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PubMed2002

The effects of tryptophan depletion on cognitive and affective processing in healthy volunteers.

RATIONALE: Cognitive impairment is a common feature of depressive illness. While accumulating evidence suggests that brain serotonin (5-HT) pathways play an important role in the neurobiology of depression, the extent to which altered 5-HT function is responsible for the associated changes in cognition and emotion remains unclear. OBJECTIVE: The present study examined the effects of acute dietary depletion of tryptophan (TRP) on cognitive and affective processing in healthy volunteers and explored the putative role of 5-HT in the neuropsychology of depression. METHODS: We administered computerised cognitive tests to healthy control participants following ingestion of TRP-free and nutritionally balanced amino acid drinks in a double-blind, placebo-controlled, crossover design. RESULTS: The TRP-free amino acid mixture significantly lowered plasma total and free TRP concentrations relative to baseline values and produced selective deficits similar to those observed previously in cases of clinical depression. In particular, TRP depletion increased response times for happy but not sad targets in an affective go/no-go task and slowed responding in a visual discrimination and reversal learning task. These deficits were not due to a global sedative effect, as planning ability was unimpaired. CONCLUSIONS: The present data indicate that serotonergic factors may be more involved in the disrupted inhibitory and emotional processing characteristic of depression than in other aspects of executive function, such as planning ability. These findings support the recent proposal that serotonergic manipulation may have greater effects on tasks mediated by frontal circuitry that includes the orbitofrontal cortex than by dorsolateral prefrontal cortex circuitry.

Adult↗
PubMedDate not supplied

AF150(S) and AF267B: M1 muscarinic agonists as innovative therapies for Alzheimer's disease.

The M1 muscarinic agonists AF102B (Cevimeline, EVOXACTM: prescribed in USA and Japan for Sjogren's Syndrome), AF150(S) and AF267B--1) are neurotrophic and synergistic with neurotrophins such as nerve growth factor and epidermal growth factor; 2) elevate the non-amyloidogenic amyloid precursor protein (alpha-APPs) in vitro and decrease beta-amyloid (A beta) levels in vitro and in vivo; and 3) inhibit A beta- and oxidative-stress-induced cell death and apoptosis in PC12 cells transfected with the M1 muscarinic receptor. These effects can be combined with the beneficial effects of these compounds on some other major hallmarks of Alzheimer's disease (AD) (e.g. tau hyperphosphorylation and paired helical filaments [PHF]; and loss of cholinergic function conducive to cognitive impairments.) These drugs restored cognitive impairments in several animal models for AD, mimicking different aspects of AD, with a high safety margin (e.g. AF150[S] >1500 and AF267B >4500). Notably, these compounds show a high bioavailability and a remarkable preference for the brain vs. plasma following p.o. administration. In mice with small hippocampi, unlike rivastigmine and nicotine, AF150(S) and AF267B restored cognitive impairments also on escape latency in a Morris water maze paradigm in reversal learning. Furthermore, in aged and cognitively impaired microcebes (a natural animal model that mimics AD pathology and cognitive impairments), prolonged treatment with AF150(S) restored cognitive and behavioral impairments and decreased tau hyperphosphorylation, PHF and astrogliosis. Our M1 agonists, alone or in polypharmacy, may present a unique therapy in AD due to their beneficial effects on major hallmarks of AD.

Alzheimer Disease↗
PubMed1996

Subchronic intraventricular infusion of quinolinic acid produces working memory impairment--a model of progressive excitotoxicity.

It has been proposed by Yamada et al. [Neurosci. Lett. 118: 128-131 (1990); J. Pharmacobiodyn. 14: 351-355 (1991)] that subchronic i.c.v. infusion of the NMDA receptor agonist quinolinic acid may serve as a model for some aspects of neurodegenerative dementia. In the present study, quinolinic acid (9 mM) was infused i.c.v. by ALZET osmotic minipumps for 2 weeks. This treatment produced a short-term working memory deficit in the T-maze (alternation) but no change in reversal learning in the same test. The working memory deficit in the T-maze was progressive i.e. seen after 14, but not 3 days of infusion and persisted for at least for 3 weeks after the termination of the infusion. Histological examination revealed a modest decrease in the number of cells in the nucleus basalis magnocellularis but not in the striatum, entorhinal cortex, or hippocampus. However, in most of the structures studied, morphological changes such as swollen somata and irregular shape were observed indicative of alterations in neuronal function. Autoradiography in the hippocampus revealed a decrease in [3H]hemicholinium and [3H]quinuclidinyl benzilate (QNB) binding to choline uptake sites and muscarinic receptors respectively. Surprisingly no change was observed in [3H]MK-801 binding to NMDA receptor channels in the hippocampus and cortex. The subchronic infusion of quinolinic acid may serve as a model of progressive deterioration of cognitive functions.

Alzheimer Disease↗
PubMed1977

Failure of interocular transfer in the pigeon (Columba livia).

Pigeons were trained on a modified jumping stand to discriminate a circle from a triangle using only one eye. Testing with the naive eye revealed no evidence of interocular transfer. This failure of transfer was also observed under more stringent testing using reversal learning. The results are discussed in terms of a selective attention model for panoramic vision.

Animals↗
PubMedDate not supplied

Retention of functional tolerance to ethanol in rhesus monkeys (Macaca mulatta).

Tolerance to ethanol (3 g/kg 90 min prior to testing) was assessed in a group of 4 rhesus monkeys in which tolerance development had been observed using the same behavioral task one year prior to the present study. Although some decrements in performance on a two-choice discrimination reversal learning task were observed, these changes were transient and statistically insignificant. Results indicate that functional tolerance persisted throughout a one year abstinence period.

Animals↗
PubMed1981

Prenatal undernutrition: effects on behavior, brain chemistry and neuroanatomy in rats.

The behavior and cerebral effects of prenatal protein-calorie undernutrition were investigated in newborn and postweanling rat pups. At birth, prenatally undernourished (PU) animals showed a deficit in body weight; however, by day 15 the difference was diminished and not significant. On days 13-18, PU pups required more trials for reversal learning of a water-escape response in a T-maze than control (C) pups; however, on days 31-35, there were no difference between groups when trained to learn an active-avoidance response. Assessment of brain development showed that at birth, DNA and protein content was severely reduced in PU animals; however, normalization was noted in regional sections of the brain at 35 days of age. Brainstem reticular cells from PU pups at birth show less dendritic arborization and less terminal branching cells from C pups. The results are discussed in terms of a delayed rate of maturation.

Animals↗
PubMed1995

NS-3 (CG3703), an analog of thyrotropin-releasing hormone, ameliorates cognitive impairment in rats.

The effects of thyrotropin-releasing hormone (TRH) and its analog, N-[[(3R,6R)-6-methyl-5-oxo-thiomorpholinyl] carbonyl]-L-histidyl-L- prolinamide tetrahydrate (NS-3, CG3703) on disturbance of memory of a passive avoidance response (PAR) and an escape response in rats were investigated. NS-3 improved amnesia caused by scopolamine, electroconvulsive shock (ECS), and cycloheximide (CXM), but TRH improved only the ECS-induced amnesia. NS-3 reversed learning deficits caused by hypercapnia, but TRH had no effect. These differences in the effect between NS-3 and TRH may be due to their biological half-life in rat plasma. These results suggest that NS-3 possesses more potent antiamnestic effects than TRH in rats.

Amino Acid Sequence↗
PubMed1994

The effects of dietary fatty acid composition combined with environmental enrichment on brain and behavior in mice.

In this study we investigated the effects of dietary fatty acid (FA) composition combined with postweaning environmental enrichment on brain fatty acid composition and behavior in mice. There were three dietary conditions: a saturated fat group deficient in essential fatty acids, a group deficient in n-3 fatty acids only, and a control group containing both n-3 and n-6 fatty acids in a ratio of 0.27. Animals were fed these diets during pregnancy and lactation and after weaning. Brain fatty acid composition was determined on days 1, 9, 17 and 25 after birth and in adult animals at 3 months. At weaning two females from each litter were assigned randomly to either an enriched or standard environmental condition. After six weeks in these environments they were tested in the Morris water maze and open field. Adult percentages of 22:6n-3 were present in the brain within the first week after birth. These values were reduced by 50% in the n-3 deficient diet and by 80% in the saturated fat diet; adult animals on the saturated fat diet were also severely retarded in growth. Animals fed the saturated fat diet were initially slightly slower in locating the hidden platform in the Morris maze relative to the control group, but this was not apparent in the reversal learning phase; a cued learning task using a visible platform indicated that these effects did not appear to be related to differences in motor or motivational capacities. The n-3 deficient group did not differ from either the saturated fat group or the controls. All dietary groups showed beneficial effects of environmental enrichment in decreasing their latency to locate the hidden platform, and these effects appeared to be partially independent of the increased swimming speed of the enriched animals. Enriched animals in all groups showed less rearing activity in the open field and spent more time stationary; the animals fed saturated fat reared less and travelled shorter distances more slowly. In all cases the effects of diet and environment were additive, thereby providing little support for the hypothesis that dietary fatty acid composition would affect the animals' capacity to benefit from the functional effects of environmental enrichment.

Animals↗
PubMed1992

A behavioral profile of autoimmune lupus-prone MRL mice.

Manifestations of the human autoimmune disease systemic lupus erythematosus (SLE) include a number of behavioral and cognitive deficits. The present study asks whether neurobehavioral dysfunction is present also in MRL mice that spontaneously develop most of the fundamental immunological aberrations of SLE. There are two congenic substrains of MRL mice that differ in the time of disease onset: MRL-lpr mice develop lupus early and MRL(-)+/+ develop the typical signs of disease relatively late in life. The behavior of these substrains was assessed at 7 to 11 weeks of age, a time that coincides with the onset of disease in MRL-lpr mice and the absence of known lupus symptoms in the MRL(-)+/+ group. When compared to the congenic MRL(-)+/+ control substrain, MRL-lpr mice were spontaneously less active, traversed a crossbeam slower, and ceased responding to the novelty of a new environment sooner. They were also more reluctant to leave their home base or travel far away from it and perseverated in their response bias during extinction and reversal learning. Immunological status was characterized by moderate proteinuria in both substrains and high titers of antinuclear antibodies in MRL-lpr but not MRL(-)+/+ mice. Histological analysis revealed minimal or no signs of joint pathology in MRL-lpr mice. Thus, this study shows the presence of behavioral dysfunction in mice with early stages of autoimmune disease and gives support for the idea that MRL mice may provide a useful model of neurobehavioral dysfunction in SLE. It is suggested that the behavioral profile of MRL-lpr mice may indicate increased "timidity," related to genetics, autoimmunity, or both.

Animals↗
PubMed1996

Comparison of cognitive function in human and non-human primates.

Fundamental to any comparative study of cognitive function in monkey and man is the demonstration of behavioral homology, viz. that the same cognitive function is being studied in both species. This paper considers a variety of psychological issues that need to be taken into account when attempting to demonstrate behavioural homology. Examples are taken from studies of attentional set-shifting, discrimination reversal learning, spatial working memory and episodic memory. Whilst highlighting the pitfalls to be avoided in the future, these examples also demonstrate the enormous contribution that such studies have had to our understanding of the functions of the temporal lobes and frontal lobes. Moreover, they also illustrate the enormous potential in defining the cognitive functions and dysfunctions of the prefronto-striatal circuitry which underlie so many neurodegenerative and neuropsychiatric disorders.

Animals↗
PubMed2005

A note on select- and reject-controlling relations in the simple discrimination of capuchin monkeys (Cebus apella).

Controlling relations in the simple discrimination performances of capuchin monkeys (Cebus apella) were studied in two experiments using a blank-comparison procedure. The main goal was to determine whether monkeys would (a) select an S+ stimulus if another stimulus was substituted for the S- (indicating a select-controlling relation) and (b) reject an S- if another stimulus was substituted for S+ (indicating a reject-controlling relation). In experiment 1, two simple simultaneous discriminations were established, one of which was reversed repeatedly until rapid reversal learning was exhibited. During subsequent probe tests, some behavior was consistent with select- and reject-controlling relations, but there was also substantial variability. To control the variability, the procedures of experiment 2 were designed to establish select- and reject-control relations directly by training with the blank-comparison procedure. On subsequent probe trials, new stimuli were substituted for the blank comparison. Both animals exhibited consistent, reliable select- and reject-controlling relations. These experiments are the first to employ the blank-comparison procedure with non-human subjects. They also demonstrate a reliable method for generating select- and reject-controlling relations for experimental study.

Animals↗
PubMed2005

Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring.

Maternal exposure to viral infection has been associated with an increased risk of schizophrenia in the offspring, and it has been suggested that the maternal immune response may interfere with normal fetal brain development. Although studies in rodents have shown that perinatal viral infections can lead to neuropathological and behavioral abnormalities considered relevant to schizophrenia, it is not clear whether these consequences are due to the infection itself or to the maternal immune response to infection. We show that an induction of maternal immune stimulation without exposure to a virus by injecting pregnant dams with the synthetic cytokine releaser polyriboinosinic-polyribocytidilic acid (poly I:C) leads to abnormal behavioral and pharmacological responses in the adult offspring. As in schizophrenia, these offspring displayed excessive behavioral switching, manifested in the loss of latent inhibition and in rapid reversal learning. Consistent with the clinical pharmacology of schizophrenia, both deficits were alleviated by antipsychotic treatment. In addition, these offspring displayed increased sensitivity to the locomotor-stimulating effects of MK-801, pointing to developmental alterations of the dopaminergic and/or glutamatergic systems. Prenatal poly I:C administration did not produce learning deficits in classical fear conditioning, active avoidance, discrimination learning and water maze. These results show that the maternal immune response is sufficient to cause behavioral and pharmacological alterations relevant to schizophrenia in the adult offspring.

Animals↗
PubMed2004

Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates.

The prefrontal cortex has been implicated in a variety of cognitive and executive processes, including working memory, decision-making, inhibitory response control, attentional set-shifting and the temporal integration of voluntary behaviour. This article reviews current progress in our understanding of the rodent prefrontal cortex, especially evidence for functional divergence of the anatomically distinct sub-regions of the rat prefrontal cortex. Recent findings suggest clear distinctions between the dorsal (precentral and anterior cingulate) and ventral (prelimbic, infralimbic and medial orbital) sub-divisions of the medial prefrontal cortex, and between the orbitofrontal cortex (ventral orbital, ventrolateral orbital, dorsal and ventral agranular cortices) and the adjacent medial wall of the prefrontal cortex. The dorso-medial prefrontal cortex is implicated in memory for motor responses, including response selection, and the temporal processing of information. Ventral regions of the medial prefrontal cortex are implicated in interrelated 'supervisory' attentional functions, including attention to stimulus features and task contingencies (or action-outcome rules), attentional set-shifting, and behavioural flexibility. The orbitofrontal cortex is implicated in lower-order discriminations, including reversal of stimulus-reward associations (reversal learning), and choice involving delayed reinforcement. It is anticipated that a greater understanding of the prefrontal cortex will come from using tasks that load specific cognitive and executive processes, in parallel with discovering new ways of manipulating the different sub-regions and neuromodulatory systems of the prefrontal cortex.

Acetylcholine↗
PubMed2005

Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia.

Epidemiological studies have indicated an association between maternal bacterial and viral infections during pregnancy and the higher incidence of schizophrenia in the resultant offspring post-puberty. One hypothesis asserts that the reported epidemiological link is mediated by prenatal activation of the foetal immune system in response to the elevation of maternal cytokine level due to infection. Here, we report that pregnant mouse dams receiving a single exposure to the cytokine-releasing agent, polyriboinosinic-polyribocytidilic acid (PolyI:C; at 2.5, 5.0, or 10.0 mg/kg) on gestation day 9 produced offspring that subsequently exhibited multiple schizophrenia-related behavioural deficits in adulthood, in comparison to offspring from vehicle injected or non-injected control dams. The efficacy of the PolyI:C challenge to induce cytokine responses in naïve non-pregnant adult female mice and in foetal brain tissue when injected to pregnant mice were further ascertained in separate subjects: (i) a dose-dependent elevation of interleukin-10 was detected in the adult female mice at 1 and 6h post-injection, (ii) 12 h following prenatal PolyI:C challenge, the foetal levels of interleukin-1beta were elevated. The spectrum of abnormalities included impairments in exploratory behaviour, prepulse inhibition, latent inhibition, the US-pre-exposure effect, spatial working memory; and enhancement in the locomotor response to systemic amphetamine (2.5 mg/kg, i.p.) as well as in discrimination reversal learning. The neuropsychological parallels between prenatal PolyI:C treatment in mice and psychosis in humans, demonstrated here, leads us to conclude that prenatal PolyI:C treatment represents one of the most powerful environmental-developmental models of schizophrenia to date. The uniqueness of this model lies in its epidemiological and immunological relevance. It is, sui generis, ideally suited for the investigation of the neuropsychoimmunological mechanisms implicated in the developmental aetiology and disease processes of schizophrenia.

Animals↗
PubMed2006

Cannabinoids and prefrontal cortical function: insights from preclinical studies.

Marijuana use has been associated with disordered cognition across several domains influenced by the prefrontal cortex (PFC). Here, we review the contribution of preclinical research to understanding the effects of cannabinoids on cognitive ability, and the mechanisms by which cannabinoids may affect the neurochemical processes in the PFC that are associated with these impairments. In rodents, acute administration of cannabinoid agonists produces deficits in working memory, attentional function and reversal learning. These effects appear to be largely dependent on CB1 cannabinoid receptor activation. Preclinical studies also indicate that the endogenous cannabinoid system may tonically regulate some mnemonic processes. Effects of cannabinoids on cognition may be mediated via interaction with neurochemical processes in the PFC and hippocampus. In the PFC, cannabinoids may alter dopaminergic, cholinergic and serotonergic transmission. These mechanisms may underlie cognitive impairments observed following marijuana intake in humans, and may also be relevant to other disorders of cognition. Preclinical research will further enhance our understanding of the interactions between the cannabinoid system and cognitive functioning.

Acetylcholine↗
PubMed2006

Beneficial effects of fruit extracts on neuronal function and behavior in a rodent model of accelerated aging.

Exposing young rats to particles of high-energy and charge (HZE particles) enhances indices of oxidative stress and inflammation and disrupts the functioning of the dopaminergic system and behaviors mediated by this system in a manner similar to that seen in aged animals. Previous research has shown that diets supplemented with 2% blueberry or strawberry extracts have the ability to retard and even reverse age-related deficits in behavior and signal transduction in rats, perhaps due to their antioxidant and anti-inflammatory properties. This study evaluated the efficacy of these diets on irradiation-induced deficits in these parameters by maintaining rats on these diets or a control diet for 8 weeks prior to being exposed to whole-body irradiation with 1.5 Gy of 1 GeV/n high-energy (56)Fe particles. Irradiation impaired performance in the Morris water maze and measures of dopamine release 1 month following radiation; these deficits were protected by the antioxidant diets. The strawberry diet offered better protection against spatial deficits in the maze because strawberry-fed animals were better able to retain place information (a hippocampally mediated behavior) compared to controls. The blueberry diet, on the other hand, seemed to improve reversal learning, a behavior more dependent on intact striatal function. These data suggest that (56)Fe particle irradiation causes deficits in behavior and signaling in rats which were ameliorated by an antioxidant diet and that the polyphenols in these fruits might be acting in different brain regions.

Aging↗
PubMed2004

Dissociation of function within the hippocampus: effects of dorsal, ventral and complete excitotoxic hippocampal lesions on spatial navigation.

The present study was designed to assess the possibility that sub-total ventral hippocampal lesions might leave intact a mechanism for only highly accurate navigation, whereas sub-total dorsal hippocampal lesions might leave intact a mechanism only for less precise navigation. Animals with selective dorsal, ventral or complete hippocampal lesions were tested in a water maze, in which the target platform was moved from trial to trial, but always within a defined area, instead of being at a fixed location. Hence, an animal that searched at exactly the point where the platform had been found on a previous trial would be disadvantaged, in comparison with an animal that searched in the right general area. This might favor animals capable of less precise navigation over those with very precise navigational abilities. In subsequent phases of the experiment, we additionally assessed, for comparison, performance with a fixed platform location, reversal learning in the water-maze, and performance on an elevated T-maze. Our results revealed no sign of any qualitative difference between the effects of the selective sub-total lesions when the water maze hidden platform location was varied within the defined area, and the effects in subsequent more conventionally used tests. Ventral hippocampal damage never led to a performance deficit. Dorsal hippocampal damage led to significantly poorer performance in only some test phases, and never led to any sign of improved performance.

Animals↗