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PubMed1978

Deficits in visual learning produced by posterior temporal lesions in cats.

Eight cats with lesions in the posterior temporal (PT) cortex, seven cats with lesions in the basolateral amygdala (BLA), and eight intact controls were observed on eight tests of visual discrimination learning and of spontaneous responses to salient visual stimuli. The effects of the two lesions were somewhat dissociable. The PT lesions were accompanied by a severe deficit in pattern discrimination learning but no loss in visual tracking or orientation to the silhouette of a threatening cat. The BLA lesions produced a milder and less consistent loss in pattern discrimination but serious defects in tracking and reponse to the cat silhouette. Both operated groups performed well on the visual cliff. The deficit from PT lesions appeared independent of damage to the geniculocortical system. The parallel of symptoms from PT lesions in cats and inferotemporal lesions in monkeys is discussed.

Amygdala↗
PubMedDate not supplied

The function of dream sleep.

We propose that the function of dream sleep (more properly rapid-eye movement or REM sleep) is to remove certain undesirable modes of interaction in networks of cells in the cerebral cortex. We postulate that this is done in REM sleep by a reverse learning mechanism (see also p. 158), so that the trace in the brain of the unconscious dream is weakened, rather than strengthened, by the dream.

Cerebral Cortex↗
PubMed2006

Methylphenidate ('Ritalin') can ameliorate abnormal risk-taking behavior in the frontal variant of frontotemporal dementia.

The frontal variant of frontotemporal dementia is a significant neurological condition worldwide. There exist few treatments available for the cognitive and behavioural sequelae of fvFTD. Previous research has shown that these patients display risky decision-making, and numerous studies have now demonstrated pathology affecting the orbitofrontal cortex. The present study uses a within-subjects, double-blind, placebo-controlled procedure to investigate the effects of a single dose of methylphenidate (40 mg) upon a range of different cognitive processes including those assessing prefrontal cortex integrity. Methylphenidate was effective in 'normalizing' the decision-making behavior of patients, such that they became less risk taking on medication, although there were no significant effects on other aspects of cognitive function, including working memory, attentional set shifting, and reversal learning. Moreover, there was an absence of the normal subjective and autonomic responses to methylphenidate seen in elderly subjects. The results are discussed in terms of the 'somatic marker' hypothesis of impaired decision-making following orbitofrontal dysfunction.

Aged↗
PubMed2007

Decoding the neural substrates of reward-related decision making with functional MRI.

Although previous studies have implicated a diverse set of brain regions in reward-related decision making, it is not yet known which of these regions contain information that directly reflects a decision. Here, we measured brain activity using functional MRI in a group of subjects while they performed a simple reward-based decision-making task: probabilistic reversal-learning. We recorded brain activity from nine distinct regions of interest previously implicated in decision making and separated out local spatially distributed signals in each region from global differences in signal. Using a multivariate analysis approach, we determined the extent to which global and local signals could be used to decode subjects' subsequent behavioral choice, based on their brain activity on the preceding trial. We found that subjects' decisions could be decoded to a high level of accuracy on the basis of both local and global signals even before they were required to make a choice, and even before they knew which physical action would be required. Furthermore, the combined signals from three specific brain areas (anterior cingulate cortex, medial prefrontal cortex, and ventral striatum) were found to provide all of the information sufficient to decode subjects' decisions out of all of the regions we studied. These findings implicate a specific network of regions in encoding information relevant to subsequent behavioral choice.

Adult↗
PubMed1996

Executive and mnemonic functions in early Huntington's disease.

Eighteen patients with early Huntington's disease were compared with age- and IQ-matched control volunteers on tests of executive and mnemonic function taken from the Cambridge Neuropsychological Test Automated Battery. Tests of pattern and spatial recognition memory, spatial span, spatial working memory, spatial planning and visual discrimination learning/attentional set shifting were employed. These tests have previously been found to be sensitive to the later stages of Huntington's disease. Patients with early Huntington's disease were found to have a wide range of cognitive impairments encompassing both visuospatial memory and executive functions, a pattern distinct from those seen in other basal ganglia disorders. In contrast to patients with more advanced Huntington's disease, early Huntington's disease patients were not impaired at simple reversal learning, but were impaired at performing an extradimensional shift (EDS). The results will be discussed in relation to the hypothesized neuropathological staging of Huntington's disease and to the anatomical connectivity of the striatum.

Adult↗
PubMed2001

Dietary trans fatty acids combined with a marginal essential fatty acid status during the pre- and postnatal periods do not affect growth or brain fatty acids but may alter behavioral development in B6D2F(2) mice.

The objective of this study was to investigate whether dietary trans fatty acids (TFA) during the pre- and postnatal periods would exacerbate the effects of marginal essential fatty acid (EFA) status on growth, brain long-chain polyunsaturated fatty acids (LC-PUFA) and behavioral development in B6D2F(2) mice. Pregnant B6D2F(1) females were randomly assigned to one of the following three diets: marginal EFA plus 22% trans 18:1 (mEFA + TFA); marginal EFA (mEFA); and control (CON). The total 18:1 content in all diets was similar. The offspring were weaned and maintained on the same diets. Both the mEFA and mEFA + TFA groups had reduced growth and brain weight compared with CON, but did not differ from one another. As expected, the mEFA and mEFA + TFA groups had reduced docosahexaenoic acid [DHA; 22:6(n-3)]) and increased 22:5(n-6) concentrations in brain phosphatidylcholine (PC) and phosphatidylethanolamine (PE) compared with the CON group, but again did not differ from one another. Reversal learning in the T-water maze was significantly slower in the mEFA + TFA groups compared with the mEFA group and both were slower than the CON group. These findings illustrate that TFA combined with a marginal EFA status do not exacerbate the effects of marginal EFA status on growth or brain LC-PUFA. However, long-term effects of dietary TFA during the pre- and postnatal period on behavioral development and neural function should be investigated in future studies.

Animals↗
PubMed2005

Lead exposure and (n-3) fatty acid deficiency during rat neonatal development affect subsequent spatial task performance and olfactory discrimination.

Docosahexaenoic acid [22:6(n-3), DHA] is important for optimal infant central nervous system development, and lead (Pb) exposure during development can produce neurological deficits. Long-Evans strain rats were fed either an (n-3) deficient [(n-3) Def] diet to produce brain DHA deficiency, or an adequate [(n-3) Adq] diet through 2 generations. At the birth of the 2nd generation, the dams were subdivided into 4 groups and supplied drinking water containing either 5.27 mmol/L (Pb) or sodium (Na) acetate until weaning. Rats were killed at 3 wk (weaning) and 11 wk (maturity) for brain Pb and fatty acid analysis. Spatial task and olfactory-cued behavioral assessments were initiated at 9 wk. Rats in the (n-3) Def group had a 79% lower concentration of brain DHA compared with the (n-3) Adq group with no effect of Pb exposure. At weaning, Pb concentrations were 7.17 +/- 0.47 nmol Pb/g of brain (wet weight) in the (n-3) Adq-Pb group and 6.49 +/- 0.63 nmol Pb/g of brain (wet weight) in the (n-3) Def-Pb group. At maturity, the brains contained 1.30 +/- 0.22 and 1.07 +/- 0.12 nmol Pb/g (wet weight), respectively. In behavioral testing, significant effects of both Pb and DHA deficiency were observed in the Morris water maze probe trial and in 2-odor olfactory discrimination acquisition and olfactory-based reversal learning tasks. Both lactational Pb exposure and (n-3) fatty acid deficiency led to behavioral deficits with additive effects observed only in the acquisition of 2-odor discriminations.

Aging↗
PubMed1997

Perseveration in schizophrenia.

Perseveration in schizophrenia may take a variety of forms, which can be conceptualized as varying manifestations of an underlying neurocognitive deficit. Comparative studies have demonstrated higher than normal levels of perseverative responding among schizophrenia patients on capacity-demanding tasks, including prompted discourse, reversal learning, and the generation of guessing sequences. There is little evidence that perseveration is associated with deficit signs of schizophrenia. However, perseveration appears to covary with both positive thought disorder and voluntary motor disturbance. Perseveration in schizophrenia thus appears to be a productive sign elicited by a failure to mobilize cognitive resources in situations requiring controlled information processing and the concomitant inhibition of activated but task-inappropriate responses. An information-processing model proposed by Shallice (1988) attributes perseveration to a failure of a higher level executive control system to modulate a lower level response selection system under a requirement for novel response generation. This model suggests that perseveration is the consequence of a failure of frontal specification of striatal outputs during controlled processing, resulting in the continued reselection of previously activated outputs.

Attention↗
PubMed2006

Abeta peptide immunization restores blood-brain barrier integrity in Alzheimer disease.

Immunization with amyloid beta (Abeta) peptides or passive immunization with antibodies against Abeta has been reported to reduce plaque burden, neuritic dystrophy, early Tau pathology, microgliosis as well as reversing learning and memory deficits. This has created a central paradox: how does vaccination in peripheral tissues reduce plaque burden in the brain? No single explanation for these phenomena has yet been presented. To reconcile these observations, we demonstrate that the integrity of the blood-brain barrier (BBB), a structural barrier between the brain and the blood, is compromised in Tg2576 Alzheimer disease (AD) model mice. We immunized Tg2576 mice with Abeta before and after the onset of AD-type neuropathology and observed that BBB permeability, amyloid burden, and microgliosis are decreased in immunized mice. It is concluded that the integrity of the BBB is disrupted in AD mice, and after Abeta immunization the immune system clears Abeta from sources in the brain as it would in peripheral organs lacking barriers. Once Abeta is removed, the integrity of the BBB is restored. The data therefore provide an intellectual framework for understanding how the immune system can clear amyloid deposits from AD brains and suggest new strategies for limiting disease progression in amyloidopathies.

Alzheimer Disease↗
PubMed2006

Neuropsychological performance, impulsivity, and comorbid psychiatric illness in patients with pathological gambling undergoing treatment at the CORE Inpatient Treatment Center.

INTRODUCTION: Pathologic gambling is a disorder with features that implicate abnormal functioning in brain regions involved in addiction, mood, anxiety, and impulse control disorders. Our goal was to examine brain function with neurocognitive tasks that target these brain regions in patients with pathologic gambling. METHODS: Patients were evaluated for comorbid psychiatric disorders, impulsivity, and performance on reversal-learning and reward-based decision-making cognitive tasks. RESULTS: Patients had higher impulsivity scores and significant deficits on both cognitive tasks compared with controls. All subjects also had comorbid psychiatric disorders, including mood, anxiety, psychotic, and substance abuse. CONCLUSION: The cognitive deficits and impulsivity are consistent with abnormal activity in orbitofrontal-limbic networks. The high level of comorbidity is consistent with the overall severity in these inpatients undergoing treatment, and adds weight to the concept of a fundamental abnormality in this network.

Anxiety↗
PubMed2004

Impaired behavioural flexibility and memory in mice lacking GDNF family receptor alpha2.

The glial cell line-derived neurotrophic factor (GDNF) family receptor GFRalpha2 is the binding receptor for neurturin (NRTN). The main biological responses of GFRalpha2 are mediated via the Ret receptor tyrosine kinase, although it may also signal independently of Ret via the neural cell adhesion molecule NCAM. GFRalpha2 is expressed in many neurons of both the central and peripheral nervous system. Mice lacking GFRalpha2 receptors do not exhibit any gross defects in the central nervous system structure. However, they display profound deficits in the parasympathetic and enteric nervous system, accompanied by significant reduction in body weight after weaning. Here we present the results of behavioural analysis of the GFRalpha2-knockout mice. The knockout mice did not differ from wild-type mice in basic tests of motor and exploratory activity. However, differences were established in several memory tasks. The knockout mice were not impaired in the acquisition of spatial escape strategy. However, the deficit in flexibility in establishing a new strategy was revealed during reversal learning with the platform in the opposite quadrant of the pool. Furthermore, the knockout mice displayed significant impairment in contextual fear conditioning and conditioned taste aversion tests of memory. The results suggest that GFRalpha2 signalling plays a role in the development or maintenance of cognitive abilities that help in solving complex learning tasks.

Animals↗
PubMed1981

Brain aging correlates: retardation by hormonal-pharmacological treatments.

Mid-aged rats were either adrenalectomized and chronically maintained, or left intact and treated daily for a 9- to 10-month period with a potent analog of the peptide adrenocorticotropin (residues 4 to 9), which has some stimulant properties, or with the neural stimulant pentylenetetrazole. All three treatments reduced hippocampal morphologic correlates of brain aging (neuronal loss, glial reactivity). The pentylenetetrazole and peptide treatments also improved reversal learning. These results suggest that certain endogenous peptides, with stimulant properties, may also exert long-term, trophic effects on brain structure and function.

Adrenalectomy↗
PubMed1977

Suckling as incentive to instrumental learning in preweanling rats.

Neonatal rats as young as 7 days of age learned, reversed, and retained a left-right discrimination with a nonlactating nipple as the incentive. These results have implications for the ontogeny of associative processes and for their neurological and neurochemical mediators.

Animals↗
PubMed2004

Passive immunotherapy against Abeta in aged APP-transgenic mice reverses cognitive deficits and depletes parenchymal amyloid deposits in spite of increased vascular amyloid and microhemorrhage.

BACKGROUND: Anti-Abeta immunotherapy in transgenic mice reduces both diffuse and compact amyloid deposits, improves memory function and clears early-stage phospho-tau aggregates. As most Alzheimer disease cases occur well past midlife, the current study examined adoptive transfer of anti-Abeta antibodies to 19- and 23-month old APP-transgenic mice. METHODS: We investigated the effects of weekly anti-Abeta antibody treatment on radial-arm water-maze performance, parenchymal and vascular amyloid loads, and the presence of microhemorrhage in the brain. 19-month-old mice were treated for 1, 2 or 3 months while 23-month-old mice were treated for 5 months. Only the 23-month-old mice were subject to radial-arm water-maze testing. RESULTS: After 3 months of weekly injections, this passive immunization protocol completely reversed learning and memory deficits in these mice, a benefit that was undiminished after 5 months of treatment. Dramatic reductions of diffuse Abeta immunostaining and parenchymal Congophilic amyloid deposits were observed after five months, indicating that even well-established amyloid deposits are susceptible to immunotherapy. However, cerebral amyloid angiopathy increased substantially with immunotherapy, and some deposits were associated with microhemorrhage. Reanalysis of results collected from an earlier time-course study demonstrated that these increases in vascular deposits were dependent on the duration of immunotherapy. CONCLUSIONS: The cognitive benefits of passive immunotherapy persist in spite of the presence of vascular amyloid and small hemorrhages. These data suggest that clinical trials evaluating such treatments will require precautions to minimize potential adverse events associated with microhemorrhage.

Journal Article↗
PubMed2004

Evidence for altered monoamine activity and emotional and cognitive disturbance in marmoset monkeys exposed to early life stress.

In common marmoset monkeys (Callithrix jacchus, order Primates), infants aged 2-28 days were deprived of parental care for 30-120 min/day in order to investigate the long-term effects of this neglect-stress model on affect and cognition in a primate species. Basal morning levels of urinary cortisol across the first year of life were unaffected in early deprived marmosets relative to their sibling controls. Basal morning levels of urinary dopamine were chronically increased. This peripheral increase in dopamine activity could represent a marker for central dopamine hyperactivity. Certainly, subadult early deprived marmosets exhibited performance deficits in two dopamine-regulated neuropsychological tasks. They demonstrated: (1) impaired behavioral inhibition in an object reaching with detour task, exhibiting significantly more nonreinforced forward reaches to a reward visible inside a cube that could only be retrieved through an opening to the side of the cube; and (2) impaired reversal learning in a two-way discrimination task based on visual icons presented on a touch-sensitive computer screen. These findings provide further evidence for the relevance of this novel primate model of parent-infant neglect to the environmental causes and mechanisms of human developmental psychopathology.

Affective Symptoms↗
PubMed2004

[Methods for assessing cognitive function utilizing operant tasks in rats].

Most human behaviors (responses) are volitional, the frequency of which is changed based on stimulus presentations contingent upon the response, that is, operant behavior. It is considered that the findings on cognitive functions based on operant behaviors are more reliable in extrapolating the results to humans. Impairment of memory function, most notably the impairments of working memory and attention, is an important research focus to elucidate the mechanism underlying the core syndrome of Alzheimer's disease. Among various methods to measure working memory and attention, a delayed matching-to-sample paradigm utilizing operant chambers equipped with 3 levers and a choice reaction time paradigm have been proven to be very useful. Aside from these, adaptation to new environment is an important function for survival, and its impairment has been considered to be one of the factors inducing psychiatric disorders. Preclinical methods to measure the adaptation ability include a position reversal learning paradigm utilizing 2-lever operant chambers. Since the findings of studies on cognitive functions utilizing operant behaviors have been in good correlation with clinical findings, it would serve as a good strategy for elucidating the causes of such disorders as well as developing therapeutic agents.

Adaptation, Psychological↗
PubMed2003

M1 muscarinic agonists can modulate some of the hallmarks in Alzheimer's disease: implications in future therapy.

M1 muscarinic receptors (M1 mAChRs) play a role in an apparent linkage of three major hallmarks of Alzheimer's disease (AD): beta-amyloid (Abeta) peptide; tau hyperphosphorylation and paired helical filaments (PHFs); and loss of cholinergic function conducive to cognitive impairments. We evaluated the M1 muscarinic agonists AF102B (Cevimeline, EVOXAC trade mark : prescribed for Sjøgren's syndrome), AF150(S), and AF267B on some of these hallmarks of AD. Activation of M1 mAChRs with these agonists leads, inter alia, to enhanced secretion of amyloid precursor protein (alpha-APP), (via alpha-secretase activation), to decreased Abeta (via gamma-secretase inhibition), and to inhibition of Abeta- and/or oxidative stress-induced cell death. In several animal models mimicking different aspects of AD, these drugs restored cognitive impairments, and in select cases induced a decrease in brain Abeta elevation, with a high safety margin, following po administration. Notably, 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. Studies from other labs showed that AF102B and talsaclidine (another M1 agonist) decreased cerbrospinal fluid (CSF) Abeta in AD patients following chronic treatment, being the first reported drugs with such a profile. The clinical significance of these studies remains to be elucidated, yet based on in vivo (rabbits) and in vitro studies (cell cultures), our M1 agonists can decrease brain Abeta, owing to a novel and dual complementary effect (e.g., inhibition of gamma-secretase and activation of alpha-secretase). Remarkably, although M1 agonists can decrease CSF Abeta in AD patients, an increased AD-type pathology in Parkinson's disease was recently been associated with chronic antimuscarinic treatment. In another aspect, these agonists decreased tau hyperphosphorylation in vitro and in vivo. Notably, nicotinic agonists or cholinesterase inhibitors increased tau hyperphosphorylation. In summary, the M1 agonists tested are effective on cognition and behavior and show unique disease-modifying properties owing to beneficial effects on major hallmarks of AD. This may place such drugs in the first line of modern AD therapies (e.g., beta- or gamma-secretase inhibitors, vaccines against Abeta, statins, and inhibitors of tau hyperphosphorylation).

Alzheimer Disease↗