Beyond the microcirculation: sequestration of infected red blood cells and reduced flow in large draining veins in experimental cerebral malaria.

Sequestration of infected red blood cells (iRBCs) in the microcirculation is a hallmark of cerebral malaria (CM) in post-mortem human brains. It remains controversial how this might be linked to the different disease manifestations, in particular brain swelling leading to brain herniation and death. The main hypotheses focus on iRBC-triggered inflammation and mechanical obstruction of blood flow. Here, we test these hypotheses using murine models of experimental CM (ECM), SPECT-imaging of radiolabeled iRBCs and cerebral perfusion, MR-angiography, q-PCR, and immunohistochemistry. We show that iRBC accumulation and reduced flow precede inflammation. Unexpectedly, we find that iRBCs accumulate not only in the microcirculation but also in large draining veins and sinuses, particularly at the rostral confluence. We identify two parallel venous streams from the superior sagittal sinus that open into the rostral rhinal veins and are partially connected to infected skull bone marrow. The flow in these vessels is reduced early, and the spatial patterns of pathology correspond to venous drainage territories. Our data suggest that venous efflux reductions downstream of the microcirculation are causally linked to ECM pathology, and that the different spatiotemporal patterns of edema development in mice and humans could be related to anatomical differences in venous anatomy.

Transcranial direct current stimulation (tDCS) over the auditory cortex modulates GABA and glutamate: a 7 T MR-spectroscopy study.

Transcranial direct current stimulation (tDCS) is one of the most prominent non-invasive electrical brain stimulation method to alter neuronal activity as well as behavioral processes in cognitive and perceptual domains. However, the exact mode of action of tDCS-related cortical alterations is still unclear as the results of tDCS studies often do not comply with the somatic doctrine assuming that anodal tDCS enhances while cathodal tDCS decreases neuronal excitability. Changes in the regional cortical neurotransmitter balance within the stimulated cortex, measured by excitatory and inhibitory neurotransmitter levels, have the potential to provide direct neurochemical underpinnings of tDCS effects. Here we assessed tDCS-induced modulations of the neurotransmitter concentrations in the human auditory cortex (AC) by using magnetic resonance spectroscopy (MRS) at ultra-high-field (7 T). We quantified inhibitory gamma-amino butyric (GABA) concentration and excitatory glutamate (Glu) and compared changes in the relative concentration of GABA to Glu before and after tDCS application. We found that both, anodal and cathodal tDCS significantly increased the relative concentration of GABA to Glu with individual temporal specificity. Our results offer novel insights for a potential neurochemical mechanism that underlies tDCS-induced alterations of AC processing.

Disrupted cross-laminar cortical processing in ß amyloid pathology precedes cell death.

Disruption of neuronal networks in the Alzheimer-afflicted brain is increasingly recognized as a key correlate of cognitive and memory decline in Alzheimer patients. We hypothesized that functional synaptic disconnections within cortical columnar microcircuits by pathological ß-amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical ß-amyloidosis with still few plaques in the transgenic 5xFAD mouse model single cell resolution mapping of neuronal thallium uptake revealed that electrical activity of pyramidal cells breaks down throughout infragranular cortical layer V long before cell death occurs. Treatment of 5xFAD mice with the glutaminyl cyclase inhibitor, PQ 529, partially prevented the decline of pyramidal cell activity, indicating pyroglutamate-modified forms, potentially mixed oligomers of Aß are contributing to neuronal impairment. Laminar investigation of cortical circuit dysfunction with current source density analysis identified an early loss of excitatory synaptic input in infragranular layers, linked to pathological recurrent activations in supragranular layers. This specific disruption of normal cross-laminar cortical processing coincided with a decline of contextual fear learning.

Multisensory processing via early cortical stages: Connections of the primary auditory cortical field with other sensory systems.

It is still a popular view that primary sensory cortices are unimodal, but recent physiological studies have shown that under certain behavioral conditions primary sensory cortices can also be activated by multiple other modalities. Here, we investigate the anatomical substrate, which may underlie multisensory processes at the level of the primary auditory cortex (field AI), and which may, in turn, enable AI to influence other sensory systems. We approached this issue by means of the axonal transport of the sensitive bidirectional neuronal tracer fluorescein-labeled dextran which was injected into AI of Mongolian gerbils (Meriones unguiculatus). Of the total number of retrogradely labeled cell bodies (i.e. cells of origin of direct projections to AI) found in non-auditory sensory and multisensory brain areas, approximately 40% were in cortical areas and 60% in subcortical structures. Of the cell bodies in the cortical areas about 82% were located in multisensory cortex, viz., the dorsoposterior and ventroposterior, posterior parietal cortex, the claustrum, and the endopiriform nucleus, 10% were located in the primary somatosensory cortex (hindlimb and trunk region), and 8% in secondary visual cortex. The cortical regions with retrogradely labeled cells also contained anterogradely labeled axons and their terminations, i.e. they are also target areas of direct projections from AI. In addition, the primary olfactory cortex was identified as a target area of projections from AI. The laminar pattern of corticocortical connections suggests that AI receives primarily cortical feedback-type inputs and projects in a feedforward manner to its target areas. Of the labeled cell bodies in the subcortical structures, approximately 90% were located in multisensory thalamic, 4% in visual thalamic, and 6% in multisensory lower brainstem structures. At subcortical levels, we observed a similar correspondence of retrogradely labeled cells and anterogradely labeled axons and terminals in visual (posterior limitans thalamic nucleus) and multisensory thalamic nuclei (dorsal and medial division of the medial geniculate body, suprageniculate nucleus, posterior thalamic cell group, zona incerta), and in the multisensory nucleus of the brachium of the inferior colliculus. Retrograde, but not anterograde, labeling was found in the multisensory pontine reticular formation, particularly in the reticulotegmental nucleus of the pons. Conversely, anterograde, but no retrograde, labeling was found in the visual laterodorsal and lateroposterior thalamic nuclei, in the multisensory peripeduncular, posterior intralaminar, and reticular thalamic nuclei, as well as in the multisensory superior and pericentral inferior colliculi (including cuneiform and sagulum nucleus), pontine nuclei, and periaqueductal gray. Our study supports the notion that AI is not merely involved in the analysis of auditory stimulus properties but also in processing of other sensory and multisensory information. Since AI is directly connected to other primary sensory cortices (viz. the somatosensory and olfactory ones) multisensory information is probably also processed in these cortices. This suggests more generally, that primary sensory cortices may not be unimodal.

Functional organization of auditory cortex in the Mongolian gerbil (Meriones unguiculatus). III. Anatomical subdivisions and corticocortical connections.

The auditory cortex of the Mongolian gerbil comprises several physiologically identified fields, including the primary (AI), anterior (AAF), dorsal (D), ventral (V), dorsoposterior (DP) and ventroposterior (VP) fields, as established previously with electrophysiological [Thomas et al. (1993) Eur. J. Neurosci., 5, 882] and functional metabolic techniques [Scheich et al. (1993) Eur. J. Neurosci., 5, 898]. Here we describe the cyto-, myelo- and chemoarchitecture and the corticocortical connections of the auditory cortex in this species. A central area of temporal cortex corresponding to AI and the rostrally adjacent AAF is distinguished from surrounding cortical areas by its koniocortical cytoarchitecture, by a higher density of myelinated fibres, predominantly in granular and infragranular layers, and by characteristic patterns of immunoreactivity for the calcium-binding protein parvalbumin (most intense staining in layers III/IV and VIa) and for the cytoskeletal neurofilament protein (antibody SMI-32; most intense staining in layers III, V and VI). Concerning the cortical connections, injections of the predominantly anterograde tracer biocytin into the four tonotopically organized fields AI, AAF, DP and VP yielded the following labelling patterns. (i) Labelled axons and terminals were seen within each injected field itself. (ii) Following injections into AI, labelled axons and terminals were also seen in the ipsilateral AAF, DP, VP, D and V, and in a hitherto undescribed possible auditory field, termed the ventromedial field (VM). Similarly, following injections into AAF, DP and VP, labelling was also seen in each of the noninjected fields, except in VM. (iii) Each field projects to its homotopic counterpart in the contralateral hemisphere. In addition, field AI projects to contralateral AAF, DP and VP, field DP to contralateral AI and VP, and field VP to contralateral AI and DP. (iv) Some retrogradely filled pyramidal neurons within the areas of terminal labelling indicate reciprocal connections between most fields, both ipsilateral and contralateral. (v) The labelled fibres within the injected and the target fields, both ipsilateral and contralateral, were arranged in continuous dorsoventral bands parallel to isofrequency contours. The more caudal the injection site in AI the more rostral was the label in AAF. This suggests divergent but frequency-specific connections within and, at least for AI and AAF, also across fields, both ipsilateral and contralateral. (vi) Projections to associative cortices (perirhinal, entorhinal, cingulate) and to other sensory cortices (olfactory, somatosensory, visual) from AAF, DP and VP appeared stronger than those from AI. These data support the differentiation of auditory cortical fields in the gerbil into at least 'core' (AI and AAF) and 'noncore' fields. They further reveal a complex pattern of interconnections within and between auditory cortical fields and other cortical areas, such that each field of auditory cortex has its unique set of connections.

Functional organization of auditory cortex in the Mongolian gerbil (Meriones unguiculatus). IV. Connections with anatomically characterized subcortical structures.

The subcortical connections of the four tonotopically organized fields of the auditory cortex of the Mongolian gerbil, namely the primary (AI), the anterior (AAF), the dorsoposterior (DP) and the ventroposterior field (VP), were studied predominantly by anterograde transport of biocytin injected into these fields. In order to allow the localization of connections with respect to subdivisions of subcortical auditory structures, their cyto-, fibre- and chemoarchitecture was characterized using staining methods for cell bodies, myelin and the calcium-binding protein parvalbumin. Each injected auditory cortical field has substantial and reciprocal connections with each of the three subdivision of the medial geniculate body (MGB), namely the ventral (MGv), dorsal (MGd) and medial division (MGm). However, the relative strengths of these connections vary: AI is predominantly connected with MGv, AAF with MGm and MGv, and DP and VP with MGd and MGv. The connections of at least AI and MGv are topographic: injections into caudal low-frequency AI label laterorostral portions of MGv, whereas injections into rostral high-frequency AI label mediocaudal portions of MGv. All investigated auditory fields send axons to the suprageniculate, posterior limitans, laterodorsal and lateral posterior thalamic nuclei, with strongest projections from DP and VP, as well as to the reticular and subgeniculate thalamic nuclei. AI, AAF, DP and VP project to all three subdivisions of the inferior colliculus, namely the dorsal cortex, external cortex and central nucleus ipsilaterally and to the dorsal and external cortex contralaterally. They also project to the deep and intermediate layers of the ipsilateral superior colliculus, with strongest projections from DP and VP to the lateral and basolateral amygdaloid nuclei, the caudate putamen, globus pallidus and the pontine nuclei. In addition, AAF and particularly DP and VP project to paralemniscal regions around the dorsal nucleus of the lateral lemniscus (DNLL), to the DNLL itself and to the rostroventral aspect of the superior olivary complex. Moreover, DP and VP send axons to the dorsal lateral geniculate nucleus. The differences with respect to the existence and/or relative strengths of subcortical connections of the examined auditory cortical fields suggest a somewhat different function of each of these fields in auditory processing.