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Representation of the body by single neurons in the dorsolateral striatum of the awake, unrestrained rat.

Single cell recordings in awake monkeys and cats have demonstrated that individual body parts are represented within striatal subregions receiving projections from somatic sensorimotor cortex. Literature indicating that the lateral striatum of the rat receives similar cortical inputs and subserves sensorimotor functions prompted a study of whether this subregion contains similar representations of the body. Single cell recordings were obtained from 923 neurons of 24 awake, unrestrained rats. Of 788 neurons categorized according to body part, 264 (34%) discharged in relation to active movement, passive manipulation, and/or cutaneous stimulation of a particular part of the body; the remainder were related to global, whole body movement (38%) or were unresponsive (28%). Neurons related to individual body parts were recorded throughout the entire anterior-posterior extent of the dorsolateral striatum (+1.60 to -2.12 mm A-P, from bregma), intermingled among each other in all 3 dimensions. Two topographic arrangements were observed. First, neurons that fired rhythmically, in phase with low frequency (5-6 Hz) whisking of the vibrissae were segregated in the caudal striatum (-0.2 to -2.12 mm A-P) from neurons related to other body parts, which were distributed from +1.6 to -0.8 mm A-P. Second, representations of the head and face were located ventral to those of the limbs, despite substantial overlap in their overall distributions. A prominent feature of individual electrode tracks was the clustering together of cells related to the same body part. Neurons related to body parts exhibited substantial diversity, which took several distinct forms. Some neurons fired during movement or sensory stimulation in any direction, whereas others showed selectivity for a particular direction. Certain neurons responded to sensory stimulation of a large unilateral region of the body (e.g., all vibrissae or the entire forelimb), whereas others responded to stimulation of highly restricted regions (e.g., a single vibrissa or a single forepaw digit). Finally, neurons differed in the extent to which they exhibited active and passive properties. Among vibrissae-related neurons, one group fired rhythmically during whisking but did not respond to sensory stimulation of the vibrissae; a second group responded to sensory stimulation of the vibrissae but did not fire rhythmically during whisking; a third group showed both properties. Among limb-related neurons, firing during active movement was a property of every cell; none showed sensory responsiveness without showing a relation to active movement of one limb. Of the limb-related neurons, 89% tested responded to passive manipulation of the limb to which the neuron was actively related, and 71% also responded to cutaneous stimulation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals

Interaction of alcohol and transdermally administered scopolamine.

In a placebo-controlled, randomized, double-blind cross-over study in 12 healthy volunteers the effect of acute alcohol intake during treatment with transdermally administered scopolamine (TTS-scopolamine) was investigated. One group of six subjects reached maximal blood alcohol concentrations (BAC) of 80 mg/dL and another group of six subjects a BAC of 130 mg/dL. There was no significant potentiation of alcohol effects on critical flicker fusion frequency by TTS-scopolamine. Sensorimotor function (choice reaction task) was also not significantly more influence by the combination. There was no effect of scopolamine on the elimination of alcohol. The urinary excretion of scopolamine was not influenced by oral intake of alcohol. TTS-scopolamine caused only minor side effects in a few volunteers, such as dry mouth (2 of 12) and blurred vision (1 of 12).

Administration, Cutaneous

[Three basic kinds of behaviour, a scheme of their neurobiological correlates (author's transl)].

The psychic sphere is to be regarded as the source of meaningful behaviour, which is carried out in the service of the cell community that makes up our body. Three fundamental types of behaviour can be distinguished: the purely practical, the theoretical-practical, and the purely theoretical. These three types of behaviour have three different reasons: the first a determining reason, the second a motivating reason, and the third a supporting reason. The threefold nature of the reasons is related to the threefold needs of the cell community (in this context man is considered as an example of an animal). Possible neurobiological bases of human behaviour are depicted in a schematic figure showing the relation of cerebral centres and sensorimotor functions of the human face including eye movements. The psychic centre may be located in the thalamus, the areas of the central sulcus are regarded as an objectivation zone. This indicates that the motor zones of the cortex, including the frontal adversive fields, are intention zones, and the sensory zones reproduction, expectation, and recollection zones. A system so composed would render possible what we see in every animal being: decision-making, foresight, and learning.

Behavior

Parametric determinants in pre-stimulus modification of acoustic startle: interaction with ketamine.

Prepulse inhibition of the acoustic startle response is a form of reflex modification known to be sensitive to drugs and to subtle procedural manipulations. The present study examined the importance of prepulse length and prepulse-pulse interval in the expression of prepulse inhibition and its modification by the noncompetitive N-methyl-D-aspartate antagonist, ketamine. In contrast to a previous report, ketamine disrupted prepulse inhibition at doses of 5.6 and 10 mg/kg when its short time course was taken into consideration. In a second experiment, the amount of prepulse inhibition was found to be directly related to prepulse length, with prepulse inhibition produced by shorter prepulse durations slightly more sensitive to disruption by ketamine. A third experiment examined prepulse-pulse time intervals (30-2000 ms). While prepulse inhibition produced by prepulses occurring 60-500 ms before the startle stimulus was disrupted by 10 mg/kg of ketamine, prepulses preceding the startle stimulus by only 30 ms produced either no effect or slight prepulse facilitation under control conditions, and significant prepulse facilitation when ketamine was administered. A fourth experiment examined the time course of prestimulus modification by continuous lead stimuli, ranging in onset from 15 to 75 ms before the startle stimulus. Prepulse facilitation, when observed, tended to occur in earlier portions of the session and was enhanced by ketamine. These results suggest that prestimulus modification of the startle reflex has important parametric and experiential determinants that may influence the effects of drugs. Some of these temporal determinants may have relevance to sensorimotor function in schizophrenia.

Acoustic Stimulation

Time-course and regional distribution of the metabolic effects of bromocriptine in the rat brain.

Local cerebral glucose utilization (LCGU) and motor behavior were examined in awake Fischer-344 rats after administration of the dopaminergic agonist bromocriptine (BROMO). LCGU was measured using the [14C]2-deoxyglucose technique in 63 brain regions at 1,2,3 or 4 h after BROMO 20 mg/kg, and at 4 h after BROMO 100 mg/kg i.p. At 2 h, LCGU was reduced significantly in 13% of the 63 regions examined. The affected regions are related to the topographical distribution of dopaminergic innervation in the brain. At 3-4 h, LCGU remained depressed in some of the above dopaminergic regions, but was elevated significantly in regions which are involved in sensorimotor function. BROMO also produced two behavioral effects depending on time after administration. Locomotor activity was depressed at 1-2 h, and stereotyped behavior appeared at 3-4 h. The time-dependent effects of BROMO may reflect progressively increasing brain concentrations of the drug or of its active metabolites. The coincidence of locomotor depression and reduction of LCGU in dopaminergic regions suggests a role of dopamine autoreceptors in regulation of motor function. Metabolic stimulation of many non-dopaminergic regions when stereotypy is evident suggests that circuit(s) involving these areas may contribute to stereotypy.

Animals

Behavioral study after local injection of 6-hydroxydopamine into the nucleus accumbens in the rat.

Anatomically, the nucleus accumbens (n.Acc.) has been considered as an interface between limbic and striatal sensorimotor structures. In the light of this hypothesis we have investigated the behavioral effects of destruction of the dopaminergic innervation of the n.Acc. after local injection of 6-hydroxydopamine. The following behavioral deficits were observed: hypoexploration in a 4-hole box and 2-compartment field, failure to inhibit response strategies either with positive reinforcement in a straight alley test or negative reinforcement in a passive avoidance test. These disturbances comprise a syndrome of perseveration, reduced distraction by irrelevant information, decreased behavioral switching and flexibility, and a paradoxical locomotor disinhibition in an emotional context. Very similar behavioral changes are found following lesions of limbic structures. In addition, these lesioned animals exhibit an enhanced latency to initiate motor responses. This deficit of behavioral initiation is classically observed in motor striatal disease. It is suggested that the n.Acc. is a key structure for the integration of limbic and striatal sensorimotor functions.

Animals

Inhibition of ornithine decarboxylase alters neurological responsiveness to a tremorigen.

Difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC; 200-800 mg/kg, s.c.), to rats has no detectable behavioral effects using a battery of tests to assess sensorimotor function. In contrast, the induction of tremor by chlordecone, a neurotoxic agent that affects neuronal ionic processes, is significantly attenuated by pretreatment with DFMO. The effects of DFMO on chlordecone-induced tremor were reversed by pretreatment with putrescine. DFMO had no effects on p,p'-DDT, a tremorigen having a mechanism of action different from chlordecone. These findings imply that polyamines may play a role in select neuronal processes.

Animals

Dopamine-rich grafts ameliorate whole body motor asymmetry and sensory neglect but not independent limb use in rats with 6-hydroxydopamine lesions.

The capacity of dopamine (DA)-rich embryonic grafts to influence performance in a skilled motor task has been assessed. In two separate experiments, unilateral 6-hydroxydopamine lesions of forebrain DA systems induced a neglect of the contralateral limb and an almost total preference for use of the ipsilateral limb when reaching through the bars of a cage for food pellets. If the food paw was restrained, either by a bracelet or by injection of a local anaesthetic, the lesioned rats would continue to make many reaching attempts with the contralateral paw, but on the great majority of these attempts they were unsuccessful in grasping or retrieving food. DA-rich grafts, reinnervating the denervated caudate-putamen, provided no detectable benefit to the lesioned rats, neither in reducing the ipsilateral bias in their side preference, nor in increasing their success when constrained to reaching with the contralateral limb. This failure to benefit from the grafts is not due to the grafts themselves not being viable, since the same rats showed substantial compensation of whole body motor asymmetries in spontaneous and drug-induced rotation, and a reduction of asymmetry in a battery of neurological tests of sensorimotor function. The results are discussed in terms of the degree of anatomical integration of the grafts into the host neural circuitry, and the neural organization necessary for the performance of different classes of behavior.

Animals

Effects of ageing on the behavioural responses to dopamine agonists: decreased yawning and locomotion, but increased stereotypy.

Sensorimotor function and the behavioural responses to a range of doses of subcutaneous apomorphine were assessed in mature (6-8 months) and old (23-26 months) Sprague-Dawley rats of comparable weight. In addition, the locomotor activity response of 12-month-old and 24-month-old rats to continuous infusions (14 days by osmotic minipump) of a selective dopamine D2 agonist. (+)-4-propyl-9-hydroxynaphthoxazine (PHNO, 10 micrograms/h) was investigated. Measures of spontaneous locomotor activity and motor coordination revealed impairments in the aged animals. Low doses of apomorphine (10-50 micrograms/kg), which preferentially activate dopamine autoreceptors, induced yawning, chewing mouth movements and penile grooming. The frequency of yawning and duration of penile grooming were significantly decreased in the old animals. In contrast, 200 micrograms/kg of apomorphine induced stereotyped sniffing and licking or gnawing, and these responses were significantly increased in the aged animals. There was a 25% decrease in striatal dopamine levels in the aged animals in this experiment. PHNO increased the amplitude of the circadian rhythms in locomotor activity exhibited by mature rats, and daytime tolerance to the stimulant effects of PHNO was reversed by stress in these animals. Both of these effects were attenuated in the aged rats. These findings suggest that (1) the dopamine receptors mediating yawning and stereotypy have different anatomical locations (2) ageing is associated with decreased responsiveness to stimulation of dopamine autoreceptors, consequent upon the loss of dopaminergic nerve terminals, and (3) while the functional response to selective stimulation of postsynaptic D2 receptors decreases with age, the postsynaptic response to a mixed D1/D2 agonist increases.

Aging

Binding of the neurotrophic peptide Org 2766 to rat spinal cord sections is affected by a sciatic nerve crush.

The binding of the neurotrophic peptide, [3H]Org 2766 (55 nM), to rat spinal cord sections was studied, employing quantitative autoradiography. The binding was unevenly distributed over spinal cord structures and was displaceable by non-labelled Org 2766 to a limited extent (35%). Binding could not be displaced by the opiate antagonist, naloxone, indicating that [3H]Org 2766 binding sites are distinct from opiate receptors. However, the exact nature of the binding sites remains to be elucidated. A marked left-right difference in [3H]Org 2766 binding in the dorsal horns of the spinal cord at level L2 was observed, 6 days after unilateral crush lesioning of the sciatic nerve. No such effect was found at level T10. After 28 days, when sensorimotor functioning had completely recovered, the [3H]Org 2766 binding pattern was comparable to that in sham-operated rats again. It is suggested that Org 2766 binds to axonal sprouts or glia in the dorsal horn of the spinal cord.

Adrenocorticotropic Hormone

Estrogen administration increases neuronal responses to excitatory amino acids as a long-term effect.

Ongoing studies from this laboratory have demonstrated marked potentiating actions of the sex steroid 17 beta-estradiol (E2) on glutamate-induced excitation. In the present study, systemic injection of a physiological dose of E2 was demonstrated to augment significantly excitatory responses of cerebellar Purkinje (Pnj) cells to iontophoretic application of the specific excitatory amino acid (e.a.a.) agonists quisqualate and N-methyl-D-aspartate. Potentiation of e.a.a. responses was observed as rapidly as 5-10 min post E2, and was, in many cases, a persistent, non-decremental effect. These observed long-term actions of E2 may provide one mechanism for the activating effects of the steroid on sensorimotor function and seizure activity.

Action Potentials

3-Acetylpyridine results in degeneration of the extrapyramidal and cerebellar motor systems: loss of the dorsolateral striatal dopamine innervation.

3-Acetylpyridine (3-AP) administration to rats results in degeneration of the dopamine (DA) innervation of the striatum as well as degeneration of the olivocerebellar system. We now report that administration of this pyridine neurotoxin results in a decrease in striatal DA concentration which is restricted to the dorsolateral aspects of the caudatoputamen. 3-AP treatment did not alter DA levels in the ventromedial striatum, the nucleus accumbens, or the anteromedial prefrontal cortex. Both 3-AP and another pyridine neurotoxin, 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP), potently inhibited in vitro MAOB activity and in contrast weakly inhibited MAOA activity. However, in vitro inhibition of MAOB by the selective inhibitor deprenyl did not prevent or attenuate 3-AP-induced striatal DA depletion. These data indicate that 3-AP administration to rats not only results in degeneration of the olivocerebellar system, but also effects degeneration of the DA innervation of the dorsolateral striatum, the striatal sector thought to subserve motoric and sensorimotor function. 3-AP-induced nigrostriatal degeneration differs from that elicited by MPTP in that the former is not prevented by deprenyl pretreatment. The 3-AP-induced degeneration of both extrapyramidal and cerebellar motor systems may offer insight into the mechanisms involved in degeneration of the two motor systems in certain strains of rodents (such as the Weaver mutant mouse), and suggests that the sequelae of administration of this pyridine may serve as a useful model for olivopontocerebellar atrophy-associated parkinsonism.

Animals

Enhancement of regeneration by Org 2766 after nerve crush depends on the type of neural injury.

The neurotrophic effects of the adrenocorticotropin (ACTH)-(4-9) analog Org 2766 (Met(O2)-Glu-His-Phe-D-Lys-Phe) were studied in rats recovering from a sciatic nerve crush. Org 2766 (10 micrograms/rat s.c., every 48 h) increased the number of myelinated axons reinnervating a previously denervated sciatic nerve by 32% (P less than 0.01), as assessed 13 days after crush lesioning, and facilitated recovery of sensorimotor functioning by 14% (P = 0.05), as measured by foot withdrawal after stimulation of the footsole with hot air. However, these facilitating effects were only seen if the nerve was lesioned using forceps with grooved jaws and not if forceps were used with cross-hatched jaws. Endoneural tubes and Schwann cells of the sciatic nerve appeared to be better preserved after crushing with grooved rather than cross-hatched jaws. Our data indicate that the regeneration-enhancing effects of Org 2766 are dependent on the type of injury applied to the endoneurium and endoneural tubes of the sciatic nerve and suggest that endoneural tissue may mediate the neurotrophic properties of Org 2766.

Adrenocorticotropic Hormone

Psychological and physiological characteristics of patients with severe idiopathic constipation.

This study prospectively evaluated psychological profiles and selected parameters of colonic and anorectal sensorimotor function in 25 consecutive patients who were referred for severe idiopathic constipation. Measurement of colonic transit of radiopaque markers divided patients into those with normal transit (n = 10) and those with slow transit (n = 15). As measured by the Hopkins Symptom Checklist, patients with normal transit constipation demonstrated significantly higher scores for psychological distress in the global symptoms index and nine clinical subscales than did those with slow transit constipation and gastrointestinal control subjects (n = 25). Both groups with constipation had decreased rectal sensation compared with controls but there was no relationship to rectal compliance or threshold of internal sphincter relaxation. There was also no relation between abnormalities of anorectal parameters, including expulsion dynamics, and psychological profiles in two groups. Measurement of colonic transit and psychological profiles in patients with severe idiopathic constipation identify two groups of patients with respect to possible pathogenesis of symptoms. Accordingly, different therapeutic approaches may be required, one behaviourally and psychologically based and the other focused on the possible modification of disordered colonic transit.

Adolescent

Active avoidance in rats with unilateral hypothalamic and optic nerve lesions.

During the height of the contralateral sensorimotor deficit that follows unilateral hypothalamic lesions, rats demonstrate severe performance deficits when tested on a two-way active avoidance task which utilizes a visual conditioned stimulus. This deficit is observed whether or not the ipsilateral or contralateral optic nerve is sectioned in conjunction with the unilateral hypothalamic lesion. With the return of sensorimotor function contralateral to the lesion, animals that had been unable to avoid shock during their debillitated phase demonstrated significant savings when tested on the original task.

Animals

Behavioral effects of centrally administered dynorphin and [D-ala2-D-leu] enkephalin (DADLE) in rats.

Dynorphin and [D-ala2-D-leu]enkephalin (DADLE) were administered directly into the cerebrolateral ventricles of rats and effects on various indices of sensorimotor function and retention of a passive avoidance task were measured. Dynorphin markedly suppressed exploratory motor activity and decreased responsiveness to an acoustic stimulus. Although increases in latency to respond to a noxious thermal stimulus were seen in rats after dynorphin, these changes were always associated with alterations in motor capacity. Injection of dynorphin immediately after a passive avoidance training trial had no significant effect on retention 1 week later. The physiological effects of DADLE were clearly different than those of dynorphin. DADLE produced a biphasic decrease followed by an increase in motor activity and an increased acoustic startle reactivity. DADLE had no effect on reactivity to a noxious thermal stimulus. Posttrial administration of DADLE significantly impaired retention of a step-through passive avoidance task 1 week after training. These data indicate different neurobiological roles for kappa and delta opiate receptors in the central nervous system.

Acoustic Stimulation

Intrinsic 5HT-immunoreactive neurons in the spinal cord of the fetal non-human primate.

Serotonin (5HT) immunoreactive neurons were identified in the late-term fetal spinal cord of normal non-human primates. These neurons were distributed throughout the spinal cord, being concentrated in lamina X and the subjacent ventral median fissure, while their immunoreactive fibers and terminals innervated the zone surrounding the central canal and the ventral spinal artery. Even at this late fetal stage, the dorsal and ventral spinal gray matter was virtually devoid of any positive 5HT immunoreactivity, in contrast to that seen in the adult primate. These findings suggest that the intrinsic 5HT neurons of the primate during development may modulate CSF composition or provide cues for spinal cord differentiation rather than regulate sensorimotor functions as they do in the adult.

Animals

Selective neocortical and thalamic cell death in the gerbil after transient ischemia.

In animal models of transients ischemia, selective vulnerability and delayed neuronal death in the hippocampus have been extensively described. However, little is known about selective damage in the neocortex and the thalamus, even though deficits in sensorimotor function are common in humans surviving hypoxic/ischemic episodes. This study investigated the neurodegenerative effects of transient ischemia in the gerbil neocortex and thalamus with use of Cresyl Violet and silver impregnation staining methods. In addition, immunohistochemistry of an astrocyte-associated protein, glial fibrillary acidic protein, was used to assess the astrocytic response to ischemia. Pyramidal cells in layers 3 and 6 of somatosensory and auditory cortex were exceptionally sensitive to ischemia, whereas the neurons in layers 2, 4 and 5 were more resistant to ischemia. More pyramidal cells were killed in layer 3 than in layer 6. This bilaminar pattern of neuronal death developed after periods of ischemia ranging from 3 to 10 min and was identifiable at post-ischemic survival times of 6 h to one month. Somatodendritic argyrophilia in the neocortex was identified as early as 6-12 h after 5 min of ischemia. The greatest number of degenerating cortical neurons were stained two to four days after ischemia. With 10 min of ischemia, argyrophilic neurites and neurons were also found as early as 8 h after the occlusion. The most extensive damage was noted in the ventroposterior nucleus, the medial geniculate nucleus, and the intralaminar nuclei two to four days after ischemia. Thus, selective vulnerability and delayed neuronal death are evident in both the neocortex and the thalamus after transient ischemia. These regions need to be examined when considering the efficacy of potential neuroprotective drugs.

Animals