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PubMed1996

On the analysis of the inverse problem of metabolic pathways using artificial neural networks.

Here we develop the use of artificial neural networks for solving the inverse metabolic problem, in other words, given a set of steady-state metabolite levels and fluxes in a pathway of known structure to obtain the parameters of the system, in this case the enzymatic limiting rate and Michaelis constants. This requires two main procedures: first the development of a computer program with which one can model metabolism in the forward direction (i.e. given the internal and parameters to determine the steady-state fluxes and metabolite concentrations), and second, given arrays of associated parameters and variables thereby obtained, to exploit artificial neural networks to form a model capable of obtaining the parameters from the variables. We studied 2-step pathways exhibiting first-order kinetics, 2-step pathways exhibiting reversible Michaelis-Menten kinetics and then 3-step pathways (again exhibiting reversible Michaelis-Menten kinetics), modelled using the program Gepasi. Whilst it was fairly easy for the networks to learn most of the parameters in the 2-step pathway, it was found helpful for the Michaelis-Menten case to vary the concentration of the starting pathway substrate for each set of internal parameters, and to train separate networks for each parameter. Some parameters were much easier to learn than others, reverse K(m) and V(max) values normally being the most difficult. For the 3-step pathway learning sometimes required as much as 3 days, and occasionally convergence was not obtained. Overall, neural networks of the present type, with fully interconnected feedforward architectures and trained according to the backpropagation algorithm, scaled poorly as the problem size was increased.

Algorithms↗
PubMed2006

Nicotine reverses adult-onset hypothyroidism-induced impairment of learning and memory: Behavioral and electrophysiological studies.

Nicotine alleviates cognitive impairment associated with a variety of health conditions. We examined the effect of chronic nicotine treatment on adult-onset hypothyroidism-induced impairment of learning and memory in rats. Hypothyroidism was induced by surgical removal of thyroid glands (thyroidectomy). One month later, chronic nicotine treatment (1 mg/kg sc, twice/day) was instituted for 4-6 weeks. Test of hippocampus-dependent spatial learning and memory in the radial arm water maze showed that hypothyroidism impaired learning as well as short-term and long-term memory retention. Chronic nicotine treatment reversed the hypothyroidism-induced learning and memory impairment. In normal rats, chronic nicotine treatment had no effect on learning and memory. Extracellular recordings from the CA1 region of anesthetized hypothyroid rats showed severe reduction of both early-phase and late-phase long-term potentiation (LTP) magnitude, which was reversed in nicotine-treated hypothyroid rats. These results show that chronic nicotine treatment prevents hypothyroidism-induced impairment of spatial cognition and LTP.

Action Potentials↗
PubMed1974

Reversal by L-dopa of impaired learning due to destruction of the dopaminergic nigro-neostriatal projection.

Rats receiving bilateral stereotaxic injections of 6-hydroxydopamine into the zona compacta of the substantia nigra failed to learn a one-way active avoidance response. Small doses of L-dopa (1.5 milligrams per kilogram of body weight) in combination with a peripheral decarboxylase inhibitor reversed this impairment. Animals with lesions which acquired the avoidance response during L-dopa administration retained this response when drug treatment was discontinued. These experiments suggest that the dopaminergic nigro-neostriatal projection serves a critical function in the acquisition of learned instrumental responses.

Animals↗
PubMed1997

Deficits in discriminated learning remain despite clearance of long-term persistent viral infection in mice.

Mice persistently infected with lymphocytic choriomeningitis virus (LCMV) exhibit impaired learning ability. In this report, we determined whether clearance of the virus was associated with restoration of behavioral function. Neonatal Balb/cByJ mice were persistently infected with LCMV and tested as adults in a nonconditional spatial discrimination task. The presence of viral proteins in neurons was confirmed immunohistochemically and infectious virus was quantified in the blood by plaque assay. LCMV-infected adult mice made more errors in a Y-maze avoidance task compared to sham-inoculated controls. After the initial behavioral analysis, infected and control mice received a dose of cytotoxic T-lymphocytes sufficient to clear virus from these mice. Following complete clearance of the virus, mice were re-tested in the behavioral task, 5 months after the original test. No reversal of the learning deficit was seen following viral clearance; mice that had been cleared of the virus and those that remained persistently infected behaved similarly. These data indicate that persistent LCMV infection of the CNS lasting up to 7 months results in discriminated learning impairments that are not reversed by subsequent anti-viral immunocytotherapy.

Aging↗
PubMed2006

Synaptic memories upside down: bidirectional plasticity at cerebellar parallel fiber-Purkinje cell synapses.

Information storage in neural circuits depends on activity-dependent alterations in synaptic weights, such as long-term potentiation (LTP) and long-term depression (LTD). Bidirectional synaptic plasticity endows synapses with mechanisms for rapid reversibility, but it remains unclear how it correlates with reversibility in behavioral learning and whether there is a universal synaptic memory mechanism that operates similarly at all types of synapses. A recently discovered postsynaptic form of LTP at cerebellar parallel fiber (PF)-Purkinje cell (PC) synapses provides a reversal mechanism for PF-LTD and enables a fresh look at the implications of bidirectional plasticity in a brain structure that is particularly suitable to correlate cellular to behavioral learning events. Here, we will review recent studies that reveal unique properties of bidirectional cerebellar plasticity and suggest that the induction cascades for cerebellar LTP and LTD provide a mirror image of their counterparts at hippocampal synapses. We will also discuss how PF-LTP helps to explain reversibility observed in cerebellar motor learning.

Animals↗
PubMed1999

Transcranial magnetic stimulation can measure and modulate learning and memory.

The potential uses for Transcranial Magnetic Stimulation (TMS) in the study of learning and memory range from a method to map the topography and intensity of motor output maps during visuomotor learning to inducing reversible lesions that allow for the precise temporal and spatial dissection of the brain processes underlying learning and remembering. Single-pulse TMS appears to be adequate to examine motor output maps but repetitive TMS (rTMS) appears necessary to affect most cognitive processes in measurable ways. The results we have reviewed in this article indicate that rTMS may have a potential clinical application in patients with epilepsy in whom it is important to identify the lateralization of verbal memory. Single-pulse TMS can help identify changes in motor output maps during training, that may indicate improved or diminished learning and memory processes following a stroke or other neurological insult. Other evidence indicates that rTMS may even have the capability of facilitating various aspects of memory performance. From a research perspective. rTMS has demonstrated site- and time-specific effects primarily in interfering with explicit retrieval of episodic information from long-term memory. rTMS may also be able to modulate retrieval from semantic memory as evidenced by response-time and accuracy changes after rTMS. All these findings suggest that the use of transcranial magnetic stimulation in the study of learning and memory will increase in the future and that it is already a valuable tool in the cognitive neuroscientists' belt.

Blinking↗
PubMed1998

The role of the central cholinergic projections in cognition: implications of the effects of scopolamine on discrimination learning by monkeys.

In humans, administration of the cholinergic antagonist scopolamine impairs the encoding of information into long-term memory and has effects on other cognitive processes. It has been supposed that it is inhibition of the rising cholinergic projections from the basal forebrain, specifically from the basal nucleus of Meynert (NBM) to the neocortex and from the medial septum/vertical limb of the diagonal band of Broca (MS/VDB) to the hippocampus, that results in these cognitive impairments. In this paper, we describe the effects of scopolamine treatment in monkeys on learning different sorts of visual discrimination and visuospatial conditional tasks and compare these results to the effects of lesions of the rising cholinergic projections. Experiments in rodents in which these projections have been selectively destroyed have failed to produce a consensus view of the functions of these two areas. In particular, highly specific immunotoxic lesions of the NBM have largely failed to produce changes in task performance that can be interpreted as resulting from a cognitive impairment. In monkeys, lesions of the NBM produce modest or short-lasting, impairments in visual discrimination learning, retention, and reversal, whereas lesions of the MS/VDB produce large and permanent impairments of certain types of conditional learning. Similar impairments produced by scopolamine in monkeys and additive effects of lesions of the NBM or MS/VDB with scopolamine suggest that scopolamine has these effects by acting on the rising cholinergic pathways rather than on other cholinergic systems in the brain. It is argued that the rising cholinergic projections sustain the functions of the target areas; in the case of the hippocampus in humans, the function is usually regarded as being the analysis of information in a way that is pertinent to the formation of episodic memories and in the case of the neocortex, is the analysis of information in a manner that is relevant to the cognitive processing of on-going events and the acquisition of semantic knowledge.

Acetylcholine↗
PubMedDate not supplied

Effects of prenatal exposure to toluene on postnatal development and behavior in rats.

Development and neurobehavioral effects of prenatal exposure to toluene (CAS 108-88-3) were studied after exposing pregnant rats (Mol:WIST) to 1800 ppm of the solvent for 6 h daily on days 7-20 of gestation. Body weights of exposed offspring were lower until day 10 after parturition. Neurobehavioral evaluation of the pups revealed no effects on motor function (rotarod), activity level (open field), acoustic startle, and prepulse inhibition. Measurements of hearing function using auditory brain stem response revealed small effects in male-exposed offspring. Performance in a Morris water maze during initial learning gave some indications of impaired cognitive functions, which was confirmed during further testing, especially in reversal and new learning. Effects on cognitive functions seemed most marked in female offspring.

Acoustic Stimulation↗
PubMed1981

[The effects of acute administration of thyrotropin-releasing hormone on conditioned active avoidance learning and passive avoidance learning in rats (author's transl)].

The effects of acute administration of thyrotropin-releasing hormone (TRH) on the fear motivated learning of male Wistar rats were studied using a shuttle box. Two kinds of experiments - active avoidance learning (shuttle avoidance learning) and passive avoidance learning were performed. TRH (500 microgram/kg) was injected subcutaneously 40 to 50 minutes before the test trials. 1. In shuttle avoidance learning, TRH facilitated the acquisition after 8 sessions-pretraining and retarded the extinction after 8 approximately 12 sessions-pretrainings compared with saline. In passive avoidance learning, however, the reverse results were obtained: TRH retarded the acquisition and facilitated the extinction. 2. In shuttle avoidance learning, the acquisition facilitating effect of TRH was seen only in poor performer rats (poor performer was defined as less than 37 median score of conditioned avoidance responses in 8 sessions-pretraining), but not in good performer rats (more than 37 conditioned avoidance responses). 3. In shuttle avoidance learning, the acquisition facilitating effect of TRH was not seen in poor performer rats after 15 sessions-pretrainings, and the extinction retarding effect of TRH was not seen in the rats after 28 sessions-pretrainings. 4. From the above results it can be concluded that TRH possesses a fear reducing effect, and the behavioral changes brought about by TRH are seen most obviously in the rats which are in highly fearful conditions.

Animals↗
PubMed1997

Age- and dose-dependent facilitation of associative eyeblink conditioning by D-cycloserine in rabbits.

Normal aging selectively impairs some forms of learning. For example, aging rabbits require more than twice as many trials to acquire 500-ms trace eyeblink conditioning than do young rabbits. N-methyl-D-aspartate (NMDA) receptor antagonists also impair trace conditioning. The effects of daily D-cycloserine (DCS; a partial agonist of the NMDA receptor-glycine site) treatment were tested on trace conditioning of young or aging rabbits using a conservative quantitative approach. DCS dose dependently improved acquisition, maximally reducing trials to criterion by approximately 50%. Dose-response curves were right-shifted by aging (twice the dose was required to achieve the same enhancement compared with controls). DCS did not affect nonassociative performance but sharpened the conditioned stimulus tone intensity discrimination. DCS thus can functionally modulate NMDA receptors in normal aging, enhance associative learning at all ages, and reduce or reverse age-dependent learning deficits.

Age Factors↗
PubMed1983

Differential effects of double and triple lesions of the cat's limbic system on subsequent learning behavior.

On the basis of recent anatomical experiments in which it was found that the anterior thalamus, the subicular cortex, and the mamillary bodies are directly and strongly interconnected, lesions were made in different combinations of two or all three of these regions in four groups of cats. These found groups and a control group were then subjected to two learning tasks: a visual reversal and an active two-way avoidance task. Compared with cats of the control group, cats with lesions of the anterior thalamus and the mamillary bodies (Group AT/MM), of the anterior thalamus and the subiculum (Group AT/SUB), or of the mamillary bodies and the subiculum (Group MM/SUB) were strongly impaired in acquiring the reversal task, whereas cats with lesions of all three structures together (Group AT/MM/SUB) were unimpaired. Similarly, in the active avoidance task, two of the three groups with double lesions (MM/SUB; AT/SUB) were imparied, but cats of Groups AT/MM and AT/MM/SUB were not, compared with the control group. Consideration is made that lesion-induced shifts possibly act upon intact cortical and/or thalamic structures that, prior to massive limbic lesions, remained inhibited or otherwise suppressed. It is assumed the influence of one of the three core regions of the modified Papez-circuit to be sufficient for inhibiting the action of such structures which following a complete lesion of the system may control essential parts of the behaviors tested.

Animals↗
PubMed1980

Mirror-reading and writing in association with right-left spatial disorientation.

A left-handed patient suddenly developed a right hemiparesis, mirror-reading, and mirror-writing. Although he could discriminate between right and left on himself, he demonstrated right/left spatial disorientation. We propose that his right/left spatial disorientation was induced by a scanning defect. It has been demonstrated that mirror-image engrams are normally available. We believe that a reversal of the learned left-to-right scanning process with the availability of mirror engrams induced mirror-reading. Similarly, reversal of the normal left-to-right writing pattern, with the availability of mirror engrams, induced mirror-writing.

Dominance, Cerebral↗
PubMed2001

Early social deprivation disrupts attentional, but not affective, shifts in rats.

This study examined the effects of early social deprivation in rats on 2 dissociable forms of inhibitory control of behavior that operate at 2 different levels of response selection: reversing the assignment of stimulus-reward associations within perceptual dimensions (affective shifts) and switching selective attention from 1 perceptual dimension to another (attentional shifts). Isolated subjects (isolates) and social controls (socials) were individually trained to spatial and nonspatial visual discrimination criteria on a radial arm maze. Whereas isolates and socials differed in neither acquisition nor reversal of both versions of the task, isolates were selectively impaired in shifting from spatial to nonspatial discrimination and vice versa. These findings demonstrate that isolation rearing selectively disrupts inhibitory control in attentional selection but leaves inhibitory control in affective processing intact.

Affect↗
PubMed1986

Appetitive learning by old mice.

Groups of C57BL/6J (B6) and DBA/2J (D2) mice, aged 100 to 700 days, were trained on 7 appetitive learning tasks in order to determine which tasks might be suitable for studies of learning by old mice. Old B6 and D2 mice were both deficient in learning a discrimination reversal and two complex maze tasks; age did not affect performance on a simple spatial discrimination by subjects from either strain. Three tasks yielded strain-specific results. Old B6, but not old D2, animals were impaired on a visual discrimination problem. On a test of latent learning, old B6 animals were superior to younger mice, but the reverse trend characterized the D2 mice. Older D2 mice were retarded on a food-seeking task; B6 mice of all ages failed this test. The deficits observed in learning by old mice are thus strain- as well as task-specific. However, the deprivation procedures of this experiment resulted in excessive mortality in the oldest groups of mice, indicating that appetitive learning is contraindicated as a method for investigating learning by old mice.

Aging↗
PubMedDate not supplied

Individual differences in aging: behavioral and neurobiological correlates.

The goal of this experiment was to determine the correlations among different behavioral and neurobiological measures in aged rats. Aged Sprague-Dawley rats were given a battery of cognitive and sensorimotor tests, followed by electrophysiological assessment of sleep and biochemical measurements of various neurotransmitter systems. The behavioral tests included the following: Activity level in an open field; short-term and long-term memory of a spatial environment as assessed by habituation: spatial navigation, discrimination reversal, and cue learning in the Morris water pool; spatial memory in a T-maze motivated by escape from water; spatial memory and reversal on the Barnes circular platform task; passive avoidance; motor skills. Sleep was assessed by electrographic cortical records. The following neurotransmitter markers were examined: Choline acetyltransferase; the density of nicotinic, benzodiazepine and glutamine receptors in the cortex and caudate nucleus; endogenous levels of norepinephrine, dopamine, and serotonin in the cortex and hippocampus. The duration of bouts of paradoxical sleep was strongly correlated with several cognitive measures and selected serotonergic markers. This finding suggests that changes in sleep patterns and brain biochemistry contribute directly to deficits in learning and memory, or that the same neurobiological defect contributes to age-related impairments in sleep and in learning and memory.

Age Factors↗
PubMed1998

Roles of kappa-opioid receptor agonists in learning and memory impairment in animal models.

The role of kappa-opioid receptor agonists on learning and memory is controversial. In this review, the effects of dynorphin A (1-13) and U-50,488H on learning and memory impairments in mice and rats are summarized. Muscarinic cholinergic antagonists and a nicotinic cholinergic antagonist significantly impaired learning and memory in various behavioral tests. Administration of dynorphin A (1-13) or U-50,488H reversed the impairment of learning and memory. U-50,488H completely blocked the decrease in acetylcholine release induced by mecamylamine, while it only partially blocked the increase of acetylcholine induced by scopolamine. The antagonistic effect of U-50,488H was abolished by pretreatment with nor-binaltorphimine, a selective kappa-opioid receptor antagonist. Dynorphin A (1-13) and U-50,488H did not affect the impairment of learning and memory induced by the blockade of NMDA-receptors by dizocilpine ((+)-MK-801. These results suggest that kappa-opioid receptor antagonist reverses the impairment of learning and memory induced by the blockade of cholinergic transmission and abolishes the decrease of acetylcholine release via the kappa-opioid receptor-mediated neuronal system.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗