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Showing papers in "The Journal of Neuroscience in 2011"


Journal ArticleDOI
TL;DR: It is demonstrated that brain hubs form a so-called “rich club,” characterized by a tendency for high-degree nodes to be more densely connected among themselves than nodes of a lower degree, providing important information on the higher-level topology of the brain network.
Abstract: The human brain is a complex network of interlinked regions. Recent studies have demonstrated the existence of a number of highly connected and highly central neocortical hub regions, regions that play a key role in global information integration between different parts of the network. The potential functional importance of these “brain hubs” is underscored by recent studies showing that disturbances of their structural and functional connectivity profile are linked to neuropathology. This study aims to map out both the subcortical and neocortical hubs of the brain and examine their mutual relationship, particularly their structural linkages. Here, we demonstrate that brain hubs form a so-called “rich club,” characterized by a tendency for high-degree nodes to be more densely connected among themselves than nodes of a lower degree, providing important information on the higher-level topology of the brain network. Whole-brain structural networks of 21 subjects were reconstructed using diffusion tensor imaging data. Examining the connectivity profile of these networks revealed a group of 12 strongly interconnected bihemispheric hub regions, comprising the precuneus, superior frontal and superior parietal cortex, as well as the subcortical hippocampus, putamen, and thalamus. Importantly, these hub regions were found to be more densely interconnected than would be expected based solely on their degree, together forming a rich club. We discuss the potential functional implications of the rich-club organization of the human connectome, particularly in light of its role in information integration and in conferring robustness to its structural core.

2,089 citations


Journal ArticleDOI
TL;DR: The overall pattern in the myelin maps also has important correlations with the developmental onset of subcortical white matter myelination, evolutionary cortical areal expansion in human compared with macaques, postnatal cortical expansion in humans, and maps of neuronal density in non-human primates.
Abstract: Noninvasively mapping the layout of cortical areas in humans is a continuing challenge for neuroscience. We present a new method of mapping cortical areas based on myelin content as revealed by T1-weighted (T1w) and T2-weighted (T2w) MRI. The method is generalizable across different 3T scanners and pulse sequences. We use the ratio of T1w/T2w image intensities to eliminate the MR-related image intensity bias and enhance the contrast to noise ratio for myelin. Data from each subject were mapped to the cortical surface and aligned across individuals using surface-based registration. The spatial gradient of the group average myelin map provides an observer-independent measure of sharp transitions in myelin content across the surface--i.e., putative cortical areal borders. We found excellent agreement between the gradients of the myelin maps and the gradients of published probabilistic cytoarchitectonically defined cortical areas that were registered to the same surface-based atlas. For other cortical regions, we used published anatomical and functional information to make putative identifications of dozens of cortical areas or candidate areas. In general, primary and early unimodal association cortices are heavily myelinated and higher, multimodal, association cortices are more lightly myelinated, but there are notable exceptions in the literature that are confirmed by our results. The overall pattern in the myelin maps also has important correlations with the developmental onset of subcortical white matter myelination, evolutionary cortical areal expansion in humans compared with macaques, postnatal cortical expansion in humans, and maps of neuronal density in non-human primates.

1,176 citations


Journal ArticleDOI
TL;DR: Volume increased significantly with age for most tracts, and longitudinal measures also demonstrated postadolescent volume increases in several association tracts, which likely reflect microstructural maturation of brain white matter tracts rather than just gross anatomy.
Abstract: Healthy human brain development is a complex process that continues during childhood and adolescence, as demonstrated by many cross-sectional and several longitudinal studies. However, whether these changes end in adolescence is not clear. We examined longitudinal white matter maturation using diffusion tensor tractography in 103 healthy subjects aged 5–32 years; each volunteer was scanned at least twice, with 221 total scans. Fractional anisotropy (FA) and mean diffusivity (MD), parameters indicative of factors including myelination and axon density, were assessed in 10 major white matter tracts. All tracts showed significant nonlinear development trajectories for FA and MD. Significant within-subject changes occurred in the vast majority of children and early adolescents, and these changes were mostly complete by late adolescence for projection and commissural tracts. However, association tracts demonstrated postadolescent within-subject maturation of both FA and MD. Diffusion parameter changes were due primarily to decreasing perpendicular diffusivity, although increasing parallel diffusivity contributed to the prolonged increases of FA in association tracts. Volume increased significantly with age for most tracts, and longitudinal measures also demonstrated postadolescent volume increases in several association tracts. As volume increases were not directly associated with either elevated FA or reduced MD between scans, the observed diffusion parameter changes likely reflect microstructural maturation of brain white matter tracts rather than just gross anatomy.

1,031 citations


Journal ArticleDOI
TL;DR: This summary is not meant to be a comprehensive review of microglia physiology, but rather to share new results and stimulate further research into the cellular and molecular mechanisms by whichmicroglia influence postnatal development, adult neuronal plasticity, and circuit function.
Abstract: Microglia were recently shown to play unexpected roles in normal brain development and adult physiology. This has begun to dramatically change our view of these resident “immune” cells. Here, we briefly review topics covered in our 2011 Society for Neuroscience minisymposium “The Role of Microglia in the Healthy Brain.” This summary is not meant to be a comprehensive review of microglia physiology, but rather to share new results and stimulate further research into the cellular and molecular mechanisms by which microglia influence postnatal development, adult neuronal plasticity, and circuit function.

857 citations


Journal ArticleDOI
TL;DR: It is reported that in human subjects with tinnitus and a normal audiogram, auditory brainstem responses show a significantly reduced amplitude of the wave I potential but normal amplitudes of the more centrally generated wave V.
Abstract: Ever since Pliny the Elder coined the term tinnitus, the perception of sound in the absence of an external sound source has remained enigmatic. Traditional theories assume that tinnitus is triggered by cochlear damage, but many tinnitus patients present with a normal audiogram, i.e., with no direct signs of cochlear damage. Here, we report that in human subjects with tinnitus and a normal audiogram, auditory brainstem responses show a significantly reduced amplitude of the wave I potential (generated by primary auditory nerve fibers) but normal amplitudes of the more centrally generated wave V. This provides direct physiological evidence of "hidden hearing loss" that manifests as reduced neural output from the cochlea, and consequent renormalization of neuronal response magnitude within the brainstem. Employing an established computational model, we demonstrate how tinnitus could arise from a homeostatic response of neurons in the central auditory system to reduced auditory nerve input in the absence of elevated hearing thresholds.

774 citations


Journal ArticleDOI
TL;DR: The hippocampus plays a role in recognition memory when such memory involves remembering that a particular stimulus occurred in a particular place or when the memory contains a temporal or object recency component.
Abstract: The role of the hippocampus in recognition memory is controversial. Recognition memory judgments may be made using different types of information, including object familiarity, an object's spatial location, or when an object was encountered. Experiment 1 examined the role of the hippocampus in recognition memory tasks that required the animals to use these different types of mnemonic information. Rats with bilateral cytotoxic lesions in the hippocampus or perirhinal or prefrontal cortex were tested on a battery of spontaneous object recognition tasks requiring the animals to make recognition memory judgments using familiarity (novel object preference); object-place information (object-in-place memory), or recency information (temporal order memory). Experiment 2 examined whether, when using different types of recognition memory information, the hippocampus interacts with either the perirhinal or prefrontal cortex. Thus, groups of rats were prepared with a unilateral cytotoxic lesion in the hippocampus combined with a lesion in either the contralateral perirhinal or prefrontal cortex. Rats were then tested in a series of object recognition memory tasks. Experiment 1 revealed that the hippocampus was crucial for object location, object-in-place, and recency recognition memory, but not for the novel object preference task. Experiment 2 revealed that object-in-place and recency recognition memory performance depended on a functional interaction between the hippocampus and either the perirhinal or medial prefrontal cortices. Thus, the hippocampus plays a role in recognition memory when such memory involves remembering that a particular stimulus occurred in a particular place or when the memory contains a temporal or object recency component.

702 citations


Journal ArticleDOI
TL;DR: Results provide evidence that the posterior cingulate cortex is involved in supporting internally directed thought, as the region is more highly integrated with the DMN at low task demands.
Abstract: The posterior cingulate cortex (PCC) is a central part of the default mode network (DMN) and part of the structural core of the brain. Although the PCC often shows consistent deactivation when attention is focused on external events, anatomical studies show that the region is not homogeneous, and electrophysiological recordings in nonhuman primates suggest that it is directly involved in some forms of attention. We report a functional magnetic resonance imaging study of an attentionally demanding task (either a zero- or two-back working memory task). Standard subtraction analysis within the PCC shows a relative deactivation as task difficulty increases. In contrast, a dual-regression functional connectivity analysis reveals a clear dissociation between ventral and dorsal parts of the PCC. As task difficulty increases, the ventral PCC shows reduced integration within the DMN and less anticorrelation with the cognitive control network (CCN) activated by the task. The dorsal PCC shows an opposite pattern, with increased DMN integration and more anticorrelation. At rest, the dorsal PCC also shows functional connectivity with both the DMN and attentional networks. As expected, these results provide evidence that the PCC is involved in supporting internally directed thought, as the region is more highly integrated with the DMN at low task demands. In contrast, the task-dependent increases in connectivity between the dorsal PCC and the CCN are consistent with a role for this region in modulating the dynamic interaction between these two networks controlling the efficient allocation of attention.

681 citations


Journal ArticleDOI
TL;DR: The results suggest that the time scale of processing is a functional property that may provide a general organizing principle for the human cerebral cortex.
Abstract: Real-life activities, such as watching a movie or engaging in conversation, unfold over many minutes. In the course of such activities, the brain has to integrate information over multiple time scales. We recently proposed that the brain uses similar strategies for integrating information across space and over time. Drawing a parallel with spatial receptive fields, we defined the temporal receptive window (TRW) of a cortical microcircuit as the length of time before a response during which sensory information may affect that response. Our previous findings in the visual system are consistent with the hypothesis that TRWs become larger when moving from low-level sensory to high-level perceptual and cognitive areas. In this study, we mapped TRWs in auditory and language areas by measuring fMRI activity in subjects listening to a real-life story scrambled at the time scales of words, sentences, and paragraphs. Our results revealed a hierarchical topography of TRWs. In early auditory cortices (A1+), brain responses were driven mainly by the momentary incoming input and were similarly reliable across all scrambling conditions. In areas with an intermediate TRW, coherent information at the sentence time scale or longer was necessary to evoke reliable responses. At the apex of the TRW hierarchy, we found parietal and frontal areas that responded reliably only when intact paragraphs were heard in a meaningful sequence. These results suggest that the time scale of processing is a functional property that may provide a general organizing principle for the human cerebral cortex.

674 citations


Journal ArticleDOI
TL;DR: This work deconstructs cortical development to reveal that distinct trajectories of anatomical change are hidden within, and give rise to, a curvilinear pattern of CV maturation.
Abstract: Understanding human cortical maturation is a central goal for developmental neuroscience. Significant advances toward this goal have come from two recent strands of in vivo structural magnetic resonance imaging research: (1) longitudinal study designs have revealed that factors such as sex, cognitive ability, and disease are often better related to variations in the tempo of anatomical change than to variations in anatomy at any one time point; (2) largely cross-sectional applications of new surface-based morphometry (SBM) methods have shown how the traditional focus on cortical volume (CV) can obscure information about the two evolutionarily and genetically distinct determinants of CV: cortical thickness (CT) and surface area (SA). Here, by combining these two strategies for the first time and applying SBM in >1250 longitudinally acquired brain scans from 647 healthy individuals aged 3–30 years, we deconstruct cortical development to reveal that distinct trajectories of anatomical change are hidden within, and give rise to, a curvilinear pattern of CV maturation. Developmental changes in CV emerge through the sexually dimorphic and age-dependent interaction of changes in CT and SA. Moreover, SA change itself actually reflects complex interactions between brain size-related changes in exposed cortical convex hull area, and changes in the degree of cortical gyrification, which again vary by age and sex. Knowing of these developmental dissociations, and further specifying their timing and sex-biases, provides potent new research targets for basic and clinical neuroscience.

619 citations


Journal ArticleDOI
TL;DR: The results indicate that Aβ, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit.
Abstract: Alzheimer's disease (AD), the most common neurodegenerative disorder, is a growing public health problem and still lacks effective treatments. Recent evidence suggests that microtubule-associated protein tau may mediate amyloid-β peptide (Aβ) toxicity by modulating the tyrosine kinase Fyn. We showed previously that tau reduction prevents, and Fyn overexpression exacerbates, cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice overexpressing Aβ. However, the mechanisms by which Aβ, tau, and Fyn cooperate in AD-related pathogenesis remain to be fully elucidated. Here we examined the synaptic and network effects of this pathogenic triad. Tau reduction prevented cognitive decline induced by synergistic effects of Aβ and Fyn. Tau reduction also prevented synaptic transmission and plasticity deficits in hAPP mice. Using electroencephalography to examine network effects, we found that tau reduction prevented spontaneous epileptiform activity in multiple lines of hAPP mice. Tau reduction also reduced the severity of spontaneous and chemically induced seizures in mice overexpressing both Aβ and Fyn. To better understand these protective effects, we recorded whole-cell currents in acute hippocampal slices from hAPP mice with and without tau. hAPP mice with tau had increased spontaneous and evoked excitatory currents, reduced inhibitory currents, and NMDA receptor dysfunction. Tau reduction increased inhibitory currents and normalized excitation/inhibition balance and NMDA receptor-mediated currents in hAPP mice. Our results indicate that Aβ, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit.

580 citations


Journal ArticleDOI
TL;DR: In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.
Abstract: Type 2 diabetes is a risk factor for Alzheimer's disease, most likely linked to an impairment of insulin signaling in the brain. The incretin hormone glucagon-like peptide-1 (GLP-1) facilitates insulin signaling, and novel long-lasting GLP-1 analogs, such as liraglutide, are on the market as diabetes therapeutics. GLP-1 has been shown to have neuroprotective properties in vitro and in vivo. Here we tested the effects of peripherally injected liraglutide in an Alzheimer mouse model, APPswe/PS1ΔE9 (APP/PS1). Liraglutide was shown to cross the blood–brain barrier in an acute study. Liraglutide was injected for 8 weeks at 25 nmol/kg body weight i.p. once daily in 7-month-old APP/PS1 and wild-type littermate controls. In APP/PS1 mice, liraglutide prevented memory impairments in object recognition and water maze tasks, and prevented synapse loss and deterioration of synaptic plasticity in the hippocampus, commonly observed in this model. Overall β-amyloid plaque count in the cortex and dense-core plaque numbers were reduced by 40–50%, while levels of soluble amyloid oligomers were reduced by 25%. The inflammation response as measured by activated microglia numbers was halved in liraglutide-treated APP/PS1 mice. Numbers of young neurons in the dentate gyrus were increased in APP/PS1 mice with treatment. Liraglutide treatment had little effect on littermate control mice, whose behavior was comparable to wild-type saline controls; however, synaptic plasticity was enhanced in the drug group. Our results show that liraglutide prevents key neurodegenerative developments found in Alzheimer's disease, suggesting that GLP-1 analogs represent a novel treatment strategy for Alzheimer's disease.

Journal ArticleDOI
TL;DR: Soluble Aβ oligomers at low nanomolar levels present in AD brain increase activation of extrasynaptic NR2B-containing receptors, thereby impairing synaptic plasticity.
Abstract: In Alzheimer's disease (AD), dementia severity correlates strongly with decreased synapse density in hippocampus and cortex. Numerous studies report that hippocampal long-term potentiation (LTP) can be inhibited by soluble oligomers of amyloid β-protein (Aβ), but the synaptic elements that mediate this effect remain unclear. We examined field EPSPs and whole-cell recordings in wild-type mouse hippocampal slices. Soluble Aβ oligomers from three distinct sources (cultured cells, AD cortex, or synthetic peptide) inhibited LTP, and this was prevented by the selective NR2B inhibitors ifenprodil and Ro 25-6981. Soluble Aβ enhanced NR2B-mediated NMDA currents and extrasynaptic responses; these effects were mimicked by the glutamate reuptake inhibitor dl-threo-β-benzyloxyaspartic acid. Downstream, an Aβ-mediated rise in p38 mitogen-activated protein kinase (MAPK) activation was followed by downregulation of cAMP response element-binding protein, and LTP impairment was prevented by inhibitors of p38 MAPK or calpain. Thus, soluble Aβ oligomers at low nanomolar levels present in AD brain increase activation of extrasynaptic NR2B-containing receptors, thereby impairing synaptic plasticity.

Journal ArticleDOI
TL;DR: It is shown that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner.
Abstract: Psychosocial stress is associated with altered immune function and development of psychological disorders including anxiety and depression. Here we show that repeated social defeat in mice increased c-Fos staining in brain regions associated with fear and threat appraisal and promoted anxiety-like behavior in a β-adrenergic receptor-dependent manner. Repeated social defeat also significantly increased the number of CD11b+/CD45high/Ly6Chigh macrophages that trafficked to the brain. In addition, several inflammatory markers were increased on the surface of microglia (CD14, CD86, and TLR4) and macrophages (CD14 and CD86) after social defeat. Repeated social defeat also increased the presence of deramified microglia in the medial amygdala, prefrontal cortex, and hippocampus. Moreover, mRNA analysis of microglia indicated that repeated social defeat increased levels of interleukin (IL)-1β and reduced levels of glucocorticoid responsive genes [glucocorticoid-induced leucine zipper (GILZ) and FK506 binding protein-51 (FKBP51)]. The stress-dependent changes in microglia and macrophages were prevented by propranolol, a β-adrenergic receptor antagonist. Microglia isolated from socially defeated mice and cultured ex vivo produced markedly higher levels of IL-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 after stimulation with lipopolysaccharide compared with microglia from control mice. Last, repeated social defeat increased c-Fos activation in IL-1 receptor type-1-deficient mice, but did not promote anxiety-like behavior or microglia activation in the absence of functional IL-1 receptor type-1. These findings indicate that repeated social defeat-induced anxiety-like behavior and enhanced reactivity of microglia was dependent on activation of β-adrenergic and IL-1 receptors.

Journal ArticleDOI
TL;DR: The results reveal that under physiological conditions, disruption in CX3CL1 signaling will lead to impairment in cognitive function and synaptic plasticity via increased action of IL-1β.
Abstract: The protective/neurotoxic role of fractalkine (CX3CL1) and its receptor CX3C chemokine receptor 1 (CX3CR1) signaling in neurodegenerative disease is an intricate and highly debated research topic and it is becoming even more complicated as new studies reveal discordant results. It appears that the CX3CL1/CX3CR1 axis plays a direct role in neurodegeneration and/or neuroprotection depending on the CNS insult. However, all the above studies focused on the role of CX3CL1/CX3CR1 signaling in pathological conditions, ignoring the relevance of CX3CL1/CX3CR1 signaling under physiological conditions. No approach to date has been taken to decipher the significance of defects in CX3CL1/CX3CR1 signaling in physiological condition. In the present study we used CX3CR1 −/− , CX3CR1 +/− , and wild-type mice to investigate the physiological role of CX3CR1 receptor in cognition and synaptic plasticity. Our results demonstrate for the first time that mice lacking the CX3CR1 receptor show contextual fear conditioning and Morris water maze deficits. CX3CR1 deficiency also affects motor learning. Importantly, mice lacking the receptor have a significant impairment in long-term potentiation (LTP). Infusion with IL-1β receptor antagonist significantly reversed the deficit in cognitive function and impairment in LTP. Our results reveal that under physiological conditions, disruption in CX3CL1 signaling will lead to impairment in cognitive function and synaptic plasticity via increased action of IL-1β.

Journal ArticleDOI
TL;DR: Assessment of neural mechanisms by which mindfulness meditation influences pain in healthy human participants indicates that meditation engages multiple brain mechanisms that alter the construction of the subjectively available pain experience from afferent information.
Abstract: The subjective experience of one's environment is constructed by interactions among sensory, cognitive, and affective processes. For centuries, meditation has been thought to influence such processes by enabling a nonevaluative representation of sensory events. To better understand how meditation influences the sensory experience, we used arterial spin labeling functional magnetic resonance imaging to assess the neural mechanisms by which mindfulness meditation influences pain in healthy human participants. After 4 d of mindfulness meditation training, meditating in the presence of noxious stimulation significantly reduced pain unpleasantness by 57% and pain intensity ratings by 40% when compared to rest. A two-factor repeated-measures ANOVA was used to identify interactions between meditation and pain-related brain activation. Meditation reduced pain-related activation of the contralateral primary somatosensory cortex. Multiple regression analysis was used to identify brain regions associated with individual differences in the magnitude of meditation-related pain reductions. Meditation-induced reductions in pain intensity ratings were associated with increased activity in the anterior cingulate cortex and anterior insula, areas involved in the cognitive regulation of nociceptive processing. Reductions in pain unpleasantness ratings were associated with orbitofrontal cortex activation, an area implicated in reframing the contextual evaluation of sensory events. Moreover, reductions in pain unpleasantness also were associated with thalamic deactivation, which may reflect a limbic gating mechanism involved in modifying interactions between afferent input and executive-order brain areas. Together, these data indicate that meditation engages multiple brain mechanisms that alter the construction of the subjectively available pain experience from afferent information.

Journal ArticleDOI
TL;DR: Findings show that prefrontal tDCS modulates resting-state functional connectivity in distinct functional networks of the human brain.
Abstract: Transcranial direct current stimulation (tDCS) has been proposed for experimental and therapeutic modulation of regional brain function. Specifically, anodal tDCS of the dorsolateral prefrontal cortex (DLPFC) together with cathodal tDCS of the supraorbital region have been associated with improvement of cognition and mood, and have been suggested for the treatment of several neurological and psychiatric disorders. Although modeled mathematically, the distribution, direction, and extent of tDCS-mediated effects on brain physiology are not well understood. The current study investigates whether tDCS of the human prefrontal cortex modulates resting-state network (RSN) connectivity measured by functional magnetic resonance imaging (fMRI). Thirteen healthy subjects underwent real and sham tDCS in random order on separate days. tDCS was applied for 20 min at 2 mA with the anode positioned over the left DLPFC and the cathode over the right supraorbital region. Patterns of resting-state brain connectivity were assessed before and after tDCS with 3 T fMRI, and changes were analyzed for relevant networks related to the stimulation-electrode localizations. At baseline, four RSNs were detected, corresponding to the default mode network (DMN), the left and right frontal-parietal networks (FPNs) and the self-referential network. After real tDCS and compared with sham tDCS, significant changes of regional brain connectivity were found for the DMN and the FPNs both close to the primary stimulation site and in connected brain regions. These findings show that prefrontal tDCS modulates resting-state functional connectivity in distinct functional networks of the human brain.

Journal ArticleDOI
TL;DR: MRI scans from chronic low back pain patients before and 6 months after treatment indicate that functional and structural brain abnormalities—specifically in the left DLPFC—are reversible, suggesting that treating chronic pain can restore normal brain function in humans.
Abstract: Chronic pain is associated with reduced brain gray matter and impaired cognitive ability. In this longitudinal study, we assessed whether neuroanatomical and functional abnormalities were reversible and dependent on treatment outcomes. We acquired MRI scans from chronic low back pain (CLBP) patients before (n = 18) and 6 months after (spine surgery or facet joint injections; n = 14) treatment. In addition, we scanned 16 healthy controls, 10 of which returned 6 months after the first visit. We performed cortical thickness analysis on structural MRI scans, and subjects performed a cognitive task during the functional MRI. We compared patients and controls, as well as patients before versus after treatment. After treatment, patients had increased cortical thickness in the left dorsolateral prefrontal cortex (DLPFC), which was thinner before treatment compared with controls. Increased DLPFC thickness correlated with the reduction of both pain and physical disability. Additionally, increased thickness in primary motor cortex was associated specifically with reduced physical disability, and right anterior insula was associated specifically with reduced pain. Left DLPFC activity during an attention-demanding cognitive task was abnormal before treatment, but normalized following treatment. These data indicate that functional and structural brain abnormalities-specifically in the left DLPFC-are reversible, suggesting that treating chronic pain can restore normal brain function in humans.

Journal ArticleDOI
TL;DR: It is concluded that the microcircuit architecture for PV+ interneurons, and probably neocortical inhibition in general, is an unspecific, densely homogenous matrix covering all nearby pyramidal cells.
Abstract: GABAergic interneurons play a major role in the function of the mammalian neocortex, but their circuit connectivity is still poorly understood. We used two-photon RuBi-Glutamate uncaging to optically map how the largest population of cortical interneurons, the parvalbumin-positive cells (PV+), are connected to pyramidal cells (PCs) in mouse neocortex. We found locally dense connectivity from PV+ interneurons onto PCs across cortical areas and layers. In many experiments, all nearby PV+ cells were connected to every local PC sampled. In agreement with this, we found no evidence for connection specificity, as PV+ interneurons contacted PC pairs similarly regardless of whether they were synaptically connected or not. We conclude that the microcircuit architecture for PV+ interneurons, and probably neocortical inhibition in general, is an unspecific, densely homogenous matrix covering all nearby pyramidal cells.

Journal ArticleDOI
TL;DR: This work investigated the topography and response profile of human parietal regions inside and outside the DMN, independently defined using task-evoked deactivations and resting-state functional connectivity, during episodic memory retrieval.
Abstract: The default mode network (DMN) is often considered a functionally homogeneous system that is broadly associated with internally directed cognition (e.g., episodic memory, theory of mind, self-evaluation). However, few studies have examined how this network interacts with other networks during putative “default” processes such as episodic memory retrieval. Using functional magnetic resonance imaging, we investigated the topography and response profile of human parietal regions inside and outside the DMN, independently defined using task-evoked deactivations and resting-state functional connectivity, during episodic memory retrieval. Memory retrieval activated posterior nodes of the DMN, particularly the angular gyrus, but also more anterior and dorsal parietal regions that were anatomically separate from the DMN. The two sets of parietal regions showed different resting-state functional connectivity and response profiles. During memory retrieval, responses in DMN regions peaked sooner than non-DMN regions, which in turn showed responses that were sustained until a final memory judgment was reached. Moreover, a parahippocampal region that showed strong resting-state connectivity with parietal DMN regions also exhibited a pattern of task-evoked activity similar to that exhibited by DMN regions. These results suggest that DMN parietal regions directly supported memory retrieval, whereas non-DMN parietal regions were more involved in postretrieval processes such as memory-based decision making. Finally, a robust functional dissociation within the DMN was observed. Whereas angular gyrus and posterior cingulate/precuneus were significantly activated during memory retrieval, an anterior DMN node in medial prefrontal cortex was strongly deactivated. This latter finding demonstrates functional heterogeneity rather than homogeneity within the DMN during episodic memory retrieval.

Journal ArticleDOI
TL;DR: In this paper, the authors measured activity patterns obtained from multisite local field potential recordings in cortex cultures, urethane-anesthetized rats, and awake macaque monkeys and found that both information capacity and information transmission are maximized at a particular intermediate E/I, at which ongoing activity emerges as neuronal avalanches.
Abstract: The repertoire of neural activity patterns that a cortical network can produce constrains the ability of the network to transfer and process information. Here, we measured activity patterns obtained from multisite local field potential recordings in cortex cultures, urethane-anesthetized rats, and awake macaque monkeys. First, we quantified the information capacity of the pattern repertoire of ongoing and stimulus-evoked activity using Shannon entropy. Next, we quantified the efficacy of information transmission between stimulus and response using mutual information. By systematically changing the ratio of excitation/inhibition (E/I) in vitro and in a network model, we discovered that both information capacity and information transmission are maximized at a particular intermediate E/I, at which ongoing activity emerges as neuronal avalanches. Next, we used our in vitro and model results to correctly predict in vivo information capacity and interactions between neuronal groups during ongoing activity. Close agreement between our experiments and model suggest that neuronal avalanches and peak information capacity arise because of criticality and are general properties of cortical networks with balanced E/I.

Journal ArticleDOI
TL;DR: The fMRI food choice task with non-dieting human subjects suggests that the neural mechanisms used in successful self-control can be activated by exogenous attention cues, and provides insights into the processes through which behavioral therapies and public policies could facilitate self- control.
Abstract: Attention is thought to play a key role in the computation of stimulus values at the time of choice, which suggests that attention manipulations could be used to improve decision-making in domains where self-control lapses are pervasive We used an fMRI food choice task with non-dieting human subjects to investigate whether exogenous cues that direct attention to the healthiness of foods could improve dietary choices Behaviorally, we found that subjects made healthier choices in the presence of health cues In parallel, stimulus value signals in ventromedial prefrontal cortex were more responsive to the healthiness of foods in the presence of health cues, and this effect was modulated by activity in regions of dorsolateral prefrontal cortex These findings suggest that the neural mechanisms used in successful self-control can be activated by exogenous attention cues, and provide insights into the processes through which behavioral therapies and public policies could facilitate self-control

Journal ArticleDOI
TL;DR: A scheme is presented for parcellation of human lateral parietal cortex into component regions on the basis of anatomical connectivity and the functional interactions of the resulting clusters with other brain regions using diffusion-weighted magnetic resonance image (MRI)-based tractography.
Abstract: Despite the prominence of parietal activity in human neuroimaging investigations of sensorimotor and cognitive processes, there remains uncertainty about basic aspects of parietal cortical anatomical organization. Descriptions of human parietal cortex draw heavily on anatomical schemes developed in other primate species, but the validity of such comparisons has been questioned by claims that there are fundamental differences between the parietal cortex in humans and other primates. A scheme is presented for parcellation of human lateral parietal cortex into component regions on the basis of anatomical connectivity and the functional interactions of the resulting clusters with other brain regions. Anatomical connectivity was estimated using diffusion-weighted magnetic resonance image (MRI)-based tractography, and functional interactions were assessed by correlations in activity measured with functional MRI at rest. Resting-state functional connectivity was also assessed directly in the rhesus macaque lateral parietal cortex in an additional experiment, and the patterns found reflected known neuroanatomical connections. Cross-correlation in the tractography-based connectivity patterns of parietal voxels reliably parcellated human lateral parietal cortex into 10 component clusters. The resting-state functional connectivity of human superior parietal and intraparietal clusters with frontal and extrastriate cortex suggested correspondences with areas in macaque superior and intraparietal sulcus. Functional connectivity patterns with parahippocampal cortex and premotor cortex again suggested fundamental correspondences between inferior parietal cortex in humans and macaques. In contrast, the human parietal cortex differs in the strength of its interactions between the central inferior parietal lobule region and the anterior prefrontal cortex.

Journal ArticleDOI
TL;DR: It is found that neuronal TRPV1 is primarily restricted to nociceptors in primary sensory ganglia, with minimal expression in a few discrete brain regions, most notably in a contiguous band of cells within and adjacent to the caudal hypothalamus.
Abstract: The heat and capsaicin receptor, TRPV1, is required for the detection of painful heat by primary afferent pain fibers (nociceptors), but the extent to which functional TRPV1 channels are expressed in the CNS is debated. Because previous evidence is based primarily on indirect physiological responses to capsaicin, here we genetically modified the Trpv1 locus to reveal, with excellent sensitivity and specificity, the distribution of TRPV1 in all neuronal and non-neuronal tissues. In contrast to reports of widespread and robust expression in the CNS, we find that neuronal TRPV1 is primarily restricted to nociceptors in primary sensory ganglia, with minimal expression in a few discrete brain regions, most notably in a contiguous band of cells within and adjacent to the caudal hypothalamus. We confirm hypothalamic expression in the mouse using several complementary approaches, including in situ hybridization, calcium imaging, and electrophysiological recordings. Additional in situ hybridization experiments in rat, monkey, and human brain demonstrate that the restricted expression of TRPV1 in the CNS is conserved across species. Outside of the CNS, we find TRPV1 expression in a subset of arteriolar smooth muscle cells within thermoregulatory tissues. Here, capsaicin increases calcium uptake and induces vasoconstriction, an effect that likely counteracts the vasodilation produced by activation of neuronal TRPV1.

Journal ArticleDOI
TL;DR: Comprehensive comparative analysis of the Drosophila olfactory subsystems that express the ionotropic receptors (IRs) and odorant receptors (ORs) identifies ligands for most IR neuron classes, revealing their specificity for select amines and acids, which complements the broader tuning of ORs for esters and alcohols.
Abstract: To sense myriad environmental odors, animals have evolved multiple, large families of divergent olfactory receptors. How and why distinct receptor repertoires and their associated circuits are functionally and anatomically integrated is essentially unknown. We have addressed these questions through comprehensive comparative analysis of the Drosophila olfactory subsystems that express the ionotropic receptors (IRs) and odorant receptors (ORs). We identify ligands for most IR neuron classes, revealing their specificity for select amines and acids, which complements the broader tuning of ORs for esters and alcohols. IR and OR sensory neurons exhibit glomerular convergence in segregated, although interconnected, zones of the primary olfactory center, but these circuits are extensively interdigitated in higher brain regions. Consistently, behavioral responses to odors arise from an interplay between IR- and OR-dependent pathways. We integrate knowledge on the different phylogenetic and developmental properties of these receptors and circuits to propose models for the functional contributions and evolution of these distinct olfactory subsystems.

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TL;DR: This study demonstrates that prestimulus alpha lateralization in the somatosensory system behaves similarly to posterior alpha activity observed in visual attention tasks, extending the notion that alpha band activity is involved in shaping the functional architecture of the working brain by determining both the engagement and disengagement of specific regions.
Abstract: The brain receives a rich flow of information which must be processed according to behavioral relevance. How is the state of the sensory system adjusted to up- or downregulate processing according to anticipation? We used magnetoencephalography to investigate whether prestimulus alpha band activity (8-14 Hz) reflects allocation of attentional resources in the human somatosensory system. Subjects performed a tactile discrimination task where a visual cue directed attention to their right or left hand. The strength of attentional modulation was controlled by varying the reliability of the cue in three experimental blocks (100%, 75%, or 50% valid cueing). While somatosensory prestimulus alpha power lateralized strongly with a fully predictive cue (100%), lateralization was decreased with lower cue reliability (75%) and virtually absent if the cue had no predictive value at all (50%). Importantly, alpha lateralization influenced the subjects' behavioral performance positively: both accuracy and speed of response improved with the degree of alpha lateralization. This study demonstrates that prestimulus alpha lateralization in the somatosensory system behaves similarly to posterior alpha activity observed in visual attention tasks. Our findings extend the notion that alpha band activity is involved in shaping the functional architecture of the working brain by determining both the engagement and disengagement of specific regions: the degree of anticipation modulates the alpha activity in sensory regions in a graded manner. Thus, the alpha activity is under top-down control and seems to play an important role for setting the state of sensory regions to optimize processing.

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TL;DR: This article found that the beat elicits a sustained periodic EEG response tuned to the beat frequency, while meter imagery elicits an additional frequency tuned to a corresponding metric interpretation of this beat.
Abstract: Feeling the beat and meter is fundamental to the experience of music. However, how these periodicities are represented in the brain remains largely unknown. Here, we test whether this function emerges from the entrainment of neurons resonating to the beat and meter. We recorded the electroencephalogram while participants listened to a musical beat and imagined a binary or a ternary meter on this beat (i.e., a march or a waltz). We found that the beat elicits a sustained periodic EEG response tuned to the beat frequency. Most importantly, we found that meter imagery elicits an additional frequency tuned to the corresponding metric interpretation of this beat. These results provide compelling evidence that neural entrainment to beat and meter can be captured directly in the electroencephalogram. More generally, our results suggest that music constitutes a unique context to explore entrainment phenomena in dynamic cognitive processing at the level of neural networks.

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TL;DR: A critical role is demonstrated for HDAC3 in the molecular mechanisms underlying long-term memory formation in mice modified with adeno-associated virus-expressing Cre recombinase and a selective inhibitor ofHDAC3 via RGFP136.
Abstract: Gene expression is dynamically regulated by chromatin modifications on histone tails, such as acetylation. In general, histone acetylation promotes transcription, whereas histone deacetylation negatively regulates transcription. The interplay between histone acetyltranserases and histone deacetylases (HDACs) is pivotal for the regulation of gene expression required for long-term memory processes. Currently, very little is known about the role of individual HDACs in learning and memory. We examined the role of HDAC3 in long-term memory using a combined genetic and pharmacologic approach. We used HDAC3–FLOX genetically modified mice in combination with adeno-associated virus-expressing Cre recombinase to generate focal homozygous deletions of Hdac3 in area CA1 of the dorsal hippocampus. To complement this approach, we also used a selective inhibitor of HDAC3, RGFP136 [N-(6-(2-amino-4-fluorophenylamino)-6-oxohexyl)-4-methylbenzamide]. Immunohistochemistry showed that focal deletion or intrahippocampal delivery of RGFP136 resulted in increased histone acetylation. Both the focal deletion of HDAC3 as well as HDAC3 inhibition via RGFP136 significantly enhanced long-term memory in a persistent manner. Next we examined expression of genes implicated in long-term memory from dorsal hippocampal punches using quantitative reverse transcription-PCR. Expression of nuclear receptor subfamily 4 group A, member 2 (Nr4a2) and c-fos was significantly increased in the hippocampus of HDAC3–FLOX mice compared with wild-type controls. Memory enhancements observed in HDAC3–FLOX mice were abolished by intrahippocampal delivery of Nr4a2 small interfering RNA, suggesting a mechanism by which HDAC3 negatively regulates memory formation. Together, these findings demonstrate a critical role for HDAC3 in the molecular mechanisms underlying long-term memory formation.

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TL;DR: This work provides the first ever in vivo visualization of myelin maturation in healthy human infancy, from 3 to 11 months of age, using a new myelin-specific MRI technique.
Abstract: Myelination, the elaboration of myelin surrounding neuronal axons, is essential for normal brain function. The development of the myelin sheath enables rapid synchronized communication across the neural systems responsible for higher order cognitive functioning. Despite this critical role, quantitative visualization of myelination in vivo is not possible with current neuroimaging techniques including diffusion tensor and structural magnetic resonance imaging (MRI). Although these techniques offer insight into structural maturation, they reflect several different facets of development, e.g., changes in axonal size, density, coherence, and membrane structure; lipid, protein, and macromolecule content; and water compartmentalization. Consequently, observed signal changes are ambiguous, hindering meaningful inferences between imaging findings and metrics of learning, behavior or cognition. Here we present the first quantitative study of myelination in healthy human infants, from 3 to 11 months of age. Using a new myelin-specific MRI technique, we report a spatiotemporal pattern beginning in the cerebellum, pons, and internal capsule; proceeding caudocranially from the splenium of the corpus callosum and optic radiations (at 3–4 months); to the occipital and parietal lobes (at 4–6 months); and then to the genu of the corpus callosum and frontal and temporal lobes (at 6–8 months). Our results also offer preliminary evidence of hemispheric myelination rate differences. This work represents a significant step forward in our ability to appreciate the fundamental process of myelination, and provides the first ever in vivo visualization of myelin maturation in healthy human infancy.

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TL;DR: It is found that spindles occur across multiple neocortical regions, and less frequently also in the parahippocampal gyrus and hippocampus, and that deeper NREM sleep is associated with a reduction in spindle occurrence and spindle frequency.
Abstract: Sleep spindles are an electroencephalographic (EEG) hallmark of non-rapid eye movement (NREM) sleep and are believed to mediate many sleep-related functions, from memory consolidation to cortical development. Spindles differ in location, frequency, and association with slow waves, but whether this heterogeneity may reflect different physiological processes and potentially serve different functional roles remains unclear. Here we used a unique opportunity to record intracranial depth EEG and single-unit activity in multiple brain regions of neurosurgical patients to better characterize spindle activity in human sleep. We find that spindles occur across multiple neocortical regions, and less frequently also in the parahippocampal gyrus and hippocampus. Most spindles are spatially restricted to specific brain regions. In addition, spindle frequency is topographically organized with a sharp transition around the supplementary motor area between fast (13–15 Hz) centroparietal spindles often occurring with slow-wave up-states, and slow (9–12 Hz) frontal spindles occurring 200 ms later on average. Spindle variability across regions may reflect the underlying thalamocortical projections. We also find that during individual spindles, frequency decreases within and between regions. In addition, deeper NREM sleep is associated with a reduction in spindle occurrence and spindle frequency. Frequency changes between regions, during individual spindles, and across sleep may reflect the same phenomenon, the underlying level of thalamocortical hyperpolarization. Finally, during spindles neuronal firing rates are not consistently modulated, although some neurons exhibit phase-locked discharges. Overall, anatomical considerations can account well for regional spindle characteristics, while variable hyperpolarization levels can explain differences in spindle frequency.

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TL;DR: It is found that functional coupling between key network nodes is stronger in adults than in children, as are causal links emanating from the right fronto-insular cortex (rFIC), and causal influence of the rFIC on nodes of the SN and CEN was significantly greater in adults compared with children.
Abstract: Brain structural and functional development, throughout childhood and into adulthood, underlies the maturation of increasingly sophisticated cognitive abilities. High-level attentional and cognitive control processes rely on the integrity of, and dynamic interactions between, core neurocognitive networks. The right fronto-insular cortex (rFIC) is a critical component of a salience network (SN) that mediates interactions between large-scale brain networks involved in externally oriented attention [central executive network (CEN)] and internally oriented cognition [default mode network (DMN)]. How these systems reconfigure and mature with development is a critical question for cognitive neuroscience, with implications for neurodevelopmental pathologies affecting brain connectivity. Using functional and effective connectivity measures applied to fMRI data, we examine interactions within and between the SN, CEN, and DMN. We find that functional coupling between key network nodes is stronger in adults than in children, as are causal links emanating from the rFIC. Specifically, the causal influence of the rFIC on nodes of the SN and CEN was significantly greater in adults compared with children. Notably, these results were entirely replicated on an independent dataset of matched children and adults. Developmental changes in functional and effective connectivity were related to structural connectivity along these links. Diffusion tensor imaging tractography revealed increased structural integrity in adults compared with children along both within- and between-network pathways associated with the rFIC. These results suggest that structural and functional maturation of rFIC pathways is a critical component of the process by which human brain networks mature during development to support complex, flexible cognitive processes in adulthood.