Yehuda Pollak | The Hebrew University of Jerusalem (original) (raw)

Papers by Yehuda Pollak

Research paper thumbnail of Do Adolescents With Attention-Deficit/Hyperactivity Disorder Show Risk Seeking? Disentangling Probabilistic Decision Making by Equalizing the Favorability of Alternatives

Journal of abnormal psychology, Jan 14, 2016

The clinical literature provides evidence for increased risk taking by individuals with attention... more The clinical literature provides evidence for increased risk taking by individuals with attention-deficit/hyperactivity disorder (ADHD). Most of the experimental tasks used to measure risk taking, confounded risky and disadvantageous alternatives, and therefore did not disentangle increased risk seeking from suboptimal decision making. The aim of the study was to examine whether adolescents with ADHD show risk seeking by equalizing the expected value of both certain and risky alternatives. In 3 different samples, adolescents with and without ADHD performed gambling tasks, in which they had to choose between certain and risky alternatives. Notably, the expected values of both alternatives were equal. Various personal and contextual intervening factors were controlled for. The rate of risky choices was compared across groups. In addition, participants reported on risk taking in real-life. We found that adolescents with ADHD did not choose the risky alternative more often than controls...

Research paper thumbnail of Feedback May Harm: Role of Feedback in Probabilistic Decision Making of Adolescents with ADHD

Journal of abnormal child psychology, Jan 12, 2015

Inept probabilistic decision making is commonly associated with ADHD. In experimental designs aim... more Inept probabilistic decision making is commonly associated with ADHD. In experimental designs aimed to model probabilistic decision making in ADHD, feedback following each choice was, in the majority of studies, part of the paradigm. This study examined whether feedback processing plays a role in the maladaptive choice behavior of subjects with ADHD by comparing feedback and no-feedback conditions. Sixty adolescents (49 males), ages 13-18, with and without ADHD, performed a descriptive probabilistic choice task in which outcomes and probabilities were explicitly provided. Subjects performed the task either with or without feedback. Under the no-feedback condition, adolescents with ADHD and controls performed similarly, whereas under the feedback condition, subjects with ADHD chose the unfavorable outcomes more frequently and risked smaller sums than controls. These finding demonstrate the crucial role of feedback in the decision making of adolescents with ADHD.

Research paper thumbnail of Administration of interleukin-1 into the hypothalamic paraventricular nucleus induces febrile and behavioral effects

Research paper thumbnail of The EAE-associated behavioral syndrome

Journal of Neuroimmunology

EAE is associated with sickness behavior symptoms that are temporally correlated with inflammator... more EAE is associated with sickness behavior symptoms that are temporally correlated with inflammatory processes. To further elucidate the role of inflammatory mediators in the behavioral syndrome, EAE mice were injected daily with anti-inflammatory drugs, beginning at disease onset. Dexamethasone or interleukin-1 (IL-1) receptor antagonist or the prostaglandins synthesis inhibitor indomethacin attenuated the behavioral symptoms. Administration of the tumor necrosis-factor α (TNF-α) synthesis inhibitor pentoxifylline or targeted deletion of the type I TNF receptor had no behavioral effects whereas administration of pentoxifylline in IL-1ra-treated mice further reversed the behavioral depression. These findings demonstrate the critical involvement of pro-inflammatory cytokines and prostaglandins in the EAE-associated behavioral syndrome, and may have implications for understanding and treating the neuropsychiatric disturbances in multiple sclerosis (MS) patients.

Research paper thumbnail of Multilevel Approaches to AChE-Induced Impairments in Learning and Memory

Structure and Function of Cholinesterases and Related Proteins, 1998

BACKGROUND Alzheimer's disease (AD) is a late-onset neurodegenerative disease charac... more BACKGROUND Alzheimer's disease (AD) is a late-onset neurodegenerative disease characterized by progressive deterioration of cholinergic functions including learning, short-term memory, problem solving and abstract thinking. The only FDA-approved drugs for AD ...

Research paper thumbnail of Cytokine-induced changes in mood and behaviour: implications for 'depression due to a general medical condition', immunotherapy and antidepressive treatment

The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2002

Several lines of evidence indicate that cytokine-mediated communication pathways between the immu... more Several lines of evidence indicate that cytokine-mediated communication pathways between the immune system and the brain are involved in the pathophysiology of depression: (1) . Depression is highly prevalent in various medical conditions, including infectious, autoimmune and neurodegenerative diseases. This clinical association cannot be attributed solely to psychological distress, and it probably reflects direct activation of illness-induced physiological processes. (2). Experiments in humans and in animals demonstrate that exposure to cytokines induces depressive-like mood and behavioural alterations. (3). Cytokine immunotherapy in cancer and hepatitis patients elicits a major depressive episode in a large percentage of the patients. (4). Several types of depression that are not directly associated with a physical disease (e.g. major depression, melancholia, dysthymia) were also associated with cytokine hypersecretion. (5). Antidepressant drugs possess anti-inflammatory character...

Research paper thumbnail of Cytokines, “Depression Due to A General Medical Condition,” and Antidepressant Drugs

Advances in Experimental Medicine and Biology, 1999

Research paper thumbnail of Neurochemical mechanisms mediating interleukin-1-induced suppression of sexual behavior in females

Neuroscience Letters, 1997

of the corresponding recombinant fusion proteins demonstrates N-Loop 710-1090 competition with sy... more of the corresponding recombinant fusion proteins demonstrates N-Loop 710-1090 competition with syntaxin and SNAP-25 for p65 binding. The results of the combined approaches provide a functional and biochemical basis for proposing that p65 together with syntaxin and SNAP-25 associated channel form an active complex. As a consequence, the affinity of syntaxin for p65 relieves channel inhibition, allowing the primed vesicles, now closely associated with the channel to fuse with the cell membrane. Wiser, O., Bennett, M. K. and Atlas, D. (1996). Functional interaction of syntaxin and SNAP-25 with voltage sensitive L-and N-type Ca 2+ channels. EMBO J. 15, 4100-4110. Wiser, O., Tobi, D., Trus, M. and D. Atlas (1997) Synaptotagmin restores kinetic properties of a syntaxin-associated N-type voltage sensitive calcium channel FEBS Lett. 404, 203-297.

Research paper thumbnail of Administration of lnterleukin-1 into the Hypothalamic Paraventricular Nucleus Induces Febrile and Behavioral Effects

Neuroimmunomodulation, 1997

Administration of intekleukin-1 (IL-1) into the cerebral ventricles produces marked physiological... more Administration of intekleukin-1 (IL-1) into the cerebral ventricles produces marked physiological and behavioral effects. However, the precise locations within the central nervous system that mediate these effects have not been determined. Previous studies indicated that IL-1 induces neurophysiological, neurochemical and neuroendocrine changes within the hypothalamic paraventricular nucleus (PVN). These findings suggest that the PVN is also involved in mediating the behavioral effects of IL-1. This hypothesis was tested by examining the effects of administration of IL-1β (10 or 50 ng/rat) or saline, either intracerebroventricularly or into the PVN, on fever and several behavioral parameters. IL-1β, administered into both locations, induced a comparable suppression of motor activity, reduction in food and saccharine consumption, and loss of body weight. The febrile response to IL-1β, assessed by a biotelemetric system, was significantly greater following administration into the PVN t...

Research paper thumbnail of The role of brain TNFA and IL-1B in mediating the behavioral and neuroendocrine effects of intracerebral mycoplasma fermentans

Neuroscience Letters, 1997

Compared with other clinically useful carbamates, the anti-Alzheimer drug, (+)S-N-ethyl-3-[(1-dim... more Compared with other clinically useful carbamates, the anti-Alzheimer drug, (+)S-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methylphenylcarbamate Exelon™, Sandoz Co. Ltd.), has a longer duration of action and preferentially inhibits acetylcholinesterase (AChE) of the brain cortex and hippocampus (Enz et al., Ann. N.Y. Acad. Sci., 640: 272-275, 1991). To understand the basic mechanism of ENA-713, we studied its reactions in vitro with AChE from Torpedo californica. The apparent bimolecular rate constant for progressive inhibition was low: K i = 6 M −1 min −1 (0.067 M Na/K phosphate buffer, pH 7.4, 25°C). Thus, carbamylation of AChE was unusually slow, and this raised the possibility that the leaving group of ENA-713, 3-[(1dimethyl-amino)ethyl] phenol, might interfere with the reaction between intact carbamate and AChE. Indeed, the measured binding constants for reversible inhibition by ENA-713 and its leaving group were 200 PM and 14 PM, respectively, at pH 7.4, 25°C; the product apparently bound more tightly to AChE than did the intact carbamate in the reversible complex. Covalent carbamylation of AChE by ENA-713 nevertheless occurred because, upon removal of excess inhibitor by gel filtration, we observed spontaneous decarbamylation with a rate constant of 0.006 min −1 (pH 7.4, 25°C) and an activation energy of 16 kcal/mole. We conclude that ENA-713 inhibits AChE by two mechanisms: (1) covalent carbamylation followed by slow decarbamylation; and (2) the carbamate acts as a vector to deliver its leaving group, which is itself a good reversible anti-AChE, to the enzyme active site. To test this hypothesis, studies are underway to measure the kinetic effects of product on carbamylation and to solve the 3D structure of a complex of AChE and ENA-713 by X-ray crystallography.

Research paper thumbnail of The role of adrenergic receptors in mediating sickness behavior

Neuroscience Letters, 1997

sequence was much reduced. However, recall performance for the second and third stimuli in the se... more sequence was much reduced. However, recall performance for the second and third stimuli in the sequence was not influenced significantly. This finding suggests that the mechanism for recall of the first image in a sequence is quite different from the recall of the second and third images, conditioned on the first.

Research paper thumbnail of Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Neuropsychopharmacology, 2001

Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavi... more Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavioral responses to immune challenges, such as lipopolysaccharide (LPS). To explore further the effects of antidepressants on neuroimmune interactions, rats were treated daily with either fluoxetine (Prozac) or saline for 5 weeks, and various behavioral, neuroendocrine, and immune functions were measured following administration of either LPS or saline. Chronic fluoxetine treatment significantly attenuated the anorexia and body weight loss, as well as the depletion of CRH-41 from the median eminence and the elevation in serum corticosterone levels induced by LPS. Chronic treatment with imipramine also attenuated LPS-induced adrenocortical activation. In rats and in mice, which normally display a biphasic body temperature response to LPS (initial hypothermia followed by hyperthermia), chronic treatment with fluoxetine completely abolished the hypothermic response and facilitated and strengthened the hyperthermic response. The effects of antidepressants on the responsiveness to LPS are probably not mediated by their effects on peripheral proinflammatory cytokine production, because LPS-induced expression of TNF ␣ and IL-1 ␤ mRNA in the spleen (assessed by semiquantitative in situ hybridization) was not altered following chronic treatment with either fluoxetine or imipramine. The effects of antidepressants on the acute phase response may have important clinical implications for the psychiatric and neuroendocrine disturbances that are commonly associated with various medical conditions.

Research paper thumbnail of Neuronal overexpression of ‘readthrough’ acetylcholinesterase is associated with antisense-suppressible behavioral impairments

Molecular Psychiatry, 2002

Molecular origin(s) of the diverse behavioral responses to anticholinesterases were explored in b... more Molecular origin(s) of the diverse behavioral responses to anticholinesterases were explored in behaviorally impaired transgenic (Tg) FVB/N mice expressing synaptic human acetylcholinesterase (hAChE-S). Untreated hAChE-S Tg, unlike naïve FVB/N mice, presented variably intense neuronal overexpression of the alternatively spliced, stress-induced mouse 'readthrough' mAChE-R mRNA. Both strains displayed similar diurnal patterns of locomotor activity that were impaired 3 days after a day-to-night switch. However, hAChE-S Tg, but not FVB/N mice responded to the circadian switch with irregular, diverse bursts of increased locomotor activity. In social recognition tests, controls displayed short-term recognition, reflected by decreased exploration of a familiar, compared to a novel juvenile conspecific as well as inverse correlation between social recognition and cortical and hippocampal AChE specific activities. In contrast, transgenics presented poor recognition, retrievable by tetrahydroaminoacridine (tacrine, 1.5 mg kg −1 ).

Research paper thumbnail of The EAE-associated behavioral syndrome I. Temporal correlation with inflammatory mediators

Journal of Neuroimmunology, 2003

To elucidate the mechanisms underlying the EAE-associated behavioral syndrome (EBS), we examined ... more To elucidate the mechanisms underlying the EAE-associated behavioral syndrome (EBS), we examined the temporal correlation between the behavioral alterations and inflammatory processes. Onset of the behavioral syndrome was associated with the onset of brain infiltration, as well as mRNA expression of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) and elevated production of interleukin 1 beta protein and prostaglandin E(2) (PGE(2)). Sickness behavior symptoms coincided with peak cytokine expression. Behavioral recovery was associated with a reduction of cytokine expression, but not infiltration, PGE(2) production or motor disturbances. These results suggest that inflammatory processes in general, and the production of pro-inflammatory cytokines in particular, are involved in mediating EAE-associated sickness behavior.

Research paper thumbnail of Behavioral aspects of experimental autoimmune encephalomyelitis

Journal of Neuroimmunology, 2000

Research paper thumbnail of Different receptor mechanisms mediate the effects of endotoxin and interleukin-1 on female sexual behavior

Brain Research, 1997

. Activation of the immune system by lipopolysaccharide LPS produces physiological, neuroendocrin... more . Activation of the immune system by lipopolysaccharide LPS produces physiological, neuroendocrine and behavioral effects, some of Ž . which are mediated by cytokine production. We have previously shown that the cytokine interleukin-1 IL-1 inhibits sexual behavior in female, but not male rats, while producing a comparable suppression of locomotion in both sexes. The present study examined the effects of LPS on sexual behavior and locomotion of male and female rats, and the involvement of IL-1 receptors in mediating the effects of IL-1 Ž . Ž . and LPS on females' behavior. Peripheral i.p. administration of LPS 50 or 250 mgrkg significantly decreased sexual behavior in females, up to 6 h after administration, while it had no effect on male sexual behavior. However, locomotor activity, measured in the Ž . open-field test, was similarly reduced by LPS in both males and females. Pretreatment with the IL-1 receptor antagonist IL-1ra either Ž . Ž .Ž . i.p. 10 mgrkg or intracerebroventricularly i.c.v. 50 mgrrat did not prevent the inhibition of female sexual behavior and locomotion Ž . Ž . induced by either i.p. 50 mgrkg or i.c.v. 200 or 400 ngrrat administration of LPS, respectively. However, identical doses of IL-1ra Ž . Ž . significantly reversed the effects of IL-1b, administered either i.p. 5 mgrkg or i.c.v. 50 ngrrat , respectively. These results demonstrate that both LPS and IL-1b produce marked inhibition of sexual behavior in female, but not in male rats. However, IL-1 receptors are not required for the effects of LPS on sexual behavior in female rats. q 1997 Elsevier Science B.V.

Research paper thumbnail of The role of brain cytokines in mediating the behavioral and neuroendocrine effects of intracerebral Mycoplasma fermentans

Brain Research, 1999

Intracerebral administration of Mycoplasma fermentans MF , a small microorganism that has been fo... more Intracerebral administration of Mycoplasma fermentans MF , a small microorganism that has been found in the brain of some AIDS Ž . patients, induces behavioral and neuroendocrine alterations in rats. To examine the role of tumor necrosis factor-a TNFa and Ž . interleukin-1 IL-1 in mediating these effects we measured MF-induced expression of TNFa and IL-1b mRNA in various brain regions, Ž . and the effects of TNFa synthesis blockers and IL-1 receptor antagonist IL-1ra on MF-induced sickness behavior and adrenocortical Ž . activation. Intracerebroventricular i.c.v. administration of heat-inactivated MF induced the expression of both TNFa and IL-1b mRNA in the cortex, dorsal hippocampus, amygdala, and hypothalamus. Pre-treatment of rats with either TNFa synthesis blockers, pentoxifylline or rolipram, or with IL-1ra did not attenuate MF-induced anorexia, body weight loss, and suppression of social behavior. However, simultaneous administration of both pentoxifylline and IL-1ra markedly attenuated MF-induced anorexia and body weight loss, but had no effect on the suppression of social behavior. Pre-treatment with pentoxifylline, but not with IL-1ra, significantly attenuated MF-induced Ž . corticosterone CS secretion. Together, these findings indicate that both TNFa and IL-1 participate, in a complementary manner, in mediating some of the behavioral effects of MF, whereas only TNFa , but not IL-1, is involved in mediating MF-induced adrenocortical activation. We suggest that cytokines within the brain are involved in mediating at least some of the neurobehavioral and neuroendocrine abnormalities that may be produced by MF in AIDS patients. q periphery and in the brain, and affect neurobehavioral functions via specific receptors found in various brain w x structures 60 . Direct administration of TNFa or IL-1b, either peripherally or into the cerebral ventricle, produces marked behavioral and neuroendocrine effects, including a suppression of appetite, motor activity, exploratory, social, and sexual behavior, increased slow wave sleep, general malaise, altered pain sensitivity, and enhanced secretion of Ž . corticotropin-releasing hormone CRH , ACTH and glucow x corticoids 6,17,32,41,67 . Moreover, antibodies against particular cytokines, or cytokine antagonists attenuate or block the behavioral effects of immune challenges w x 4, and the activation of the HPA axis in w x various medical conditions 20,51,54,57 .

Research paper thumbnail of Experimental autoimmune encephalomyelitis: Association with mutual regulation of RelA (p65)/NF-κB and phospho-IκB in the CNS

Biochemical and Biophysical Research Communications, 2011

Recently emerging evidence that the NF-κB family plays an important role in autoimmune disease ha... more Recently emerging evidence that the NF-κB family plays an important role in autoimmune disease has produced very broad and sometimes paradoxical conclusions. In the present study, we elucidated that the activation of RelA (p65) of NF-κB and IκB dissociation assumes a distinct role in experimental autoimmune encephalomyelitis (EAE) progression by altering IκB phosphorylation and/or degradation. In the present study of factors that govern EAE, the presence and immunoreactivity of nuclear RelA and phospho-IκB were recorded at the initiation and peak stage, and degradation of IκBα progressed rapidly at an early stage then stabilized during recovery. The immunoreactivity to RelA and phospho-IκB occurred mainly in inflammatory cells and microglial cells but only slightly in astrocytes. Subsequently, the blockade of IκB dissociation from NF-κB reduced the severity of disease by decreasing antigen-specific T cell response and production of IL-17 in EAE. Thus, blocking the dissociation of IκB from NF-κB can be utilized as a strategy to inhibit the NF-κB signal pathway thereby to reduce the initiation, progression, and severity of EAE.

Research paper thumbnail of Illness, Cytokines, and Depression

Annals of the New York Academy of Sciences, 2006

A BSTRACT : Various medical conditions that involve activation of the immune system are associate... more A BSTRACT : Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPSinduced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF-␣ mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.

Research paper thumbnail of Medical Decisions of Pediatric Residents Turn Riskier after a 24-Hour Call with No Sleep

Medical decision making : an international journal of the Society for Medical Decision Making, Jan 27, 2016

Despite a gradual reduction in the workload during residency, 24-hour calls are still an integral... more Despite a gradual reduction in the workload during residency, 24-hour calls are still an integral part of most training programs. While sleep deprivation increases the risk propensity, the impact on medical risk taking has not been studied. This study aimed to assess the clinical decision making and psychomotor performance of pediatric residents following a limited nap time during a 24-hour call. A neurocognitive battery (IntegNeuro) and a medical decision questionnaire were completed by 44 pediatric residents at 2 time points: after a 24-hour call and following 3 nights with no calls (sleep ≥5 hours). To monitor sleep, residents wore actigraphs and completed sleep logs. Nap time during the shift was <1 hour in 14 cases (32%), 1 to 2 hours in 16 cases (35%), and 2 to 3 hours in 14 cases (32%). Residents who napped less than 1 hour chose the riskier medical option in 50% of cases compared with 36% when answering the same questionnaire after 3 nights with no calls (P = 0.002). This...

Research paper thumbnail of Do Adolescents With Attention-Deficit/Hyperactivity Disorder Show Risk Seeking? Disentangling Probabilistic Decision Making by Equalizing the Favorability of Alternatives

Journal of abnormal psychology, Jan 14, 2016

The clinical literature provides evidence for increased risk taking by individuals with attention... more The clinical literature provides evidence for increased risk taking by individuals with attention-deficit/hyperactivity disorder (ADHD). Most of the experimental tasks used to measure risk taking, confounded risky and disadvantageous alternatives, and therefore did not disentangle increased risk seeking from suboptimal decision making. The aim of the study was to examine whether adolescents with ADHD show risk seeking by equalizing the expected value of both certain and risky alternatives. In 3 different samples, adolescents with and without ADHD performed gambling tasks, in which they had to choose between certain and risky alternatives. Notably, the expected values of both alternatives were equal. Various personal and contextual intervening factors were controlled for. The rate of risky choices was compared across groups. In addition, participants reported on risk taking in real-life. We found that adolescents with ADHD did not choose the risky alternative more often than controls...

Research paper thumbnail of Feedback May Harm: Role of Feedback in Probabilistic Decision Making of Adolescents with ADHD

Journal of abnormal child psychology, Jan 12, 2015

Inept probabilistic decision making is commonly associated with ADHD. In experimental designs aim... more Inept probabilistic decision making is commonly associated with ADHD. In experimental designs aimed to model probabilistic decision making in ADHD, feedback following each choice was, in the majority of studies, part of the paradigm. This study examined whether feedback processing plays a role in the maladaptive choice behavior of subjects with ADHD by comparing feedback and no-feedback conditions. Sixty adolescents (49 males), ages 13-18, with and without ADHD, performed a descriptive probabilistic choice task in which outcomes and probabilities were explicitly provided. Subjects performed the task either with or without feedback. Under the no-feedback condition, adolescents with ADHD and controls performed similarly, whereas under the feedback condition, subjects with ADHD chose the unfavorable outcomes more frequently and risked smaller sums than controls. These finding demonstrate the crucial role of feedback in the decision making of adolescents with ADHD.

Research paper thumbnail of Administration of interleukin-1 into the hypothalamic paraventricular nucleus induces febrile and behavioral effects

Research paper thumbnail of The EAE-associated behavioral syndrome

Journal of Neuroimmunology

EAE is associated with sickness behavior symptoms that are temporally correlated with inflammator... more EAE is associated with sickness behavior symptoms that are temporally correlated with inflammatory processes. To further elucidate the role of inflammatory mediators in the behavioral syndrome, EAE mice were injected daily with anti-inflammatory drugs, beginning at disease onset. Dexamethasone or interleukin-1 (IL-1) receptor antagonist or the prostaglandins synthesis inhibitor indomethacin attenuated the behavioral symptoms. Administration of the tumor necrosis-factor α (TNF-α) synthesis inhibitor pentoxifylline or targeted deletion of the type I TNF receptor had no behavioral effects whereas administration of pentoxifylline in IL-1ra-treated mice further reversed the behavioral depression. These findings demonstrate the critical involvement of pro-inflammatory cytokines and prostaglandins in the EAE-associated behavioral syndrome, and may have implications for understanding and treating the neuropsychiatric disturbances in multiple sclerosis (MS) patients.

Research paper thumbnail of Multilevel Approaches to AChE-Induced Impairments in Learning and Memory

Structure and Function of Cholinesterases and Related Proteins, 1998

BACKGROUND Alzheimer&amp;#x27;s disease (AD) is a late-onset neurodegenerative disease charac... more BACKGROUND Alzheimer&amp;#x27;s disease (AD) is a late-onset neurodegenerative disease characterized by progressive deterioration of cholinergic functions including learning, short-term memory, problem solving and abstract thinking. The only FDA-approved drugs for AD ...

Research paper thumbnail of Cytokine-induced changes in mood and behaviour: implications for 'depression due to a general medical condition', immunotherapy and antidepressive treatment

The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2002

Several lines of evidence indicate that cytokine-mediated communication pathways between the immu... more Several lines of evidence indicate that cytokine-mediated communication pathways between the immune system and the brain are involved in the pathophysiology of depression: (1) . Depression is highly prevalent in various medical conditions, including infectious, autoimmune and neurodegenerative diseases. This clinical association cannot be attributed solely to psychological distress, and it probably reflects direct activation of illness-induced physiological processes. (2). Experiments in humans and in animals demonstrate that exposure to cytokines induces depressive-like mood and behavioural alterations. (3). Cytokine immunotherapy in cancer and hepatitis patients elicits a major depressive episode in a large percentage of the patients. (4). Several types of depression that are not directly associated with a physical disease (e.g. major depression, melancholia, dysthymia) were also associated with cytokine hypersecretion. (5). Antidepressant drugs possess anti-inflammatory character...

Research paper thumbnail of Cytokines, “Depression Due to A General Medical Condition,” and Antidepressant Drugs

Advances in Experimental Medicine and Biology, 1999

Research paper thumbnail of Neurochemical mechanisms mediating interleukin-1-induced suppression of sexual behavior in females

Neuroscience Letters, 1997

of the corresponding recombinant fusion proteins demonstrates N-Loop 710-1090 competition with sy... more of the corresponding recombinant fusion proteins demonstrates N-Loop 710-1090 competition with syntaxin and SNAP-25 for p65 binding. The results of the combined approaches provide a functional and biochemical basis for proposing that p65 together with syntaxin and SNAP-25 associated channel form an active complex. As a consequence, the affinity of syntaxin for p65 relieves channel inhibition, allowing the primed vesicles, now closely associated with the channel to fuse with the cell membrane. Wiser, O., Bennett, M. K. and Atlas, D. (1996). Functional interaction of syntaxin and SNAP-25 with voltage sensitive L-and N-type Ca 2+ channels. EMBO J. 15, 4100-4110. Wiser, O., Tobi, D., Trus, M. and D. Atlas (1997) Synaptotagmin restores kinetic properties of a syntaxin-associated N-type voltage sensitive calcium channel FEBS Lett. 404, 203-297.

Research paper thumbnail of Administration of lnterleukin-1 into the Hypothalamic Paraventricular Nucleus Induces Febrile and Behavioral Effects

Neuroimmunomodulation, 1997

Administration of intekleukin-1 (IL-1) into the cerebral ventricles produces marked physiological... more Administration of intekleukin-1 (IL-1) into the cerebral ventricles produces marked physiological and behavioral effects. However, the precise locations within the central nervous system that mediate these effects have not been determined. Previous studies indicated that IL-1 induces neurophysiological, neurochemical and neuroendocrine changes within the hypothalamic paraventricular nucleus (PVN). These findings suggest that the PVN is also involved in mediating the behavioral effects of IL-1. This hypothesis was tested by examining the effects of administration of IL-1β (10 or 50 ng/rat) or saline, either intracerebroventricularly or into the PVN, on fever and several behavioral parameters. IL-1β, administered into both locations, induced a comparable suppression of motor activity, reduction in food and saccharine consumption, and loss of body weight. The febrile response to IL-1β, assessed by a biotelemetric system, was significantly greater following administration into the PVN t...

Research paper thumbnail of The role of brain TNFA and IL-1B in mediating the behavioral and neuroendocrine effects of intracerebral mycoplasma fermentans

Neuroscience Letters, 1997

Compared with other clinically useful carbamates, the anti-Alzheimer drug, (+)S-N-ethyl-3-[(1-dim... more Compared with other clinically useful carbamates, the anti-Alzheimer drug, (+)S-N-ethyl-3-[(1-dimethyl-amino)ethyl]-N-methylphenylcarbamate Exelon™, Sandoz Co. Ltd.), has a longer duration of action and preferentially inhibits acetylcholinesterase (AChE) of the brain cortex and hippocampus (Enz et al., Ann. N.Y. Acad. Sci., 640: 272-275, 1991). To understand the basic mechanism of ENA-713, we studied its reactions in vitro with AChE from Torpedo californica. The apparent bimolecular rate constant for progressive inhibition was low: K i = 6 M −1 min −1 (0.067 M Na/K phosphate buffer, pH 7.4, 25°C). Thus, carbamylation of AChE was unusually slow, and this raised the possibility that the leaving group of ENA-713, 3-[(1dimethyl-amino)ethyl] phenol, might interfere with the reaction between intact carbamate and AChE. Indeed, the measured binding constants for reversible inhibition by ENA-713 and its leaving group were 200 PM and 14 PM, respectively, at pH 7.4, 25°C; the product apparently bound more tightly to AChE than did the intact carbamate in the reversible complex. Covalent carbamylation of AChE by ENA-713 nevertheless occurred because, upon removal of excess inhibitor by gel filtration, we observed spontaneous decarbamylation with a rate constant of 0.006 min −1 (pH 7.4, 25°C) and an activation energy of 16 kcal/mole. We conclude that ENA-713 inhibits AChE by two mechanisms: (1) covalent carbamylation followed by slow decarbamylation; and (2) the carbamate acts as a vector to deliver its leaving group, which is itself a good reversible anti-AChE, to the enzyme active site. To test this hypothesis, studies are underway to measure the kinetic effects of product on carbamylation and to solve the 3D structure of a complex of AChE and ENA-713 by X-ray crystallography.

Research paper thumbnail of The role of adrenergic receptors in mediating sickness behavior

Neuroscience Letters, 1997

sequence was much reduced. However, recall performance for the second and third stimuli in the se... more sequence was much reduced. However, recall performance for the second and third stimuli in the sequence was not influenced significantly. This finding suggests that the mechanism for recall of the first image in a sequence is quite different from the recall of the second and third images, conditioned on the first.

Research paper thumbnail of Effects of Antidepressant Drugs on the Behavioral and Physiological Responses to Lipopolysaccharide (LPS) in Rodents

Neuropsychopharmacology, 2001

Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavi... more Antidepressants produce various immunomodulatory effects, as well as an attenuation of the behavioral responses to immune challenges, such as lipopolysaccharide (LPS). To explore further the effects of antidepressants on neuroimmune interactions, rats were treated daily with either fluoxetine (Prozac) or saline for 5 weeks, and various behavioral, neuroendocrine, and immune functions were measured following administration of either LPS or saline. Chronic fluoxetine treatment significantly attenuated the anorexia and body weight loss, as well as the depletion of CRH-41 from the median eminence and the elevation in serum corticosterone levels induced by LPS. Chronic treatment with imipramine also attenuated LPS-induced adrenocortical activation. In rats and in mice, which normally display a biphasic body temperature response to LPS (initial hypothermia followed by hyperthermia), chronic treatment with fluoxetine completely abolished the hypothermic response and facilitated and strengthened the hyperthermic response. The effects of antidepressants on the responsiveness to LPS are probably not mediated by their effects on peripheral proinflammatory cytokine production, because LPS-induced expression of TNF ␣ and IL-1 ␤ mRNA in the spleen (assessed by semiquantitative in situ hybridization) was not altered following chronic treatment with either fluoxetine or imipramine. The effects of antidepressants on the acute phase response may have important clinical implications for the psychiatric and neuroendocrine disturbances that are commonly associated with various medical conditions.

Research paper thumbnail of Neuronal overexpression of ‘readthrough’ acetylcholinesterase is associated with antisense-suppressible behavioral impairments

Molecular Psychiatry, 2002

Molecular origin(s) of the diverse behavioral responses to anticholinesterases were explored in b... more Molecular origin(s) of the diverse behavioral responses to anticholinesterases were explored in behaviorally impaired transgenic (Tg) FVB/N mice expressing synaptic human acetylcholinesterase (hAChE-S). Untreated hAChE-S Tg, unlike naïve FVB/N mice, presented variably intense neuronal overexpression of the alternatively spliced, stress-induced mouse 'readthrough' mAChE-R mRNA. Both strains displayed similar diurnal patterns of locomotor activity that were impaired 3 days after a day-to-night switch. However, hAChE-S Tg, but not FVB/N mice responded to the circadian switch with irregular, diverse bursts of increased locomotor activity. In social recognition tests, controls displayed short-term recognition, reflected by decreased exploration of a familiar, compared to a novel juvenile conspecific as well as inverse correlation between social recognition and cortical and hippocampal AChE specific activities. In contrast, transgenics presented poor recognition, retrievable by tetrahydroaminoacridine (tacrine, 1.5 mg kg −1 ).

Research paper thumbnail of The EAE-associated behavioral syndrome I. Temporal correlation with inflammatory mediators

Journal of Neuroimmunology, 2003

To elucidate the mechanisms underlying the EAE-associated behavioral syndrome (EBS), we examined ... more To elucidate the mechanisms underlying the EAE-associated behavioral syndrome (EBS), we examined the temporal correlation between the behavioral alterations and inflammatory processes. Onset of the behavioral syndrome was associated with the onset of brain infiltration, as well as mRNA expression of interleukin 1 beta (IL-1 beta) and tumor necrosis factor alpha (TNF-alpha) and elevated production of interleukin 1 beta protein and prostaglandin E(2) (PGE(2)). Sickness behavior symptoms coincided with peak cytokine expression. Behavioral recovery was associated with a reduction of cytokine expression, but not infiltration, PGE(2) production or motor disturbances. These results suggest that inflammatory processes in general, and the production of pro-inflammatory cytokines in particular, are involved in mediating EAE-associated sickness behavior.

Research paper thumbnail of Behavioral aspects of experimental autoimmune encephalomyelitis

Journal of Neuroimmunology, 2000

Research paper thumbnail of Different receptor mechanisms mediate the effects of endotoxin and interleukin-1 on female sexual behavior

Brain Research, 1997

. Activation of the immune system by lipopolysaccharide LPS produces physiological, neuroendocrin... more . Activation of the immune system by lipopolysaccharide LPS produces physiological, neuroendocrine and behavioral effects, some of Ž . which are mediated by cytokine production. We have previously shown that the cytokine interleukin-1 IL-1 inhibits sexual behavior in female, but not male rats, while producing a comparable suppression of locomotion in both sexes. The present study examined the effects of LPS on sexual behavior and locomotion of male and female rats, and the involvement of IL-1 receptors in mediating the effects of IL-1 Ž . Ž . and LPS on females' behavior. Peripheral i.p. administration of LPS 50 or 250 mgrkg significantly decreased sexual behavior in females, up to 6 h after administration, while it had no effect on male sexual behavior. However, locomotor activity, measured in the Ž . open-field test, was similarly reduced by LPS in both males and females. Pretreatment with the IL-1 receptor antagonist IL-1ra either Ž . Ž .Ž . i.p. 10 mgrkg or intracerebroventricularly i.c.v. 50 mgrrat did not prevent the inhibition of female sexual behavior and locomotion Ž . Ž . induced by either i.p. 50 mgrkg or i.c.v. 200 or 400 ngrrat administration of LPS, respectively. However, identical doses of IL-1ra Ž . Ž . significantly reversed the effects of IL-1b, administered either i.p. 5 mgrkg or i.c.v. 50 ngrrat , respectively. These results demonstrate that both LPS and IL-1b produce marked inhibition of sexual behavior in female, but not in male rats. However, IL-1 receptors are not required for the effects of LPS on sexual behavior in female rats. q 1997 Elsevier Science B.V.

Research paper thumbnail of The role of brain cytokines in mediating the behavioral and neuroendocrine effects of intracerebral Mycoplasma fermentans

Brain Research, 1999

Intracerebral administration of Mycoplasma fermentans MF , a small microorganism that has been fo... more Intracerebral administration of Mycoplasma fermentans MF , a small microorganism that has been found in the brain of some AIDS Ž . patients, induces behavioral and neuroendocrine alterations in rats. To examine the role of tumor necrosis factor-a TNFa and Ž . interleukin-1 IL-1 in mediating these effects we measured MF-induced expression of TNFa and IL-1b mRNA in various brain regions, Ž . and the effects of TNFa synthesis blockers and IL-1 receptor antagonist IL-1ra on MF-induced sickness behavior and adrenocortical Ž . activation. Intracerebroventricular i.c.v. administration of heat-inactivated MF induced the expression of both TNFa and IL-1b mRNA in the cortex, dorsal hippocampus, amygdala, and hypothalamus. Pre-treatment of rats with either TNFa synthesis blockers, pentoxifylline or rolipram, or with IL-1ra did not attenuate MF-induced anorexia, body weight loss, and suppression of social behavior. However, simultaneous administration of both pentoxifylline and IL-1ra markedly attenuated MF-induced anorexia and body weight loss, but had no effect on the suppression of social behavior. Pre-treatment with pentoxifylline, but not with IL-1ra, significantly attenuated MF-induced Ž . corticosterone CS secretion. Together, these findings indicate that both TNFa and IL-1 participate, in a complementary manner, in mediating some of the behavioral effects of MF, whereas only TNFa , but not IL-1, is involved in mediating MF-induced adrenocortical activation. We suggest that cytokines within the brain are involved in mediating at least some of the neurobehavioral and neuroendocrine abnormalities that may be produced by MF in AIDS patients. q periphery and in the brain, and affect neurobehavioral functions via specific receptors found in various brain w x structures 60 . Direct administration of TNFa or IL-1b, either peripherally or into the cerebral ventricle, produces marked behavioral and neuroendocrine effects, including a suppression of appetite, motor activity, exploratory, social, and sexual behavior, increased slow wave sleep, general malaise, altered pain sensitivity, and enhanced secretion of Ž . corticotropin-releasing hormone CRH , ACTH and glucow x corticoids 6,17,32,41,67 . Moreover, antibodies against particular cytokines, or cytokine antagonists attenuate or block the behavioral effects of immune challenges w x 4, and the activation of the HPA axis in w x various medical conditions 20,51,54,57 .

Research paper thumbnail of Experimental autoimmune encephalomyelitis: Association with mutual regulation of RelA (p65)/NF-κB and phospho-IκB in the CNS

Biochemical and Biophysical Research Communications, 2011

Recently emerging evidence that the NF-κB family plays an important role in autoimmune disease ha... more Recently emerging evidence that the NF-κB family plays an important role in autoimmune disease has produced very broad and sometimes paradoxical conclusions. In the present study, we elucidated that the activation of RelA (p65) of NF-κB and IκB dissociation assumes a distinct role in experimental autoimmune encephalomyelitis (EAE) progression by altering IκB phosphorylation and/or degradation. In the present study of factors that govern EAE, the presence and immunoreactivity of nuclear RelA and phospho-IκB were recorded at the initiation and peak stage, and degradation of IκBα progressed rapidly at an early stage then stabilized during recovery. The immunoreactivity to RelA and phospho-IκB occurred mainly in inflammatory cells and microglial cells but only slightly in astrocytes. Subsequently, the blockade of IκB dissociation from NF-κB reduced the severity of disease by decreasing antigen-specific T cell response and production of IL-17 in EAE. Thus, blocking the dissociation of IκB from NF-κB can be utilized as a strategy to inhibit the NF-κB signal pathway thereby to reduce the initiation, progression, and severity of EAE.

Research paper thumbnail of Illness, Cytokines, and Depression

Annals of the New York Academy of Sciences, 2006

A BSTRACT : Various medical conditions that involve activation of the immune system are associate... more A BSTRACT : Various medical conditions that involve activation of the immune system are associated with psychological and neuroendocrine changes that resemble the characteristics of depression. In this review we present our recent studies, designed to investigate the relationship between the behavioral effects of immune activation and depressive symptomatology. In the first set of experiments, we used a double-blind prospective design to investigate the psychological consequences of illness in two models: (1) vaccination of teenage girls with live attenuated rubella virus, and (2) lipopolysaccharide (LPS) administration in healthy male volunteers. In the rubella study, we demonstrated that, compared to control group subjects and to their own baseline, a subgroup of vulnerable individuals (girls from low socioeconomic status) showed a significant virus-induced increase in depressed mood up to 10 weeks after vaccination. In an ongoing study on the effects of LPS, we demonstrated significant LPSinduced elevation in the levels of depression and anxiety as well as memory deficits. These psychological effects were highly correlated with the levels of LPS-induced cytokine secretion. In parallel experiments, we demonstrated in rodents that immune activation with various acute and chronic immune challenges induces a depressive-like syndrome, characterized by anhedonia, anorexia, body weight loss, and reduced locomotor, exploratory, and social behavior. Chronic treatment with antidepressants (imipramine or fluoxetine) attenuated many of the behavioral effects of LPS, as well as LPS-induced changes in body temperature, adrenocortical activation, hypothalamic serotonin release, and the expression of splenic TNF-␣ mRNA. Taken together, these findings suggest that cytokines are involved in the etiology and symptomatology of illness-associated depression.

Research paper thumbnail of Medical Decisions of Pediatric Residents Turn Riskier after a 24-Hour Call with No Sleep

Medical decision making : an international journal of the Society for Medical Decision Making, Jan 27, 2016

Despite a gradual reduction in the workload during residency, 24-hour calls are still an integral... more Despite a gradual reduction in the workload during residency, 24-hour calls are still an integral part of most training programs. While sleep deprivation increases the risk propensity, the impact on medical risk taking has not been studied. This study aimed to assess the clinical decision making and psychomotor performance of pediatric residents following a limited nap time during a 24-hour call. A neurocognitive battery (IntegNeuro) and a medical decision questionnaire were completed by 44 pediatric residents at 2 time points: after a 24-hour call and following 3 nights with no calls (sleep ≥5 hours). To monitor sleep, residents wore actigraphs and completed sleep logs. Nap time during the shift was <1 hour in 14 cases (32%), 1 to 2 hours in 16 cases (35%), and 2 to 3 hours in 14 cases (32%). Residents who napped less than 1 hour chose the riskier medical option in 50% of cases compared with 36% when answering the same questionnaire after 3 nights with no calls (P = 0.002). This...