Dissecting neural circuits for multisensory integration and crossmodal processing

We rely on rich and complex sensory information to perceive and understand our environment. Our multisensory experience of the world depends on the brain''s remarkable ability to combine signals across sensory systems. Behavioural, neurophysiological and neuroimaging experiments have established principles of multisensory integration and candidate neural mechanisms. Here we review how targeted manipulation of neural activity using invasive and non-invasive neuromodulation techniques have advanced our understanding of multisensory processing. Neuromodulation studies have provided detailed characterizations of brain networks causally involved in multisensory integration. Despite substantial progress, important questions regarding multisensory networks remain unanswered. Critically, experimental approaches will need to be combined with theory in order to understand how distributed activity across multisensory networks collectively supports perception.     

The Arabidopsis cax1 mutant exhibits impaired ion homeostasis,development, and hormonal responses and reveals interplay among vacuolar transporters

The Arabidopsis Ca(2+)/H(+) transporter CAX1 (Cation Exchanger1) may be an important regulator of intracellular Ca(2+) levels. Here, we describe the preliminary localization of CAX1 to the tonoplast and the molecular and biochemical characterization of cax1 mutants. We show that these mutants exhibit a 50% reduction in tonoplast Ca(2+)/H(+) antiport activity, a 40% reduction in tonoplast V-type H(+)-translocating ATPase activity, a 36% increase in tonoplast Ca(2+)-ATPase activity, and increased expression of the putative vacuolar Ca(2+)/H(+) antiporters CAX3 and CAX4. Enhanced growth was displayed by the cax1 lines under Mn(2+) and Mg(2+) stress conditions. The mutants exhibited altered plant development, perturbed hormone sensitivities, and altered expression of an auxin-regulated promoter-reporter gene fusion. We propose that CAX1 regulates myriad plant processes and discuss the observed phenotypes with regard to the compensatory alterations in other transporters.     

Personality influences the neural responses to viewing facial expressions of emotion

Cognitive research has long been aware of the relationship between individual differences in personality and performance on behavioural tasks. However, within the field of cognitive neuroscience, the way in which such differences manifest at a neural level has received relatively little attention. We review recent research addressing the relationship between personality traits and the neural response to viewing facial signals of emotion. In one section, we discuss work demonstrating the relationship between anxiety and the amygdala response to facial signals of threat. A second section considers research showing that individual differences in reward drive (behavioural activation system), a trait linked to aggression, influence the neural responsivity and connectivity between brain regions implicated in aggression when viewing facial signals of anger. Finally, we address recent criticisms of the correlational approach to fMRI analyses and conclude that when used appropriately, analyses examining the relationship between personality and brain activity provide a useful tool for understanding the neural basis of facial expression processing and emotion processing in general.     

The interplay between BRCA1 and 53BP1 influences death,aging, senescence and cancer

In proliferating cells DNA double strand breaks (DSBs) are a common occurrence during DNA replication. DSB repair using homologous recombination is essential for the error-free repair of such breaks and proliferating cells require some level of HR activity for their viability. The BRCA1 tumour suppressor has an important role in this process and is believed to channel the DSBs into the HR pathway. The related 53BP1 gene is known to positively regulate repair of DSBs outside of S phase, but via the NHEJ pathway. Two new studies suggest a new role for 53BP1 as an inhibitor of HR [1], [2]. These genetic studies establish that 53BP1, but not other components of the NHEJ machinery, can inhibit the early resection step of HR. In cells defective for BRCA1, which is required for efficient HR, the balance between promoting and inhibiting HR is thrown towards inhibition. Simultaneous loss of 53BP1 can rescue the HR defect of BRCA1-defective cells and restore cellular viability. Here, I provide an overview of these studies and discuss their implications for tumourigenesis.     

Environmental influences on neural crest cell migration

Neural crest cells migrate extensively and interact with numerous tissues and extracellular matrix components during their movement. Cell marking techniques have shown that neural crest cells in the trunk of the avian embryo migrate through the anterior, but not posterior, half of each sclerotome and avoid the region around the notochord. A possible mechanism to account for this migratory pattern is that neural crest cells may be inhibited from entering the posterior sclerotome and the perinotochordal space. Thus, interactions with other tissue may prescribe the pattern of neural crest cell migration in the trunk. In contrast, interactions between neural crest cells and the extracellular matrix may mediate the primary interactions controlling neural crest cells migration in the head region. © 1993 John Wiley & Sons, Inc.     

Neonatal rat microglia derived from different brain regions have distinct activation responses

The regional heterogeneity of neuronal phenotypes is a well-known phenomenon. Whether or not glia derived from different brain regions are phenotypically and functionally distinct is less clear. Here, we show that microglia, the resident immune cells of the brain, display region-specific responses for activating agents including glutamate (GLU), lipopolysaccharide (LPS) and adenosine 5'-triphosphate (ATP). Primary microglial cultures were prepared from brainstem (Brs), cortex (Ctx), hippocampus (Hip), striatum (Str) and thalamus (Thl) of 1-day-old rats and were shown to upregulate the release of nitric oxide (NO) and brain-derived neurotrophic factor (BDNF) in a region- and activator-specific manner. With respect to ATP specifically, ATP-induced changes in microglial tumor necrosis factor-α (TNF-α) release, GLU uptake and purinergic receptor expression were also regionally different. When co-cultured with hypoxia (Hyp)-injured neurons, ATP-stimulated microglia from different regions induced different levels of neurotoxicity. These region-specific responses could be altered by pre-conditioning the microglia in a different neurochemical milieu, with taurine (TAU) being one of the key molecules involved. Together, our results demonstrate that microglia display a regional heterogeneity when activated, and this heterogeneity likely arises from differences in the environment surrounding the microglia. These findings present an additional mechanism that may help to explain the regional selectiveness of various brain pathologies.     

Mapping of the presumptive brain regions in the neural plate of Xenopus laevis

Two cell autonomous fluorescent labels (DiI and Hoechst) were used as vital markers in a fate map study of the Xenopus neural plate and ridge. Most areas of the brain derive from the neural plate in a fate map that is consistent with the topology of a sheet rolling into a tube, i.e., neighboring areas are maintained as neighbors. This has enabled us not only to plot the fates of larval brain structures, but also to suggest their primordial orientation in the neural plate. Since overlapping areas of the plate gave rise to overlapping regions of the central nervous system (CNS), we have been able to construct a space-filling model of the neural plate, whereby the number of founder cells for each brain region fate-mapped may be estimated roughly. Much of the telencephalon, ventral forebrain, and dorsal brain stem derives from the neural ridge and not the neural plate in the stage 15 Xenopus embryo. The structures of the forebrain were examined in detail because there were indications of substantial cell movements in this region. The anterior pituitary arises from the mid-anterior ridge, while hypothalamic structures arise from the midline regions of the anterior neural plate. Consistent groups of ventral hypothalamic structures were labeled when fluorescent markers were applied to these parts of the neural plate, indicating stereotyped cell movements. Detailed comparisons were made between the fate map of the Ambystoma neural plate (Jacobson, 1959) and that of Xenopus.     

High-speed imaging of developing heart valves reveals interplay of morphogenesis and function

Knowing how mutations disrupt the interplay between atrioventricular valve (AVV) morphogenesis and function is crucial for understanding how congenital valve defects arise. Here, we use high-speed fluorescence microscopy to investigate AVV morphogenesis in zebrafish at cellular resolution. We find that valve leaflets form directly through a process of invagination, rather than first forming endocardial cushions. There are three phases of valve function in embryonic development. First, the atrioventricular canal (AVC) is closed by the mechanical action of the myocardium, rolls together and then relaxes. The growing valve leaflets serve to block the canal during the roll and, depending on the developmental stage, either expand or hang down as a leaflet to block the canal. These steps are disrupted by the subtle morphological changes that result from inhibiting ErbB-, TGFbeta-or Cox2 (Ptgs2)-dependent signaling. Cox2 inhibition affects valve development due to its effect on myocardial cell size and shape, which changes the morphology of the ventricle and alters valve geometry. Thus, different signaling pathways regulate distinct aspects of the behavior of individual cells during valve morphogenesis, thereby influencing specific facets of valve function.     

Metabolic responses in discrete regions of rat brain following acute administration of glutamate

Glutamate is a major excitatory neurotransmitter in the mammalian brain. Nevertheless, high extracellular levels of this amino acid have been shown to be toxic to several neuronal populations, but no data are available to show how glutamate homeostasis is altered in response to local infusion of glutamate. In the present study, 1 M of glutamate was stereotactically injected into cerebral cortex, striatum, and hippocampus of adult rat brain, and the activities of key metabolic enzymes, lactate dehydrogenase, glutamate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase were evaluated by postmortem analysis in tissue homogenates. The results show that glutamate bolus, induced significant alterations in vivo glutamate and energy metabolism, as evidenced by marked alterations in these enzyme activities, whereas dizocilpine, a glutamate receptor antagonist, negated many of the effects induced by high glutamate. However, the degree of involvement of these observations in glutamate-induced neurotoxicity remains to be ascertained.     

Visualizing genetic influences on human brain functions

, in this issue of Cell, integrate genetics and functional brain imaging by showing that variation in the human brain-derived neurotrophic factor (BDNF) gene is associated with variation in episodic memory ability and in hippocampal neurochemistry and function.     

Thermodynamic constraints on neural dimensions,firing rates,brain temperature and size

There have been suggestions that heat caused by cerebral metabolic activity may constrain mammalian brain evolution, architecture, and function. This article investigates physical limits on brain wiring and corresponding changes in brain temperature that are imposed by thermodynamics of heat balance determined mainly by Na⁺/K⁺-ATPase, cerebral blood flow, and heat conduction. It is found that even moderate firing rates cause significant intracellular Na⁺ build-up, and the ATP consumption rate associated with pumping out these ions grows nonlinearly with frequency. Surprisingly, the power dissipated by the Na⁺/K⁺ pump depends biphasically on frequency, which can lead to the biphasic dependence of brain temperature on frequency as well. Both the total power of sodium pumps and brain temperature diverge for very small fiber diameters, indicating that too thin fibers are not beneficial for thermal balance. For very small brains blood flow is not a sufficient cooling mechanism deep in the brain. The theoretical lower bound on fiber diameter above which brain temperature is in the operational regime is strongly frequency dependent but finite due to synaptic depression. For normal neurophysiological conditions this bound is at least an order of magnitude smaller than average values of empirical fiber diameters, suggesting that neuroanatomy of the mammalian brains operates in the thermodynamically safe regime. Analytical formulas presented can be used to estimate average firing rates in mammals, and relate their changes to changes in brain temperature, which can have important practical applications. In general, activity in larger brains is found to be slower than in smaller brains.     

Brain 12-HETE formation in different species,brain regions,and in brain microvessels

We used gas chromatography/mass spectrometry to measure brain 12-HETE (12-Hydroxy-5,8,10,14-eicosatetraenoic acid) formation from endogenous arachidonic acid in different species and different brain regions and in isolated brain microvessels. When blood-free brain slices were incubated for 20 minutes we found that the rabbit and cat brain incubates contained little 12-HETE when compared to rat and mouse brain incubates. Further in vitro studies of various rat brain regions showed a generally even distribution of 12-HETE. When isolated rat or rabbit microvessels were incubated and analyzed, we found 1 and 0.25 g, respectively, of 12-HETE/mg of microvessel protein. Also, rabbit brain had limited or no capacity to actively metabolize tritiated 12-HETE. In summary, these studies show substantial species variation with respect to brain formation of 12-HETE and indicate that the vasculature is a potentially significant contributor to the 12-HETE found in whole brain tissue.     

Genetic influences on the neural basis of social cognition

The neural basis of social cognition has been the subject of intensive research in both human and non-human primates. Exciting, provocative and yet consistent findings are emerging. A major focus of interest is the role of efferent and afferent connectivity between the amygdala and the neocortical brain regions, now believed to be critical for the processing of social and emotional perceptions. One possible component is a subcortical neural pathway, which permits rapid and preconscious processing of potentially threatening stimuli, and it leads from the retina to the superior colliculus, to the pulvinar nucleus of the thalamus and then to the amygdala. This pathway is activated by direct eye contact, one of many classes of potential threat, and may be particularly responsive to the 'whites of the eyes'. In humans, autonomic arousal evoked by this stimulus is associated with the activity in specific cortical regions concerned with processing visual information from faces. The integrated functioning of these pathways is modulated by one or more X-linked genes, yet to be identified. The emotional responsiveness of the amygdala, and its associated circuits, to social threat is also influenced by functional polymorphisms in the promoter of the serotonin transporter gene. We still do not have a clear account of how specific allelic variation, in candidate genes, increases susceptibility to developmental disorders, such as autism, or psychiatric conditions, such as anxiety or depressive illness. However, the regulation of emotional responsiveness to social cues lies at the heart of the problem, and recent research indicates that we may be nearing a deeper and more comprehensive understanding.     

Multisensory integration: space, time and superadditivity

The superior colliculus generates and controls eye and head movements based on signals from different senses. The latest research on this structure enhances our understanding of the mechanisms of multisensory integration in the brain.     

Multisensory integration: methodological approaches and emerging principles in the human brain.

Understanding the conditions under which the brain integrates the different sensory streams and the mechanisms supporting this phenomenon is now a question at the forefront of neuroscience. In this paper, we discuss the opportunities for investigating these multisensory processes using modern imaging techniques, the nature of the information obtainable from each method and their benefits and limitations. Despite considerable variability in terms of paradigm design and analysis, some consistent findings are beginning to emerge. The detection of brain activity in human neuroimaging studies that resembles multisensory integration responses at the cellular level in other species, suggests similar crossmodal binding mechanisms may be operational in the human brain. These mechanisms appear to be distributed across distinct neuronal networks that vary depending on the nature of the shared information between different sensory cues. For example, differing extents of correspondence in time, space or content seem to reliably bias the involvement of different integrative networks which code for these cues. A combination of data obtained from haemodynamic and electromagnetic methods, which offer high spatial or temporal resolution respectively, are providing converging evidence of multisensory interactions at both "early" and "late" stages of processing--suggesting a cascade of synergistic processes operating in parallel at different levels of the cortex.     

Imaging taste responses in the fly brain reveals a functional map of taste category and behavior

The sense of taste allows animals to distinguish nutritious and toxic substances and elicits food acceptance or avoidance behaviors. In Drosophila, taste cells that contain the Gr5a receptor are necessary for acceptance behavior, and cells with the Gr66a receptor are necessary for avoidance. To determine the cellular substrates of taste behaviors, we monitored taste cell activity in vivo with the genetically encoded calcium indicator G-CaMP. These studies reveal that Gr5a cells selectively respond to sugars and Gr66a cells to bitter compounds. Flies are attracted to sugars and avoid bitter substances, suggesting that Gr5a cell activity is sufficient to mediate acceptance behavior and that Gr66a cell activation mediates avoidance. As a direct test of this hypothesis, we inducibly activated different taste neurons by expression of an exogenous ligand-gated ion channel and found that cellular activity is sufficient to drive taste behaviors. These studies demonstrate that taste cells are tuned by taste category and are hardwired to taste behaviors.     

Changes in energy metabolism in several brain regions and vegetative responses of white rats during neurotization

Changes of vegetative reactions and cytochrome oxidase (CChO) activity in various brain structures were studied in rats during neurotization. One week neurotization led to an increase of arterial blood pressure, respiration rate, cardiac stroke volume and heart rate. In three weeks of neurotization there was a decrease of stroke volume accompanied by an increase of heart rate and some decrease or respiration rate leading to a reduction of oxygen consumption. Neurotization during one and especially three weeks elicited an enhancement of CChO activity in various brain areas, more pronounced in the cerebral cortex. A four week "rest" after neurotization during three weeks normalized the CChO activity. CChO activation during neurotization is supposed to be one of the mechanisms of adaptation to hypoxia accompanying neurosis.