Neuronal Plasticity

Recognition that inflammation may represent a common mechanism of disease has been extended to include neuropsychiatric disorders including major depression. Patients with major depression have been found to exhibit increased peripheral blood inflammatory biomarkers, including inflammatory cytokines, which have been shown to access the brain and interact with virtually every pathophysiologic domain known to be involved in depression, including neurotransmitter metabolism, neuroendocrine function, and neural plasticity. Indeed, activation of inflammatory pathways within the brain is believed to contribute to a confluence of decreased neurotrophic support and altered glutamate release/reuptake, as well as oxidative stress, leading to excitotoxicity and loss of glial elements, consistent with neuropathologic findings that characterize depressive disorders. Further instantiating the link between inflammation and depression are data demonstrating that psychosocial stress, a well-known precipitant of mood disorders, is capable of stimulating inflammatory signaling molecules, including nuclear factor kappa B, in part, through activation of sympathetic nervous system outflow pathways. Interestingly, depressed patients with increased inflammatory biomarkers have been found to be more likely to exhibit treatment resistance, and in several studies, antidepressant therapy has been associated with decreased inflammatory responses. Finally, preliminary data from patients with inflammatory disorders, as well as medically healthy depressed patients, suggest that inhibiting proinflammatory cytokines or their signaling pathways may improve depressed mood and increase treatment response to conventional antidepressant medication. Translational implications of these findings include the unique opportunity to identify relevant patient populations, apply immune-targeted therapies, and monitor therapeutic efficacy at the level of the immune system in addition to behavior.

Changing the strength of connections between neurons is widely assumed to be the mechanism by which memory traces are encoded and stored in the central nervous system. In its most general form, the synaptic plasticity and memory hypothesis states that "activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for the information storage underlying the type of memory mediated by the brain area in which that plasticity is observed." We outline a set of criteria by which this hypothesis can be judged and describe a range of experimental strategies used to investigate it. We review both classical and newly discovered properties of synaptic plasticity and stress the importance of the neural architecture and synaptic learning rules of the network in which it is embedded. The greater part of the article focuses on types of memory mediated by the hippocampus, amygdala, and cortex. We conclude that a wealth of data supports the notion that synaptic plasticity is necessary for learning and memory, but that little data currently supports the notion of sufficiency. Annu. Rev. Neurosci. 2000.23:649-711. Downloaded from arjournals.annualreviews.org by Iowa State University on 02/10/05. For personal use only. Annu. Rev. Neurosci. 2000.23:649-711. Downloaded from arjournals.annualreviews.org by Iowa State University on 02/10/05. For personal use only.

Central sensitization represents an enhancement in the function of neurons and circuits in nociceptive pathways caused by increases in membrane excitability and synaptic efficacy as well as to reduced inhibition and is a manifestation of the remarkable plasticity of the somatosensory nervous system in response to activity, inflammation, and neural injury. The net effect of central sensitization is to recruit previously subthreshold synaptic inputs to nociceptive neurons, generating an increased or augmented action potential output: a state of facilitation, potentiation, augmentation, or amplification. Central sensitization is responsible for many of the temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings and exemplifies the fundamental contribution of the central nervous system to the generation of pain hypersensitivity. Because central sensitization results from changes in the properties of neurons in the central nervous system, the pain is no longer coupled, as acute nociceptive pain is, to the presence, intensity, or duration of noxious peripheral stimuli. Instead, central sensitization produces pain hypersensitivity by changing the sensory response elicited by normal inputs, including those that usually evoke innocuous sensations.

Peripheral tissue damage or nerve injury often leads to pathological pain processes, such as spontaneous pain, hyperalgesia and allodynia, that persist for years or decades after all possible tissue healing has occurred. Although peripheral neural mechanisms, such as nociceptor sensitization and neuroma formation, contribute to these pathological pain processes, recent evidence indicates that changes in central neural function may also playa significant role. In this review, we examine the clinical and experimental evidence which points to a contribution of central neural plasticity to the development of pathological pain. We also assess the physiological, biochemical, cellular and molecular mechanisms that underlie plasticity induced in the central nervous system (eNS) in response to noxious peripheral stimulation. Finally, we examine theories which have been proposed to explain how injury or noxious stimulation lead to alterations in eNS function which influence subsequent pain experience.

The dentate granule cell layer of the rodent hippocampal formation has the distinctive property of ongoing neurogenesis that continues throughout adult life. In both human temporal lobe epilepsy and rodent models of limbic epilepsy, this same neuronal population undergoes extensive remodeling, including reorganization of mossy fibers, dispersion of the granule cell layer, and the appearance of granule cells in ectopic locations within the dentate gyrus. The mechanistic basis of these abnormalities, as well as their potential relationship to dentate granule cell neurogenesis, is unknown. We used a systemic chemoconvulsant model of temporal lobe epilepsy and bromodeoxyuridine (BrdU) labeling to investigate the effects of prolonged seizures on dentate granule cell neurogenesis in adult rats, and to examine the contribution of newly differentiated dentate granule cells to the network changes seen in this model. Pilocarpine-induced status epilepticus caused a dramatic and prolonged incre...

Magnetic source imaging revealed that the cortical representation of the digits of the left hand of string players was larger than that in controls. The effect was smallest for the left thumb, and no such differences were observed for the representations of the right hand digits. The amount of cortical reorganization in the representation of the fingering digits was correlated

Do new synapses form in the adult cortex to support experience-dependent plasticity? To address this question, we repeatedly imaged individual pyramidal neurons in the mouse barrel cortex over periods of weeks. We found that, although dendritic structure is stable, some spines appear and disappear. Spine lifetimes vary greatly: stable spines, about 50% of the population, persist for at least a month, whereas the remainder are present for a few days or less. Serial-section electron microscopy of imaged dendritic segments revealed retrospectively that spine sprouting and retraction are associated with synapse formation and elimination. Experience-dependent plasticity of cortical receptive fields was accompanied by increased synapse turnover. Our measurements suggest that sensory experience drives the formation and elimination of synapses and that these changes might underlie adaptive remodelling of neural circuits. articles NATURE | VOL 420 | 19/26 DECEMBER 2002 | www.nature.com/nature 788

N-methyl-d-aspartate receptors (NMDARs) are present at many excitatory glutamate synapses in the central nervous system and display unique properties that depend on their subunit composition. Biophysical, pharmacological and molecular methods have been used to determine the key features conferred by the various NMDAR subunits, and have helped to establish which NMDAR subtypes are present at particular synapses. Recent studies are

Whole-cell perforated recording from RGCs or tectal cells were made under visual control by methods described previously 28 . The micropipettes were made from borosilicate glass capillaries (Kimax), had a resistance in the range of 2-3 MQ, and were tip-filled with internal solution and then were back-filled with internal solution containing 200 mg ml 21 amphotericin B. The internal solution contained: 115 mM K-gluconate, 4 mM NaCl, 1.5 mM MgCl 2 , 20 mM HEPES at pH 7.3 and 0.5 mM EGTA. Recordings were made with a patch clamp amplifier (Axopatch 200A; Axon Instruments). The whole cell capacitance was fully compensated and the series resistance (10-20 MQ) was compensated at 75-80% (lag 60 ms) and monitored during the experiment. The data were discarded if the series resistance varied by .20%. The input resistance of RGCs at 260 to 270 mV was usually in the range of 0.5 to 1 GQ. Signals were filtered at 5 kHz and sampled at 10 kHz using Axoscope software (Axon Instruments). For cell-attached recording, the pipette was filled with bath solution and a loose seal was made. To record mEPSCs from RGCs or tectal neurons, TTX (1 mM) was added to external solution. A total amount of 400 ng BDNF (PeproTech), dissolved in 15 ml bath solution containing 0.1% bovine serum albumin (BSA), was puffed into the third ventricle near the tectum through a Picospritzer II (General Valve), using a micropipette with a tip opening of 6 mm and repetitive pressure pulses (5 psi, 0.5 Hz, 1 s duration). It usually took 15 min for the BDNF-containing solution to be completely ejected. A small LCD-screen (Sony, PLM-A35) was mounted on the camera port of the microscope, allowing projection of computer-generated images onto the retina of the tadpole. Light responses were evoked by whole-field stimulations with a step (4 s) increase in the whole-field light illumination. All drugs were from Sigma.

Human sleep is a global state whose functions remain unclear. During much of sleep, cortical neurons undergo slow oscillations in membrane potential, which appear in electroencephalograms as slow wave activity (SWA) of <4 Hz 1 . The amount of SWA is homeostatically regulated, increasing after wakefulness and returning to baseline during sleep 2 . It has been suggested that SWA homeostasis may reflect synaptic changes underlying a cellular need for sleep 3 . If this were so, inducing local synaptic changes should induce local SWA changes, and these should benefit neural function. Here we show that sleep homeostasis indeed has a local component, which can be triggered by a learning task involving specific brain regions. Furthermore, we show that the local increase in SWA after learning correlates with improved performance of the task after sleep. Thus, sleep homeostasis can be induced on a local level and can benefit performance.

Over more than a century of research has established the fact that sleep benefits the retention of memory. In this review we aim to comprehensively cover the field of “sleep and memory” research by providing a historical perspective on concepts and a discussion of more recent key findings. Whereas initial theories posed a passive role for sleep enhancing memories by protecting them from interfering stimuli, current theories highlight an active role for sleep in which memories undergo a process of system consolidation during sleep. Whereas older research concentrated on the role of rapid-eye-movement (REM) sleep, recent work has revealed the importance of slow-wave sleep (SWS) for memory consolidation and also enlightened some of the underlying electrophysiological, neurochemical, and genetic mechanisms, as well as developmental aspects in these processes. Specifically, newer findings characterize sleep as a brain state optimizing memory consolidation, in opposition to the waking bra...

Plasticity is an intrinsic property of the human brain and represents evolution's invention to enable the nervous system to escape the restrictions of its own genome and thus adapt to environmental pressures, physiologic changes, and experiences. Dynamic shifts in the strength of preexisting connections across distributed neural networks, changes in task-related cortico-cortical and corticosubcortical coherence and modifications of the mapping between behavior and neural activity take place in response to changes in afferent input or efferent demand. Such rapid, ongoing changes may be followed by the establishment of new connections through dendritic growth and arborization. However, they harbor the danger that the evolving pattern of neural activation may in itself lead to abnormal behavior. Plasticity is the mechanism for development and learning, as much as a cause of pathology. The challenge we face is to learn enough about the mechanisms of plasticity to modulate them to achieve the best behavioral outcome for a given subject. 377 Annu. Rev. Neurosci. 2005.28:377-401. Downloaded from arjournals.annualreviews.org by HARVARD COLLEGE on 07/17/05. For personal use only. Pascual-Leone et al. Annu. Rev. Neurosci. 2005.28:377-401. Downloaded from arjournals.annualreviews.org by HARVARD COLLEGE on 07/17/05. For personal use only. www.annualreviews.org • The Plastic Human Brain Cortex 389 Annu. Rev. Neurosci. 2005.28:377-401. Downloaded from arjournals.annualreviews.org by HARVARD COLLEGE on 07/17/05. For personal use only.

Microglia are the resident macrophages of the CNS, and their functions have been extensively studied in various brain pathologies. The physiological roles of microglia in brain plasticity and function, however, remain unclear. To address this question, we generated CX3CR1(CreER) mice expressing tamoxifen-inducible Cre recombinase that allow for specific manipulation of gene function in microglia. Using CX3CR1(CreER) to drive diphtheria toxin receptor expression in microglia, we found that microglia could be specifically depleted from the brain upon diphtheria toxin administration. Mice depleted of microglia showed deficits in multiple learning tasks and a significant reduction in motor-learning-dependent synapse formation. Furthermore, Cre-dependent removal of brain-derived neurotrophic factor (BDNF) from microglia largely recapitulated the effects of microglia depletion. Microglial BDNF increases neuronal tropomyosin-related kinase receptor B phosphorylation, a key mediator of syna...

One of the major limitations in the use of genetically modified mice for studying cognitive functions is the lack of regional and temporal control of gene function. To overcome these limitations, a forebrain-specific promoter was c o m b i n e d with the tetracycline transactivator system to achieve both regional and temporal control of transgene expression. Expression of an activated calcium-independent form of c a l c i u m -c a l m o d u l i n -d e p e ndent kinase II (CaMKII) resulted in a loss of h i p p o c a m p a l long-term potentiation in response to 10-hertz stimulation and a deficit in spatial memory, a form of explicit memory. Suppression of transgene expression reversed both the physiological and the memory deficit. When the transgene was expressed at high levels in the lateral amygdala and the striatum but not other forebrain structures, there was a deficit in fear conditioning, an implicit m e m o r y task, that also was reversible. Thus, the CaMKII signaling pathway is critical for both explicit and implicit m e m o r y storage, in a manner that is independent of its potential role in development.

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor (NGF) gene family, has been shown to influence the survival and differentiation of specific classes of neurons in vitro and in vivo. The possibility that neurotrophins are also involved in processes of neuronal plasticity has only recently begun to receive attention. To determine whether BDNF has a function in processes such as long-term potentiation (LTP), we produced a strain of mice with a deletion in the coding sequence of the BDNF gene. We then used hippocampal slices from these mice to investigate whether LTP was affected by this mutation. Homo- and heterozygous mutant mice showed significantly reduced LTP in the CA1 region of the hippocampus. The magnitude of the potentiation, as well as the percentage of cases in which LTP could be induced successfully, was clearly affected. According to the criteria tested, important pharmacological, anatomical, and morphological parameters in the hippocampus of these animals appear to be normal. These results suggest that BDNF might have a functional role in the expression of LTP in the hippocampus.

Neuropathic pain is triggered by lesions to the somatosensory nervous system that alter its structure and function so that pain occurs spontaneously and responses to noxious and innocuous stimuli are pathologically amplified. The pain is an expression of maladaptive plasticity within the nociceptive system, a series of changes that constitute a neural disease state. Multiple alterations distributed widely across the nervous system contribute to complex pain phenotypes. These alterations include ectopic generation of action potentials, facilitation and disinhibition of synaptic transmission, loss of synaptic connectivity and formation of new synaptic circuits, and neuroimmune interactions. Although neural lesions are necessary, they are not sufficient to generate neuropathic pain; genetic polymorphisms, gender, and age all influence the risk of developing persistent pain. Treatment needs to move from merely suppressing symptoms to a disease-modifying strategy aimed at both preventing maladaptive plasticity and reducing intrinsic risk.

protein expression. In contrast, neither BDNF nor TrkB-Fc was able to modulate myelin protein expression when injected into the p75 NTR-/mice, in agreement with the premise that p75 NTR is the functional receptor for BDNF. The lack of BDNF activity was in sharp contrast with that of NT3. In both wild-type and p75 NTR-/mice, injection with NT3 inhibited myelination and injection with TrkC-Fc enhanced myelination to the same degree. Similar conclusions were obtained with mouse SC/ DRG cocultures (12). Myelin protein expression was enhanced by BDNF and decreased by TrkB-Fc in myelinating cocultures from wildtype embryos , C and D), whereas neither BDNF nor TrkB-Fc had any effect in cocultures from p75 NTR-/embryos. Furthermore, NT3 inhibited and TrkC-Fc enhanced myelination in both wild-type and p75 NTR-/cocultures with the same efficiency, again indicating that p75 NTR is the functional receptor for BDNF but not for NT3.

Schizophrenia is a heritable brain illness with unknown pathogenic mechanisms. Schizophrenia's strongest genetic association at a population level involves variation in the Major Histocompatibility Complex (MHC) locus, but the genes and molecular mechanisms accounting for this have been challenging to recognize. We show here that schizophrenia's association with the MHC locus arises in substantial part from many structurally diverse alleles of the complement component 4 (C4) genes. We found that these alleles promoted widely varying levels of C4A and C4B expression and associated with schizophrenia in proportion to their tendency to promote greater expression of C4A in the brain. Human C4 protein localized at neuronal synapses, Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Therapeutic interventions that incorporate training in mindfulness meditation have become increasingly popular, but to date little is known about neural mechanisms associated with these interventions. Mindfulness-Based Stress Reduction (MBSR), one of the most widely used mindfulness training programs, has been reported to produce positive effects on psychological well-being and to ameliorate symptoms of a number of disorders. Here, we report a controlled longitudinal study to investigate pre-post changes in brain gray matter concentration attributable to participation in an MBSR program. Anatomical magnetic resonance (MR) images from 16 healthy, meditation-naïve participants were obtained before and after they underwent the 8-week program. Changes in gray matter concentration were investigated using voxel-based morphometry, and compared with a waiting list control group of 17 individuals. Analyses in a priori regions of interest confirmed increases in gray matter concentration within the left hippocampus. Whole brain analyses identified increases in the posterior cingulate cortex, the temporo-parietal junction, and the cerebellum in the MBSR group compared with the controls. The results suggest that participation in MBSR is associated with changes in gray matter concentration in brain regions involved in learning and memory processes, emotion regulation, self-referential processing, and perspective taking.

Background and Purpose-Injury-induced cortical reorganization is a widely recognized phenomenon. In contrast, there is almost no information on treatment-induced plastic changes in the human brain. The aim of the present study was to evaluate reorganization in the motor cortex of stroke patients that was induced with an efficacious rehabilitation treatment. Methods-We used focal transcranial magnetic stimulation to map the cortical motor output area of a hand muscle on both sides in 13 stroke patients in the chronic stage of their illness before and after a 12-day-period of constraint-induced movement therapy. Results-Before treatment, the cortical representation area of the affected hand muscle was significantly smaller than the contralateral side. After treatment, the muscle output area size in the affected hemisphere was significantly enlarged, corresponding to a greatly improved motor performance of the paretic limb. Shifts of the center of the output map in the affected hemisphere suggested the recruitment of adjacent brain areas. In follow-up examinations up to 6 months after treatment, motor performance remained at a high level, whereas the cortical area sizes in the 2 hemispheres became almost identical, representing a return of the balance of excitability between the 2 hemispheres toward a normal condition. Conclusions-This is the first demonstration in humans of a long-term alteration in brain function associated with a therapy-induced improvement in the rehabilitation of movement after neurological injury. (Stroke. 2000;31:1210-1216.)

The cortical representations ofthe hand in area 3b in adult owl monkeys were defined with use of microelectrode mapping techniques 2-8 months after surgical amputation of digit 3, or of both digits 2 and 3. Digital nerves were tied to prevent their regeneration within the amputation stump. Successive maps were derived in several monkeys to determine the nature of changes in map organization in the same individuals over time.

Previous studies have shown that the tonotopic organization of primary auditory cortex is altered subsequent to restricted cochlear lesions (Robertson and Irvine, 1989) and that the topographic reorganization of the primary somatosensory cortex is correlated with changes in the perceptual acuity of the animal (Recanzone et al., 1992a-d). Here we report an increase in the cortical area of representation of a restricted frequency range in primary auditory cortex of adult owl monkeys that is correlated with the animal&#39;s performance at a frequency discrimination task. Monkeys trained for several weeks to discriminate small differences in the frequency of sequentially presented tonal stimuli revealed a progressive improvement in performance with training. At the end of the training period, the tonotopic organization of Al was defined by recording multiple-unit responses at 70-258 cortical locations. These responses were compared to those derived from three normal monkeys and from two...

Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing.

Human learning is a complex phenomenon requiring flexibility to adapt existing brain function and precision in selecting new neurophysiological activities to drive desired behavior [1, 2]. These two attributes -flexibility and selection -must operate over multiple temporal scales as performance of a skill changes from being slow and challenging to being fast and automatic [3, 4]. Such selective adaptability is naturally provided by modular structure [5, 6, 7], which plays a critical role in evolution [8], development [6], and optimal network function [7, 9]. Using functional connectivity measurements of brain activity acquired from initial training through mastery of a simple motor skill, we investigate the role of modularity in human learning by identifying dynamic changes of modular organization spanning multiple temporal scales. Our results indicate that flexibility, which we measure by the allegiance of nodes to modules, in one experimental session predicts the relative amount of learning in a future session. We also develop a general statistical framework for the identification of modular architectures in evolving systems, which is broadly applicable to disciplines where network adaptability is crucial to the understanding of system performance.

of mitochondria in the perinuclear region of cultured cells (Smirnova et al., 1998, 2001), and protect cells from apoptosis (Frank et al., 2001). To date, OPA1 and Drp1 functions have been studied only in nonneuronal cells, and their effects on neuronal mitochondria are unknown. It is generally believed that the intracellular distribution of mitochondria is adapted to cellular physiology. Cambridge, Massachusetts 02139 However, the functional significance of proper mitochondrial distribution within cells is largely unknown. This may be because experimental perturbations of mitochondrial distribution are usually performed in cell Summary lines with low morphological complexity, in which the consequences of improper mitochondrial targeting are The proper intracellular distribution of mitochondria is assumed to be critical for normal physiology of neu-difficult to assess. Neurons, on the other hand, are elongated cells with multiple compartments (e.g., dendrites, ronal cells, but direct evidence for this idea is lacking. Extension or movement of mitochondria into dendritic axons, and synapses) that are located far from the cell body. It should be easier to determine the effects of protrusions correlates with the development and morphological plasticity of spines. Molecular manipula-defective mitochondrial distribution in neurons, because certain cellular functions, such as synaptic transmission tions of dynamin-like GTPases Drp1 and OPA1 that reduce dendritic mitochondria content lead to loss of and plasticity, are mediated by distant subdomains that can become isolated from their nearest mitochondria. synapses and dendritic spines, whereas increasing dendritic mitochondrial content or mitochondrial ac-The local need for ATP and Ca 2ϩ handling is especially great at synapses, and mitochondria are frequently tivity enhances the number and plasticity of spines and synapses. Thus, the dendritic distribution of mito-found in axon terminals (Rowland et al., 2000; Shepherd and Harris, 1998). In the Drosophila mutant Milton, de-chondria is essential and limiting for the support of synapses. Reciprocally, synaptic activity modulates fective synaptic transmission is associated with the loss of mitochondria from axon terminals (Stowers et al., the motility and fusion/fission balance of mitochondria and controls mitochondrial distribution in dendrites. 2002), supporting the functional importance of presynaptically targeted mitochondria. On the postsynaptic side, however, little is known about the importance of Introduction proper mitochondrial distribution in dendrites. In contrast to the abundance of mitochondria in presynaptic Mitochondria are vital organelles present in all eukaryotic cells. In addition to carrying out aerobic respiration, terminals, mitochondria are rarely found in dendritic spines (Adams and Jones, 1982; Cameron et al., 1991; mitochondria function actively in the buffering of intracellular Ca 2ϩ and in the mechanisms of apoptosis. Mito-Chicurel and Harris, 1992), the postsynaptic compartment of most excitatory synapses. chondria usually exist as tubules of variable size that fuse, divide, and branch in a dynamic reticular network Mitochondria are believed to concentrate in subcellular regions with high metabolic requirements. For in-(Karbowski and Youle, 2003; Yaffe, 1999). Individual mitochondria can also move within the cytoplasm, thus stance, they accumulate in the vicinity of active growth cones of developing neurons (Morris and Hollenbeck, allowing them to distribute within cells and to partition between dividing cells (Yaffe, 1999). 1993). However, whether or how this subcellular distribution is regulated by neuronal activity is unknown. The fission and fusion of mitochondria is regulated by large GTPases of the dynamin family, in particular, To address these questions, we investigated the distribution of mitochondria in dendrites of living hippo-Drp1 (dynamin-related protein-1) and OPA1 (optic atro-phy1) (Westermann, 2002; Yoon and McNiven, 2001). campal neurons. Our studies reveal that mitochondria dynamically redistribute into dendritic protrusions in re-Drp1, a primarily cytoplasmic protein, regulates mitochondrial morphology and distribution but apparently sponse to synaptic excitation and correlated with synaptogenesis and spine formation. The dendritic distribu-does not affect the transport functions of the secretory and endocytic pathways (Pitts et al., 1999; Smirnova tion of mitochondria, which is regulated by Drp1, OPA1, and neuronal activity, appears to be an essential and et al., 1998). OPA1 protein is located in mitochondria (Olichon et al., 2002). Mutation of the OPA1 gene causes limiting factor for synapse density and plasticity. the most common form of hereditary optic atrophy (Delettre et al., 2002). By regulating mitochondrial fission/ Results fusion, Drp1 and OPA1 control the morphology and distribution of mitochondria (Misaka et al., 2002; Olichon Morphology and Distribution of Dendritic et al., 2003; Yaffe, 1999). Dominant-negative mutants of Mitochondria in Cultured Hippocampal Neurons Drp1 inhibit mitochondrial division, cause aggregation We used time-lapse confocal microscopy to study the distribution and movement of mitochondria labeled with "MitoDsRed" (DsRed2 fused to the mitochondrial tar-*Correspondence: [email protected] Cell 874

Behavioral and neurophysiological studies suggest that skill learning can be mediated by discrete, experience-driven changes within specific neural representations subserving the performance of the trained task. We have shown that a few minutes of daily practice on a sequential finger opposition task induced large, incremental performance gains over a few weeks of training. These gains did not generalize to the contralateral hand nor to a matched sequence of identical component movements, suggesting that a lateralized representation of the learned sequence of movements evolved through practice. This interpretation was supported by functional MRI data showing that a more extensive representation of the trained sequence emerged in primary motor cortex after 3 weeks of training. The imaging data, however, also indicated important changes occurring in primary motor cortex during the initial scanning sessions, which we proposed may ref lect the setting up of a task-specific motor processing routine. Here we provide behavioral and functional MRI data on experience-dependent changes induced by a limited amount of repetitions within the first imaging session. We show that this limited training experience can be sufficient to trigger performance gains that require time to become evident. We propose that skilled motor performance is acquired in several stages: "fast" learning, an initial, withinsession improvement phase, followed by a period of consolidation of several hours duration, and then "slow" learning, consisting of delayed, incremental gains in performance emerging after continued practice. This time course may ref lect basic mechanisms of neuronal plasticity in the adult brain that subserve the acquisition and retention of many different skills.

We found that a short exercise period enhanced cognitive function on the Morris water maze (MWM), such that exercised animals were significantly better than sedentary controls at learning and recalling the location of the platform. The finding that exercise increased brain-derived neurotrophic factor (BDNF), a molecule important for synaptic plasticity and learning and memory, impelled us to examine whether a BDNF-mediated mechanism subserves the capacity of exercise to improve hippocampal-dependent learning. A specific immunoadhesin chimera (TrkB-IgG), that mimics the BDNF receptor, TrkB, to selectively bind BDNF molecules, was used to block BDNF in the hippocampus during a 1-week voluntary exercise period. After this, a 2-trial-per-day MWM was performed for 5 consecutive days, succeeded by a probe trial 2 days later. By inhibiting BDNF action we blocked the benefit of exercise on cognitive function, such that the learning and recall abilities of exercising animals receiving the BDNF blocker were reduced to sedentary control levels. Inhibiting BDNF action also blocked the effect of exercise on downstream systems regulated by BDNF and important for synaptic plasticity, cAMP response-element-binding protein (CREB) and synapsin I. Specific to exercise, we found an association between CREB and BDNF expression and cognitive function, such that animals who were the fastest learners and had the best recall showed the highest expression of BDNF and associated CREB mRNA levels. These findings suggest a functional role for CREB under the control of BDNF in mediating the exercise-induced enhancement in learning and memory. Our results indicate that synapsin I might also contribute to this BDNF-mediated mechanism.

Several lines of investigation have helped clarify the role of GAP-43 (F1, B-50 or neuromodulin) in regulating the growth state of axon terminals. In transgenic mice, overexpression of GAP-43 leads to the spontaneous formation of new synapses and enhanced sprouting after injury. Null mutation of the GAP-43 gene disrupts axonal pathfinding and is generally lethal shortly after birth. Manipulations of GAP-43 expression likewise have profound effects on neurite outgrowth for cells in culture. GAP-43 appears to be involved in transducing intra-and extracellular signals to regulate cytoskeletal organization in the nerve ending. Phosphorylation by protein kinase C is particularly significant in this regard, and is linked with both nerve-terminal sprouting and long-term potentiation. In the brains of humans and other primates, high levels of GAP-43 persist in neocortical association areas and in the limbic system throughout life, where the protein might play an important role in mediating experience-dependent plasticity.

The natural history of recovery of motor function after stroke is described using data from a 1-year community-based study in Auckland, New Zealand. Of 680 patients, 88% presented with a hemiparesis; the proportion of survivors with a persisting deficit declined to 71% at 1 month and 62% at 6 months after the onset of the stroke. At onset, there were equal proportions of people with mild, moderate, and severe motor deficits, but the majority (76%) of those who survived 6 months had either no or only a mild deficit. Recovery of motor function was associated with the stroke severity but not with age or sex; patients with a mild motor deficit at onset were 10 times more likely to recover their motor function than those with a severe stroke. Our results confirm the reasonably optimistic outcome for survivors of stroke and further suggest that recovery of motor function is confined to patients whose motor deficit at onset is either mild or moderate.

In recent years, studies ranging from single-unit recordings in animals to electroencephalography and magnetoencephalography studies in humans have demonstrated the pivotal role of phase synchronization in memory processes. Phase synchronization - here referring to the synchronization of oscillatory phases between different brain regions - supports both working memory and long-term memory and acts by facilitating neural communication and by promoting neural plasticity. There is evidence that processes underlying working and long-term memory might interact in the medial temporal lobe. We propose that this is accomplished by neural operations involving phase-phase and phase-amplitude synchronization. A deeper understanding of how phase synchronization supports the flexibility of and interaction between memory systems may yield new insights into the functions of phase synchronization in general.

Converging evidence indicates that a profound reorganization of human brain function takes place during adolescence: the amount of deep sleep and the rate of brain metabolism fall sharply; the latency of certain event-related potentials declines; the capacity to recover function after brain injury diminishes;

samples treated as above or at llOO°C for >32 hours showed no trace of crystalline silicate by XRD and have very weak luminescence (in contrast to the films), and the optimal stoichiometry coincides with Gd3Ga5OI2. However, x-ray photoemission spectroscopy (XPS) and energy-dispersive xray analysis confirmed the presence of S i 0 2 in the sample. The measured percentage of SiO, in the sample was higher than that expected from the deposition stoichiometry, which suggests that SiO, is on the surfaces of the particles of Gd3Ga501,. XPS measurements also ruled out the presence of residual carbon in the sample. Consistent with these results, pure Gd,03, Ga,03 and Gd3Ga50,, thin films made on an LaA10, substrate using the same procedures showed no PL in the same spectral region.

profound changes in both sleep (23) and the sleep EEG (24, 25), with a major decrease in delta activity and increase in sleep fragmentation being the hallmarks of older age in humans (26). These changes parallel those of Rarb expression (27) in rats, suggesting a correlated tuning of both variables. We also hypothesize that both sleepiness and slow waves in the EEG induced by dopaminergic drugs (28) might be explained by the close interaction between the retinoic acid receptors and the mesolimbic dopaminergic pathway (11).