal activation of structurally intact dorsal and ventral parietal regions that mediate related attentional operations in the normal brain. Furthermore, recovery of these attention deficits correlates with the restoration and rebalancing of activity within these regions. These results support a model of recovery based on the re-weighting of activity within a distributed neuronal architecture, and they show that behavioral deficits depend not only on structural changes at the locus of injury, but also on physiological changes in distant but functionally related brain areas.
TL;DR: This tool shows that the strength of the negative afterimage of an adaptor was reduced by half when it was perceptually suppressed by input from the other eye, implying that formation of afterimages involves neuronal structures that access input from both eyes but that do not correspond to the neuronal correlates of perceptual awareness.
Abstract: Illusions that produce perceptual suppression despite constant retinal input are used to manipulate visual consciousness. Here we report on a powerful variant of existing techniques, continuous flash suppression. Distinct images flashed successively at approx10 Hz into one eye reliably suppress an image presented to the other eye. The duration of perceptual suppression is at least ten times greater than that produced by binocular rivalry. Using this tool we show that the strength of the negative afterimage of an adaptor was reduced by half when it was perceptually suppressed by input from the other eye. The more completely the adaptor was suppressed, the more strongly the afterimage intensity was reduced. Paradoxically, trial-to-trial visibility of the adaptor did not correlate with the degree of reduction. Our results imply that formation of afterimages involves neuronal structures that access input from both eyes but that do not correspond directly to the neuronal correlates of perceptual awareness.
TL;DR: It is reported that proBDNF, by activating p75NTR, facilitates hippocampal long-term depression (LTD) and the finding that mature BDNF promotes synaptic potentiation, suggest a bidirectional regulation of synaptic plasticity by proBD NF and matureBDNF.
Abstract: Pro- and mature brain-derived neurotrophic factor (BDNF) activate two distinct receptors: p75 neurotrophin receptor (p75(NTR)) and TrkB. Mature BDNF facilitates hippocampal synaptic potentiation through TrkB. Here we report that proBDNF, by activating p75(NTR), facilitates hippocampal long-term depression (LTD). Electron microscopy showed that p75(NTR) localized in dendritic spines, in addition to afferent terminals, of CA1 neurons. Deletion of p75(NTR) in mice selectively impaired the NMDA receptor-dependent LTD, without affecting other forms of synaptic plasticity. p75(NTR-/-) mice also showed a decrease in the expression of NR2B, an NMDA receptor subunit uniquely involved in LTD. Activation of p75(NTR) by proBDNF enhanced NR2B-dependent LTD and NR2B-mediated synaptic currents. These results show a crucial role for proBDNF-p75(NTR) signaling in LTD and its potential mechanism, and together with the finding that mature BDNF promotes synaptic potentiation, suggest a bidirectional regulation of synaptic plasticity by proBDNF and mature BDNF.
TL;DR: In the absence of caudalizing signals, floating aggregates of ES cells generate naive telencephalic precursors that acquire subregional identities by responding to extracellular patterning signals.
Abstract: We demonstrate directed differentiation of telencephalic precursors from mouse embryonic stem (ES) cells using optimized serum-free suspension culture (SFEB culture). Treatment with Wnt and Nodal antagonists (Dkk1 and LeftyA) during the first 5 d of SFEB culture causes nearly selective neural differentiation in ES cells ( approximately 90%). In the presence of Dkk1, with or without LeftyA, SFEB induces efficient generation ( approximately 35%) of cells expressing telencephalic marker Bf1. Wnt3a treatment during the late culture period increases the pallial telencephalic population (Pax6(+) cells yield up to 75% of Bf1(+) cells), whereas Shh promotes basal telencephalic differentiation (into Nkx2.1(+) and/or Islet1/2(+) cells) at the cost of pallial telencephalic differentiation. Thus, in the absence of caudalizing signals, floating aggregates of ES cells generate naive telencephalic precursors that acquire subregional identities by responding to extracellular patterning signals.
TL;DR: A reduction of ventral striatal and ventromedial prefrontal activation in the pathological gamblers was observed that was negatively correlated with gambling severity, linking hypoactivation of these areas to disease severity.
Abstract: By analogy to drug dependence, it has been speculated that the underlying pathology in pathological gambling is a reduction in the sensitivity of the reward system. Studying pathological gamblers and controls during a guessing game using functional magnetic resonance imaging, we observed a reduction of ventral striatal and ventromedial prefrontal activation in the pathological gamblers that was negatively correlated with gambling severity, linking hypoactivation of these areas to disease severity.
TL;DR: Using transneuronal transport of rabies virus in macaques, it is found that a disynaptic pathway links an output stage of cerebellar processing, the dentate nucleus, with an input stage of basal gangliaprocessing, the striatum.
Abstract: The cerebral cortex is interconnected with two major subcortical structures: the basal ganglia and the cerebellum. How and where cerebellar circuits interact with basal ganglia circuits has been a longstanding question. Using transneuronal transport of rabies virus in macaques, we found that a disynaptic pathway links an output stage of cerebellar processing, the dentate nucleus, with an input stage of basal ganglia processing, the striatum.
TL;DR: The multifaceted regulation of energy homeostasis by endocannabinoids is discussed, together with its applications to the treatment of eating disorders and metabolic syndromes.
Abstract: Marijuana and its major psychotropic component, Delta(9)-tetrahydrocannabinol, stimulate appetite and increase body weight in wasting syndromes, suggesting that the CB(1) cannabinoid receptor and its endogenous ligands, the endocannabinoids, are involved in controlling energy balance. The endocannabinoid system controls food intake via both central and peripheral mechanisms, and it may also stimulate lipogenesis and fat accumulation. Here we discuss the multifaceted regulation of energy homeostasis by endocannabinoids, together with its applications to the treatment of eating disorders and metabolic syndromes.
TL;DR: It is demonstrated that induced selective ablation of AgRP-expressing neurons in adult mice results in acute reduction of feeding, demonstrating direct evidence for a critical role of these neurons in the regulation of energy homeostasis.
Abstract: Multiple hormones controlling energy homeostasis regulate the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP) in the arcuate nucleus of the hypothalamus. Nevertheless, inactivation of the genes encoding NPY and/or AgRP has no impact on food intake in mice. Here we demonstrate that induced selective ablation of AgRP-expressing neurons in adult mice results in acute reduction of feeding, demonstrating direct evidence for a critical role of these neurons in the regulation of energy homeostasis.