Distribution of the Noradrenaline Innervation and Adrenoceptors in the Macaque Monkey Thalamus.

Noradrenaline (NA) in the thalamus has important roles in physiological, pharmacological, and pathological neuromodulation. In this work, a complete characterization of NA axons and Alpha adrenoceptors distributions is provided. NA axons, revealed by immunohistochemistry against the synthesizing enzyme and the NA transporter, are present in all thalamic nuclei. The most densely innervated ones are the midline nuclei, intralaminar nuclei (paracentral and parafascicular), and the medial sector of the mediodorsal nucleus (MDm). The ventral motor nuclei and most somatosensory relay nuclei receive a moderate NA innervation. The pulvinar complex receives a heterogeneous innervation. The lateral geniculate nucleus (GL) has the lowest NA innervation. Alpha adrenoceptors were analyzed by in vitro quantitative autoradiography. Alpha-1 receptor densities are higher than Alpha-2 densities. Overall, axonal densities and Alpha adrenoceptor densities coincide; although some mismatches were identified. The nuclei with the highest Alpha-1 values are MDm, the parvocellular part of the ventral posterior medial nucleus, medial pulvinar, and midline nuclei. The nucleus with the lowest Alpha-1 receptor density is GL. Alpha-2 receptor densities are highest in the lateral dorsal, centromedian, medial and inferior pulvinar, and midline nuclei. These results suggest a role for NA in modulating thalamic involvement in consciousness, limbic, cognitive, and executive functions.

Brain dynamics and connectivity networks under natural auditory stimulation.

The analysis of functional magnetic resonance imaging (fMRI) data is challenging when subjects are under exposure to natural sensory stimulation. In this study, a two-stage approach was developed to enable the identification of connectivity networks involved in the processing of information in the brain under natural sensory stimulation. In the first stage, the degree of concordance between the results of inter-subject and intra-subject correlation analyses is assessed statistically. The microstructurally (i.e., cytoarchitectonically) defined brain areas are designated either as concordant in which the results of both correlation analyses are in agreement, or as discordant in which one analysis method shows a higher proportion of supra-threshold voxels than does the other. In the second stage, connectivity networks are identified using the time courses of supra-threshold voxels in brain areas contingent upon the classifications derived in the first stage. In an empirical study, fMRI data were collected from 40 young adults (19 males, average age 22.76 ±â€¯3.25), who underwent auditory stimulation involving sound clips of human voices and animal vocalizations under two operational conditions (i.e., eyes-closed and eyes-open). The operational conditions were designed to assess confounding effects due to auditory instructions or visual perception. The proposed two-stage analysis demonstrated that stress modulation (affective) and language networks in the limbic and cortical structures were respectively engaged during sound stimulation, and presented considerable variability among subjects. The network involved in regulating visuomotor control was sensitive to the eyes-open instruction, and presented only small variations among subjects. A high degree of concordance was observed between the two analyses in the primary auditory cortex which was highly sensitive to the pitch of sound clips. Our results have indicated that brain areas can be identified as concordant or discordant based on the two correlation analyses. This may further facilitate the search for connectivity networks involved in the processing of information under natural sensory stimulation.

Distribution of serotonin 5-HT1A-binding sites in the brainstem and the hypothalamus, and their roles in 5-HT-induced sleep and ingestive behaviors in rock pigeons (Columba livia).

Serotonin 1A receptors (5-HT1ARs), which are widely distributed in the mammalian brain, participate in cognitive and emotional functions. In birds, 5-HT1ARs are expressed in prosencephalic areas involved in visual and cognitive functions. Diverse evidence supports 5-HT1AR-mediated 5-HT-induced ingestive and sleep behaviors in birds. Here, we describe the distribution of 5-HT1ARs in the hypothalamus and brainstem of birds, analyze their potential roles in sleep and ingestive behaviors, and attempt to determine the involvement of auto-/hetero-5-HT1ARs in these behaviors. In 6 pigeons, the anatomical distribution of [(3)H]8-OH-DPAT binding in the rostral brainstem and hypothalamus was examined. Ingestive/sleep behaviors were recorded (1h) in 16 pigeons pretreated with MM77 (a heterosynaptic 5-HT1AR antagonist; 23 or 69 nmol) for 20 min, followed by intracerebroventricular ICV injection of 5-HT (N:8; 150 nmol), 8-OH-DPAT (DPAT, a 5-HT1A,7R agonist, 30 nmol N:8) or vehicle. 5-HT- and DPAT-induced sleep and ingestive behaviors, brainstem 5-HT neuronal density and brain 5-HT content were examined in 12 pigeons, pretreated by ICV with the 5-HT neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) or vehicle (N:6/group). The distribution of brainstem and diencephalic c-Fos immunoreactivity after ICV injection of 5-HT, DPAT or vehicle (N:5/group) into birds provided with or denied access to water is also described. 5-HT1ARs are concentrated in the brainstem 5-HTergic areas and throughout the periventricular hypothalamus, preoptic nuclei and circumventricular organs. 5-HT and DPAT produced a complex c-Fos expression pattern in the 5-HT1AR-enriched preoptic hypothalamus and the circumventricular organs, which are related to drinking and sleep regulation, but modestly affected c-Fos expression in 5-HTergic neurons. The 5-HT-induced ingestivebehaviors and the 5-HT- and DPAT-induced sleep behaviors were reduced by MM77 pretreatment. 5,7-DHT increased sleep per se, decreased tryptophan hydroxylase expression in the raphe nuclei and decreased prosencephalic 5-HT release but failed to affect 5-HT- or DPAT-induced drinking or sleep behavior. 5-HT- and DPAT-induced ingestive and sleep behaviors in pigeons appear to be mediated by heterosynaptic and/or non-somatodendritic presynaptic 5-HT1ARs localized to periventricular diencephalic circuits.

Detection of remote neuronal reactions in the Thalamus and Hippocampus induced by rat glioma using the PET tracer cis-4-[¹8F]fluoro-D-proline.

After cerebral ischemia or trauma, secondary neurodegeneration may occur in brain regions remote from the lesion. Little is known about the capacity of cerebral gliomas to induce secondary neurodegeneration. A previous study showed that cis-4-[(18)F]fluoro-D-proline (D-cis-[(18)F]FPro) detects secondary reactions of thalamic nuclei after cortical infarction with high sensitivity. Here we investigated the potential of D-cis-[(18)F]FPro to detect neuronal reactions in remote brain areas in the F98 rat glioma model using ex vivo autoradiography. Although the tumor tissue of F98 gliomas showed no significant D-cis-[(18)F]FPro uptake, we observed prominent tracer uptake in 7 of 10 animals in the nuclei of the ipsilateral thalamus, which varied with the specific connectivity with the cortical areas affected by the tumor. In addition, strong D-cis-[(18)F]FPro accumulation was noted in the hippocampal area CA1 in two animals with ipsilateral F98 gliomas involving hippocampal subarea CA3 rostral to that area. Furthermore, focal D-cis-[(18)F]FPro uptake was present in the necrotic center of the tumors. Cis-4-[(18)F]fluoro-D-proline uptake was accompanied by microglial activation in the thalamus, in the hippocampus, and in the necrotic center of the tumors. The data suggest that brain tumors induce secondary neuronal reactions in remote brain areas, which may be detected by positron emission tomography (PET) using D-cis-[(18)F]FPro.

Incongruence effects in crossmodal emotional integration.

Emotions are often encountered in a multimodal fashion. Consequently, contextual framing by other modalities can alter the way that an emotional facial expression is perceived and lead to emotional conflict. Whole brain fMRI data was collected when 35 healthy subjects judged emotional expressions in faces while concurrently being exposed to emotional (scream, laughter) or neutral (yawning) sounds. The behavioral results showed that subjects rated fearful and neutral faces as being more fearful when accompanied by screams than compared to yawns (and laughs for fearful faces). Moreover, the imaging data revealed that incongruence of emotional valence between faces and sounds led to increased activation in the middle cingulate cortex, right superior frontal cortex, right supplementary motor area as well as the right temporoparietal junction. Against expectations no incongruence effects could be found in the amygdala. Further analyses revealed that, independent of emotional valence congruency, the left amygdala was consistently activated when the information from both modalities was emotional. If a neutral stimulus was present in one modality and emotional in the other, activation in the left amygdala was significantly attenuated. These results indicate that incongruence of emotional valence in audiovisual integration activates a cingulate-fronto-parietal network involved in conflict monitoring and resolution. Furthermore in audiovisual pairing amygdala responses seem to signal also the absence of any neutral feature rather than only the presence of an emotionally charged one.

Neurotransmitter receptor imbalances in motor cortex and basal ganglia in hepatic encephalopathy.

Hepatic encephalopathy (HE) in chronic liver disease is characterized by neuropsychiatric and motor disturbances and associated with a net increase of inhibitory neurotransmission. Though many studies, mostly carried out in animal models, have linked dysfunctions of single neurotransmitter systems with the pathogenesis of HE, reports concerning neurotransmitter receptor alterations are controversial. Little is known about the situation in humans. We carried out a multireceptor assessment of HE-associated changes in neurotransmitter receptor densities and affinities in human post-mortem brain samples. Dissociation constants and densities of different binding sites for glutamate, GABA, acetylcholine, norepinephrine, serotonin, dopamine and adenosine were determined by in vitro binding assays and quantitative receptor autoradiography in the motor cortex and putamen of HE and control brains. HE cases do not build a homogeneous group, but differ concerning direction and intensity of binding site density divergences from control values. The acetylcholine M2 binding site dissociation constant was significantly higher in HE brains. Nicotinic acetylcholine and adenosine type 1 and 2A densities were significantly down-regulated in the putamen of HE brains. Our data suggest that neurotransmitter alterations are probably not the primary key factor responsible for the neuropsychiatric and motor disturbances associated with HE.

Element distribution is altered in a zone surrounding human glioblastoma multiforme.

Recent data indicate that A(1) adenosine receptor (A(1)AR) density is increased in a zone surrounding human and experimental gliomas. On the contrary, tumor tissue and adjacent brain tissue show low to intermediate A(1)AR densities. In order to assess whether changes in A(1)AR expression are indicating further processes of a chemical reorganization of the peritumoral zone, we investigated element concentrations and distribution patterns of copper and zinc in six human glioblastoma multiforme (GBM) specimens by laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS). Uranium and lead were used as external standards. Copper and zinc levels were increased in a peritumoral zone corresponding to the region of elevated A(1)AR density. They showed a lower density in the solid tumor in comparison to surrounding brain tissue, although the cellular density was higher within GBM. Our findings suggest that the immediate vicinity of GBM is characterized by increased levels of copper and zinc supporting the view that higher A(1)AR density surrounding GBM is not an isolated alteration of peritumoral tissue but an indicator of complex changes in the vicinity of infiltrative tumors. Further research is needed to explore the pathophysiological consequences of altered peritumoral element distribution.

Detection of secondary thalamic degeneration after cortical infarction using cis-4-18F-fluoro-D-proline.

UNLABELLED: The amino acid cis-4-(18)F-fluoro-D-proline (D-cis-(18)F-FPro) exhibits preferential uptake in the brain compared with its L-isomer, but the clinical potential of the tracer is as yet unknown. In this study we explored the cerebral uptake of D-cis-(18)F-FPro in rats with focal cortical infarctions. METHODS: Focal cortical infarctions were induced in different areas of the cortex of 20 Fisher CDF rats by photothrombosis (PT). At variable time points after PT (1 d to 4 wk), the rats were injected intravenously with D-cis-(18)F-FPro. For comparison, 12 rats were injected simultaneously with (3)H-deoxyglucose ((3)H-DG), 3 rats were injected with (3)H-methyl-L-methionine ((3)H-MET), and 2 rats were injected with (3)H-PK11195. Within 2 h after injection of the tracers, coronal cryosections of the brains were produced and evaluated by dual-tracer autoradiography. Lesion-to-brain ratios (L/B ratios) were calculated by dividing the maximal uptake in areas with increased tracer uptake by the mean uptake in normal brain tissue. Histologic slices were stained by toluidine blue and by immunostainings for glial fibrillary acidic protein (GFAP), CD68 for macrophages, and CD11b for microglia. RESULTS: Prominent uptake of D-cis-(18)F-FPro was found in ipsilateral thalamic nuclei (TN) and partially in the corpus striatum starting at 3 d after infarction with increasing L/B ratios up to 4 wk (mean L/B ratio +/- SD, 6.7 +/- 3.5). The involved TN varied with the site of the cortical lesion corresponding to their thalamocortical projections connecting them with their specific target region in the cerebral cortex. The TN were positive for CD11b and GFAP from day 7 onward, whereas uptake of (3)H-DG, (3)H-MET, and (3)H-PK11195 and immunostaining for CD68 were similar to that of normal brain. Furthermore, increased uptake of D-cis-(18)F-FPro was found in the area of the cortical infarctions (mean L/B ratio +/- SD, 12.1 +/- 8.1). From day 5 onward, the pattern of uptake was congruent with that of immunostaining for CD11b and CD68 but was different from that of GFAP. CONCLUSION: D-cis-(18)F-FPro appears to be a sensitive PET tracer for detection of secondary degeneration of TN after cortical injury. The uptake mechanisms of D-cis-(18)F-FPro remain to be elucidated, but the relationship to microglial activation suggests a diagnostic potential in various brain diseases.

Neural correlates of working memory dysfunction in first-episode schizophrenia patients: an fMRI multi-center study.

Working memory dysfunction is a prominent impairment in patients with schizophrenia. Our aim was to determine cerebral dysfunctions by means of functional magnetic resonance imaging (fMRI) in a large sample of first-episode schizophrenia patients during a working memory task. 75 first-episode schizophrenia patients and 81 control subjects, recruited within a multi-center study, performed 2- and 0-back tasks while brain activation was measured with fMRI. In order to guarantee comparability between data quality from different scanners, we developed and adopted a standardized, fully automated quality assurance of scanner hard- and software as well as a measure for in vivo data quality. After these quality-control measures had been implemented, 48 patients and 57 controls were included in the final analysis. During attention-related processes, even when the performance between patients and controls was comparable, there was a recognizable emergence of cerebral dysfunctions with hypoactivations in the ventrolateral prefrontal cortex (VLPFC), in the superior temporal cortex and in the thalamus. During working memory performance, parietal hypoactivations, especially in the precuneus, were prominent and were accompanied by poorer performance in patients. A hyperfrontality emerged in the ventrolateral prefrontal cortex. Hence, results point to a dysfunctional ventrolateral prefrontal-parietal network during working memory in patients, suggesting impairments in basic functions such as retrieval, storage and maintenance. The brain activation pattern of this large and significant sample of first-episode schizophrenia patients indicates an imbalanced system failing to adjust the amount of brain activity required in the cerebral network involved in attention and working memory.

When visual perception causes feeling: enhanced cross-modal processing in grapheme-color synesthesia.

In synesthesia, stimulation of one sensory modality (e.g., hearing) triggers a percept in another, non-stimulated sensory modality (e.g., vision). Likewise, perception of a form (e.g., a letter) may induce a color percept (i.e., grapheme-color synesthesia). To date, the neural mechanisms underlying synesthesia remain to be elucidated. We disclosed by fMRI, while controlling for surface color processing, enhanced activity in the left intraparietal cortex during the experience of grapheme-color synesthesia (n = 9). In contrast, the perception of surface color per se activated the color centers in the fusiform gyrus bilaterally. The data support theoretical accounts that grapheme-color synesthesia may originate from enhanced cross-modal binding of form and color. A mismatch of surface color and grapheme induced synesthetically felt color additionally activated the left dorsolateral prefrontal cortex (DLPFC). This suggests that cognitive control processes become active to resolve the perceptual conflict resulting from synesthesia.

Hierarchical processing of sound location and motion in the human brainstem and planum temporale.

Horizontal sound localization relies on the extraction of binaural acoustic cues by integration of the signals from the two ears at the level of the brainstem. The present experiment was aimed at detecting the sites of binaural integration in the human brainstem using functional magnetic resonance imaging and a binaural difference paradigm, in which the responses to binaural sounds were compared with the sum of the responses to the corresponding monaural sounds. The experiment also included a moving sound condition, which was contrasted against a spectrally and energetically matched stationary sound condition to assess which of the structures that are involved in general binaural processing are specifically specialized in motion processing. The binaural difference contrast revealed a substantial binaural response suppression in the inferior colliculus in the midbrain, the medial geniculate body in the thalamus and the primary auditory cortex. The effect appears to reflect an actual reduction of the underlying activity, probably brought about by binaural inhibition or refractoriness at the level of the superior olivary complex. Whereas all structures up to and including the primary auditory cortex were activated as strongly by the stationary as by the moving sounds, non-primary auditory fields in the planum temporale responded selectively to the moving sounds. These results suggest a hierarchical organization of auditory spatial processing in which the general analysis of binaural information begins as early as the brainstem, while the representation of dynamic binaural cues relies on non-primary auditory fields in the planum temporale.

Anxiety-related behavior and densities of glutamate, GABAA, acetylcholine and serotonin receptors in the amygdala of seven inbred mouse strains.

The amygdala is a brain region involved in the regulation of anxiety-related behavior. The purpose of this study was to correlate anxiety-related behavior of inbred mouse strains (BA//c, BALB/cJ, C3H/HeJ, C57BL/6J, CPB-K, DBA/2J, NMRI) to receptor binding in the amygdala. Binding site densities of receptors (NMDA, AMPA, kainate, GABA(A), serotonin, muscarinergic M(1)-M(2)) were measured with quantitative receptor autoradiography using tritiated ligands. Measurements of fear-sensitized acoustic startle response (ASR; induced by footshocks), elevated plus maze (EPM) behavior and receptor binding studies showed differences between the strains except for AMPA and muscarinergic M(2) receptors. Factor analysis revealed a Startle Factor with positive loadings of the density of serotonin and kainate receptors, and the amplitudes of the baseline and fear-sensitized ASRs. A second Anxiety-related Factor only correlated with the fear-sensitized ASR and anxiety parameters on the EPM but not receptor densities. There were also two General Activity Factors defined by (negative) correlations with entries to closed arms of the EPM. Because the density of NMDA and muscarinergic M(1) receptors also correlated negatively with the two factors, these receptors had a positive effect on general activity. In contrast, correlations of GABA(A), serotonin, and kainate receptors had the opposite sign as compared to closed arm entries. It is concluded that hereditary variations in the amygdala, particularly in kainate and serotonin receptors, play a role for the baseline and fear-sensitized ASR, whereas the general activity is influenced by many neurotransmitter receptor systems.

Differential involvement of parietal and precentral regions in movement preparation and motor intention.

Flexible goal-oriented behavior relies on spatial coordinate transformations and motor control mechanisms, but also on the capability to take advantage of contextual information for steering the sensorimotor machinery. Although accurate performance of a sensorimotor task requires parietal and frontal regions, their differential contribution and functional relationship with other associative regions remains obscure. We have used event-related functional magnetic resonance imaging to measure human cerebral activity associated with motor cognitive processes in the context of delayed performance of an associative visuomotor task. Movement instruction (specified by visual cues) and motor performance (specified by an auditory cue) were separated by a variable delay period. By manipulating the predictive value of the instruction cue, we distinguished delay-related activity influenced by response probabilities (motor preparation and motor inhibition) from delay-related activity unaffected by the likelihood of providing a motor response (motor intention). We found delay-related activity distributed across a cerebral network involving not only frontal circuitry, but also extrastriate and mediotemporal regions. Areas showing motor intentions and preparatory responses were spatially intermingled. Posterior parietal cortex deviated from this pattern, showing delay-related activity regardless of movement probability, but no specific preparatory responses. These results suggest that posterior parietal cortex and dorsal precentral cortex play different strategic roles in handling associative visuomotor problems. While parietal regions cover a range of potential responses defined by the task setting, precentral regions focus on a likely movement. Temporo-prefrontal regions might incorporate contextual information in the visuomotor process by defining potential and probable responses on the basis of the task contingencies.

Expression of c-Fos, ICER, Krox-24 and JunB in the whisker-to-barrel pathway of rats: time course of induction upon whisker stimulation by tactile exploration of an enriched environment.

Modified tactile information has been shown to induce adaptive plasticity in the somatosensory cortex of rat. The cellular mechanisms resulting in plastic neuronal responses, however, are largely unknown. Inducible transcription factors have been proposed as one major link in the cascade from modified input to altered neuronal structure and function. We investigated the spatial and temporal patterns of transcription factor induction in the rat whisker-to-barrel pathway by placing the animals in a novel, enriched environment while having clipped sets of whiskers on one side of the face. Such stimulation resulted not only in a specific c-Fos induction in brainstem barrelettes and thalamic barreloids, but also in the barrel-related cortical columns, each with different time courses. In the barrel cortex, c-Fos and Krox-24 immunostaining showed a rapid induction with peak levels at 1 h and a return to basal levels after 14 h. JunB was induced after 1 h of exploration, declined at 6 h and returned to basal levels after this time point. The inducible cyclic AMP early repressor (ICER), a transcription factor of the cAMP signaling pathway, showed a maximum after 6 h, decreased slowly, but elevated levels were still detectable after 5 days. Our data demonstrate that upon whisker stimulation by exploration of a novel, enriched environment, (i) subcortical relay stations in the whisker-to-barrel pathway are able to express elevated levels of c-Fos and (ii) in the barrel cortex c-Fos, JunB, Krox-24 and ICER are differentially regulated in the temporal domain.