Biomedical subjects

Hymie Anisman

Publications and source records attributed to Hymie Anisman.

At least 37 records · Page 2Linked to original sources

PubMed2004

Working and reference memory in seizure-prone and seizure-resistant rats: impact of amygdala kindling.

In rat selectively bred for different amygdala kindling rates (Fast vs. Slow), comorbid differences in learning were detected. Here, performance was tested in a delayed alternation task before, during, and after kindling. Although similar reference memory was evident, Fast rats showed working memory deficits with increasing delays between information and choice trials. Further, seizures shortly before learning disrupted both reference and working memory in Fast, but not Slow, rats. Weeks after kindling, progressive delays further disrupted Fast rats, but only longer delays disrupted Slow rats. Clearly relevant to individual differences in human epilepsy, a temporal lobe, seizure-prone genetic background in rats provides poorer original learning and easier disruption of new learning by recent and past seizures than a seizure-resistant background.

Amygdala↗

PubMed2004

Maternal behavior regulates benzodiazepine/GABAA receptor subunit expression in brain regions associated with fear in BALB/c and C57BL/6 mice.

Inbred strains of mice, such as BALB/cByJ and C57BL/6ByJ, have been used repeatedly to study genotype-phenotype relations. These strains differ on behavioral measures of fear. In novel environments, for example, BALB/c mice are substantially more neophobic than C57BL/6 animals. The benzodiazepine (BZ)/GABAA receptor system has been proposed as a regulator of behavioral responses to stress, and BALB/c and C57BL/6 mice differ in BZ/GABAA receptor binding. In the present study, we found increased BZ receptor levels in C57BL/6 mice in the central and basolateral nuclei of the amygdala as well as the locus coeruleus using either flunitrazepam (nonselective) or zolpidem (alpha1 subtype selective) as radioligands. Differences in receptor binding were most pronounced in the amygdala and locus coeruleus using [3H]zolpidem. C57BL/6 mice showed increased alpha1 mRNA levels in the locus coeuruleus compared to BALB/c mice. In addition, gamma2 mRNA expression in BALB/c mice was decreased in the central nucleus of the amygdala to levels that were 2-2.5-fold lower than those of C57BL/6 mice. The results of an adoption study revealed that the biological offspring of C57BL/6 mothers fostered after birth to BALB/c dams showed decreased levels of gamma2 mRNA expression in the central nucleus of the amygdala in comparison to peers fostered to other C57BL/6 mothers (the reverse was found for the biological offspring of BALB/c mothers). In a step-down exploration paradigm, BALB/cByJ mice crossfostered onto a C57BL/6ByJ dam expressed reduced anxiety responses. However, among C57BL/6ByJ mice, the relatively low levels of anxiety ordinarily evident were not increased when mice of this strain were reared by a BALB/cByJ dam. These preliminary findings suggest that the strain differences in the BZ/GABAA receptor system occur, at least in part, as a function of parental care. Such findings may reflect a mammalian example of an indirect genetic effect mediated by maternal care.

Adoption↗

PubMed2004

Anticipatory cues differentially provoke in vivo peptidergic and monoaminergic release at the medial prefrontal cortex.

Like primary reinforcers, the anticipation of reward ought to affect neurochemical release in brain regions, such as the medial prefrontal cortex (mPFC), which are associated with appraisal processes. To assess the neurochemical changes associated with anticipation, rats were exposed to the pairing of auditory (60-dB white noise), visual, and olfactory cues with the daily presentation of a palatable snack (Cue Relevant group). Rats of a second group were similarly trained, but for a 2-week period, the snack was no longer provided following cue presentation (Extinction group). In the third condition, the presentation of the snack and cues was uncorrelated (Cue Irrelevant group). Analyses of dialysates collected in vivo from the mPFC revealed that release of corticotropin-releasing hormone (CRH), gastrin-releasing peptide (GRP), and the 5-HT catabolite, 5-hydroxyindole acetic acid (5-HIAA), had increased bilaterally in response to the anticipatory cues, whereas DA release increased only within the right mPFC. In the case of CRH and GRP, these increases were also apparent in the extinction condition, despite the fact that behavioral arousal to the anticipatory cues (increased exploration, rearing, grooming, and vigilance) was only evident in the Cue Relevant condition. In contrast, the elevated DA and 5-HIAA were apparent exclusively in the Cue Relevant condition. Thus, CRH and GRP systems may serve to allocate salience and/or incentive reward value to biologically significant stimuli or reflect the emotional response to the anticipatory stimulus. The activity of DA and 5-HT neurons, in contrast, is more closely aligned with the cognitive appraisal of predictor stimuli.

Animals↗

PubMed2004

Amygdala amino acid and monoamine levels in genetically Fast and Slow kindling rat strains during massed amygdala kindling: a microdialysis study.

We investigated the neurochemistry of epileptic seizures in rats selectively bred to be seizure-prone (Fast) vs. seizure-resistant (Slow) to amygdala kindling. Microdialysis was used to measure levels of amino acids [glutamate, aspartate and gamma-aminobutyric acid (GABA)] and monoamines (noradrenaline, dopamine and serotonin) during 'massed' stimulation (MS) (every 6 min) of the ipsilateral amygdala for a total of 40 stimulation trials. Behavioral seizure profiles together with their afterdischarge thresholds (ADTs) and associated durations were assessed during the procedure, and subsequently were redetermined 1, 7 and 14 days later. Then normal 'daily' kindling commenced and continued until the animal reached the fully kindled state. During MS, several generalized seizures were triggered in Fast rats that were associated with long afterdischarge (AD) durations and intermittent periods of elevated thresholds, but in Slow rats, most stimulations were associated with stable ADTs and short ADs. Progressively increasing extracellular glutamate and decreasing GABA was observed in Fast rats during the MS, whereas Slow rats showed levels similar to baseline values. Levels of noradrenaline and dopamine, but not of serotonin, were also increased in both strains throughout the MS treatment. In Fast rats, a dramatic lengthening of AD durations occurred 7 and 14 days following MS, as well as subsequent strong positive transfer to daily kindling, all of which were not seen in Slow rats. Together, these results show that repeated, closely spaced stimulations of the amygdala can differentially alter excitatory and/or inhibitory transmitter levels in a seizure network, and that sensitivity to this manipulation is genetically determined.

Amino Acids↗

PubMed2004

Corticosterone changes in response to stressors, acute and protracted actions of tumor necrosis factor-alpha, and lipopolysaccharide treatments in mice lacking the tumor necrosis factor-alpha p55 receptor gene.

UNLABELLED: Systemic administration of the proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has acute as well as sensitizing effects on behavioral and neurochemical functioning. OBJECTIVES: As many of the central consequences of TNF-alpha are mediated by its p55 receptor, the present investigation determined the role of this receptor on the plasma corticosterone increase associated with the acute TNF-alpha treatment and the sensitized response evident upon reexposure to the cytokine. Moreover, the role of p55 in the provocation of corticosterone release engendered by lipopolysaccharide (LPS) and psychogenic stressors (noise or restraint) was also determined. METHODS: Plasma corticosterone levels were determined in wild-type and p55-deficient mice that received systemic treatments with TNF-alpha and LPS, as well as exposure to auditory and restraint stressors. RESULTS: Mice deficient for p55 displayed a greatly attenuated plasma corticosterone response to TNF-alpha irrespective of whether they had been previously exposed to the cytokine. In contrast, p55 deletion did not affect corticosterone responses elicited by LPS and by stressors. CONCLUSIONS: It appears that although p55 modulates the corticosterone-inducing effects of TNF-alpha, the receptor does not play a critical role in the activation of the HPA axis by 'traditional' psychogenic stressors (noise, restraint) or systemic endotoxin challenge.

Acute Disease↗

PubMed2004

Influence of chronic interleukin-2 infusion and stressors on sickness behaviors and neurochemical change in mice.

OBJECTIVES: Major depression is associated with increased circulating interleukin-2 (IL-2) levels, and IL-2 immunotherapy may provoke depressive symptoms, leading to the suggestion that this cytokine may contribute to the evolution of affective disorders. Although depression is a relatively chronic condition, and immunotherapy involves repeated cytokine administration, animal studies have typically assessed the consequences of acute cytokine treatment. The present investigation assessed several behavioral and neurochemical effects of chronic IL-2 infusion. METHODS: Behaviors reflecting anhedonia and/or anorexia, sickness behavior, plasma corticosterone and norepinephrine (NE) activity in the paraventricular nucleus (PVN) of the hypothalamus were assessed following continuous infusion of IL-2 over 7 days in CD-1 mice. RESULTS: The cytokine treatment reduced the consumption of a highly favored palatable substance (chocolate milk) and reduced locomotor activity monitored over the course of the 7-day period. Although sickness behaviors were also increased significantly by the treatment, the degree of sickness behavior was actually modest. While a chronic, variable stressor also affected consumption of the palatable food, this treatment did not enhance the effects of IL-2. Furthermore, in contrast to acute and chronic stressors that increased plasma corticosterone levels and the utilization of NE within the PVN of the hypothalamus, IL-2 did not promote such effects and did not modify the impact of the stressors. CONCLUSION: While IL-2 may induce anorexia or anhedonia, the effects of this treatment are distinguishable from those elicited by stressors and those typically elicited by proinflammatory cytokines. The data are related to findings suggesting a link between IL-2 and depressive illness.

Acute Disease↗

PubMed2003

Cyclin-dependent kinase 5 is a mediator of dopaminergic neuron loss in a mouse model of Parkinson's disease.

Recent evidence indicates that cyclin-dependent kinases (CDKs, cdks) may be inappropriately activated in several neurodegenerative conditions. Here, we report that cdk5 expression and activity are elevated after administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a toxin that damages the nigrostriatal dopaminergic pathway. Supporting the pathogenic significance of the cdk5 alterations are the findings that the general cdk inhibitor, flavopiridol, or expression of dominant-negative cdk5, and to a lesser extent dominant-negative cdk2, attenuates the loss of dopaminergic neurons caused by MPTP. In addition, CDK inhibition strategies attenuate MPTP-induced hypolocomotion and markers of striatal function independent of striatal dopamine. We propose that cdk5 is a key regulator in the degeneration of dopaminergic neurons in Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2003

Impact of life-long macronutrient choice on neuroendocrine and cognitive functioning in aged mice: differential effects in stressor-reactive and stressor-resilient mouse strains.

Nutrient selection emerges as a result of both genetic and environmental factors and may be further modified by stressors. The impact of this complex interrelationship on pathological outcomes is poorly understood. In the present investigation the stressor-reactive BALB/cByJ and the relatively stressor resilient C57BL/6ByJ mice were maintained on a macronutrient selection protocol or given free access to chow for 20 months. The C57BL/6ByJ mice exhibited a marked preference for fat over carbohydrates, whereas BALB/cByJ mice preferred carbohydrates over fat. Cognitive testing in a Morris water maze indicated that while BALB/cByJ mice were clearly more impaired in this task relative to their C57BL/6ByJ counterparts, there was no substantial effect of the diet at either 13 or 19 months of age. Furthermore, despite their stressor resiliency, at 19 months of age, C57BL/6ByJ mice who invariably consumed fat, exhibited greater plasma corticosterone responses to a 20-min period of restraint than chow fed animals. Indeed, the corticosterone rise was as pronounced as in the more reactive BALB/cByJ strain. Furthermore, the C57BL/6ByJ diet-fed mice showed features of insulin insensitivity and increased adiposity. These data suggest that the adverse effects of fat consumption need to be considered in the context of genetically determined vulnerability/resilience factors.

Aging↗

PubMed2003

Validation of a simple, ethologically relevant paradigm for assessing anxiety in mice.

Although numerous behavioral tests are available to assess anxiety, we introduce a simplified version of a previously established test that is exquisitely sensitive and reliable. The latency to consume a palatable snack (graham wafer crumbs) was assessed among mice in their home cage and in an unfamiliar environment, as well as in the presence or absence of predator scent. The effects of various anxiolytics and nonanxiolytics were evaluated in these paradigms. When offered the palatable snack in a familiar environment, mice readily approached and began consumption; however, in a novel environment (cage with fresh bedding), or in the presence of predator scent (rat feces), response latencies increased 10-fold. Anxiolytics, including diazepam, chlordiazepoxide, propranolol, or chronic treatment with either buspirone or the antidepressant desmethylimipramine attenuated the effects in the novel environment without affecting home-cage responding. In contrast, nonanxiolytic agents (haloperidol, amphetamine, acute buspirone or desmethylimipramine) failed to exclusively affect novel environment-induced prolongation of response latencies. The simplicity of design, the absence of food deprivation or neurogenic stressors, the possibility of using it in a repeated measures design, the reliability and magnitude of response, and the specificity and sensitivity to anxiolytic drugs makes this an ideal preparation with which to assess anxiety and anxiety-altering manipulations.

Animals↗

PubMed2003

Inhibition of calpains prevents neuronal and behavioral deficits in an MPTP mouse model of Parkinson's disease.

The molecular mechanisms mediating degeneration of midbrain dopamine neurons in Parkinson's disease (PD) are poorly understood. Here, we provide evidence to support a role for the involvement of the calcium-dependent proteases, calpains, in the loss of dopamine neurons in a mouse model of PD. We show that administration of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) evokes an increase in calpain-mediated proteolysis in nigral dopamine neurons in vivo. Inhibition of calpain proteolysis using either a calpain inhibitor (MDL-28170) or adenovirus-mediated overexpression of the endogenous calpain inhibitor protein, calpastatin, significantly attenuated MPTP-induced loss of nigral dopamine neurons. Commensurate with this neuroprotection, MPTP-induced locomotor deficits were abolished, and markers of striatal postsynaptic activity were normalized in calpain inhibitor-treated mice. However, behavioral improvements in MPTP-treated, calpain inhibited mice did not correlate with restored levels of striatal dopamine. These results suggest that protection against nigral neuron degeneration in PD may be sufficient to facilitate normalized locomotor activity without necessitating striatal reinnervation. Immunohistochemical analyses of postmortem midbrain tissues from human PD cases also displayed evidence of increased calpain-related proteolytic activity that was not evident in age-matched control subjects. Taken together, our findings provide a potentially novel correlation between calpain proteolytic activity in an MPTP model of PD and the etiology of neuronal loss in PD in humans.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2003

Differential impact of audiogenic stressors on Lewis and Fischer rats: behavioral, neurochemical, and endocrine variations.

Exposure to intense noise can trigger a cascade of neuroendocrine events reminiscent of a stress response, including activation of the hypothalamic-pituitary-adrenocortical (HPA) axis. Using male Fischer and Lewis rats, which exhibit differences in their corticosterone response to stressors, this investigation assessed effects of acute noise exposure on neurochemical and neuroendocrine responses. In response to the noise exposure, Fischer rats displayed greater plasma adrenocorticotropin-releasing hormone (ACTH) and corticosterone responses than their Lewis counterparts. However, both strains responded with similar increases of plasma prolactin, suggesting that strain differences in the HPA response were not likely because of differences in noise perception. Post-mortem analyses revealed that noise exposure induced strain-dependent variations of corticotropin-releasing hormone (CRH) across several brain regions. These effects were evident irrespective of whether the rats were noise exposed in a familiar (home cage) or unfamiliar environment. In vivo, dynamic assessment of immunoreactive (ir)-CRH at the pituitary gland revealed that noise exposure elicited an immediate rise in ir-CRH among Fischer rats, relative to the delayed response in Lewis rats. Similarly, the rise in local interstitial corticosterone was more rapid and pronounced in Fischer rats. In contrast to these differences, ir-CRH released at the central nucleus of the amygdala (CeA) was gradual and protracted following noise exposure in both strains. Behaviorally, the Fischer rats displayed an active stress response, whereas the Lewis strain adopted freezing as a defensive style. The role of CRH in the genesis of the overall strain-dependent response to stressors is discussed.

Acoustic Stimulation↗

PubMed2003

Impact of chronic intermittent challenges in stressor-susceptible and resilient strains of mice.

BACKGROUND: Stressors promote altered neurochemical functioning that may be of adaptive value. The sustained elevations of neurochemical activity elicited by chronic stressors may exact excessive demands on biological systems (allostatic load), thereby rendering the organism more vulnerable to pathology, but such effects may be dependent on individual characteristics. METHODS: Stressor reactive BALB/cByJ mice and the relatively resilient C57BL/6ByJ mice were exposed to a variety of psychogenic and neurogenic stressors, twice a day over 60 days. The resultant neurochemical and behavioral changes in these strains was assessed relative to the effects of acute stressors. RESULTS: Acute restraint elicited more pronounced and more widespread variations of norepinephrine and serotonin utilization in BALB/cByJ than in C57BL/6ByJ mice. Following the chronic stressor, BALB/cByJ mice showed marked behavioral alterations thought to be indicative of depression- and anxiety-like states. The chronic stressor was also associated with moderation of amine utilization in the C57BL/6ByJ mice, whereas such an outcome was less prominent or entirely absent in BALB/cByJ mice. CONCLUSIONS: The sustained increase of amine activity in the BALB/cByJ, coupled with the marked depressionogenic-anxiogenic characteristics of this strain, may provide a useful preparation to assess the impact of chronic stressors on the development of behavioral and physical pathology.

Animals↗

PubMed2003

Neurochemical sensitization associated with systemic administration of tumor necrosis factor-alpha: adjuvant action in combination with bovine serum albumin.

Tumor necrosis factor-alpha (TNF-alpha) provokes a time-dependent sensitization of brain monoamine activity, plasma corticosterone activity and sickness behavior, the latter being reminiscent of septic or anaphylactic shock. In this investigation, bovine serum albumin (BSA) elicited similar corticosterone and sickness profiles, whereas the monoamine changes were not observed. The sensitization elicited by mTNF-alpha plus BSA was markedly greater than that elicited by BSA alone. Carrier-free TNF-alpha promoted the sensitization of brain monoamine activity, but not sickness or corticosterone. It is suggested that mTNF-alpha acts as an adjuvant to the anaphylactic actions elicited by BSA, but may provoke a sensitization of monoamine activity which is time-dependent and varies across brain regions.

Adjuvants, Immunologic↗

PubMed2003

Differential involvement of amygdaloid CRH system(s) in the salience and valence of the stimuli.

Anxiety is a heterogeneous term encompassing not only state or trait characteristics but also a wide range of pathologies such as generalized anxiety disorders, phobias, panic and obsessive-compulsive disorders, acute stress disorder, and posttraumatic stress disorder. Given that diverse forms of anxiety exist, numerous animal models have been developed, which are considered to be useful in identifying mechanisms underlying anxiety states. Examples of such animal models include paradigms that assess the behavioral response to neurogenic (or painful stimuli) or psychogenic stressors or to cues that had previously been associated with painful stimuli. The present report presents data regarding the impact of stressors on corticotropin-releasing hormone (CRH), and relates these to changes in anxiety-like states. Specifically, we demonstrate that (1) psychogenic stressors influence the in vivo release of CRH at the central nucleus of the amygdala (CeA); (2) although CRH changes within the CeA are exquisitely sensitive to stressors, they are also elicited by positive stimuli; and (3) while treatment with diazepam attenuates behavioral signs of anxiety, the CRH release associated with a stressor is unaffected by the treatment. The position is offered that although release of CRH within the CeA is increased under stressful conditions, it is not a necessary condition for the consequent behavioral expression of anxiety-like reactions, at least not in minimally threatening situations. We suggest that the CRH responses at the CeA may be involved in a preparatory capacity and, as such, may accompany a range of emotionally significant stimuli, be they appetitive or aversive.

Amygdala↗

PubMed2003

Sensitization associated with stressors and cytokine treatments.

Like stressors, interleukin-1beta and tumor necrosis factor-alpha (TNF-alpha) increase hypothalamic-pituitary-adrenal (HPA) activity and monoamine turnover at hypothalamic and extrahypothalamic sites. These effects can be re-elicited more readily upon reintroduction of these challenges (sensitization), depending on their time of re-exposure and the particular system being assessed. Following TNF-alpha administration, the co-expression of corticotropin releasing hormone (CRH) and arginine vasopressin increased within the median eminence, peaking 7-14 days after treatment, and was associated with an early corticosterone sensitization. However, the re-elicitation of sickness symptoms and corticosterone release was most pronounced at lengthy re-exposure intervals (28 days), possibly reflecting histamine release from mast cells. In addition, the cytokine engendered the sensitization of norepinephrine and serotonin utilization, and CRH immunoreactivity at mesocorticolimbic sites, but these effects were most prominent at brief re-exposure intervals (1-7 days). Cytokines may independently prime multiple regulatory systems, and by virtue of the neurochemical changes imparted, have both immediate and proactive influences on the evolution of psychopathology.

Animals↗

PubMed2003

Cytokines, stress and depressive illness: brain-immune interactions.

Cytokines, signaling molecules of the immune system, have been implicated as a contributing factor for mood disorders such as depression. Several lines of evidence supporting this contention are briefly reviewed and caveats are introduced. Essentially, a relationship between cytokines and depression is based on the findings that: 1) proinflammatory cytokines (interleukin-1, interleukin-6, tumor necrosis factor-alpha) and bacterial endotoxins elicit sickness behaviors (e.g., fatigue, soporific effects) and symptoms of anxiety/depression that may be attenuated by chronic antidepressant treatment, 2) cytokines induce neuroendocrine and central neurotransmitter changes reminiscent of those implicated in depression, and these effects are exacerbated by stressors, 3) severe depressive illness is accompanied by signs of immune activation and by elevations of cytokine production or levels, and 4) immunotherapy, using interleukin-2 or interferon-alpha, promotes depressive symptoms that are attenuated by antidepressant treatment. It is argued that cytokine synthesis and release, elicited upon activation of the inflammatory response system, provoke neuroendocrine and brain neurotransmitter changes that are interpreted by the brain as being stressors, and contribute to the development of depression. Furthermore, such effects are subject to a sensitization effect so that a history of stressful experiences or cytokine activation augment the response to later challenges and hence the evolution of depression

Antidepressive Agents↗

PubMed2003

Stress and cytokine-elicited neuroendocrine and neurotransmitter sensitization: implications for depressive illness.

Stressful events, by their effects on neurotransmitter and neuroendocrine processes, are thought to favor the development or exacerbation of depressive illness. In as much as immunological challenge, may provoke stressor-like neuroendocrine and central neurochemical changes, the view was offered that immune activation essentially acts like a stressor and may contribute to the evolution of affective illness. In this respect, viral and bacterial infections appear to influence behavioral/metabolic (e.g. fever, anorexia, somnolence) and neurotransmitter functioning through the release of cytokines, which act as messengers between the immune system and brain. The present report provides a brief overview of the neurochemical consequences of proinflammatory cytokine treatments, particularly the actions of interleukin (IL)-1beta and tumor necrosis factor-alpha. As well, synergy with psychogenic and neurogenic stressors are described, as are data showing that cytokines, like stressors, may have time-dependent proactive (sensitization) effects, so that reexposure to the treatments greatly augments hypothalamic-pituitary-adrenal activity, as well as central neurochemical changes. Indeed, the neurotransmitter alterations are not restricted to hypothalamic nuclei, but occur in several extrahypothalamic sites, including various limbic regions. It is suggested that by virtue of these neurochemical changes, cytokines may have both immediate and proactive effects on mood states.

Animals↗

PubMed2003

Systems of coping associated with dysphoria, anxiety and depressive illness: a multivariate profile perspective.

As numerous coping strategies to deal with stressors can be used concurrently or sequentially, it may be productive to consider coping from a broad, systemic perspective. Using profile analysis and multivariate techniques, we demonstrated that coping profiles comprising multiple strategies distinguished between various mood states (dysphoria, anxiety, major depression, dysthymia and obsessive-compulsive disorder (OCD)). Generally, affective disturbances were associated with increased levels of rumination, cognitive distraction and emotion-focused coping (emotional expression, other-blame, self-blame, emotional containment and passive resignation) coupled with diminished problem solving and social support seeking. These coping profiles, however, varied as a function of anxiety vs. dysphoria, and severity of dysphoric symptoms, although the profile of dysphoric individuals was similar to that of clinically diagnosed dysthymic and major depressive patients. While coping profiles were generally stable over time (6 months), improvement or deterioration of mood was accompanied by corresponding alterations of coping profiles. Importantly, coping profile was not simply a correlate of dysphoric mood, but was also found to be an antecedent condition that favored the evolution of more severe affective problems. It is suggested that a multidimensional approach may prove useful in understanding coping as a dynamic system, and may have implications for clinical intervention.

Adaptation, Psychological↗