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Abstract and effector-specific representations of motor sequences identified with PET.

Positron emission tomography was used to identify neural systems involved in the acquisition and expression of sequential movements produced by different effectors. Subjects were tested on the serial reaction time task under implicit learning conditions. In the initial acquisition phase, subjects responded to the stimuli with keypresses using the four fingers of the right hand. During this phase, the stimuli followed a fixed sequence for one group of subjects (group A) and were randomly selected for another group (group B). In the transfer phase, arm movements were used to press keys on a substantially larger keyboard, and for both groups, the stimuli followed the sequence. Behavioral indices provided clear evidence of learning during the acquisition phase for group A and transfer when switched to the large keyboard. Sequence acquisition was associated with learning-related increases in regional cerebral blood flow (rCBF) in a network of areas in the contralateral left hemisphere, including sensorimotor cortex, supplementary motor area, and rostral inferior parietal cortex. After transfer, activity in inferior parietal cortex remained high, suggesting that this area had encoded the sequence at an abstract level independent of the particular effectors used to perform the task. In contrast, activity in sensorimotor cortex shifted to a more dorsal locus, consistent with motor cortex somatotopy. Thus, activity here was effector-specific. An increase in rCBF was also observed in the cingulate motor area at transfer, suggesting a role linking the abstract sequential representations with the task-relevant effector system. These results highlight a network of areas involved in sequence encoding and retrieval.

Adult↗

Anxiolytic-like properties of the anandamide transport inhibitor AM404.

The endocannabinoids anandamide and 2-arachidonoyglycerol (2-AG) may contribute to the regulation of mood and emotion. In this study, we investigated the impact of the endocannabinoid transport inhibitor AM404 on three rat models of anxiety: elevated plus maze, defensive withdrawal and separation-induced ultrasonic vocalizations. AM404 (1-5 mg kg(-1), intraperitoneal (i.p.)) exerted dose-dependent anxiolytic-like effects in the three models. These behavioral effects were associated with increased levels of anandamide, but not 2-AG, in the prefrontal cortex and were prevented by the CB(1) cannabinoid antagonist rimonabant (SR141716A), suggesting that they were dependent on anandamide-mediated activation of CB(1) cannabinoid receptors. We also evaluated whether AM404 might influence motivation (in the conditioned place preference (CPP) test), sensory reactivity (acoustic startle reflex) and sensorimotor gating (prepulse inhibition (PPI) of the startle reflex). In the CPP test, AM404 (1.25-10 mg kg(-1), i.p.) elicited rewarding effects in rats housed under enriched conditions, but not in rats kept in standard cages. Moreover, AM404 did not alter reactivity to sensory stimuli or cause overt perceptual distortion, as suggested by its lack of effect on startle or PPI of startle. These results support a role of anandamide in the regulation of emotion and point to the anandamide transport system as a potential target for anxiolytic drugs.

Animals↗

Superior water maze performance and increase in fear-related behavior in the endothelial nitric oxide synthase-deficient mouse together with monoamine changes in cerebellum and ventral striatum.

Nitric oxide (NO) has been implicated in the control of emotion, learning, and memory. We have examined endothelial NO synthase-deficient mice (eNOS-/-) in terms of habituation to an open field, elevated plus-maze behavior, Morris water maze performance, and changes in cerebral monoamines. In the open field, eNOS-/- animals were less active than wild-type controls but showed unimpaired habituation. In the plus-maze, an anxiogenic effect was observed. Proceeding from previous findings of deficits in hippocampal and neocortical long-term potentiation (LTP) in our eNOS-/- mice, we investigated whether these animals also express deficits in learning tasks that have been linked to hippocampal function and LTP. Unexpectedly, eNOS gene disruption led to accelerated place learning in the water maze. Furthermore, during long-term retention and reversal learning, eNOS-/- mice showed improved performance. In a cued version of the water maze task, eNOS-/- and control mice did not differ, implying that the superior performance of eNOS-/- animals on the former tasks cannot be attributed solely to differences in sensorimotor capacities. The neurochemical evaluation of the eNOS-/- mice revealed increases in the concentrations of the serotonin metabolite 5-HIAA in the cerebellum, together with an accelerated serotonin turnover in the frontal cortex. Furthermore, eNOS-/- mice had a higher dopamine turnover in the ventral striatum. These findings are discussed in terms of possible concomitant effects on physiological parameters, such as a decreased reactivity of GABAergic neurotransmission or changes in vascular functions, and effects on behavioral processes related to reinforcement, learning, and emotion.

3,4-Dihydroxyphenylacetic Acid↗

The opposite effect of a low and a high dose of serotonin-1A agonist on behavior induced by MK-801.

The purpose of the present study was to investigate the opposite effect of the pre- and postsynaptic serotonin-1A (5-HT(1A)) receptors on the psychotic-like behavior induced by a non-competitive antagonist of the NMDA receptor, dizocilpine (MK-801). Male Wistar rats received two doses (0.025mg/kg and 1mg/kg) of 5-HT(1A) receptor agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino) tetralin) and/or MK-801 in two different doses, 0.1mg/kg or 0.3mg/kg. We measured sensorimotor gating by testing prepulse inhibition of acoustic startle response (PPI) and locomotor activity of rats. We found an opposite effect of the low and high 5-HT(1A) receptor agonist doses on MK-801 induced deficit in PPI and hyperlocomotion in habituated rats. The low dose of 8-OH-DPAT, which preferentially acts on presynaptic 5-HT(1A) receptors, restored the deficit in PPI and hyperlocomotion in MK-801 (0.1mg/kg)-treated habituated rats. However, the high dose of 8-OH-DPAT, which activates both pre- and postsynaptic 5-HT(1A) receptors, decreased PPI and increased locomotor activity after administration of the low dose of MK-801. Administration of 8-OH-DPAT itself dose-dependently decreased PPI. However, only the high dose of 8-OH-DPAT increased spontaneous locomotor activity of rats. Our results indicate that there is an interaction between the NMDA and 5-HT(1A) receptors. In addition, these findings could indicate that activation of the 5-HT(1A) autoreceptor could be effective as a treatment in schizophrenia, but full potent agonism of the receptor could worsen the psychotic symptoms.

8-Hydroxy-2-(di-n-propylamino)tetralin↗

An alpha(2)-adrenergic antagonist, atipamezole, facilitates behavioral recovery after focal cerebral ischemia in rats.

Previous studies suggest that enhanced noradrenergic neurotransmission promotes functional recovery following cerebral lesions. The present study investigated whether systemic administration of an alpha(2)-adrenergic antagonist, atipamezole, facilitates recovery following transient focal cerebral ischemia in rats. The effect of atipamezole therapy on recovery from ischemia was compared with the effect of enriched-environment housing in rats. Ischemia was induced by occlusion of the right middle cerebral artery (MCA) for 120 min using the intraluminal filament model. Daily atipamezole treatment (1 mg/kg, subcutaneously) was started on day 2 after ischemia induction and drug administration stopped after 10 days. Another group of rats was housed in an enriched environment from day 2 following ischemia induction until the end of the experiment. Several different behavioral tests were used to measure functional recovery during the 26 days following the induction of focal cerebral ischemia. There was improved performance in the limb-placing test from the beginning of atipamezole treatment to day 8, and in wheel-running in the foot-slip test on days 2 and 4. Enriched-environment housing facilitated recovery in the foot-slip test in a later phase of the test period (days 8 to 10). Discovery of a hidden platform in a water-maze task was also facilitated in rats housed in the enriched environment, but this was probably due to the increased swimming speed of these rats. The present data suggest that the alpha(2)-adrenergic antagonist, atipamezole, facilitates sensorimotor recovery after focal ischemia, but has no effect on subsequent water-maze tests assessing spatial learning and memory, when assessed 11 days after the cessation of drug administration.

Adrenergic alpha-2 Receptor Antagonists↗

Serotonergic modulation in aplysia. II. Cellular and behavioral consequences of increased serotonergic tone.

Serotonin (5-HT) plays an important role in sensitization of defensive reflexes in Aplysia and is also involved in several aspects of arousal, such as the control of locomotion and of cardiovascular tone. In the preceding paper, we showed that tail-nerve shock, a noxious stimulus that readily induces sensitization, increases the firing rate of a large number of serotonergic neurons throughout the CNS. However, the functional consequences of such an increase in serotonergic tone are still poorly understood. In this study, we examined this question by using the 5-HT precursor 5-hydroxytryptophan (5-HTP) to specifically increase 5-HT release in the CNS. Increased tonic 5-HT release after 5-HTP treatment was manifested by facilitation of sensorimotor (SN-MN) synapses, increased firing rate of serotonergic neurons in the pedal and abdominal ganglia, and enhanced 5-HT release evoked by tail-nerve shock. When 5-HTP was administered to freely moving animals, it produced a strong arousal response characterized by increased locomotion and heart rate, which was reminiscent of the defensive arousal reaction triggered by noxious stimulation such as tail-shock. In contrast, 5-HTP actually inhibited the tail-induced siphon-withdrawal reflex. It is possible that 5-HT-induced facilitation of SN-MN synapses was counteracted by inhibition of polysynaptic reflex pathways between SNs and MNs, resulting in transient behavioral inhibition of the reflex, which could favor escape locomotion and/or respiration shortly after an aversive stimulus. We conclude that a major function associated with the activation of the Aplysia serotonergic system evoked by noxious stimuli is the triggering of a defensive arousal response. It is known that tail-shock-induced serotonergic activation contributes to memory encoding at least in part by facilitating SN-MN synapses. However, this effect in isolation might not be sufficient for the behavioral expression of sensitization.

5,7-Dihydroxytryptamine↗

Acute injections of brain-derived neurotrophic factor in a vocal premotor nucleus reversibly disrupt adult birdsong stability and trigger syllable deletion.

Behavioral variability serves an essential role in motor learning by enabling sensory feedback to select those motor patterns that minimize error. Birds use auditory feedback to learn how to sing, and their songs lose variability and become highly stereotyped, or crystallized, at the end of a sensitive period for sensorimotor learning. The molecular cues that regulate song variability are not well understood. In other systems, neurotrophins, and brain-derived neurotrophic factor (BDNF) in particular, can mediate various forms of neural plasticity, including sensitive period neural circuit plasticity and activity-dependent synapse formation, and may also influence learning and memory. Here, we have tested the hypothesis that neurotrophin expression in the robust nucleus of the arcopallium (RA), the telencephalic output controlling song, regulates song variability. BDNF and its receptor trkB are expressed in RA, and BDNF expression in RA appears to be highest in juveniles, when song is most variable and plastic, and synapse density highest. Thus, song variability and synaptic connectivity could be enhanced by augmented expression of BDNF in RA. In support of this idea, we found that BDNF injections into the adult RA induced the re-expression of juvenile-like phenotypes, including song variability and an increased synaptic density in RA. Furthermore, BDNF treatment also induced vocal plasticity, characterized by syllable deletions and persistent changes to the song patterns. These results suggest that endogenous BDNF could be a molecular regulator of the song variability essential to vocal plasticity and, ultimately, to song learning.

Animals↗

Interactions between motor commands and somatic perception in sensorimotor cortex.

For many years, it has been postulated that interactions between motor commands and somatic perception in the sensorimotor cortices exist, but they have been difficult to demonstrate. Recent studies have made demonstration of this interaction easier and suggest that cortical activity related to somatic sensation and perception is modified by movement-generating mechanisms. Corollary discharge and efference copy may also play a role in motor behavior.

Animals↗

Does endogenous progesterone promote recovery of chronic sensorimotor deficits following contusion to the forelimb representation of the sensorimotor cortex?

We studied sensorimotor recovery in male, normal-cycling and pseudopregnant female rats following unilateral FL-SMC contusions. Forelimb use (push off before a rear, support against the walls, and landing after a rear) and the foot fault test (foot misplacements during locomotion on an elevated grid) were analyzed from videotapes taken before surgery, and then again on post-surgical days 2 and 36. High endogenous progesterone levels in females at the time of injury did not affect recovery as there were no differences between males, pseudopregnant females and normal-cycling female rats on these behaviors. None of the brain-injured rats recovered symmetrical forelimb use between 2 and 36 days after injury (P>0.05) and they also showed foot misplacements (P>0.05) in the foot fault test. Male and female rats with contusions had fewer mean foot misplacements on day 36 than 2 days after injury (P<0.001), indicating that there was partial recovery on this task. These results were taken to show that there were no sex differences in motor deficits caused by unilateral FL-SMC injury. In addition, higher endogenous progesterone levels in females did not protect them from the chronic sensorimotor deficits caused by unilateral FL-SMC contusions.

Animals↗

Facilitation of somatosensory evoked potentials by exploratory finger movements.

Modification of somatosensory processing depending on the behavioral setting was studied. Active alternating movements of the fingers, passive tactile stimuli to the hand, and active exploration of objects were performed during recording of somatosensory evoked potentials (SEPs). SEPs were elicited by compound electrical median nerve stimulation and electrical stimulation at detection threshold of cutaneous median nerve fascicles identified by microneurography. Electrical stimulation was not time-locked to the studied condition. In comparison with SEPs at rest there was attenuation of early cortical potentials up to 25 ms post-trigger in all nonresting conditions. In stimulation of the compound median nerve as well as of isolated cutaneous fascicles of a hand actively exploring an object there was an additional increased negativity, peaking at 28 ms. This facilitory effect was independent of attentional focusing and was absent during exploration using the ipsilateral, non-electrically stimulated hand. In patients with parietal lesions the facilitatory effect was diminished on the affected side. Spline interpolated brain maps at this latency based on 32-channel recordings in healthy volunteers showed a shift of local contralateral positive maximum from frontal to parietal during exploration, indicating enhancement of a tangential dipole. It is suggested that in conditions involving close sensorimotor interaction such as exploratory hand movements there is preactivation of a cortical area which is located in the central sulcus and receives cutaneous somatosensory inputs.

Adult↗

Telencephalic nuclei control late but not early nestling calls in the budgerigar.

Bilateral lesions targeting the central nucleus of the anterior archistriatum (AAc) were placed in nestling budgerigars (Melopsittacus undulatus) aged 5, 9, 13, 22, 26, and 33 days post-hatch in order to evaluate the role of the telencephalon in producing nestling vocalizations in this species. In budgerigars, AAc is the final common pathway from telencephalic vocal control nuclei to brainstem respiratory and syringeal motorneuron pools. The results show that lesions destroying AAc bilaterally in addition to surrounding archistriatum and neostriatum do not alter the production of early simple patterned foodbegging calls but do prevent both the normal transition at 3-4 weeks post-hatch to more complex begging calls as well as the emergence of individually-distinctive contact calls around the time of fledging. These vocal results are strikingly similar to those obtained in previous studies in which early deafening of nestlings (Heaton and Brauth, 1999) and early lesioning of auditory areas in the anterior telencephalon (Hall WS, Brauth SE, Heaton JT. Comparison of the effects of lesions in nucleus basalis and field 'L' on vocal control learning and performance in the budgerigar (M. undulatus), Brain Behav. Evol., 1994;44:133-148) did not affect call production until 3-4 weeks post-hatch. These data combined support the idea that neither auditory feedback nor telencephalic sensorimotor circuits are necessary for the production of nestling calls before 3 weeks post-hatch.

Age Factors↗

Do autistic children differ from retarded and normal children in Piagetian sensorimotor functioning?

Piagetian sensorimotor functioning of 10 autistic, 10 retarded, and 10 normal children, closely matched on mental age, was assessed with the Dunst revision of the Uzgiris and Hunt scales of infant psychological development. The three groups showed no significant differences in overall performance or specific subtest performance as revealed by estimated developmental ages, number of failed items, and Piagetian stage levels. These findings, which are contrary to previous reports of early sensorimotor deficits specific to autism, suggest that the long-term cognitive deficits in autism are more in symbolic thinking, which does not emerge until the end of the sensorimotor period.

Autistic Disorder↗

The effects of postpartum exposure to triethyl tin on the neurobehavioral functioning of rats.

Male and female Fischer rat pups received sc injections of 1.5 or 3 mg/kg of triethyl tin bromide (TET), ethanol vehicle or distilled water on day 5 postpartum. At 21, 28, 60, and 90 days of age, the rats were weighed and assessed in a battery of tests which included fore- and hindlimb grip strength, negative geotaxis, startle responsiveness and spontaneous motor activity. Animals at 60 days of age were also tested in a two-way shuttle box avoidance procedure. Exposure to TET did not affect body weight at any time during testing, nor did it affect negative geotaxis of grip strength, Startle response to an air puff stimulus was decreased in males and females at 21 and 60 days of age, while no effects were observed at 28 or 90 days of age. Responsiveness to an acoustic stimulus was decreased at 60 days of age only. Spontaneous motor activity of males was increased at 21, and 28 and 60 days of age, while females had elevated activity at 28 and 60 days of age. Relative to ethanol controls, rats of both sexes were significantly hypoactive at 90 days of age. In a two-way shuttle box procedure, latencies to emerge prior to the first trial were elevated in TET exposed male and female rats. The number of discriminated avoidance responses made during a 60 trial session was decreased in females receiving the 3 mg/kg dose. Activity during the intertrial interval was not affected. A single postnatal exposure to TET can produce long-term alterations in the sensorimotor capabilities of rats; the effect appears to occur equally in both sexes and is independent of toxicant-induced body weight changes.

Aging↗

Giant neurons in the rat reticular formation: a sensorimotor interface in the elementary acoustic startle circuit?

The mammalian acoustic startle response (ASR) is a relatively simple motor response that can be elicited by sudden and loud acoustic stimuli. The ASR shows several forms of plasticity, such as habituation, sensitization, and prepulse inhibition, thereby making it an interesting model for studying the underlying neuronal mechanisms. Among the neurons that compose the elementary startle circuit are giant neurons in the caudal pontine reticular nucleus (PnC), which may be good candidates for analyzing the neuronal basis of mammalian behavior. In a first step of this study, we employed retrograde and anterograde tracing techniques to identify the possible sources of input and the efferent targets of these neurons. In a second step, we performed intracellular recordings in vivo, followed by subsequent injections of HRP for morphological identification, thereby investigating whether characteristic features of the ASR are reflected by physiological properties of giant PnC neurons. Our observations demonstrate convergent, bilateral input from several auditory brainstem nuclei to the PnC, predominantly originating from neurons in the cochlear nuclear complex and the superior olivary complex. Almost no input neurons were found in the nuclei of the lateral lemniscus. As the relatively long neuronal response latencies in several of these auditory nuclei appear to be incompatible with the primary ASR, we conclude that neurons in the cochlear root nuclei most likely provide the auditory input to PnC neurons that is required to elicit the ASR. The giant PnC neurons have a remarkable number of physiological features supporting the hypothesis that they may be a neural correlate of the ASR: (1) they receive short-latency auditory input, (2) they have high firing thresholds and broad frequency tuning, (3) they are sensitive to changes in stimulus rise time and to paired-pulse stimulation, (4) repetitive acoustic stimulation results in habituation of their response, and (5) amygdaloid activity enhances their response to acoustic stimuli. Anterograde tracing showed that most giant PnC neurons are reticulospinal cells. Axon collaterals and terminal arbors were found in the reticular formation as well as in cranial and spinal motoneuron pools. The results of this study indicate that giant PnC neurons form a sensorimotor interface between the cochlear nuclear complex and cranial and spinal motoneurons. This neuronal pathway implies that the elementary acoustic startle circuit is composed of only three central relay stations and thus appears to be organized more simply than assumed in the past.

Acoustic Stimulation↗

Oral dyskinesia in brain-damaged rats withdrawn from a neuroleptic: implication for models of tardive dyskinesia.

Rats with ablated frontal sensorimotor cortex and one with ablated sensorimotor connections to forebrain showed more vacuous chewing movements following 6-week chronic administration of a neuroleptic than did occipitally damaged rats or normal controls who were treated in the same way. The effect was still present 1 month after withdrawal. It was not clearly enhanced by subsequent treatments. Other behaviors (e.g., walking, rearing, or grooming) were not similarly affected by drug withdrawal. Additional results of terminal probes with amphetamine, apormorphine, and haloperidol are described, including movements labeled 'sham eating', observed only in frontal rats given apomorphine (AP). The results are interpreted in terms of a Jacksonina model of levels of brain organization; such a model may be applicable to tardive dyskinesia, seen in many schizophrenic patients who are maintained on neuroleptics for long periods.

Amphetamine↗

Behavioral and electrophysiological evidence for gestational age effects in healthy preterm and fullterm infants studied two weeks after expected due date.

We investigated the effects of gestational age at birth on behavioral and electrophysiological measures of 135 medically healthy infants, studied at 42 weeks postconception, and stratified into 3 groups--early-born preterms, 26-32 weeks (n = 55); middle-group preterms, 33-37 weeks (n = 43); and fullterms, 38-41 weeks (n = 37). Subjects were studied behaviorally with the Assessment of Preterm Infants' Behavior (APIB) and electrophysiologically with brain electrical activity mapping (BEAM). Fullterms showed significantly better behavioral function than both preterm groups. Less difference was found between the preterm groups. EEG spectral and photic evoked response were of significantly less amplitude for the preterms than the fullterms. Path analysis showed gestational age effects on behavioral (3 of 6) and electrophysiological (13 of 17) variables due to postnatal complications. We conclude that some differences attributable to gestational age at birth are explained by the cumulative effect of minor but unavoidable complications associated with premature birth. We speculate that remaining effects may result from developmentally inappropriate sensorimotor stimulation consequent to the premature experience of an extrauterine environment.

Arousal↗

Insular cortical projections to functional regions of the striatum correlate with cortical cytoarchitectonic organization in the primate.

We examined the striatal projections from different cytoarchitectonic regions of the insular cortex using anterograde and retrograde techniques. The shell and medial ventral striatum receive inputs primarily from the agranular and ventral dysgranular insula. The central ventral striatum receives inputs primarily from the dorsal agranular and dysgranular insula. Projections to the central ventral striatum originate from more posterior and dorsal insular regions than projections to the medial ventral striatum. The dorsolateral striatum receives projections primarily from the dorsal dysgranular and granular insula. These results show that cytoarchitectonically less differentiated (agranular) insular regions project to the ventromedial "limbic" part of the ventral striatum, whereas more differentiated (granular) insular regions project to the dorsolateral "sensorimotor" part of the striatum. The finding that the ventral "limbic" striatum receives inputs from less differentiated regions of the insula is consistent with the general principle that less differentiated cortical regions project primarily to the "limbic" striatum. Functionally, the ventral striatum receives insular projections primarily related to integrating feeding behavior with rewards and memory, whereas the dorsolateral striatum receives insular inputs related to the somatosensation. Information regarding food acquisition in the insula may be sent to the intermediate area of the striatum.

Animals↗