In the nervous system, the induction of plasticity is coded by patterns of synaptic activity. Glial cells are now recognized as dynamic partners in a wide variety of brain functions, including the induction and modulation of various forms of synaptic plasticity. However, it appears that glial cells are usually activated by stereotyped, sustained neuronal activity, and little attention has been given to more subtle changes in the patterns of synaptic activation. To this end, we used the mouse neuromuscular junction as a simple and useful model to study glial modulation of synaptic plasticity. We used two patterns of motor nerve stimulation that mimic endogenous motor-neuronal activity. A continuous stimulation induced a post-tetanic potentiation and a phasic Ca(2+) response in perisynaptic Schwann cells (PSCs), glial cells at this synapse. A bursting pattern of activity induced a post-tetanic depression and oscillatory Ca(2+) responses in PSCs. The different Ca(2+) responses in PSCs indicate that they decode the pattern of synaptic activity. Furthermore, the chelation of glial Ca(2+) impaired the production of the sustained plasticity events indicating that PSCs govern the outcome of synaptic plasticity. The mechanisms involved were studied using direct photo-activation of PSCs with caged Ca(2+) that mimicked endogenous plasticity. Using specific pharmacology and transgenic knock-out animals for adenosine receptors, we showed that the sustained depression was mediated by A1 receptors while the sustained potentiation is mediated by A(2A) receptors. These results demonstrate that glial cells decode the pattern of synaptic activity and subsequently provide bidirectional feedback to synapses.

Cortical axons contain a diverse range of voltage-activated ion channels, including Ca(2+) currents. Interestingly, Ca(2+) channels are not only located at presynaptic terminals, but also in the axon initial segment (AIS), suggesting a potentially important role in the regulation of action potential generation and neuronal excitability. Here, using two-photon microscopy and whole-cell patch-clamp recording, we examined the properties and role of calcium channels located in the AIS and presynaptic terminals of ferret layer 5 prefrontal cortical pyramidal cells in vitro. Subthreshold depolarization of the soma resulted in an increase in baseline and spike-triggered calcium concentration in both the AIS and nearby synaptic terminals. The increase in baseline calcium concentration rose with depolarization and fell with hyperpolarization with a time constant of approximately 1 s and was blocked by removal of Ca(2+) from the bathing medium. The increases in calcium concentration at the AIS evoked by subthreshold or suprathreshold depolarization of the soma were blocked by the P/Q-channel antagonist omega-agatoxin IVA or the N-channel antagonist omega-conotoxin GVIA or both. The presence of these channels in the AIS pyramidal cells was confirmed with immunochemistry. Block of these channels slowed axonal action potential repolarization, apparently from reduction of the activation of a Ca(2+)-activated K(+) current, and increased neuronal excitability. These results demonstrate novel mechanisms by which calcium currents may control the electrophysiological properties of axonal spike generation and neurotransmitter release in the neocortex.

Locus ceruleus (LC) is the main subcortical site of norepinephrine synthesis. In Alzheimer's disease (AD) patients and rodent models, degeneration of LC neurons and reduced levels of norepinephrine in LC projection areas are significantly correlated with the increase in amyloid plaques, neurofibrillary tangles, and severity of dementia. Activated microglia play a pivotal role in the progression of AD by either clearing amyloid beta peptide (Abeta) deposits through uptake of Abeta or releasing cytotoxic substances and proinflammatory cytokines. Here, we investigated the effect of norepinephrine on Abeta uptake and clearance by murine microglia and explored the underlying mechanisms. We found that murine microglia cell line N9 and primary microglia expressed beta(2) adrenergic receptor (AR) but not beta(1) and beta(3)AR. Norepinephrine and isoproterenol upregulated the expression of Abeta receptor mFPR2, a mouse homolog of human formyl peptide receptor FPR2, through activation of beta(2)AR in microglia. Norepinephrine also induced mFPR2 expression in mouse brain. Activation of beta(2)AR in microglia promoted Abeta(42) uptake through upregulation of mFPR2 and enhanced spontaneous cell migration but had no effect on cell migration in response to mFPR2 agonists. Furthermore, activation of beta(2)AR on microglia induced the expression of insulin-degrading enzyme and increased the degradation of Abeta(42). Mechanistic studies showed that isoproterenol induced mFPR2 expression through ERK1/2-NF-kappaB and p38-NF-kappaB signaling pathways. These findings suggest that noradrenergic innervation from LC is needed to maintain adequate Abeta uptake and clearance by microglia, and norepinephrine is a link between neuron and microglia to orchestrate the host response to Abeta in AD.

Although the calcium/calmodulin-activated phosphatase calcineurin may dephosphorylate many endocytic proteins, it is not considered a key molecule in mediating the major forms of endocytosis at synapses-slow, clathrin-dependent and the rapid, clathrin-independent endocytosis. Here we studied the role of calcineurin in endocytosis by reducing calcium influx, inhibiting calmodulin with pharmacological blockers and knockdown of calmodulin, and by inhibiting calcineurin with pharmacological blockers and knock-out of calcineurin. These manipulations significantly inhibited both rapid and slow endocytosis at the large calyx-type synapse in 7- to 10-d-old rats and mice, and slow, clathrin-dependent endocytosis at the conventional cultured hippocampal synapse of rats and mice. These results suggest that calcium influx during nerve firing activates calcium/calmodulin-dependent calcineurin, which controls the speed of both rapid and slow endocytosis at synapses by dephosphorylating endocytic proteins. The calcium/calmodulin/calcineurin signaling pathway may underlie regulation of endocytosis by nerve activity and calcium as reported at many synapses over the last several decades.

Fast-spiking perisomatic-inhibitory interneurons (PIIs) receive convergent excitation and mediate both feedforward and feedback inhibition in cortical microcircuits. However, it remains poorly understood how convergent excitatory inputs recruit PIIs to produce precisely timed inhibition. Here, we analyzed the interaction of inputs from the entorhinal cortex [perforant path (PP)] and from local granule cells [mossy fibers (MFs)] onto PIIs in the rat dentate gyrus (DG). PP stimulation alone activates PIIs with low temporal precision. Interestingly, when PP and MFs are coactivated with a 10 ms delay, PIIs discharge with precise timing. Moreover, repeated coactivation of the two inputs induces associative long-term potentiation (LTP) at MF synapses. Under these conditions, a single potentiated MF input is sufficient to recruit PIIs in a reliable and highly precise manner to provide feedback inhibition. MF-LTP depends on the discharge of PIIs, indicating Hebbian plasticity. However, MF-LTP is preserved when NMDA receptors are blocked but depends on transmission through Ca(2+)-permeable AMPA receptors (AMPARs). PP-PII synapses, in contrast, lack Ca(2+)-permeable AMPARs and do not show plasticity on associative activation. Thus, precise recruitment of PIIs requires excitation through MF-PII synapses during feedforward activation. We propose that associative plasticity at these synapses is a central mechanism that adjusts inhibition levels to maintain sparse activity and to improve signal-to-noise ratio in the DG network.

Sirt1 has been associated with various effects of calorie restriction, including an increase in lifespan. Here we show in mice that a central regulatory component in energy metabolism, the hypothalamic melanocortin system, is affected by Sirt1, which promotes the activity and connectivity of this system resulting in negative energy balance. In adult mice, the pharmacological inhibition of brain Sirt1 activity decreased Agrp neuronal activity and the inhibitory tone on the anorexigenic POMC neurons, as measured by the number of synaptic inputs to these neurons. When a Sirt1 inhibitor (EX-527) was injected either peripherally (i.p., 10 mg/kg) or directly into the brain (i.c.v., 1.5 nmol/mouse), it decreased both food intake during the dark cycle and ghrelin-induced food intake. This effect on feeding is mediated by upstream melanocortin receptors, because the MC4R antagonist, SHU9119, reversed Sirt1's effect on food intake. This action of Sirt1 required an appropriate shift in the mitochondrial redox state: in the absence of such an adaptation enabled by the mitochondrial protein, UCP2, Sirt1-induced cellular and behavioral responses were impaired. In accordance with the pharmacological results, the selective knock-out of Sirt1 in hypothalamic Agrp neurons through the use of Cre-Lox technology decreased electric responses of Agrp neurons to ghrelin and decreased food intake, leading to decreased lean mass, fat mass, and body weight. The present data indicate that Sirt1 has a central mode of action by acting on the NPY/Agrp neurons to affect body metabolism.

Parkinson's disease (PD) is a common neurodegenerative disease that involves the deterioration of dopaminergic neurons in the substantia nigra pars compacta. Although the etiology of PD remains poorly understood, recent genetic, postmortem, and experimental evidence shows that abnormal protein accumulation and subsequent aggregate formation are prominent features of both sporadic and familial PD. While proteasome dysfunction is observed in PD, diverse mutations in the parkin gene are linked to early-onset autosomal-recessive forms of familial PD. We demonstrate that parkin, an E3 ubiquitin ligase, activates the 26S proteasome in an E3 ligase activity-independent manner. Furthermore, an N-terminal ubiquitin-like domain within parkin is critical for the activation of the 26S proteasome through enhancing the interaction between 19S proteasomal subunits, whereas the PD-linked R42P mutant abolishes this action. The current findings point to a novel role for parkin for 26S proteasome assembly and suggest that parkin mutations contribute to the proteasomal dysfunction in PD.

Gating in the NMDA receptor is initiated in the extracellular ligand-binding domain (LBD) and is ultimately propagated via three linkers-S1-M1, M3-S2, and S2-M4-to the ion channel. M3-S2 directly couples LBD movements into channel gating, but the functional and structural contributions of S1-M1 and S2-M4 to the overall gating process are unknown. A scan of substituted cysteines in and around the NMDA receptor S1-M1 and S2-M4 with a bulky cysteine-reactive reagent identified numerous positions that showed potentiation of glutamate-activated as well as leak currents. As indexed by MK801 (dizocilpine hydrogen maleate), an open channel blocker, this potentiation was attributable to an increase in open probability, an interpretation confirmed for a subset of positions with single-channel recordings. The magnitude of this gating effect, acting through S1-M1 or S2-M4, was dependent on the intrinsic gating properties of the NMDA receptors, being more effective in the inherently low open probability GluN2C- than the higher open probability GluN2A-subunit-containing receptors. For the majority of these potentiation positions, we propose that alteration of gating arises from steric destabilization of contact interfaces where close apposition of the contacting partners is necessary for efficient channel closure. Our results therefore indicate that the NMDA receptor S1-M1 and S2-M4 linkers are dynamic during gating and can modulate the overall energetics of this process. Furthermore, the results conceptualize a mechanistic, as well as a possible structural, framework for pharmacologically targeting the linkers through noncompetitive and subunit-specific modes of action.

Cocaine and amphetamine-regulated transcript peptide (CART) is present in a subset of sympathetic preganglionic neurons in the rat. We examined the distribution of CART-immunoreactive terminals in rat stellate and superior cervical ganglia and adrenal gland and found that they surround neuropeptide Y-immunoreactive postganglionic neurons and noradrenergic chromaffin cells. The targets of CART-immunoreactive preganglionic neurons in the stellate and superior cervical ganglia were shown to be vasoconstrictor neurons supplying muscle and skin and cardiac-projecting postganglionic neurons: they did not target non-vasoconstrictor neurons innervating salivary glands, piloerector muscle, brown fat, or adrenergic chromaffin cells. Transneuronal tracing using pseudorabies virus demonstrated that many, but not all, preganglionic neurons in the vasoconstrictor pathway to forelimb skeletal muscle were CART immunoreactive. Similarly, analysis with the confocal microscope confirmed that 70% of boutons in contact with vasoconstrictor ganglion cells contained CART, whereas 30% did not. Finally, we show that CART-immunoreactive cells represented 69% of the preganglionic neuron population expressing c-Fos after systemic hypoxia. We conclude that CART is present in most, although not all, cardiovascular preganglionic neurons but not thoracic preganglionic neurons with non-cardiovascular targets. We suggest that CART immunoreactivity may identify the postulated "accessory" preganglionic neurons, whose actions may amplify vasomotor ganglionic transmission.

The serotonin (5-HT) system in the brain has been studied more than any other neurotransmitter for its role in the neurobiological basis of aggression. However, which mechanisms modulate the 5-HT system to promote escalated aggression is not clear. We here explore the role of GABAergic modulation in the raphé nuclei, from which most 5-HT in the forebrain originates, on escalated aggression in male mice. Pharmacological activation of GABA(B), but not GABA(A), receptors in the dorsal raphé nucleus (DRN) escalated aggressive behaviors. In contrast, GABA agonists did not escalate aggressive behaviors after microinjection into the median raphé nucleus. The aggression-heightening effect of the GABA(B) agonist baclofen depended on the activation of 5-HT neurons in the DRN because it was blocked by coadministration of the 5-HT(1A) agonist 8-OH-DPAT [((+/-)-8-hydroxy-2-(di-n-propylamino)tetralin) hydrobromide] (DPAT), which acts on autoreceptors and inhibits 5-HT neural activity. In vivo microdialysis showed that GABA(B) activation in the DRN increased extracellular 5-HT level in the medial prefrontal cortex. This may be attributable to an indirect action via presynaptic GABA(B) receptors. The presynaptic GABA(B) receptors suppress Ca(2+) channel activity and inhibit neurotransmission, and the coadministration of N-type Ca(2+) channel blocker facilitated the effect of baclofen. These findings suggest that the indirect disinhibition of 5-HT neuron activity by presynaptic GABA(B) receptors on non-5-HT neurons in the DRN is one of the neurobiological mechanisms of escalated aggression.

Testosterone contributes to sex differences in hypothalamic-pituitary-adrenal (HPA) function in humans and rodents, but the central organization of this regulation remains unclear. The medial preoptic nucleus (MPN) stands out as an important candidate in this regard because it contains androgen receptors and projects to forebrain nuclei integrating cognitive-affective information and regulating HPA responses to homeostatic threat. These include the HPA effector neurons of the paraventricular nucleus (PVN) of the hypothalamus, medial amygdala, and lateral septum. To test the extent to which androgen receptors in the MPN engage these cell groups, we compared in adult male rats the effects of unilateral microimplants of testosterone and the androgen receptor antagonist hydroxyflutamide into the MPN on acute restraint induced activation and/or neuropeptide expression levels. The basic effects of these implants were lateralized to the sides of the nuclei ipsilateral to the implants. Testosterone, but not hydroxyflutamide implants, decreased stress-induced Fos and arginine vasopressin (AVP) heteronuclear RNA expression in the PVN, as well as Fos expression in the lateral septum. In unstressed animals, AVP mRNA expression in the PVN decreased and increased in response to testosterone and hydroxflutamide MPN implants, respectively. The differential influences of these implants on AVP mRNA expression were opposite in the medial amygdala. These results confirm a role for androgen receptors in the MPN to concurrently modulate neuropeptide expression and activational responses in the PVN and its extended circuitries. This suggests that the MPN is capable of bridging converging limbic influences to the HPA axis with changes in gonadal status.

Seizures induce excitatory shifts in the reversal potential for GABA(A)-receptor-mediated responses, which may contribute to the intractability of electro-encephalographic seizures and preclude the efficacy of widely used GABAergic anticonvulsants such as phenobarbital. We now report that, in intact hippocampi prepared from neonatal rats and transgenic mice expressing Clomeleon, recurrent seizures progressively increase the intracellular chloride concentration ([Cl(-)](i)) assayed by Clomeleon imaging and invert the net effect of GABA(A) receptor activation from inhibition to excitation assayed by the frequency of action potentials and intracellular Ca(2+) transients. These changes correlate with increasing frequency of seizure-like events and reduction in phenobarbital efficacy. The Na(+)-K(+)-2Cl(-) (NKCC1) cotransporter blocker bumetanide inhibited seizure-induced neuronal Cl(-) accumulation and the consequent facilitation of recurrent seizures. Our results demonstrate a novel mechanism by which seizure activity leads to [Cl(-)](i) accumulation, thereby increasing the probability of subsequent seizures. This provides a potential mechanism for the early crescendo phase of neonatal seizures.

Cocaine self-administration alters patterns of gene expression in the brain that may underlie cocaine-induced neuronal plasticity. In the present study, male Sprague Dawley rats were allowed to self-administer cocaine (0.25 mg/infusion) 2 h/d for 14 d, followed by 7 d of forced abstinence. Compared with yoked saline control rats, cocaine self-administration resulted in increased brain-derived neurotrophic factor (BDNF) protein levels in the rat medial prefrontal cortex (mPFC). To examine the functional relevance of this finding, cocaine self-administration maintained under a progressive ratio schedule of reinforcement was assessed after short hairpin RNA-induced suppression of BDNF expression in the mPFC. Decreased BDNF expression in the mPFC increased the cocaine self-administration breakpoint. Next, the effect of cocaine self-administration on specific BDNF exons was assessed; results revealed selectively increased BDNF exon IV-containing transcripts in the mPFC. Moreover, there were significant cocaine-induced increases in acetylated histone H3 (AcH3) and phospho-cAMP response element binding protein (pCREB) association with BDNF promoter IV. In contrast, there was decreased methyl-CpG-binding protein 2 (MeCP2) association with BDNF promoter IV in the mPFC of rats that previously self-administered cocaine. Together, these results indicate that cocaine-induced increases in BDNF promoter IV transcript in the mPFC are driven by increased binding of AcH3 and pCREB as well as decreased MeCP2 binding at this BDNF promoter. Collectively, these results indicate that cocaine self-administration remodels chromatin in the mPFC, resulting in increased expression of BDNF, which appears to represent a compensatory neuroadaptation that reduces the reinforcing efficacy of cocaine.

Small conductance Ca(2+)-activated K(+) type 2 (SK2) channels are expressed in the postsynaptic density of CA1 neurons where they are activated by synaptically evoked Ca(2+) influx to limit the size of EPSPs and spine Ca(2+) transients. At Schaffer collateral synapses, the induction of long-term potentiation (LTP) increases the alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate receptor (AMPAR)-mediated contribution to synaptic transmission and decreases the synaptic SK2 channel contribution through protein kinase A-dependent channel endocytosis. Using a combination of electrophysiology and immunoelectron microscopy in mice, the relationship between the dynamics of spine SK2 channels and AMPARs was investigated. Unlike AMPARs, synaptic SK2 channels under basal conditions do not rapidly recycle. Furthermore, SK2 channels occupy a distinct population of endosomes separate from AMPARs. However, blocking vesicular exocytosis or the delivery of synaptic GluA1-containing AMPARs during the induction of LTP blocks SK2 channel endocytosis. By approximately 2 h after the induction of LTP, synaptic SK2 channel expression and function are restored. Thus, LTP-dependent endocytosis of SK2 is coupled to LTP-dependent AMPA exocytosis, and the approximately 2 h window after the induction of LTP during which synaptic SK2 activity is absent may be important for consolidating the later phases of LTP.

In this time-resolved functional magnetic resonance imaging (fMRI) study, we aimed to trace the neuronal correlates of covert planning processes that precede visually guided motor behavior. Specifically, we asked whether human posterior parietal cortex has prospective planning activity that can be distinguished from activity related to retrospective visual memory and attention. Although various electrophysiological studies in monkeys have demonstrated such motor planning at the level of parietal neurons, comparatively little support is provided by recent human imaging experiments. Rather, a majority of experiments highlights a role of human posterior parietal cortex in visual working memory and attention. We thus sought to establish a clear separation of visual memory and attention from processes related to the planning of goal-directed motor behaviors. To this end, we compared delayed-response tasks with identical mnemonic and attentional demands but varying degrees of motor planning. Subjects memorized multiple target locations, and in a random subset of trials targets additionally instructed (1) desired goals or (2) undesired goals for upcoming finger reaches. Compared with the memory/attention-only conditions, both latter situations led to a specific increase of preparatory fMRI activity in posterior parietal and dorsal premotor cortex. Thus, posterior parietal cortex has prospective plans for upcoming behaviors while considering both types of targets relevant for action: those to be acquired and those to be avoided.

The recycling pathway is a major route for delivering signaling receptors to the somatodendritic plasma membrane. We investigated the cell biological basis for the remarkable selectivity and speed of this process. We focused on the mu-opioid neuropeptide receptor and the beta(2)-adrenergic catecholamine receptor, two seven-transmembrane signaling receptors that traverse the recycling pathway efficiently after ligand-induced endocytosis and localize at steady state throughout the postsynaptic surface. Rapid recycling of each receptor in dissociated neuronal cultures was mediated by a receptor-specific cytoplasmic sorting sequence. Total internal reflection fluorescence microscopy imaging revealed that both sequences drive recycling via discrete vesicular fusion events in the cell body and dendritic shaft. Both sequences promoted recycling via "transient"-type events characterized by nearly immediate lateral spread of receptors after vesicular insertion resembling receptor insertion events observed previously in non-neural cells. The sequences differed in their abilities to produce distinct "persistent"-type events at which inserted receptors lingered for a variable time period before lateral spread. Both types of insertion event generated a uniform distribution of receptors in the somatodendritic plasma membrane when imaged over a 1 min interval, but persistent events uniquely generated a punctate surface distribution over a 10 s interval. These results establish sequence-directed recycling of signaling receptors in CNS neurons and show that this mechanism has the ability to generate receptor-specific patterns of local surface distribution on a timescale overlapping that of rapid physiological signaling.

Interaural time differences (ITDs) are the primary cue for the localization of low-frequency sound sources in the azimuthal plane. For decades, it was assumed that the coding of ITDs in the mammalian brain was similar to that in the avian brain, where information is sparsely distributed across individual neurons, but recent studies have suggested otherwise. In this study, we characterized the representation of ITDs in adult male and female gerbils. First, we performed behavioral experiments to determine the acuity with which gerbils can use ITDs to localize sounds. Next, we used different decoders to infer ITDs from the activity of a population of neurons in central nucleus of the inferior colliculus. These results show that ITDs are not represented in a distributed manner, but rather in the summed activity of the entire population. To contrast these results with those from a population where the representation of ITDs is known to be sparsely distributed, we performed the same analysis on activity from the external nucleus of the inferior colliculus of adult male and female barn owls. Together, our results support the idea that, unlike the avian brain, the mammalian brain represents ITDs in the overall activity of a homogenous population of neurons within each hemisphere.

When we visualize scenes, either from our own past or invented, we impose a viewpoint for our "mind's eye" and we experience the resulting image as spatially coherent from that viewpoint. The hippocampus has been implicated in this process, but its precise contribution is unknown. We tested a specific hypothesis based on the spatial firing properties of neurons in the hippocampal formation of rats, that this region supports the construction of spatially coherent mental images by representing the locations of the environmental boundaries surrounding our viewpoint. Using functional magnetic resonance imaging, we show that hippocampal activation increases parametrically with the number of enclosing boundaries in the imagined scene. In contrast, hippocampal activity is not modulated by a nonspatial manipulation of scene complexity nor to increasing difficulty of imagining the scenes in general. Our findings identify a specific computational role for the hippocampus in mental imagery and episodic recollection.

Traumatic brain injury (TBI) is a major cause of epilepsy, yet the mechanisms underlying the progression from TBI to epilepsy are unknown. TBI induces the expression of COX-2 (cyclooxygenase-2) and increases levels of prostaglandin E2 (PGE2). Here, we demonstrate that acutely applied PGE2 (2 mum) decreases neocortical network activity by postsynaptically reducing excitatory synaptic transmission in acute and organotypic neocortical slices of mice. In contrast, long-term exposure to PGE2 (2 mum; 48 h) presynaptically increases excitatory synaptic transmission, leading to a hyperexcitable network state that is characterized by the generation of paroxysmal depolarization shifts (PDSs). PDSs were also evoked as a result of depriving organotypic slices of activity by treating them with tetrodotoxin (TTX, 1 mum; 48 h). This treatment predominantly increased postsynaptically excitatory synaptic transmission. The network and cellular effects of PGE2 and TTX treatments reversed within 1 week. Differences in the underlying mechanisms (presynaptic vs postsynaptic) as well as occlusion experiments in which slices were exposed to TTX plus PGE2 suggest that the two substances evoke distinct forms of homeostatic plasticity, both of which result in a hyperexcitable network state. PGE2 and TTX (alone or together with PGE2) also increased levels of apoptotic cell death in organotypic slices. Thus, we hypothesize that the increase in excitability and apoptosis may constitute the first steps in a cascade of events that eventually lead to epileptogenesis triggered by TBI.

Recent findings in neuroscience suggest that adult brain structure changes in response to environmental alterations and skill learning. Whereas much is known about structural changes after intensive practice for several months, little is known about the effects of single practice sessions on macroscopic brain structure and about progressive (dynamic) morphological alterations relative to improved task proficiency during learning for several weeks. Using T1-weighted and diffusion tensor imaging in humans, we demonstrate significant gray matter volume increases in frontal and parietal brain areas following only two sessions of practice in a complex whole-body balancing task. Gray matter volume increase in the prefrontal cortex correlated positively with subject's performance improvements during a 6 week learning period. Furthermore, we found that microstructural changes of fractional anisotropy in corresponding white matter regions followed the same temporal dynamic in relation to task performance. The results make clear how marginal alterations in our ever changing environment affect adult brain structure and elucidate the interrelated reorganization in cortical areas and associated fiber connections in correlation with improvements in task performance.