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PubMed2003

Metabotropic glutamate subtype 5 receptors modulate locomotor activity and sensorimotor gating in rodents.

Use-dependent N-methyl-d-aspartate receptor (NMDAR) antagonists produce behaviors in human volunteers that resemble schizophrenia and exacerbate those behaviors in schizophrenic patients, suggesting that hypofunction of NMDAR-mediated neuronal circuitry may be involved in the etiology of clinical schizophrenia. Activation of the metabotropic glutamate receptor subtype 5 (mGluR5) enhances NMDAR-mediated currents in vitro. Thus, activation of mGluR5 could potentiate hypofunctional NMDARs in neuronal circuitry relevant to schizophrenia. To further elucidate the role of mGluR5, the present study examined the effects of mGluR5 antagonist administration, with and without coadministration of the use-dependent NMDAR antagonist phencyclidine (PCP), on locomotor activity and prepulse inhibition (PPI) of the acoustic startle response in rodents. We further examined PPI in mGluR5 knockout mice. Finally, we examined PPI after administration of the mGluR5 agonist 2-chloro-5-hydroxyphenylglycine (CHPG) alone and in combination with amphetamine. The data indicate that the mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine has no effect on locomotor activity or PPI by itself but does potentiate both PCP-induced locomotor activity and disruption of PPI. We further found that mGluR5 knockout mice display consistent deficits in PPI relative to their wild-type controls. Finally, the data indicate that CHPG has no effect on PPI by itself, but ameliorates amphetamine-induced disruption of PPI. Collectively, these data suggest that mGlu5 receptors play a modulatory role on rodent PPI and locomotor behaviors and are consistent with the hypothesis that mGlu5 agonist/potentiators may represent a novel approach for antipsychotic drug development.

Animals↗
PubMed2006

Behavioral reference frames for planning human reaching movements.

At some stage in the process of a sensorimotor transformation for a reaching movement, information about the current position of the hand and information about the location of the target must be encoded in the same frame of reference to compute the hand-to-target difference vector. Two main hypotheses have been proposed regarding this reference frame: an eye-centered and a body-centered frame. Here we evaluated these hypotheses using the pointing errors that subjects made when planning and executing arm movements to memorized targets starting from various initial hand positions while keeping gaze fixed in various directions. One group of subjects (n = 10) was tested without visual information about hand position during movement planning (unseen-hand condition); another group (n = 8) was tested with hand and target position simultaneously visible before movement onset (seen-hand condition). We found that both initial hand position and gaze fixation direction had a significant effect on the magnitude and direction of the pointing error. Errors were significantly smaller in the seen-hand condition. For both conditions, though, a reference frame analysis showed that the errors arose at an eye- or hand-centered stage or both, but not at a body-centered stage. As a common reference frame is required to specify a movement vector, these results suggest that an eye-centered mechanism is involved in integrating target and hand position in programming reaching movements. We discuss how simple gain elements modulating the eye-centered target and hand-position signals can account for these results.

Adult↗
PubMed1997

Site-specific and sensory neuron-dependent increases in postsynaptic glutamate sensitivity accompany serotonin-induced long-term facilitation at Aplysia sensorimotor synapses.

Long-term changes in the efficacy of Aplysia sensory neuron (SN) connections accompany behavioral training or applications with 5-HT. The changes evoked by training or 5-HT include formation of new SN varicosities and transmitter release sites. Because new synapse formation requires proper alignment of presynaptic structures with postsynaptic zones containing a high density of transmitter receptors, we examined whether changes in postsynaptic sensitivity to the presumed SN transmitter (glutamate) were correlated with formation and distribution of new SN varicosities in contact with motor cell L7 in cell culture. The formation of stable SN connections after 4 d in culture did not significantly change overall responses to focal applications of glutamate. However, specific sites along L7's axon apposed to SN varicosities expressed larger responses to glutamate compared with adjacent sites with few SN varicosities. After treatments with 5-HT that evoked long-term changes in both the structure and the function of SN-L7 synaptic interaction, glutamate responses increased selectively at sites along the surface of L7's axon with preexisting or new SN varicosities. Increases in postsynaptic response to glutamate 24 hr after 5-HT treatment required interaction with an SN. These results suggest that new synapse formation between neurons, either with regeneration or after external stimuli that evoke increases in synaptic efficacy, involves site-specific changes in expression of functional neurotransmitter receptors on the postsynaptic cell that is regulated by interaction with the presynaptic neuron.

Animals↗
PubMed2002

Crickets in space: morphological, physiological and behavioral alterations induced by space flight and hypergravity.

"Crickets in Space" was a Neurolab experiment by which the balance between genetic programs and the gravitational environment for the development of a gravity sensitive neuronal system was studied. The model character of crickets was justified by their external gravity receptors, identified position-sensitive interneurons (PSI) and gravity-related compensatory head response, and by the specific relation of this behavior to neuronal arousal systems activated by locomotion. These advantages allowed to study the impact of modified gravity on cellular processes in a complex organism. Eggs, 1st, 4th and 6th stage larvae of Acheta domesticus were used. Post-flight experiments revealed a low susceptibility of the behavior to micro- and hypergravity while the physiology of the PSI was significantly affected. Immunocytological investigations revealed a stage-dependent sensitivity of thoracic GABAergic motoneurons to 3 g-conditions concerning their soma sizes but not their topographical arrangement. The morphology of neuromuscular junctions was not affected by 3 g-hypergravity. Peptidergic neurons from cerebral sensorimotor centers revealed no significant modifications by microgravity (micro g). The contrary physiological and behavioral results indicate a facilitation of 1 g-readaptation originating from accessory gravity, proprioceptive and visual sense organs. Absence of anatomical modifications point to an effective time window of micro g or 3 g-expo-sure related to the period of neuronal proliferation. The analysis of basic mechanisms of how animals and man adapt to altered gravitational conditions will profit from a continuation of the project "Crickets in Space".

Adaptation, Physiological↗
PubMed1989

Intelligence and behavior problems in 5-year-olds in relation to representational abilities in the second year of life.

Assessments of sensorimotor skill, play, language, and developmental level were administered to 20 preterm and 20 full-term infants during sessions at 13 1/2 and 22 months of age. At 5-year follow-up, children were tested with the Wechsler Preschool and Primary Scale of Intelligence (WIPPSI) and the Developmental Test of Visual-Motor Integration (VMI). Behavior problems were also assessed. At 5 years, the preterm sample showed slight delays in cognitive functioning. Measures of development and language at 13 1/2 and 22 months and relational play at 22 months were most predictive of cognitive outcome. Children with behavior problems at 5 years differed from those without problems in terms of their play and language skills. These data suggest that measures of development, particularly language development, and of play are predictive of later cognitive and behavioral functioning.

Child Behavior Disorders↗
PubMed1998

Behavioral assessment of the senescence-accelerated mouse (SAM P8 and R1).

Senescence-accelerated mice (SAM P8 and R1) were behaviorally assessed in a cross-sectional study at 4 and 15 months of age. Behavioral measures included memory (place discrimination and repeated acquisition in a water maze), sensorimotor performance (turning in an alley, traversing bridges, wire rod hanging, and falls from a wire screen), psychomotor performance (open-field exploration), and emotionality (entries in a plus maze, grooming, and defecation in a plus maze and in an open field). In the water maze, aged P8 mice were impaired in place discrimination and in repeated acquisition tasks, demonstrating evidence of an age-related decline in spatial memory processing abilities. The demonstration of this impairment, however, was complicated by noncognitive factors, such as the tendency of many older P8 mice to float. Sensorimotor skill impairment was accelerated with age in P8 mice, but not in R1 mice, and this impairment was present despite the lack of age-related changes in body weight in P8 mice. Although P8 and R1 mice were not different in general activity at old age, P8 mice were substantially more hyperactive in an open field and in the plus maze than R1 mice when compared at young age. Independent of age, P8 mice demonstrated a reduction of anxiety-like behavior in the plus maze. Taken as a whole, the data suggest that although age-related behavioral alterations occur in the P8 mice, some of these changes are evident at 4 months of age. Thus, the behavioral abnormalities that exist not only represent an accelerated aging phenomenon but may also be considered a developmental pathology.

Aging, Premature↗
PubMed2026

Cerebellar iTBS enhances gait adaptation by modulating cortical sensorimotor network dynamics: a randomized controlled trial.

Gait adaptation enables individuals to maintain locomotor stability under persistent perturbations. Although the cerebellum is critical for sensory prediction error-based (SPE) adaptation, how cerebellar neuromodulation reshapes cortical sensorimotor networks to enhance gait adaptation remains unclear. This study investigated the behavioral effects and underlying cortical neurodynamic mechanisms of cerebellar intermittent theta-burst stimulation (iTBS) on gait adaptation. Thirty-two healthy adults received either active or sham cerebellar iTBS. Participants performed a split-belt treadmill adaptation task before and after intervention. Cortical responsiveness was evaluated using TMS-evoked EEG over primary motor cortex (M1), while resting-state EEG was analyzed to assess spectral power and directional functional connectivity. Compared to sham, cerebellar iTBS significantly enhanced gait adaptation, evidenced by a faster adaptation rate (p = 0.035) and enhanced Early Adaptation SLS (p = 0.011), without altering initial perturbation responses or post-adaptation outcomes. The iTBS increased TMS-evoked α (p = 0.031) and γ (p = 0.022) power in M1, while the α power was correlated with faster adaptation (r = 0.526, p = 0.002). Furthermore, iTBS strengthened PPC-to-M1 directed connectivity in the β (p = 0.025) and γ (p = 0.013) bands. Enhanced parieto-motor directionality were positively associated with adaptation rate (β: r = 0.515, p = 0.003; γ: r = 0.463, p = 0.009). These findings suggest that cerebellar iTBS facilitates gait adaptation by modulating cortical responsiveness and directional sensorimotor network connectivity, providing multi-level neurodynamic evidence for the cerebello-cortical modulation during gait adaptation and offering a strong physiological rationale for targeted neuromodulation in gait rehabilitation strategies.

Humans↗
PubMedDate not supplied

Behavior and brain uptake of fluorodeoxyglucose in mature and aged C57BL/6 mice.

This paper describes regional brain energy metabolism, sensorimotor, and memory functions in mature (12 months) and old (24 months) C57BL/6 mice. Male mice were tested across a variety of sensorimotor procedures and in the Morris water maze before evaluating brain uptake of fluorodeoxyglucose (FDG) in the resting state. Mature mice outperformed older mice during the difficult sensorimotor and memory tasks, but not the easier tasks. This suggested that the greater sensorimotor and memory demands of a task compromised the performance of the older mice. This conclusion was consistent with the relative FDG uptake decreases found in regions mediating sensorimotor coordination (vestibular, cerebellar, ventral thalamic regions) and some limbic regions linked to memory (mammillary body, posterior cingulate, and piriform cortices). The inferior colliculus and flocculus had the greatest metabolism in mature mice, as shown by resting FDG uptake, and these regions showed the most marked hypometabolism in the older mice. The data also showed that the neurobehavioral correlative pattern in older mice was modified. In conclusion, brain regions with higher energy metabolism, and the behaviors to which they are related, were affected most greatly by aging in C57BL/6 mice-suggesting that these areas are more metabolically vulnerable to aging effects.

Aging↗
PubMed1995

Striatal dopamine-mediated motor behavior is altered following occlusion of the middle cerebral artery.

Cerebral infarct (stroke) causes striatal damage with subsequent deterioration of sensorimotor and cognitive functions that may be mediated by the dopamine receptor system. In the present study, transient, focal ischemia was induced in Sprague-Dawley rats by middle cerebral artery occlusion. Ischemic animals exhibited significantly less dopamine antagonist (haloperidol)-induced catalepsy and more dopamine agonist (amphetamine)-induced hyperactivity than sham-operated animals. Younger ischemic animals showed more profound behavioral alteration but also displayed greater recovery over time than older ischemic animals. Histologic data revealed a lateral striatal lesion in all ischemic animals. These results place the striatal dopaminergic system as a possible strategic venue for the treatment of cerebral ischemia. In addition, aging is found to be a risk factor for stroke as noted in humans.

Animals↗
PubMed2001

Selective immunolesioning of cholinergic neurons in nucleus basalis magnocellularis impairs prepulse inhibition of acoustic startle.

Information processing and attentional abnormalities are prominent in neuropsychiatric disorders. Since the cholinergic neurons located in the nucleus basalis magnocellularis have been shown to be involved in attentional performance and information processing, recent efforts to analyze the significance of the basal forebrain in the context of schizophrenia have focused on this nucleus and its projections to the cerebral cortex. We report here that bilateral selective immunolesioning of the cholinergic neurons in the nucleus basalis magnocellularis is followed by significant deficits in sensorimotor gating measured by prepulse inhibition of the startle reflex in adult rats. This behavioral approach is used in both humans and rodents and has been proposed as a valuable model contributing to the understanding of the neurobiological substrates of schizophrenia. The disruption of prepulse inhibition persisted over repeated testing. The selective lesions were induced by bilateral intraparenchymal infusions of 192 IgG saporin at a concentration having minimal diffusion into adjacent nuclei of the basal forebrain. The infusions were followed by extensive loss of choline acetyltransferase-immunopositive neurons. Our results show that the cholinergic neurons of the nucleus basalis magnocellularis represent a critical station of the startle gating circuitry and suggest that dysfunction of these neurons may result in impaired sensorimotor gating characteristic of schizophrenia.

Acetylcholine↗
PubMed1998

Behavior in mice with targeted disruption of single genes.

The use of mice with targeted deletion, or knockout, of specific genes provides a relatively new approach to establish the molecular bases of behavior. As with all ablation studies, the interpretation of behavioral data may be limited by the technique. For example, indirect effects of the missing gene may affect behavior, rather than the missing gene per se. Also, because the missing gene might affect many developmental processes throughout ontogeny and because up-regulation or compensatory mechanisms may be activated in knockouts, behavioral data from mice with targeted gene deletions should be interpreted with caution. The development of conditional knockouts, in which a specific gene can be inactivated any time during ontogeny, should allow investigators to avoid these conceptual shortcomings associated with behavioral data from knockouts in the near future. The behavioral alterations reported in knockout mice are reviewed here. Many dramatic changes in complex motivated behaviors including aggression, sexual, ingestive, and parental behaviors, have been reported for knockouts. There have also been many reports of alterations in sensorimotor abilities and spontaneous activity, as well as impairments in balance, coordination, and gait. Impaired learning and memory have also been reported for mice with targeted disruption of specific genes. Taken together, the use of knockouts will provide an important new tool to understand the mechanisms underlying behavior.

Animals↗
PubMed2005

Isolation-induced changes in ultrasonic vocalization, fear-potentiated startle and prepulse inhibition in rats.

Isolation causes important changes in the behavioral reactivity of rats to environmental stimuli. These changes include deficit in sensorimotor gating and altered fear-like responses to aversive stimuli. Measures of ultrasound vocalizations at 20-22 kHz when rats are exposed to threatening conditions, such as novelty, have been taken as a good measure of fear. The fear-potentiated startle to loud sounds and the prepulse inhibition tests have been considered reliable indicators of anxiety and attention impairments, respectively. Rats reared under conditions of isolation from weaning display clear deficits in prepulse inhibition. Taking into account that housing condition changes the emotional state of the animals, we evaluated in this work the performance of rats in the fear-potentiated startle test, prepulse inhibition and emission of ultrasound vocalizations to novelty when isolated for 10 days and after resocialization for 1 week in comparison to grouped rats. Isolated rats showed greater reactivity to loud sounds in the fear-potentiated startle test than grouped animals. They also emitted less ultrasound vocalizations at 20-22 kHz than grouped animals when exposed to a novel environment. In contrast to the well-known deficit in prepulse inhibition displayed by isolation-reared animals, in the present study isolation for 10 days caused a significant increase in prepulse inhibition. Resocialization was not able to counteract the effects of isolation in all three tests. The results suggest that the emotional state of the animals is altered by 10 days of isolation; they do not vocalize characteristically as grouped rats when submitted to novelty; unconditioned responses to loud sounds are enhanced and increased prepulse inhibition is shown rather than a deficit as largely documented in studies with isolation-reared animals. It is suggested that the assessment of the emotional state of the animals is a prerequisite in the evaluation of prepulse inhibition. The level of defensive reactivity displayed by isolated animals is crucial for the functioning of sensory gating and, by extension, to the expression of prepulse inhibition.

Acoustic Stimulation↗
PubMed2001

Unilateral lesions of the pedunculopontine nucleus do not alleviate subthalamic nucleus-mediated anticipatory responding in a delayed sensorimotor task in the rat.

Lesions of the subthalamic nucleus (STN) in the rat are known to cause anticipated movements in behavioral tasks requiring a preparatory period before the execution of externally cued conditioned movements. In the present study, we describe the effects of lesions of the pedunculopontine nucleus (PPN), a structure located on the outflow of the STN to lower brainstem and spinal motor nuclei, on the anticipatory responding caused by a unilateral lesion of the STN in a delayed sensorimotor task. Rats were instructed to keep a lever pressed down by the presentation of a composite visual and acoustic signal, and were required to hold the lever pressed until a trigger stimulus occurred after an unpredictable delay. The trigger stimulus required the animals to release the lever and to press a second lever for food reinforcement. The task was evaluated according to analysis of movement parameters and errors made by the animals during the preparative and executive phases of the conditioned movement. An ibotenate lesion was placed into the STN in either side of the brain. This lesion was followed 3 weeks later by an ibotenate lesion of the PPN ipsilaterally to the STN previously lesioned. The results indicate that the anticipatory responding induced by the STN lesion was not alleviated by the subsequent PPN lesion. However, the animals bearing the combined lesion were severely impaired in conditioned responding to salient stimuli involved in the paradigm and showed side-specific lengthening of reaction and movement times without global motor impairments. The results suggest that the anticipatory responses caused by STN lesions do not require the intervention of the PPN and that the disruption of the dopaminergic nigrostriatal pathway following the combined lesion may be responsible for impairments observed.

Animals↗
PubMed1998

Use-dependent exacerbation of brain damage occurs during an early post-lesion vulnerable period.

For a period of time after unilateral brain injury, surviving neural tissue surrounding the lesion may be vulnerable to extremely high behavioral demand. Previously, we found that lesions of the forelimb representation area of the sensorimotor cortex (FL-SMC) in rats increase in size substantially when the intact forelimb is immobilized with a plaster of paris cast during the first 15 days after surgery, which forces overuse of the impaired forelimb. The present study was designed to determine whether the adult brain is more vulnerable to forced overuse of the impaired forelimb during the first 7 days post-lesion than during the second 7 days post-lesion. Using behavioral tests of forelimb use and stereological analysis of remaining tissue volume 40 days after FL-SMC lesions, we found that forced overuse of the impaired forelimb during the first 7 days after the initial damage caused expansion of neural injury and greatly interfered with restoration of function. In contrast, forced overuse of the impaired forelimb during the second 7 days had no significant effect on lesion size but nevertheless interfered with restoration of function. Thus, surviving neural tissue in the damaged hemisphere and recovery of function appear to be vulnerable to prolonged forced overuse of the impaired forelimb throughout the first 15 days, but tissue loss was detectable only when the animal was forced to use the impaired forelimb during the first 7 days after injury.

Animals↗
PubMed2006

Vascular endothelial growth factor improves recovery of sensorimotor and cognitive deficits after focal cerebral ischemia in the rat.

Vascular endothelial growth factor (VEGF) is an angiogenesis factor with neurotrophic, neuroprotective and neuroproliferative effects. Depending on the dose, route and time of administration in relation to focal cerebral ischemia, VEGF can improve histological outcome and sensorimotor function in rodents. However, VEGF also increases vascular permeability, which can lead to brain edema and exacerbate ischemic brain injury. Thus, although VEGF is a candidate therapeutic for stroke and other ischemic disorders, its benefit relative to risk is uncertain. Considering that functional rather than histological measures of outcome are probably most relevant to therapeutic prospects for human stroke, we investigated the effects of VEGF after middle cerebral artery occlusion in rats using a series of behavioral tests. We report that VEGF improves functional outcome in ischemic rats, including both sensorimotor and cognitive deficiencies.

Animals↗
PubMed2001

Cerebral networks in sensorimotor disturbances.

Increasing evidence suggests that the human brain employs multiple, interconnected brain areas for information processing and control of behavior, including the performance of laboratory tasks. Brain diseases are expected to affect these networks directly by interference and indirectly as a consequence of deficit compensation. Covariance analyses applied to functional brain imaging data open the opportunity to study neural networks and their disease-related changes in the human brain. Here, we review our analytic approach based on principal component analysis (PCA) to address such questions. We will discuss its methodological foundations and applications in patients with sensorimotor disorders. We will show that PCA in combination with, both, hypothesis-driven testing and correlation statistics provides a powerful tool for elucidating disease-related abnormalities and postlesional reorganization of neural networks in the human brain.

Adult↗
PubMed1976

Acetylcholine release from visual and sensorimotor cortices of conditioned rabbits: the effects of sensory cuing and patterns of responding.

A technique was devised for the collection of acetylcholine (ACh) released from the cerebral cortex of awake rabbits while they were performing a previously learned operant task. Based on the assumption that ACh release is directly proportional to the activity of cholinergic synapses under the area of collection, two hypotheses of the functional role of cortical cholinergic mechanisms were examined: (1) that activity in cholinergic neurons is related to the inhibition of responding; (2) that cholinergic activity is related to the perception of a 'significant' stimulus. Five groups trained on different behavioral paradigms were used to test these hypotheses. ACh release was collected concurrently from visual and sensorimotor cortices to differentiate diffuse from specific cortical effects. A small (50-100%) increase in ACh release was found in all groups and from both cortical areas. In the case of one group (visually cued, reinforced for low response rates) a significantly greater increase occurred from sensorimotor cortex only. These findings do not support either hypothesis alone, and are interpreted as evidence for two cholinergic systems within, or projecting to the cortex. One is related to generalized behavioral arousal and desynchronization of the electroencephalogram. Activation of the second cholinergic system is dependent on both response inhibition and the presence of a significant stimulus of the visual (but not of the auditory) modality.

Acetylcholine↗
PubMed1998

Spatial disparity affects visual-auditory interactions in human sensorimotor processing.

Information from the auditory and visual systems converges in the nervous system with physiological and behavioral consequences. Most of our knowledge about the rules governing such convergence has been obtained in experiments where the strength or the timing of the individual auditory and visual stimuli has been varied. Relatively little attention has been paid to the spatial relationship between different modalities of stimuli in multisensory experiments. We studied saccadic reaction times of human subjects to bimodal auditory and visual stimulus presentations under two conditions: first, with the targets spatially coincident and, second, with various degrees of spatial separation or disparity. In the first experiment, we found that the saccadic reaction times were consistently shorter than would be predicted by independent processing of information about the visual and auditory targets. These results suggest convergence of multimodal information at one or more loci within the nervous system. In the second experiment, we found that saccadic latency gradually increased as spatial distance between the auditory and visual targets increased. Evidence for neural summation was found over a wide range of spatial disparities. These results suggest that multisensory information can be integrated and have significant influences on behavior over a surprisingly large range of spatial disparity.

Eye Movements↗