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PubMed2002

Postischemic administration of basic fibroblast growth factor improves sensorimotor function and reduces infarct size following permanent focal cerebral ischemia in the rat.

Basic fibroblast growth factor (bFGF) is a polypeptide with potent trophic and protective effects on the brain. bFGF has been reported to exert neuroprotection against a wide variety of insults, including ischemic neuronal injury. To date, animal models of focal ischemia have not been translated to efficacy in stroke clinically with respect to testing of neuroprotective agents. Because functional outcome is the measurement of efficacy for putative neuroprotective agents in the clinic, we sought to evaluate the functional consequences of bFGF administration in rats subjected to focal ischemia. In this study, we assessed the effects of bFGF on functional outcome as well as infarct size in rats subjected to severe cerebral ischemia by permanent occlusion of the middle cerebral artery (MCAO). Male Sprague-Dawley rats were subjected to permanent MCAO by the intraluminal filament technique. Two hours following occlusion, rats were infused intravenously with either bFGF, at a dose of 150 microg/kg, or vehicle alone. Functional sensorimotor impairment, which was assessed by the accelerating rotarod test, was recorded at baseline and compared to performance assessed at 24 h after MCAO. Permanent occlusion of the MCA caused marked impairment in rotarod performance in both groups. Treatment of rats with bFGF showed a significant 46% improvement in rotarod fall latency when compared with that from the animals treated with vehicle alone. The volume of cortical infarction was significantly reduced by 32% as a function of bFGF treatment. These results suggest that the delayed intravenous administration of bFGF improves sensorimotor function as well as reduces infarct size following permanent focal ischemia in rat.

Animals↗
PubMed1994

Impaired simultaneous cognitive task performance in Parkinson's disease: a dopamine-related dysfunction.

Patients with Parkinson's disease (PD) have trouble programming two separate motor acts concurrently. We tested the hypotheses that (1) PD patients may also have difficulty processing two cognitive tasks simultaneously, and (2) the expected deficit may be related to the striatal dopaminergic depletion. We used auditory and visual choice reaction time (CRT) tasks, presented either separately or concurrently, and compared the performance of three groups of PD patients: a group of patients under their usual dose of levodopa ("standard"); a group assessed both at the time of maximal clinical benefit ("on" state) and at the time of minimal clinical benefit (treatment withdrawn for about 18 hours; "off" state); and a group of recently diagnosed untreated patients ("de novo"). Compared with controls, standard and "on" state patients had a normal performance for both separate and concurrent CRT tasks. In contrast, "off" state and de novo patients had a normal performance in the separate CRT tasks but significant deficits in the concurrent CRT tasks. These results suggest that adequate dopaminergic transmission is necessary for concurrent processing of cognitive information and that the striatum integrates the sensorimotor information required to program cognitive acts.

Acoustic Stimulation↗
PubMed1992

Motor and nonmotor behavioral deficits in monkeys made hemiparkinsonian by intracarotid MPTP infusion.

We tested five monkeys (three Macaca mulatta, two Macaca nemistrina) made hemiparkinsonian by internal carotid artery infusion of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) for lateralized motor function using a bar press task and a reaction time/movement time task and for hemispatial neglect or hemi-inattention using a double simultaneous stimulation (DSS) task, a lateralized reward retrieval task, and a task that assessed response to lateralized moving stimuli. All monkeys had impaired bar press performance and prolonged reaction and movement times with the limb contralateral to the lesion. However, using the limb ipsilateral to the lesion, all animals showed extinction to DSS, that is, they responded to single stimuli presented on the impaired side (contralateral to the MPTP lesion) more often than to stimuli presented on the impaired side that were presented simultaneously with stimuli on the unimpaired side (ipsilateral to the lesion). There was a response bias toward the side ipsilateral to the lesion in the lateralized retrieval task and a deficit in the ability to direct attention toward the side contralateral to the lesion when moving stimuli were employed. These latter results could not be explained by primary motor or sensory impairments. We conclude that unilateral MPTP-induced dopamine depletion in monkeys causes a complex syndrome characterized by overt motor disturbances contralateral to the side of lesion and less overtly apparent sensorimotor integration deficits.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Human nerve growth factor improves spatial memory in aged but not in young rats.

The behavioral effects of human nerve growth factor (NGF) were assessed in Fischer-344 rats of two ages: 4 months old (4MO) and 23 months old (23MO). Recent memory was tested in delayed alteration (T maze), reference memory in a place discrimination (water maze), and sensorimotor skills in a battery of sensorimotor tasks. Each rat was preoperatively trained in each task, given either a control procedure (CON), or continuous infusion of human NGF via an osmotic minipump, and retested again 3 weeks later. Two doses of NGF were delivered: 40 micrograms and 160 micrograms (total amount infused over a period of 4 weeks). In 23MO-NGF rats, both doses improved performance in the recent memory task, and in some measures of the place learning task, but had no effect on sensorimotor skills. In 4MO-NGF rats, the low dose impaired performance in the recent memory task, but not in the place discrimination or in the sensorimotor tasks. These data indicate that human NGF can reverse age-related cognitive impairments in old rats. However, the present study also raises the issue of potential detrimental effects that NGF may exert in young normal subjects.

Aging↗
PubMed1998

Specificity in the interaction of HVA Ca2+ channel types with Ca2+-dependent AHPs and firing behavior in neocortical pyramidal neurons.

Intracellular recordings and organic and inorganic Ca2+ channel blockers were used in a neocortical brain slice preparation to test whether high-voltage-activated (HVA) Ca2+ channels are differentially coupled to Ca2+-dependent afterhyperpolarizations (AHPs) in sensorimotor neocortical pyramidal neurons. For the most part, spike repolarization was not Ca2+ dependent in these cells, although the final phase of repolarization (after the fast AHP) was sensitive to block of N-type current. Between 30 and 60% of the medium afterhyperpolarization (mAHP) and between approximately 80 and 90% of the slow AHP (sAHP) were Ca2+ dependent. Based on the effects of specific organic Ca2+ channel blockers (dihydropyridines, omega-conotoxin GVIA, omega-agatoxin IVA, and omega-conotoxin MVIIC), the sAHP is coupled to N-, P-, and Q-type currents. P-type currents were coupled to the mAHP. L-type current was not involved in the generation of either AHP but (with other HVA currents) contributes to the inward currents that regulate interspike intervals during repetitive firing. These data suggest different functional consequences for modulation of Ca2+ current subtypes.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2005

Dopamine, the medial preoptic area, and male sexual behavior.

The medial preoptic area (MPOA), at the rostral end of the hypothalamus, is important for the regulation of male sexual behavior. Results showing that male sexual behavior is impaired following MPOA lesions and enhanced with MPOA stimulation support this conclusion. The neurotransmitter dopamine (DA) facilitates male sexual behavior in all studied species, including rodents and humans. Here, we review data indicating that the MPOA is one site where DA may act to regulate male sexual behavior. DA agonists microinjected into the MPOA facilitate sexual behavior, whereas DA antagonists impair copulation, genital reflexes, and sexual motivation. Moreover, microdialysis experiments showed increased release of DA in the MPOA as a result of precopulatory exposure to an estrous female and during copulation. DA may remove tonic inhibition in the MPOA, thereby enhancing sensorimotor integration, and also coordinate autonomic influences on genital reflexes. In addition to sensory stimulation, other factors influence the release of DA in the MPOA, including testosterone, nitric oxide, and glutamate. Here we summarize and interpret these data.

Animals↗
PubMed2002

Dopamine receptor blockade in the rat medial prefrontal cortex reduces spontaneous and amphetamine-induced activity and does not affect prepulse inhibition.

The functions and interactions of cortical and subcortical dopamine systems are of interest because alterations in these systems have been implicated in neuropsychiatric diseases, such as schizophrenia. It has been proposed that prefrontal dopamine transmission may oppose dopamine transmission in subcortical sites, such as the nucleus accumbens. Accordingly, reduced prefrontal dopamine transmission would be expected to enhance or induce behavioral effects that have been associated with stimulation of accumbal dopamine receptors. In rats, spontaneous and amphetamine-induced activity is supported by dopamine receptor stimulation in the nucleus accumbens, while prepulse inhibition (PPI) of the acoustic startle response, which is used to measure sensorimotor gating and is disrupted in schizophrenia, is reduced by increased accumbal dopamine receptor stimulation. In the present experiments, we found that bilateral infusion of the dopamine D1/D2 receptor antagonist cis-flupenthixol dihydrochloride into the medial prefrontal cortex of Wistar rats (25 microg each side) reduced spontaneous activity and completely blocked induction of hyperactivity by systemic administration of D-amphetamine sulfate (1 mg/kg), while not affecting PPI. These findings do not support an antagonism between prefrontal and accumbal dopamine in the control of behavior. Rather, our data demonstrate that prefrontal dopamine transmission may modulate some behavioral processes in a similar way to accumbal dopamine.

Acoustic Stimulation↗
PubMed2004

Rostral agranular insular cortex and pain areas of the central nervous system: a tract-tracing study in the rat.

The rostral agranular insular cortex (RAIC) has recently been identified as a site where local changes in GABA and dopamine levels, or application of opioids, can alter nociceptive thresholds in awake animals. The connections of the cortex dorsal to the rhinal fissure that includes the RAIC have been examined previously, with emphasis on visceral and gustatory functions but not nociception. Here we examined the afferent and efferent connections of the RAIC with sites implicated in nociceptive processing. Sensory information from the thalamus reaches the RAIC via the submedius and central lateral nuclei and the parvicellular part of the ventral posterior nucleus. The RAIC has extensive reciprocal cortico-cortical connections with the orbital, infralimbic, and anterior cingulate cortices and with the contralateral RAIC. The amygdala, particularly the basal complex, and the nucleus accumbens are important targets of RAIC efferent fibers. Other connections include projections to lateral hypothalamus, dorsal raphe, periaqueductal gray matter, pericerulear region, rostroventral medulla, and parabrachial nuclei. The connectivity of the RAIC suggests it is involved in multiple aspects of pain behavior. Projections to the RAIC from medial thalamic nuclei are associated with motivational/affective components of pain. RAIC projections to mesolimbic/mesocortical ventral forebrain circuits are likely to participate in the sensorimotor integration of nociceptive processing, while its brainstem projections are most likely to contribute to descending pain inhibitory control.

Animals↗
PubMed2005

Beyond the reward hypothesis: alternative functions of nucleus accumbens dopamine.

According to the dopamine (DA) hypothesis of reward, DA systems in the brain, particularly in the nucleus accumbens, are thought to directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food, water and sex, as well as various drugs of abuse. However, there are numerous problems associated with this hypothesis. Interference with accumbens DA transmission does not substantially blunt primary motivation for natural rewards such as food, but it does disrupt the propensity of animals to engage in effortful responding to obtain food. Electrophysiological and voltammetric studies indicate that novel stimuli, conditioned stimuli that predict reward, and instrumental behaviors that deliver natural rewards all act to stimulate DA activity. Accumbens DA acts as a modulator of several functions related to motivated behavior, and can influence normal and pathological cognitive function, activational aspects of motivation, anergia or psychomotor slowing in depression, the impact of conditioned stimuli, plasticity and a variety of sensorimotor functions.

Animals↗
PubMed1984

Brain catecholamines and the central control of food intake.

Analysis of motivated behaviors indicates the presence of two components, a component that is specific to a particular behavior and a nonspecific component that they all share. Thus, feeding and drinking may be readily differentiated from each other, yet behavioral arousal is a feature of both. Accumulating evidence now suggests that brain catecholamines are involved in the nonspecific aspects of behavior. For example, a variety of sensory stimuli have been shown to increase activity in central catecholaminergic systems measured by electrophysiological, biochemical and electrochemical techniques. Conversely, destruction of these systems leads to a profound decrease in sensory responsiveness. We have been studying the role of the dopamine-containing neurons of the nigrostriatal bundle in motivated behavior. Studies in which dopaminergic activity was monitored in striatum indicate that dopamine release is markedly, though briefly, elevated in response to a variety of intense environmental stimuli, including cold and tail shock. On the other hand, lesions of this pathway impair sensorimotor integration and, thereby, lead to akinesia, sensory neglect and the virtual elimination of all voluntary activities. Moreover, although there is a gradual recovery of function in these brain-damaged animals, they remain less sensitive to stimulation than control animals. For example, they eat but maintain body weight at a level considerably lower than controls, presumably because it takes a greater stimulus of hunger to provoke feeding and less food intake to cause that stimulus to slip below threshold levels of activation. These, and other findings, suggest an important role of brain catecholamines in behavioral arousal, that is, in permitting animals to remain alert and to respond appropriately to relevant sensory stimuli.

Animals↗
PubMed2002

Methamphetamine exposure from postnatal day 11 to 20 causes impairments in both behavioral strategies and spatial learning in adult rats.

Spatial learning and memory deficits in a water maze have been observed in adult animals exposed to a regimen of 4 daily doses of d-methamphetamine (MA) at 2 h intervals from postnatal day 11 to 20. An interpretational issue for these long-term effects of MA is whether they are truly spatial deficits or are secondary to alterations in sensorimotor systems. In this experiment, we evaluated the effects of a pretraining procedure shown to minimize the influence of drug-induced sensorimotor deficits. Animals within a litter were treated with MA or saline. Animals were either pretrained for nonspatial task requirements in the water maze (i.e., swimming and platform climbing) or were nai;ve to the task. Animals that received the pretraining did better than the nai;ve animals. The nai;ve MA animals performed worse than the nai;ve control animals as previously observed. By contrast, no difference in search time was noted between pretrained MA- and SAL-treated animals during the acquisition phase of testing. When the platform was relocated in a novel position, spatial learning was impaired for MA animals, regardless of pretraining. No increase in the number of platform nonrecognition events (swimovers, deflections, or jump-offs) occurred among pretrained or nai;ve groups compared to controls. These data suggest that sensorimotor deficits do not account for the spatial learning and memory deficits in animals exposed neonatally to MA.

Animals↗
PubMed1992

Coherent 25- to 35-Hz oscillations in the sensorimotor cortex of awake behaving monkeys.

Synchronous 25- to 35-Hz oscillations were observed in local field potentials and unit activity in sensorimotor cortex of awake rhesus monkeys. The oscillatory episodes occurred often when the monkeys retrieved raisins from a Klüver board or from unseen locations using somatosensory feedback; they occurred less often during performance of repetitive wrist flexion and extension movements. The amplitude, duration, and frequency of oscillations were not directly related to movement parameters in behaviors studied so far. The occurrence of the oscillations was not consistently related to bursts of activity in forearm muscles, but cycle-triggered averages of electromyograms revealed synchronous modulation in flexor and extensor muscles. The phase of the oscillations changed continuously from the surface to the deeper layers of the cortex, reversing their polarity completely at depths exceeding 800 microns. The oscillations could become synchronized over a distance of 14 mm mediolaterally in precentral cortex. Coherent oscillations could also occur at pre- and postcentral sites separated by an estimated tangential intracortical distance of 20 mm. Activity of single units was commonly seen to burst in synchrony with field potential oscillations. These findings suggest that such oscillations may facilitate interactions between cells during exploratory and manipulative movements, requiring attention to sensorimotor integration.

Animals↗
PubMed2006

Tourette syndrome: the self under siege.

Tourette syndrome is a neurodevelopmental disorder characterized by motor and vocal tics--rapid, repetitive, stereotyped movements or vocalizations. Tourette syndrome typically has a prepubertal onset, and boys are more commonly affected than girls. Symptoms usually begin with transient bouts of simple motor tics. By age 10 years, most children are aware of nearly irresistible somatosensory urges that precede the tics. These urges likely reflect a defect in sensorimotor gating because they intrude into the child's conscious awareness and become a source of distraction and distress. A momentary sense of relief typically follows the completion of a tic. Over the course of hours, tics occur in bouts, with a regular intertic interval. Tics increase during periods of emotional excitement and fatigue. Tics can become "complex" in nature and appear to be purposeful. Tics can be willfully suppressed for brief intervals and can be evoked by the mere mention of them. Tics typically diminish during periods of goal-directed behavior, especially those that involve both heightened attention and fine motor or vocal control, as occur in musical and athletic performances. Over the course of months, tics wax and wane. New tics appear, often in response to new sources of somatosensory irritation, such as the appearance of a persistent vocal tic (a cough) following a cold. Over the course of years, tic severity typically peaks between 8 and 12 years of age. By the end of the second decade of life, many individuals are virtually tic free. Less than 20% of cases continue to experience clinically impairing tics as adults. Tics rarely occur in isolation, and other coexisting conditions--such as behavioral disinhibition, hypersensitivity to a broad range of sensory stimuli, problems with visual motor integration, procedural learning difficulties, attention-deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder, depression, anxiety, and emotional instability--are often a greater source of impairment than the tics themselves. Emerging behavioral treatments of Tourette syndrome are based in part on an understanding of the moment-to-moment experience of somatosensory urges and motor response. With identification of specific genes of major effect and advances in our understanding of the neural circuitry of sensorimotor gating, habit formation, and procedural memory--together with insights from postmortem brain studies, in vivo brain imaging, and electrophysiologic recordings--we might be on the threshold of a deeper understanding of the phenomenology and natural history of Tourette syndrome.

Adolescent↗
PubMed2005

Dissociation of sensorimotor deficits after rostral versus caudal lesions in the primary motor cortex hand representation.

Primary motor cortex (M1) has traditionally been considered a motor structure. Although neurophysiologic studies have demonstrated that M1 is also influenced by somatosensory inputs (cutaneous and proprioceptive), the behavioral significance of these inputs has yet to be fully defined in primates. The present study describes differential sensory-related deficits after small ischemic lesions in either the rostral or caudal subregion of the M1 hand area in a nonhuman primate. Squirrel monkeys retrieved food pellets out of different sized wells drilled into a Plexiglas board. Before the lesion, monkeys retrieved pellets by directing the hand to the well, inserting fingers directly into it, and extracting the pellet. After a lesion to the rostral portion of M1, monkeys frequently failed to direct the hand accurately to the well. Instead, fingers contacted the surface of the board outside the well before entering the well. These aiming errors are consistent with both the large amount of proximal motor outputs and the predominant proprioceptive inputs of rostral M1. Overall, these aiming errors are suggestive of dysfunctional processing of proprioceptive information or the failure to integrate proprioceptive information with motor commands. In contrast, after a lesion to the caudal portion of M1, monkeys frequently examined their palm visually for the presence of the pellet after an attempted retrieval. These errors are consistent with both the large amount of distal motor outputs and the predominant cutaneous inputs of caudal M1. Thus these errors are suggestive of a deficit in processing of cutaneous information or the failure to integrate cutaneous information with motor commands. Rostral and caudal M1 lesions result in different deficits in sensory-dependent motor control that appear to correlate with broad segregation of motor outputs and previously described sensory inputs of M1.

Animals↗
PubMed2004

Prepulse inhibition of the acoustically evoked startle reflex in patients with an acute schizophrenic psychosis--a longitudinal study.

Deficits in sensorimotor gating as assessed by prepulse inhibition (PPI) of the startle reflex have been reported in schizophrenia. However, the state or trait nature of these deficits and the relationships with clinical features and psychopathological symptoms are not clear. To explore these issues, we performed a longitudinal study with schizophrenia inpatients. We examined 36 medicated schizophrenia inpatients twice in the course of an acute psychotic episode: recently after admission and after psychopathological improvement 2-3 weeks later. In addition, we examined 18 healthy control subjects twice (two weeks apart). Relative to control subjects, patients with schizophrenia had lower PPI only in the acute, but not in the improved clinical state. Larger PPI deficits were associated with more severe formal thought disorder and bizarre behavior. In the present longitudinal study, PPI deficits in schizophrenic patients appeared to be state dependent. Taking into account recent evidence from the literature we propose that reduced PPI may be a mediating vulnerability marker of schizophrenia: Impairments in sensorimotor mechanisms which subserve PPI of the startle reflex may both predispose individuals to develop psychosis, and, in addition, may covary with the presence of acute positive symptoms.

Adult↗
PubMed2006

Chronic low-dose administration of nicotine facilitates recovery and synaptic change after focal ischemia in rats.

The current study examines the effects of chronic administration of nicotine on motor behavior after focal stroke in rats. Animals were trained in a tray-reaching task for 2weeks and then they were divided into: (1) control+saline (2) control+nicotine (3) stroke+saline, and (4) stroke+nicotine groups. Lesions were produced by devascularization of the surface blood vessels of the sensorimotor cortex contralateral to the forepaw used for reaching. Forty-eight hours after the lesions, and for a total of 12days, animals received two daily injections of either nicotine (0.3mg/kg) or saline (0.9%). Animals were tested in a motor battery 1week after the lesions and every other week for a total of 7weeks. Pyramidal cells in forelimb and cingulate areas were then examined for dendritic length and branching using a Golgi-Cox procedure. Behavioral results demonstrated that by the end of the testing stroke+nicotine animals showed significant behavioral improvement relative to stroke+saline animals. Stroke+nicotine animals showed an increase in dendritic length and branching in pyramidal cells of the forelimb and cingulate areas. The results suggest that the behavioral enhancement in the stroke+nicotine group might be attributable to the enhanced dendritic growth in residual cortical motor regions.

Animals↗
PubMed1991

Dopamine receptors in the ventral tegmental area affect motor, but not motivational or reflexive, components of copulation in male rats.

Microinjection of apomorphine into the ventral tegmental area (VTA) of male rats was previously shown to delay the onset of copulation and slow its rate, presumably by stimulating impulse-regulating autoreceptors on cell bodies of the A10 mesocorticolimbic dopamine tract. Such stimulation would be expected to slow the firing rate of these neurons and, thereby, to impair locomotion and/or motivational processes. The present experiments tested whether the delayed onset and slowed rate of copulation were related to deficits in motor performance, sexual motivation, and/or genital reflexes. In X-maze tests the speed of running to all 4 goal boxes was slowed; however, the percentage of trials on which the male chose the female's goal box was not decreased. Examination of videotaped copulation tests revealed that the male showed fewer complete copulatory behaviors (mounts, intromissions, and ejaculations), but more misdirected or incomplete copulatory attempts after apomorphine in the VTA. There were also fewer scores of active, as opposed to inactive, behaviors, and the onset and rate of copulation were slowed. The total number of female directed behaviors was not different in apomorphine tests, compared to vehicle. Finally, tests of ex copula genital reflexes revealed no significant effects of apomorphine in the VTA on erections, penile movements, or seminal emissions. These data suggest a role of the VTA in the motor aspects and/or sensorimotor integration of copulation. Sexual motivation and ex copula genital reflexes appeared to be unaffected by apomorphine in the VTA.

Animals↗