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Hebbian learning in parallel and modular memories.

Many cognitive and sensorimotor functions in the brain involve parallel and modular memory subsystems that are adapted by activity-dependent Hebbian synaptic plasticity. This is in contrast to the multilayer perceptron model of supervised learning where sensory information is presumed to be integrated by a common pool of hidden units through backpropagation learning. Here we show that Hebbian learning in parallel and modular memories is more advantageous than backpropagation learning in lumped memories in two respects: it is computationally much more efficient and structurally much simpler to implement with biological neurons. Accordingly, we propose a more biologically relevant neural network model, called a tree-like perceptron, which is a simple modification of the multilayer perceptron model to account for the general neural architecture, neuronal specificity, and synaptic learning rule in the brain. The model features a parallel and modular architecture in which adaptation of the input-to-hidden connection follows either a Hebbian or anti-Hebbian rule depending on whether the hidden units are excitatory or inhibitory, respectively. The proposed parallel and modular architecture and implicit interplay between the types of synaptic plasticity and neuronal specificity are exhibited by some neocortical and cerebellar systems.

Cerebellum↗

AF64A, a cholinergic neurotoxin, selectively depletes acetylcholine in hippocampus and cortex, and produces long-term passive avoidance and radial-arm maze deficits in the rat.

The behavioral and biochemical effects of AF64A, a presynaptic cholinergic neurotoxin, were investigated. Bilateral administration of this compound into the lateral cerebral ventricles produced transient and dose-related effects on sensorimotor function and long-term impairments of cognitive behavior. Male Fischer-F344 rats dosed with either 15 or 30 nmol of AF64A reacted 29-62% faster than CSF-injected controls in a hot-plate test 14 (but not 1, 7, 21 or 28) days following dosing. The group administered 15 nmol of AF64A was also significantly more active (41%) than controls 28 days following dosing. The activity level of this group was comparable to that of controls at other times and hyperactivity was never observed in the 30 nmol group. Retention of a step-through passive avoidance task, assessed 35 days after dosing, was impaired in both the 15 and the 30 nmol groups. Their step-through latencies were significantly shorter than the control latencies, and they exhibited more partial entries during the 24-h retention test. Radial-arm maze performance, measured 60-80 days following treatment, was markedly impaired in the treated groups. Animals treated with AF64A made fewer correct responses in their first 8 choices, required more total selections to complete the task, and had an altered pattern of spatial responding in the maze. The neurochemical changes produced by AF64A, determined 120 days after dosing, were specific to the cholinergic system and consisted of decreases of ACh in both the hippocampus (15 and 30 nmol groups) and the frontal cortex (30 nmol group). The concentrations of catecholamines, indoleamines, their metabolites and choline in various brain regions were not affected by AF64A. Furthermore, histological analysis revealed that the doses of AF64A used in the present study did not damage the hippocampus, the fimbria-fornix, the septum or the caudate nucleus. These data support the contention that cholinergic processes in the hippocampus and/or frontal cortex play an important role in learning and memory processes. Furthermore, based upon the behavioral and biochemical data presented, it is suggested that AF64A could be a useful pharmacological tool for examining the neurobiological substrates of putative cholinergic disorders such as senile dementia of the Alzheimer's type.

Acetylcholine↗

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↗

An assessment of the state hypothesis of animal "hypnosis' through an analysis of neocortical and hippocampal EEG in spontaneously immobile and hypnotized rabbits.

Hippocampal and neocortical EEG was studied in spontaneously immobile rabbits and in immobilized rabbits, "animal hypnosis.' Neocortical low voltage fast activity (LVFA) and hippocampal rhythmical slow activity (RSA) occurred spontaneously and were elicited by sensory stimulation, eserine and brain stimulation in normally immobile and hypnotized animals. Atropine sulfate blocked the LVFA and RSA that occurred during spontaneous immobility and hypnosis but not the LVFA and RSA that occurred during movement. RSA was also recorded from both CAI and dentate gyrus generators of the hippocampus during both types of immobility. The results show that hypnotized rabbits have the same type II (atropine-sensitive) EEG that is found in spontaneously immobile rabbits. The presence of type II EEG during hypnosis and its sustained sensitivity to stimulation is compatible with the view that the EEG activity is not uncoupled from its normal behavioral correlates. Perhaps normal EEG during animal hypnosis allows normal sensorimotor functions. This may permit the possibility of escape from predators at opportune moments once the immobility has served its defensive function.

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↗

Development of some early sensorimotor behaviors in sodium-restricted rats.

Rats exposed to low levels of dietary sodium throughout development exhibit reduced chorda tympani nerve taste responses to sodium stimuli during adulthood, apparently due to altered activity of some hormone(s) or growth factor(s) during early development. We were concerned that such an alternation in the activity of some humoral factor(s) could affect development globally. To test this possibility, we utilized a battery of morphological and behavioral measures in neonatal, sodium-restricted rats, expecting serious deficits to be reflected in altered onset and expression of these behaviors. As compared with control rat pups, preweanling sodium-restricted rat pups exhibited greatly diminished body weight gain and delayed acquisition of several morphological features. However, in terms of sensorimotor development, no significant differences between sodium-restricted and control rat pups were found. We interpret these results to indicate that despite significant somatic effects, sodium restriction may not influence the development of physical prowess or of early sensorimotor function in a global manner.

Animals↗

Ventriculolumbar perfusion chemotherapy with methotrexate and cytosine arabinoside for meningeal carcinomatosis: a pilot study in 13 patients.

Thirteen patients with meningeal carcinomatosis were treated by ventriculolumbar perfusion using methotrexate (MTX) and cytosine arabinoside (Ara-C). MTX (10-30 mg) and Ara-C (40 mg) were infused at 8- to 12-hour intervals on six or nine occasions via an Ommaya reservoir placed in the lateral ventricle. Nine of thirteen patients had evaluable response (69% response rate with a mean survival of 8.8 months among responders) and ventriculolumbar perfusion therapy was effective in improving cerebral, cranial nerve, and spinal root signs and symptoms, especially sensorimotor disturbance in the lower limbs. Three of the six bedridden patients became ambulatory without assistance and two of the four patients who were walking with assistance became ambulatory without assistance. Urinary incontinence also markedly improved, except in one nonresponder. Lumbar cerebrospinal fluid parameters (cytological findings and tumor markers) also improved in association with the clinical improvement. Our pilot results were encouraging, especially the improvement of sensorimotor function in the lower limbs. However, the toxicity was unacceptable when compared with that of standard intrathecal chemotherapy. Thus, this therapy needs to be investigated further to establish the most appropriate drug doses and perfusate volume to reduce toxicity as well as determine its true efficacy in the treatment of meningeal carcinomatosis.

Adult↗

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↗