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PubMed1995

Alterations in dopamine uptake sites and D1 and D2 receptors in cats symptomatic for and recovered from experimental parkinsonism.

The administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult cats severely disrupts the dopaminergic innervation of the striatum. Animals display a parkinson-like syndrome, consisting of akinesia, bradykinesia, postural instability, and rigidity, which spontaneously recovers by 4-6 weeks after the last administration of MPTP. In this study we used quantitative receptor autoradiography to examine changes in DA uptake sites and DA receptors in the basal ganglia of normal, and symptomatic and recovered MPTP-treated cats. Consistent with the destruction of the nigrostriatal DA pathway, there was a severe loss of DA uptake sites, labeled with [3H]-mazindol, in the caudate nucleus (64-82%), nucleus accumbens (44%), putamen (63%), and substantia nigra pars compacta (SNc, 53%) of symptomatic cats. Following behavioral recovery, there were no significant changes in DA uptake site density. Significant increases of [3H]-SCH 23390 binding to D1 DA receptors were observed in the dorsal caudate (> 24%; P < 0.05) of symptomatic cats and in all regions of the caudate-putamen (> 30%; P < 0.05) of recovered animals. [3H]-SCH 23390 binding in the substantia nigra pars reticulata was half of that in the striatum and showed no changes in symptomatic or recovered animals. No alterations in the binding of [125I]-epidepride to D2 receptors was observed in any region of the striatum in either symptomatic or recovered animals. [125I]-Epidepride binding in the SNc was decreased by > 36% (P < 0.05) following MPTP treatment. These data show that cats made parkinsonian by MPTP exposure have a significant decrease in the number of DA reuptake sites throughout the striatum and that recovery of sensorimotor function in these animals is not correlated with an increase in the number of striatal reuptake sites. Behavioral recovery, however, does seem to be correlated with a general elevation of D1 receptors throughout the striatal complex. The present data also show that direct correlations between changes in DA receptor regulation after a large DA depleting lesion and behavioral deficits or recovery from those deficits are difficult and that the relationships between DA receptors/transporters and behavior require further study.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Absence of sparing of spatial navigation, skilled forelimb and tongue use and limb posture in the rat after neonatal dopamine depletion.

Depletion of caudate-putamen dopamine (DA) was produced by intraventricular injection of 6-hydroxydopamine (6-OHDA) in three day old rats. When adult, the rats were given cognitive and motor tasks sensitive to adult dopamine depletion, including: tests of cue and place spatial navigation in a swimming pool, a test of skilled forelimb use, requiring reaching for small pellets of food, a test of tongue protrusion, requiring tongue extension to lick mash from a spatula, a test of limb posture, sensorimotor tests of orienting to tactile stimulation and catalepsy. Despite apparent normal physical appearance and locomotor behavior, the rats were impaired on all tasks except orienting to tactile stimulation and catalepsy. There was a significant positive correlation between the degree of impairment on the behavioral tasks and the extent of caudate-putamen dopamine depletion. The results show that sparing of function following neonatal dopamine depletion is selective and incomplete. The results are discussed with respect to the questions of sparing of function following neonatal lesions, the heterogeneous nature of the neonatal depletions and the contributions of dopamine to complex spatial and motor behavior in the rat.

Animals↗
PubMed2006

Effects of topiramate on the prepulse inhibition of the acoustic startle in rats.

The anticonvulsant topiramate (TPM) has been recently proposed as a novel adjuvant therapy for bipolar disorder and schizophrenia, yet its efficacy remains controversial. As both disorders are characterized by gating deficits, we tested the effects of TPM on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle response, a validated animal model of sensorimotor gating. TPM (10, 18, 32, 58, 100 mg/kg, intraperitoneal, i.p.) enhanced PPI in rats in a dose-dependent fashion, prevented the PPI reduction mediated by the dopaminergic agonist apomorphine (0.25 mg/kg, subcutaneous, s.c.) and potentiated the effects of the antipsychotic drugs haloperidol (0.05, 0.1 mg/kg, i.p.) and clozapine (2.5, 5 mg/kg, i.p.). Conversely, TPM elicited no significant effect on the PPI disruption mediated by the NMDA receptor antagonist dizocilpine (0.05, 0.1 mg/kg, s.c.) and surprisingly antagonized the attenuation of dizocilpine-induced PPI disruption mediated by clozapine (5 mg/kg, i.p.). Our results suggest that TPM may exert diverse actions on the neural substrates of sensorimotor gating. While the pharmacological mechanisms of such effects are still elusive, our findings might contribute to shed light on some controversies on the therapeutic action of TPM, and point to this drug as a putative novel adjuvant therapy for some clusters of gating disturbances.

Animals↗
PubMed2004

fMRI of generalized absence status epilepticus in conscious marmoset monkeys reveals corticothalamic activation.

PURPOSE: A nonhuman primate model of generalized absence status epilepticus was developed for use in functional magnetic resonance imaging (fMRI) experiments to elucidate the brain mechanisms underlying this disorder. METHODS: Adult male marmoset monkeys (Callithrix jacchus) were treated with gamma-butyrolactone (GBL) to induce prolonged absence seizures, and the resulting spike-wave discharges (SWDs) were analyzed to determine the similarity to the 3-Hz SWDs that characterize the disorder. In addition, blood-oxygenation-level-dependent (BOLD) fMRI was measured at 4.7 Tesla after absence seizure induction with GBL. RESULTS: Electroencephalographic recordings during imaging showed 3-Hz SWDs typical of human absence seizures. This synchronized EEG pattern started within 15 to 20 min of drug administration and persisted for >60 min. In addition, pretreatment with the antiepileptic drug, ethosuximide (ESM), blocked the behavioral and EEG changes caused by GBL. Changes in BOLD signal intensity in the thalamus and sensorimotor cortex correlated with the onset of 3-Hz SWDs. The change in BOLD signal intensity was bilateral but heterogeneous, affecting some brain areas more than others. No significant negative BOLD changes were seen. CONCLUSIONS: The BOLD fMRI data obtained in this marmoset monkey model of absence status epilepticus shows activation within the thalamus and cortex.

4-Butyrolactone↗
PubMed1994

Cerebral perfusion studies during maturation using single photon emission computed tomography in the neonatal period.

In this study, we used single photon emission computed tomography (SPECT) radiolabelled 99mTc HMPAO to assess cerebral perfusion during maturation in the neonatal period. Results of SPECT examinations in 18 newborn infants, in whom gestational age ranged form 30 to 41 weeks, and who were found to be neurologically normal in retrospect, were reviewed. The developmental changes in cerebral perfusion during the neonatal period shown by SPECT parallel findings of other methods on maturational changes of the central nervous system (neuropathological studies, positron emission tomography scan, magnetic resonance imaging). Cerebral perfusion progresses from the central part of the brain to the cerebellum, sensorimotor and then visual cortex. A close relation seems to exist between cerebral perfusion, metabolism and behavior under normal conditions in the neonatal period.

Brain↗
PubMed1993

Premonitory urges in Tourette's syndrome.

OBJECTIVE: Tourette's syndrome traditionally has been viewed as a hyperkinetic movement disorder characterized by involuntary motor and phonic tics. Many patients, however, describe their tics as a voluntary response to premonitory urges. This cross-sectional study evaluated premonitory urges and related phenomena in subjects with tic disorders. METHOD: A total of 135 subjects with tic disorders, aged 8 to 71 years, completed a questionnaire concerning their current and past tic symptoms. Subjects were asked to describe and, if possible, localize their premonitory urges. The Yale Global Tic Severity Scale was used to assess current tic severity. The method of case finding does not provide prevalence data for premonitory urges. RESULTS: Ninety-three percent of the subjects reported premonitory urges. Anatomical regions with the greatest density of urges were the palms, shoulders, midline abdomen, and throat. Eighty-four percent of the subjects reported that tics were associated with a feeling of relief. A substantial majority (92%) also indicated that their tics were either fully or partially a voluntary response to the premonitory urges. CONCLUSIONS: While epidemiological studies of tic disorders have yet to incorporate questions concerning premonitory urges, these results suggest that such urges may be commonplace in adolescent and adult subjects with tic disorders. These results challenge the conventional wisdom that tic behaviors are wholly involuntary in character. They also implicate brain regions involved in the processing of sensorimotor information in the pathobiology of tic disorders.

Adolescent↗
PubMed2004

Dopamine transmission in the human striatum during monetary reward tasks.

Previous studies have demonstrated the ability of the [11C]raclopride positron emission tomography (PET) technique to measure behaviorally induced changes in endogenous dopamine transmission in humans. However, these studies have lacked well matched sensorimotor control conditions, making it difficult to know what sensory, cognitive, or motor features contributed to changes in dopaminergic activity. Here we report on [11C]raclopride PET studies in which healthy humans performed card selection tasks for monetary rewards. During separate scans, subjects completed a variable ratio (VR) reward schedule with a 25% reward rate in which they did not know the outcome of their responses in advance, a fixed ratio (FR) 25% reward schedule in which outcomes were fully predictable, and a sensorimotor control (SC) condition involving similar sensory and motor demands but no rewards. Relative to the SC condition, the FR schedule produced only modest increases in dopamine transmission and no decreases relative to the SC condition. In contrast, the VR schedule produced significant increases in dopamine transmission in the left medial caudate nucleus while simultaneously producing significant decreases in other areas of the caudate and putamen. These data indicate: (1) the feasibility of measuring alterations in dopamine transmission even after controlling for sensorimotor features and (2) the complex and regionally specific influence of VR schedules on dopamine transmission. The implications of these results are discussed in relation to conflicting models of dopaminergic functioning arising from studies using electrophysiological and microdialysis techniques in animals.

Adult↗
PubMed2006

Normal prepulse inhibition and habituation of acoustic startle response in suicidal depressive patients without psychotic symptoms.

BACKGROUND: Until now, there is a lack of useful biological markers to predict suicidal behavior in depressive patients. However, it is consistently found that suicidality is associated with a central serotonin deficit. Animal data suggest that prepulse inhibition (PPI) as well as habituation of the acoustic startle response (ASR), which are established as operational measures for sensorimotor gating, decreases after serotonin depletion. Thus, we investigated PPI and habituation of ASR in suicidal patients with depressive disorders as potential biological markers for suicidal behavior. METHODS: PPI and habituation of ASR was measured in 20 depressive patients who had at least one suicide attempt within the last three month. Eighteen healthy matched controls were examined likewise. RESULTS: Suicidal depressive patients did not differ from healthy controls in PPI, startle reactivity and habituation of ASR. Subgroup analyses showed that factors such as severity of depression, impulsiveness, gender, smoking, lethality of the last suicide attempt, number of suicide attempts, and medication had no influence on the results. CONCLUSIONS: These results suggest that neither PPI nor habituation of ASR could serve as useful markers for suicidality.

Acoustic Stimulation↗
PubMed2001

Ipsilateral sensorimotor regions and motor sequence learning.

Recently, Boyd and Winstein tested three groups of individuals with damage to unilateral sensorimotor areas on a version of the serial reaction time task performed with the ipsilesional hand. Only when the individuals were provided in advance with explicit knowledge of the motor sequence were they able to benefit behaviorally from the sequence. Despite aspects of the experimental procedure and the subject selection that make it difficult to draw strong conclusions, these results add to growing evidence that sensorimotor structures contribute to the formation of abstract representations that affect more than ipsilateral effectors.

Journal Article↗
PubMed2006

Difference in sensorimotor adaptation to horizontal and vertical mirror distortions during ballistic arm movements.

When learning a novel motor task, the sensorimotor system must develop new strategies to efficiently control the limb(s) involved, and this adaptation appears to be developed through the construction of a behavioral map known as an 'internal model'. A common method to uncover the mechanisms of adaptation and reorganization processes is to expose the system to new environmental conditions, typically by introducing visual or mechanical distortions. The present study investigated the adaptation mechanisms of the human sensorimotor system to horizontal and vertical mirror distortions (HMD and VMD) during the execution of fast goal-directed arm movements. Mirror distortions (MDs) were created by means of virtual visual feedback on a computer screen while the movement was executed on a graphics tablet. Twenty healthy adult participants were recruited and assigned to one of two groups of 10 people each. Tests were divided in two subsequent blocks of five trials. The first block consisted of trials with no mirror distortion (NMD), while the second block was recorded when exposing one group to HMD and the other to VMD. Both MDs resulted in kinematic changes: during the tests with the MDs the participants did not reach the performance level found at the NMD test. Motor performance during HMD appeared to be globally better than during VMD and the adaptation process to VMD appeared to be slower than to HMD, but data interpretation was hampered by large within-participant and between-participant variability. In-depth analyses of the data revealed that most of the motor performance information was contained in the direction of movement. The data supported the idea that the internal model for HMD was already partially built.

Adult↗
PubMed2005

Behavioral effects in adult rats of chronic prepubertal treatment with the cannabinoid receptor agonist WIN 55,212-2.

Human and animal studies provide evidence for vulnerable periods of brain development for deleterious effects of cannabinoids. We have recently shown that pubertal chronic cannabinoid treatment leads to long-lasting behavioral deficits, whereas a comparable treatment in adult rats did not affect the animals' behavior. In the present study we examined the effects of an identical chronic cannabinoid treatment in juvenile rats, just before the onset of puberty. Treatment with the synthetic cannabinoid agonist WIN 55,212-2 (WIN) (1.2 mg/kg) or vehicle was extended over 25 days throughout the prepubertal period (postnatal days 15-40) in juvenile rats. The rats received a total of 20 injections intraperitoneally. Adult rats were tested for object recognition memory, performance in a progressive ratio (PR) operant behavior task, locomotor activity and prepulse inhibition (PPI) of the acoustic startle response. Juvenile chronic WIN administration had no effect on object recognition memory, PR performance and locomotor activity in adulthood. However, a PPI deficit was observed in WIN-treated rats when tested as adults that could be reversed by the acute administration of the dopamine receptor antagonist haloperidol (0.1 mg/kg). Additionally, juvenile cannabinoid treatment reduced the number of rearings, as well as the time spent in the center of the open field in adult rats, suggesting increased anxiety. Juvenile chronic cannabinoid treatment induced behavioral disturbances in adult rats that are less severe than those observed after pubertal cannabinoid administration. However, based on the observations of sensorimotor gating deficits and increased anxiety, we conclude that the prepubertal developmental phase, in addition to puberty, also represents a vulnerable time period for persistent adverse effects of cannabinoids.

Aging↗
PubMed1984

Trigeminal sensorimotor mechanisms and eating in the rat.

Photographic, electrophysiological and neurobehavioral analyses were used to examine the contribution of trigeminal inputs to the behavioral organization of eating in the rat. During eating, jaw opening was always preceded by a period of perioral contact with the food source. Mechanical or electrical stimulation of oral and perioral areas in anesthetized animals elicited compound action potentials in the mylohyoid nerve (jaw-opener innervation) at short latencies and low stimulus intensities. Trigeminal orosensory deafferentation (sparing jaw muscle afferents and efferents) abolished or significantly reduced mouth opening during eating. We conclude that trigeminal orosensory inputs provide an essential link in the stimulus-response chain mediating eating in the rat.

Animals↗
PubMedDate not supplied

Mesostriatal dopamine markers in aged Long-Evans rats with sensorimotor impairment.

Changes in the mesostriatal dopamine system associated with normal aging are observed in both human and laboratory animals, but the specific behavioral consequences of these nonpathological changes are largely unexplored. The present study (a) assessed the effects of normal aging on markers for the mesostriatal dopamine system, and (b) examined the relationship of age-related changes in this system to decline in reaction time performance. Decreased levels of midbrain dopamine (DA) and dihydroxyphenylacetic acid (DOPAC) were observed in the aged rats as compared to young, but there was no evidence for age-related changes in the density of D1 or D2 receptor binding or the density of dopamine uptake sites. Some differences were observed when the aged rats were grouped according to reaction time performance. Aged RT-unimpaired rats exhibited higher density of D1 binding in rostrodorsal striatal patch areas, but lower overall levels of DA. In caudal striatum, aged RT-unimpaired rats exhibited lower DA and higher DOPAC levels.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

'Mouth-feeding' in monkeys after sensorimotor system lesions: an analysis based upon the Denny-Brown collection.

Utilizing the Denny-Brown collection, we investigated an unusual feeding behavior exhibited by monkeys after sequential pre- and post-central gyrus lesions. The behavior involves ingestion of food by placing the lips directly over the food object, i.e., 'mouth-feeding.' Interestingly, this behavior persists long after recovery of the ability to hand-feed. In all of the cases within the collection and in descriptions of mouth-feeding found in the literature, mouth-feeding occurs only after bilateral lesions. We suggest that the co-existence of mouth- and hand-feeding behavior in animals with pre- and post-central gyrus lesions results partly from the sparing of corticospinal projections arising outside these gyri, e.g., the cingulate region, thereby preserving to a certain extent discrete use of the forelimbs.

Animals↗
PubMed2001

Progressive, age-related behavioral impairments in transgenic mice carrying both mutant amyloid precursor protein and presenilin-1 transgenes.

This study provides a comprehensive behavioral characterization during aging of transgenic mice bearing both presenilin-1 (PS1) and amyloid precursor protein (APP(670,671)) mutations. Doubly transgenic mice and non-transgenic controls were evaluated at ages wherein beta-amyloid (Abeta) neuropathology in APP+PS1 mice is low (5-7 months) or very extensive (15-17 months). Progressive cognitive impairment was observed in transgenic mice for both water maze acquisition and radial arm water maze working memory. However, transgenicity did not affect Y-maze alternations, circular platform performance, standard water maze retention, or visible platform recognition at either age, nor did transgenicity affect anxiety levels in elevated plus-maze testing. In sensorimotor tasks, transgenic mice showed a progressive increase in open field activity, a progressive impairment in string agility, and an early-onset impairment in balance beam. None of these sensorimotor changes appeared to be contributory to any cognitive impairments observed, however. Non-transgenic mice showed no progressive behavioral change in any measure evaluated. Given the age-related cognitive impairments presently observed in APP+PS1 transgenic mice and their progressive Abeta deposition/neuroinflammation, Abeta neuropathology could be involved in these progressive cognitive impairments. As such, the APP+PS1 transgenic mouse offers unique opportunities to develop therapeutics to treat or prevent Alzheimer's Disease through modulation of Abeta deposition/neuroinflammation.

Aging↗
PubMed2002

[Treatment dynamics in sensorimotor disorders: the contribution of electrophysiology].

In the field of sensorimotor activities, progresses achieved over the last fifty years have been largely driven by the Reaction Time (RT) paradigm. Information processing models are set in the context of a global breakdown of sensorimotor activities in multiple concatenated stages, each aggregated in many fundamental operations that are functionally linked. If there is a consensus today about this breakdown, the way stages organize themselves in time however is still much debated. According to one hypothesis, there is no temporal overlap between each stages: the process occurs sequentially. According to another theory, the stages overlap over in time: the process occurs in a parallel manner. A behavioral analysis does not allow to determine between these two hypothesis because the RT represents the final product of the whole sensorimotor pathway, while the temporal organization of the processing of information depends on the nature of the transfer between individual stages. An all-or-nothing information transfer, also called discrete, leads to a sequential organization, while a progressive or continuous transfer brings about a parallel organization. Moreover, contrary to a preconceived notion, data obtained from classical neurophysiology are compatible with both a sequential organization and a parallel organization. Particularly, the great number of connections between the different elements of the nervous system has often seemed difficult to conciliate with a sequential organization. In fact, this argument is inadmissible because it stems from confusion between a temporal organization and an anatomical organization of the processing of information. More generally, our knowledge of the functional anatomy of sensorimotor activities imposes but few constraints on the temporal organization patterns of the processing of information. The lack of interest for the neurophysiological argument seems essentially due to the fact that theses arguments rest on research which is not aimed at the temporal organization of the sensorimotor information processing. Recently, approaches that integrate concepts and methods used in experimental psychology and neurosciences have contributed to putting in perspective the organization of information processing. Electromyography, EEG, reflexology and neuronal recording techniques have been used in the context of two inference logics. The first logic, that we call "factual", is based on the study of functional relations between RT and certain neuronal events. The second logic, that we call "chronometric", is based on the study of the relationships between RT and intervals resulting from the breakdown of the RT in relation to certain neuronal events. Generally speaking, most studies suggest that in tasks where the stimulus is composed of numerous attributes, information processing operates in parallel. On the other hand, when the stimulus is made up of a single attribute, information processing could be operating in a sequential manner. One weakness of this electrophysiological approach is that it has so far only examined relationships between physiological indicators and means RT. We propose here to offset these weaknesses by examining functional relationships between RT distribution variances and certain neuronal events linked to information processing.

Electrophysiology↗
PubMed2006

Limbic system participates in mediating the effects of general anesthetics.

In a previous study, we reported that inactivation of the medial septum or the hippocampus by muscimol, a GABA(A) receptor agonist, potentiated the effects of a general anesthetic. In this study, we further investigated whether other structures that are connected to the septohippocampal system are involved in mediating general anesthesia. In freely behaving rats, muscimol (0.25 microg) or saline was infused intracerebrally into one of four areas-the supramammillary area (SUM), nucleus accumbens (NAC), ventral pallidum (VP), and ventral tegmental area (VTA)-and righting, pain, and EEG responses were recorded following either halothane or sodium pentobarbital, representing inhalational and injectable general anesthetic, respectively. The effect of halothane (2%) or pentobarbital (20 mg/kg i.p.) in abolishing the righting, pain response, or low-voltage neocortical activity was enhanced, and the initial behavioral hyperactivity (delirium) was reduced, after muscimol as compared to after saline infusion in SUM, NAC, VP, and VTA. EEGs in the hippocampus and the sensorimotor cortex following halothane or pentobarbital showed increased delta, and decreased hippocampal theta and gamma waves after muscimol infusion as compared to saline infusion in SUM, NAC, VP, and VTA. By contrast, infusion of muscimol in the median raphe increased locomotion and did not significantly alter the behavioral or EEG effects of halothane or pentobarbital. It is suggested that structures that activate the limbic cortices (MS, SUM, and VTA but not the median raphe) or mediate the output of the hippocampus (NAC and VP) normally participate in maintaining consciousness and inactivation of these structures potentiates the response to a general anesthetic.

Anesthetics↗
PubMed1998

The ventral pallidum mediates disruption of prepulse inhibition of the acoustic startle response induced by dopamine agonists, but not by NMDA antagonists.

Prepulse inhibition (PPI) of the acoustic startle response is observed when the startling noise pulse is preceded by a weak, non-startling stimulus. PPI has been considered as a measure for sensorimotor gating mechanisms. Disruption of PPI can be found in schizophrenic patients as well as after blockade of NMDA receptors or stimulation of dopamine receptors in rats. The neuronal circuitry which regulates PPI consists of cortico-limbic brain structures where the nucleus accumbens (NAC) plays a key role. The NAC exerts its modulating effects on PPI by way of a projection from the ventral pallidum (VP) to the pedunculopontine tegmental nucleus (PPTg). We recently postulated that the reduction of PPI by intra-NAC infusion of glycine-site NMDA antagonists is not mediated by the VP. We tested here this hypothesis in rats with excitotoxic lesions of the VP which were systemically treated with apomorphine or MK-801 or received intraNAC infusions of dopamine or the glycine-site NMDA antagonist 7-chlorokynurenic acid. Lesioned rats showed a marked deficit in PPI after MK-801 and 7-chlorokynurenate treatment but not after apomorphine or dopamine injection, in contrast to sham-lesioned controls showing deficits in PPI under all conditions. These data provide behavioral evidence for the existence of a pathway which does not include the VP for the mediation of sensorimotor gating deficits. We propose that a direct connection between the NAC and PPTg may be responsible for the effects of NMDA/glycine receptor blockade, whereas the VP is an indispensable relay for the disruptive effects on PPI exerted by the NAC dopamine system.

Acoustic Stimulation↗