Characterization of progressive motor deficits in mice transgenic for the human Huntington's disease mutation.
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Transgenic mice expressing exon 1 of the human Huntington's disease (HD) gene carrying a 141-157 CAG repeat (line R6/2) develop a progressive neurological phenotype with motor symptoms resembling those seen in HD. We have characterized the motor deficits in R6/2 mice using a battery of behavioral tests selected to measure motor aspects of swimming, fore- and hindlimb coordination, balance, and sensorimotor gating [swimming tank, rotarod, raised beam, fore- and hindpaw footprinting, and acoustic startle/prepulse inhibition (PPI)]. Behavioral testing was performed on female hemizygotic R6/2 transgenic mice (n = 9) and female wild-type littermates (n = 22) between 5 and 14 weeks of age. Transgenic mice did not show an overt behavioral phenotype until around 8 weeks of age. However, as early as 5-6 weeks of age they had significant difficulty swimming, traversing the narrowest square (5 mm) raised beam, and maintaining balance on the rotarod at rotation speeds of 33-44 rpm. Furthermore, they showed significant impairment in prepulse inhibition (an impairment also seen in patients with HD). Between 8 and 15 weeks, R6/2 transgenic mice showed a progressive deterioration in performance on all of the motor tests. Thus R6/2 mice show measurable deficits in motor behavior that begin subtly and increase progressively until death. Our data support the use of R6/2 mice as a model of HD and indicate that they may be useful for evaluating therapeutic strategies for HD, particularly those aimed at reducing the severity of motor symptoms or slowing the course of the disease. (+info)
Reinstatement of alcohol-seeking behavior by drug-associated discriminative stimuli after prolonged extinction in the rat.
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Clinical observations suggest that stimuli associated with the availability or consumption of ethanol can evoke subjective feelings of craving and trigger episodes of relapse in abstinent alcoholics. To study the motivational significance of alcohol-related environmental cues experimentally, the effects of discriminative stimuli previously predictive of alcohol availability on the reinstatement of ethanol-seeking behavior were examined. Wistar rats were trained to lever-press for 10% (w/v) ethanol or water in the presence of distinct auditory cues. The rats were then subjected to an extinction phase where lever presses had no scheduled consequences. After extinction, the animals were exposed to the respective auditory cues without the availability of ethanol or water. Neither the ethanol (SA+) nor water-associated (SA-) auditory cue increased responding over extinction levels. In contrast, subsequent presentation of an olfactory cue associated with ethanol (SO+), but not a water-associated (SO-) cue significantly reinstated lever pressing behavior in the absence of the primary reinforcer. Moreover, responding elicited by the concurrent presentation of the SO+ and SA+ was selectively attenuated by the opiate antagonist naltrexone (0.25 mg/kg; s.c.). The results suggest that ethanol-associated cues can reinstate extinguished ethanol-seeking behavior in rats, but that the efficacy of these stimuli may be modality-specific. In addition, the present procedures may be useful for studying neurobiological mechanisms of alcohol-seeking behavior and relapse. (+info)
Expiratory time determined by individual anxiety levels in humans.
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We have previously found that individual anxiety levels influence respiratory rates in physical load and mental stress (Y. Masaoka and I. Homma. Int. J. Psychophysiol. 27: 153-159, 1997). On the basis of that study, in the present study we investigated the metabolic outputs during tests and analyzed the respiratory timing relationship between inspiration and expiration, taking into account individual anxiety levels. Disregarding anxiety levels, there were correlations between O2 consumption (VO2) and minute ventilation (VE) and between VO2 and tidal volume in the physical load test, but no correlations were observed in the noxious audio stimulation test. There was a volume-based increase in respiratory patterns in physical load; however, VE increased not only for the adjustment of metabolic needs but also for individual mental factors; anxiety participated in this increase. In the high-anxiety group, the VE-to-VO2 ratio, indicating ventilatory efficiency, increased in both tests. In the high-anxiety group, increases in respiratory rate contributed to a VE increase, and there were negative correlations between expiratory time and anxiety scores in both tests. In an awake state, the higher neural structure may dominantly affect the mechanism of respiratory rhythm generation. We focus on the relationship between expiratory time and anxiety and show diagrams of respiratory output, allowing for individual personality. (+info)
Plasticity of temporal information processing in the primary auditory cortex.
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Neurons in the rat primary auditory cortex (A1) generally cannot respond to tone sequences faster than 12 pulses per second (pps). To test whether experience can modify this maximum following rate in adult rats, trains of brief tones with random carrier frequency but fixed repetition rate were paired with electrical stimulation of the nucleus basalis (NB) 300 to 400 times per day for 20-25 days. Pairing NB stimulation with 5-pps stimuli markedly decreased the cortical response to rapidly presented stimuli, whereas pairing with 15-pps stimuli significantly increased the maximum cortical following rate. In contrast, pairing with fixed carrier frequency 15-pps trains did not significantly increase the mean maximum following rate. Thus this protocol elicits extensive cortical remodeling of temporal response properties and demonstrates that simple differences in spectral and temporal features of the sensory input can drive very different cortical reorganizations. (+info)
Activation of Heschl's gyrus during auditory hallucinations.
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Apart from being a common feature of mental illness, auditory hallucinations provide an intriguing model for the study of internally generated sensory perceptions that are attributed to external sources. Until now, the knowledge about the cortical network that supports such hallucinations has been restricted by methodological limitations. Here, we describe an experiment with paranoid schizophrenic patients whose on- and offset of auditory hallucinations could be monitored within one functional magnetic resonance imaging (fMRI) session. We demonstrate an increase of the blood oxygen level-dependent (BOLD) signal in Heschl's gyrus during the patients' hallucinations. Our results provide direct evidence of the involvement of primary auditory areas in auditory verbal hallucinations and establish novel constraints for psychopathological models. (+info)
Discharge profiles of abducens, accessory abducens, and orbicularis oculi motoneurons during reflex and conditioned blinks in alert cats.
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The discharge profiles of identified abducens, accessory abducens, and orbicularis oculi motoneurons have been recorded extra- and intracellularly in alert behaving cats during spontaneous, reflexively evoked, and classically conditioned eyelid responses. The movement of the upper lid and the electromyographic activity of the orbicularis oculi muscle also were recorded. Animals were conditioned by short, weak air puffs or 350-ms tones as conditioned stimuli (CS) and long, strong air puffs as unconditioned stimulus (US) using both trace and delayed conditioning paradigms. Motoneurons were identified by antidromic activation from their respective cranial nerves. Orbicularis oculi and accessory abducens motoneurons fired an early, double burst of action potentials (at 4-6 and 10-16 ms) in response to air puffs or to the electrical stimulation of the supraorbital nerve. Orbicularis oculi, but not accessory abducens, motoneurons fired in response to flash and tone presentations. Only 10-15% of recorded abducens motoneurons fired a late, weak burst after air puff, supraorbital nerve, and flash stimulations. Spontaneous fasciculations of the orbicularis oculi muscle and the activity of single orbicularis oculi motoneurons that generated them also were recorded. The activation of orbicularis oculi motoneurons during the acquisition of classically conditioned eyelid responses happened in a gradual, sequential manner. Initially, some putative excitatory synaptic potentials were observed in the time window corresponding to the CS-US interval; by the second to the fourth conditioning session, some isolated action potentials appeared that increased in number until some small movements were noticed in eyelid position traces. No accessory abducens motoneuron fired and no abducens motoneuron modified their discharge rate for conditioned eyelid responses. The firing of orbicularis oculi motoneurons was related linearly to lid velocity during reflex blinks but to lid position during conditioned responses, a fact indicating the different neural origin and coding of both types of motor commands. The power spectra of both reflex and conditioned lid responses showed a dominant peak at approximately 20 Hz. The wavy appearance of both reflex and conditioned eyelid responses was clearly the result of the high phasic activity of orbicularis oculi motor units. Orbicularis oculi motoneuron membrane potentials oscillated at approximately 20 Hz after supraorbital nerve stimulation and during other reflex and conditioned eyelid movements. The oscillation seemed to be the result of both intrinsic (spike afterhyperpolarization lasting approximately 50 ms, and late depolarizations) and extrinsic properties of the motoneuronal pool and of the circuits involved in eye blinks. (+info)
Patterned ballistic movements triggered by a startle in healthy humans.
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1. The reaction time to a visual stimulus shortens significantly when an unexpected acoustic startle is delivered together with the 'go' signal in healthy human subjects. In this paper we have investigated the physiological mechanisms underlying this effect. If the commands for the startle and the voluntary reaction were superimposed at some level in the CNS, then we would expect to see alterations in the configuration of the voluntary response. Conversely, if the circuit activated by the startling stimulus is somehow involved in the execution of voluntary movements, then reaction time would be sped up but the configuration of the motor programme would be preserved. 2. Fourteen healthy male and female volunteers were instructed to react as fast as possible to a visual 'go' signal by flexing or extending their wrist, or rising onto tiptoe from a standing position. These movements generated consistent and characteristic patterns of EMG activation. In random trials, the 'go' signal was accompanied by a very loud acoustic stimulus. This stimulus was sufficient to produce a startle reflex when given unexpectedly on its own. 3. The startling stimulus almost halved the latency of the voluntary response but did not change the configuration of the EMG pattern in either the arm or the leg. In some subjects the reaction times were shorter than the calculated minimum time for processing of sensory information at the cerebral cortex. Most subjects reported that the very rapid responses were produced by something other than their own will. 4. We conclude that the very short reaction times were not produced by an early startle reflex adding on to a later voluntary response. This would have changed the form of the EMG pattern associated with the voluntary response. Instead, we suggest that such rapid reactions were triggered entirely by activity at subcortical levels, probably involving the startle circuit. 5. The implication is that instructions for voluntary movement can in some circumstances be stored and released from subcortical structures. (+info)
Spatial characteristics of visual-auditory summation in human saccades.
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Bimodal (auditory + visual) stimuli reduce saccade latencies in human observers to a degree that exceeds levels predictable by probabilistic summation between parallel, independent unimodal pathways. These interactions have been interpreted in terms of converging visual and auditory afferents within the oculomotor pathways, specifically within the superior colliculus (SC). The present work describes the spatial tuning of auditory-visual summation in human saccades, using diagnostics derived from stochastic models of information processing. Consistent with expectations based on the electrophysiology of the SC, the magnitude of facilitation varied with the degree of spatial correspondence, and the spatial tuning was quite coarse. (+info)