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T Steckler

Publications and source records attributed to T Steckler.

At least 37 records · Page 2Linked to original sources
PubMed2000

Glucocorticoid receptor impairment enhances impulsive responding in transgenic mice performing on a simultaneous visual discrimination task.

Transgenic mice with impaired glucocorticoid receptor (GR) function were tested for their ability to learn and perform a series of simultaneous visual discriminations which allowed a dissociation between accuracy of discrimination from those of motivation and behavioural disinhibition. Animals were first trained on an operant five-choice simultaneous discrimination autoshaping procedure, followed by a continuous reinforcement schedule on that task. Subsequently, the number of choices was limited to two and data were analysed according to the mathematical methods of signal detection theory (SDT). The effects of GR-antisense expression on accuracy when different rates of responding were required were studied under different fixed ratio response requirements (FR1-FR10). Autoshaping was retarded in transgenic animals and accuracy was impaired in both the five-choice and the two-choice discrimination tasks, although transgenic mice showed clear evidence for learning. Under conditions of low response requirements, transgenic mice showed increased response and cognitive biases, but reduced perceptual bias, and a behavioural disinhibition, characterized by a reduction in errors of omission, decreased response latencies and increased number of responses during the inter-trial interval. Increasing the response requirement improved performance in transgenic animals as reflected by enhanced accuracy. Moreover, transgenics were less susceptible to the deleterious effects of higher response requirements, as indicated by relatively unaffected bias measures in this group, while bias increased in controls. These results indicate that altered performance in GR-antisense transgenic animals cannot simply be interpreted as a mnemonic deficit, but that altered motivation and enhanced impulsive responding may account for some of these impairments.

Animals↗
PubMed1999

Corticotropin-releasing hormone receptor subtypes and emotion.

Preclinical data indicate that corticotropin-releasing hormone (CRH) has anxiogenic properties and a dysregulation in CRH systems has been suggested to play a role in a variety of stress-related psychiatric disorders, such as anxiety, depression, and eating disorders. Two CRH receptor subtypes have been identified, termed CRH1 receptor (CRH1) and CRH2 receptor (CRH2), with its splice variants CRH2 alpha and CRH2 beta. These receptor subtypes differ in their pharmacology and expression pattern in the brain. Mouse mutants in which the CRH1 receptor subtype has been deleted show an impaired stress response, reduced anxiety-related behavior, and cognitive deficits. Studies using antisense oligodeoxynucleotides directed against CRH1 or CRH2 alpha identified the CRH1 receptor as the main target for CRH in mediating anxiogenesis, although recent data also suggest a possible role for CRH2 alpha. More clearly, CRH2 alpha is involved in the CRH effects on food intake. Moreover, local injection of CRH into areas rich in CRH2 alpha also result in altered sexual female behavior. Therefore, it is suggested that the CRH2 alpha may primarily influence a system concerned with implicit processes necessary for survival, i.e., with motivational types of behavior including feeding, reproduction, and possibly defense, whereas the CRH1 may be more concerned with explicit processes, including attention, executive functions, the conscious experience of emotions, and possibly learning and memory related to these emotions. This also suggests that patients suffering from anxiety and depression may benefit from treatment with CRH1 antagonistic drugs, while drugs targeting CRH2 alpha may be of particular benefit for patients with eating disorders.

Animals↗
PubMed1999

Disrupted allocentric but preserved egocentric spatial learning in transgenic mice with impaired glucocorticoid receptor function.

Spatial and non-spatial learning of mice with an incorporated antisense RNA complementary to a fragment of cDNA coding for the glucocorticoid receptor (GR) were evaluated in allocentric and egocentric radial maze and water maze tasks, and in spontaneous object recognition and sensorimotor learning paradigms. Mice with impaired GR function did not acquire two maze paradigms based on allocentric spatial navigation, radial maze non-matching to position and water maze spatial discrimination learning. Comparison of performance in spaced and massed trials indicated that this may be due to a general inability to store information into allocentric reference memory or in retrieval processes. However, both groups of animals learned the rules of an egocentric radial maze task at similar rates and there was no difference in their ability to recognise objects once animals had equal opportunity to explore the sample objects. Sensorimotor performance was impaired in transgenic animals, but it is suggested that this is due to non-specific factors rather than to disrupted sensorimotor learning per se. These results are consistent with a disruption of hippocampal function. Histological examination of the hippocampus revealed no obvious structural abnormalities in transgenic animals. Therefore, the data suggest that functional underactivity of GRs at the level of the hippocampus induces a deficit in allocentric navigation while sparing egocentric navigation and object recognition.

Animals↗
PubMed1999

Enhanced conditioned approach responses in transgenic mice with impaired glucocorticoid receptor function.

The long-term consequences of impaired glucocorticoid receptor (GR) function on reward-related learning were studied in transgenic mice with impaired GR function in a series of experiments taxing conditioned and unconditioned approach responses to stimuli predictive of food. There was a double-dissociation in that transgenic mice with impaired GR activity showed enhanced conditioned exploration in situations when stimuli predicted reward, while free-feeding food consumption over 24 h was reduced. Previous experiments have shown altered accumbens dopaminergic activity in these animals. In line with these findings, we observed an enhanced behavioural stimulation of transgenic mice following administration of d-amphetamine (2 mg/kg). This suggests that the increase in preparatory responses in transgenic mice may be mediated via an enhanced accumbens dopaminergic activity, possibly secondary to alterations in other brain systems.

Animals↗
PubMed1999

Excitotoxic hippocampal lesions disrupt allocentric spatial learning in mice: effects of strain and task demands.

Spatial discrimination of ibotenic acid-lesioned C57BL/6 (B6) and DBA/2 (D2) mice was tested in two-choice water maze and plus maze tasks. B6 but not D2 mice learned the spatial discrimination in the water maze, but strains did not differ in learning a spatial discrimination in the plus maze paradigm. Ibotenic acid lesions of the hippocampus impaired percentage correct choices in the water maze spatial discrimination task in B6 but not in D2 mice, the latter of which may have been due to a floor effect. Furthermore, lesioned mice were more thigmotaxic, the distance travelled until a choice was made was longer and animals made more errors of omission. Despite the poor performance during water maze acquisition, lesioned animals, as well as sham-lesioned D2 mice, eventually acquired some place response in the water maze, as was evident when the location of the platform was reversed. However, hippocampus-lesioned mice of both strains were impaired when tested in the plus maze spatial discrimination task. Thus, ibotenic acid-induced lesions of the hippocampus impair acquisition of spatial discrimination in mice. These deficits were strain-dependent and likely comprise impaired accuracy as well as changes in non-mnemonic types of behaviour. Importantly, lesions in both strains impaired spatial learning, and whether a deficit was seen in mice of the D2 strain seemed to depend on the demands of the task.

Animals↗
PubMed1999

Glucocorticoids and depression.

Depression has been associated with impaired mineralocorticoid receptor function, restrained glucocorticoid receptor feedback at the level of the hypothalamic-pituitary-adrenal (HPA) axis, raised cortisol level and increased corticotropin-releasing factor activity, which may act in concert to induce the signs and symptoms of the disorder. Pre-clinical and clinical evidence suggests that both genetic and environmental factors contribute to the development of these HPA axis abnormalities in depressed patients. Support for this view derives from models using genetically modified animals and/or chronic stress exposure at different developmental stages, although all of the current approaches have to be viewed within their limitations to model the disease. However, both animal and human studies challenging the HPA system show at least some neuroendocrine and behavioural changes comparable to those seen in depression, suggesting that some of the depressive symptoms can be attributed to HPA axis hyperactivity. Moreover, normalization of the neuroendocrine function following chronic antidepressant drug treatment seems to be a prerequisite for stable remission of depressive psychopathology, i.e. that normalization of HPA function is critical for relief of the clinical symptomatology of this disorder.

Animals↗
PubMed1998

Recognition memory in rats--I. Concepts and classification.

Recognition is the process by which a subject is aware that a stimulus has been previously experienced. It requires that the characteristics of events are perceived, discriminated, identified and then compared (matched) against a memory of the characteristics of previously experienced events. Understanding recognition memory, its underlying neuronal mechanisms, its dysfunction and alleviation of the latter by putative cognition enhancing drugs is a major research target and has triggered a wealth of animal studies. One of the most widely used animals for this purpose is the rat, and it is the rat's recognition memory which is the focus of this review. In this first part, concepts of recognition memory, stages of mnemonic processing and paradigms for the measurement of the rat's recognition memory will be discussed. In two subsequent articles (parts II and III) we will focus on the neuronal mechanisms underlying recognition memory in rats. Three major points arise from the comparison of paradigms that have in the past been used to assess recognition memory in rats. First, it should be realized that some tasks which, at face value, can all be considered to measure recognition memory in rats, may not assess recognition memory at all but may, for example, be based on recall rather than recognition. Second, it is evident that different types of recognition memory can be distinguished and that tasks differ in the type of recognition memory taxed. Some paradigms, for example, measure familiarity, whereas others assess recency. Furthermore, paradigms differ as to whether spatial stimuli or items are employed. Third, different processes, ranging from stimulus-response learning to the formation of concepts, may be involved to varying extent in different tasks. These are important considerations and question the predictive validity of the results obtained from studies examining, for example, the effects of putative cognition enhancing drugs.

Animals↗
PubMed1998

Recognition memory in rats--II. Neuroanatomical substrates.

A discussion of the neuroanatomical systems thought to be of importance for the mediation of recognition memory in the rat warrants consideration of different, but not necessarily exclusive concepts. An important concept is the hypothesis that a dichotomy in the neural systems mediating spatial and non-spatial (item) memory exists in the rat. We have adopted a model of recognition memory suggesting that information about previously encountered items is stored in a dynamic pattern of neural activity and not in a localized representation. These patterns are features of distributed neuronal networks and different networks may process different forms of recognition memory. Two parallel-distributed neuronal networks are proposed in the rat. Network 1 is essential for the processing of non-spatial/item recognition memory processes and incorporates the cortical association areas such as TE1, TE2 and TE3, the rhinal cortices, the mediodorsal thalamic nucleus and prefrontal cortical areas. Network 2 comprises the hippocampus, mamillary bodies, anterior thalamic nuclei and medial prefrontal areas, especially the prelimbic cortex, and is suggested to be pivotal for the processing of spatial recognition memory.

Animals↗
PubMed1998

Recognition memory in rats--III. Neurochemical substrates.

In the first part of three overviews on recognition memory in the rat, we discussed the tasks employed to study recognition memory. In the second part, we discussed the neuroanatomical systems thought to be of importance for the mediation of recognition memory in the rat. In particular, we delineated two parallel-distributed neuronal networks, one that is essential for the processing of non-spatial/item recognition memory processes and incorporates the cortical association areas such as TE1, TE2 and TE3, the rhinal cortices, the mediodorsal thalamic nucleus and prefrontal cortical areas (Network 1), the other comprising of the hippocampus, mamillary bodies, anterior thalamic nuclei and medial prefrontal areas (Network 2), suggested to be pivotal for the processing of spatial recognition memory. The next step will progress to the level of the neurotransmitters thought to be involved. Current data suggest that the majority of drugs have non-specific, i.e. delay-independent effects in tasks measuring recognition memory. This may be due to attentional, motivational or motoric changes. Alternatively, delay-independent effects may result from altered acquisition/encoding rather than from altered retention. Furthermore, the neurotransmitter systems affected by these drugs could be important as modulators rather than as mediators of recognition memory per se. It could, of course, also be the case that systemic treatment induces non-specific effects which overshadow any specific, delay-dependent, effect. This possibility receives support from lesion experiments (for example, of the septohippocampal cholinergic system) or studies employing local intracerebral infusion techniques. However, it is evident that those delay-dependent effects are relatively subtle and more readily seen in delayed response paradigms, which tax spatial recognition memory. One interpretation of these results could be that some neurotransmitter systems are more involved in spatial than in item recognition memory processes. However, performance in delayed response tasks can be aided by mediating strategies. Drugs or lesions can alter those strategies, which could equally explain some of the (delay-dependent) drug effects on delayed responding. Thus, it is evident that neither of the neurotransmitter systems reviewed (glutamate, GABA, acetylcholine, serotonin, dopamine and noradrenaline) can be viewed as being directly and exclusively concerned with storage/retention. Rather, our model of recognition memory suggests that information about previously encountered items is differentially processed by distinct neural networks and is not mediated by a single neurotransmitter type.

Animals↗
PubMed1998

Impaired stress response and reduced anxiety in mice lacking a functional corticotropin-releasing hormone receptor 1.

Corticotropin-releasing hormone (CRH) is a potent mediator of endocrine, autonomic, behavioural and immune responses to stress, and has been implicated in the stress-like and other aversive consequences of drug abuse, such as withdrawal from alcohol. Two CRH receptors, Crhr1 and Crhr2, have been identified in the mouse. Crhr1 is highly expressed in the anterior pituitary, neocortex, hippocampus, amygdala and cerebellum, and activation of this receptor stimulates adenylate cyclase. Here we show that in mice lacking Crhr1, the medulla of the adrenal gland is atrophied and stress-induced release of adrenocorticotropic hormone (ACTH) and corticosterone is reduced. The homozygous mutants exhibit increased exploratory activity and reduced anxiety-related behaviour under both basal conditions and following alcohol withdrawal. Our results demonstrate a key role of the Crhr1 receptor in mediating the stress response and anxiety-related behaviour.

Adrenocorticotropic Hormone↗
PubMed1996

Effects of procedural parameters on response accuracy: lessons from delayed (non-)matching procedures in animals.

The experimental analysis of behaviour in operant paradigms has identified numerous variables which affect performance. We will focus on the delayed (non-)matching tasks in order to illustrate the influence of procedural variables on acquisition and performance in operant tasks of cognitive function. Systematic variation of these parameters can help dissociate different cognitive processes which may be differentially affected by drug treatment or brain lesions. Use of different parameters, however, could equally account for controversial drug or lesion effects reported in the literature. Consideration of these factors will increase our understanding of the relative contribution of these and other features and parameters of the procedural arrangements to the final behavioural outcome.

Animals↗
PubMed1996

Further developments in the measurement of working memory in rodents.

This article reviews automated test procedures that can be used to study memory for discrete/trial-unique events in rodents and other animals. A distinction is made between delayed response tasks, i.e. those tasks for which all information necessary to determine the correct response is available prior to the retention interval, and delayed comparison tasks, i.e. tasks in which the subject must compare stimuli presented prior to and after the retention interval in order to determine the correct response. Delayed comparison procedures potentially provide a purer estimate of the subject's memory capacities, but have also been more difficult for rodents to acquire. Suggestions are offered for potential directions for improved delayed comparison tasks.

Animals↗
PubMed1996

Measurement of cognitive function: relating rodent performance with human minds.

Rodents are the most commonly employed animals to model human cognitive dysfunction, but many of the behavioural paradigms employed for evaluation of rodent cognitive abilities measure functions rather different from those generally assessed in humans. This may be one reason for the failure of these models to allow valid predictions about drug effects in demented patients. One solution to this may be the use of a more comparative approach. Careful experimental designs indicate that comparative attentional as well as mnemonic processes can be assessed in rat and human subjects. This could be an essential step towards the successful development of drugs with therapeutic potential in cognitive disorders.

Animals↗
PubMed1996

Animal models in cognitive behavioural pharmacology: an overview.

Most studies in cognitive behavioural pharmacology have used rodents as subjects and simple learning tasks. This approach is regarded as acceptable because the cognitive abilities of rats may not differ from those of non-human primates and the modelling in animals of those advanced cognitive abilities possessed by humans may be of limited utility. A strength of many existing models lies in their construct validity. However, the face, concurrent and predictive validities of many animal models are low. In part, this is due to the need to take account of species specific characteristics in experimental design. Thus, inter-species differences in learning may be explained not by differences in cognitive ability but by differences in species specific morphological, physiological and behavioural characteristics. Features of the 'ideal' animal model of human cognitive function are listed and potential strategies for future research in cognitive behavioural pharmacology assessed.

Animals↗
PubMed1995

Psychopharmacological studies in rats responding at touch-sensitive devices.

A multiple choice serial reaction time task was used to investigate visual attention in rats. The intelligence panel consisted of a transparent touch-sensitive device, placed directly in front of a video monitor. Amphetamine (0.2-1.6 mg/kg IP) increased errors of omission and decreased latency to respond, but had no effect on accuracy. The 5-HT agonist quipazine (0.6-2.4 mg/kg IP) increased errors of omission, but did not affect other parameters. ICV administration of hemicholinium-3 (1-4 micrograms) had no effect upon performance. Thus, psychopharmacological manipulations can reliably alter performance in the touch window box, suggesting potential new avenues for rat cognitive testing.

Amphetamine↗
PubMed1995

The role of serotonergic-cholinergic interactions in the mediation of cognitive behaviour.

Cholinergic systems have been linked to cognitive processes such as attention, learning and mnemonic function. However, other neurotransmitter systems, such as the serotonergic one, which may have only minor effects on cognitive function on their own, interact with cholinergic function and their combined effects may have marked behavioural actions. Some studies have dealt with serotonergic-cholinergic interactions, but it is unclear whether both systems affect cognition directly or whether interactions at a behavioural level result from additional alterations in non-cognitive factors. This distinction is difficult, since it is possible that the diverse cholinergic and serotonergic systems serve different roles in the mediation of cognitive processes, both at the neuroanatomical and neurochemical level. Nevertheless, it is possible that cholinergic systems primarily alter accuracy in cognitive tasks, whereas serotonergic neurotransmission modulates behaviour by altering bias (motivation, motor processes). Whether serotonin alters accuracy or bias, however, may also depend on the cognitive process under investigation: it is suggested that attention, stimulus processing and/or arousal can be influenced by both cholinergic and serotonergic systems independently from each other. Cholinergic and serotonergic projections to cortex and thalamus may be of importance in the mediation of these cognitive processes. Serotonergic-cholinergic interactions could also be of importance in the mediation of learning processes and trial-by-trial working memory. The data available do not allow an unambiguous conclusion about the role of these interactive processes in the mediation of long-term reference memory. These processes may rely on serotonergic-cholinergic interactions at the hippocampal level. It is concluded that serotonergic-cholinergic interactions play an important role in the mediation of behavioural, including cognitive, performance, but that further studies are necessary in order to elucidate the exact nature of these interactions.

Acetylcholine↗
PubMed1995

Cholinergic lesions by 192 IgG-saporin and short-term recognition memory: role of the septohippocampal projection.

Two experiments examined the effects of cholinergic basal forebrain lesions by intraventricular and intrahippocampal infusions of the immunotoxin 192 IgG-saporin on recognition memory in an operant delayed-non-matching-to-position task in rats. Intraventricular infusions produced extensive reductions in cortical and hippocampal choline acetyltransferase activity in the first experiment. Behaviourally, a mixed delay-dependent/independent accuracy deficit and increased biased responding was observed post-lesioning. Thus, both mnemonic as well as non-mnemonic processes were affected by the lesion. This performance deficit was indistinguishable from the impairment induced by acute intraventricular injections of the choline uptake inhibitor hemicholinium-3, which suggests that cholinergic damage induced by 192 IgG-saporin disrupted performance. In the second experiment more discrete intrahippocampal 192 IgG-saporin lesions were made, which reduced hippocampal choline acetyltransferase activity about 57%, although this reduction was not as extensive as following intraventricular injections. Although intrahippocampal lesions also impaired non-matching accuracy, this effect failed to reach significance during most stages of the experiment. Scopolamine just failed to significantly impair (P = 0.053) performance in hippocampal lesioned rats more than in controls. The nicotinic antagonist mecamylamine did not affect the lesion-induced changes in performance. These results suggest that the cholinergic basal forebrain, including the septohippocampal system, is important for the mediation of recognition memory, and muscarinic receptor-mediated mechanisms may be of greater importance than alterations of nicotinic receptor-mediated processes in the septohippocampal system.

Acetylcholinesterase↗