Exploratory whisking in rat is an example of self-generated movement on multiple time scales, from slow variations in the envelope of whisking to the rapid sequence of muscle contractions during a single whisk cycle. We find that, as a population, spike trains of single units in primary vibrissa motor cortex report the absolute angle of vibrissa position. This representation persists after sensory nerve transection, indicating an efferent source. About two-thirds of the units are modulated by slow variations in the envelope of whisking while relatively few units report rapid changes in position within the whisk cycle. The combined results from this study and past measurements, which show that primary sensory cortex codes the whisking envelope as a motor copy signal, imply that signals present in both sensory and motor cortices are necessary to compute coordinates based on vibrissa touch.

Sensory perception involves the dual challenge of encoding external stimuli and managing the influence of changes in body position that alter the sensory field. To examine mechanisms used to integrate sensory signals elicited by both external stimuli and motor activity, we recorded from rats trained to rhythmically sweep their vibrissa in search of a target. We found a select population of neurons in primary somatosensory cortex that are transiently excited by the confluence of touch by a single vibrissa and the phase of vibrissa motion in the whisk cycle; different units have different preferred phases. This conditional response enables the rodent to estimate object position in a coordinate frame that is normalized to the trajectory of the motor output, as defined by phase in the whisk cycle, rather than angle of the vibrissa relative to the face. The underlying computation is consistent with gating by an inhibitory shunt.The perception of object location relative to the body depends on tracking sensor positioneyes for seeing or fingers for touching-as much as on the activation of those sensors by features of an object. Over a half century ago, von Holst 1 emphasized that one cannot hope to understand sensation without consideration of the effects "produced on the sensoryreceptors by the motor impulses which initiate a muscular movement." von Holst factored the signals required for sensation into three components. One is an afferent signal that originates from environmental influences-for example, light for the case of looking and pressure for the case of touching-and is denoted ex-afference. A second component is an afferent signal that results from activation of sensory receptors by self-motion and is called reafference. The motor-driven sensory input can involve the same receptors that encode external stimuli, as in the case of peripheral reafference, or a separate group of receptors, as in the case of proprioception. A final sensory component may be provided by an efference copy of the motor command; this corresponds to the intended rather than actual motor activation of sensory receptors. The ex-afferent component can interact with one or both motor signals (that is, reafference or efference copy) to produce a perceptually stable representation of the identity and location of external stimuli relative to a changing body configuration. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe coexistence and possible interaction of ex-afference, reafference and efference copy signals has been demonstrated from peripheral to thalamocortical levels 2 . In gaze control, reafferent signals of actual eye position and efference copy of the intended position of gaze3 gate the input to vestibular nuclei as part of the vestibular ocular response4. In the visual system, neurons in cat thalamus5 and primary visual cortex 6 respond to visual stimuli (the ex-afferent signal) and to the stimulation of extra-ocular muscle proprioceptors (a reafferent signal). Further, interactions between ex-af...

Rett syndrome (RTT) is a severe neurological disorder caused by mutations in the X-linked MECP2 gene, which encodes a methyl-CpG binding transcriptional repressor. Using the Mecp2-null mouse (an animal model for RTT) and differential display, we found that mice with neurological symptoms overexpress the nuclear gene for ubiquinol-cytochrome c reductase core protein 1 (Uqcrc1). Chromatin immunoprecipitation demonstrated that MeCP2 interacts with the Uqcrc1 promoter. Uqcrc1 encodes a subunit of mitochondrial respiratory complex III, and isolated mitochondria from the Mecp2-null brain showed elevated respiration rates associated with respiratory complex III and an overall reduction in coupling. A causal link between Uqcrc1 gene overexpression and enhanced complex III activity was established in neuroblastoma cells. Our findings raise the possibility that mitochondrial dysfunction contributes to pathology of the Mecp2-null mouse and may contribute to the long-known resemblance between Rett syndrome and certain mitochondrial disorders.

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The increasing use of patterned neural networks in multielectrode arrays and similar devices drives the constant development and evaluation of new biomaterials. Recently, we presented a promising technique to guide neurons and glia reliably and effectively. Parylene-C, a common hydrophobic polymer, was photolithographically patterned on silicon oxide (SiO(2)) and subsequently activated via immersion in serum. In this article, we explore the effects of ultraviolet (UV)-induced oxidation on parylene's ability to pattern neurons and glia. We exposed parylene-C stripe patterns to increasing levels of UV radiation and found a dose-dependent reduction in the total mass of patterned cells, as well as a gradual loss of glial and neuronal conformity to the patterns. In contrast, nonirradiated patterns had superior patterning results and increased presence of cells. The reduced cell adhesion and patterning after the formation of aldehyde and carboxyl groups on UV-radiated parylene-C supports our hypothesis that cell adhesion and growth on parylene is facilitated by hydrophobic adsorption of serum proteins. We conclude that unlike other cell patterning schemes, our technique does not rely on photooxidation of the polymer. Nonetheless, the precise control of oxygenated groups on parylene could pave the way for the differential binding of proteins and other molecules on the surface, aiding in the adhesion of alternative cell types. (c) 2010 Wiley Periodicals, Inc. J Biomed Mater Res, 2010.

Effective relief from chronic hypersensitive pain states remains an unmet need. Here we report the discovery that the TRPM8 ion channel, co-operating with the 5-HT(1B) receptor (5-HT(1B)R) in a subset of sensory afferents, exerts an influence at the spinal cord level to suppress central hypersensitivity in pain processing throughout the central nervous system. Using cell line models, ex vivo rat neural tissue and in vivo pain models, we assessed functional Ca(2+) fluorometric responses, protein:protein interactions, immuno-localisation and reflex pain behaviours, with pharmacological and molecular interventions. We report 5-HT(1B)R expression in many TRPM8-containing afferents and direct interaction of these proteins in a novel multi-protein signalling complex, which includes phospholipase D1 (PLD1). We provide evidence that the 5-HT(1B)R activates PLD1 to subsequently activate PIP 5-kinase and generate PIP2, an allosteric enhancer of TRPM8, achieving a several-fold increase in potency of TRPM8 activation. The enhanced activation responses of synaptoneurosomes prepared from spinal cord and cortical regions of animals with a chronic inflammatory pain state are inhibited by TRPM8 activators that were applied in vivo topically to the skin, an effect potentiated by co-administered 5-HT(1B)R agonists and attenuated by 5-HT(1B)R antagonists, while 5-HT(1B)R agents alone had no detectable effect. Corresponding results are seen when assessing reflex behaviours in inflammatory and neuropathic pain models. Control experiments with alternative receptor/TRP channel combinations reveal no such synergy. Identification of this novel receptor/effector/channel complex and its impact on nociceptive processing give new insights into possible strategies for enhanced analgesia in chronic pain.

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