The neural dynamics of hierarchical Bayesian causal inference in multisensory perception.

Transforming the barrage of sensory signals into a coherent multisensory percept relies on solving the binding problem - deciding whether signals come from a common cause and should be integrated or, instead, segregated. Human observers typically arbitrate between integration and segregation consistent with Bayesian Causal Inference, but the neural mechanisms remain poorly understood. Here, we presented people with audiovisual sequences that varied in the number of flashes and beeps, then combined Bayesian modelling and EEG representational similarity analyses. Our data suggest that the brain initially represents the number of flashes and beeps independently. Later, it computes their numbers by averaging the forced-fusion and segregation estimates weighted by the probabilities of common and independent cause models (i.e. model averaging). Crucially, prestimulus oscillatory alpha power and phase correlate with observers' prior beliefs about the world's causal structure that guide their arbitration between sensory integration and segregation.

Structural covariability hubs in old age.

Studies have shown that inter-individual differences in grey matter, as measured by voxel-based morphometry, are coordinated between voxels. This has been done by studying covariance maps based on a limited number of seed regions. Here, we used GPU-based (Graphics Processing Unit) accelerated computing to calculate, for the first time, the aggregated map of the total structural topographical organisation in the brain on voxel level in a large sample of 960 healthy individuals in the age range 68-83 years. This map describes for each voxel the number of significant correlations with all other grey matter voxels in the brain. Voxels that correlate significantly with many other voxels are called hubs. A majority of these hubs were found in the basal ganglia, the thalamus, the brainstem, and the cerebellum; subcortical regions that have been preserved through vertebrate evolution, interact with large portions of the neocortex and play fundamental roles for the control of a wide range of behaviours. No significant difference in the level of covariability could be found with increasing age or between men and women in these hubs.

Shared and distinct transcriptomic cell types across neocortical areas.

The neocortex contains a multitude of cell types that are segregated into layers and functionally distinct areas. To investigate the diversity of cell types across the mouse neocortex, here we analysed 23,822 cells from two areas at distant poles of the mouse neocortex: the primary visual cortex and the anterior lateral motor cortex. We define 133 transcriptomic cell types by deep, single-cell RNA sequencing. Nearly all types of GABA (γ-aminobutyric acid)-containing neurons are shared across both areas, whereas most types of glutamatergic neurons were found in one of the two areas. By combining single-cell RNA sequencing and retrograde labelling, we match transcriptomic types of glutamatergic neurons to their long-range projection specificity. Our study establishes a combined transcriptomic and projectional taxonomy of cortical cell types from functionally distinct areas of the adult mouse cortex.

Microstructural imaging of human neocortex in vivo.

The neocortex of the human brain is the seat of higher brain function. Modern imaging techniques, chief among them magnetic resonance imaging (MRI), allow non-invasive imaging of this important structure. Knowledge of the microstructure of the neocortex has classically come from post-mortem histological studies of human tissue, and extrapolations from invasive animal studies. From these studies, we know that the scale of important neocortical structure spans six orders of magnitude, ranging from the size of axonal diameters (microns), to the size of cortical areas responsible for integrating sensory information (centimetres). MRI presents an opportunity to move beyond classical methods, because MRI is non-invasive and MRI contrast is sensitive to neocortical microstructure over all these length scales. MRI thus allows inferences to be made about neocortical microstructure in vivo, i.e. MRI-based in vivo histology. We review recent literature that has applied and developed MRI-based in vivo histology to probe the microstructure of the human neocortex, focusing specifically on myelin, iron, and neuronal fibre mapping. We find that applications such as cortical parcellation (using [Formula: see text] maps as proxies for myelin content) and investigation of cortical iron deposition with age (using [Formula: see text] maps) are already contributing to the frontiers of knowledge in neuroscience. Neuronal fibre mapping in the cortex remains challenging in vivo, but recent improvements in diffusion MRI hold promise for exciting applications in the near future. The literature also suggests that utilising multiple complementary quantitative MRI maps could increase the specificity of inferences about neocortical microstructure relative to contemporary techniques, but that further investment in modelling is required to appropriately combine the maps. In vivo histology of human neocortical microstructure is undergoing rapid development. Future developments will improve its specificity, sensitivity, and clinical applicability, granting an ever greater ability to investigate neuroscientific and clinical questions about the human neocortex.

Integration the Highest Function of Brain as the Basis of Cognition.

Based on the process needs, motivations and emotions, are describing molecular, cellular and systemic mechanisms of goal-direction motivated behavior. Goal-direction behavior is impossible without the orientation in space and forming a cognitive map. This process implements the hippocampus, via the neocortical connections. The hippocampus is linked to the amygdala, which is involved in the implementation of emotional behavior and organizing emotionally intense cognitive map or context of the environment.

Map transfer from the thalamus to the neocortex: inputs from the barrel field.

Sensory perception relies on the formation of stereotyped maps inside the brain. This feature is particularly well illustrated in the mammalian neocortex, which is subdivided into distinct cortical sensory areas that comprise topological maps, such as the somatosensory homunculus in humans or the barrel field of the large whiskers in rodents. How somatosensory maps are formed and relayed into the neocortex remain essential questions in developmental neuroscience. Here, we will present our current knowledge on whisker map transfer in the mouse model, with the goal of linking embryonic and postnatal studies into a comprehensive framework.

Drivers of the primate thalamus.

The activity of thalamocortical neurons is primarily determined by giant excitatory terminals, called drivers. These afferents may arise from neocortex or from subcortical centers; however, their exact distribution, segregation, or putative absence in given thalamic nuclei are unknown. To unravel the nucleus-specific composition of drivers, we mapped the entire macaque thalamus using vesicular glutamate transporters 1 and 2 to label cortical and subcortical afferents, respectively. Large thalamic territories were innervated exclusively by either giant vGLUT2- or vGLUT1-positive boutons. Codistribution of drivers with different origin was not abundant. In several thalamic regions, no giant terminals of any type could be detected at light microscopic level. Electron microscopic observation of these territories revealed either the complete absence of large multisynaptic excitatory terminals (basal ganglia-recipient nuclei) or the presence of both vGLUT1- and vGLUT2-positive terminals, which were significantly smaller than their giant counterparts (intralaminar nuclei, medial pulvinar). In the basal ganglia-recipient thalamus, giant inhibitory terminals replaced the excitatory driver inputs. The pulvinar and the mediodorsal nucleus displayed subnuclear heterogeneity in their driver assemblies. These results show that distinct thalamic territories can be under pure subcortical or cortical control; however, there is significant variability in the composition of major excitatory inputs in several thalamic regions. Because thalamic information transfer depends on the origin and complexity of the excitatory inputs, this suggests that the computations performed by individual thalamic regions display considerable variability. Finally, the map of driver distribution may help to resolve the morphological basis of human diseases involving different parts of the thalamus.

The development of audiovisual multisensory integration across childhood and early adolescence: a high-density electrical mapping study.

The integration of multisensory information is essential to forming meaningful representations of the environment. Adults benefit from related multisensory stimuli but the extent to which the ability to optimally integrate multisensory inputs for functional purposes is present in children has not been extensively examined. Using a cross-sectional approach, high-density electrical mapping of event-related potentials (ERPs) was combined with behavioral measures to characterize neurodevelopmental changes in basic audiovisual (AV) integration from middle childhood through early adulthood. The data indicated a gradual fine-tuning of multisensory facilitation of performance on an AV simple reaction time task (as indexed by race model violation), which reaches mature levels by about 14 years of age. They also revealed a systematic relationship between age and the brain processes underlying multisensory integration (MSI) in the time frame of the auditory N1 ERP component (∼ 120 ms). A significant positive correlation between behavioral and neurophysiological measures of MSI suggested that the underlying brain processes contributed to the fine-tuning of multisensory facilitation of behavior that was observed over middle childhood. These findings are consistent with protracted plasticity in a dynamic system and provide a starting point from which future studies can begin to examine the developmental course of multisensory processing in clinical populations.

The columnar and laminar organization of inhibitory connections to neocortical excitatory cells.

The cytoarchitectonic similarities of different neocortical regions have given rise to the idea of 'canonical' connectivity between excitatory neurons of different layers within a column. It is unclear whether similarly general organizational principles also exist for inhibitory neocortical circuits. Here we delineate and compare local inhibitory-to-excitatory wiring patterns in all principal layers of primary motor (M1), somatosensory (S1) and visual (V1) cortex, using genetically targeted photostimulation in a mouse knock-in line that conditionally expresses channelrhodopsin-2 in GABAergic neurons. Inhibitory inputs to excitatory neurons derived largely from the same cortical layer within a three-column diameter. However, subsets of pyramidal cells in layers 2/3 and 5B received extensive translaminar inhibition. These neurons were prominent in V1, where they might correspond to complex cells, less numerous in barrel cortex and absent in M1. Although inhibitory connection patterns were stereotypical, the abundance of individual motifs varied between regions and cells, potentially reflecting functional specializations.

An architectonic study of the neocortex of the short-tailed opossum (Monodelphis domestica).

Short-tailed opossums (Monodelphis domestica) belong to the branch of marsupial mammals that diverged from eutherian mammals approximately 180 million years ago. They are small in size, lack a marsupial pouch, and may have retained more morphological characteristics of early marsupial neocortex than most other marsupials. In the present study, we used several different histochemical and immunochemical procedures to reveal the architectonic characteristics of cortical areas in short-tailed opossums. Subdivisions of cortex were identified in brain sections cut in the coronal, sagittal, horizontal or tangential planes and processed for a calcium-binding protein, parvalbumin (PV), neurofilament protein epitopes recognized by SMI-32, the vesicle glutamate transporter 2 (VGluT2), myelin, cytochrome oxidase (CO), and Nissl substance. These different procedures revealed similar boundaries among areas, suggesting that functionally relevant borders were detected. The results allowed a fuller description and more precise demarcation of previously identified sensory areas, and the delineation of additional subdivisions of cortex. Area 17 (V1) was especially prominent, with a densely populated layer 4, high myelination levels, and dark staining of PV and VGluT2 immunopositive terminations. These architectonic features were present, albeit less pronounced, in somatosensory and auditory cortex. The major findings support the conclusion that short-tailed opossums have fewer cortical areas and their neocortex is less distinctly laminated than most other mammals.

Architectonic subdivisions of neocortex in the tree shrew (Tupaia belangeri).

Tree shrews are small mammals that bear some semblance to squirrels, but are actually close relatives of primates. Thus, they have been extensively studied as a model for the early stages of primate evolution. In this study, subdivisions of cortex were reconstructed from brain sections cut in the coronal, sagittal, or horizontal planes, and processed for parvalbumin, SMI-32-immunopositive neurofilament protein epitopes, vesicle glutamate transporter 2 (VGluT2), free ionic zinc, myelin, cytochrome oxidase, and Nissl substance. These different procedures revealed similar boundaries between areas, suggesting the detection of functionally relevant borders and allowed a more precise demarcation of cortical areal boundaries. Primary cortical areas were most clearly revealed by the zinc stain, because of the poor staining of layer 4, as thalamocortical terminations lack free ionic zinc. Area 17 (V1) was especially prominent, as the broad layer 4 was nearly free of zinc stain. However, this feature was less pronounced in primary auditory and somatosensory cortex. In primary sensory areas, thalamocortical terminations in layer 4 densely express VGluT2. Auditory cortex consists of two architectonically distinct subdivisions, a primary core region (Ac), surrounded by a belt region (Ab) that had a slightly less developed koniocellular appearance. Primary motor cortex (M1) was identified by the absence of VGluT2 staining in the poorly developed granular layer 4 and the presence of SMI-32-labeled pyramidal cells in layers 3 and 5. The presence of well-differentiated cortical areas in tree shrews indicates their usefulness in studies of cortical organization and function.

Thalamic input to distal apical dendrites in neocortical layer 1 is massive and highly convergent.

Input to apical dendritic tufts is now deemed crucial for associative learning, attention, and similar "feedback" interactions in the cerebral cortex. Excitatory input to apical tufts in neocortical layer 1 has been traditionally assumed to be predominantly cortical, as thalamic pathways directed to this layer were regarded relatively scant and diffuse. However, the sensitive tracing methods used in the present study show that, throughout the rat neocortex, large numbers (mean approximately 4500/mm(2)) of thalamocortical neurons converge in layer 1 and that this convergence gives rise to a very high local density of thalamic terminals. Moreover, we show that the layer 1-projecting neurons are present in large numbers in most, but not all, motor, association, limbic, and sensory nuclei of the rodent thalamus. Some layer 1-projecting axons branch to innervate large swaths of the cerebral hemisphere, whereas others arborize within only a single cortical area. Present data imply that realistic modeling of cortical circuitry should factor in a dense axonal canopy carrying highly convergent thalamocortical input to pyramidal cell apical tufts. In addition, they are consistent with the notion that layer 1-projecting axons may be a robust anatomical substrate for extensive "feedback" interactions between cortical areas via the thalamus.

Architectonic subdivisions of neocortex in the gray squirrel (Sciurus carolinensis).

Squirrels are highly visual mammals with an expanded cortical visual system and a number of well-differentiated architectonic fields. To describe and delimit cortical fields, subdivisions of cortex were reconstructed from serial brain sections cut in the coronal, sagittal, or horizontal planes. Architectonic characteristics of cortical areas were visualized after brain sections were processed with immunohistochemical and histochemical procedures for revealing parvalbumin, calbindin, neurofilament protein, vesicle glutamate transporter 2, limbic-associated membrane protein, synaptic zinc, cytochrome oxidase, myelin or Nissl substance. In general, these different procedures revealed similar boundaries between areas, suggesting that functionally relevant borders were being detected. The results allowed a more precise demarcation of previously identified areas as well as the identification of areas that had not been previously described. Primary sensory cortical areas were characterized by sparse zinc staining of layer 4, as thalamocortical terminations lack zinc, as well as by layer 4 terminations rich in parvalbumin and vesicle glutamate transporter 2. Primary areas also expressed higher levels of cytochrome oxidase and myelin. Primary motor cortex was associated with large SMI-32 labeled pyramidal cells in layers 3 and 5. Our proposed organization of cortex in gray squirrels includes both similarities and differences to the proposed of cortex in other rodents such as mice and rats. The presence of a number of well-differentiated cortical areas in squirrels may serve as a guide to the identification of homologous fields in other rodents, as well as a useful guide in further studies of cortical organization and function.

Dissociation of corticothalamic and thalamocortical axon targeting by an EphA7-mediated mechanism.

Molecular mechanisms generating the topographic organization of corticothalamic (CT) circuits, which comprise more than three-quarters of the synaptic inputs onto sensory relay neurons, and their interdependence with thalamocortical (TC) axon development are unknown. Using in utero electroporation-mediated gene transfer, we show that EphA7-mediated signaling on neocortical axons controls the within-nucleus topography of CT projections in the thalamus. Notably, CT axons that mis-express EphA7 do not shift the relative positioning of their pathway within the subcortical telencephalon (ST), indicating that they do not depend upon EphA7/ephrin-A signaling in the ST for establishing this topography. Moreover, mis-expression of cortical EphA7 results in disrupted topography of CT projections, but unchanged inter- and intra-areal topography of TC projections. Our results support a model in which EphA/ephrin-A signaling controls independently the precision with which CT and TC projections develop, yet is essential for establishing their topographic reciprocity.

Mirror symmetric topographic maps can arise from activity-dependent synaptic changes.

Multiple adjacent, roughly mirror-image topographic maps are commonly observed in the sensory neocortex of many species. The cortical regions occupied by these maps are generally believed to be determined initially by genetically controlled chemical markers during development, with thalamocortical afferent activity subsequently exerting a progressively increasing influence over time. Here we use a computational model to show that adjacent topographic maps with mirror-image symmetry can arise from activity-dependent synaptic changes whenever the distribution radius of afferents sufficiently exceeds that of horizontal intracortical interactions. Which map edges become adjacent is strongly influenced by the probability distribution of input stimuli during map formation. Our results suggest that activity-dependent synaptic changes may play a role in influencing how adjacent maps become oriented following the initial establishment of cortical areas via genetically determined chemical markers. Further, the model unexpectedly predicts the occasional occurrence of adjacent maps with a different rotational symmetry. We speculate that such atypically oriented maps, in the context of otherwise normally interconnected cortical regions, might contribute to abnormal cortical information processing in some neurodevelopmental disorders.

A supramodal limbic-paralimbic-neocortical network supports goal-directed stimulus processing.

Limited processing resources are allocated preferentially to events that are relevant for behavior. Research using the novelty "oddball" paradigm suggests that a widespread network of limbic, paralimbic, and association areas supports the goal-directed processing of task-relevant target events. In that paradigm, greater activity in diverse brain areas is elicited by rare task-relevant events that require a subsequent motor response than by rare task-irrelevant novel events that require no response. Both stimulus infrequency (unexpectedness) and novelty, however, may contribute to the pattern of activity observed using that paradigm. The goal of the present study was to examine the supramodal neural activity elicited by regularly occurring, equiprobable, and non-novel stimuli that differed in the subsequent behavior they prescribed. We employed event-related functional magnetic resonance imaging (fMRI) during auditory and visual versions of a Go/NoGo task. Participants made a motor response to the designated "Go" (target) stimulus, and no motor response to the equiprobable "NoGo" (nontarget) stimulus. We hypothesized that task-relevant Go events would elicit relatively greater hemodynamic activity than would NoGo events throughout a network of limbic, paralimbic, and association areas. Indeed, Go events elicited greater activity than did NoGo events in the amygdala-hippocampus, paralimbic cortex at the anterior superior temporal sulcus, insula, posterior orbitofrontal cortex, and anterior and posterior cingulate cortex, as well as in heteromodal association areas located at the temporoparietal junction, anterior intraparietal sulcus and precuneus, and premotor cortex. Paralimbic cortex offers an important site for the convergence of motivational/goal-directed influences from limbic cortex with stimulus processing and response selection mediated within the frontoparietal areas.

Mouse brain organization revealed through direct genome-scale TF expression analysis.

In the developing brain, transcription factors (TFs) direct the formation of a diverse array of neurons and glia. We identifed 1445 putative TFs in the mouse genome. We used in situ hybridization to map the expression of over 1000 of these TFs and TF-coregulator genes in the brains of developing mice. We found that 349 of these genes showed restricted expression patterns that were adequate to describe the anatomical organization of the brain. We provide a comprehensive inventory of murine TFs and their expression patterns in a searchable brain atlas database.

The acetylcholine fiber density of the neocortex is altered by isolated rearing and early methamphetamine intoxication in rodents.

Alterations in the cholinergic physiology of the brain were the first to be observed when research on environmental influences on postnatal brain development began 35 years ago. Since then, the effects of isolated rearing (IR) or early pharmacological insults have been shown not only on the physiology, but also the anatomy of a variety of transmitter systems. The cholinergic fiber density, however, still remained to be assessed. We therefore used a histochemical procedure to stain cholinergic fibers in the brains of young adult gerbils reared either in groups in enriched environments or isolated in standard makrolon cages. Half of the animals from each rearing condition had received a single high dose of methamphetamine on postnatal day 14. Fiber densities were measured by computerized image analysis in the medial and orbital prefrontal cortex (PFC), dysgranular and granular insular cortex, sensorimotor cortices, and the entorhinal cortex of both hemispheres. Isolation rearing increased the cholinergic fiber densities in the prefrontal cortices of the left hemisphere and in the entorhinal cortex of the right hemisphere by about 10%, with no effect in the respective contralateral side. The early methamphetamine intoxication showed no influence in prefrontal and entorhinal cortices, but diminished the acetylcholine (ACh) innervation of the forelimb area of cortex in both hemispheres in IR gerbils and of the left hemisphere in ER gerbils, and reduced the acetylcholine innervation in the hindlimb area in both sides in both rearing groups. These results demonstrate that (a) cholinergic fiber density is differentially regulated in different cortical areas and (b) the plasticity of the cholinergic system can only be understood in the interplay with other neuromodulatory innervations.

Sensitivity to auditory object features in human temporal neocortex.

This positron emission tomography study examined the hemodynamic response of the human brain to auditory object feature processing. A continuum of object feature variation was created by combining different numbers of stimuli drawn from a diverse sample of 45 environmental sounds. In each 60 sec scan condition, subjects heard either a distinct individual sound on each trial or simultaneous combinations of sounds that varied systematically in their similarity or distinctiveness across conditions. As more stimuli are combined they become more similar and less distinct from one another; the limiting case is when all 45 are added together to form a noise that is repeated on each trial. Analysis of covariation of cerebral blood flow elicited by this parametric manipulation revealed a response in the upper bank of the right anterior superior temporal sulcus (STS): when sounds were identical across trials (i.e., a noise made up of 45 sounds), activity was at a minimum; when stimuli were different from one another, activity was maximal. A right inferior frontal area was also revealed. The results are interpreted as reflecting sensitivity of this region of temporal neocortex to auditory object features, as predicted by neurophysiological and anatomical models implicating an anteroventral functional stream in object processing. The findings also fit with evidence that voice processing may involve regions within the anterior STS. The data are discussed in light of these models and are related to the concept that this functional stream is sensitive to invariant sound features that characterize individual auditory objects.

Neural cell adhesion molecule L1 is required for fasciculation and routing of thalamocortical fibres and corticothalamic fibres.

To examine the role of neural cell adhesion molecule L1 in thalamocortical projections, we analysed L1 deficient (L1-/y) mice. Immunohistochemistry of pleiotrophin/HB-GAM, a marker for thalamocortical axons and axonal tracing experiments showed that thalamocortical axons were abnormally and highly fasciculated when they pass through the developing internal capsule. Within the cortex, however, their course was more diffuse. The corticofugal fibres immunoreactive for TAG-1 were also more strongly fasciculated and their number was decreased in L1-/y mice. Furthermore, no TAG-1-positive corticofugal axons reached the dorsal thalamus. These data suggest that L1 plays an important role in the fasciculation and routing of axons connecting between the thalamus and the cortex.