Showing papers in "The Journal of Neuroscience in 2006"
TL;DR: 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal Aβ42-induced neurodegeneration and amyloids plaque formation.
Abstract: Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase production of β-amyloid 42 (Aβ42) and cause familial Alzheimer's disease (FAD). Transgenic mice that express FAD mutant APP and PS1 overproduce Aβ42 and exhibit amyloid plaque pathology similar to that found in AD, but most transgenic models develop plaques slowly. To accelerate plaque development and investigate the effects of very high cerebral Aβ42 levels, we generated APP/PS1 double transgenic mice that coexpress five FAD mutations (5XFAD mice) and additively increase Aβ42 production. 5XFAD mice generate Aβ42 almost exclusively and rapidly accumulate massive cerebral Aβ42 levels. Amyloid deposition (and gliosis) begins at 2 months and reaches a very large burden, especially in subiculum and deep cortical layers. Intraneuronal Aβ42 accumulates in 5XFAD brain starting at 1.5 months of age (before plaques form), is aggregated (as determined by thioflavin S staining), and occurs within neuron soma and neurites. Some amyloid deposits originate within morphologically abnormal neuron soma that contain intraneuronal Aβ. Synaptic markers synaptophysin, syntaxin, and postsynaptic density-95 decrease with age in 5XFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum are lost. In addition, levels of the activation subunit of cyclin-dependent kinase 5, p25, are elevated significantly at 9 months in 5XFAD brain, although an upward trend is observed by 3 months of age, before significant neurodegeneration or neuron loss. Finally, 5XFAD mice have impaired memory in the Y-maze. Thus, 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal Aβ42-induced neurodegeneration and amyloid plaque formation.
2,471 citations
TL;DR: It is concluded that correlated, low-frequency oscillations in human fMRI data have a small-world architecture that probably reflects underlying anatomical connectivity of the cortex, and could provide a physiological substrate for segregated and distributed information processing.
Abstract: Small-world properties have been demonstrated for many complex networks. Here, we applied the discrete wavelet transform to functional magnetic resonance imaging (fMRI) time series, acquired from healthy volunteers in the resting state, to estimate frequency-dependent correlation matrices characterizing functional connectivity between 90 cortical and subcortical regions. After thresholding the wavelet correlation matrices to create undirected graphs of brain functional networks, we found a small-world topology of sparse connections most salient in the low-frequency interval 0.03–0.06 Hz. Global mean path length (2.49) was approximately equivalent to a comparable random network, whereas clustering (0.53) was two times greater; similar parameters have been reported for the network of anatomical connections in the macaque cortex. The human functional network was dominated by a neocortical core of highly connected hubs and had an exponentially truncated power law degree distribution. Hubs included recently evolved regions of the heteromodal association cortex, with long-distance connections to other regions, and more cliquishly connected regions of the unimodal association and primary cortices; paralimbic and limbic regions were topologically more peripheral. The network was more resilient to targeted attack on its hubs than a comparable scale-free network, but about equally resilient to random error. We conclude that correlated, low-frequency oscillations in human fMRI data have a small-world architecture that probably reflects underlying anatomical connectivity of the cortex. Because the major hubs of this network are critical for cognition, its slow dynamics could provide a physiological substrate for segregated and distributed information processing.
2,345 citations
TL;DR: Results provide convergent data for a role for the subthalamic nucleus in Stop-signal response inhibition and suggest that the speed of Go and Stop processes could relate to the relative activation of different neural pathways.
Abstract: Suppressing an already initiated manual response depends critically on the right inferior frontal cortex (IFC), yet it is unclear how this inhibitory function is implemented in the motor system. It has been suggested that the subthalamic nucleus (STN), which is a part of the basal ganglia, may play a role because it is well placed to suppress the “direct” fronto-striatal pathway that is activated by response initiation. In two experiments, we investigated this hypothesis with functional magnetic resonance imaging and a Stop-signal task. Subjects responded to Go signals and attempted to inhibit the initiated response to occasional Stop signals. In experiment 1, Going significantly activated frontal, striatal, pallidal, and motor cortical regions, consistent with the direct pathway, whereas Stopping significantly activated right IFC and STN. In addition, Stopping-related activation was significantly greater for fast inhibitors than slow ones in both IFC and STN, and activity in these regions was correlated across subjects. In experiment 2, high-resolution functional and structural imaging confirmed the location of Stopping activation within the vicinity of the STN. We propose that the role of the STN is to suppress thalamocortical output, thereby blocking Go response execution. These results provide convergent data for a role for the STN in Stop-signal response inhibition. They also suggest that the speed of Go and Stop processes could relate to the relative activation of different neural pathways. Future research is required to establish whether Stop-signal inhibition could be implemented via a direct functional neuroanatomic projection between IFC and STN (a “hyperdirect” pathway).
1,553 citations
TL;DR: Electroencephalography data indicate that collateral modulations of posterior α-activity, the momentary bias of visuospatial attention, and imminent visual processing are linked, and suggest that the Momentary direction of attention, predicting spatial biases in imminent visualprocessing, can be estimated from a lateralization index of posterior β-activity.
Abstract: Covertly directing visual attention toward a spatial location in the absence of visual stimulation enhances future visual processing at the attended position. The neuronal correlates of these attention shifts involve modulation of neuronal "baseline" activity in early visual areas, presumably through top-down control from higher-order attentional systems. We used electroencephalography to study the largely unknown relationship between these neuronal modulations and behavioral outcome in an attention orienting paradigm. Covert visuospatial attention shifts to either a left or right peripheral position in the absence of visual stimulation resulted in differential modulations of oscillatory alpha-band (8-14 Hz) activity over left versus right posterior sites. These changes were driven by varying degrees of alpha-decreases being maximal contralateral to the attended position. When expressed as a lateralization index, these alpha-changes differed significantly between attention conditions, with negative values (alpha_right < alpha_left) indexing leftward and more positive values (alpha_left < or = alpha_right) indexing rightward attention. Moreover, this index appeared deterministic for processing of forthcoming visual targets. Collapsed over trials, there was an advantage for left target processing in accordance with an overall negative bias in alpha-index values. Across trials, left targets were detected most rapidly when preceded by negative index values. Detection of right targets was fastest in trials with most positive values. Our data indicate that collateral modulations of posterior alpha-activity, the momentary bias of visuospatial attention, and imminent visual processing are linked. They suggest that the momentary direction of attention, predicting spatial biases in imminent visual processing, can be estimated from a lateralization index of posterior alpha-activity.
1,394 citations
TL;DR: The study reveals the key morphological transitions of newborn granule neurons during their course of maturation and shows that the morphological maturation is differentially affected by age and experience, as shown by comparisons between adult and postnatal brains and between housing conditions.
Abstract: Adult neurogenesis in the dentate gyrus may contribute to hippocampus-dependent functions, yet little is known about when and how newborn neurons are functional because of limited information about the time course of their connectivity. By using retrovirus-mediated gene transduction, we followed the dendritic and axonal growth of adult-born neurons in the mouse dentate gyrus and identified distinct morphological stages that may indicate different levels of connectivity. Axonal projections of newborn neurons reach the CA3 area 10–11 d after viral infection, 5–6 d before the first spines are formed. Quantitative analyses show that the peak of spine growth occurs during the first 3–4 weeks, but further structural modifications of newborn neurons take place for months. Moreover, the morphological maturation is differentially affected by age and experience, as shown by comparisons between adult and postnatal brains and between housing conditions. Our study reveals the key morphological transitions of newborn granule neurons during their course of maturation.
1,204 citations
TL;DR: It is suggested that maturing subcortical systems become disproportionately activated relative to later maturing top–down control systems, biasing the adolescent's action toward immediate over long-term gains.
Abstract: Adolescence has been characterized by risk-taking behaviors that can lead to fatal outcomes. This study examined the neurobiological development of neural systems implicated in reward-seeking behaviors. Thirty-seven participants (7-29 years of age) were scanned using event-related functional magnetic resonance imaging and a paradigm that parametrically manipulated reward values. The results show exaggerated accumbens activity, relative to prefrontal activity in adolescents, compared with children and adults, which appeared to be driven by different time courses of development for these regions. Accumbens activity in adolescents looked like that of adults in both extent of activity and sensitivity to reward values, although the magnitude of activity was exaggerated. In contrast, the extent of orbital frontal cortex activity in adolescents looked more like that of children than adults, with less focal patterns of activity. These findings suggest that maturing subcortical systems become disproportionately activated relative to later maturing top-down control systems, biasing the adolescent's action toward immediate over long-term gains.
1,179 citations
TL;DR: Evidence is provided that dopamine in the dorsal striatum is involved with craving and is a fundamental component of addiction, and strategies aimed at inhibiting dopamine increases from conditioned responses are likely to be therapeutically beneficial in cocaine addiction.
Abstract: The ability of drugs of abuse to increase dopamine in nucleus accumbens underlies their reinforcing effects. However, preclinical studies have shown that with repeated drug exposure neutral stimuli paired with the drug (conditioned stimuli) start to increase dopamine by themselves, which is an effect that could underlie drug-seeking behavior. Here we test whether dopamine increases occur to conditioned stimuli in human subjects addicted to cocaine and whether this is associated with drug craving. We tested eighteen cocaine-addicted subjects using positron emission tomography and [11C]raclopride (dopamine D2 receptor radioligand sensitive to competition with endogenous dopamine). We measured changes in dopamine by comparing the specific binding of [11C]raclopride when subjects watched a neutral video (nature scenes) versus when they watched a cocaine-cue video (scenes of subjects smoking cocaine). The specific binding of [11C]raclopride in dorsal (caudate and putamen) but not in ventral striatum (in which nucleus accumbens is located) was significantly reduced in the cocaine-cue condition and the magnitude of this reduction correlated with self-reports of craving. Moreover, subjects with the highest scores on measures of withdrawal symptoms and of addiction severity that have been shown to predict treatment outcomes, had the largest dopamine changes in dorsal striatum. This provides evidence that dopamine in the dorsal striatum (region implicated in habit learning and in action initiation) is involved with craving and is a fundamental component of addiction. Because craving is a key contributor to relapse, strategies aimed at inhibiting dopamine increases from conditioned responses are likely to be therapeutically beneficial in cocaine addiction.
1,095 citations
TL;DR: Individual differences yielded the predicted link between brain function while reducing negative affect in the laboratory and diurnal regulation of endocrine activity in the home environment.
Abstract: Among younger adults, the ability to willfully regulate negative affect, enabling effective responses to stressful experiences, engages regions of prefrontal cortex (PFC) and the amygdala. Because regions of PFC and the amygdala are known to influence the hypothalamic-pituitary-adrenal axis, here we test whether PFC and amygdala responses during emotion regulation predict the diurnal pattern of salivary cortisol secretion. We also test whether PFC and amygdala regions are engaged during emotion regulation in older (62- to 64-year-old) rather than younger individuals. We measured brain activity using functional magnetic resonance imaging as participants regulated (increased or decreased) their affective responses or attended to negative picture stimuli. We also collected saliva samples for 1 week at home for cortisol assay. Consistent with previous work in younger samples, increasing negative affect resulted in ventral lateral, dorsolateral, and dorsomedial regions of PFC and amygdala activation. In contrast to previous work, decreasing negative affect did not produce the predicted robust pattern of higher PFC and lower amygdala activation. Individuals demonstrating the predicted effect (decrease < attend in the amygdala), however, exhibited higher signal in ventromedial prefrontal cortex (VMPFC) for the same contrast. Furthermore, participants displaying higher VMPFC and lower amygdala signal when decreasing compared with the attention control condition evidenced steeper, more normative declines in cortisol over the course of the day. Individual differences yielded the predicted link between brain function while reducing negative affect in the laboratory and diurnal regulation of endocrine activity in the home environment.
1,004 citations
TL;DR: An ongoing temporal evolution between excitation and inhibition, which exhibits remarkable proportionality within and across neurons in active local networks, may allow for rapid transitions between relatively stable network states, permitting the modulation of neuronal responsiveness in a behaviorally relevant manner.
Abstract: The recurrent excitatory and inhibitory connections between and within layers of the cerebral cortex are fundamental to the operation of local cortical circuits. Models of cortical function often assume that recurrent excitation and inhibition are balanced, and we recently demonstrated that spontaneous network activity in vitro contains a precise balance of excitation and inhibition; however, the existence of a balance between excitation and inhibition in the intact and spontaneously active cerebral cortex has not been directly tested. We examined this hypothesis in the prefrontal cortex in vivo , during the slow (
962 citations
TL;DR: The number of oligodendrocytes derived from type B cells in vivo increased fourfold after a demyelinating lesion in corpus callosum, indicating that SVZ astrocyes participate in myelin repair in the adult brain.
Abstract: Glial fibrillary acidic protein (GFAP)-positive astrocytes (type B cells) in the subventricular zone (SVZ) generate large numbers of new neurons in the adult brain. SVZ stem cells can also generate oligodendrocytes in vitro, but it is not known whether these adult primary progenitors generate oligodendrocytes in vivo. Myelin repair and oligodendrocyte formation in the adult brain is instead associated with glial-restricted progenitors cells, known as oligodendrocyte progenitor cells (OPCs). Here we show that type B cells also generate a small number of nonmyelinating NG2-positive OPCs and mature myelinating oligodendrocytes. Some type B cells and a small subpopulation of actively dividing type C (transit-amplifying) cells expressed oligodendrocyte lineage transcription factor 2 (Olig2), suggesting that oligodendrocyte differentiation in the SVZ begins early in the lineage. Olig2-positive, polysialylated neural cell adhesion molecule-positive, PDGF receptor α-positive, and β-tubulin-negative cells originating in the SVZ migrated into corpus callosum, striatum, and fimbria fornix to differentiate into the NG2-positive nonmyelinating and mature myelinating oligodendrocytes. Furthermore, primary clonal cultures of type B cells gave rise to oligodendrocytes alone or oligodendrocytes and neurons. Importantly, the number of oligodendrocytes derived from type B cells in vivo increased fourfold after a demyelinating lesion in corpus callosum, indicating that SVZ astrocytes participate in myelin repair in the adult brain. Our work identifies SVZ type B cells as progenitors of oligodendrocytes in normal and injured adult brain.
953 citations
TL;DR: This picture provides a rigorous and quantitative explanation for the dependence of performance and response time on the degree of task difficulty, and the reason for which reaction times are longer in error trials than in correct trials as observed in the monkey experiment.
Abstract: Recent physiological studies using behaving monkeys revealed that, in a two-alternative forced-choice visual motion discrimination task, reaction time was correlated with ramping of spike activity of lateral intraparietal cortical neurons. The ramping activity appears to reflect temporal accumulation, on a timescale of hundreds of milliseconds, of sensory evidence before a decision is reached. To elucidate the cellular and circuit basis of such integration times, we developed and investigated a simplified two-variable version of a biophysically realistic cortical network model of decision making. In this model, slow time integration can be achieved robustly if excitatory reverberation is primarily mediated by NMDA receptors; our model with only fast AMPA receptors at recurrent synapses produces decision times that are not comparable with experimental observations. Moreover, we found two distinct modes of network behavior, in which decision computation by winner-take-all competition is instantiated with or without attractor states for working memory. Decision process is closely linked to the local dynamics, in the "decision space" of the system, in the vicinity of an unstable saddle steady state that separates the basins of attraction for the two alternative choices. This picture provides a rigorous and quantitative explanation for the dependence of performance and response time on the degree of task difficulty, and the reason for which reaction times are longer in error trials than in correct trials as observed in the monkey experiment. Our reduced two-variable neural model offers a simple yet biophysically plausible framework for studying perceptual decision making in general.
TL;DR: This study provides the first direct evidence that dendritic remodeling in the prefrontal cortex may underlie the functional deficits in attentional control that are symptomatic of stress-related mental illnesses.
Abstract: Stressful life events have been implicated clinically in the pathogenesis of mental illness, but the neural substrates that may account for this observation remain poorly understood. Attentional impairments symptomatic of these psychiatric conditions are associated with structural and functional abnormalities in a network of prefrontal cortical structures. Here, we examine whether chronic stress-induced dendritic alterations in the medial prefrontal cortex (mPFC) and orbital frontal cortex (OFC) underlie impairments in the behaviors that they subserve. After 21 d of repeated restraint stress, rats were tested on a perceptual attentional set-shifting task, which yields dissociable measures of reversal learning and attentional set-shifting, functions that are mediated by the OFC and mPFC, respectively. Intracellular iontophoretic injections of Lucifer yellow were performed in a subset of these rats to examine dendritic morphology in layer II/III pyramidal cells of the mPFC and lateral OFC. Chronic stress induced a selective impairment in attentional set-shifting and a corresponding retraction (20%) of apical dendritic arbors in the mPFC. In stressed rats, but not in controls, decreased dendritic arborization in the mPFC predicted impaired attentional set-shifting performance. In contrast, stress was not found to adversely affect reversal learning or dendritic morphology in the lateral OFC. Instead, apical dendritic arborization in the OFC was increased by 43%. This study provides the first direct evidence that dendritic remodeling in the prefrontal cortex may underlie the functional deficits in attentional control that are symptomatic of stress-related mental illnesses.
TL;DR: Investigating the functional connectivity between the PCC and MFG/vACC during a working memory task and at rest by examining temporal correlations in magnetic resonance signal levels found the two regions were functionally connected in both conditions.
Abstract: Several brain areas show signal decreases during many different cognitive tasks in functional imaging studies, including the posterior cingulate cortex (PCC) and a medial frontal region incorporating portions of the medial frontal gyrus and ventral anterior cingulate cortex (MFG/vACC). It has been suggested that these areas are components in a default mode network that is engaged during rest and disengaged during cognitive tasks. This study investigated the functional connectivity between the PCC and MFG/vACC during a working memory task and at rest by examining temporal correlations in magnetic resonance signal levels between the regions. The two regions were functionally connected in both conditions. In addition, performance on the working memory task was positively correlated with the strength of this functional connection not only during the working memory task, but also at rest. Thus, it appears these regions are components of a network that may facilitate or monitor cognitive performance, rather than becoming disengaged during cognitive tasks. In addition, these data raise the possibility that the individual differences in coupling strength between these two regions at rest predict differences in cognitive abilities important for this working memory task.
TL;DR: A novel brain environment for neuronal regeneration after stroke is defined and molecular mechanisms that are shared between angiogenesis and neurogenesis during functional recovery from brain injury are identified.
Abstract: Stroke causes cell death but also birth and migration of new neurons within sites of ischemic damage. The cellular environment that induces neuronal regeneration and migration after stroke has not been defined. We have used a model of long-distance migration of newly born neurons from the subventricular zone to cortex after stroke to define the cellular cues that induce neuronal regeneration after CNS injury. Mitotic, genetic, and viral labeling and chemokine/growth factor gain- and loss-of-function studies show that stroke induces neurogenesis from a GFAP-expressing progenitor cell in the subventricular zone and migration of newly born neurons into a unique neurovascular niche in peri-infarct cortex. Within this neurovascular niche, newly born, immature neurons closely associate with the remodeling vasculature. Neurogenesis and angiogenesis are causally linked through vascular production of stromal-derived factor 1 (SDF1) and angiopoietin 1 (Ang1). Furthermore, SDF1 and Ang1 promote post-stroke neuroblast migration and behavioral recovery. These experiments define a novel brain environment for neuronal regeneration after stroke and identify molecular mechanisms that are shared between angiogenesis and neurogenesis during functional recovery from brain injury.
TL;DR: Key recent advances that unite optical and genetic approaches are explored, focusing on promising techniques that either allow novel studies of neural dynamics and behavior or provide fresh perspectives on classic model systems.
Abstract: Emerging technologies from optics, genetics, and bioengineering are being combined for studies of intact neural circuits. The rapid progression of such interdisciplinary "optogenetic" approaches has expanded capabilities for optical imaging and genetic targeting of specific cell types. Here we explore key recent advances that unite optical and genetic approaches, focusing on promising techniques that either allow novel studies of neural dynamics and behavior or provide fresh perspectives on classic model systems.
TL;DR: It is demonstrated that the effects of maternal immune challenge between middle and late gestation periods in mice are dissociable in terms of fetal brain cytokine responses to maternal inflammation and the pathological consequences in brain and behavior.
Abstract: Disturbance to early brain development is implicated in several neuropsychiatric disorders including autism, schizophrenia, and mental retardation. Epidemiological studies have indicated that the risk of developing these disorders is enhanced by prenatal maternal infection, presumably as a result of neurodevelopmental defects triggered by cytokine-related inflammatory events. Here, we demonstrate that the effects of maternal immune challenge between middle and late gestation periods in mice are dissociable in terms of fetal brain cytokine responses to maternal inflammation and the pathological consequences in brain and behavior. Specifically, the relative expression of pro- and anti-inflammatory cytokines in the fetal brains in response to maternal immune challenge may be an important determinant among other developmental factors for the precise pathological profile emerging in later life. Thus, the middle and late gestation periods correspond to two windows with differing vulnerability to adult behavioral dysfunction, brain neuropathology in early adolescence, and of the acute cytokine responses in the fetal brain.
TL;DR: It is suggested that abnormal accumulation of APP across mitochondrial import channels, causing mitochondrial dysfunction, is a hallmark of human AD pathology.
Abstract: Mitochondrial dysfunction is one of the major intracellular lesions of Alzheimer's disease (AD). However, the causative factors involved in the mitochondrial dysfunction in human AD are not well understood. Here we report that nonglycosylated full-length and C-terminal truncated amyloid precursor protein (APP) accumulates exclusively in the protein import channels of mitochondria of human AD brains but not in age-matched controls. Furthermore, in AD brains, mitochondrially associated APP formed stable approximately 480 kDa complexes with the translocase of the outer mitochondrial membrane 40 (TOM40) import channel and a super complex of approximately 620 kDa with both mitochondrial TOM40 and the translocase of the inner mitochondrial membrane 23 (TIM23) import channel TIM23 in an "N(in mitochondria)-C(out cytoplasm)" orientation. Accumulation of APP across mitochondrial import channels, which varied with the severity of AD, inhibited the entry of nuclear-encoded cytochrome c oxidase subunits IV and Vb proteins, which was associated with decreased cytochrome c oxidase activity and increased levels of H2O2. Regional distribution of mitochondrial APP showed higher levels in AD-vulnerable brain regions, such as the frontal cortex, hippocampus, and amygdala. Mitochondrial accumulation of APP was also observed in the cholinergic, dopaminergic, GABAergic, and glutamatergic neuronal types in the category III AD brains. The levels of translocationally arrested mitochondrial APP directly correlated with mitochondrial dysfunction. Moreover, apolipoprotein genotype analysis revealed that AD subjects with the E3/E4 alleles had the highest content of mitochondrial APP. Collectively, these results suggest that abnormal accumulation of APP across mitochondrial import channels, causing mitochondrial dysfunction, is a hallmark of human AD pathology.
TL;DR: The results indicate that explicit strategies cannot substitute for implicit adaptation to a visuomotor rotation and are in fact overridden by the motor planning system, suggesting that the motor system requires that planned and executed trajectories remain congruous in visual space, and enforces this correspondence even at the expense of an opposing explicit task goal.
Abstract: The relationship between implicit and explicit processes during motor learning, and for visuomotor adaptation in particular, is poorly understood. We set up a conflict between implicit and explicit processes by instructing subjects to counter a visuomotor rotation using a cognitive strategy in a pointing task. Specifically, they were told the exact nature of the directional perturbation, a rotation that directed them 45° counterclockwise from the desired target, and they were instructed to counter it by aiming for the neighboring clockwise target, 45° away. Subjects were initially successful in completely negating the rotation with this strategy. Surprisingly, however, they were unable to sustain explicit control and made increasingly large errors to the desired target. The cognitive strategy failed because subjects simultaneously adapted unconsciously to the rotation to the neighboring target. Notably, the rate of implicit adaptation to the neighboring target was not significantly different from rotation adaptation in the absence of an opposing explicit strategy. These results indicate that explicit strategies cannot substitute for implicit adaptation to a visuomotor rotation and are in fact overridden by the motor planning system. This suggests that the motor system requires that planned and executed trajectories remain congruous in visual space, and enforces this correspondence even at the expense of an opposing explicit task goal.
TL;DR: These findings show that the rostral striatum is in a unique position to mediate different aspects of incentive learning, and areas of convergence may be particularly sensitive to dopamine modulation during decision making and habit formation.
Abstract: The anterior cingulate and orbital cortices and the ventral striatum process different aspects of reward evaluation, whereas the dorsolateral prefrontal cortex and the dorsal striatum are involved in cognitive function. Collectively, these areas are critical to decision making. We mapped the striatal area that receives information about reward evaluation. We also explored the extent to which terminals from reward-related cortical areas converge in the striatum with those from cognitive regions. Using three-dimensional-rendered reconstructions of corticostriatal projection fields along with two-dimensional chartings, we demonstrate the reward and cognitive territories in the primate striatum and show the convergence between these cortical inputs. The results show two labeling patterns: a focal projection field that consists of densely distributed terminal patches, and a diffuse projection consisting of clusters of fibers, extending throughout a wide area of the striatum. Together, these projection fields demonstrate a remarkably large, rostral, reward-related striatal territory that reaches into the dorsal striatum. Fibers from different reward-processing and cognitive cortical areas occupy both separate and converging territories. Furthermore, the diffuse projection may serve a separate integrative function by broadly disseminating general cortical activity. These findings show that the rostral striatum is in a unique position to mediate different aspects of incentive learning. Furthermore, areas of convergence may be particularly sensitive to dopamine modulation during decision making and habit formation.
TL;DR: The results indicate that the acquisition of a great amount of highly abstract information may be related to a particular pattern of structural gray matter changes in particular brain areas.
Abstract: The current view regarding human long-term memory as an active process of encoding and retrieval includes a highly specific learning-induced functional plasticity in a network of multiple memory systems. Voxel-based morphometry was used to detect possible structural brain changes associated with learning. Magnetic resonance images were obtained at three different time points while medical students learned for their medical examination. During the learning period, the gray matter increased significantly in the posterior and lateral parietal cortex bilaterally. These structural changes did not change significantly toward the third scan during the semester break 3 months after the exam. The posterior hippocampus showed a different pattern over time: the initial increase in gray matter during the learning period was even more pronounced toward the third time point. These results indicate that the acquisition of a great amount of highly abstract information may be related to a particular pattern of structural gray matter changes in particular brain areas.
TL;DR: It is suggested that subjective spontaneous pain of CBP involves specific spatiotemporal neuronal mechanisms, distinct from those observed for acute experimental pain, implicating a salient role for emotional brain concerning the self.
Abstract: Living with unrelenting pain (chronic pain) is maladaptive and is thought to be associated with physiological and psychological modifications, yet there is a lack of knowledge regarding brain elements involved in such conditions. Here, we identify brain regions involved in spontaneous pain of chronic back pain (CBP) in two separate groups of patients (n = 13 and n = 11), and contrast brain activity between spontaneous pain and thermal pain (CBP and healthy subjects, n = 11 each). Continuous ratings of fluctuations of spontaneous pain during functional magnetic resonance imaging were separated into two components: high sustained pain and increasing pain. Sustained high pain of CBP resulted in increased activity in the medial prefrontal cortex (mPFC; including rostral anterior cingulate). This mPFC activity was strongly related to intensity of CBP, and the region is known to be involved in negative emotions, response conflict, and detection of unfavorable outcomes, especially in relation to the self. In contrast, the increasing phase of CBP transiently activated brain regions commonly observed for acute pain, best exemplified by the insula, which tightly reflected duration of CBP. When spontaneous pain of CBP was contrasted to thermal stimulation, we observe a double-dissociation between mPFC and insula with the former correlating only to intensity of spontaneous pain and the latter correlating only to pain intensity for thermal stimulation. These findings suggest that subjective spontaneous pain of CBP involves specific spatiotemporal neuronal mechanisms, distinct from those observed for acute experimental pain, implicating a salient role for emotional brain concerning the self.
TL;DR: Reduced complex I function in PD brain mitochondria appears to arise from oxidation of its catalytic subunits from internal processes, not from external oxidative stress, and correlates with complex I misassembly.
Abstract: Loss of mitochondrial complex I catalytic activity in the electron transport chain (ETC) is found in multiple tissues from individuals with sporadic Parkinson's disease (PD) and is a property of some PD model neurotoxins. Using special ETC subunit-specific and complex I immunocapture antibodies directed against the entire complex I macroassembly, we quantified ETC proteins and protein oxidation of complex I subunits in brain mitochondria from 10 PD and 12 age-matched control (CTL) samples. We measured nicotinamide adenine dinucleotide (NADH)-driven electron transfer rates through complex I and correlated these with complex I subunit oxidation levels and reductions of its 8 kDa subunit. PD brain complex I shows 11% increase in ND6, 34% decrease in its 8 kDa subunit and contains 47% more protein carbonyls localized to catalytic subunits coded for by mitochondrial and nuclear genomes We found no changes in levels of ETC proteins from complexes II-V. Oxidative damage patterns to PD complex I are reproduced by incubation of CTL brain mitochondria with NADH in the presence of rotenone but not by exogenous oxidant. NADH-driven electron transfer rates through complex I inversely correlate with complex I protein oxidation status and positively correlate with reduction in PD 8 kDa subunit. Reduced complex I function in PD brain mitochondria appears to arise from oxidation of its catalytic subunits from internal processes, not from external oxidative stress, and correlates with complex I misassembly. This complex I auto-oxidation may derive from abnormalities in mitochondrial or nuclear encoded subunits, complex I assembly factors, rotenone-like complex I toxins, or some combination.
TL;DR: Evidence is reported that, after a stroke, subventricular zone GFAP-expressing cells are capable of producing new neurons outside the olfactory bulbs, and long-term tracing of the green fluorescent-labeled cells revealed that the SVZ-derived neuroblasts differentiated into mature neurons in the striatum, in which they expressed neuronal-specific nuclear protein and formed synapses with neighboring striatal cells.
Abstract: Recent studies have revealed that the adult mammalian brain has the capacity to regenerate some neurons after various insults. However, the precise mechanism of insult-induced neurogenesis has not been demonstrated. In the normal brain, GFAP-expressing cells in the subventricular zone (SVZ) of the lateral ventricles include a neurogenic cell population that gives rise to olfactory bulb neurons only. Herein, we report evidence that, after a stroke, these cells are capable of producing new neurons outside the olfactory bulbs. SVZ GFAP-expressing cells labeled by a cell-type-specific viral infection method were found to generate neuroblasts that migrated toward the injured striatum after middle cerebral artery occlusion. These neuroblasts in the striatum formed elongated chain-like cell aggregates similar to those in the normal SVZ, and these chains were observed to be closely associated with thin astrocytic processes and blood vessels. Finally, long-term tracing of the green fluorescent-labeled cells with a Cre-loxP system revealed that the SVZ-derived neuroblasts differentiated into mature neurons in the striatum, in which they expressed neuronal-specific nuclear protein and formed synapses with neighboring striatal cells. These results highlight the role of the SVZ in neuronal regeneration after a stroke and its potential as an important therapeutic target for various neurological disorders.
TL;DR: These data may also provide functional evidence of the interaction between neocortical and medial temporal lobe pathology in early AD, and suggest that loss of functional integrity of the hippocampal-based memory systems is directly related to alterations of neural activity in parietal regions seen over the course of MCI and AD.
Abstract: Memory function is likely subserved by multiple distributed neural networks, which are disrupted by the pathophysiological process of Alzheimer's disease (AD). In this study, we used multivariate analytic techniques to investigate memory-related functional magnetic resonance imaging (fMRI) activity in 52 individuals across the continuum of normal aging, mild cognitive impairment (MCI), and mild AD. Independent component analyses revealed specific memory-related networks that activated or deactivated during an associative memory paradigm. Across all subjects, hippocampal activation and parietal deactivation demonstrated a strong reciprocal relationship. Furthermore, we found evidence of a nonlinear trajectory of fMRI activation across the continuum of impairment. Less impaired MCI subjects showed paradoxical hyperactivation in the hippocampus compared with controls, whereas more impaired MCI subjects demonstrated significant hypoactivation, similar to the levels observed in the mild AD subjects. We found a remarkably parallel curve in the pattern of memory-related deactivation in medial and lateral parietal regions with greater deactivation in less-impaired MCI and loss of deactivation in more impaired MCI and mild AD subjects. Interestingly, the failure of deactivation in these regions was also associated with increased positive activity in a neocortical attentional network in MCI and AD. Our findings suggest that loss of functional integrity of the hippocampal-based memory systems is directly related to alterations of neural activity in parietal regions seen over the course of MCI and AD. These data may also provide functional evidence of the interaction between neocortical and medial temporal lobe pathology in early AD.
TL;DR: It is proposed that the theta activity is directly engaged in mnemonic operations and the increase in neuronal synchronization in the gamma band in occipital areas may result in a stronger drive to subsequent areas, thus facilitating both memory encoding and retrieval.
Abstract: Although studies in animals and patients have demonstrated that brain oscillations play a role in declarative memory encoding and retrieval, little has been done to investigate the temporal dynamics and sources of brain activity in healthy human subjects performing such tasks. In a magnetoencephalography study using pictorial stimuli, we have now identified oscillatory activity in the gamma (60-90 Hz) and theta (4.5-8.5 Hz) band during declarative memory operations in healthy participants. Both theta and gamma activity was stronger for the later remembered compared with the later forgotten items (the "subsequent memory effect"). In the retrieval session, theta and gamma activity was stronger for recognized items compared with correctly rejected new items (the "old/new effect"). The gamma activity was also stronger for recognized compared with forgotten old items (the "recognition effect"). The effects in the theta band were observed over right parietotemporal areas, whereas the sources of the effects in the gamma band were identified in Brodmann area 18/19. We propose that the theta activity is directly engaged in mnemonic operations. The increase in neuronal synchronization in the gamma band in occipital areas may result in a stronger drive to subsequent areas, thus facilitating both memory encoding and retrieval. Alternatively, the gamma synchronization might reflect representations being reinforced by top-down activity from higher-level memory areas. Our results provide additional insight on human declarative memory operations and oscillatory brain activity that complements previous electrophysiological and brain imaging studies.
TL;DR: The complex spatiotemporal characteristics of the muscles patterns for reaching were captured by the combinations of a small number of components, suggesting that the mechanisms involved in the generation of the muscle patterns exploit this low dimensionality to simplify control.
Abstract: How the CNS selects the appropriate muscle patterns to achieve a behavioral goal is an open question. To gain insight into this process, we characterized the spatiotemporal organization of the muscle patterns for fast-reaching movements. We recorded electromyographic activity from up to 19 shoulder and arm muscles during point-to-point movements between a central location and 8 peripheral targets in each of 2 vertical planes. We used an optimization algorithm to identify a set of time-varying muscle synergies, i.e., the coordinated activations of groups of muscles with specific time-varying profiles. For each one of nine subjects, we extracted four or five synergies whose combinations, after scaling in amplitude and shifting in time each synergy independently for each movement condition, explained 73–82% of the data variation. We then tested whether these synergies could reconstruct the muscle patterns for point-to-point movements with different loads or forearm postures and for reversal and via-point movements. We found that reconstruction accuracy remained high, indicating generalization across these conditions. Finally, the synergy amplitude coefficients were directionally tuned according to a cosine function with a preferred direction that showed a smaller variability with changes of load, posture, and endpoint than the preferred direction of individual muscles. Thus the complex spatiotemporal characteristics of the muscles patterns for reaching were captured by the combinations of a small number of components, suggesting that the mechanisms involved in the generation of the muscle patterns exploit this low dimensionality to simplify control.
TL;DR: A symmetric, locally connected neural network, or spin glass model, that spontaneously produces a hexagonal grid of activity bumps on a two-dimensional sheet of units is described that supports the conjecture that an attractor network in dMEC may be the source of path integration information afferent to hippocampus.
Abstract: Electrophysiological recording studies in the dorsocaudal region of medial entorhinal cortex (dMEC) of the rat reveal cells whose spatial firing fields show a remarkably regular hexagonal grid pattern (Fyhn et al., 2004; Hafting et al., 2005). We describe a symmetric, locally connected neural network, or spin glass model, that spontaneously produces a hexagonal grid of activity bumps on a two-dimensional sheet of units. The spatial firing fields of the simulated cells closely resemble those of dMEC cells. A collection of grids with different scales and/or orientations forms a basis set for encoding position. Simulations show that the animal's location can easily be determined from the population activity pattern. Introducing an asymmetry in the model allows the activity bumps to be shifted in any direction, at a rate proportional to velocity, to achieve path integration. Furthermore, information about the structure of the environment can be superimposed on the spatial position signal by modulation of the bump activity levels without significantly interfering with the hexagonal periodicity of firing fields. Our results support the conjecture of Hafting et al. (2005) that an attractor network in dMEC may be the source of path integration information afferent to hippocampus.
TL;DR: Mitochondria in neurons had terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive matrices and p53 at the outer membrane and A53T mutant mice develop intraneuronal inclusions, mitochondrial DNA damage and degeneration, and apoptotic-like death of neocortical, brainstem, and motor neurons.
Abstract: α-Synuclein (α-Syn) is enriched in nerve terminals. Two mutations in the α- Syn gene (Ala53→ Thr and Ala30→ Pro) occur in autosomal dominant familial Parkinson9s disease. Mice overexpressing the human A53T mutant α-Syn develop a severe movement disorder, paralysis, and synucleinopathy, but the mechanisms are not understood. We examined whether transgenic mice expressing human wild-type or familial Parkinson9s disease-linked A53T or A30P mutant α-syn develop neuronal degeneration and cell death. Mutant mice were examined at early- to mid-stage disease and at near end-stage disease. Age-matched nontransgenic littermates were controls. In A53T mice, neurons in brainstem and spinal cord exhibited large axonal swellings, somal chromatolytic changes, and nuclear condensation. Spheroid eosinophilic Lewy body-like inclusions were present in the cytoplasm of cortical neurons and spinal motor neurons. These inclusions contained human α-syn and nitrated synuclein. Motor neurons were depleted (∼75%) in A53T mice but were affected less in A30P mice. Axonal degeneration was present in many regions. Electron microscopy confirmed the cell and axonal degeneration and revealed cytoplasmic inclusions in dendrites and axons. Some inclusions were degenerating mitochondria and were positive for humanα-syn. Mitochondrial complex IV and V proteins were at control levels, but complex IV activity was reduced significantly in spinal cord. Subsets of neurons in neocortex, brainstem, and spinal cord ventral horn were positive for terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling, cleaved caspase-3, and p53. Mitochondria in neurons had terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive matrices and p53 at the outer membrane. Thus, A53T mutant mice develop intraneuronal inclusions, mitochondrial DNA damage and degeneration, and apoptotic-like death of neocortical, brainstem, and motor neurons.
TL;DR: A significant impairment of remyelination is found, attributable to an arrest of the differentiation and not the recruitment of oligodendrocyte precursor cells, which identifies myelin as an inhibitor of remYelination as well as its well documented inhibition of axon regeneration.
Abstract: Demyelination in the adult CNS can be followed by extensive repair. However, in multiple sclerosis, the differentiation of oligodendrocyte lineage cells present in demyelinated lesions is often inhibited by unknown factors. In this study, we test whether myelin debris, a feature of demyelinated lesions and an in vitro inhibitor of oligodendrocyte precursor differentiation, affects remyelination efficiency. Focal demyelinating lesions were created in the adult rat brainstem, and the naturally generated myelin debris was augmented by the addition of purified myelin. After quantification of myelin basic protein mRNA expression from lesion material obtained by laser capture microdissection and supported by histological data, we found a significant impairment of remyelination, attributable to an arrest of the differentiation and not the recruitment of oligodendrocyte precursor cells. These data identify myelin as an inhibitor of remyelination as well as its well documented inhibition of axon regeneration.
TL;DR: A triplet rule is examined, a rule which considers sets of three spikes and is possible to fit experimental data from visual cortical slices as well as from hippocampal cultures and can be mapped to a Bienenstock–Cooper–Munro learning rule.
Abstract: Classical experiments on spike timing-dependent plasticity (STDP) use a protocol based on pairs of presynaptic and postsynaptic spikes repeated at a given frequency to induce synaptic potentiation or depression. Therefore, standard STDP models have expressed the weight change as a function of pairs of presynaptic and postsynaptic spike. Unfortunately, those paired-based STDP models cannot account for the dependence on the repetition frequency of the pairs of spike. Moreover, those STDP models cannot reproduce recent triplet and quadruplet experiments. Here, we examine a triplet rule (i.e., a rule which considers sets of three spikes, i.e., two pre and one post or one pre and two post) and compare it to classical pair-based STDP learning rules. With such a triplet rule, it is possible to fit experimental data from visual cortical slices as well as from hippocampal cultures. Moreover, when assuming stochastic spike trains, the triplet learning rule can be mapped to a Bienenstock–Cooper–Munro learning rule.