Showing papers in "Nature Neuroscience in 2004"
TL;DR: It is shown that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible, suggesting a causal relation among epigenomicState, GR expression and the maternal effect on stress responses in the offspring.
Abstract: Here we report that increased pup licking and grooming (LG) and arched-back nursing (ABN) by rat mothers altered the offspring epigenome at a glucocorticoid receptor (GR) gene promoter in the hippocampus. Offspring of mothers that showed high levels of LG and ABN were found to have differences in DNA methylation, as compared to offspring of 'low-LG-ABN' mothers. These differences emerged over the first week of life, were reversed with cross-fostering, persisted into adulthood and were associated with altered histone acetylation and transcription factor (NGFI-A) binding to the GR promoter. Central infusion of a histone deacetylase inhibitor removed the group differences in histone acetylation, DNA methylation, NGFI-A binding, GR expression and hypothalamic-pituitary-adrenal (HPA) responses to stress, suggesting a causal relation among epigenomic state, GR expression and the maternal effect on stress responses in the offspring. Thus we show that an epigenomic state of a gene can be established through behavioral programming, and it is potentially reversible.
5,514 citations
TL;DR: In right anterior insular/opercular cortex, neural activity predicted subjects' accuracy in the heartbeat detection task and local gray matter volume correlated with both interoceptive accuracy and subjective ratings of visceral awareness.
Abstract: Influential theories of human emotion argue that subjective feeling states involve representation of bodily responses elicited by emotional events. Within this framework, individual differences in intensity of emotional experience reflect variation in sensitivity to internal bodily responses. We measured regional brain activity by functional magnetic resonance imaging (fMRI) during an interoceptive task wherein subjects judged the timing of their own heartbeats. We observed enhanced activity in insula, somatomotor and cingulate cortices. In right anterior insular/opercular cortex, neural activity predicted subjects' accuracy in the heartbeat detection task. Furthermore, local gray matter volume in the same region correlated with both interoceptive accuracy and subjective ratings of visceral awareness. Indices of negative emotional experience correlated with interoceptive accuracy across subjects. These findings indicate that right anterior insula supports a representation of visceral responses accessible to awareness, providing a substrate for subjective feeling states.
2,972 citations
TL;DR: It is shown here that neurons are generated in two proliferative zones by distinct patterns of division, and newborn neurons do not migrate directly to the cortex; instead, most exhibit four distinct phases of migration, including a phase of retrograde movement toward the ventricle before migration to the cortical plate.
Abstract: Precise patterns of cell division and migration are crucial to transform the neuroepithelium of the embryonic forebrain into the adult cerebral cortex. Using time-lapse imaging of clonal cells in rat cortex over several generations, we show here that neurons are generated in two proliferative zones by distinct patterns of division. Neurons arise directly from radial glial cells in the ventricular zone (VZ) and indirectly from intermediate progenitor cells in the subventricular zone (SVZ). Furthermore, newborn neurons do not migrate directly to the cortex; instead, most exhibit four distinct phases of migration, including a phase of retrograde movement toward the ventricle before migration to the cortical plate. These findings provide a comprehensive and new view of the dynamics of cortical neurogenesis and migration.
2,062 citations
TL;DR: Large-scale recordings from neuronal ensembles now offer the opportunity to test competing theoretical frameworks and require further development of the neuron–electrode interface, automated and efficient spike-sorting algorithms for effective isolation and identification of single neurons, and new mathematical insights for the analysis of network properties.
Abstract: How does the brain orchestrate perceptions, thoughts and actions from the spiking activity of its neurons? Early single-neuron recording research treated spike pattern variability as noise that needed to be averaged out to reveal the brain's representation of invariant input. Another view is that variability of spikes is centrally coordinated and that this brain-generated ensemble pattern in cortical structures is itself a potential source of cognition. Large-scale recordings from neuronal ensembles now offer the opportunity to test these competing theoretical frameworks. Currently, wire and micro-machined silicon electrode arrays can record from large numbers of neurons and monitor local neural circuits at work. Achieving the full potential of massively parallel neuronal recordings, however, will require further development of the neuron–electrode interface, automated and efficient spike-sorting algorithms for effective isolation and identification of single neurons, and new mathematical insights for the analysis of network properties.
1,714 citations
TL;DR: This work has redefined optimality in terms of feedback control laws, and focused on the mechanisms that generate behavior online, allowing researchers to fit previously unrelated concepts and observations into what may become a unified theoretical framework for interpreting motor function.
Abstract: The sensorimotor system is a product of evolution, development, learning and adaptation-which work on different time scales to improve behavioral performance. Consequently, many theories of motor function are based on 'optimal performance': they quantify task goals as cost functions, and apply the sophisticated tools of optimal control theory to obtain detailed behavioral predictions. The resulting models, although not without limitations, have explained more empirical phenomena than any other class. Traditional emphasis has been on optimizing desired movement trajectories while ignoring sensory feedback. Recent work has redefined optimality in terms of feedback control laws, and focused on the mechanisms that generate behavior online. This approach has allowed researchers to fit previously unrelated concepts and observations into what may become a unified theoretical framework for interpreting motor function. At the heart of the framework is the relationship between high-level goals, and the real-time sensorimotor control strategies most suitable for accomplishing those goals.
1,650 citations
TL;DR: Differential regulation of neuropeptide receptor expression may explain species differences in the ability to form pair bonds and have intriguing implications for the neurobiology of social attachment in the authors' own species.
Abstract: A neurobiological model for pair-bond formation has emerged from studies in monogamous rodents. The neuropeptides oxytocin and vasopressin contribute to the processing of social cues necessary for individual recognition. Mesolimbic dopamine is involved in reinforcement and reward learning. Concurrent activation of neuropeptide and dopamine receptors in the reward centers of the brain during mating results in a conditioned partner preference, observed as a pair bond. Differential regulation of neuropeptide receptor expression may explain species differences in the ability to form pair bonds. These and other studies discussed here have intriguing implications for the neurobiology of social attachment in our own species.
1,287 citations
TL;DR: The changes in brain activity that are induced by working memory training could be evidence of training-induced plasticity in the neural systems that underlie working memory.
Abstract: Working memory capacity has traditionally been thought to be constant. Recent studies, however, suggest that working memory can be improved by training. In this study, we have investigated the changes in brain activity that are induced by working memory training. Two experiments were carried out in which healthy, adult human subjects practiced working memory tasks for 5 weeks. Brain activity was measured with functional magnetic resonance imaging (fMRI) before, during and after training. After training, brain activity that was related to working memory increased in the middle frontal gyrus and superior and inferior parietal cortices. The changes in cortical activity could be evidence of training-induced plasticity in the neural systems that underlie working memory.
1,281 citations
TL;DR: The anatomical basis of this recovery was investigated and it was found that after incomplete spinal cord injury in rats, transected hindlimb corticospinal tract axons sprouted into the cervical gray matter to contact short and long propriospinal neurons (PSNs).
Abstract: In contrast to peripheral nerves, central axons do not regenerate. Partial injuries to the spinal cord, however, are followed by functional recovery. We investigated the anatomical basis of this recovery and found that after incomplete spinal cord injury in rats, transected hindlimb corticospinal tract (CST) axons sprouted into the cervical gray matter to contact short and long propriospinal neurons (PSNs). Over 12 weeks, contacts with long PSNs that bridged the lesion were maintained, whereas contacts with short PSNs that did not bridge the lesion were lost. In turn, long PSNs arborize on lumbar motor neurons, creating a new intraspinal circuit relaying cortical input to its original spinal targets. We confirmed the functionality of this circuit by electrophysiological and behavioral testing before and after CST re-lesion. Retrograde transynaptic tracing confirmed its integrity, and revealed changes of cortical representation. Hence, after incomplete spinal cord injury, spontaneous extensive remodeling occurs, based on axonal sprout formation and removal. Such remodeling may be crucial for rehabilitation in humans.
1,035 citations
TL;DR: It is found that virtually indistinguishable network activity can arise from widely disparate sets of underlying mechanisms, suggesting that there could be considerable animal-to-animal variability in many of the parameters that control network activity.
Abstract: Although common sense tells us that no two brains are identical, a series of experimental strategies has evolved, on the basis of studies into the influence of controlled variables on neuronal or network function, that are designed to remove the influence of the underlying variance in neuronal properties and synaptic strengths. These strategies include averaging or normalizing data and comparing each preparation to its own control before and after a treatment. Successful as these strategies may be, they implicitly assume that variability between preparations or animals is ‘experimental noise’ rather than an essential characteristic of the nervous system. We used computational models to study this underlying variability in synaptic strengths and neuronal properties in the production of a simple motor pattern. Specifically, we searched for combinations of synaptic strengths and intrinsic properties in threeneuron model networks that produced output patterns within the range of the pyloric rhythms generated by the stomatogastric ganglia of 99 lobsters (Homarus americanus). Here we argue that network output might be more tightly regulated than many of the underlying cellular and synaptic properties. Previous computational work using models of single neurons has shown that similar electrical activity can be achieved with varying combinations of ion channels in the neuron’s membrane 1–4 . Experimental measurements of single membrane currents in the same individually identified neurons in different preparations show severalfold ranges in conductance densities 2,3,5 . Together, these data suggest that individual neurons ‘tune’ themselves to achieve combinations of conductance densities that are consistent with a given target excitability 6–9 . This conceptual framework fits with the compensation that occurs after genetic manipulation of channelgene expression, as alterations in the expression of one channel may be compensated by changes in the density of one or more other channels 10 . We also argue that compensation may occur at the network level as well: that is, each animal’s network has a target activity level, and mechanisms exist that allow each animal to produce a target network performance despite having differing sets of synaptic strengths and intrinsic membrane properties. The present study supports this notion by demonstrating that similar and functional network behavior can result from widely differing combinations of intrinsic and synaptic properties. RESULTS The pyloric rhythm of the crustacean stomatogastric ganglion (STG) is an ideal test bed for studies of how network performance depends on the properties of the neurons and synapses within a functional circuit 11 . Unlike many preparations with relatively ill-defined outputs or connectivity, this ganglion has a small number of neurons and a stereotyped motor pattern, making it relatively easy to determine when and how network behavior is influenced by changes in synaptic strength or intrinsic membrane properties 12,13 .
1,001 citations
TL;DR: These findings identify morphologically distinctive GFAP-expressing progenitor cells as the predominant sources of constitutive adult neurogenesis, and provide new methods for manipulating and investigating these cells.
Abstract: Establishing the cellular identity in vivo of adult multipotent neural progenitors is fundamental to understanding their biology. We used two transgenic strategies to determine the relative contribution of glial fibrillary acidic protein (GFAP)-expressing progenitors to constitutive neurogenesis in the adult forebrain. Transgenically targeted ablation of dividing GFAP-expressing cells in the adult mouse subependymal and subgranular zones stopped the generation of immunohistochemically identified neuroblasts and new neurons in the olfactory bulb and the hippocampal dentate gyrus. Transgenically targeted cell fate mapping showed that essentially all neuroblasts and neurons newly generated in the adult mouse forebrain in vivo, and in adult multipotent neurospheres in vitro, derived from progenitors that expressed GFAP. Constitutively dividing GFAP-expressing progenitors showed predominantly bipolar or unipolar morphologies with significantly fewer processes than non-neurogenic multipolar astrocytes. These findings identify morphologically distinctive GFAP-expressing progenitor cells as the predominant sources of constitutive adult neurogenesis, and provide new methods for manipulating and investigating these cells.
956 citations
TL;DR: The pubertal transition to adulthood involves both gonadal and behavioral maturation, and reproductive maturity is the product of developmentally timed, brain-driven and recurrent interactions between steroid hormones and the adolescent nervous system.
Abstract: The pubertal transition to adulthood involves both gonadal and behavioral maturation. A developmental clock, along with permissive signals that provide information on somatic growth, energy balance and season, time the awakening of gonadotropin releasing hormone (GnRH) neurons at the onset of puberty. High-frequency GnRH release results from disinhibition and activation of GnRH neurons at puberty onset, leading to gametogenesis and an increase in gonadal steroid hormone secretion. Steroid hormones, in turn, both remodel and activate neural circuits during adolescent brain development, leading to the development of sexual salience of sensory stimuli, sexual motivation, and expression of copulatory behaviors in specific social contexts. These influences of hormones on reproductive behavior depend in part on changes in the adolescent brain that occur independently of gonadal maturation. Reproductive maturity is therefore the product of developmentally timed, brain-driven and recurrent interactions between steroid hormones and the adolescent nervous system.
TL;DR: The results indicate that the FFA is involved in both detection and identification of faces, but that it has little involvement in within-category identification of non-face objects (including objects of expertise).
Abstract: The function of the fusiform face area (FFA), a face-selective region in human extrastriate cortex, is a matter of active debate. Here we measured the correlation between FFA activity measured by functional magnetic resonance imaging (fMRI) and behavioral outcomes in perceptual tasks to determine the role of the FFA in the detection and within-category identification of faces and objects. Our data show that FFA activation is correlated on a trial-by-trial basis with both detecting the presence of faces and identifying specific faces. However, for most non-face objects (including cars seen by car experts), within-category identification performance was correlated with activation in other regions of the ventral occipitotemporal cortex, not the FFA. These results indicate that the FFA is involved in both detection and identification of faces, but that it has little involvement in within-category identification of non-face objects (including objects of expertise).
TL;DR: Statistical methods for the analysis of multiple neural spike-train data are reviewed and future challenges for methodology research are discussed.
Abstract: Multiple electrodes are now a standard tool in neuroscience research that make it possible to study the simultaneous activity of several neurons in a given brain region or across different regions. The data from multi-electrode studies present important analysis challenges that must be resolved for optimal use of these neurophysiological measurements to answer questions about how the brain works. Here we review statistical methods for the analysis of multiple neural spike-train data and discuss future challenges for methodology research.
TL;DR: In this article, the authors provided ultrastructural evidence showing that highly proliferative precursors in the adult subependymal zone express dopamine receptors and receive dopaminergic afferents.
Abstract: Cerebral dopamine depletion is the hallmark of Parkinson disease. Because dopamine modulates ontogenetic neurogenesis, depletion of dopamine might affect neural precursors in the subependymal zone and subgranular zone of the adult brain. Here we provide ultrastructural evidence showing that highly proliferative precursors in the adult subependymal zone express dopamine receptors and receive dopaminergic afferents. Experimental depletion of dopamine in rodents decreases precursor cell proliferation in both the subependymal zone and the subgranular zone. Proliferation is restored completely by a selective agonist of D2-like (D2L) receptors. Experiments with neural precursors from the adult subependymal zone grown as neurosphere cultures confirm that activation of D2L receptors directly increases the proliferation of these precursors. Consistently, the numbers of proliferating cells in the subependymal zone and neural precursor cells in the subgranular zone and olfactory bulb are reduced in postmortem brains of individuals with Parkinson disease. These observations suggest that the generation of neural precursor cells is impaired in Parkinson disease as a consequence of dopaminergic denervation.
TL;DR: The data show that combining the fMRI and lesion approaches can help reveal the source of functional modulatory influences between distant but interconnected brain regions.
Abstract: Emotional visual stimuli evoke enhanced responses in the visual cortex. To test whether this reflects modulatory influences from the amygdala on sensory processing, we used event-related functional magnetic resonance imaging (fMRI) in human patients with medial temporal lobe sclerosis. Twenty-six patients with lesions in the amygdala, the hippocampus or both, plus 13 matched healthy controls, were shown pictures of fearful or neutral faces in task-releant or task-irrelevant positions on the display. All subjects showed increased fusiform cortex activation when the faces were in task-relevant positions. Both healthy individuals and those with hippocampal damage showed increased activation in the fusiform and occipital cortex when they were shown fearful faces, but this was not the case for individuals with damage to the amygdala, even though visual areas were structurally intact. The distant influence of the amygdala was also evidenced by the parametric relationship between amygdala damage and the level of emotional activation in the fusiform cortex. Our data show that combining the fMRI and lesion approaches can help reveal the source of functional modulatory influences between distant but interconnected brain regions.
TL;DR: It is shown that attention alters appearance; it boosts the apparent stimulus contrast, consistent with neurophysiological findings suggesting that attention changes the strength of a stimulus by increasing its 'effective contrast' or salience.
Abstract: At any given moment, our visual system is confronted with far more information than it can process effectively. The high energy cost of neuronal activity involved in cortical computation severely limits our capacity to process this information 1 .V isual attention serves as a mediating mechanism, enabling us to selectively grant priority of processing to certain aspects of the visual scene. One means of granting priority is to direct one’s gaze towards the relevant location. However, many situations call for one to attend to an area in the periphery without actually directing gaze toward it. For example, when driving it is generally best to keep your eyes on the road ahead while covertly monitoring the periphery for cars, pedestrians and potential road hazards. The impact of covert attention 2 on visual performance is well-documented across a range of perceptual tasks, such as visual search 3‐6 ,l etter identification 7,8 ,c ontrast sensitivity 9‐12 and spatial resolution 13‐16 .S everal studies that used single-cell recording 17‐22 ,e vent-related potentials 23,24 and functional magnetic resonance imaging (fMRI) 25‐27 indicate that attentional modulation
TL;DR: It is found that rostral ACC was strongly activated by infrequent threat-related distractors, consistent with a role for this area in responding to unexpected processing conflict caused by salient emotional stimuli and supports the proposal that anxiety is associated with reduced top-down control over threat- related distractors.
Abstract: Threat-related stimuli are strong competitors for attention, particularly in anxious individuals. We used functional magnetic resonance imaging (fMRI) with healthy human volunteers to study how the processing of threat-related distractors is controlled and whether this alters as anxiety levels increase. Our work builds upon prior analyses of the cognitive control functions of lateral prefrontal cortex (lateral PFC) and anterior cingulate cortex (ACC). We found that rostral ACC was strongly activated by infrequent threat-related distractors, consistent with a role for this area in responding to unexpected processing conflict caused by salient emotional stimuli. Participants with higher anxiety levels showed both less rostral ACC activity overall and reduced recruitment of lateral PFC as expectancy of threat-related distractors was established. This supports the proposal that anxiety is associated with reduced top-down control over threat-related distractors. Our results suggest distinct roles for rostral ACC and lateral PFC in governing the processing of task-irrelevant, threat-related stimuli, and indicate reduced recruitment of this circuitry in anxiety.
TL;DR: The findings of this fMRI study support the view that the motor system is recruited in mapping acoustic inputs to a phonetic code.
Abstract: To examine the role of motor areas in speech perception, we carried out a functional magnetic resonance imaging (fMRI) study in which subjects listened passively to monosyllables and produced the same speech sounds. Listening to speech activated bilaterally a superior portion of ventral premotor cortex that largely overlapped a speech production motor area centered just posteriorly on the border of Brodmann areas 4a and 6, which we distinguished from a more ventral speech production area centered in area 4p. Our findings support the view that the motor system is recruited in mapping acoustic inputs to a phonetic code.
TL;DR: In non-neuronal cells, coexpression of human NgR1, p75 and LINGO-1 conferred responsiveness to oligodendrocyte myelin glycoprotein, as measured by RhoA activation, which suggests that Lingo-1 has an important role in CNS biology.
Abstract: Axon regeneration in the adult CNS is prevented by inhibitors in myelin. These inhibitors seem to modulate RhoA activity by binding to a receptor complex comprising a ligand-binding subunit (the Nogo-66 receptor NgR1) and a signal transducing subunit (the neurotrophin receptor p75). However, in reconstituted non-neuronal systems, NgR1 and p75 together are unable to activate RhoA, suggesting that additional components of the receptor may exist. Here we describe LINGO-1, a nervous system-specific transmembrane protein that binds NgR1 and p75 and that is an additional functional component of the NgR1/p75 signaling complex. In non-neuronal cells, coexpression of human NgR1, p75 and LINGO-1 conferred responsiveness to oligodendrocyte myelin glycoprotein, as measured by RhoA activation. A dominant-negative human LINGO-1 construct attenuated myelin inhibition in transfected primary neuronal cultures. This effect on neurons was mimicked using an exogenously added human LINGO-1-Fc fusion protein. Together these observations suggest that LINGO-1 has an important role in CNS biology.
TL;DR: It is shown here that tetanic stimulation causes a rapid, persistent shift of actin equilibrium toward F-actin in the dendritic spines of rat hippocampal neurons, which enlarges the spines and increases postsynaptic binding capacity.
Abstract: The synapse is a highly organized cellular specialization whose structure and composition are reorganized, both positively and negatively, depending on the strength of input signals. The mechanisms orchestrating these changes are not well understood. A plausible locus for the reorganization of synapse components and structure is actin, because it serves as both cytoskeleton and scaffold for synapses and exists in a dynamic equilibrium between F-actin and G-actin that is modulated bidirectionally by cellular signaling. Using a new FRET-based imaging technique to monitor F-actin/G-actin equilibrium, we show here that tetanic stimulation causes a rapid, persistent shift of actin equilibrium toward F-actin in the dendritic spines of rat hippocampal neurons. This enlarges the spines and increases postsynaptic binding capacity. In contrast, prolonged low-frequency stimulation shifts the equilibrium toward G-actin, resulting in a loss of postsynaptic actin and of structure. This bidirectional regulation of actin is actively involved in protein assembly and disassembly and provides a substrate for bidirectional synaptic plasticity.
TL;DR: Brain mechanisms for reward prediction at different time scales in a Markov decision task and graded maps of time scale within the insula and the striatum suggest differential involvement of the cortico-basal ganglia loops in reward prediction in different time scale.
Abstract: Evaluation of both immediate and future outcomes of an action is a critical requirement for intelligent behavior. We investigated brain mechanisms for reward prediction at different time scales in an fMRI experiment using a Markov decision task. When subjects learned actions from immediate rewards, significant activity was found in the lateral orbitofrontal cortex and the striatum. When subjects learned to acquire large future rewards despite small immediate losses, the dorsolateral prefrontal cortex, inferior parietal cortex, dorsal raphe nucleus, and cerebellum were also activated. Computational model-based regression analysis using the predicted future rewards and prediction errors estimated from subjects’ performance data revealed graded maps of time scale within the insula and the striatum, where ventroanterior parts were responsible for predicting immediate rewards and dorsoposterior parts for future rewards. These results suggest differential involvement of the cortico-basal ganglia loops in reward prediction at different time scales.
TL;DR: This work combined confocal imaging and dual-site focal synaptic stimulation of identified thin dendrites in rat neocortical pyramidal neurons found that nearby inputs on the same branch summed sigmoidally, whereas widely separated inputs or inputs to different branches summed linearly.
Abstract: The thin basal and oblique dendrites of cortical pyramidal neurons receive most of the synaptic inputs from other cells, but their integrative properties remain uncertain. Previous studies have most often reported global linear or sublinear summation. An alternative view, supported by biophysical modeling studies, holds that thin dendrites provide a layer of independent computational 'subunits' that sigmoidally modulate their inputs prior to global summation. To distinguish these possibilities, we combined confocal imaging and dual-site focal synaptic stimulation of identified thin dendrites in rat neocortical pyramidal neurons. We found that nearby inputs on the same branch summed sigmoidally, whereas widely separated inputs or inputs to different branches summed linearly. This strong spatial compartmentalization effect is incompatible with a global summation rule and provides the first experimental support for a two-layer 'neural network' model of pyramidal neuron thin-branch integration. Our findings could have important implications for the computing and memory-related functions of cortical tissue.
TL;DR: These synthetic photoisomerizable azobenzene-regulated K+ (SPARK) channels allow rapid, precise and reversible control over neuronal firing, with potential applications for dissecting neural circuits and controlling activity downstream from sites of neural damage or degeneration.
Abstract: Neurons have ion channels that are directly gated by voltage, ligands and temperature but not by light. Using structure-based design, we have developed a new chemical gate that confers light sensitivity to an ion channel. The gate includes a functional group for selective conjugation to an engineered K+ channel, a pore blocker and a photoisomerizable azobenzene. Long-wavelength light drives the azobenzene moiety into its extended trans configuration, allowing the blocker to reach the pore. Short-wavelength light generates the shorter cis configuration, retracting the blocker and allowing conduction. Exogenous expression of these channels in rat hippocampal neurons, followed by chemical modification with the photoswitchable gate, enables different wavelengths of light to switch action potential firing on and off. These synthetic photoisomerizable azobenzene-regulated K+ (SPARK) channels allow rapid, precise and reversible control over neuronal firing, with potential applications for dissecting neural circuits and controlling activity downstream from sites of neural damage or degeneration.
TL;DR: The existence of a Ca2+-dependent quantal glutamate release activity in glia that was previously considered to be specific to synapses is document the existence of an astrocytic vesicular compartment that is competent for glutamate exocytosis.
Abstract: Astrocytes establish rapid cell-to-cell communication through the release of chemical transmitters. The underlying mechanisms and functional significance of this release are, however, not well understood. Here we identify an astrocytic vesicular compartment that is competent for glutamate exocytosis. Using postembedding immunogold labeling of the rat hippocampus, we show that vesicular glutamate transporters (VGLUT1/2) and the vesicular SNARE protein, cellubrevin, are both expressed in small vesicular organelles that resemble synaptic vesicles of glutamatergic terminals. Astrocytic vesicles, which are not as densely packed as their neuronal counterparts, can be observed in small groups at sites adjacent to neuronal structures bearing glutamate receptors. Fluorescently tagged VGLUT-containing vesicles were studied dynamically in living astrocytes by total internal reflection fluorescence (TIRF) microscopy. After activation of metabotropic glutamate receptors, astrocytic vesicles underwent rapid (milliseconds) Ca2+- and SNARE-dependent exocytic fusion that was accompanied by glutamate release. These data document the existence of a Ca2+-dependent quantal glutamate release activity in glia that was previously considered to be specific to synapses.
TL;DR: The role of prefrontal cortex (PFC) in dynamic decision making in monkeys was investigated and it was found that neurons in the dorsolateral prefrontal cortex encoded the animal's past decisions and payoffs, as well as the conjunction between the two, providing signals necessary to update the estimates of expected reward.
Abstract: In a multi-agent environment, where the outcomes of one's actions change dynamically because they are related to the behavior of other beings, it becomes difficult to make an optimal decision about how to act. Although game theory provides normative solutions for decision making in groups, how such decision-making strategies are altered by experience is poorly understood. These adaptive processes might resemble reinforcement learning algorithms, which provide a general framework for finding optimal strategies in a dynamic environment. Here we investigated the role of prefrontal cortex (PFC) in dynamic decision making in monkeys. As in reinforcement learning, the animal's choice during a competitive game was biased by its choice and reward history, as well as by the strategies of its opponent. Furthermore, neurons in the dorsolateral prefrontal cortex (DLPFC) encoded the animal's past decisions and payoffs, as well as the conjunction between the two, providing signals necessary to update the estimates of expected reward. Thus, PFC might have a key role in optimizing decision-making strategies.
TL;DR: It is shown that in vivo mammalian FMRP interacts with microRNAs and the components of the microRNA pathways including Dicer and the mammalian ortholog of Argonaute 1 (AGO1), and that AGO1 is critical for F MRP function in neural development and synaptogenesis.
Abstract: Fragile X syndrome is caused by a loss of expression of the fragile X mental retardation protein (FMRP). FMRP is a selective RNA-binding protein which forms a messenger ribonucleoprotein (mRNP) complex that associates with polyribosomes. Recently, mRNA ligands associated with FMRP have been identified. However, the mechanism by which FMRP regulates the translation of its mRNA ligands remains unclear. MicroRNAs are small noncoding RNAs involved in translational control. Here we show that in vivo mammalian FMRP interacts with microRNAs and the components of the microRNA pathways including Dicer and the mammalian ortholog of Argonaute 1 (AGO1). Using two different Drosophila melanogaster models, we show that AGO1 is critical for FMRP function in neural development and synaptogenesis. Our results suggest that FMRP may regulate neuronal translation via microRNAs and links microRNAs with human disease.
TL;DR: Some of the events triggered by testosterone that masculinize the developing and adult nervous system, promote male behaviors and suppress female behaviors are reviewed.
Abstract: The steps leading to masculinization of the body are remarkably consistent across mammals: the paternally contributed Y chromosome contains the sex-determining region of the Y (Sry) gene, which induces the undifferentiated gonads to form as testes (rather than ovaries). The testes then secrete hormones to masculinize the rest of the body. Two of these masculinizing testicular hormones are antimullerian hormone, a protein that suppresses female reproductive tract development, and testosterone, a steroid that promotes development of the male reproductive tract and masculine external genitalia. In masculinizing the body, testosterone first binds to the androgen receptor protein, and then this steroid-receptor complex binds to DNA, where it modulates gene expression and promotes differentiation as a male. If the Sry gene is absent (as in females, who receive an X chromosome from the father), the gonad develops as an ovary, and the body, unexposed to testicular hormones, forms a feminine configuration. The genitalia will only respond to testicular hormones during a particular time in development, which constitutes a sensitive period for hormone action: hormonal treatment of females in adulthood has negligible effects on genital morphology 1 . Of the two gonadal hormones that masculinize the body, it is testosterone that also masculinizes the brain. Scientists first demonstrated this by exposing female guinea pigs to testosterone in utero ,w hich permanently interfered with the animals’ tendency to show female reproductive behaviors in adulthood 2 .T reating adult females with testosterone had a transient effect, or none at all, on these behaviors. Early exposure to steroids such as testosterone also masculinizes brain structures. In this review, we will contrast the various mechanisms by which testosterone masculinizes the central nervous system, discuss the unknowns that remain and relate these findings to human behavior.
TL;DR: The results suggest that early adverse experience inhibits structural plasticity via hypersensitivity to glucocorticoids and diminishes the ability of the hippocampus to respond to stress in adulthood.
Abstract: Maternal deprivation produces persistent abnormalities in behavioral and neuroendocrine functions associated with the hippocampus, a brain region that shows considerable structural change in response to experience throughout life. Here we show that adverse experience early in life affects the regulation of adult neurogenesis in the hippocampus. More specifically, a decrease in cell proliferation and immature neuron production are observed in the dentate gyrus of adult rats that are maternally separated as pups. Although maternally separated rats show normal basal levels of corticosterone, the suppression of cell proliferation in these rats can be reversed by lowering corticosterone below the control value. In addition, normal stress-induced suppression of cell proliferation and neurogenesis, despite normal activation of the hypothalamic pituitary adrenal (HPA) axis, is not observed in maternally separated rats. Our results suggest that early adverse experience inhibits structural plasticity via hypersensitivity to glucocorticoids and diminishes the ability of the hippocampus to respond to stress in adulthood.
TL;DR: The sequence in which different afferents initially discharge in response to mechanical fingertip events provides information about these events faster than the fastest possible rate code and fast enough to account for the use of tactile signals in natural manipulation.
Abstract: It is generally assumed that primary sensory neurons transmit information by their firing rates. However, during natural object manipulations, tactile information from the fingertips is used faster than can be readily explained by rate codes. Here we show that the relative timing of the first impulses elicited in individual units of ensembles of afferents reliably conveys information about the direction of fingertip force and the shape of the surface contacting the fingertip. The sequence in which different afferents initially discharge in response to mechanical fingertip events provides information about these events faster than the fastest possible rate code and fast enough to account for the use of tactile signals in natural manipulation.
TL;DR: Functional magnetic resonance imaging evidence that the EBA is strongly modulated by limb (arm, foot) movements to a visual target stimulus, even in the absence of visual feedback from the movement is reported.
Abstract: A region in human lateral occipital cortex (the 'extrastriate body area' or EBA) has been implicated in the perception of body parts. Here we report functional magnetic resonance imaging (fMRI) evidence that the EBA is strongly modulated by limb (arm, foot) movements to a visual target stimulus, even in the absence of visual feedback from the movement. Therefore, the EBA responds not only during the perception of other people's body parts, but also during goal-directed movements of the observer's body parts. In addition, both limb movements and saccades to a detected stimulus produced stronger signals than stimulus detection without motor movements ('covert detection') in the calcarine sulcus and lingual gyrus. These motor-related modulations cannot be explained by simple visual or attentional factors related to the target stimulus, and suggest a potentially widespread influence of actions on visual cortex.