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C T Wotjak

Publications and source records attributed to C T Wotjak.

At least 19 recordsLinked to original sources
PubMed2006

A hitchhiker's guide to behavioral analysis in laboratory rodents.

Genes and environment are both essential and interdependent determinants of behavioral responses. Behavioral genetics focuses on the role of genes on behavior. In this article, we aim to provide a succinct, but comprehensive, overview of the different means through which behavioral analysis may be performed in rodents. We give general recommendations for planning and performing behavioral experiments in rats and mice, followed by brief descriptions of experimental paradigms most commonly used for the analysis of reflexes, sensory function, motor function and exploratory, social, emotional and cognitive behavior. We end with a discussion of some of the shortcomings of current concepts of genetic determinism and argue that the genetic basis of behavior should be analyzed in the context of environmental factors.

Animals↗
PubMed2005

Learning and memory.

Learning and memory processes are thought to underlie a variety of human psychiatric disorders, including generalised anxiety disorder and post-traumatic stress disorder. Basic research performed in laboratory animals may help to elucidate the aetiology of the respective diseases. This chapter gives a short introduction into theoretical and practical aspects of animal experiments aimed at investigating acquisition, consolidation and extinction of aversive memories. It describes the behavioural paradigms most commonly used as well as neuroanatomical, cellular and molecular correlates of aversive memories. Finally, it discusses clinical implications of the results obtained in animal experiments in respect to the development of novel pharmacotherapeutic strategies for the treatment of human patients.

Animals↗
PubMed2001

Potentiated amygdaloid auditory-evoked potentials and freezing behavior after fear conditioning in mice.

Elucidation of cellular and molecular mechanisms underlying fear-related memory would greatly benefit from the possibility of combined behavioral and electrophysiological recordings in genetically modified mice. As a first step to this goal, we implanted adult C57BL/6J mice with recording electrodes aimed at the basolateral amygdaloid complex and trained them in an auditory fear conditioning paradigm. After conditioning, animals with paired tone and footshock presentation showed not only intensified freezing behavior lasting for 2 days, but also increases, lasting 4 days, in slope and amplitude of the most negative component of auditory-evoked potentials triggered by the conditioned stimulus. These effects could not be observed in animals with unpaired tone and footshock presentation. Thus, our data show that a long-lasting association of a former neutral tone with an aversive situation is accompanied by a long-lasting increase of auditory-evoked potentials in freely moving mice. However, extinction of the potentiation of auditory-evoked potentials and freezing behavior followed different time courses, thus making a direct relationship between these responses unlikely.

Acoustic Stimulation↗
PubMed2001

Intrahippocampal administration of an antibody against the HNK-1 carbohydrate impairs memory consolidation in an inhibitory learning task in mice.

Many cell adhesion molecules express the HNK-1 carbohydrate involved in formation and functioning of synapses. To assess its role in learning, we injected the monoclonal HNK-1 antibody or nonimmune IgG into the hippocampus of C57BL/6J mice 1 h after training in a step-down avoidance task. In animals treated with the HNK-1 antibody, latencies of step down in a recall session 48 h after injection did not change compared to training values and were significantly shorter versus IgG-treated controls, which acquired the task normally. Similar differences between the two treatments were also observed after a stronger training protocol in a step-down avoidance paradigm. The HNK-1 antibody was effective only when injected 1 h, but not 48 h after training, thus affecting memory consolidation but not memory recall itself. The HNK-1 antibody impaired memory also in tenascin-R knock-out mice, indicating that extracellular matrix molecule tenascin-R, one of the carriers of the HNK-1epitope in the hippocampus, does not mediate the function of the HNK-1 carbohydrate in this task. Our observations show that the HNK-1 carbohydrate is critically involved in memory consolidation in hippocampus-dependent learning in mammals.

Animals↗
PubMed2001

Forced swimming stimulates the expression of vasopressin and oxytocin in magnocellular neurons of the rat hypothalamic paraventricular nucleus.

Previous studies have shown that a 10-min forced swimming session triggers the release of both vasopressin and oxytocin into the extracellular fluid of the hypothalamic paraventricular (PVN) and supraoptic nuclei (SON) in rats. At the same time oxytocin, but not vasopressin, was released from the axon terminals into the blood. Here we combined forced swimming with in situ hybridization to investigate whether (i) the stressor-induced release of vasopressin and oxytocin within the PVN originates from parvo- or magnocellular neurons of the nucleus, and (ii) central release with or without concomitant peripheral secretion is followed by changes in the synthesis of vasopressin and/or oxytocin. Adult male Wistar rats were killed 2, 4 or 8 h after a 10-min forced swimming session and their brains processed for in situ hybridization using 35S-labelled oligonucleotide probes. As measured on photo-emulsion-coated slides, cellular vasopressin mRNA concentration increased in magnocellular PVN neurons 2 and 4 h after swimming (P < 0.05). Similarly, oxytocin mRNA concentration was significantly increased in magnocellular neurons of the PVN at 2 and 8 h (P < 0.05). We failed to observe significant effects on vasopressin and oxytocin mRNA levels in the parvocellular PVN and in the SON. Taken together with results from previous studies, our data suggest that magnocellular neurons are the predominant source of vasopressin and oxytocin released within PVN in response to forced swimming. Furthermore, in the case of vasopressin, central release in the absence of peripheral secretion is followed by increased mRNA levels, implying a refill of depleted somato-dendritic vasopressin stores. Within the SON, however, mRNA levels are poor indicators of the secretory activity of magnocellular neurons during stress.

Animals↗
PubMed2001

Taurine selectively modulates the secretory activity of vasopressin neurons in conscious rats.

Previous experiments have shown that a 10-min forced swimming session triggers the release of vasopressin from somata and dendrites, but not axon terminals, of neurons of the hypothalamic-neurohypophysial system. To further investigate regulatory mechanisms underlying this dissociated release, we forced male Wistar rats to swim in warm (20 degrees C) water and monitored release of the potentially inhibitory amino acids gamma amino butyric acid (GABA) and taurine into the hypothalamic supraoptic nucleus using microdialysis. Forced swimming caused a significant increase in the release of taurine (up to 350%; P < 0.05 vs. prestress release), but not GABA. To reveal the physiological significance of centrally released taurine, the specific taurine antagonist 6-aminomethyl-3-methyl-4H-1,2,4-benzothiadiazine-1,1-dioxide was administered into the supraoptic nucleus via retrodialysis. Administration of this antagonist caused a significant increase in the release of vasopressin within the supraoptic nucleus and into the blood both under basal conditions and during stress (up to 800%; P < 0.05 vs. basal values), without affecting hypothalamic or plasma oxytocin. Local administration of the GABA(A) receptor antagonist bicuculline, in contrast, failed to influence vasopressin secretion at either time point. In a separate series of in vivo electrophysiological experiments, administration of the same dosage of the taurine antagonist into the supraoptic nucleus via microdialysis resulted in an increased electrical activity of identified vasopressinergic, but not oxytocinergic, neurons. Taken together our data demonstrate that taurine is released within the supraoptic nucleus during physical/emotional stress. Furthermore, at the level of the supraoptic nucleus, taurine inhibits not only the electrical activity of vasopressin neurons but also acts as an inhibitor of both central and peripheral vasopressin secretion during different physiological states.

Action Potentials↗
PubMed2000

A single social defeat experience selectively stimulates the release of oxytocin, but not vasopressin, within the septal brain area of male rats.

The naturally occurring social conflict situation to be confronted with an aggressive dominant conspecific was used to study the effects of emotional stress on the release of oxytocin (OXT) and arginine vasopressin (AVP) within the mediolateral septum of the rat brain. Male rats were chronically implanted with a microdialysis probe into this brain area. Local release patterns of both, OXT and AVP were monitored in response to a 30 min social defeat. Social defeat caused a significant increase in the release of OXT (to 254%+/-43%, P<0.01). In contrast, the release of AVP was not affected. In a preliminary experiment, to assess the physiological significance of stress-induced intraseptal OXT release, a separate group of animals received the OXT receptor antagonist des-Gly-NH(2)d(CH(2))(5)[Tyr(Me)(2)Thr(4)]OVT into the mediolateral septum via inverse microdialysis prior to and during the social defeat procedure. However, no difference could be observed in submissive freezing (passive coping) or in exploratory behavior (active coping) when compared to vehicle-treated animals, neither acutely nor 24 h after antagonist administration. Taken together, our results demonstrate that emotional stress activates the septal oxytocinergic, but not vasopressinergic, system. The physiological significance of intraseptally released OXT remains unclear and has to be elucidated in future studies.

Adaptation, Psychological↗
PubMed2000

Ageing alters intrahypothalamic release patterns of vasopressin and oxytocin in rats.

The ageing process has been shown to have a profound impact on the hypothalamo-neurohypophysial system (HNS) and the hypothalamo-pituitary-adrenocortical (HPA) axis in humans as well as in rodents. Therefore, in this study, the intracerebral and peripheral release patterns of both vasopressin and oxytocin have been studied in aged male Wistar rats under basal conditions and in response to ethologically relevant stressors, using intracerebral microdialysis and chronic blood sampling techniques, respectively. Approximately a twofold higher basal release of arginine vasopressin (AVP) within the hypothalamic paraventricular nucleus (PVN), but not within the supraoptic nucleus (SON), was found in aged rats, whereas basal oxytocin (OXT) release did not differ in comparison with young rats. With increasing age the rise in intra-PVN release of both AVP and OXT was blunted in response to forced swimming. In contrast, the intra-SON release of AVP was unrelated to age. Simultaneously recorded basal secretion of both AVP and OXT from the neurohypophysis into blood was increased in aged rats, with a blunted OXT response to swim stress. Opposed to that, plasma AVP levels remained unchanged in both groups. Basal plasma levels of corticotropin (ACTH) and corticosterone were elevated in aged rats, whereas stress-elicited ACTH and corticosterone responses were indistinguishable. These results indicate age-related changes in the HNS and HPA axis with an enhanced basal activity opposed to a blunted response to stressors with increasing age. The increased basal release of AVP within the PVN suggests a role of intracerebral AVP in age-associated alterations of HPA axis regulation.

Adrenocorticotropic Hormone↗
PubMed2000

Acute transcranial magnetic stimulation of frontal brain regions selectively modulates the release of vasopressin, biogenic amines and amino acids in the rat brain.

Using intracerebral microdialysis in urethane-anaesthetized adult male Wistar rats, we monitored the effects of acute repetitive transcranial magnetic stimulation (rTMS; 20 trains of 20 Hz, 2.5 s) on the intrahypothalamic release of arginine vasopressin (AVP) and selected amino acids (glutamate, glutamine, aspartate, serine, arginine, taurine, gamma-aminobutyric acid) and the intrahippocampal release of monoamines (dopamine, noradrenaline, serotonin) and their metabolites (homovanillic acid, 3,4-dihydroxyphenylacetic acid, 5-hydroxyindoleacetic acid). The stimulation parameters were adjusted according to the results of accurate computer reconstructions of the current density distributions induced by rTMS in the rat and human brains, ensuring similar stimulation patterns in both cases. There was a continuous reduction in AVP release of up to 50% within the hypothalamic paraventricular nucleus in response to rTMS. In contrast, the release of taurine, aspartate and serine was selectively stimulated within this nucleus by rTMS. Furthermore, in the dorsal hippocampus the extracellular concentration of dopamine was elevated in response to rTMS. Taken together, these data provide the first in vivo evidence that acute rTMS of frontal brain regions has a differentiated modulatory effect on selected neurotransmitter/neuromodulator systems in distinct brain areas.

Amino Acids↗
PubMed2000

Behavioural impact of intraseptally released vasopressin and oxytocin in rats.

The two nonapeptides arginine vasopressin and oxytocin are not only secreted from the neurohypophysis into the general circulation but are also released intracerebrally. Our recent research has focused on the release patterns and effects of oxytocin and vasopressin in brain areas, such as the septum and hypothalamus, that are thought to be involved in the regulation of (1) behavioural responses and (2) responses of the hypothalamo-neurohypophysial system (HNS) to stressor exposure in rats. The results demonstrate that combined physical and emotional stress (induced by exposure to forced swimming) selectively triggers the release of vasopressin within all brain areas under study but not into the general circulation. Under emotional stress conditions (induced by exposure to the 'social defeat' procedure), however, oxytocin rather than vasopressin release increased within the hypothalamus and septum. Experiments aimed at revealing the neuroendocrine and behavioural relevance of the local nonapeptide release provided evidence for an involvement of vasopressin in the regulation of HNS activity (within the hypothalamus) and, moreover, in acute stress-coping strategies, anxiety-related behaviour and learning and memory processes (within the septum). The observed dissociation between central and peripheral nonapeptide release not only supports the hypothesis that plasma vasopressin and oxytocin concentrations do not necessarily reflect central release patterns but also suggests vasopressin and oxytocin neurones are able to independently release their nonapeptide from different parts of their neuronal surface (e.g. from somata/dendrites vs. axon terminals). This remarkable regulatory capacity provides the basis for an differential involvement of vasopressin, and probably also oxytocin, in the co-ordination of neuroendocrine activity, emotionality and cognition at different brain levels to ensure an appropriate behavioural response of the organism to stressful stimuli.

Animals↗
PubMed2000

Endogenous vasopressin contributes to hypothalamic-pituitary-adrenocortical alterations in aged rats.

The ageing process in animals and humans is thought to be accompanied by a gradual impairment of corticosteroid receptor function, which is reflected by increased pituitary-adrenocortical hormone secretion at baseline and a number of aberrant neuroendocrine function test results. The latter include the ACTH and corticosteroid responses to a combined dexamethasone (DEX)/corticotropin-releasing hormone (CRH) challenge. The excessive hormonal response to this test among aged individuals has been taken as indirect evidence of enhanced endogenous arginine vasopressin (AVP) release, which - together with peripherally administered CRH - is capable of overriding DEX-induced ACTH suppression. The current study was designed to explore the role of endogenous AVP in mediating excessive hypothalamic-pituitary-adrenocortical (HPA) activity in ageing. The combined DEX/CRH test was administered to aged (22-24 months old) Wistar rats and the effect of the AVP type 1 (V1) receptor antagonist, d(CH(2))(5)Tyr(Me)AVP, on ACTH release was studied. Infusion of the V1 receptor antagonist after DEX pretreatment and before CRH administration prevented the CRH-induced rise in ACTH secretion in comparison with vehicle-treated aged rats (area under the concentration-time curve: 699+/-479 versus 2896+/-759; P<0.01). This difference was absent in young (3 months old) control rats. In situ hybridization showed an increased number of AVP mRNA-expressing neurons in the parvocellular but not the magnocellular, portion of the hypothalamic paraventricular nucleus in DEX-pretreated aged rats. The number and synthetic activity of parvocellular neurons expressing CRH mRNA was also increased. We have concluded that the increased HPA activity in aged rats involves enhanced synthesis and release of AVP from parvocellular neurons, possibly secondary to impaired corticosteroid receptor function.

Adrenocorticotropic Hormone↗
PubMed1999

Vasopressin selectively modulates the release of taurine within the septum of the rat brain.

Previous experiments have shown that arginine vasopressin (AVP) released within the septal brain area of adult male rats in response to defined stressor exposure is involved in emotionality-related behavior. We report here that a 10-min forced swimming session stimulated the release of glutamate, aspartate, arginine, gamma-aminobutyric acid (GABA) and taurine but not alanine and serine in the medio-lateral part of this brain structure. Local administration of the AVP V1 receptor antagonist d(CH2)5Tyr(Me)AVP by inverse microdialysis caused a significant increase in the concentration of taurine in microdialysates under resting conditions that was further potentiated during forced swimming. In contrast, the release of alanine, arginine, GABA and serine was unaffected by antagonist treatment. Taken together with previous data, our results suggest that the effects of intraseptally released AVP on stress-coping strategies might be mediated at least in part via its influence on the local release of taurine.

Animals↗
PubMed1999

Anxiety and increased 5-HT1A receptor response in NCAM null mutant mice.

Mice deficient in the neural cell adhesion molecule (NCAM) show behavioral abnormalities as adults, including altered exploratory behavior, deficits in spatial learning, and increased intermale aggression. Here, we report increased anxiety-like behavior of homozygous (NCAM-/-) and heterozygous (NCAM/-) mutant mice in a light/dark avoidance test, independent of genetic background and gender. Anxiety-like behavior was reduced in both NCAM+/+ and NCAM-/- mice by systemic administration of the benzodiazepine agonist diazepam and the 5-HT1A receptor agonists buspirone and 8-OH-DPAT. However, NCAM-/- mice showed anxiolytic-like effects at lower doses of buspirone and 8-OH-DPAT than NCAM+/+ mice. Such increased response to 5-HT1A receptor stimulation suggests a functional change in the serotonergic system of NCAM-/- mice, likely involved in the control of anxiety and aggression. However, 5-HT1A receptor binding and tissue content of serotonin and its metabolite 5-hydroxyindolacetic acid were found unaltered in every brain area of NCAM-/- mice investigated, indicating that expression of 5-HT1A receptors as well as synthesis and release of serotonin are largely unchanged in NCAM-/- mice. We hypothesize a critical involvement of endogenous NCAM in serotonergic transmission via 5-HT1A receptors and inwardly rectifying K+ channels as the respective effector systems.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Vasopressin released within the septal brain area during swim stress modulates the behavioural stress response in rats.

The aim of the present study was to investigate the physiological significance of the neuropeptide arginine vasopressin (AVP) released within the septum, in the behavioural response of rats to stress. In the first experiment, rats were chronically implanted with a microdialysis probe aimed at the mediolateral or ventral septum to monitor the local release of AVP in response to 10 min of forced swimming in 20 degrees C warm water. Exposure to this stressor caused a significant increase in AVP release in both the mediolateral (174 +/- 21%, P < 0.01) and ventral septum (220 +/- 33%, P < 0.01). In contrast, microdialysates collected outside the mediolateral septum or in the lateral ventricle remained at prestress levels throughout the dialysis period. Furthermore, unstressed control animals failed to show significant alterations in vasopressin release in the mediolateral septum. In a second experiment, the introduction of the V1 receptor antagonist d(CH2)5Tyr(Me)AVP into the mediolateral septum via inverse microdialysis concomitant with stressor exposure caused the rats to spend an increased time floating and a reduced time swimming compared to vehicle-treated rats. This effect was acute and also detected 24 h after antagonist administration. Taken together, these findings demonstrate a significant activation of the septal vasopressinergic system in response to swim stress. Furthermore, our data support the view that AVP released within this brain area is involved in the generation of active behavioural strategies aimed at coping with new and challenging situations.

Adaptation, Psychological↗
PubMed1998

Swim stress triggers the release of vasopressin within the suprachiasmatic nucleus of male rats.

The hypothalamic suprachiasmatic nucleus (SCN) is the predominant pacemaker of the mammalian brain that generates and controls circadian rhythms of various endocrine and behavioral processes. Different lines of evidence suggest that stress interferes with the maintenance of such rhythms. As a first approach to investigate whether the neuropeptide arginine vasopressin (AVP), which shows circadian rhythms of synthesis and release within the SCN, might contribute to this stress-induced alterations in circadian rhythms, we monitored acute effects of swim stress on the intra-SCN release of AVP in male rats by means of the microdialysis technique. A 10-min forced swimming session triggered a marked but relatively short-lasting increase in the intranuclear release of AVP (to approx. 440%). This effect was restricted to the area containing predominantly somata and dendrites of vasopressinergic neurons, since no changes in AVP release could be measured in one of their major projection areas, the nucleus of the dorsomedial hypothalamus. Our data provide evidence that the amount of AVP released within the SCN can vary widely not only in accordance with AVP's intrinsically regulated circadian rhythm but also in response to a physiologically relevant stressor. In this way, the neuropeptide may contribute to the regulation of endocrine and behavioral rhythms particularly in challenging situations associated with resettings of the endogenous clock.

Animals↗
PubMed1998

Release of vasopressin within the brain contributes to neuroendocrine and behavioral regulation.

In addition to its peripheral secretion from the neurohypophysis, the neuropeptide vasopressin (VP) is released within the mammalian brain from probably all parts of the neuronal membrane. In particular the development of brain microdialysis in vivo together with blood microdialysis or blood sampling provides the advantage of being able to reliably compare the dynamic release patterns into different compartments of the organism. The central VP release within hypothalamic (e.g., supraoptic, paraventricular and suprachiasmatic nuclei) and limbic (e.g., septum, amygdala) rat brain areas is stimulated by a variety of substances and stressors, including interleukin-1 beta, social defeat and forced swimming. Furthermore, it is characterized by positive and negative feedback mechanisms and the capacity of the VP system for co-ordinated or independent release, the latter being observed, for example, during social defeat. This emotional stressor, in contrast to exposure to a novel cage, increased VP release within the supraoptic nucleus, but not into plasma. This failure to release VP peripherally could be observed also during forced swimming, despite a dramatic rise in plasma osmolality and a markedly stimulated central release. In another series of experiments we studied the effects of centrally-released VP on cognitive and emotional aspects of behavior using reverse microdialysis for antagonist administration during the behavioral tests and antisense targeting to downregulate either VP or its local V1 receptor subtype. In this way, centrally (in particular septally) released VP could be shown to be causally involved in short-term memory and anxiety-related behavior. Furthermore, VP release within the hypothalamic paraventricular nucleus is likely to provide a negative tonus on the activity of the hypothalamic-pituitary-adrenocortical axis. This neuroendocrine effect together with cognitive, emotional and immunological effects of centrally released VP is thought to be essential to ensure adequate behavior of the animal during challenging situations and to contribute to the development of efficient coping strategies.

Animals↗
PubMed1998

Endogenous oxytocin is involved in short-term olfactory memory in female rats.

To investigate the involvement of oxytocin in their short-term lasting olfactory memory performance, adult female Wistar rats (n = 12) were tested for their juvenile discrimination abilities. As measured by their exploratory behavior towards juveniles, the adult rats were able to discriminate between a previously exposed juvenile and a novel one as long as the interval between the two exposures was less than 180 min. This ability was maintained across all days of the estrous cycle and was unaffected by intracerebroventricular administration of synthetic oxytocin (1 ng/5 microl Ringer's solution) or Ringer's solution immediately after the first exposure. However, treatment with the oxytocin receptor antagonist des-Gly-NH2 d(CH2)5[Tyr(Me)2Thr4]OVT interfered with the ability to establish this kind of olfactory memory although the vasopressin V1 receptor antagonist d(CH2)5Tyr(Me)AVP (100 ng/5 microl each) via the same route did not. This suggests that within a narrow range of concentrations endogenous oxytocin, but not vasopressin, is critically involved in short-term olfactory memory for juvenile conspecifics in female rats. These data are discussed in the light of sexual dimorphic brain development.

Animals↗