Cortical control of reaching movements

Recent studies provide further support for the hypothesis that spatial representations of limb position, target locations, and potential motor actions are expressed in the neuronal activity in parietal cortex. In contrast, precentral cortical activity more strongly expresses processes involved in the selection and execution of motor actions. As a general conceptual framework, these processes may be interpreted in terms of such formalisms as sensorimotor transformation and ‘internal models’.     

Population coding and behavioral choice

Many individual behavioral acts are produced by the combined activity of large populations of broadly tuned neurons, and the neuronal populations for different behaviors can overlap. Recent experiments monitoring and manipulating neuronal activity during behavioral decisions have begun to shed light on the mechanisms that enable overlapping populations of neurons to generate choices between categorically distinct behaviors.     

Visuomotor transformations: early cortical mechanisms of reaching

Recent studies of visually guided reaching in monkeys support the hypothesis that the visuomotor transformations underlying arm movements to spatial targets involve a parallel mechanism that simultaneously engages functionally related frontal and parietal areas linked by reciprocal cortico-cortical connections. The neurons in these areas possess similar combinations of response properties. The multimodal combinatorial properties of these neurons and the gradient architecture of the parieto-frontal network emerge as a potential substrate to link the different sensory and motor signals that arise during reaching behavior into common hybrid reference frames. This convergent combinatorial process is evident at early stages of visual information processing in the occipito-parietal cortex, suggesting the existence of re-entrant motor influences on cortical areas once believed to have only visual functions.     

Genes and photons: new avenues into the neuronal basis of behavior

A convergence of advances in optical methods and a better understanding of the genetics of development promise to revolutionize the study of neuronal circuits and their links to behavior. One of the great challenges in systems neurobiology has been to monitor and perturb activity in populations of identified neurons in vivo. Recent work has begun to achieve this goal through a combination of modern imaging methods with genetic labeling and perturbation.     

Contributions of functional imaging to understanding parkinsonian symptoms

Brain imaging experiments identify plausible circuits involved in the genesis of the cardinal symptoms of Parkinson's disease. Akinesia is linked to hypoactivation of the supplementary motor area secondary to insufficient thalamocortical facilitation. Overactivation in other areas such as the lateral premotor and parietal cortex probably represents a compensatory mechanism. Bradykinesia is associated with abnormal functioning within intrinsic basal ganglia circuitry for scaling movements to appropriate magnitude. Parkinson's disease tremor is localized to pontine- and mesencephalic-cerebellar-thalamic circuits, with abnormalities of both dopamine and serotonin neurotransmission. There is a need to understand the anatomic intersections where information is shared across these circuits.     

A platypus' eye view of the mammalian genome

The genome of monotremes, like the animals themselves, is unique and strange. The importance of monotremes to genomics depends on their position as the earliest offshoot of the mammalian lineage. Although there has been controversy in the literature over the phylogenetic position of monotremes, this traditional interpretation is now confirmed by recent sequence comparisons. Characterizing the monotreme genome will therefore be important for studying the evolution and organization of the mammalian genome, and the proposal to sequence the platypus genome has been received enthusiastically by the genomics community. Recent investigations of X-chromosome inactivation, genomic imprinting and sex chromosome evolution provide good examples of the power of the monotreme genome to inform us about mammalian genome organization and evolution.     

New concepts of the supplementary motor area

The supplementary motor area, although traditionally defined as a single motor area, is not viewed as including at least three different areas that can be distinguished anatomically and physiologically. The differential use of these three areas for various motor behaviors has been the subject of recent studies that are beginning to provide novel concepts of the functional differentiation of each area.     

Visuomotor functions of the lateral pre-motor cortex

Recent studies have provided new insights into the visuomotor functions of the dorsal and ventral regions of the lateral pre-motor cortex. Anatomical and physiological investigations in non-human primates have demonstrated that these regions have differing patterns of cortical connectivity and distinctive neuronal responses. Brain-imaging techniques and lesion studies have begun to probe the functions of homologous regions in humans.     

Interactions between motor commands and somatic perception in sensorimotor cortex

For many years, it has been postulated that interactions between motor commands and somatic perception in the sensorimotor cortices exist, but they have been difficult to demonstrate. Recent studies have made demonstration of this interaction easier and suggest that cortical activity related to somatic sensation and perception is modified by movement-generating mechanism. Corollary discharge and efference copy may also play a role in motor behavior.     

plusTipTracker: Quantitative image analysis software for the measurement of microtubule dynamics

Here we introduce plusTipTracker, a Matlab-based open source software package that combines automated tracking, data analysis, and visualization tools for movies of fluorescently-labeled microtubule (MT) plus end binding proteins (+TIPs). Although +TIPs mark only phases of MT growth, the plusTipTracker software allows inference of additional MT dynamics, including phases of pause and shrinkage, by linking collinear, sequential growth tracks. The algorithm underlying the reconstruction of full MT trajectories relies on the spatially and temporally global tracking framework described in Jaqaman et al. (2008). Post-processing of track populations yields a wealth of quantitative phenotypic information about MT network architecture that can be explored using several visualization modalities and bioinformatics tools included in plusTipTracker. Graphical user interfaces enable novice Matlab users to track thousands of MTs in minutes. In this paper, we describe the algorithms used by plusTipTracker and show how the package can be used to study regional differences in the relative proportion of MT subpopulations within a single cell. The strategy of grouping +TIP growth tracks for the analysis of MT dynamics has been introduced before (Matov et al., 2010). The numerical methods and analytical functionality incorporated in plusTipTracker substantially advance this previous work in terms of flexibility and robustness. To illustrate the enhanced performance of the new software we thus compare computer-assembled +TIP-marked trajectories to manually-traced MT trajectories from the same movie used in Matov et al. (2010).     

Functions and structures of the motor cortices in humans

Humans and non-human primates have several motor areas. Exactly how many is a matter of current debate. A proper parcellation of motor areas must be based on correlated structural and functional differences. Recent studies indicate that the primary motor cortex may be, in reality, two areas (4a and 4p). Similarly, there are undoubtedly two or more cingulate motor areas and perhaps two supplementary motor areas. The homologies between human and monkey brains are striking in some cases, making monkey models of human motor cortices attractive. The doctrine of a strict ‘homuncular’ somatotopical organization of motor areas will have to be abandoned. The engagement of motor areas in different types of voluntary seems merely a matter of degree of activation rather than exclusive specific contributions.     

Inhibition by purine nucleotides of the release of reactive oxygen species from muscle mitochondria: indication for a function of uncoupling proteins as superoxide anion transporters

Release of reactive oxygen species (ROS), measured as the sum of hydrogen peroxide (H₂O₂) and superoxide anion radical (), from respiring rat heart and skeletal muscle mitochondria was significantly decreased by millimolar concentrations of GTP or GDP. Attempts to differentiate between the two forms of ROS showed that the release of rather than that of H₂O₂ was affected. Meanwhile, intramitochondrial ROS accumulation, measured by inactivation of aconitase, increased. These results suggest that guanine nucleotides inhibit the release of from mitochondria. As these nucleotides are known inhibitors of uncoupling proteins (UCPs), it is proposed that UCPs may function as carriers of , thus enabling its removal from the matrix compartment.     

Sensory pathways and their modulation in the control of locomotion

Recent experiments have extended our understanding of how sensory information in premotor networks controlling motor output is processed during locomotion, and at what level the efficacy of specific sensory—motor pathways is determined. Phasic presynaptic inhibition of sensory transmission combined with postsynaptic alterations of excitatory and inhibitory synaptic transmission from interneurons of the premotor networks contribute to the modulation of reflex pathways and to the generation of reflex reversal. These mechanisms play an important role in adapting the operation of central networks to external demands and thus help optimize sensory—motor integration.     

JWA regulates chronic morphine dependence via the delta opioid receptor

Opioid dependence is correlated with the adaptive changes at the cellular level following chronic opioid use, and believed to be the main cause for the relapse of drug taking behavior of addicts. Despite decades of intensive studies, the underlying mechanisms of morphine dependence are still unclear. Here, we present evidence that JWA was induced by chronic morphine treatment in specific brain regions, and knockdown of JWA expression significantly reduced the withdrawal response to chronic morphine treatment in rats. We further demonstrated that the morphine induced DOR expression, while activation of DARPP-32 and MAP kinase was suppressed by JWA knockdown. Through an in vitro cell model of chronic morphine exposure, we also found that JWA is required for maintaining the stability of DOR via the ubiquitin–proteasome pathway. These observations suggest that JWA is directly involved in the regulation of chronic morphine dependence.     

Melittin activates TRPV1 receptors in primary nociceptive sensory neurons via the phospholipase A2 cascade pathways

Previous studies demonstrated that melittin, the main peptide in bee venom, could cause persistent spontaneous pain, primary heat and mechanical hyperalgesia, and enhance the excitability of spinal nociceptive neurons. However, the underlying mechanism of melittin-induced cutaneous hypersensitivity is unknown. Effects of melittin applied topically to acutely dissociated rat dorsal root ganglion neurons were studied using whole-cell patch clamp and calcium imaging techniques. Melittin induced intracellular calcium increases in 60% of small (<25 μm) and medium (<40 μm) diameter sensory neurons. In current clamp, topical application of melittin evoked long-lasting firing in 55% of small and medium-sized neurons tested. In voltage clamp, melittin evoked inward currents in sensory neurons in a concentration-dependent manner. Repeated application of melittin caused increased amplitude of the inward currents. Most melittin-sensitive neurons were capsaicin-sensitive, and 65% were isolectin B4 positive. Capsazepine, the TRPV1 receptor inhibitor, completely abolished the melittin-induced inward currents and intracellular calcium transients. Inhibitions of signaling pathways showed that phospholipase A₂, but not phospholipase C, was involved in producing the melittin-induced inward currents. Inhibitors of cyclooxygenases (COX) and lipoxygenases (LOX), two key components of the arachidonic acid metabolism pathway, each partially suppressed the inward current evoked by melittin. Inhibitors of protein kinase A (PKA), but not of PKC, also abolished the melittin-induced inward currents. These results indicate that melittin can directly excite small and medium-sized sensory neurons at least in part by activating TRPV1 receptors via PLA2-COXs/LOXs cascade pathways.     

Functional imaging of membrane potential at the single mitochondrion level: Possible application for diagnosis of human diseases

Functional biochemical tests are the gold standard for the diagnosis of mitochondria-related diseases. However, the availability of the biological samples from patients' tissues represents a severe limitation to the number of screenable enzymatic activities. In this study we developed a fluorescent probe-assisted microscopy protocol enabling to assess the ΔΨ_m-generating capacity by mitochondria immobilized on a glass surface at the single organelle resolution-level. The advantage of this assay over others is to scale-down the amount of the biological sample required to test in a short time the functional activity of all the components of the oxidative phosphorylation system without loss of accuracy. Furthermore, the distribution of a given enzymatic activity can also be evaluated within the mitochondrial population enabling to measure the level of functional heterogeneity of the respiratory chain dysfunction.     

Indocyanine green clearance varies as a function of N-acetylcysteine treatment in a murine model of acetaminophen toxicity

Standard assays to assess acetaminophen (APAP) toxicity in animal models include determination of ALT (alanine aminotransferase) levels and examination of histopathology of liver sections. However, these assays do not reflect the functional capacity of the injured liver. To examine a functional marker of liver injury, the pharmacokinetics of indocyanine green (ICG) were examined in mice treated with APAP, saline, or APAP followed by N-acetylcysteine (NAC) treatment.Male B6C3F1 mice were administered APAP (200 mg/kg IP) or saline. Two additional groups of mice received APAP followed by NAC at 1 or 4 h after APAP. At 24 h, mice were injected with ICG (10 mg/kg IV) and serial blood samples (0, 2, 10, 30, 50 and 75 min) were obtained for determination of serum ICG concentrations and ALT. Mouse livers were removed for measurement of APAP protein adducts and examination of histopathology. Toxicity (ALT values and histology) was significantly increased above saline treated mice in the APAP and APAP/NAC 4 h mice. Mice treated with APAP/NAC 1 h had complete protection from toxicity. APAP protein adducts were increased in all APAP treated groups and were highest in the APAP/NAC 1 h group. Pharmacokinetic analysis of ICG demonstrated that the total body clearance (Cl_T) of ICG was significantly decreased and the mean residence time (MRT) was significantly increased in the APAP mice compared to the saline mice. Mice treated with NAC at 1 h had Cl_T and MRT values similar to those of saline treated mice. Conversely, mice that received NAC at 4 h had a similar ICG pharmacokinetic profile to that of the APAP only mice. Prompt treatment with NAC prevented loss of functional activity while late treatment with NAC offered no improvement in ICG clearance at 24 h. ICG clearance in mice with APAP toxicity can be utilized in future studies testing the effects of novel treatments for APAP toxicity.     

A Simplified Mass-Transfer Model for Visual Pigments in Amphibian Retinal-Cone Outer Segments

When radiolabeled precursors and autoradiography are used to investigate turnover of protein components in photoreceptive cone outer segments (COSs), the labeled components—primarily visual pigment molecules (opsins)—are diffusely distributed along the COS. To further assess this COS labeling pattern, we derive a simplified mass-transfer model for quantifying the contributions of advective and diffusive mechanisms to the distribution of opsins within COSs of the frog retina. Two opsin-containing regions of the COS are evaluated: the core axial array of disks and the plasmalemma. Numerical solutions of the mass-transfer model indicate three distinct stages of system evolution. In the first stage, plasmalemma diffusion is dominant. In the second stage, the plasmalemma density reaches a metastable state and transfer between the plasmalemma and disk region occurs, which is followed by an increase in density that is qualitatively similar for both regions. The final stage consists of both regions slowly evolving to the steady-state solution. Our results indicate that autoradiographic and cognate approaches for tracking labeled opsins in the COS cannot be effective methodologies for assessing new disk formation at the base of the COS.