Showing papers in "Nature Neuroscience in 2009"
TL;DR: Findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.
Abstract: Maternal care influences hypothalamic-pituitary-adrenal (HPA) function in the rat through epigenetic programming of glucocorticoid receptor expression. In humans, childhood abuse alters HPA stress responses and increases the risk of suicide. We examined epigenetic differences in a neuron-specific glucocorticoid receptor (NR3C1) promoter between postmortem hippocampus obtained from suicide victims with a history of childhood abuse and those from either suicide victims with no childhood abuse or controls. We found decreased levels of glucocorticoid receptor mRNA, as well as mRNA transcripts bearing the glucocorticoid receptor 1F splice variant and increased cytosine methylation of an NR3C1 promoter. Patch-methylated NR3C1 promoter constructs that mimicked the methylation state in samples from abused suicide victims showed decreased NGFI-A transcription factor binding and NGFI-A–inducible gene transcription. These findings translate previous results from rat to humans and suggest a common effect of parental care on the epigenetic regulation of hippocampal glucocorticoid receptor expression.
3,087 citations
TL;DR: It is argued that systems neuroscience needs to adjust some widespread practices to avoid the circularity that can arise from selection, and 'double dipping' the use of the same dataset for selection and selective analysis is suggested.
Abstract: A neuroscientific experiment typically generates a large amount of data, of which only a small fraction is analyzed in detail and presented in a publication. However, selection among noisy measurements can render circular an otherwise appropriate analysis and invalidate results. Here we argue that systems neuroscience needs to adjust some widespread practices to avoid the circularity that can arise from selection. In particular, ‘double dipping’, the use of the same dataset for selection and selective analysis, will give distorted descriptive statistics and invalid statistical inference whenever the results statistics are not inherently independent of the selection criteria under the null hypothesis. To demonstrate the problem, we apply widely used analyses to noise data known to not contain the experimental effects in question. Spurious effects can appear in the context of both univariate activation analysis and multivariate pattern-information analysis. We suggest a policy for avoiding circularity.
2,511 citations
TL;DR: This paper will demonstrate how the understanding of speech perception, one important facet of language, has profited from findings and theory in nonhuman primate studies, and identify roles for different cortical areas in the perceptual processing of speech.
Abstract: Speech and language are considered uniquely human abilities: animals have communication systems, but they do not match human linguistic skills in terms of recursive structure and combinatorial power. Yet, in evolution, spoken language must have emerged from neural mechanisms at least partially available in animals. In this paper, we will demonstrate how our understanding of speech perception, one important facet of language, has profited from findings and theory in nonhuman primate studies. Chief among these are physiological and anatomical studies showing that primate auditory cortex, across species, shows patterns of hierarchical structure, topographic mapping and streams of functional processing. We will identify roles for different cortical areas in the perceptual processing of speech and review functional imaging work in humans that bears on our understanding of how the brain decodes and monitors speech. A new model connects structures in the temporal, frontal and parietal lobes linking speech perception and production.
1,482 citations
TL;DR: Using diffusion imaging, a localized increase in fractional anisotropy is detected in white matter underlying the intraparietal sulcus following training of a complex visuo-motor skill, the first evidence for training-related changes in white-matter structure in the healthy human adult brain.
Abstract: Although previous work has shown that extensive training in the complex visuo-motor skills involved in juggling results in adult gray-matter changes, it is unclear whether such practice can produce similar changes in adult white matter. This paper now uses diffusion tensor imaging to demonstrate structural white-matter changes when adults practice juggling.
1,324 citations
TL;DR: It is found that selective elimination of SPW-Rs during post-training consolidation periods resulted in performance impairment in rats trained on a hippocampus-dependent spatial memory task, providing evidence for a prominent role of hippocampal SPW -Rs in memory consolidation.
Abstract: Sharp wave-ripple (SPW-R) complexes in the hippocampus-entorhinal cortex are believed to be important for transferring labile memories from the hippocampus to the neocortex for long-term storage. We found that selective elimination of SPW-Rs during post-training consolidation periods resulted in performance impairment in rats trained on a hippocampus-dependent spatial memory task. Our results provide evidence for a prominent role of hippocampal SPW-Rs in memory consolidation.
1,229 citations
TL;DR: It is found that neuronal activity controlled the ability of MeCP2 to regulate activity-dependent transcription of the Avp gene and induced epigenetic marking, which can dynamically control DNA methylation in postmitotic neurons to generate stable changes in Avp expression that trigger neuroendocrine and behavioral alterations that are frequent features in depression.
Abstract: Adverse early life events can induce long-lasting changes in physiology and behavior. We found that early-life stress (ELS) in mice caused enduring hypersecretion of corticosterone and alterations in passive stress coping and memory. This phenotype was accompanied by a persistent increase in arginine vasopressin (AVP) expression in neurons of the hypothalamic paraventricular nucleus and was reversed by an AVP receptor antagonist. Altered Avp expression was associated with sustained DNA hypomethylation of an important regulatory region that resisted age-related drifts in methylation and centered on those CpG residues that serve as DNA-binding sites for the methyl CpG-binding protein 2 (MeCP2). We found that neuronal activity controlled the ability of MeCP2 to regulate activity-dependent transcription of the Avp gene and induced epigenetic marking. Thus, ELS can dynamically control DNA methylation in postmitotic neurons to generate stable changes in Avp expression that trigger neuroendocrine and behavioral alterations that are frequent features in depression.
1,132 citations
TL;DR: It is found that over 80% of the attentional improvement in the population signal was caused by decreases in the correlations between the trial-to-trial fluctuations in the responses of pairs of neurons, suggesting that the representation of sensory information in populations of neurons may only be understood by considering the interactions between neurons.
Abstract: Previous work has suggested that visual attention improves behavioral performance by increasing the firing rates of individual sensory neurons. Recording from populations of neurons in monkey visual area V4, this study finds that most of the attentional improvement in the population signal results from decreases in interneuronal correlations.
1,086 citations
TL;DR: The SRY-box transcription factor Sox9 is identified as being a physiological target of miR-124 at the transition from the transit amplifying cell to the neuroblast stage, which is important for progression along the SVZ stem cell lineage to neurons.
Abstract: The subventricular zone (SVZ) is the largest neurogenic niche in the adult mammalian brain. We found that the brain-enriched microRNA miR-124 is an important regulator of the temporal progression of adult neurogenesis in mice. Knockdown of endogenous miR-124 maintained purified SVZ stem cells as dividing precursors, whereas ectopic expression led to precocious and increased neuron formation. Furthermore, blocking miR-124 function during regeneration led to hyperplasias, followed by a delayed burst of neurogenesis. We identified the SRY-box transcription factor Sox9 as being a physiological target of miR-124 at the transition from the transit amplifying cell to the neuroblast stage. Sox9 overexpression abolished neuronal differentiation, whereas Sox9 knockdown led to increased neuron formation. Thus miR-124-mediated repression of Sox9 is important for progression along the SVZ stem cell lineage to neurons.
901 citations
TL;DR: During soft brush stroking, low-threshold unmyelinated mechanoreceptors (C-tactile), but not myelinated afferents, responded most vigorously at intermediate brushing velocities, which were perceived by subjects as being the most pleasant.
Abstract: Pleasant touch sensations may begin with neural coding in the periphery by specific afferents. We found that during soft brush stroking, low-threshold unmyelinated mechanoreceptors (C-tactile), but not myelinated afferents, responded most vigorously at intermediate brushing velocities (1-10 cm s(-1)), which were perceived by subjects as being the most pleasant. Our results indicate that C-tactile afferents constitute a privileged peripheral pathway for pleasant tactile stimulation that is likely to signal affiliative social body contact.
851 citations
TL;DR: Oral administration of the β-adrenergic receptor antagonist propranolol before memory reactivation in humans erased the behavioral expression of the fear memory 24 h later and prevented the return of fear.
Abstract: Animal studies have shown that fear memories can change when recalled, a process referred to as reconsolidation. We found that oral administration of the beta-adrenergic receptor antagonist propranolol before memory reactivation in humans erased the behavioral expression of the fear memory 24 h later and prevented the return of fear. Disrupting the reconsolidation of fear memory opens up new avenues for providing a long-term cure for patients with emotional disorders.
737 citations
TL;DR: Findings indicate that trait anxiety is linked to impoverished recruitment of prefrontal attentional control mechanisms to inhibit distractor processing even when threat-related stimuli are absent.
Abstract: Many neurocognitive models of anxiety emphasize the importance of a hyper-responsive threat-detection system centered on the amygdala, with recent accounts incorporating a role for prefrontal mechanisms in regulating attention to threat. Here we investigated whether trait anxiety is associated with a much broader dysregulation of attentional control. Volunteers performed a response-conflict task under conditions that posed high or low demands on attention. High trait-anxious individuals showed reduced prefrontal activity and slower target identification in response to processing competition when the task did not fully occupy attentional resources. The relationship between trait anxiety and prefrontal recruitment remained after controlling for state anxiety. These findings indicate that trait anxiety is linked to impoverished recruitment of prefrontal attentional control mechanisms to inhibit distractor processing even when threat-related stimuli are absent. Notably, this deficit was observed when ongoing task-related demands on attention were low, potentially explaining the day-to-day difficulties in concentration that are associated with clinical anxiety.
TL;DR: Recording neuron ensembles in the rat medial prefrontal cortex to study memory trace reactivation during SWS following learning and execution of cross-modal strategy shifts found that learning influenced which patterns were most strongly encoded and successively reactivated in the hippocampal/prefrontal network.
Abstract: Slow-wave sleep (SWS) is important for memory consolidation. During sleep, neural patterns reflecting previously acquired information are replayed. One possible reason for this is that such replay exchanges information between hippocampus and neocortex, supporting consolidation. We recorded neuron ensembles in the rat medial prefrontal cortex (mPFC) to study memory trace reactivation during SWS following learning and execution of cross-modal strategy shifts. In general, reactivation of learning-related patterns occurred in distinct, highly synchronized transient bouts, mostly simultaneous with hippocampal sharp wave/ripple complexes (SPWRs), when hippocampal ensemble reactivation and cortico-hippocampal interaction is enhanced. During sleep following learning of a new rule, mPFC neural patterns that appeared during response selection replayed prominently, coincident with hippocampal SPWRs. This was learning dependent, as the patterns appeared only after rule acquisition. Therefore, learning, or the resulting reliable reward, influenced which patterns were most strongly encoded and successively reactivated in the hippocampal/prefrontal network.
TL;DR: It is demonstrated that region- and pathway-specific plasticity sculpts the circuits involved in the performance of the skill as it becomes automatized.
Abstract: The learning of new skills is characterized by an initial phase of rapid improvement in performance and a phase of more gradual improvements as skills are automatized and performance asymptotes. Using in vivo striatal recordings, we observed region-specific changes in neural activity during the different phases of skill learning, with the associative or dorsomedial striatum being preferentially engaged early in training and the sensorimotor or dorsolateral striatum being engaged later in training. Ex vivo recordings from medium spiny striatal neurons in brain slices of trained mice revealed that the changes observed in vivo corresponded to regional- and training-specific changes in excitatory synaptic transmission in the striatum. Furthermore, the potentiation of glutamatergic transmission observed in dorsolateral striatum after extensive training was preferentially expressed in striatopallidal neurons, rather than striatonigral neurons. These findings demonstrate that region- and pathway-specific plasticity sculpts the circuits involved in the performance of the skill as it becomes automatized.
TL;DR: It is shown that stored representations are reactivated during both waking and sleep replay, and that the hippocampus consistently replays past experiences during brief pauses in waking behavior, suggesting a role for waking replay in memory consolidation and retrieval.
Abstract: Hippocampal replay is thought to be essential for the consolidation of event memories in hippocampal-neocortical networks. Replay is present during both sleep and waking behavior, but although sleep replay involves the reactivation of stored representations in the absence of specific sensory inputs, awake replay is thought to depend on sensory input from the current environment. Here, we show that stored representations are reactivated during both waking and sleep replay. We found frequent awake replay of sequences of rat hippocampal place cells from a previous experience. This spatially remote replay was as common as local replay of the current environment and was more robust when the rat had recently been in motion than during extended periods of quiescence. Our results indicate that the hippocampus consistently replays past experiences during brief pauses in waking behavior, suggesting a role for waking replay in memory consolidation and retrieval.
TL;DR: It is proposed that, in the absence of supraspinal input, spinal locomotion can emerge from a combination of central pattern-generating capability and the ability of these spinal circuits to use sensory afferent input to control stepping.
Abstract: After complete spinal cord transections that removed all supraspinal inputs in adult rats, combinations of serotonergic agonists and epidural electrical stimulation were able to acutely transform spinal networks from nonfunctional to highly functional and adaptive states as early as 1 week after injury. Using kinematics, physiological and anatomical analyses, we found that these interventions could recruit specific populations of spinal circuits, refine their control via sensory input and functionally remodel these locomotor pathways when combined with training. The emergence of these new functional states enabled full weight-bearing treadmill locomotion in paralyzed rats that was almost indistinguishable from voluntary stepping. We propose that, in the absence of supraspinal input, spinal locomotion can emerge from a combination of central pattern-generating capability and the ability of these spinal circuits to use sensory afferent input to control stepping. These findings provide a strategy by which individuals with spinal cord injuries could regain substantial levels of motor control.
TL;DR: Bi-stable channelrhodopsins that convert a brief pulse of light into a stable step in membrane potential are described that retain millisecond-scale temporal precision and offer important new capabilities for a broad range of in vivo applications.
Abstract: Here we describe bi-stable channelrhodopsins that convert a brief pulse of light into a stable step in membrane potential. These molecularly engineered probes nevertheless retain millisecond-scale temporal precision. Photocurrents can be precisely initiated and terminated with different colors of light, but operate at vastly longer time scales than conventional channelrhodopsins as a result of modification at the C128 position that extends the lifetime of the open state. Because of their enhanced kinetic stability, these step-function tools are also effectively responsive to light at orders of magnitude lower intensity than wild-type channelrhodopsins. These molecules therefore offer important new capabilities for a broad range of in vivo applications.
TL;DR: A previously unknown Wnt-mediated regulatory mechanism that simultaneously coordinates activation of NeuroD1 and LINE-1 is described, which is important for adult neurogenesis and survival of neuronal progenitors.
Abstract: In adult hippocampus, new neurons are continuously generated from neural stem cells (NSCs), but the molecular mechanisms regulating adult neurogenesis remain elusive. We found that Wnt signaling, together with the removal of Sox2, triggered the expression of NeuroD1 in mice. This transcriptional regulatory mechanism was dependent on a DNA element containing overlapping Sox2 and T-cell factor/lymphoid enhancer factor (TCF/LEF)-binding sites (Sox/LEF) in the promoter. Notably, Sox/LEF sites were also found in long interspersed nuclear element 1 (LINE-1) elements, consistent with their critical roles in the transition of NSCs to proliferating neuronal progenitors. Our results describe a previously unknown Wnt-mediated regulatory mechanism that simultaneously coordinates activation of NeuroD1 and LINE-1, which is important for adult neurogenesis and survival of neuronal progenitors. Moreover, the discovery that LINE-1 retro-elements embedded in the mammalian genome can function as bi-directional promoters suggests that Sox/LEF regulatory sites may represent a general mechanism, at least in part, for relaying environmental signals to other nearby loci to promote adult hippocampal neurogenesis.
TL;DR: Modeling studies and simultaneous somatic and axonal recordings showed that distal Nav1.6 promotes action potential initiation, whereas proximal Nav 1.2 promotes its backpropagation to the soma.
Abstract: The distal end of the axon initial segment (AIS) is the preferred site for action potential initiation in cortical pyramidal neurons because of its high Na(+) channel density. However, it is not clear why action potentials are not initiated at the proximal AIS, which has a similarly high Na(+) channel density. We found that low-threshold Na(v)1.6 and high-threshold Na(v)1.2 channels preferentially accumulate at the distal and proximal AIS, respectively, and have distinct functions in action potential initiation and backpropagation. Patch-clamp recording from the axon cut end of pyramidal neurons in the rat prefrontal cortex revealed a high density of Na(+) current and a progressive reduction in the half-activation voltage (up to 14 mV) with increasing distance from the soma at the AIS. Further modeling studies and simultaneous somatic and axonal recordings showed that distal Na(v)1.6 promotes action potential initiation, whereas proximal Na(v)1.2 promotes its backpropagation to the soma.
TL;DR: This paper carried out a longitudinal analysis in vivo of identified motoneurons selectively vulnerable (VUL) or resistant (RES) to motoneuron disease (amyotrophic lateral sclerosis, ALS) and show that subtype-selective endoplasmic reticulum (ER) stress responses influence disease manifestations.
Abstract: The mechanisms underlying disease manifestations in neurodegeneration remain unclear, but their understanding is critical to devising effective therapies. We carry out a longitudinal analysis in vivo of identified motoneurons selectively vulnerable (VUL) or resistant (RES) to motoneuron disease (amyotrophic lateral sclerosis, ALS) and show that subtype-selective endoplasmic reticulum (ER) stress responses influence disease manifestations. VUL motoneurons were selectively prone to ER stress and showed gradually upregulated ER stress markers from birth on in three mouse models of familial ALS (FALS). 25-30 days before the earliest denervations, ubiquitin signals increased in both VUL and RES motoneurons, but an unfolded protein response coupled with microglial activation was initiated selectively in VUL motoneurons. This transition was followed by selective axonal degeneration and spreading stress. The ER stress-protective agent salubrinal attenuated disease manifestations and delayed progression, whereas chronic enhancement of ER stress promoted disease. Thus, whereas all motoneurons are preferentially affected in ALS, ER stress responses in specific motoneuron subtypes influence the progressive manifestations of weakening and paralysis.
TL;DR: Using polytrode recording in rat visual cortex, it is found that nucleus basalis stimulation caused prominent decorrelation between neurons and marked improvement in the reliability of neuronal responses to natural scenes, which improved cortical representation of natural stimuli in a complementary manner.
Abstract: The nucleus basalis of the basal forebrain is an essential component of the neuromodulatory system controlling the behavioral state of an animal and it is thought to be important in regulating arousal and attention. However, the effect of nucleus basalis activation on sensory processing remains poorly understood. Using polytrode recording in rat visual cortex, we found that nucleus basalis stimulation caused prominent decorrelation between neurons and marked improvement in the reliability of neuronal responses to natural scenes. The decorrelation depended on local activation of cortical muscarinic acetylcholine receptors, whereas the increased reliability involved distributed neural circuits, as evidenced by nucleus basalis-induced changes in thalamic responses. Further analysis showed that the decorrelation and increased reliability improved cortical representation of natural stimuli in a complementary manner. Thus, the basal forebrain neuromodulatory circuit, which is known to be activated during aroused and attentive states, acts through both local and distributed mechanisms to improve sensory coding.
TL;DR: The results indicate that motivation is a dissociable function, reveal how the PFC integrates motivation and cognitive control in the service of decision-making, and have major implications for current theories of prefrontal executive function.
Abstract: The prefrontal cortex (PFC) subserves cognitive control, that is, the ability to select thoughts or actions in relation to internal goals. Little is known, however, about how the PFC combines motivation and the selection processes underlying cognitive control. We used functional magnetic resonance imaging in humans and found that the medial and lateral PFC have a parallel hierarchical organization from posterior to anterior regions for motivating and selecting behaviors, respectively. Moreover, using functional connectivity analyses, we found that functional interactions in this parallel system from medial to lateral PFC regions convey motivational incentives on the basis of rewards/penalties regulating the differential engagement of lateral PFC regions in top-down selection. Our results indicate that motivation is a dissociable function, reveal how the PFC integrates motivation and cognitive control in the service of decision-making, and have major implications for current theories of prefrontal executive function.
TL;DR: Crosstalk between HDAC1/2 and the canonical Wnt signaling pathway mediated by TCF7L2 serves as a regulatory mechanism for oligodendrocyte differentiation.
Abstract: Oligodendrocyte development is regulated by the interaction of repressors and activators in a complex transcriptional network. We found that two histone-modifying enzymes, HDAC1 and HDAC2, were required for oligodendrocyte formation. Genetic deletion of both Hdac1 and Hdac2 in oligodendrocyte lineage cells resulted in stabilization and nuclear translocation of beta-catenin, which negatively regulates oligodendrocyte development by repressing Olig2 expression. We further identified the oligodendrocyte-restricted transcription factor TCF7L2/TCF4 as a bipartite co-effector of beta-catenin for regulating oligodendrocyte differentiation. Targeted disruption of Tcf7l2 in mice led to severe defects in oligodendrocyte maturation, whereas expression of its dominant-repressive form promoted precocious oligodendrocyte specification in developing chick neural tube. Transcriptional co-repressors HDAC1 and HDAC2 compete with beta-catenin for TCF7L2 interaction to regulate downstream genes involved in oligodendrocyte differentiation. Thus, crosstalk between HDAC1/2 and the canonical Wnt signaling pathway mediated by TCF7L2 serves as a regulatory mechanism for oligodendrocyte differentiation.
TL;DR: NADPH oxidase is identified as the primary source of NMDA-induced superoxide production and neuronal death, and is blocked by the NADPH oxid enzyme inhibitor apocynin and in neurons lacking the p47phox subunit, which is required for NADPH oxidation.
Abstract: Neuronal NMDA receptor (NMDAR) activation leads to the formation of superoxide, which normally acts in cell signaling. With extensive NMDAR activation, the resulting superoxide production leads to neuronal death. It is widely held that NMDA-induced superoxide production originates from the mitochondria, but definitive evidence for this is lacking. We evaluated the role of the cytoplasmic enzyme NADPH oxidase in NMDA-induced superoxide production. Neurons in culture and in mouse hippocampus responded to NMDA with a rapid increase in superoxide production, followed by neuronal death. These events were blocked by the NADPH oxidase inhibitor apocynin and in neurons lacking the p47phox subunit, which is required for NADPH oxidase assembly. Superoxide production was also blocked by inhibiting the hexose monophosphate shunt, which regenerates the NADPH substrate, and by inhibiting protein kinase C zeta, which activates the NADPH oxidase complex. These findings identify NADPH oxidase as the primary source of NMDA-induced superoxide production.
TL;DR: Conditioned place preference is used to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it and provides a new approach for investigating tonicPain in animals and for evaluating the analgesic effects of drugs.
Abstract: Tonic pain has been difficult to demonstrate in animals. Because relief of pain is rewarding, analgesic agents that are not rewarding in the absence of pain should become rewarding only when there is ongoing pain. We used conditioned place preference to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it. This provides a new approach for investigating tonic pain in animals and for evaluating the analgesic effects of drugs.
TL;DR: A LRRK2 transgenic mouse model is created that recapitulates cardinal features of Parkinson's disease: an age-dependent and levodopa-responsive slowness of movement associated with diminished dopamine release and axonal pathology of nigrostriatal dopaminergic projection.
Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. We created a LRRK2 transgenic mouse model that recapitulates cardinal features of the disease: an age-dependent and levodopa-responsive slowness of movement associated with diminished dopamine release and axonal pathology of nigrostriatal dopaminergic projection. These mice provide a valid model of Parkinson's disease and are a resource for the investigation of pathogenesis and therapeutics.
TL;DR: The results suggest that the lateral habenula has the potential to adaptively control both reward-seeking and punishment-avoidance behaviors, presumably through its projections to dopaminergic and serotonergic systems.
Abstract: An action may lead to either a reward or a punishment. Therefore, an appropriate action needs to be chosen on the basis of the values of both expected rewards and expected punishments. To understand the underlying neural mechanisms, we conditioned monkeys using a Pavlovian procedure with two distinct contexts: one in which rewards were available and another in which punishments were feared. We found that the population of lateral habenula neurons was most strongly excited by a conditioned stimulus associated with the most unpleasant event in each context: the absence of the reward or the presence of the punishment. The population of lateral habenula neurons was also excited by the punishment itself and inhibited by the reward itself, especially when they were less predictable. These results suggest that the lateral habenula has the potential to adaptively control both reward-seeking and punishment-avoidance behaviors, presumably through its projections to dopaminergic and serotonergic systems.
TL;DR: The results suggest that the surface compartments formed by the ECM hinder lateral diffusion of AMPA receptors and may therefore modulate short-term synaptic plasticity.
Abstract: Most synapses in the mature CNS are wrapped by a dense extracellular matrix (ECM). The authors show that removing the ECM increased the lateral diffusion of AMPA receptors and affected short-term synaptic plasticity. This suggests that the ECM may modulate synaptic transmission by restricting receptor diffusion. Many synapses in the mature CNS are wrapped by a dense extracellular matrix (ECM). Using single-particle tracking and fluorescence recovery after photobleaching, we found that this net-like ECM formed surface compartments on rat primary neurons that acted as lateral diffusion barriers for AMPA-type glutamate receptors. Enzymatic removal of the ECM increased extrasynaptic receptor diffusion and the exchange of synaptic AMPA receptors. Whole-cell patch-clamp recording revealed an increased paired-pulse ratio as a functional consequence of ECM removal. These results suggest that the surface compartments formed by the ECM hinder lateral diffusion of AMPA receptors and may therefore modulate short-term synaptic plasticity.
TL;DR: Neural stem cells control their status, at least partly, through Sox2-dependent autocrine mechanisms, and their replication was partially rescued by the addition of SHH and was almost fully rescued by conditioned medium from normal cells.
Abstract: Neural stem cells (NSCs) are controlled by diffusible factors. The transcription factor Sox2 is expressed by NSCs and Sox2 mutations in humans cause defects in the brain and, in particular, in the hippocampus. We deleted Sox2 in the mouse embryonic brain. At birth, the mice showed minor brain defects; shortly afterwards, however, NSCs and neurogenesis were completely lost in the hippocampus, leading to dentate gyrus hypoplasia. Deletion of Sox2 in adult mice also caused hippocampal neurogenesis loss. The hippocampal developmental defect resembles that caused by late sonic hedgehog (Shh) loss. In mutant mice, Shh and Wnt3a were absent from the hippocampal primordium. A SHH pharmacological agonist partially rescued the hippocampal defect. Chromatin immunoprecipitation identified Shh as a Sox2 target. Sox2-deleted NSCs did not express Shh in vitro and were rapidly lost. Their replication was partially rescued by the addition of SHH and was almost fully rescued by conditioned medium from normal cells. Thus, NSCs control their status, at least partly, through Sox2-dependent autocrine mechanisms.
TL;DR: It is demonstrated that CREB modulates the allocation of fear memory to specific cells in lateral amygdala and suggest that neuronal excitability is important in this process.
Abstract: The mechanisms that determine how information is allocated to specific regions and cells in the brain are important for memory capacity, storage and retrieval, but are poorly understood. We manipulated CREB in a subset of lateral amygdala neurons in mice with a modified herpes simplex virus (HSV) and reversibly inactivated transfected neurons with the Drosophila allatostatin G protein–coupled receptor (AlstR)/ligand system. We found that inactivation of the neurons transfected with HSV-CREB during training disrupted memory for tone conditioning, whereas inactivation of a similar proportion of transfected control neurons did not. Whole-cell recordings of fluorescently tagged transfected neurons revealed that neurons with higher CREB levels are more excitable than neighboring neurons and showed larger synaptic efficacy changes following conditioning. Our findings demonstrate that CREB modulates the allocation of fear memory to specific cells in lateral amygdala and suggest that neuronal excitability is important in this process.
TL;DR: Observations suggest that endogenous Aβ peptides have a crucial role in activity-dependent regulation of synaptic vesicle release and might point to the primary pathological events that lead to compensatory synapse loss in Alzheimer's disease.
Abstract: Accumulation of cerebral amyloid-beta peptide (Abeta) is essential for developing synaptic and cognitive deficits in Alzheimer's disease. However, the physiological functions of Abeta, as well as the primary mechanisms that initiate early Abeta-mediated synaptic dysfunctions, remain largely unknown. Here we examine the acute effects of endogenously released Abeta peptides on synaptic transfer at single presynaptic terminals and synaptic connections in rodent hippocampal cultures and slices. Increasing extracellular Abeta by inhibiting its degradation enhanced release probability, boosting ongoing activity in the hippocampal network. Presynaptic enhancement mediated by Abeta was found to depend on the history of synaptic activation, with lower impact at higher firing rates. Notably, both elevation and reduction in Abeta levels attenuated short-term synaptic facilitation during bursts in excitatory synaptic connections. These observations suggest that endogenous Abeta peptides have a crucial role in activity-dependent regulation of synaptic vesicle release and might point to the primary pathological events that lead to compensatory synapse loss in Alzheimer's disease.