Functional β2-adrenoceptors in rat left atria: effect of foot-shock stress.

PubMed

Moura, André Luiz de; Hyslop, Stephen; Grassi-Kassisse, Dora M; Spadari, Regina C

2017-09-01

Altered sensitivity to the chronotropic effect of catecholamines and a reduction in the β 1 /β 2 -adrenoceptor ratio have previously been reported in right atria of stressed rats, human failing heart, and aging. In this report, we investigated whether left atrial inotropism was affected by foot-shock stress. Male rats were submitted to 3 foot-shock sessions and the left atrial inotropic response, adenylyl cyclase activity, and β-adrenoceptor expression were investigated. Left atria of stressed rats were supersensitive to isoprenaline when compared with control rats and this effect was abolished by ICI118,551, a selective β 2 -receptor antagonist. Schild plot slopes for the antagonism between CGP20712A (a selective β 1 -receptor antagonist) and isoprenaline differed from unity in atria of stressed but not control rats. Atrial sensitivity to norepinephrine, as well as basal and forskolin- or isoprenaline-stimulated adenylyl cyclase activities were not altered by stress. The effect of isoprenaline on adenylyl cyclase stimulation was partially blocked by ICI118,551 in atrial membranes of stressed rats. These findings indicate that foot-shock stress equally affects inotropism and chronotropism and that β 2 -adrenoceptor upregulation contributes to the enhanced inotropic response to isoprenaline.

Early life stress impairs contextual threat expression in female, but not male, mice.

PubMed

Manzano-Nieves, Gabriela; Gaillard, Mizan; Gallo, Meghan; Bath, Kevin G

2018-05-21

Early life stress (ELS) is associated with altered processing of threat signals, and increased lifetime risk of anxiety and affective pathology, disorders that disproportionately affect females. We tested the impact of a limited bedding paradigm of ELS (from P4-11) on contextual threat learning, context memory, footshock sensitivity, and anxietylike behavior, in adult male and female mice. To examine contextual threat learning, mice conditioned by context/footshock association were tested 24 hr later for the context memory. To determine the effect of ELS on footshock sensitivity, a separate cohort of mice were exposed to footshocks of increasing intensity (0.06 to 0.40 mA) and behavioral responses (jump and audible vocalization) were assessed by observers blind to treatment condition, sex, and cycle stage. ELS impaired context memory in female, but not male, mice. ELS increased footshock-induced threshold to vocalize, but not to jump, in both sexes. In female mice, this effect was most apparent during estrus. Decreased body weight, indicative of higher stress incurred by an individual mouse, correlated with increased threshold to jump in both sexes reared in ELS, and to audibly vocalize in ELS females. As ELS effects on shock sensitivity were present in both sexes, the contextual recall deficit in females was not likely driven by changes in the salience of aversive footshocks. No effects on anxietylike behavior, as measured in the elevated plus maze (EPM), were observed. More work is needed to better understand the impact of ELS on both somatic and gonadal development, and their potential contribution to threat learning. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Increases in extracellular zinc in the amygdala in acquisition and recall of fear experience and their roles in response to fear.

PubMed

Takeda, A; Tamano, H; Imano, S; Oku, N

2010-07-14

The amygdala is enriched with histochemically reactive zinc, which is dynamically coupled with neuronal activity and co-released with glutamate. The dynamics of the zinc in the amygdala was analyzed in rats, which were subjected to inescapable stress, to understand the role of the zinc in emotional behavior. In the communication box, two rats were subjected to foot shock stress and anxiety stress experiencing emotional responses of foot-shocked rat under amygdalar perfusion. Extracellular zinc was increased by foot shock stress, while decreased by anxiety stress, suggesting that the differential changes in extracellular zinc are associated with emotional behavior. In rats conditioned with foot shock, furthermore, extracellular zinc was increased again in the recall of fear (foot shock) in the same box without foot shock. When this recall was performed under perfusion with CaEDTA, a membrane-impermeable zinc chelator, to examine the role of the increase in extracellular zinc, the time of freezing behavior was more increased, suggesting that zinc released in the lateral amygdala during the recall of fear participates in freezing behavior. To examine the role of the increase in extracellular zinc during fear conditioning, fear conditioning was also performed under perfusion with CaEDTA. The time of freezing behavior was more increased in the contextual recall, suggesting that zinc released in the lateral nucleus during fear conditioning also participates in freezing behavior in the recall. In brain slice experiment, CaEDTA enhanced presynaptic activity (exocytosis) in the lateral nucleus after activation of the entorhinal cortex. The present paper demonstrates that zinc released in the lateral amygdala may participate in emotional behavior in response to fear. Copyright 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Opioid/NMDA receptors blockade reverses the depressant-like behavior of foot shock stress in the mouse forced swimming test.

PubMed

Haj-Mirzaian, Arya; Ostadhadi, Sattar; Kordjazy, Nastaran; Dehpour, Ahmad Reza; Ejtemaei Mehr, Shahram

2014-07-15

Opioid and glutamatergic receptors have a key role in depression following stress. In this study, we assessed opioid and glutamatergic receptors interaction with the depressant-like behavior of acute foot-shock stress in the mouse forced swimming test. Stress was induced by intermittent foot shock stimulation during 30min and swim periods were afterwards conducted by placing mice in separated glass cylinders filled with water for 6min. The immobility time during the last 4min of the test was considered. Acute foot-shock stress significantly increased the immobility time of mice compared to non-stressed control group (P≤0.01). Administration of non-selective opioid receptors antagonist, naltrexone (1 and 2mg/kg, i.p.), and the selective non-competitive NMDA receptor antagonist, MK-801 (0.05mg/kg, i.p.), and the selective serotonin reuptake inhibitor, fluoxetine (5mg/kg), significantly reduced the immobility time in stressed animals (P≤0.01). Lower doses of MK-801 (0.01mg/kg), naltrexone (0.3mg/kg), NMDA (75mg/kg) and morphine(5mg/kg) had no effect on foot-shock stressed mice. Combined treatment of sub-effective doses of naltrexone and MK-801 significantly showed an antidepressant-like effect (P≤0.001). On the other hand, co-administration of non-effective doses of NMDA and morphine with effective doses of naltrexone and MK-801 reversed the anti-immobility effect of these drugs. Taken together, we have for the first time demonstrated the possible role of opioid/NMDA receptors signaling in the depressant-like effect of foot-shock stress, and proposed the use of drugs that act like standard anti-depressants in stress-induced depression. Copyright © 2014. Published by Elsevier B.V.

Effects of Optogenetic inhibition of BLA on Sleep Brief Optogenetic Inhibition of the Basolateral Amygdala in Mice Alters Effects of Stressful Experiences on Rapid Eye Movement Sleep.

PubMed

Machida, Mayumi; Wellman, Laurie L; Fitzpatrick Bs, Mairen E; Hallum Bs, Olga; Sutton Bs, Amy M; Lonart, György; Sanford, Larry D

2017-04-01

Stressful events can directly produce significant alterations in subsequent sleep, in particular rapid eye movement sleep (REM); however, the neural mechanisms underlying the process are not fully known. Here, we investigated the role of the basolateral nuclei of the amygdala (BLA) in regulating the effects of stressful experience on sleep. We used optogenetics to briefly inhibit glutamatergic cells in BLA during the presentation of inescapable footshock (IS) and assessed effects on sleep, the acute stress response, and fear memory. c-Fos expression was also assessed in the amygdala and the medial prefrontal cortex (mPFC), both regions involved in coping with stress, and in brain stem regions implicated in the regulation of REM. Compared to control mice, peri-shock inhibition of BLA attenuated an immediate reduction in REM after IS and produced a significant overall increase in REM. Moreover, upon exposure to the shock context alone, mice receiving peri-shock inhibition of BLA during training showed increased REM without altered freezing (an index of fear memory) or stress-induced hyperthermia (an index of acute stress response). Inhibition of BLA during REM under freely sleeping conditions enhanced REM only when body temperature was high, suggesting the effect was influenced by stress. Peri-shock inhibition of BLA also led to elevated c-Fos expression in the central nucleus of the amygdala and mPFC and differentially altered c-Fos activity in the selected brain stem regions. Glutamatergic cells in BLA can modulate the effects of stress on REM and can mediate effects of fear memory on sleep that can be independent of behavioral fear. © Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.

Differential effects of voluntary wheel running and toy rotation on the mRNA expression of neurotrophic factors and FKBP5 in a post-traumatic stress disorder rat model with the shuttle-box task.

PubMed

Tanichi, Masaaki; Toda, Hiroyuki; Shimizu, Kunio; Koga, Minori; Saito, Taku; Enomoto, Shingo; Boku, Shuken; Asai, Fumiho; Mitsui, Yumi; Nagamine, Masanori; Fujita, Masanori; Yoshino, Aihide

2018-06-18

Life-threatening experiences can result in the development of post-traumatic stress disorder. We have developed an animal model for post-traumatic stress disorder (PTSD) using a shuttle box in rats. In this paradigm, the rats were exposed to inescapable foot-shock stress (IS) in a shuttle box, and then an avoidance/escape task was performed in the same box 2 weeks after IS. A previous study using this paradigm revealed that environmental enrichment (EE) ameliorated avoidance/numbing-like behaviors, but not hyperarousal-like behaviors, and EE also elevated hippocampal brain-derived neurotrophic factor (BDNF) expression. However, the differential effects of EE components, i.e., running wheel (RW) or toy rotation, on PTSD-like behaviors has remained unclear. In this experiment, we demonstrated that RW, toy rotation, and EE (containing RW and toy rotation) ameliorated avoidance/numbing-like behaviors, induced learning of avoidance responses, and improved depressive-like behaviors in traumatized rats. The RW increased the hippocampal mRNA expression of neurotrophic factors, especially BDNF and glial-cell derived neurotrophic factor. Toy rotation influenced FK506 binding protein 5 mRNA expression, which is believed to be a regulator of the hypothalamic-pituitary-adrenal (HPA)-axis system, in the hippocampus and amygdala. This is the first report to elucidate the differential mechanistic effects of RW and toy rotation. The former appears to exert its effects via neurotrophic factors, while the latter exerts its effects via the HPA axis. Further studies will lead to a better understanding of the influence of environmental factors on PTSD. Copyright © 2018 Elsevier Inc. All rights reserved.

Stress-induced enhancement of fear conditioning and sensitization facilitates extinction-resistant and habituation-resistant fear behaviors in a novel animal model of posttraumatic stress disorder.

PubMed

Corley, Michael J; Caruso, Michael J; Takahashi, Lorey K

2012-01-18

Posttraumatic stress disorder (PTSD) is characterized by stress-induced symptoms including exaggerated fear memories, hypervigilance and hyperarousal. However, we are unaware of an animal model that investigates these hallmarks of PTSD especially in relation to fear extinction and habituation. Therefore, to develop a valid animal model of PTSD, we exposed rats to different intensities of footshock stress to determine their effects on either auditory predator odor fear extinction or habituation of fear sensitization. In Experiment 1, rats were exposed to acute footshock stress (no shock control, 0.4 mA, or 0.8 mA) immediately prior to auditory fear conditioning training involving the pairing of auditory clicks with a cloth containing cat odor. When presented to the conditioned auditory clicks in the next 5 days of extinction testing conducted in a runway apparatus with a hide box, rats in the two shock groups engaged in higher levels of freezing and head out vigilance-like behavior from the hide box than the no shock control group. This increase in fear behavior during extinction testing was likely due to auditory activation of the conditioned fear state because Experiment 2 demonstrated that conditioned fear behavior was not broadly increased in the absence of the conditioned auditory stimulus. Experiment 3 was then conducted to determine whether acute exposure to stress induces a habituation resistant sensitized fear state. We found that rats exposed to 0.8 mA footshock stress and subsequently tested for 5 days in the runway hide box apparatus with presentations of nonassociative auditory clicks exhibited high initial levels of freezing, followed by head out behavior and culminating in the occurrence of locomotor hyperactivity. In addition, Experiment 4 indicated that without delivery of nonassociative auditory clicks, 0.8 mA footshock stressed rats did not exhibit robust increases in sensitized freezing and locomotor hyperactivity, albeit head out vigilance-like behavior continued to be observed. In summary, our animal model provides novel information on the effects of different intensities of footshock stress, auditory-predator odor fear conditioning, and their interactions on facilitating either extinction-resistant or habituation-resistant fear-related behavior. These results lay the foundation for exciting new investigations of the hallmarks of PTSD that include the stress-induced formation and persistence of traumatic memories and sensitized fear. Copyright © 2011 Elsevier Inc. All rights reserved.

The basolateral amygdala can mediate the effects of fear memory on sleep independently of fear behavior and the peripheral stress response.

PubMed

Wellman, Laurie L; Fitzpatrick, Mairen E; Hallum, Olga Y; Sutton, Amy M; Williams, Brook L; Sanford, Larry D

2017-01-01

Fear conditioning associated with inescapable shock training (ST) and fearful context re-exposure (CR) alone can produce significant behavioral fear, a stress response and alterations in subsequent REM sleep. These alterations may vary among animals and are mediated by the basolateral nucleus of the amygdala (BLA). Here, we used the GABA A agonist, muscimol (Mus), to inactivate BLA prior to CR and examined the effects on sleep, freezing and stress-induced hyperthermia (SIH). Wistar rats (n=28) were implanted with electrodes for recording sleep, data loggers for recording core body temperature, and with cannulae aimed bilaterally into BLA. After recovery, the animals were habituated to the injection procedure and baseline sleep was recorded. On experimental day 1, rats received ST (20 footshocks, 0.8mA, 0.5s duration, 60s interstimulus interval). On experimental day 7, the rats received microinjections (0.5μl) into BLA of either Mus (1.0μM; n=13) or vehicle (Veh; n=15) prior to CR (CR1). On experimental day 21, the animals experienced a second CR (CR2) without Mus. For analysis, the rats were separated into 4 groups: (Veh-vulnerable (Veh-Vul; n=8), Veh-resilient (Veh-Res; n=7), Mus-vulnerable (Mus-Vul; n=7), and Mus-resilient (Mus-Res; n=6)) based on whether or not REM was decreased, compared to baseline, during the first 4h following ST. Pre-CR1 inactivation of BLA did not alter freezing or SIH, but did block the reduction in REM in the Mus-Vul group compared to the Veh-Vul group. These data indicate that BLA is an important region for mediating the effects of fearful memories on sleep. Copyright © 2016 Elsevier Inc. All rights reserved.

The Basolateral Amygdala Can Mediate the Effects of Fear Memory on Sleep Independently of Fear Behavior and the Peripheral Stress Response

PubMed Central

Wellman, Laurie L.; Fitzpatrick, Mairen E.; Hallum, Olga Y.; Sutton, Amy M.; Williams, Brook L.; Sanford, Larry D.

2016-01-01

Fear conditioning associated with inescapable shock training (ST) and fearful context re-exposure (CR) alone can produce significant behavioral fear, a stress response and alterations in subsequent REM sleep. These alterations may vary among animals and are mediated by the basolateral nucleus of the amygdala (BLA). Here, we used the GABAA agonist, muscimol (Mus), to inactivate BLA prior to CR and examined the effects on sleep, freezing and stress-induced hyperthermia (SIH). Wistar rats (n=28) were implanted with electrodes for recording sleep, data loggers for recording core body temperature, and with cannulae aimed bilaterally into BLA. After recovery, the animals were habituated to the injection procedure and baseline sleep was recorded. On experimental day 1, rats received ST (20 footshocks, 0.8mA, 0.5s duration, 60s interstimulus interval). On experimental day 7, the rats received microinjections (0.5ul) into BLA of either Mus (1.0uM; n = 13) or vehicle (Veh; n = 15) prior to CR (CR1). On experimental day 21, the animals experienced a second CR (CR2) without Mus. For analysis, the rats were separated into 4 groups: (Veh-vulnerable (Veh-Vul; n=8), Veh-resilient (Veh-Res; n=7), Mus-vulnerable (Mus-Vul; n=7), and Mus-resilient (Mus-Res; n=6)) based on whether or not REM was decreased, compared to baseline, during the first 4 h following ST. Pre-CR1 inactivation of BLA did not alter freezing or SIH, but did block the reduction in REM in the Mus-Vul group compared to the Veh-Vul group. These data indicate that BLA is an important region for mediating the effects of fearful memories on sleep. PMID:27818268

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats

PubMed Central

Blacktop, Jordan M.; Vranjkovic, Oliver; Mayer, Matthieu; Van Hoof, Matthew; Baker, David A.; Mantsch, John R.

2015-01-01

Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 × 6 hrs/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5” duration, average every 40 sec; range 10–70 sec) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2-hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced cocaine seeking at either dose tested. By contrast, 2-hydroxysaclofen (0.2 or 2 µg/side) prevented reinstatement by both footshock and intra-VTA CRF at a concentration that failed to attenuate food-reinforced lever pressing (45 mg sucrose-sweetened pellets; FR4 schedule) in a separate group of rats. These data suggest that GABA-B receptor-dependent CRF actions in the VTA mediate stress-induced cocaine seeking and that GABA-B receptor antagonists may have utility for the management of stress-induced relapse in cocaine addicts. PMID:26596556

Abnormal stress responsivity in a rodent developmental disruption model of schizophrenia.

PubMed

Zimmerman, Eric C; Bellaire, Mark; Ewing, Samuel G; Grace, Anthony A

2013-10-01

Although numerous studies have implicated stress in the pathophysiology of schizophrenia, less is known about how the effects of stress interact with genetic, developmental, and/or environmental determinants to promote disease progression. In particular, it has been proposed that in humans, stress exposure in adolescence could combine with a predisposition towards increased stress sensitivity, leading to prodromal symptoms and eventually psychosis. However, the neurobiological substrates for this interaction are not fully characterized. Previous work in our lab has demonstrated that rats born to dams administered with the DNA-methylating agent methylazoxymethanol acetate (MAM) at gestational day 17 exhibit as adults behavioral and anatomical abnormalities consistent with those observed in patients with schizophrenia. Here, we examined behavioral and neuroendocrine responses to stress in the MAM model of schizophrenia. MAM-treated male rats were exposed to acute and repeated footshock stress at prepubertal, peripubteral, and adult ages. Ultrasonic vocalizations (USVs), freezing, and corticosterone responses were quantified. We found that juvenile MAM-treated rats emitted significantly more calls, spent more time vocalizing, emitted calls at a higher rate, and showed more freezing in response to acute footshock stress when compared with their saline (SAL) treated counterparts, and that this difference is not present in older animals. In addition, adolescent MAM-treated animals displayed a blunted HPA axis corticosterone response to acute footshock that did not adapt after 10 days of stress exposure. These data demonstrate abnormal stress responsivity in the MAM model of schizophrenia and suggest that these animals are more sensitive to the effects of stress in youth.

Antagonism of GABA-B but not GABA-A receptors in the VTA prevents stress- and intra-VTA CRF-induced reinstatement of extinguished cocaine seeking in rats.

PubMed

Blacktop, Jordan M; Vranjkovic, Oliver; Mayer, Matthieu; Van Hoof, Matthew; Baker, David A; Mantsch, John R

2016-03-01

Stress-induced reinstatement of cocaine seeking requires corticotropin releasing factor (CRF) actions in the ventral tegmental area (VTA). However the mechanisms through which CRF regulates VTA function to promote cocaine use are not fully understood. Here we examined the role of GABAergic neurotransmission in the VTA mediated by GABA-A or GABA-B receptors in the reinstatement of extinguished cocaine seeking by a stressor, uncontrollable intermittent footshock, or bilateral intra-VTA administration of CRF. Rats underwent repeated daily cocaine self-administration (1.0 mg/kg/ing; 14 × 6 h/day) and extinction and were tested for reinstatement in response to footshock (0.5 mA, 0.5" duration, average every 40 s; range 10-70 s) or intra-VTA CRF delivery (500 ng/side) following intra-VTA pretreatment with the GABA-A antagonist, bicuculline, the GABA-B antagonist, 2-hydroxysaclofen or vehicle. Intra-VTA bicuculline (1, 10 or 20 ng/side) failed to block footshock- or CRF-induced cocaine seeking at either dose tested. By contrast, 2-hydroxysaclofen (0.2 or 2 μg/side) prevented reinstatement by both footshock and intra-VTA CRF at a concentration that failed to attenuate food-reinforced lever pressing (45 mg sucrose-sweetened pellets; FR4 schedule) in a separate group of rats. These data suggest that GABA-B receptor-dependent CRF actions in the VTA mediate stress-induced cocaine seeking and that GABA-B receptor antagonists may have utility for the management of stress-induced relapse in cocaine addicts. Copyright © 2015 Elsevier Ltd. All rights reserved.

Distinct mechanisms underlie activation of hypothalamic neurosecretory neurons and their medullary catecholaminergic afferents in categorically different stress paradigms.

PubMed Central

Li, H Y; Ericsson, A; Sawchenko, P E

1996-01-01

Intermittent electrical footshock induces c-fos expression in parvocellular neurosecretory neurons expressing corticotropin-releasing factor and in other visceromotor cell types of the paraventricular hypothalamic nucleus (PVH). Since catecholaminergic neurons of the nucleus of the solitary tract and ventrolateral medulla make up the dominant loci of footshock-responsive cells that project to the PVH, these were evaluated as candidate afferent mediators of hypothalamic neuroendocrine responses. Rats bearing discrete unilateral transections of this projection system were exposed to a single 30-min footshock session and sacrificed 2 hr later. Despite depletion of the aminergic innervation on the ipsilateral side, shock-induced up-regulation of Fos protein and corticotropin-releasing factor mRNA were comparable in strength and distribution in the PVH on both sides of the brain. This lesion did, however, result in a substantial reduction of Fos expression in medullary aminergic neurons on the ipsilateral side. These results contrast diametrically with those obtained in a systemic cytokine (interleukin 1) challenge paradigm, where similar cuts ablated the Fos response in the ipsilateral PVH but left intact the induction seen in the ipsilateral medulla. We conclude that (i) footshock-induced activation of medullary aminergic neurons is a secondary consequence of stress, mediated via a descending projection transected by our ablation, (ii) stress-induced activation of medullary aminergic neurons is not necessarily predictive of an involvement of these cell groups in driving hypothalamic visceromotor responses to a given stressor, and (iii) despite striking similarities in the complement of hypothalamic effector neurons and their afferents that may be activated by stresses of different types, distinct mechanisms may underlie adaptive hypothalamic responses in each. Images Fig. 1 Fig. 3 Fig. 4 Fig. 5 PMID:8637878

Effects of comfort food on food intake, anxiety-like behavior and the stress response in rats.

PubMed

Ortolani, D; Oyama, L M; Ferrari, E M; Melo, L L; Spadari-Bratfisch, R C

2011-07-06

It has been suggested that access to high caloric food attenuates stress response. The present paper investigates whether access to commercial chow enriched with glucose and fat, here referred to as comfort food alters behavioral, metabolic, and hormonal parameters of rats submitted to three daily sessions of foot-shock stress. Food intake, anxiety-like behaviors, and serum levels of insulin, leptin, corticosterone, glucose and triglycerides were determined. The rats submitted to stress decreased the intake of commercial chow, but kept unaltered the intake of comfort food. During the elevated plus maze (EPM) test, stressed rats increased the number of head dipping, entries into the open arms, as well as the time spent there, and decreased the number of stretched-attend posture and risk assessment. These effects of stress were independent of the type of food consumed. Non-stressed rats ingesting comfort food decreased risk assessment as well. Stress and comfort food increased time spent in the center of the open field and delayed the first crossing to a new quadrant. Stress increased the plasma level of glucose and insulin, and reduced triglycerides, although consumption of comfort food increases glucose, triglyceride and leptin levels; no effect on leptin level was associated to stress. The stress induced increase in serum corticosterone was attenuated when rats had access to comfort food. It was concluded that foot-shock stress has an anorexigenic effect that is independent of leptin and prevented upon access to comfort food. Foot-shock stress also has an anxiolytic effect that is potentiated by the ingestion of comfort food and that is evidenced by both EPM and open field tests. Copyright © 2011 Elsevier Inc. All rights reserved.

Stress triggers anhedonia in rats bred for learned helplessness.

PubMed

Enkel, Thomas; Spanagel, Rainer; Vollmayr, Barbara; Schneider, Miriam

2010-05-01

Congenitally helpless (cLH) rats, a well-accepted model for depression, show reduced consumption of sweet solutions only under single-housing conditions, indicating anhedonia under stress. We investigated if anhedonic-like behaviour, measured by a reduction of sweetened-condensed milk (SCM) intake and the pleasure-attenuated startle response (PAS), could be induced by an electric foot-shock stress challenge in group-housed rats. After foot-shock stress, reduced SCM intake was observed in cLH rats compared to non-helpless (cNLH) rats. Furthermore, cLH rats also showed a decreased PAS, indicating deficient reward perception. In summary, we demonstrate that a predisposition for learned helplessness interacts with stress to trigger anhedonic-like behaviour in cLH rats. These findings further add to the validity of congenitally learned helplessness as an animal model of depression, since gene-environment interactions are considered to play a role in the etiology of this disorder.

Effects of stressor predictability and controllability on sleep, temperature, and fear behavior in mice.

PubMed

Yang, Linghui; Wellman, Laurie L; Ambrozewicz, Marta A; Sanford, Larry D

2011-06-01

Predictability and controllability are important factors in the persisting effects of stress. We trained mice with signaled, escapable shock (SES) and with signaled, inescapable shock (SIS) to determine whether shock predictability can be a significant factor in the effects of stress on sleep. Male BALB/cJ mice were implanted with transmitters for recording EEG, activity, and temperature via telemetry. After recovery from surgery, baseline sleep recordings were obtained for 2 days. The mice were then randomly assigned to SES (n = 9) and yoked SIS (n = 9) conditions. The mice were presented cues (90 dB, 2 kHz tones) that started 5.0 sec prior to and co-terminated with footshocks (0.5 mA; 5.0 sec maximum duration). SES mice always received shock but could terminate it by moving to the non-occupied chamber in a shuttlebox. SIS mice received identical tones and shocks, but could not alter shock duration. Twenty cue-shock pairings (1.0-min interstimulus intervals) were presented on 2 days (ST1 and ST2). Seven days after ST2, SES and SIS mice, in their home cages, were presented with cues identical to those presented during ST1 and ST2. NA. NA. NA. On each training and test day, EEG, activity and temperature were recorded for 20 hours. Freezing was scored in response to the cue alone. Compared to SIS mice, SES mice showed significantly increased REM after ST1 and ST2. Compared to SES mice, SIS mice showed significantly increased NREM after ST1 and ST2. Both groups showed reduced REM in response to cue presentation alone. Both groups showed similar stress-induced increases in temperature and freezing in response to the cue alone. These findings indicate that predictability (modeled by signaled shock) can play a significant role in the effects of stress on sleep.

Repeated treatment with nitric oxide synthase inhibitor attenuates learned helplessness development in rats and increases hippocampal BDNF expression.

PubMed

Stanquini, Laura Alves; Biojone, Caroline; Guimarães, Francisco Silveira; Joca, Sâmia Regiane

2017-11-20

Nitric oxide synthase (NOS) inhibitors induce antidepressant-like effects in animal models sensitive to acute drug treatment such as the forced swimming test. However, it is not yet clear if repeated treatment with these drugs is required to induce antidepressant-like effects in preclinical models. The aim of this study was to test the effect induced by acute or repeated (7 days) treatment with 7-nitroindazole (7-NI), a preferential inhibitor of neuronal NOS, in rats submitted to the learned helplessness (LH) model. In addition, we aimed at investigating if 7-NI treatment would increase brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus, similarly to the effect of prototype antidepressants. Animals were submitted to a pre-test (PT) session with inescapable footshocks or habituation (no shocks) to the experimental shuttle box. Six days later they were exposed to a test with escapable footshocks. Independent groups received acute (a single injection after PT or before test) or repeated (once a day for 7 days) treatment with vehicle or 7-NI (30 mg/kg). Repeated, but not acute, treatment with 7-NI attenuated LH development. The effect was similar to repeated imipramine treatment. Moreover, in an independent experimental group, only repeated treatment with 7-NI and imipramine increased BDNF protein levels in the hippocampus. The results suggest the nitrergic system could be a target for the treatment of depressive-like conditions. They also indicate that, similar to the positive control imipramine, the antidepressant-like effects of NOS inhibition could involve an increase in hippocampal BDNF levels.

Metformin and ascorbic acid combination therapy ameliorates type 2 diabetes mellitus and comorbid depression in rats.

PubMed

Shivavedi, Naveen; Kumar, Mukesh; Tej, Gullanki Naga Venkata Charan; Nayak, Prasanta Kumar

2017-11-01

Diabetes mellitus and depression are the common comorbid disorders affecting humans worldwide. There is an unmet need to develop therapeutic strategies to treat both diabetes mellitus and comorbid depression. The present study evaluated the effectiveness of metformin and ascorbic acid against type 2 diabetes mellitus and comorbid depression in rats. Four groups of diabetic rats were orally administered with vehicle (1mL/kg), metformin (25mg/kg), ascorbic acid (25mg/kg), or combination of metformin (25mg/kg) and ascorbic acid (25mg/kg) for 11 consecutive days. Diabetes was induced by single-dose administration of streptozotocin (65mg/kg, i.p.) with nicotinamide (120mg/kg, i.p.). Comorbid depression was induced by five inescapable foot-shocks (2mA, 2ms duration) at 10s intervals on days 1, 5, 7, and 10. One group of healthy rats received only vehicles to serve as nondiabetic control group. On day 11, animals were sacrificed, and blood and brain samples were collected from each rat following forced swim test. Plasma glucose, insulin, and corticosterone levels were estimated in plasma. The levels of monoamines, proinflammatory cytokines, and oxidative stress were measured in prefrontal cortex. The combination therapy significantly reduced immobility period, glucose, and corticosterone levels relative to diabetes with comorbid depression group. Furthermore, the combination therapy increased the levels of insulin and monoamines, and caused a significant reductions in oxidative stress and proinflammatory cytokines. In conclusion, the present study revealed that metformin and ascorbic acid combination therapy could be a potential strategy to treat type 2 diabetes mellitus and comorbid depression. Copyright © 2017 Elsevier B.V. All rights reserved.

Remodeling of hippocampal spine synapses in the rat learned helplessness model of depression.

PubMed

Hajszan, Tibor; Dow, Antonia; Warner-Schmidt, Jennifer L; Szigeti-Buck, Klara; Sallam, Nermin L; Parducz, Arpad; Leranth, Csaba; Duman, Ronald S

2009-03-01

Although it has been postulated for many years that depression is associated with loss of synapses, primarily in the hippocampus, and that antidepressants facilitate synapse growth, we still lack ultrastructural evidence that changes in depressive behavior are indeed correlated with structural synaptic modifications. We analyzed hippocampal spine synapses of male rats (n=127) with electron microscopic stereology in association with performance in the learned helplessness paradigm. Inescapable footshock (IES) caused an acute and persistent loss of spine synapses in each of CA1, CA3, and dentate gyrus, which was associated with a severe escape deficit in learned helplessness. On the other hand, IES elicited no significant synaptic alterations in motor cortex. A single injection of corticosterone reproduced both the hippocampal synaptic changes and the behavioral responses induced by IES. Treatment of IES-exposed animals for 6 days with desipramine reversed both the hippocampal spine synapse loss and the escape deficit in learned helplessness. We noted, however, that desipramine failed to restore the number of CA1 spine synapses to nonstressed levels, which was associated with a minor escape deficit compared with nonstressed control rats. Shorter, 1-day or 3-day desipramine treatments, however, had neither synaptic nor behavioral effects. These results indicate that changes in depressive behavior are associated with remarkable remodeling of hippocampal spine synapses at the ultrastructural level. Because spine synapse loss contributes to hippocampal dysfunction, this cellular mechanism may be an important component in the neurobiology of stress-related disorders such as depression.

Post-stress facilitation of serotonergic, but not noradrenergic, neurotransmission in the dorsal hippocampus prevents learned helplessness development in rats.

PubMed

Joca, Sâmia Regiane Lourenço; Zanelati, Tatiane; Guimarães, Francisco Silveira

2006-05-04

Recent pieces of evidence suggest that the dorsal hippocampus may mediate adaptation to severe and inescapable stress, possibly by the facilitation of serotonergic and/or noradrenergic neurotransmission. Chronic social stress and high corticosteroid levels would impair this coping mechanism, predisposing animals to learned helplessness. To test the hypothesis that increasing serotonin or noradrenaline levels in the dorsal hippocampus would attenuate the development of learned helplessness (LH), rats received inescapable foot shock (IS) and were tested in a shuttle box 24 h latter. Prestressed animals showed impairment of escape responses. This effect was prevented by bilateral intrahippocampal injections of zimelidine (100 nmol/0.5 microl), a serotonin reuptake blocker, immediately after IS. This effect was not observed when zimelidine was administered before or 2 h after IS. Bilateral intrahippocampal injections of desipramine (3 or 30 nmol/0.5 microl), a noradrenaline reuptake blocker, before IS or immediately after it did not prevent LH development. Desipramine (30 nmol) enhanced LH development when injected before IS. These data suggest that poststress facilitation of hippocampal serotonergic, but not noradrenergic, neurotransmission in the dorsal hippocampus facilitates adaptation to severe inescapable stress. Antidepressant effects of noradrenaline-selective drugs seem to depend on other structures than the dorsal hippocampus.

Adolescent social defeat increases adult amphetamine conditioned place preference and alters D2 dopamine receptor expression

PubMed Central

Burke, Andrew R.; Watt, Michael J.; Forster, Gina L.

2011-01-01

Components of the brain’s dopaminergic system, such as dopamine receptors, undergo final maturation in adolescence. Exposure to social stress during human adolescence contributes to substance abuse behaviors. We utilized a rat model of adolescent social stress to investigate the neural mechanisms underlying this correlation. Rats exposed to repeated social defeat in adolescence (P35–P39) exhibited increased conditioned place preference (CPP) for amphetamine (1 mg/kg) in adulthood (P70). In contrast, rats experiencing foot-shock during the same developmental period exhibited amphetamine CPP levels similar to non-stressed controls. Our previous experiments suggested adolescent defeat alters dopamine activity in the mesocorticolimbic system. Furthermore, dopamine receptors have been implicated in the expression of amphetamine CPP. Therefore, we hypothesized that alteration to dopamine receptor expression in the mesocorticolimbic system may be associated with to heightened amphetamine CPP of adult rats exposed to adolescence defeat. We measured D1 and D2 dopamine receptor protein content in the medial prefrontal cortex, nucleus accumbens (NAc) and dorsal striatum following either adolescent social defeat or foot-shock stress and then adult amphetamine CPP. In controls, amphetamine CPP training reduced D2 receptor protein content in the NAc core. However, this down-regulation of NAc core D2 receptors was blocked by exposure to social defeat but not foot-shock stress in adolescence. These results suggest social defeat stress in adolescence alters the manner in which later amphetamine exposure down-regulates D2 receptors. Furthermore, persistent alterations to adult D2 receptor expression and amphetamine responses may depend on the type of stress experienced in adolescence. PMID:21933700

Neurobehavioral, neuropathological and biochemical profiles in a novel mouse model of co-morbid post-traumatic stress disorder and mild traumatic brain injury

PubMed Central

Ojo, Joseph O.; Greenberg, M. Banks; Leary, Paige; Mouzon, Benoit; Bachmeier, Corbin; Mullan, Michael; Diamond, David M.; Crawford, Fiona

2014-01-01

Co-morbid mild traumatic brain injury (mTBI) and post-traumatic stress disorder (PTSD) has become the signature disorder for returning combat veterans. The clinical heterogeneity and overlapping symptomatology of mTBI and PTSD underscore the need to develop a preclinical model that will enable the characterization of unique and overlapping features and allow discrimination between both disorders. This study details the development and implementation of a novel experimental paradigm for PTSD and combined PTSD-mTBI. The PTSD paradigm involved exposure to a danger-related predator odor under repeated restraint over a 21 day period and a physical trauma (inescapable footshock). We administered this paradigm alone, or in combination with a previously established mTBI model. We report outcomes of behavioral, pathological and biochemical profiles at an acute timepoint. PTSD animals demonstrated recall of traumatic memories, anxiety and an impaired social behavior. In both mTBI and combination groups there was a pattern of disinhibitory like behavior. mTBI abrogated both contextual fear and impairments in social behavior seen in PTSD animals. No major impairment in spatial memory was observed in any group. Examination of neuroendocrine and neuroimmune responses in plasma revealed a trend toward increase in corticosterone in PTSD and combination groups, and an apparent increase in Th1 and Th17 proinflammatory cytokine(s) in the PTSD only and mTBI only groups respectively. In the brain there were no gross neuropathological changes in any groups. We observed that mTBI on a background of repeated trauma exposure resulted in an augmentation of axonal injury and inflammatory markers, neurofilament L and ICAM-1 respectively. Our observations thus far suggest that this novel stress-trauma-related paradigm may be a useful model for investigating further the overlapping and distinct spatio-temporal and behavioral/biochemical relationship between mTBI and PTSD experienced by combat veterans. PMID:25002839

Differential Effects of Inescapable Stress on Locus Coeruleus GRK3, Alpha2-Adrenoceptor and CRF1 Receptor Levels in Learned Helpless and Non-Helpless Rats: A potential link to stress resilience

PubMed Central

Taneja, Manish; Salim, Samina; Saha, Kaustuv; Happe, H. Kevin; Qutna, Nidal; Petty, Frederick; Bylund, David B.; Eikenburg, Douglas C.

2011-01-01

Exposure of rats to unpredictable, inescapable stress results in two distinct behaviors during subsequent escape testing. One behavior, suggestive of lack of stress resilience, is prolonged escape latency compared to non-stressed rats and is labeled learned helplessness (LH). The other behavior suggestive of stress resilience is normal escape latency and is labeled non-helpless (NH). This study examines the effects of unpredictable, inescapable tail-shock stress (TSS) on alpha2-adrenoceptor (α2-AR) and corticotropin-releasing factor 1 receptor (CRF1) regulation as well as protein levels of G protein-coupled receptor kinase 3 (GRK3), GRK2, tyrosine hydroxylase (TH) plus carbonylated protein levels in locus coeruleus (LC), amygdala (AMG), cortex (COR) and striatum (STR). In NH rats, α2-AR and CRF1 receptors were significantly down-regulated in LC after TSS. No changes in these receptor levels were observed in the LC of LH rats. GRK3, which phosphorylates receptors and thereby contributes to α2-AR and CRF1 receptor down-regulation, was reduced in the LC of LH but not NH rats. GRK2 levels were unchanged. In AMG, GRK3 but not GRK2 levels were reduced in LH but not NH rats, and receptor regulation was impaired in LH rats. In STR, no changes in GRK3 or GRK2 levels were observed. Finally, protein carbonylation, an index of oxidative stress, was increased in the LC and AMG of LH but not NH rats. We suggest that reduced stress resilience after TSS may be related to oxidative stress, depletion of GRK3 and impaired regulation of α2-AR and CRF1 receptor in LC. PMID:21333691

Prior stress exposure increases pain behaviors in a rat model of full thickness thermal injury.

PubMed

Nyland, Jennifer E; McLean, Samuel A; Averitt, Dayna L

2015-12-01

Thermal burns among individuals working in highly stressful environments, such as firefighters and military Service Members, are common. Evidence suggests that pre-injury stress may exaggerate pain following thermal injury; however current animal models of burn have not evaluated the potential influence of pre-burn stress. This sham-controlled study evaluated the influence of prior stress exposure on post-burn thermal and mechanical sensitivity in male Sprague-Dawley rats. Rats were exposed to 20 min of inescapable swim stress or sham stress once per day for three days. Exposure to inescapable swim stress (1) increased the intensity and duration of thermal hyperalgesia after subsequent burn and (2) accelerated the onset of thermal hyperalgesia and mechanical allodynia after subsequent burn. This stress-induced exacerbation of pain sensitivity was reversed by pretreatment and concurrent treatment with the serotonin-norepinephrine reuptake inhibitor (SNRI) duloxetine. These data suggest a better understanding of mechanisms by which prior stress augments pain after thermal burn may lead to improved pain treatments for burn survivors. Copyright © 2015 Elsevier Ltd and ISBI. All rights reserved.

Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus

PubMed Central

Greenwood, Benjamin N.; Strong, Paul V.; Foley, Teresa E.; Thompson, Robert; Fleshner, Monika

2007-01-01

Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein. The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 hours later. Finally, bilateral injections of BDNF (1 μg) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats. These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not necessary for the protective effect of wheel running against learned helplessness. PMID:17161541

Learned helplessness is independent of levels of brain-derived neurotrophic factor in the hippocampus.

PubMed

Greenwood, B N; Strong, P V; Foley, T E; Thompson, R S; Fleshner, M

2007-02-23

Reduced levels of brain-derived neurotrophic factor (BDNF) in the hippocampus have been implicated in human affective disorders and behavioral stress responses. The current studies examined the role of BDNF in the behavioral consequences of inescapable stress, or learned helplessness. Inescapable stress decreased BDNF mRNA and protein in the hippocampus of sedentary rats. Rats allowed voluntary access to running wheels for either 3 or 6 weeks prior to exposure to stress were protected against stress-induced reductions of hippocampal BDNF protein. The observed prevention of stress-induced deceases in BDNF, however, occurred in a time course inconsistent with the prevention of learned helplessness by wheel running, which is evident following 6 weeks, but not 3 weeks, of wheel running. BDNF suppression in physically active rats was produced by administering a single injection of the selective serotonin reuptake inhibitor fluoxetine (10 mg/kg) just prior to stress. Despite reduced levels of hippocampal BDNF mRNA following stress, physically active rats given the combination of fluoxetine and stress remained resistant against learned helplessness. Sedentary rats given both fluoxetine and stress still demonstrated typical learned helplessness behaviors. Fluoxetine by itself reduced BDNF mRNA in sedentary rats only, but did not affect freezing or escape learning 24 h later. Finally, bilateral injections of BDNF (1 mug) into the dentate gyrus prior to stress prevented stress-induced reductions of hippocampal BDNF but did not prevent learned helplessness in sedentary rats. These data indicate that learned helplessness behaviors are independent of the presence or absence of hippocampal BDNF because blocking inescapable stress-induced BDNF suppression does not always prevent learned helplessness, and learned helplessness does not always occur in the presence of reduced BDNF. Results also suggest that the prevention of stress-induced hippocampal BDNF suppression is not necessary for the protective effect of wheel running against learned helplessness.

Remodeling of Hippocampal Spine Synapses in the Rat Learned Helplessness Model of Depression

PubMed Central

Hajszan, Tibor; Dow, Antonia; Warner-Schmidt, Jennifer L.; Szigeti-Buck, Klara; Sallam, Nermin L.; Parducz, Arpad; Leranth, Csaba; Duman, Ronald S.

2009-01-01

Background Although it has been postulated for many years that depression is associated with loss of synapses, primarily in the hippocampus, and that antidepressants facilitate synapse growth, we still lack ultrastructural evidence that changes in depressive behavior are indeed correlated with structural synaptic modifications. Methods We analyzed hippocampal spine synapses of male rats (n=127) with electron microscopic stereology in association with performance in the learned helplessness paradigm. Results Inescapable footshock (IES) caused an acute and persistent loss of spine synapses in each of CA1, CA3, and dentate gyrus, which was associated with a severe escape deficit in learned helplessness. On the other hand, IES elicited no significant synaptic alterations in motor cortex. A single injection of corticosterone reproduced both the hippocampal synaptic changes and the behavioral responses induced by IES. Treatment of IES-exposed animals for six days with desipramine reversed both the hippocampal spine synapse loss and the escape deficit in learned helplessness. We noted, however, that desipramine failed to restore the number of CA1 spine synapses to nonstressed levels, which was associated with a minor escape deficit compared to nonstressed controls. Shorter, one-day or three-day desipramine treatments, however, had neither synaptic nor behavioral effects. Conclusions These results indicate that changes in depressive behavior are associated with remarkable remodeling of hippocampal spine synapses at the ultrastructural level. Because spine synapse loss contributes to hippocampal dysfunction, this cellular mechanism may be an important component in the neurobiology of stress-related disorders such as depression. PMID:19006787

Effects of Stressor Predictability and Controllability on Sleep, Temperature, and Fear Behavior in Mice

PubMed Central

Yang, Linghui; Wellman, Laurie L.; Ambrozewicz, Marta A.; Sanford, Larry D.

2011-01-01

Study Objectives: Predictability and controllability are important factors in the persisting effects of stress. We trained mice with signaled, escapable shock (SES) and with signaled, inescapable shock (SIS) to determine whether shock predictability can be a significant factor in the effects of stress on sleep. Design: Male BALB/cJ mice were implanted with transmitters for recording EEG, activity, and temperature via telemetry. After recovery from surgery, baseline sleep recordings were obtained for 2 days. The mice were then randomly assigned to SES (n = 9) and yoked SIS (n = 9) conditions. The mice were presented cues (90 dB, 2 kHz tones) that started 5.0 sec prior to and co-terminated with footshocks (0.5 mA; 5.0 sec maximum duration). SES mice always received shock but could terminate it by moving to the non-occupied chamber in a shuttlebox. SIS mice received identical tones and shocks, but could not alter shock duration. Twenty cue-shock pairings (1.0-min interstimulus intervals) were presented on 2 days (ST1 and ST2). Seven days after ST2, SES and SIS mice, in their home cages, were presented with cues identical to those presented during ST1 and ST2. Setting: NA. Patients or Participants: NA. Interventions: NA. Measurements and Results: On each training and test day, EEG, activity and temperature were recorded for 20 hours. Freezing was scored in response to the cue alone. Compared to SIS mice, SES mice showed significantly increased REM after ST1 and ST2. Compared to SES mice, SIS mice showed significantly increased NREM after ST1 and ST2. Both groups showed reduced REM in response to cue presentation alone. Both groups showed similar stress-induced increases in temperature and freezing in response to the cue alone. Conclusions: These findings indicate that predictability (modeled by signaled shock) can play a significant role in the effects of stress on sleep. Citation: Yang L; Wellman LL; Ambrozewicz MA; Sanford LD. Effects of stressor predictability and controllability on sleep, temperature, and fear behavior in mice. SLEEP 2011;34(6):759-771. PMID:21629364

Serotonin transporter deficient mice are vulnerable to escape deficits following inescapable shocks.

PubMed

Muller, J M; Morelli, E; Ansorge, M; Gingrich, J A

2011-03-01

Modulation of serotonin transporter (5-HTT) function causes changes in affective behavior, both in humans and rodents. Stressful life events likewise affect emotional behavior. In humans, a low-expressing genetic 5-htt variant, the s allele of the 5-htt linked promoter region, has been associated with increased risk for depression only where there was a history of stressful life events. To investigate this gene by environment interaction in mice, we compared the effects of inescapable shocks on the behavior of wild-type (5-htt+/+), heterozygote (5-htt+/-) and serotonin transporter deficient (5-htt-/-) mice. Inescapable shocks induce behavioral changes including a shock escape deficit, in a subsequent test when escape is possible. Confirming a gene by environment interaction, we found that stress increases escape latencies in a gene-dose dependent manner (5-htt-/->5-htt+/->5-htt +/+), where as there were no differences among the genotypes in the unstressed condition. The vulnerability to increased escape latency could not be accounted for by enhanced fear learning, as 5-htt-/- mice did not show heightened fear conditioning. The interaction of 5-htt genotype and stress appeared to produce a selective behavioral vulnerability, because no interaction of 5-htt genotype and stress was observed in other measures of anxiety and depression-linked behavior, including the open field, novelty suppressed feeding, and forced swim tests. We replicated prior findings that the 5-htt-/- displays heightened anxiety and depression-like behavior at baseline (unstressed condition). In conclusion, our data offer the possibility for future investigation of the neural basis underlying 5-htt genotype-by-stress interaction shown here. © 2010 The Authors. Genes, Brain and Behavior © 2010 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Chronic Desipramine Prevents Acute Stress-Induced Reorganization of Medial Prefrontal Cortex Architecture by Blocking Glutamate Vesicle Accumulation and Excitatory Synapse Increase

PubMed Central

Treccani, Giulia; Liebenberg, Nico; Chen, Fenghua; Popoli, Maurizio; Wegener, Gregers; Nyengaard, Jens Randel

2015-01-01

Background: Although a clear negative influence of chronic exposure to stressful experiences has been repeatedly demonstrated, the outcome of acute stress on key brain regions has only just started to be elucidated. Although it has been proposed that acute stress may produce enhancement of brain plasticity and that antidepressants may prevent such changes, we still lack ultrastructural evidence that acute stress-induced changes in neurotransmitter physiology are coupled with structural synaptic modifications. Methods: Rats were pretreated chronically (14 days) with desipramine (10mg/kg) and then subjected to acute foot-shock stress. By means of serial section electron microscopy, the structural remodeling of medial prefrontal cortex glutamate synapses was assessed soon after acute stressor cessation and stress hormone levels were measured. Results: Foot-shock stress induced a remarkable increase in the number of docked vesicles and small excitatory synapses, partially and strongly prevented by desipramine pretreatment, respectively. Acute stress-induced corticosterone elevation was not affected by drug treatment. Conclusions: Since desipramine pretreatment prevented the stress-induced structural plasticity but not the hormone level increase, we hypothesize that the preventing action of desipramine is located on pathways downstream of this process and/or other pathways. Moreover, because enhancement of glutamate system remodeling may contribute to overexcitation dysfunctions, this aspect could represent a crucial component in the pathophysiology of stress-related disorders. PMID:25522419

Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats

PubMed Central

Gilbert, Jeremy; Campos, Arlene C.; Kline, Nicole; Ashby, Charles R.; Hagan, Jim J.; Heidbreder, Christian A.; Gardner, Eliot L.

2013-01-01

Rationale The dopamine (DA) D3 receptor is preferentially expressed in the mesolimbic system. We have previously shown that selective D3 receptor blockade by the novel D3 antagonist SB-277011A inhibits cocaine’s reinforcing action and cocaine-induced reinstatement of cocaine-seeking behavior. Objective In the present study, we investigated whether SB-277011A similarly inhibits stress-induced reinstatement of cocaine-seeking behavior. Methods Rats were allowed to self-administer cocaine (0.5 mg/kg per infusion, 3 h per session) for 10–14 days, followed by a once-daily extinction session for 7–14 days during which saline was substituted for cocaine. Extinction criteria were fewer than ten lever-presses per 3-h session for at least 3 consecutive days. After cocaine-seeking behavior was extinguished, each animal was tested twice for footshock-stress-induced reinstatement, once with vehicle (25% hydroxypropyl-β-cyclodextrin) and once with one of three doses of SB-277011A in counterbalanced fashion. Results During the last 3 days of cocaine self-administration (SA), active lever-presses were approximately 100 per session under fixed-ratio 2 reinforcement (~25 mg/kg cocaine per session). After extinction, intermittent footshock (10 min, 0.5 mA, 0.5 s on with a mean inter-shock interval of 40 s) robustly reinstated the cocaine-seeking behavior (8.4±3.6 active lever-presses in last extinction session to 35.3±5.2 in animals after footshock stress). Intraperitoneal (IP) injections of SB-277011A (3, 6, and 12 mg/kg) dose-dependently blocked stress-induced reinstatement of cocaine-seeking. Reinstatement was also blocked by microinjections of SB-277011A (1.5 μg/0.5 μl per side) bilaterally into the nucleus accumbens, but not into the dorsal striatum. Conclusions The mesolimic DA D3 receptor plays an important role in mediating stress-induced reinstatement. PMID:15083257

The effects of post-extinction exercise on cocaine-primed and stress-induced reinstatement of cocaine seeking in rats.

PubMed

Ogbonmwan, Yvonne E; Schroeder, Jason P; Holmes, Philip V; Weinshenker, David

2015-04-01

Voluntary aerobic exercise has shown promise as a treatment for substance abuse, reducing relapse in cocaine-dependent people. Wheel running also attenuates drug-primed and cue-induced reinstatement of cocaine seeking in rats, an animal model of relapse. However, in most of these studies, wheel access was provided throughout cocaine self-administration and/or extinction and had effects on several parameters of drug seeking. Moreover, the effects of exercise on footshock stress-induced reinstatement have not been investigated. The purposes of this study were to isolate and specifically examine the protective effect of exercise on relapse-like behavior elicited by a drug prime or stress. Rats were trained to self-administer cocaine at a stable level, followed by extinction training. Once extinction criteria were met, rats were split into exercise (24 h, continuous access to running wheel) and sedentary groups for 3 weeks, after which, drug-seeking behavior was assessed following a cocaine prime or footshock. We also measured galanin messenger RNA (mRNA) in the locus coeruleus and A2 noradrenergic nucleus. Exercising rats ran ∼4-6 km/day, comparable to levels previously reported for rats without a history of cocaine self-administration. Post-extinction exercise significantly attenuated cocaine-primed, but not footshock stress-induced, reinstatement of cocaine seeking, and increased galanin mRNA expression in the LC but not A2. These results indicate that chronic wheel running can attenuate some forms of reinstatement, even when initiated after the cessation of cocaine self-administration, supporting the idea that voluntary exercise programs may help maintain abstinence in clinical populations.

Prime-, Stress- and Cue-Induced Reinstatement of Extinguished Drug-Reinforced Responding in Rats: Cocaine as the Prototypical Drug of Abuse

PubMed Central

Beardsley, Patrick M.; Shelton, Keith L.

2012-01-01

This unit describes the testing of rats in prime-, footshock- and cue-induced reinstatement procedures. Evaluating rats in these procedures enables the assessment of treatments on behavior thought to model drug relapse precipitated by re-contact with an abused drug (prime-induced), induced by stress (footshock-induced), or by stimuli previously associated with drug administration (cue-induced). For instance, levels of reinstatement under the effects of test compound administration could be compared to levels under vehicle administration to help identify potential treatments for drug relapse, or reinstatement levels of different rat strains could be compared to identify potential genetic determinants of perseverative drug-seeking behavior. Cocaine is used as a prototypical drug of abuse, and relapse to its use serves as the model in this unit, but other self-administered drugs could readily be substituted with little modification to the procedures. PMID:23093352

Effects of Swim Stress on Neophobia and Reconditioning Using a Conditioned Taste Aversion Procedure

ERIC Educational Resources Information Center

Walker, Jennifer M.; Ramsey, Ashley K.; Fowler, Stephanie W.; Schachtman, Todd R.

2012-01-01

Previous research has found that swim stress during a classical conditioning trial attenuates conditioned taste aversion (CTA). In the current study, rats were used to examine the effects of inescapable swim stress on the habituation of neophobia to a flavored solution and reacquisition of an extinguished conditioned taste aversion. In Experiment…

Investigating the role of nisoldipine in foot-shock-induced post-traumatic stress disorder in mice.

PubMed

Verma, Meenu; Bali, Anjana; Singh, Nirmal; Jaggi, Amteshwar S

2016-04-01

This study was designed to investigate the effectiveness of nisoldipine, an L-type voltage-sensitive calcium channel blocker, to ameliorate anxiety and fear response in a mouse model of post-traumatic stress disorder (PTSD). Acute trauma was induced in Swiss albino mice in a 2-day electric foot-shock paradigm consisting of 15 intermittent foot-shocks of 0.8 mA intensity, 10-s duration and 10-s intershock interval, during 5 min, followed by 3 weekly situational reminders, that is, once per week in the same context on three successive weeks. PTSD-induced behavioral changes were assessed using actophotometer, open-field, social interaction test, and freezing behavior. Biochemically, the serum corticosterone levels were estimated. Electric foot-shock and situational reminders produced behavioral alterations and decreased corticosterone levels, assessed on the 21st day following the traumatic event. Administration of sertraline (Ser 15 mg/kg), a selective serotonin reuptake inhibitor (SSRI) and nisoldipine (20 and 40 mg/kg), significantly attenuated the foot-shock-trauma-induced behavioral changes along with normalization of the corticosterone levels. It may be concluded that nisoldipine produces beneficial effects in re-establishing behavioral alterations, which may be due to normalization of reduced corticosterone levels in PTSD in mice. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Restoring mood balance in depression: ketamine reverses deficit in dopamine-dependent synaptic plasticity.

PubMed

Belujon, Pauline; Grace, Anthony A

2014-12-15

One of the most novel and exciting findings in major depressive disorder research over the last decade is the discovery of the fast-acting and long-lasting antidepressant effects of ketamine. Indeed, the therapeutic effects of classic antidepressants, such as selective serotonin reuptake inhibitors, require a month or longer to be expressed, with about a third of major depressive disorder patients resistant to treatment. Clinical studies have shown that a low dose of ketamine exhibits fast-acting relatively sustained antidepressant action, even in treatment-resistant patients. However, the mechanisms of ketamine action at a systems level remain unclear. Wistar-Kyoto rats were exposed to inescapable, uncontrollable footshocks. To evaluate learned helplessness behavior, we used an active avoidance task in a shuttle box equipped with an electrical grid floor. After helplessness assessment, we performed in vivo electrophysiological recordings first from ventral tegmental area dopaminergic (DA) neurons and second from accumbens neurons responsive to fimbria stimulation. Ketamine was injected and tested on helpless behavior and electrophysiological recordings. We show that ketamine is able to restore the integrity of a network by acting on the DA system and restoring synaptic dysfunction observed in stress-induced depression. We show that part of the antidepressant effect of ketamine is via the DA system. Indeed, injection of ketamine restores a decreased dopamine neuron population activity, as well as synaptic plasticity (long-term potentiation) in the hippocampus-accumbens pathway, via, in part, activation of D1 receptors. This work provides a unique systems perspective on the mechanisms of ketamine on a disrupted limbic system. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Mouse model of fragile X syndrome: behavioral and hormonal response to stressors.

PubMed

Nielsen, Darci M; Evans, Jeffrey J; Derber, William J; Johnston, Kenzie A; Laudenslager, Mark L; Crnic, Linda S; Maclean, Kenneth N

2009-06-01

Fragile X syndrome, a form of mental retardation caused by inadequate levels of fragile X mental retardation protein (FMRP), is characterized by extreme sensitivity to sensory stimuli and increased behavioral and hormonal reactivity to stressors. Fmr1 knockout mice lack FMRP and exhibit abnormal responses to auditory stimuli. This study sought to determine whether Fmr1 knockout mice on an F1 hybrid background are normal in their response to footshock. Knockout mice were also examined for signs of hyperexcitation across an extended trial range, and serum corticosterone levels were evaluated in response to various stressors. The ability to acquire conditioned taste aversion was also assessed. Knockout mice exhibited no impairment in associative aversive learning or memory, since they successfully expressed conditioned taste aversion. Footshock-sensitivity, freezing behavior, and corticosterone response to various stressors did not differ between knockout and wild-type mice. However, knockout mice exhibited significantly increased responses during the extended test. The knockout mice's increased responsiveness to footshock in the extended test may be an indication of increased vulnerability to stress or enhanced emotional reactivity. Copyright (c) 2009 APA, all rights reserved.

Stressor controllability modulates fear extinction in humans

PubMed Central

Hartley, Catherine A.; Gorun, Alyson; Reddan, Marianne C.; Ramirez, Franchesca; Phelps, Elizabeth A.

2014-01-01

Traumatic events are proposed to play a role in the development of anxiety disorders, however not all individuals exposed to extreme stress experience a pathological increase in fear. Recent studies in animal models suggest that the degree to which one is able to control an aversive experience is a critical factor determining its behavioral consequences. In this study, we examined whether stressor controllability modulates subsequent conditioned fear expression in humans. Participants were randomly assigned to an escapable stressor condition, a yoked inescapable stressor condition, or a control condition involving no stress exposure. One week later, all participants underwent fear conditioning, fear extinction, and a test of extinction retrieval the following day. Participants exposed to inescapable stress showed impaired fear extinction learning and increased fear expression the following day. In contrast, escapable stress improved fear extinction and prevented the spontaneous recovery of fear. Consistent with the bidirectional controllability effects previously reported in animal models, these results suggest that one's degree of control over aversive experiences may be an important factor influencing the development of psychological resilience or vulnerability in humans. PMID:24333646

Effect of Cafeteria Diet History on Cue-, Pellet-Priming-, and Stress-Induced Reinstatement of Food Seeking in Female Rats

PubMed Central

Chen, Yu-Wei; Fiscella, Kimberly A.; Bacharach, Samuel Z.; Calu, Donna J.

2014-01-01

Background Relapse to unhealthy eating habits is a major problem in human dietary treatment. The individuals most commonly seeking dietary treatment are overweight or obese women, yet the commonly used rat reinstatement model to study relapse to palatable food seeking during dieting primarily uses normal-weight male rats. To increase the clinical relevance of the relapse to palatable food seeking model, here we pre-expose female rats to a calorically-dense cafeteria diet in the home-cage to make them overweight prior to examining the effect of this diet history on cue-, pellet-priming- and footshock-induced reinstatement of food seeking. Methods Post-natal day 32 female Long-Evans rats had seven weeks of home-cage access to either chow only or daily or intermittent cafeteria diet alongside chow. Next, they were trained to self-administer normally preferred 45 mg food pellets accompanied by a tone-light cue. After extinction, all rats were tested for reinstatement induced by discrete cue, pellet-priming, and intermittent footshock under extinction conditions. Results Access to daily cafeteria diet and to a lesser degree access to intermittent cafeteria diet decreased food pellet self-administration compared to chow-only. Prior history of these cafeteria diets also reduced extinction responding, cue- and pellet-priming-induced reinstatement. In contrast, modest stress-induced reinstatement was only observed in rats with a history of daily cafeteria diet. Conclusion A history of cafeteria diet does not increase the propensity for cue- and pellet-priming-induced relapse in the rat reinstatement model but does appear to make rats more susceptible to footshock stress-induced reinstatement. PMID:25025329

Antidepressant activity of nociceptin/orphanin FQ receptor antagonists in the mouse learned helplessness.

PubMed

Holanda, Victor A D; Medeiros, Iris U; Asth, Laila; Guerrini, Remo; Calo', Girolamo; Gavioli, Elaine C

2016-07-01

Pharmacological and genetic evidence support antidepressant-like effects elicited by the blockade of the NOP receptor. The learned helplessness (LH) model employs uncontrollable and unpredictable electric footshocks as a stressor stimulus to induce a depressive-like phenotype that can be reversed by classical antidepressants. The present study aimed to evaluate the action of NOP receptor antagonists in helpless mice. Male Swiss mice were subjected to the three steps of the LH paradigm (i.e., (1) induction, (2) screening, and (3) test). Only helpless animals were subjected to the test session. During the test session, animals were placed in the electrified chamber and the latency to escape after the footshock and the frequency of escape failures were recorded. The effect of the following treatments administered before the test session were evaluated: nortriptyline (30 mg/kg, ip, 60 min), fluoxetine (30 mg/kg, ip, four consecutive days of treatment), and NOP antagonists SB-612111 (1-10 mg/kg, ip, 30 min) and UFP-101 (1-10 nmol, icv, 5 min). To rule out possible biases, the effects of treatments on controllable stressful and non stressful situations were assessed. In helpless mice, nortriptyline, fluoxetine, UFP-101 (3-10 nmol), and SB-612111 (3-10 mg/kg) significantly reduced escape latencies and escape failures. No effects of drug treatments were observed in mice subjected to the controllable electric footshocks and non stressful situations. Acute treatment with NOP antagonists reversed helplessness similarly to the classical antidepressants. These findings support the proposal that NOP receptor antagonists are worthy of development as innovative antidepressant drugs.

Chronic stress and sex differences on the recall of fear conditioning and extinction.

PubMed

Baran, Sarah E; Armstrong, Charles E; Niren, Danielle C; Hanna, Jeffery J; Conrad, Cheryl D

2009-03-01

Chronic stress effects and sex differences were examined on conditioned fear extinction. Male and female Sprague-Dawley rats were chronically stressed by restraint (6 h/d/21 d), conditioned to tone and footshock, followed by extinction after 1 h and 24 h delays. Chronic stress impaired the recall of fear extinction in males, as evidenced by high freezing to tone after the 24 h delay despite exposure to the previous 1 h delay extinction trials, and this effect was not due to ceiling effects from overtraining during conditioning. In contrast, chronic stress attenuated the recall of fear conditioning acquisition in females, regardless of exposure to the 1 h extinction exposure. Since freezing to tone was reinstated following unsignalled footshocks, the deficit in the stressed rats reflected impaired recall rather than impaired consolidation. Sex differences in fear conditioning and extinction were observed in nonstressed controls as well, with control females resisting extinction to tone. Analysis of contextual freezing showed that all groups (control, stress, male, female) increased freezing immediately after the first tone extinction trial, demonstrating contextual discrimination. These findings show that chronic stress and sex interact to influence fear conditioning, with chronic stress impairing the recall of delayed fear extinction in males to implicate the medial prefrontal cortex, disrupting the recall of the fear conditioning acquisition in females to implicate the amygdala, and nonstressed controls exhibiting sex differences in fear conditioning and extinction, which may involve the amygdala and/or corticosterone levels.

The combined effects of pyridostigmine and chronic stress on brain cortical and blood acetylcholinesterase, corticosterone, prolactin and alternation performance in rats.

PubMed

Kant, G J; Bauman, R A; Feaster, S R; Anderson, S M; Saviolakis, G A; Garcia, G E

2001-01-01

Thousands of soldiers who served in the Gulf War have symptoms that have been collectively termed Gulf War Illness (GWI). It has been suggested that a combination of operational stress and pyridostigmine, a drug given as a pretreatment to protect soldiers against the effects of exposure to nerve agents, might have had unexpected adverse health effects causing these symptoms. Our laboratory has previously modeled operational stress in rats using a paradigm of around-the-clock intermittent signalled footshock. In the present studies, this model was used to investigate the potential synergistic effects of chronic stress and pyridostigmine on physiology and behavior. Seventy-two rats were trained to perform an alternation lever pressing task to earn their entire daily food intake. The rats were then implanted with osmotic minipumps containing vehicle, pyridostigmine (25 mg/ml pyridostigmine bromide) or physostigmine (20 mg/ml eserine hemisulfate). The pumps delivered 1 microl/h, which resulted in a cumulative dosing of approximately 1.5 mg/kg/day of pyridostigmine or 1.2 mg/kg/day of physostigmine, equimolar doses of the two drugs. The rats were then returned to their home cages where performance continued to be measured 24 h/day. After 4 days, 24 of the 72 rats were trained to escape signalled footshock (avoidance-escape group) and 24 other rats (yoked-stressed group) were each paired to a rat in the avoidance-escape group. The remaining 24 rats were not subjected to footshock (unstressed group). Shock trials were intermittently presented in the home cage 24 h/day for 3 days, while alternation performance continued to be measured. Since only 12 test cages were available, each condition was repeated to achieve a final n of six rats per group. Pyridostigmine and physostigmine each decreased blood acetylcholinesterase levels by approximately 50%. Physostigmine also decreased brain cortical acetylcholinesterase levels by approximately 50%, while pyridostigmine had no effect on cortical acetylcholinesterase activity. Alternation performance was impaired on the first day of stress and then recovered. Neither pyridostigmine nor physostigmine affected performance in the absence of stress or increased the effects of stress alone. Corticosterone was significantly increased in the yoked stress group compared to unstressed controls. These data suggest that pyridostigmine does not exacerbate the effects of stress on performance or levels of stress hormones. Furthermore, these data do not suggest that stress enables pyridostigmine to cross the blood brain barrier.

GENETIC MAPPING OF VOCALIZATION TO A SERIES OF INCREASING ACUTE FOOTSHOCKS USING B6.A CONSOMIC AND B6.D2 CONGENIC MOUSE STRAINS

DOE Office of Scientific and Technical Information (OSTI.GOV)

Matthews, Douglas B; Chesler, Elissa J; Cook, Melloni N.

2008-01-01

Footshock response is used to study biological functions in mammals. However, the genetics underlying variability in footshock sensitivity are not well understood. In the current studies, a panel of B6.A consomic mouse strains, two B6.D2 congenic mouse strains and the progenitor strains were screened for footshock sensitivity as measured by audible vocalization. It was found that A/J (A) mice and C57BL/6J (B6) mice with an A Chromosome 1 (Chr 1) were less sensitive to footshock compared to B6 animals. Furthermore, the offspring of Chr 1 consomic mice crossed with B6 mice had vocalization levels that were intermediate to A/J andmore » B6 animals. A F2 mapping panel revealed two significant QTLs for footshock vocalization centered around D1Mit490 and D1Mit206 on Chr 1. The role of these Chr 1 loci in footshock sensitivity was confirmed in B6.D2 congenic mice. These data identify genetic regions involved in footshock sensitivity and establish additional mouse resources for use in investigating complex behaviors.« less

Strain, Sex, and Open-Field Behavior: Factors Underlying the Genetic Susceptibility to Helplessness

PubMed Central

Padilla, Eimeira; Barrett, Douglas W.; Shumake, Jason D.; Gonzalez-Lima, F.

2009-01-01

Learned helplessness represents a failure to escape after exposure to inescapable stress and may model human psychiatric disorders related to stress. Previous work has demonstrated individual differences in susceptibility to learned helplessness. In this study, we assessed different factors associated with this susceptibility, including strain, sex, and open-field behavior. Testing of three rat strains (Holtzman, Long-Evans, and Sprague-Dawley) revealed that Holtzman rats were the most susceptible to helplessness. Holtzman rats not only had the longest escape latencies following inescapable shock, but also showed spontaneous escape deficits in the absence of prior shock when tested with a fixed-ratio 2 (FR2) running response. Moreover, when tested with fixed-ratio 1 (FR1) running—an easy response normally unaffected by helplessness training in rats—inescapable shock significantly increased the escape latencies of Holtzman rats. Within the Holtzman strain, we confirmed recent findings that females showed superior escape performance and therefore appeared more resistant to helplessness than males. However, regression and covariance analyses suggest that this sex difference may be explained by more baseline ambulatory activity among females. In addition, some indices of novelty reactivity (greater exploration of novel vs. familiar open-field) predicted subsequent helpless behavior. In conclusion, Holtzman rats, and especially male Holtzman rats, have a strong predisposition to become immobile when stressed which interferes with their ability to learn active escape responses. The Holtzman strain therefore appears to be a commercially available model for studying susceptibility to helplessness in males, and novelty-seeking may be a marker of this susceptibility. PMID:19428642

Lithium attenuated the behavioral despair induced by acute neurogenic stress through blockade of opioid receptors in mice.

PubMed

Khaloo, Pegah; Sadeghi, Banafshe; Ostadhadi, Sattar; Norouzi-Javidan, Abbas; Haj-Mirzaian, Arya; Zolfagharie, Samira; Dehpour, Ahmad-Reza

2016-10-01

Major depressive disorder is disease with high rate of morbidity and mortality. Stressful events lead to depression and they can be used as a model of depression in rodents. In this study we aimed to investigate whether lithium modifies the stressed-induced depression through blockade of opioid receptors in mice. We used foot shock stress as stressor and forced swimming test (FST), tail suspension test (TST) and open field test (OFT) to evaluation the behavioral responses in mice. We also used naltrexone hydrochloride (as opioid receptor antagonist), and morphine (as opioid receptor agonist). Our results displayed that foot-shock stress significantly increased the immobility time in TST and FST but it could not change the locomotor behavior in OFT. When we combined the low concentrations of lithium and naltrexone a significant reduction in immobility time was seen in the FST and TST in comparison with control foot-shock stressed group administered saline only. Despite the fact that our data showed low concentrations of lithium, when administered independently did not significantly affect the immobility time. Also our data indicated that concurrent administration of lithium and naltrexone had no effect on open field test. Further we demonstrated that simultaneous administration of morphine and lithium reverses the antidepressant like effect of active doses of lithium. Our data acclaimed that we lithium can augment stressed-induced depression and opioid pathways are involved in this action. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The influence of gender and the estrous cycle on learned helplessness in the rat.

PubMed

Jenkins, J A; Williams, P; Kramer, G L; Davis, L L; Petty, F

2001-11-01

Although the etiology of clinical depression is unknown, women are more likely to suffer from major depressive disorder than men. In addition, in some women, there is a clear association between depression and specific phases of the menstrual cycle. Surprisingly little research has examined gender differences and the influences of the estrous cycle in this and other animal behavioral models of clinical depression. Learned helplessness is a valid animal model of stress-induced behavioral depression in which prior exposure to inescapable stress produces deficits in escape testing. Learned helplessness was studied in rats using an inescapable tail shock stress followed by a shuttle box test to determine escape latencies. Animals with mean escape latencies of >or=20 s after shuttle-box testing are defined as learned helpless. Males and normal cycling female rats in the estrus and diestrus II phases were studied. Female rats in the diestrus II phase had significantly higher escape latencies and exhibited a more helpless behavior than female rats in the estrus phase. Male rat escape latencies were intermediate between the two female phases. These results suggest a role for gonadal hormones in the development of stress-induced behavioral depression or 'learned helplessness.'

Effects of chilling temperatures on photosynthesis

USDA-ARS?s Scientific Manuscript database

Environmental stress is an inescapable reality for most plants growing in natural settings. Conditions of sub or supra-optimal temperatures, water deficit, water logging, salinity, and pollution can have dramatic effects on plant growth and development, and in agricultural settings, yield. In cotton...

Gastro-protective and Anti-stress Efficacies of Monomethyl Fumarate and a Fumaria indica Extract in Chronically Stressed Rats.

PubMed

Shakya, Anshul; Soni, Upendra Kumar; Rai, Geeta; Chatterjee, Shyam Sunder; Kumar, Vikas

2016-05-01

Results of the very first experiments conducted to evaluate therapeutic potentials of a fumarate containing Fumaria indica extract and of fairly low daily oral doses of monomethyl fumarate for prevention of chronic unavoidable foot-shock stress-induced gastric ulcers, and possible involvement of diverse neuro-hormonal and oxidative process in their stress response desensitizing effects are reported and discussed in this article. Preventive effects of 21 daily oral 60, 120, and 240 mg/kg doses of a standardized 50 % methanolic F. indica extract (MFI) and 1.25, 2.50, and 5.00 mg/kg/day of pure monomethyl fumarate (MMF) were compared in rats subjected to one hour daily unavoidable foot-shocks. A pharmaceutically well-standardized Withania somnifera (WS) root extract was used as a reference herbal anti-stress agent in all experiments. Effects of the treatments on stress-induced alterations in body weight, adrenal and spleen weights, gastric ulcer and ulcer index, weight of glandular stomach, protective mucosal glycoprotein content, cellular proliferation, oxidative stress on stomach fundus, and brain tissues of male rats were quantified. Other parameters quantified were plasma corticosterone levels, brain monoamine levels, and expressions of the cytokines TNF-α, IL-10, and IL-1β in blood and brain of stressed and treated rats. Most but not every observed stress-induced anomalies were suppressed or completely prevented by both MFI and pure MMF treatments in dose-dependent manner. Qualitatively, the observed activity profiles of both of them were similar to those of WS dose tested. These results reveal that both MFI and MMF are potent gastro-protective agents against chronic unavoidable stress-induced ulcers and strongly suggest that they act as regulators or modulators of monoamine, corticosterone, and cytokine homeostasis.

Use of the Exponential and Exponentiated Demand Equations to Assess the Behavioral Economics of Negative Reinforcement

PubMed Central

Fragale, Jennifer E. C.; Beck, Kevin D.; Pang, Kevin C. H.

2017-01-01

Abnormal motivation and hedonic assessment of aversive stimuli are symptoms of anxiety and depression. Symptoms influenced by motivation and anhedonia predict treatment success or resistance. Therefore, a translational approach to the study of negatively motivated behaviors is needed. We describe a novel use of behavioral economics demand curve analysis to investigate negative reinforcement in animals that separates hedonic assessment of footshock termination (i.e., relief) from motivation to escape footshock. In outbred Sprague Dawley (SD) rats, relief increased as shock intensity increased. Likewise, motivation to escape footshock increased as shock intensity increased. To demonstrate the applicability to anxiety disorders, hedonic and motivational components of negative reinforcement were investigated in anxiety vulnerable Wistar Kyoto (WKY) rats. WKY rats demonstrated increased motivation for shock cessation with no difference in relief as compared to control SD rats, consistent with a negative bias for motivation in anxiety vulnerability. Moreover, motivation was positively correlated with relief in SD, but not in WKY. This study is the first to assess the hedonic and motivational components of negative reinforcement using behavioral economic analysis. This procedure can be used to investigate positive and negative reinforcement in humans and animals to gain a better understanding of the importance of motivated behavior in stress-related disorders. PMID:28270744

Reinstatement of cocaine-seeking by hypocretin (orexin) in the ventral tegmental area: Independence from the local CRF network

PubMed Central

Wang, Bin; You, Zhi-Bing; Wise, Roy A

2009-01-01

Background Hypocretin (Hcrt), an arousal- and feeding-associated peptide is expressed in lateral hypothalamic neurons that project to the ventral tegmental area (VTA). Intra-VTA Hcrt reinstates morphine-conditioned place preferences, and intracerebroventricular and intra-VTA corticotropin-releasing factor (CRF) reinstate cocaine-seeking. Each is presumed to act at least in part through actions local to the VTA. Here we examined the possibility that VTA perfusion of Hcrt reinstates cocaine-seeking and, if so, whether it does so through the VTA mechanism that is implicated in reinstatement by CRF. Methods Rats were trained to lever-press for intravenous cocaine (2 weeks) and then underwent extinction training (saline substituted for cocaine: 3 weeks). Reinstatement behavior was tested and VTA dialysates were collected and assayed for glutamate or dopamine following footshock or perfusion of Hcrt or CRF, with or without Hcrt or CRF antagonists, into the VTA. Results VTA perfusion of Hcrt-1 or footshock stress reinstated cocaine-seeking and caused release of VTA glutamate and dopamine. The effects of Hcrt-1 were blocked by a selective Hcrt-1 antagonist but not a CRF antagonist, and were not mimicked by Hcrt-2. The Hcrt-1 antagonist did not block CRF-dependent footshock-induced reinstatement or glutamate or dopamine release. The behavioral and neurochemical effects of Hcrt-1 were attenuated but not blocked by kynurenic acid, an ionotropic glutamate antagonist that blocks footshock-induced reinstatement and glutamate release. Conclusions While Hcrt and CRF are known to interact in some area of the brain, in the VTA proper they appear to have largely independent actions on the mesolimbic dopamine mechanisms of cocaine-seeking. PMID:19251246

High-fat diet with stress impaired islets' insulin secretion by reducing plasma estradiol and pancreatic GLUT2 protein levels in rats' proestrus phase.

PubMed

Salimi, M; Zardooz, H; Khodagholi, F; Rostamkhani, F; Shaerzadeh, F

2016-10-01

This study was conducted to determine whether two estrus phases (proestrus and diestrus) in female rats may influence the metabolic response to a high-fat diet and/or stress, focusing on pancreatic insulin secretion and content. Animals were divided into high-fat and normal diet groups, then each group was subdivided into stress and non-stress groups, and finally, each one of these was divided into proestrus and diestrus subgroups. At the end of high-fat diet treatment, foot-shock stress was applied to the animals. Then, blood samples were taken to measure plasma factors. Finally, the pancreas was removed for determination of glucose transporter 2 (GLUT2) protein levels and assessment of insulin content and secretion of the isolated islets. In the normal and high-fat diet groups, stress increased plasma corticosterone concentration in both phases. In both study phases, high-fat diet consumption decreased estradiol and increased leptin plasma levels. In the high-fat diet group in response to high glucose concentration, a reduction in insulin secretion was observed in the proestrus phase compared with the same phase in the normal diet group in the presence and absence of stress. Also, high-fat diet decreased the insulin content of islets in the proestrus phase compared with the normal diet. High-fat diet and/or stress caused a reduction in islet GLUT2 protein levels in both phases. In conclusion, it seems possible that high-fat diet alone or combined with foot-shock, predispose female rats to impaired insulin secretion, at least in part, by interfering with estradiol levels in the proestrus phase and decreasing pancreatic GLUT2 protein levels.

Neurokinin-1 receptor antagonism attenuates neuronal activity triggered by stress-induced reinstatement of alcohol seeking.

PubMed

Schank, J R; Nelson, B S; Damadzic, R; Tapocik, J D; Yao, M; King, C E; Rowe, K E; Cheng, K; Rice, K C; Heilig, M

2015-12-01

Substance P (SP) and its cognate neurokinin-1 receptor (NK1R) are involved in alcohol-related behaviors. We have previously reported that NK1R antagonism attenuates stress-induced reinstatement of alcohol seeking and suppresses escalated alcohol self-administration, but does not affect primary reinforcement or cue-induced reinstatement. Here, we administered an NK1R antagonist or vehicle prior to footshock-induced reinstatement of alcohol seeking, and mapped the resulting neuronal activation using Fos immunohistochemistry. As expected, vehicle treated animals exposed to footshock showed induction of Fos immunoreactivity in several regions of the brain stress circuitry, including the amygdala (AMG), nucleus accumbens (NAC), dorsal raphe nucleus (DR), prefrontal cortex (PFC), and bed nucleus of the stria terminalis (BNST). NK1R antagonism selectively suppressed the stress-induced increase in Fos in the DR and NAC shell. In the DR, Fos-induction by stress largely overlapped with tryptophan hydroxylase (TrpH), indicating activation of serotonergic neurons. Of NAC shell neurons activated during stress-induced reinstatement of alcohol seeking, about 30% co-expressed dynorphin (DYN), while 70% co-expressed enkephalin (ENK). Few (<1%) activated NAC shell neurons coexpressed choline acetyltransferase (ChAT), which labels the cholinergic interneurons of this region. Infusion of the NK1R antagonist L822429 into the NAC shell blocked stress-induced reinstatement of alcohol seeking. In contrast, L822429 infusion into the DR had no effect, suggesting that the influence of NK1R signaling on neuronal activity in the DR is indirect. Taken together, our results outline a potential pathway through which endogenous NK1R activation mediates stress-induced alcohol seeking. Copyright © 2015 Elsevier Ltd. All rights reserved.

Neuroplasticity to a single-episode traumatic stress revealed by resting-state fMRI in awake rats.

PubMed

Liang, Zhifeng; King, Jean; Zhang, Nanyin

2014-12-01

Substantial evidence has suggested that the brain structures of the medial prefrontal cortex (mPFC) and amygdala (AMYG) are implicated in the pathophysiology of stress-related disorders. However, little is known with respect to the system-level adaptation of their neural circuitries to the perturbations of traumatic stressors. By utilizing behavioral tests and an awake animal imaging approach, in the present study we non-invasively investigated the impact of single-episode predator odor exposure in an inescapable environment on behaviors and neural circuits in rodents. We found that predator odor exposure significantly increased the freezing behavior. In addition, animals exhibited heightened anxiety levels seven days after the exposure. Intriguingly, we also found that the intrinsic functional connectivity within the AMYG-mPFC circuit was considerably compromised seven days after the traumatic event. Our data provide neuroimaging evidence suggesting that prolonged neuroadaptation induced by a single episode of traumatic stress can be non-invasively detected in rodents. These results also support the face validity and construction validity of using the paradigm of single trauma exposure in an inescapable environment as an animal model for post-traumatic stress disorder. Taken together, the present study has opened a new avenue to investigating animal models of stress-related mental disorders by going beyond static neuroanatomy, and ultimately bridging the gap between basic biomedical and human imaging research. Copyright © 2014 Elsevier Inc. All rights reserved.

Impact of water temperature and stressor controllability on swim stress-induced changes in body temperature, serum corticosterone, and immobility in rats.

PubMed

Drugan, Robert C; Eren, Senem; Hazi, Agnes; Silva, Jennifer; Christianson, John P; Kent, Stephen

2005-10-01

The present study compared the effects of three different water temperatures (20, 25, and 30 degrees C) and stressor controllability on several physiological and behavioral endpoints in an intermittent swim stress paradigm. The escape latency of rats in the 20 and 25 degrees C water was less than that observed for the 30 degrees C group. Both escape and yoked groups at 20 and 25 degrees C exhibited moderate to severe hypothermia following the swim stress session that returned to prestress levels 30-40 min post-stress. At 30 degrees C core body temperature (Tb) only decreased by 1 degree C for either swim group. Following swim, serum corticosterone (CORT) levels were significantly elevated in both escape and yoked groups in comparison to confined and home cage controls. The confined control group showed a significant elevation that was approximately halfway between the home cage control and the swim stress groups. At 30 degrees C, there was still a significant elevation of serum CORT in both swim groups in comparison to confined and home cage controls. Therefore, 30 degrees C appears to be the optimal water temperature to evaluate stress controllability effects in the current paradigm. In a final experiment, swim stressor controllability effects were examined in a 5 min forced swim test (FST) 24 h following the initial stress exposure. Rats exposed to yoked-inescapable swim stress at 30 degrees C exhibited more immobility than their escapable swim stress and confined counterparts, while the escape and confined controls did not differ. These results demonstrate that the behavioral deficits observed in the FST are attributable to the stress of inescapable swim and not swim stress per se.

Stress and Neuroendocrine Regulation of Immune Responses.

DTIC Science & Technology

1986-04-20

in spleen and thymus weights, and in T- cell responsivity to mitogens following * , rief periods of restraint or electric footshock, especially with...antigen (NDV), in addition to the previously * reported increases in plasma corticosterone . The cerebral responses are particularly i-vident in...hypophysectomized mice. in which we do not observe substantial increases in * lasma corticosterone . We have not observed consistent changes in cerebral amines

Early life diets with prebiotics and bioactive milk fractions attenuate the impact of stress on learned helplessness behaviours and alter gene expression within neural circuits important for stress resistance.

PubMed

Mika, Agnieszka; Day, Heidi E W; Martinez, Alexander; Rumian, Nicole L; Greenwood, Benjamin N; Chichlowski, Maciej; Berg, Brian M; Fleshner, Monika

2017-02-01

Manipulating gut microbes may improve mental health. Prebiotics are indigestible compounds that increase the growth and activity of health-promoting microorganisms, yet few studies have examined how prebiotics affect CNS function. Using an acute inescapable stressor known to produce learned helplessness behaviours such as failure to escape and exaggerated fear, we tested whether early life supplementation of a blend of two prebiotics, galactooligosaccharide (GOS) and polydextrose (PDX), and the glycoprotein lactoferrin (LAC) would attenuate behavioural and biological responses to stress later in life. Juvenile, male F344 rats were fed diets containing either GOS and PDX alone, LAC alone, or GOS, PDX and LAC. All diets altered gut bacteria, while diets containing GOS and PDX increased Lactobacillus spp. After 4 weeks, rats were exposed to inescapable stress, and either immediately killed for blood and tissues, or assessed for learned helplessness 24 h later. Diets did not attenuate stress effects on spleen weight, corticosterone and blood glucose; however, all diets differentially attenuated stress-induced learned helplessness. Notably, in situ hybridization revealed that all diets reduced stress-evoked cfos mRNA in the dorsal raphe nucleus (DRN), a structure important for learned helplessness behaviours. In addition, GOS, PDX and LAC diet attenuated stress-evoked decreases in mRNA for the 5-HT 1A autoreceptor in the DRN and increased basal BDNF mRNA within the prefrontal cortex. These data suggest early life diets containing prebiotics and/or LAC promote behavioural stress resistance and uniquely modulate gene expression in corresponding circuits. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Changes in Galanin Systems in a Rat Model of Post-Traumatic Stress Disorder (PTSD).

PubMed

Barnabas, Karen; Zhang, Lin; Wang, Huiying; Kirouac, Gilbert; Vrontakis, Maria

2016-01-01

Post-traumatic stress disorder (PTSD) is a chronic syndrome triggered by exposure to trauma and a failure to recover from a normal negative emotional reaction to traumatic stress. The neurobiology of PTSD and the participation of neuropeptides in the neural systems and circuits that control fear and anxiety are not fully understood. The long-term dysregulation of neuropeptide systems contributes to the development of anxiety disorders, including PTSD. The neuropeptide galanin (Gal) and its receptors participate in anxiety-like and depression-related behaviors via the modulation of neuroendocrine and monoaminergic systems. The objective of this research was to investigate how Gal expression changes in the brain of rats 2 weeks after exposure to footshock. Rats exposed to footshocks were subdivided into high responders (HR; immobility>60%) and low responders (LR; immobility<40%) based on immobility elicited by a novel tone one day after exposure. On day 14, rats were anesthetized, and the amygdala, hypothalamus, pituitary and adrenal glands were removed for analysis using real-time polymerase chain reaction (RT-PCR). Gal mRNA levels were increased in the amygdala and hypothalamus of HR compared with the control and LR. In contrast, Gal mRNA levels were decreased in the adrenal and pituitary glands of HR compared with the control and LR. Thus, the differential regulation (dysregulation) of the neuropeptide Gal in these tissues may contribute to anxiety and PTSD development.

Sex differences in the outcome of juvenile social isolation on HPA axis function in rats.

PubMed

Pisu, M G; Garau, A; Boero, G; Biggio, F; Pibiri, V; Dore, R; Locci, V; Paci, E; Porcu, P; Serra, M

2016-04-21

Women are more likely than men to suffer from anxiety disorders and major depression. These disorders share hyperresponsiveness to stress as an etiological factor. Thus, sex differences in brain arousal systems and their regulation by chronic stress may account for the increased vulnerability to these disorders in women. Social isolation is a model of early life stress that results in neurobiological alterations leading to increased anxiety-like and depressive-like behaviors. Here we investigated the sex difference in the effects of post-weaning social isolation on acute stress sensitivity and behavior in rats. In both sexes, social isolation at weaning reduced basal levels of the neuroactive steroid allopregnanolone in the brain and of corticosterone in plasma. Moreover, acute stress increased plasma corticosterone levels in both group-housed and socially isolated male and female rats; however this effect was greater in male than female rats subjected to social isolation. Intriguingly, group-housed female rats showed no change in plasma and brain levels of allopregnanolone after acute foot-shock stress. The absence of stress-induced effects on allopregnanolone synthesis might be due to the physiologically higher levels of this hormone in females vs. males. Accordingly, increasing allopregnanolone levels in male rats blunted the response to foot-shock stress in these animals. Socially isolated male, but not female, rats also display depressive-like behavior and increased hippocampal brain-derived neurotrophic factor (BDNF). The ovarian steroids could "buffer" the effect of this adverse experience in females on these parameters. Finally, the dexamethasone (DEX) suppression test indicated that the chronic stress associated with social isolation impairs feedback inhibition in both sexes in which an increase in the abundance of glucocorticoid receptors (GRs) in the hippocampus was found. Altogether, these results demonstrate that social isolation affects neuroendocrine reactivity to stress, plasticity and emotionality in a sexually dimorphic manner. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Biochemical correlates in an animal model of depression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Johnson, J.O.

1986-01-01

A valid animal model of depression was used to explore specific adrenergic receptor differences between rats exhibiting aberrant behavior and control groups. Preliminary experiments revealed a distinct upregulation of hippocampal beta-receptors (as compared to other brain regions) in those animals acquiring a response deficit as a result of exposure to inescapable footshock. Concurrent studies using standard receptor binding techniques showed no large changes in the density of alpha-adrenergic, serotonergic, or dopaminergic receptor densities. This led to the hypothesis that the hippocampal beta-receptor in responses deficient animals could be correlated with the behavioral changes seen after exposure to the aversive stimulus.more » Normalization of the behavior through the administration of antidepressants could be expected to reverse the biochemical changes if these are related to the mechanism of action of antidepressant drugs. This study makes three important points: (1) there is a relevant biochemical change in the hippocampus of response deficient rats which occurs in parallel to a well-defined behavior, (2) the biochemical and behavioral changes are normalized by antidepressant treatments exhibiting both serotonergic and adrenergic mechanisms of action, and (3) the mode of action of antidepressants in this model is probably a combination of serotonergic and adrenergic influences modulating the hippocampal beta-receptor. These results are discussed in relation to anatomical and biochemical aspects of antidepressant action.« less

Stress induces equivalent remodeling of hippocampal spine synapses in a simulated postpartum environment and in a female rat model of major depression.

PubMed

Baka, Judith; Csakvari, Eszter; Huzian, Orsolya; Dobos, Nikoletta; Siklos, Laszlo; Leranth, Csaba; MacLusky, Neil J; Duman, Ronald S; Hajszan, Tibor

2017-02-20

Stress and withdrawal of female reproductive hormones are known risk factors of postpartum depression. Although both of these factors are capable of powerfully modulating neuronal plasticity, there is no direct electron microscopic evidence of hippocampal spine synapse remodeling in postpartum depression. To address this issue, hormonal conditions of pregnancy and postpartum period were simulated in ovariectomized adult female Sprague-Dawley rats (n=76). The number of hippocampal spine synapses and the depressive behavior of rats in an active escape task were investigated in untreated control, hormone-withdrawn 'postpartum', simulated proestrus, and hormone-treated 'postpartum' animals. After 'postpartum' withdrawal of gonadal steroids, inescapable stress caused a loss of hippocampal spine synapses, which was related to poor escape performance in hormone-withdrawn 'postpartum' females. These responses were equivalent with the changes observed in untreated controls that is an established animal model of major depression. Maintaining proestrus levels of ovarian hormones during 'postpartum' stress exposure did not affect synaptic and behavioral responses to inescapable stress in simulated proestrus animals. By contrast, maintaining pregnancy levels of estradiol and progesterone during 'postpartum' stress exposure completely prevented the stress-induced loss of hippocampal spine synapses, which was associated with improved escape performance in hormone-treated 'postpartum' females. This protective effect appears to be mediated by a muted stress response as measured by serum corticosterone concentrations. In line with our emerging 'synaptogenic hypothesis' of depression, the loss of hippocampal spine synapses may be a novel perspective both in the pathomechanism and in the clinical management of postpartum affective illness. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Stress Induces Equivalent Remodeling of Hippocampal Spine Synapses in a Simulated Postpartum Environment and in a Female Rat Model of Major Depression

PubMed Central

Baka, Judith; Csakvari, Eszter; Huzian, Orsolya; Dobos, Nikoletta; Siklos, Laszlo; Leranth, Csaba; MacLusky, Neil J; Duman, Ronald S; Hajszan, Tibor

2017-01-01

Stress and withdrawal of female reproductive hormones are known risk factors of postpartum depression. Although both of these factors are capable of powerfully modulating neuronal plasticity, there is no direct electron microscopic evidence of hippocampal spine synapse remodeling in postpartum depression. To address this issue, hormonal conditions of pregnancy and postpartum period were simulated in ovariectomized adult female Sprague-Dawley rats (n=76). The number of hippocampal spine synapses and the depressive behavior of rats in an active escape task were investigated in untreated control, hormone-withdrawn ‘postpa rtum’, simulated proestrus, and hormone-treated ‘postpartum’ animals. After ‘postpartum’ withdrawal of gonadal steroids, inescapable stress caused a loss of hippocampal spine synapses, which was related to poor escape performance in hormone-withdrawn ‘postpartum’ females. These responses were equivalent with the changes observed in untreated controls that is an established animal model of major depression. Maintaining proestrus levels of ovarian hormones during ‘postpartum’ stress exposure did not affect synaptic and behavioral responses to inescapable stress in simulated proestrus animals. By contrast, maintaining pregnancy levels of estradiol and progesterone during ‘postpartum’ stress exposure completely prevented the stress-induced loss of hippocampal spine synapses, which was associated with improved escape performance in hormone-treated ‘postpartum’ females. This protective effect appears to be mediated by a muted stress response as measured by serum corticosterone concentrations. In line with our emerging ‘synaptogenic hypothesis’ of depression, the loss of hippocampal spine synapses may be a novel perspective both in the pathomechanism and in the clinical management of postpartum affective illness. PMID:28012870

Leptin inhibits and ghrelin augments hypothalamic noradrenaline release after stress.

PubMed

Kawakami, Akio; Okada, Nobukazu; Rokkaku, Kumiko; Honda, Kazufumi; Ishibashi, Shun; Onaka, Tatsushi

2008-09-01

Metabolic conditions affect hypothalamo-pituitary-adrenal responses to stressful stimuli. Here we examined effects of food deprivation, leptin and ghrelin upon noradrenaline release in the hypothalamic paraventricular nucleus (PVN) and plasma adrenocorticotropic hormone (ACTH) concentrations after stressful stimuli. Food deprivation augmented both noradrenaline release in the PVN and the increase in plasma ACTH concentration following electrical footshocks (FSs). An intracerebroventricular injection of leptin attenuated the increases in hypothalamic noradrenaline release and plasma ACTH concentrations after FSs, while ghrelin augmented these responses. These data suggest that leptin inhibits and ghrelin facilitates neuroendocrine stress responses via noradrenaline release and indicate that a decrease in leptin and an increase in ghrelin release after food deprivation might contribute to augmentation of stress-induced ACTH release in a fasting state.

The Defecation Index as a Measure of Emotionality: Questions Raised by HPA Axis and Prolactin Response to Stress in the Maudsley Model.

PubMed

Blizard, David A; Eldridge, J Charles; Jones, Byron C

2015-05-01

The Maudsley Reactive and Maudsley Non-Reactive strains have been selectively bred for differences in open-field defecation (OFD), a putative index of stress. We investigated whether variations in the hypothalamic-pituitary-adrenal (HPA) axis are correlated with strain differences in OFD in the Maudsley model. Exposure to the open-field test did not result in increases in ACTH in male rats of either strain and there were no strain differences in the large increases in ACTH and corticosteroid that occurred in response to intermittent footshock. Parallel studies of prolactin showed that Maudsley Reactive rats had greater response to the open-field and to footshock than Maudsley Non-Reactive rats. The lack of correlation between strain differences in OFD and reactivity of the HPA axis is consistent with the idea that HPA response to stress and OFD reflect the output of different neural systems and that individual differences in emotionality, as indexed by OFD do not influence other measures of stress-reactivity in a simple manner, if at all. The reactivity of the prolactin system to the open-field test and lack of response of ACTH to the same situation is consistent with the idea that the prolactin system is sensitive to lower levels of stress than the HPA axis, a finding at variance with the presumed extreme sensitivity of the latter system. Earlier comparisons of the HPA axis in these strains implicate local factors such as neuropeptide-Y peptide in the adrenal in attenuating the response of the adrenal cortex to ACTH and hints at the complexity of regulation of the HPA axis.

Stress-induced alterations in interferon production and class II histocompatibility antigen expression

NASA Technical Reports Server (NTRS)

Sonnenfeld, G.; Cunnick, J. E.; Armfield, A. V.; Wood, P. G.; Rabin, B. S.

1992-01-01

Mild electric foot-shock has been shown to be a stressor that can alter immune responses. Male Lewis rats were exposed to one session of 16 5.0-s 1.6-mA foot-shocks. Production of interferon-gamma by splenocytes in response to concanavalin-A was decreased in spleens from the shocked rats compared to control spleens. Spleen cells from rats treated with nadolol, a peripherally acting beta-adrenergic receptor antagonist, and then shocked, showed dose-dependent attenuation of the suppression of interferon-gamma production. This suggests that catecholamines mediate shock-induced suppression of interferon-gamma production. The percentage of splenic mononuclear cells expressing class II histocompatibility (Ia) antigens on their surfaces from spleens of shocked rats was determined by flow cytometry. Significantly decreased class II positive mononuclear cells were present in the spleens of shocked rats in comparison to the spleens of control rats. This may reflect an alteration of cell trafficking or decreased production of class II antigens.

Examinations of the reward comparison hypothesis: The modulation of gender and footshock.

PubMed

Huang, Andrew Chih Wei; Wang, Cheng Chung; Wang, Shiun

2015-11-01

The reward comparison hypothesis suggests that drugs of abuse-induced conditioned saccharin suppression intake is due to the reward value of drugs of abuse that outweighs that of a saccharin solution dissociating from the aversive LiCl-induced conditioned taste aversion (CTA). Huang and Hsiao (2008) provided some conflict data to challenge the reward comparison hypothesis. Whether the rewarding drugs of abuse-induced conditioned suppression and the aversive LiCl-induced CTA resulted from aversion or reward should be addressed. The present study investigated how gender and footshock affect aversive LiCl- and rewarding morphine- and methamphetamine (MAMPH)-induced conditioned suppression to re-examine the reward comparison hypothesis. The results indicated that gender and footshock did not directly influence the aversive LiCl-induced CTA or rewarding morphine- and MAMPH-induced conditioned suppression. The gender effect interacted with the drug effect in the aversive LiCl- and rewarding MAMPH-induced conditioned suppression but did not interact with the drug effect in the rewarding morphine-induced conditioned suppression. Footshock interacted with the drug effect in rewarding morphine- and MAMPH-induced conditioned suppression, but footshock did not interact with the drug effect in the aversive LiCl-induced CTA. Therefore, the gender and footshock effects might play a modulatory (but not a mediating) role with the drug effect. The present data indicated that footshock modulates drugs of abuse-induced conditioned suppression, which is consistent with the reward comparison hypothesis, but our findings with regard to the modulatory role of the gender effect and the drug effect do not support this hypothesis. The reward comparison hypothesis should be discussed and possibly reconsidered. Copyright © 2015. Published by Elsevier Inc.

Nicotine Effects on the Impact of Stress

DTIC Science & Technology

2016-03-01

CONTRACTING ORGANIZATION: McLean Hospital Belmont, MA 02478 REPORT DATE: March 2016 TYPE OF REPORT: Final PREPARED FOR: U.S. Army Medical Research...Hospital AND ADDRESS(ES) 8. PERFORMING ORGANIZATION REPORT NUMBER 115 Mill Street Belmont, MA 02478 9. SPONSORING / MONITORING AGENCY NAME(S) AND...conditioned stimulus; CS) co-terminating with a 0.5-sec 0.6 mA footshock. Two different patterns of post-training nicotine intake were examined: for

Escape Performance Following Exposure to Inescapable Shock: Deficits in Motor Response Maintenance

ERIC Educational Resources Information Center

Anisman, Hymie; And Others

1978-01-01

A series of 13 experiments employing mice systematically investigated shock-elicited activity in a circular field and escape performance in a shuttle box following exposure to either escapable or inescapable shock. Results show that escape interference induced by inescapable shock may be comfortably interpreted in terms of a decreased tendency for…

Stress-dependent changes in neuroinflammatory markers observed after common laboratory stressors are not seen following acute social defeat of the Sprague Dawley rat.

PubMed

Hueston, Cara M; Barnum, Christopher J; Eberle, Jaime A; Ferraioli, Frank J; Buck, Hollin M; Deak, Terrence

2011-08-03

Exposure to acute stress has been shown to increase the expression of pro-inflammatory cytokines in brain, blood and peripheral organs. However, the nature of the inflammatory response evoked by acute stress varies depending on the stressor used and species examined. The goal of the following series of studies was to characterize the consequences of social defeat in the Sprague Dawley (SD) rat using three different social defeat paradigms. In Experiments 1 and 2, adult male SD rats were exposed to a typical acute resident-intruder paradigm of social defeat (60 min) by placement into the home cage of a larger, aggressive Long Evans rat and brain tissue was collected at multiple time points for analysis of IL-1β protein and gene expression changes in the PVN, BNST and adrenal glands. In subsequent experiments, rats were exposed to once daily social defeat for 7 or 21 days (Experiment 3) or housed continuously with an aggressive partner (separated by a partition) for 7 days (Experiment 4) to assess the impact of chronic social stress on inflammatory measures. Despite the fact that social defeat produced a comparable corticosterone response as other stressors (restraint, forced swim and footshock; Experiment 5), acute social defeat did not affect inflammatory measures. A small but reliable increase in IL-1 gene expression was observed immediately after the 7th exposure to social defeat, while other inflammatory measures were unaffected. In contrast, restraint, forced swim and footshock all significantly increased IL-1 gene expression in the PVN; other inflammatory factors (IL-6, cox-2) were unaffected in this structure. These findings provide a comprehensive evaluation of stress-dependent inflammatory changes in the SD rat, raising intriguing questions regarding the features of the stress challenge that may be predictive of stress-dependent neuroinflammation. Copyright © 2011 Elsevier Inc. All rights reserved.

Gender specific influence of endogenous glutamate release on stress-induced fear in rats.

PubMed

Jain, S K; Zelena, D

2011-01-01

Stress, fear and anxiety are among major public health concerns. The role of glutamate in these processes is becoming more recognized with promising new drug targets. The aim of this study was to establish the gender specificity of a possible treatment of fear by glutamate antagonists in correspondence with changes in stress-hormone release. Footshock-induced fear was used as an anxiogenic situation in rats. A combination of two ionotrop receptor antagonists such as MK-801 (dizocilpine; 0.2 mg/kg) for NMDA (N-methyl-D-aspartic acid) and GYKI 52466 (benzodiazepine derivative; 10 mg/kg) for AMPA/kainate receptors were used for 5 days following the hypothesis that they potentiate each other the main action, but at the same time the side effects may be minimized. Female rats tried to avoid the electrical stimulus more actively than males, as they spent more time with exploration and jumping and less time with freezing or rest. Ionotropic glutamate receptor antagonists have anxiolytic action. MK-801 was more effective in females, as it prevented the footshock-induced freezing per se, while in males it was effective only in combination with GyKI 52466. The locomotor side effect of MK-801 was not visible after repeated administration. The freezing behavior was positively correlated with the changes in prolactin but not with adrenocorticotropin levels. We proved the involvement of endogenous glutamate neurotransmission in stress-induced fear. Therapeutical usage may involve a combination of different receptor antagonists. Special attention should be paid to the gender, as females seem to be more sensitive, therefore they require smaller doses. During the treatment the prolactin levels should be monitored.

Genetic deletion of P-glycoprotein alters stress responsivity and increases depression-like behavior, social withdrawal and microglial activation in the hippocampus of female mice.

PubMed

Brzozowska, Natalia I; Smith, Kristie L; Zhou, Cilla; Waters, Peter M; Cavalcante, Ligia Menezes; Abelev, Sarah V; Kuligowski, Michael; Clarke, David J; Todd, Stephanie M; Arnold, Jonathon C

2017-10-01

P-glycoprotein (P-gp) is an ABC transporter expressed at the blood brain barrier and regulates the brain uptake of various xenobiotics and endogenous mediators including glucocorticoid hormones which are critically important to the stress response. Moreover, P-gp is expressed on microglia, the brain's immune cells, which are activated by stressors and have an emerging role in psychiatric disorders. We therefore hypothesised that germline P-gp deletion in mice might alter the behavioral and microglial response to stressors. Female P-gp knockout mice displayed an unusual, frantic anxiety response to intraperitoneal injection stress in the light-dark test. They also tended to display reduced conditioned fear responses compared to wild-type (WT) mice in a paradigm where a single electric foot-shock stressor was paired to a context. Foot-shock stress reduced social interaction and decreased microglia cell density in the amygdala which was not varied by P-gp genotype. Independently of stressor exposure, female P-gp deficient mice displayed increased depression-like behavior, idiosyncratic darting behavior, age-related social withdrawal and hyperactivity, facilitated sensorimotor gating and altered startle reactivity. In addition, P-gp deletion increased microglia cell density in the CA3 region of the hippocampus, and the microglial cells exhibited a reactive, hypo-ramified morphology. Further, female P-gp KO mice displayed increased glucocorticoid receptor (GR) expression in the hippocampus. In conclusion, this research shows that germline P-gp deletion affected various behaviors of relevance to psychiatric conditions, and that altered microglial cell activity and enhanced GR expression in the hippocampus may play a role in mediating these behaviors. Copyright © 2017 Elsevier Inc. All rights reserved.

Differential levels of brain amino acids in rat models presenting learned helplessness or non-learned helplessness.

PubMed

Muneoka, Katsumasa; Shirayama, Yukihiko; Horio, Mao; Iyo, Masaomi; Hashimoto, Kenji

2013-09-01

Glutamatergic and γ-aminobutyric acid (GABA)ergic abnormalities have recently been proposed to contribute to depression. The learned helplessness (LH) paradigm produces a reliable animal model of depression that expresses a deficit in escape behavior (LH model); an alternative phenotype that does not exhibit LH is a model of resilience to depression (non-LH model). We measured the contents of amino acids in the brain to investigate the mechanisms involved in the pathology of depression. LH and non-LH models were subjected to inescapable electric footshocks at random intervals following a conditioned avoidance test to determine acquirement of predicted escape deficits. Tissue amino acid contents in eight brain regions were measured via high-performance liquid chromatography. The non-LH model showed increased GABA levels in the dentate gyrus and nucleus accumbens and increased glutamine levels in the dentate gyrus and the orbitofrontal cortex. The LH model had reduced glutamine levels in the medial prefrontal cortex. Changes in the ratios of GABA, glutamine, and glutamate were detected in the non-LH model, but not in the LH model. Reductions in threonine levels occurred in the medial prefrontal cortex in both models, whereas elevated alanine levels were detected in the medial prefrontal cortex in non-LH animals. The present study demonstrates region-specific compensatory elevations in GABA levels in the dentate gyrus and nucleus accumbens of non-LH animals, supporting the implication of the GABAergic system in the recovery of depression.

Enduring sensorimotor gating abnormalities following predator exposure or corticotropin-releasing factor in rats: a model for PTSD-like information-processing deficits?

PubMed

Bakshi, Vaishali P; Alsene, Karen M; Roseboom, Patrick H; Connors, Elenora E

2012-02-01

A deficit in prepulse inhibition (PPI) can be one of the clinically observed features of post-traumatic stress disorder (PTSD) that is seen long after the acute traumatic episode has terminated. Thus, reduced PPI may represent an enduring psychophysiological marker of this illness in some patients. PPI is an operational measure of sensorimotor gating and refers to the phenomenon in which a weak stimulus presented immediately before an intense startling stimulus inhibits the magnitude of the subsequent startle response. The effects of stress on PPI have been relatively understudied, and in particular, there is very little information on PPI effects of ethologically relevant psychological stressors. We aimed to develop a paradigm for evaluating stress-induced sensorimotor gating abnormalities by comparing the effects of a purely psychological stressor (predator exposure) to those of a nociceptive physical stressor (footshock) on PPI and baseline startle responses in rats over an extended period of time following stressor presentation. Male Sprague-Dawley rats were exposed (within a protective cage) to ferrets for 5 min or left in their homecage and then tested for PPI immediately, 24 h, 48 h, and 9 days after the exposure. The effects of footshock were evaluated in a separate set of rats. The effects seen with stressor presentation were compared to those elicited by corticotropin-releasing factor (CRF; 0.5 and 3 μg/6 μl, intracerebroventricularly). Finally, the effects of these stressors and CRF administration on plasma corticosterone were measured. PPI was disrupted 24 h after ferret exposure; in contrast, footshock failed to affect PPI at any time. CRF mimicked the predator stress profile, with the lowdose producing a PPI deficit 24 h after infusion. Interestingly, the high dose also produced a PPI deficit 24 h after infusion, but with this dose, the PPI deficit was evident even 9d later. Plasma corticosterone levels were elevated acutely (before PPI deficits emerged) by both stressors and CRF, but returned to normal control levels 24 h later, when PPI deficits were present. Thus, predator exposure produces a delayed disruption of PPI, and stimulation of CRF receptors recapitulates these effects. Contemporaneous HPA axis activation is neither necessary nor sufficient for these PPI deficits. These results indicate that predator exposure, perhaps acting through CRF, may model the delayed-onset and persistent sensorimotor gating abnormalities that have been observed clinically in PTSD, and that further studies using this model may shed insight on the mechanisms of information-processing deficits in this disorder. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Effects of signaling inescapable shock on subsequent escape learning: implications for theories of coping and "learned helplessness".

PubMed

Jackson, R L; Minor, T R

1988-10-01

The present experiments reveal that shuttle-escape performance deficits are eliminated when exteroceptive cues are paired with inescapable shock. Experiment 1 indicated that, as in instrumental control, a signal following inescapable shock eliminated later escape performance deficits. Subsequent experiments revealed that both forward and backward pairings between signals and inescapable shock attenuated performance deficits. However, the data also suggest that the impact of these temporal relations may be modulated by qualitative aspects of the cues because the effects of these relations depended upon whether an increase or decrease in illumination (Experiment 2) or a compound auditory cue (Experiment 4) was used. Preliminary evidence suggests that the ability of illumination cues to block escape learning deficits may be related to their to reduce contextual fear (Experiment 3). The implications of these data for conceptions of instrumental control and the role of fear in the etiology of effects of inescapable shock exposure are discussed.

Effects of apomorphine on the expression of learned helplessness behavior.

PubMed

Wang, Wen-Fu; Lei, Yen-Ping; Tseng, Ting; Hsu, Wen-Yu; Wang, Ching-Fu; Hsu, Cheng-Chin; Ho, Ying-Jui

2007-04-30

Dopaminergic system and its D1 as well as D2 receptors are involved in the modulation of emotional behavior. This experiment investigated the role of dopaminergic activity in the inescapable stress-induced learned helplessness, a widely used depression animal model, by using the pharmacological manipulation through the apomorphine (APO), an agonist for D1 and D2 receptors, and sulpiride (SUL), a selective D2 antagonist. Male Sprague Dawley rats were used and tested in a shuttle box. In the day-1 session, the rats received a 10-trial (1 min/trial) inescapable stressor: a 3 sec conditioned stimulus (CS; 75 db sound and 250 lux red light) followed by a 10 sec unconditioned stimulus (UCS; electrical foot shock, 0.5 mA). In the day-2 session, a 15-trial active avoidance test, 3 sec CS followed by UCS, was performed 30 min after the administration of APO (0, 0.05, 0.5, 1, and 5 mg/kg, i.p.). The number of failures was counted and the UCS was stopped when the rats did not escape after 15 sec UCS. The results showed that APO at the dosage of 0.5 mg/kg had a tendency to enhance the avoidance behavior. In contrast, the treatment of higher dose of APO, 1 and 5 mg/kg, reduced the number of escape but increased the number of failure. Pretreatment of SUL (5 mg/kg, i.p.), 10 min before 1 mg/kg of APO, significantly enhanced the failure behavior. The present data suggest that the activity of D2 receptor may be associated with the adaptive or protective role in the prevention of escape deficits after exposure to inescapable stress. However, the excessive stimulation of D1 receptor may participate in the failure of coping behavior leading to learned helplessness and therefore in the pathophysiological mechanisms underling the development of depression.

Profiling and Co-expression Network Analysis of Learned Helplessness Regulated mRNAs and lncRNAs in the Mouse Hippocampus

PubMed Central

Li, Chaoqun; Cao, Feifei; Li, Shengli; Huang, Shenglin; Li, Wei; Abumaria, Nashat

2018-01-01

Although studies provide insights into the neurobiology of stress and depression, the exact molecular mechanisms underlying their pathologies remain largely unknown. Long non-coding RNA (lncRNA) has been implicated in brain functions and behavior. A potential link between lncRNA and psychiatric disorders has been proposed. However, it remains undetermined whether IncRNA regulation, in the brain, contributes to stress or depression pathologies. In this study, we used a valid animal model of depression-like symptoms; namely learned helplessness, RNA-seq, Gene Ontology and co-expression network analyses to profile the expression pattern of lncRNA and mRNA in the hippocampus of mice. We identified 6346 differentially expressed transcripts. Among them, 340 lncRNAs and 3559 protein coding mRNAs were differentially expressed in helpless mice in comparison with control and/or non-helpless mice (inescapable stress resilient mice). Gene Ontology and pathway enrichment analyses indicated that induction of helplessness altered expression of mRNAs enriched in fundamental biological functions implicated in stress/depression neurobiology such as synaptic, metabolic, cell survival and proliferation, developmental and chromatin modification functions. To explore the possible regulatory roles of the altered lncRNAs, we constructed co-expression networks composed of the lncRNAs and mRNAs. Among our differentially expressed lncRNAs, 17% showed significant correlation with genes. Functional co-expression analysis linked the identified lncRNAs to several cellular mechanisms implicated in stress/depression neurobiology. Importantly, 57% of the identified regulatory lncRNAs significantly correlated with 18 different synapse-related functions. Thus, the current study identifies for the first time distinct groups of lncRNAs regulated by induction of learned helplessness in the mouse brain. Our results suggest that lncRNA-directed regulatory mechanisms might contribute to stress-induced pathologies; in particular, to inescapable stress-induced synaptic modifications. PMID:29375311

Profiling and Co-expression Network Analysis of Learned Helplessness Regulated mRNAs and lncRNAs in the Mouse Hippocampus.

PubMed

Li, Chaoqun; Cao, Feifei; Li, Shengli; Huang, Shenglin; Li, Wei; Abumaria, Nashat

2017-01-01

Although studies provide insights into the neurobiology of stress and depression, the exact molecular mechanisms underlying their pathologies remain largely unknown. Long non-coding RNA (lncRNA) has been implicated in brain functions and behavior. A potential link between lncRNA and psychiatric disorders has been proposed. However, it remains undetermined whether IncRNA regulation, in the brain, contributes to stress or depression pathologies. In this study, we used a valid animal model of depression-like symptoms; namely learned helplessness, RNA-seq, Gene Ontology and co-expression network analyses to profile the expression pattern of lncRNA and mRNA in the hippocampus of mice. We identified 6346 differentially expressed transcripts. Among them, 340 lncRNAs and 3559 protein coding mRNAs were differentially expressed in helpless mice in comparison with control and/or non-helpless mice (inescapable stress resilient mice). Gene Ontology and pathway enrichment analyses indicated that induction of helplessness altered expression of mRNAs enriched in fundamental biological functions implicated in stress/depression neurobiology such as synaptic, metabolic, cell survival and proliferation, developmental and chromatin modification functions. To explore the possible regulatory roles of the altered lncRNAs, we constructed co-expression networks composed of the lncRNAs and mRNAs. Among our differentially expressed lncRNAs, 17% showed significant correlation with genes. Functional co-expression analysis linked the identified lncRNAs to several cellular mechanisms implicated in stress/depression neurobiology. Importantly, 57% of the identified regulatory lncRNAs significantly correlated with 18 different synapse-related functions. Thus, the current study identifies for the first time distinct groups of lncRNAs regulated by induction of learned helplessness in the mouse brain. Our results suggest that lncRNA-directed regulatory mechanisms might contribute to stress-induced pathologies; in particular, to inescapable stress-induced synaptic modifications.

The Role of Neuropeptide Y (NPY) in Uncontrolled Alcohol Drinking and Relapse Behavior Resulting from Exposure to Stressful Events

DTIC Science & Technology

2011-01-01

effects of stressors on excessive and uncontrolled drinking and relapse-like drinking. We proposed to use foot-shock as the stressor to elicit increase...did significantly increase deprivation-induced relapse-like drinking, and that this effect was more robust in mutant mice lacking the NPY Y1R. Thus...ethanol consumption using a models of excessive uncontrolled drinking, and mutant mice lacking NPY or the Y1R were more sensitive to the effects of

High-fat diet effects on metabolic responses to chronic stress.

PubMed

Nemati, Marzieh; Zardooz, Homeira; Rostamkhani, Fatemeh; Abadi, Alireza; Foroughi, Forough

2017-07-01

High-fat diets and chronic stress are prevalent risk factors for various chronic diseases in modern societies. This study investigated the effect of high-fat diet on glucose-related metabolic responses to chronic foot-shock stress. Male rats were divided into high-fat diet (containing 54.21% saturated and 44.89% unsaturated fatty acids) and normal diet groups and then into stress and non-stress subgroups. The diets were applied for 5 weeks, and stress was induced during the last week of the diet course. Plasma levels of metabolic parameters, HOMA-IR index, intra-abdominal fat weight, and islets' insulin secretion were assessed. High-fat diet increased abdominal fat weight and plasma leptin, and insulin levels in response to stress without affecting HOMA-IR index and islets' insulin secretion. High proportion of unsaturated fat may not lead to deleterious metabolic responses; however combined with chronic stress has a synergistic and adverse effect on visceral adiposity and results in elevated plasma leptin.

[The expression of the c-fos gene in the brain of mice in the dynamic acquisition of defensive behavioral habits].

PubMed

Anokhin, K V; Riabinin, A E; Sudakov, K V

2000-01-01

Levels of c-fos mRNA expression in mouse cerebral cortex and hippocampus at different stages of footshock escape and avoidance learning were studied by Northern hydridization. In the first series of experiments a mouse was presented with 30 electric footshock daily in a chamber where it could escape from the floor by jumping on the safe platform attached to the wall. A large increase in c-fos mRNA level in the cerebral cortex and hippocampus was observed during the first day of training. Mice that were trained for 9 consecutive days and acquired a footshock escape reaction showed no elevation of c-fos expression in the brain as compared to the quiet control group. In the second series of experiments the levels of c-fos expression were compared in individual mice trained to avoid the footshock by jumping on the platform in response to an auditory conditioned stimulus. Mice which acquired avoidance behavior more rapidly had lower c-fos mRNA levels than slow learners. There was no such to difference between the corresponding yoked control groups which consisted of animals matched the rapid and slow learners by the number of footshocks received. It is concluded that achievement of adaptive results in the course of learning leads to a suppression of further c-fos induction by motivational excitation.

Activation of the medial prefrontal cortex by escapable stress is necessary for protection against subsequent inescapable stress-induced potentiation of morphine conditioned place preference.

PubMed

Rozeske, Robert R; Der-Avakian, Andre; Watkins, Linda R; Maier, Steven F

2012-01-01

Stress can be a predisposing factor in the development of psychiatric disorders. However, not all individuals develop psychiatric disorders following a traumatic event. An attempt to understand these individual differences has led to a focus on factors that produce resistance. Interestingly, in rats, an experience with escapable tailshock (ES) before inescapable tailshock (IS) prevents the typical anxiety-like behavioral outcomes of IS. This type of resistance has been termed 'behavioral immunization', and it depends on activation of the medial prefrontal cortex (mPFC) during ES. However, one outcome of IS that is not anxiety-related is potentiation of morphine conditioned place preference (CPP). The present experiments investigated whether prior ES would block IS-induced potentiation of morphine CPP. Rats received either ES, IS or homecage control treatment on day 1 and then either IS or homecage control treatment on day 2. Twenty-four hours following day 2, rats underwent morphine conditioning, and CPP was subsequently assessed. In a second experiment, rats received ES 3, 14 or 56 days prior to IS to determine the duration of behavioral immunization. In a final experiment, rats were microinjected with the GABA(A) agonist muscimol (50 ng/0.5 μL) or saline in the mPFC before day 1 of stress. Prior ES blocked IS-induced potentiation of morphine CPP. This immunizing effect of ES lasted for at least 56 days. Additionally, intra-mPFC muscimol during ES prevented behavioral immunization. These results suggest that prior experience with ES activates the mPFC and produces long-lasting neural alterations that block subsequent IS-induced potentiation of morphine CPP. © 2011 The Authors. European Journal of Neuroscience © 2011 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Repeated exposure to immobilization or two different footshock intensities reveals differential adaptation of the hypothalamic-pituitary-adrenal axis.

PubMed

Rabasa, Cristina; Muñoz-Abellán, Cristina; Daviu, Núria; Nadal, Roser; Armario, Antonio

2011-05-03

Factors involved in adaptation to repeated stress are not well-characterized. For instance, acute footshock (FS) of high intensity appears to be less severe than immobilization (IMO) in light of the speed of post-stress recovery of the hypothalamic-pituitary-adrenal (HPA) axis and other physiological variables. However, repeated exposure to IMO consistently resulted in reduction of the HPA response to the same stressor (adaptation), whereas failure to adapt has been usually reported after FS. Thus, in the present work we directly compared the activation of HPA axis and other physiological changes in response to both acute and repeated exposure to IMO and two intensities of FS (medium and high) in adult male rats. Control rats were exposed to the FS boxes but they did not receive shocks. Daily repeated exposure to IMO resulted in significant adaptation of the overall ACTH and corticosterone responses to the stressor. Such a reduction was also observed with repeated exposure to FS boxes and FS-medium, whereas repeated exposure to FS-high only resulted in a small reduction of the corticosterone response during the post-stress period. This suggests that some properties of FS-high make adaptation to it difficult. Interestingly, overall changes in food intake and body weight gain throughout the week of exposure to the stressors reveal a greater impact of IMO than FS-high, indicating that factors other than the intensity of a stressor, at least when evaluated in function of the above physiological variables, can influence HPA adaptation. Since FS exposure is likely to cause more pain than IMO, activation of nociceptive signals above a certain level may negatively affect HPA adaptation to repeated stressors. Copyright © 2011 Elsevier Inc. All rights reserved.

Long-term effects of a single exposure to stress in adult rats on behavior and hypothalamic-pituitary-adrenal responsiveness: comparison of two outbred rat strains.

PubMed

Belda, Xavier; Márquez, Cristina; Armario, Antonio

2004-10-05

We have previously observed that a single exposure to immobilization (IMO), a severe stressor, caused long-term (days to weeks) desensitization of the response of the hypothalamic-pituitary-adrenal (HPA) axis to the homotypic stressor, with no changes in behavioral reactivity to novel environments. In contrast, other laboratories have reported that a single exposure to footshock induced a long-term sensitization of both HPA and behavioral responses to novel environments. To test whether these apparent discrepancies can be explained by the use of different stressors or different strains of rats, we studied in the present work the long-term effects of a single exposure to two different stressors (footshock or IMO) in two different strains of rats (Sprague-Dawley from Iffa-Credo and Wistar rats from Harlan). We found that both strains showed desensitization of the HPA response to the same (homotypic) stressor after a previous exposure to either shock or IMO. The long-term effects were higher after IMO than shock. No major changes in behavior in two novel environments (circular corridor, CC and elevated plus-maze, EPM) were observed after a single exposure to shock or IMO in neither strain, despite the fact that shocked rats showed a conditioned freezing response to the shock boxes. The present results demonstrate that long-term stress-induced desensitization of the HPA axis is a reliable phenomenon that can be observed with different stressors and strains. However, only behavioral changes related to shock-induced conditioned fear were found, which suggests that so far poorly characterized factors are determining the long-term behavioral consequences of a single exposure to stress.

Incubation of Fear Is Regulated by TIP39 Peptide Signaling in the Medial Nucleus of the Amygdala

PubMed Central

Tsuda, Mumeko C.; Yeung, Ho-Man; Kuo, Jonathan

2015-01-01

Fear-related psychopathologies such as post-traumatic stress disorder are characterized by impaired extinction of fearful memories. Recent behavioral evidence suggests that the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39), via its receptor, the parathyroid hormone 2 receptor (PTH2R), modulates fear memory. Here we examined the anatomical and cellular localization of TIP39 signaling that contributes to the increase in fear memory over time following a traumatic event, called fear memory incubation. Contextual freezing, a behavioral sign of fear memory, was significantly greater in PTH2R knock-out than wild-type male mice 2 and 4 weeks after a 2 s 1.5 mA footshock. PTH2R knock-out mice had significantly reduced c-Fos activation in the medial amygdala (MeA) following both footshock and fear recall, but had normal activation in the hypothalamic paraventricular nucleus and the amygdalar central nucleus compared with wild-type. We therefore investigated the contribution of MeA TIP39 signaling to fear incubation. Similar to the effect of global TIP39 signaling loss, blockade of TIP39 signaling in the MeA by lentivirus-mediated expression of a secreted PTH2R antagonist augmented fear incubation. Ablation of MeA PTH2R-expressing neurons also strengthened the fear incubation effect. Using the designer receptor exclusively activated by designer drug pharmacogenetic approach, transient inhibition of MeA PTH2R-expressing neurons before or immediately after the footshock, but not at the time of fear recall, enhanced fear incubation. Collectively, the findings demonstrate that TIP39 signaling within the MeA at the time of an aversive event regulates the increase over time in fear associated with the event context. SIGNIFICANCE STATEMENT Fear-related psychopathologies such as post-traumatic stress disorder (PTSD) are characterized by excessive responses to trauma-associated cues. Fear responses can increase over time without additional cue exposure or stress. This work shows that modulatory processes within the medial nucleus of the amygdala near the time of a traumatic event influence the strength of fear responses that occur much later. The modulatory processes include signaling by the neuropeptide TIP39 and neurons that express its receptor. These findings will help in the understanding of why traumatic events sometimes have severe psychological consequences. One implication is that targeting neuromodulation in the medial amygdala could potentially help prevent development of PTSD. PMID:26338326

Incubation of Fear Is Regulated by TIP39 Peptide Signaling in the Medial Nucleus of the Amygdala.

PubMed

Tsuda, Mumeko C; Yeung, Ho-Man; Kuo, Jonathan; Usdin, Ted B

2015-09-02

Fear-related psychopathologies such as post-traumatic stress disorder are characterized by impaired extinction of fearful memories. Recent behavioral evidence suggests that the neuropeptide tuberoinfundibular peptide of 39 residues (TIP39), via its receptor, the parathyroid hormone 2 receptor (PTH2R), modulates fear memory. Here we examined the anatomical and cellular localization of TIP39 signaling that contributes to the increase in fear memory over time following a traumatic event, called fear memory incubation. Contextual freezing, a behavioral sign of fear memory, was significantly greater in PTH2R knock-out than wild-type male mice 2 and 4 weeks after a 2 s 1.5 mA footshock. PTH2R knock-out mice had significantly reduced c-Fos activation in the medial amygdala (MeA) following both footshock and fear recall, but had normal activation in the hypothalamic paraventricular nucleus and the amygdalar central nucleus compared with wild-type. We therefore investigated the contribution of MeA TIP39 signaling to fear incubation. Similar to the effect of global TIP39 signaling loss, blockade of TIP39 signaling in the MeA by lentivirus-mediated expression of a secreted PTH2R antagonist augmented fear incubation. Ablation of MeA PTH2R-expressing neurons also strengthened the fear incubation effect. Using the designer receptor exclusively activated by designer drug pharmacogenetic approach, transient inhibition of MeA PTH2R-expressing neurons before or immediately after the footshock, but not at the time of fear recall, enhanced fear incubation. Collectively, the findings demonstrate that TIP39 signaling within the MeA at the time of an aversive event regulates the increase over time in fear associated with the event context. Fear-related psychopathologies such as post-traumatic stress disorder (PTSD) are characterized by excessive responses to trauma-associated cues. Fear responses can increase over time without additional cue exposure or stress. This work shows that modulatory processes within the medial nucleus of the amygdala near the time of a traumatic event influence the strength of fear responses that occur much later. The modulatory processes include signaling by the neuropeptide TIP39 and neurons that express its receptor. These findings will help in the understanding of why traumatic events sometimes have severe psychological consequences. One implication is that targeting neuromodulation in the medial amygdala could potentially help prevent development of PTSD. Copyright © 2015 the authors 0270-6474/15/3512152-10$15.00/0.

Learned helplessness in the rat: improvements in validity and reliability.

PubMed

Vollmayr, B; Henn, F A

2001-08-01

Major depression has a high prevalence and a high mortality. Despite many years of research little is known about the pathophysiologic events leading to depression nor about the causative molecular mechanisms of antidepressant treatment leading to remission and prevention of relapse. Animal models of depression are urgently needed to investigate new hypotheses. The learned helplessness paradigm initially described by Overmier and Seligman [J. Comp. Physiol. Psychol. 63 (1967) 28] is the most widely studied animal model of depression. Animals are exposed to inescapable shock and subsequently tested for a deficit in acquiring an avoidance task. Despite its excellent validity concerning the construct of etiology, symptomatology and prediction of treatment response [Clin. Neurosci. 1 (1993) 152; Trends Pharmacol. Sci. 12 (1991) 131] there has been little use of the model for the investigation of recent theories on the pathogenesis of depression. This may be due to reported difficulties in reliability of the paradigm [Animal Learn. Behav. 4 (1976) 401; Pharmacol. Biochem. Behav. 36 (1990) 739]. The aim of the current study was therefore to improve parameters for inescapable shock and learned helplessness testing to minimize artifacts and random error and yield a reliable fraction of helpless animals after shock exposure. The protocol uses mild current which induces helplessness only in some of the animals thereby modeling the hypothesis of variable predisposition for depression in different subjects [Psychopharmacol. Bull. 21 (1985) 443; Neurosci. Res. 38 (200) 193]. This allows us to use animals which are not helpless after inescapable shock as a stressed control, but sensitivity, specificity and variability of test results have to be reassessed.

The inhibitory avoidance discrimination task to investigate accuracy of memory.

PubMed

Atucha, Erika; Roozendaal, Benno

2015-01-01

The present study was aimed at developing a new inhibitory avoidance task, based on training and/or testing rats in multiple contexts, to investigate accuracy of memory. In the first experiment, male Sprague-Dawley rats were given footshock in an inhibitory avoidance apparatus and, 48 h later, retention latencies of each rat were assessed in the training apparatus (Shock box) as well as in a novel, contextually modified, apparatus. Retention latencies in the Shock box were significantly longer than those in the Novel box, indicating accurate memory of the training context. When the noradrenergic stimulant yohimbine (0.3 mg/kg, sc) was administered after the training, 48-h retention latencies in the Shock box, but not Novel box, were increased, indicating that the noradrenergic activation enhanced memory of the training experience without reducing memory accuracy. In the second experiment, rats were trained on an inhibitory avoidance discrimination task: They were first trained in an inhibitory avoidance apparatus without footshock (Non-Shock box), followed 1 min later by footshock training in a contextually modified apparatus (Shock box). Forty-eight-hour retention latencies in the Shock and Non-Shock boxes did not differ from each other but were both significantly longer than those in a Novel box, indicating that rats remembered the two training contexts but did not have episodic-like memory of the association of footshock with the correct training context. When the interval between the two training episodes was increased to 2 min, rats showed accurate memory of the association of footshock with the training context. Yohimbine administered after the training also enhanced rats' ability to remember in which training context they had received actual footshock. These findings indicate that the inhibitory avoidance discrimination task is a novel variant of the well-established inhibitory avoidance task suitable to investigate accuracy of memory.

Experience Modulates Vicarious Freezing in Rats: A Model for Empathy

PubMed Central

Atsak, Piray; Orre, Marie; Bakker, Petra; Cerliani, Leonardo; Roozendaal, Benno

2011-01-01

The study of the neural basis of emotional empathy has received a surge of interest in recent years but mostly employing human neuroimaging. A simpler animal model would pave the way for systematic single cell recordings and invasive manipulations of the brain regions implicated in empathy. Recent evidence has been put forward for the existence of empathy in rodents. In this study, we describe a potential model of empathy in female rats, in which we studied interactions between two rats: a witness observes a demonstrator experiencing a series of footshocks. By comparing the reaction of witnesses with or without previous footshock experience, we examine the role of prior experience as a modulator of empathy. We show that witnesses having previously experienced footshocks, but not naïve ones, display vicarious freezing behavior upon witnessing a cage-mate experiencing footshocks. Strikingly, the demonstrator's behavior was in turn modulated by the behavior of the witness: demonstrators froze more following footshocks if their witness froze more. Previous experiments have shown that rats emit ultrasonic vocalizations (USVs) when receiving footshocks. Thus, the role of USV in triggering vicarious freezing in our paradigm is examined. We found that experienced witness-demonstrator pairs emitted more USVs than naïve witness-demonstrator pairs, but the number of USVs was correlated with freezing in demonstrators, not in witnesses. Furthermore, playing back the USVs, recorded from witness-demonstrator pairs during the empathy test, did not induce vicarious freezing behavior in experienced witnesses. Thus, our findings confirm that vicarious freezing can be triggered in rats, and moreover it can be modulated by prior experience. Additionally, our result suggests that vicarious freezing is not triggered by USVs per se and it influences back onto the behavior of the demonstrator that had elicited the vicarious freezing in witnesses, introducing a paradigm to study empathy as a social loop. PMID:21765921

Adaptogenic activity of Siotone, a polyherbal formulation of Ayurvedic rasayanas.

PubMed

Bhattacharya, S K; Bhattacharya, A; Chakrabarti, A

2000-02-01

Siotone (ST) is a herbal formulation comprising of Withania somnifera, Ocimum sanctum, Asparagus racemosus, Tribulus terristris and shilajit, all of which are classified in Ayurveda as rasayanas which are reputed to promote physical and mental health, improve defence mechanisms of the body and enhance longevity. These attributes are similar to the modern concept of adaptogenic agents, which are, known to afford protection of the human physiological system against diverse stressors. The present study was undertaken to investigate the adaptogenic activity of ST against chronic unpredictable, but mild, footshock stress induced perturbations in behaviour (depression), glucose metabolism, suppressed male sexual behaviour, immunosuppression and cognitive dysfunction in CF strain albino rats. Gastric ulceration, adrenal gland and spleen weights, ascorbic acid and corticosterone concentrations of adrenal cortex, and plasma corticosterone levels, were used as the stress indices. Panax ginseng (PG) was used as the standard adaptogenic agent for comparison. Additionally, rat brain levels of tribulin, an endogenous endocoid postulated to be involved in stress, were also assessed in terms of endogenous monoamine oxidase (MAO) A and MAOB inhibitory activity. Chronic unpredictable footshock induced marked gastric ulceration, significant increase in adrenal gland weight and plasma corticosterone levels, with concomitant decreases in spleen weight, and concentrations of adrenal gland ascorbic acid and corticosterone. These effects were attenuated by ST (50 and 100 mg/kg, p.o.) and PG (100 mg/kg, p.o.), administered once daily over a period of 14 days, the period of stress induction. Chronic stress also induced glucose intolerance, suppressed male sexual behaviour, induced behavioural depression (Porsolt's swim despair test and learned helplessness test) and cognitive dysfunction (attenuated retention of learning in active and passive avoidance tests), and immunosuppression (leucocyte migration inhibition and sheep RBC challenged increase in paw oedema in sensitized rats). All these chronic stress-induced perturbations were attenuated, dose-dependently by ST (50 and 100 mg/kg, p.o.) and PG (100 mg/kg, p.o.). Chronic stress-induced increase in rat brain tribulin activity was also reversed by these doses of ST and by PG. The results indicate that ST has significant adaptogenic activity, qualitatively comparable to PG, against a variety of behavioural, biochemical and physiological perturbations induced by unpredictable stress, which has been proposed to be a better indicator of clinical stress than acute stress parameters. The likely contribution of the individual constituents of ST in the observed adaptogenic action of the polyherbal formulation, have been discussed.

Hippocampal glycogen synthase kinase 3β is critical for the antidepressant effect of cyclin-dependent kinase 5 inhibitor in rats.

PubMed

Li, Gang; Liu, Ting; Kong, Xiangqian; Wang, Lei; Jin, Xing

2014-09-01

Cdk5 is a member of cyclin-dependent kinase (Cdk), a proline-directed serine/threonine kinase, and plays a key role in normal neural development and function. Evidence of previous study showed that chronic inhibition of Cdk5 in hippocampal dentate gyrus (DG) blocked the development of depressive-like symptoms, suggesting that Cdk5 plays a role in development of depression. Forced swim test, novelty-suppressed feeding test, and learned helplessness were used to evaluate the cellular and molecular mechanisms underlying the behavioral regulation of Cdk5 inhibitors in rats. Two Cdk5 inhibitors butyrolactone and roscovitine were used to investigate the possible antidepressant-like actions of Cdk5 blockade and the potential mechanisms. Systemic administration of butyrolactone (200 mg/kg, IP) or roscovitine (100 mg/kg, IP) produced effective antidepressant-like actions. Moreover, infusion (5 mM) of GSK3β activator LY294002 into DG abolished the antidepressant-like actions of butyrolactone and roscovitine, suggesting that inhibition of GSK3β might be involved in the antidepressant effect of Cdk5 inhibitors. Moreover, pretreatment of LY294002 (5 mM) blocked the antidepressant-like effect of butyrolactone and roscovitine in learned helplessness. Additionally, inescapable footshock induced a significant increase of GSK3β activity, while butyrolactone and roscovitine decreased GSK3β activity. In contrast, pretreatment of LY294002 prevented the inhibitory effects of butyrolactone and roscovitine on GSK3β activation. Finally, a specific GSK3β inhibitor, SB216763 (1 ng, DG), demonstrated an effective antidepressant-like action. These findings demonstrate that systemic administration of Cdk5 inhibitors produced antidepressant-like actions and that inhibition of GSK3β is involved in behavioral response of Cdk5 inhibitors.

Mice subjected to uncontrollable electric shocks show depression-like behaviors irrespective of their state of helplessness.

PubMed

Kim, Jin Yong; Yang, Soo Hyun; Kwon, Jihyun; Lee, Hyun Woo; Kim, Hyun

2017-03-30

The unpredictable and inescapable electric shock-induced "learned helplessness" paradigm has long been used to produce an animal model of depression to identify the molecules associated with depressive symptoms or to assess the efficacy of pharmacological treatments for depression. After exposure to unpredictable and inescapable shocks (uncontrollable stress), most of mice showed defect in escape behavior in active avoidance test (learned helplessness, LH), while others did not (non-learned helplessness, NLH). Here, we investigated whether mice with LH or NLH exhibited depressive symptoms, including anhedonia, anxiety, and despair. We found that compared with control naïve mice, both uncontrollable shocks-induced LH and NLH mice showed increased anhedonia- and anxiety- but not despair-like behaviors. Notably, mice subjected to uncontrollable shocks showed similar behaviors, irrespective of whether they also showed LH or NLH. Furthermore, since both LH and NLH mice showed only anhedonia- and anxiety- but not despair-like behaviors, this model may be generally inadequate for classic depression-like behavior assessment. In conclusion, uncontrollable electric shock induces depression-like behavior, irrespective of the state of helplessness. Copyright © 2017 Elsevier B.V. All rights reserved.

Parameters of hormetic stress and resilience to trauma in rats.

PubMed

Plumb, Traci N; Cullen, Patrick K; Minor, Thomas R

2015-01-01

Hormesis is the process by which small stresses build resilience to large stresses. We pre-exposed rats to various parameters of mild-to-moderate stress prior to traumatic stress in the present experiments to assess the potential benefits of hormetic training on resilience to traumatic, uncontrollable stress. Rats underwent varying stress pre-training parameters prior to exposure to uncontrollable traumatic stress in the learned helplessness procedure. The ability to prevent the exaggerated fear responding and escape deficits that normally follow experience with traumatic stress were used as a measure of the benefits of hormetic training. Four experiments examined the effects of number of training sessions, stressor severity and pattern of rest between pre-training stress sessions. Repeated exposure to mild restraint stress or moderate shock stress eliminated both the enhanced fear conditioning and shuttle-escape deficits that result from exposure to traumatic, inescapable shock. The pattern of rest did not contribute to resilience when the pre-exposure stressor was mild, but was vital when the pre-exposure stressor was moderate, with an alternation of stress and rest being the most effective procedure. The data also suggest that the level of resilience may increase with the number of pre-exposure sessions.

Short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 reversibly improves spatial memory but persistently impairs contextual fear memory in aged mice

PubMed Central

Wheelan, Nicola; Webster, Scott P.; Kenyon, Christopher J.; Caughey, Sarah; Walker, Brian R.; Holmes, Megan C.; Seckl, Jonathan R.; Yau, Joyce L.W.

2015-01-01

High glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11β-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11β-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design. Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11β-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals. PMID:25497454

Short-term inhibition of 11β-hydroxysteroid dehydrogenase type 1 reversibly improves spatial memory but persistently impairs contextual fear memory in aged mice.

PubMed

Wheelan, Nicola; Webster, Scott P; Kenyon, Christopher J; Caughey, Sarah; Walker, Brian R; Holmes, Megan C; Seckl, Jonathan R; Yau, Joyce L W

2015-04-01

High glucocorticoid levels induced by stress enhance the memory of fearful events and may contribute to the development of anxiety and posttraumatic stress disorder. In contrast, elevated glucocorticoids associated with ageing impair spatial memory. We have previously shown that pharmacological inhibition of the intracellular glucocorticoid-amplifying enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) improves spatial memory in aged mice. However, it is not known whether inhibition of 11β-HSD1 will have any beneficial effects on contextual fear memories in aged mice. Here, we examined the effects of UE2316, a selective 11β-HSD1 inhibitor which accesses the brain, on both spatial and contextual fear memories in aged mice using a vehicle-controlled crossover study design. Short-term UE2316 treatment improved spatial memory in aged mice, an effect which was reversed when UE2316 was substituted with vehicle. In contrast, contextual fear memory induced by foot-shock conditioning was significantly reduced by UE2316 in a non-reversible manner. When the order of treatment was reversed following extinction of the original fear memory, and a second foot-shock conditioning was given in a novel context, UE2316 treated aged mice (previously on vehicle) now showed increased fear memory compared to vehicle-treated aged mice (previously on UE2316). Renewal of the original extinguished fear memory triggered by exposure to a new environmental context may explain these effects. Thus 11β-HSD1 inhibition reverses spatial memory impairments with ageing while reducing the strength and persistence of new contextual fear memories. Potentially this could help prevent anxiety-related disorders in vulnerable elderly individuals. Copyright © 2014 Elsevier Ltd. All rights reserved.

Lisdexamfetamine reduces the compulsive and perseverative behaviour of binge-eating rats in a novel food reward/punished responding conflict model.

PubMed

Heal, David J; Goddard, Simon; Brammer, Richard J; Hutson, Peter H; Vickers, Steven P

2016-07-01

Compulsive and perseverative behaviour in binge-eating, female, Wistar rats was investigated in a novel food reward/punished responding conflict model. Rats were trained to perform the conditioned avoidance response task. When proficient, the paradigm was altered to a food-associated conflict test by placing a chocolate-filled jar (empty jar for controls) in one compartment of the shuttle box. Entry into the compartment with the jar triggered the conditioning stimulus after a variable interval, and foot-shock 10 seconds later if the rat did not leave. Residence in the 'safe' compartment with no jar did not initiate trials or foot-shocks. By frequently entering the chocolate-paired compartment, binge-eating rats completed their 10 trials more quickly than non-binge controls. Binge-eating rats spent a greater percentage of the session in the chocolate-paired compartment, received foot-shocks more frequently, and tolerated foot-shocks for longer periods; all consistent with compulsive and perseverative behaviour. The d-amphetamine prodrug, lisdexamfetamine, has recently received US approval for the treatment of moderate to severe binge-eating disorder in adults. Lisdexamfetamine (0.8 mg/kg po [d-amphetamine base]) decreased chocolate consumption by binge-eating rats by 55% and markedly reduced compulsive and perseverative responding in the model. These findings complement clinical results showing lisdexamfetamine reduced compulsiveness scores in subjects with binge-eating disorder. © The Author(s) 2016.

Psychological Stress Induces Temporary Masticatory Muscle Mechanical Sensitivity in Rats

PubMed Central

Huang, Fei; Zhang, Min; Chen, Yong-Jin; Li, Qiang; Wu, An-Zhen

2011-01-01

To explore the relationship between psychological stress and masticatory muscle pain, we created a communication stress animal model to determine whether psychological stress could induce increased mechanical sensitivity in masticatory muscles and to study the changes of mechanical nociceptive thresholds after stress removal. Forty-eight male Sprague-Dawley rats were divided into a control group (CON), a foot-shocked group (FS, including 3 subgroups recorded as FS-1, FS-2, and FS-3), a psychological stress group (PS), and a drug treatment group (DT). PS and DT rats were confined in a communication box for one hour a day to observe the psychological responses of neighboring FS rats.Measurements of the mechanical nociceptive thresholds of the bilateral temporal and masseter muscles showed a stimulus-response relationship between psychological stress and muscle mechanical sensitivity. The DT rats, who received a diazepam injection, showed almost the same mechanical sensitivity of the masticatory muscles to that of the control in response to psychological stress. Fourteen days after the psychological stressor was removed, the mechanical nociceptive thresholds returned to normal. These findings suggest that psychological stress is directly related to masticatory muscle pain. Removal of the stressor could be a useful method for relieving mechanical sensitivity increase induced by psychological stress. PMID:21331360

Age and adolescent social stress effects on fear extinction in female rats.

PubMed

McCormick, C M; Mongillo, D L; Simone, J J

2013-11-01

We previously observed that social instability stress (SS: daily 1 h isolation and change of cage partners for 16 days) in adolescence, but not in adulthood, decreased context and cue memory after fear conditioning in male rats. Effects of stress are typically sex-specific, and so here we investigated adolescent and adult SS effects in females on the strength of acquired contextual and cued fear conditioning, as well as extinction learning, beginning either the day after the stress procedure or four weeks later. For SS in adolescence, SS females spent more time freezing (fear measure) during extinction than did controls, whereas SS in adulthood had no effect on any measure of fear conditioning. The results also indicated an effect of age: females in late adolescence show more rapid extinction of cue and better memory of extinction of context compared to adult females, which may indicate resilience to acute footshock in adolescence. Thus fear circuitry continues to mature into late adolescence, which may underlie the heightened plasticity in response to chronic stressors of adolescents compared to adults.

Rodent models of depression: learned helplessness using a triadic design in rats.

PubMed

Durgam, R C

2001-05-01

Certain types of human depression are precipitated by stressful life events, and vulnerable individuals experiencing these stressors may develop clinical depression. Understanding the neurobiology of stress vulnerability (depression) as well as stress resiliency (coping) is critical for guiding the development of novel pharmacotherapeutic agents for stress-related disorders such as depression in humans. The use of a triadic design (escapable shock, yoked-inescapable shock and restrained control) allows the investigator to examine the various sequella of stress exposure, while manipulating and quantifying the impact of psychological dynamics of stress such as active behavioral coping (i.e., stress control). Both escape and yoked subjects are exposed to the identical amount, intensity, pattern and duration of stress. The critical distinction between these two groups is that the escape group has the opportunity to terminate the shock stress by turning a wheel at the front of a chamber, while wheel-turning for the yoked subject is of no consequence. Any difference observed between the escape and yoked subjects is a result of the effects of coping, rather than stress exposure per se. The restrained group is included to control for the effects of handling. Any differences between this group and the escape and yoked subjects reflects the impact of stress per se.

Acute stress blocks the caffeine-induced enhancement of contextual memory retrieval in mice.

PubMed

Pierard, Chistophe; Krazem, Ali; Henkous, Nadia; Decorte, Laurence; Béracochéa, Daniel

2015-08-15

This study investigated in mice the dose-effect of caffeine on memory retrieval in non-stress and stress conditions. C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four-hole board which involved either distinct contextual (CSD) or similar contextual (SSD) cues. All mice received an i.p. injection of vehicle or caffeine (8, 16 or 32mg/kg) 30min before the test session. Results showed that in non-stress conditions, the 16mg/kg caffeine dose induced a significant enhancement of D1 performance in CSD but not in SSD. Hence, we studied the effect of an acute stress (electric footshocks) administered 15min before the test session on D1 performance in caffeine-treated mice. Results showed that stress significantly decreased D1 performance in vehicle-treated controls and the memory-enhancing effect induced by the 16mg/kg caffeine dose in non-stress condition is no longer observed. Interestingly, whereas caffeine-treated mice exhibited weaker concentrations of plasma corticosterone as compared to vehicles in non-stress condition, stress significantly increased plasma corticosterone concentrations in caffeine-treated mice which reached similar level to that of controls. Overall, the acute stress blocked both the endocrinological and memory retrieval enhancing effects of caffeine. Copyright © 2015 Elsevier B.V. All rights reserved.

Exercise and Prebiotics Produce Stress Resistance: Converging Impacts on Stress-Protective and Butyrate-Producing Gut Bacteria.

PubMed

Mika, A; Rumian, N; Loughridge, A B; Fleshner, M

2016-01-01

The gut microbial ecosystem can mediate the negative health impacts of stress on the host. Stressor-induced disruptions in microbial ecology (dysbiosis) can lead to maladaptive health effects, while certain probiotic organisms and their metabolites can protect against these negative impacts. Prebiotic diets and exercise are feasible and cost-effective strategies that can increase stress-protective bacteria and produce resistance against the detrimental behavioral and neurobiological impacts of stress. The goal of this review is to describe research demonstrating that both prebiotic diets and exercise produce adaptations in gut ecology and the brain that arm the organism against inescapable stress-induced learned helplessness. The results of this research support the novel hypothesis that some of the stress-protective effects of prebiotics and exercise are due to increases in stress-protective gut microbial species and their metabolites. In addition, new evidence also suggests that prebiotic diet or exercise interventions are most effective if given early in life (juvenile-adolescence) when both the gut microbial ecosystem and the brain are plastic. Based on our new understanding of the mechanistic convergence of these interventions, it is feasible to propose that in adults, both interventions delivered in combination may elevate their efficacy to promote a stress-resistant phenotype. © 2016 Elsevier Inc. All rights reserved.

Synaptic Modifications in the Medial Prefrontal Cortex in Susceptibility and Resilience to Stress

PubMed Central

Wang, Minghui; Perova, Zinaida; Arenkiel, Benjamin R.

2014-01-01

When facing stress, most individuals are resilient whereas others are prone to developing mood disorders. The brain mechanisms underlying such divergent behavioral responses remain unclear. Here we used the learned helplessness procedure in mice to examine the role of the medial prefrontal cortex (mPFC), a brain region highly implicated in both clinical and animal models of depression, in adaptive and maladaptive behavioral responses to stress. We found that uncontrollable and inescapable stress induced behavioral state-dependent changes in the excitatory synapses onto a subset of mPFC neurons: those that were activated during behavioral responses as indicated by their expression of the activity reporter c-Fos. Whereas synaptic potentiation was linked to learned helplessness, a depression-like behavior, synaptic weakening, was associated with resilience to stress. Notably, enhancing the activity of mPFC neurons using a chemical–genetic method was sufficient to convert the resilient behavior into helplessness. Our results provide direct evidence that mPFC dysfunction is linked to maladaptive behavioral responses to stress, and suggest that enhanced excitatory synaptic drive onto mPFC neurons may underlie the previously reported hyperactivity of this brain region in depression. PMID:24872553

Different neural circuitry is involved in physiological and psychological stress-induced PTSD-like “nightmares” in rats

PubMed Central

Yu, Bin; Cui, Su-Ying; Zhang, Xue-Qiong; Cui, Xiang-Yu; Li, Sheng-Jie; Sheng, Zhao-Fu; Cao, Qing; Huang, Yuan-Li; Xu, Ya-Ping; Lin, Zhi-Ge; Yang, Guang; Song, Jin-Zhi; Ding, Hui; Zhang, Yong-He

2015-01-01

Posttraumatic nightmares are a core component of posttraumatic stress disorder (PTSD) and mechanistically linked to the development and maintenance of this disorder, but little is known about their mechanism. We utilized a communication box to establish an animal model of physiological stress (foot-shock [FS]) and psychological stress (PS) to mimic the direct suffering and witnessing of traumatic events. Twenty-one days after traumatic stress, some of the experimental animals presented startled awakening (i.e., were startled awake by a supposed “nightmare”) with different electroencephalographic spectra features. Our neuroanatomical results showed that the secondary somatosensory cortex and primary auditory cortex may play an important role in remote traumatic memory retrieval in FS “nightmare” (FSN) rats, whereas the temporal association cortex may play an important role in PS “nightmare” (PSN) rats. The FSN and PSN groups possessed common emotion evocation circuits, including activation of the amygdala and inactivation of the infralimbic prefrontal cortex and ventral anterior cingulate cortex. The decreased activity of the granular and dysgranular insular cortex was only observed in PSN rats. The present results imply that different types of stress may cause PTSD-like “nightmares” in rodents and identified the possible neurocircuitry of memory retrieval and emotion evocation. PMID:26530305

Anxiogenic effects of brief swim stress are sensitive to stress history.

PubMed

Christianson, John P; Drugan, Robert C; Flyer, Johanna G; Watkins, Linda R; Maier, Steven F

2013-07-01

Stressors that are controllable not only protect an individual from the acute consequences of the stressor, but also the consequences of stressors that occur later. This phenomenon, termed "behavioral immunization", is studied in the rat by first administering tailshocks each of which can be terminated (escapable tailshock) by an instrumental wheel-turn response prior to exposure to a second stressor. Previous research has shown that exposure to escapable tailshock blocks the neurochemical and behavioral consequences of later inescapable tailshock or social defeat stress. Here we explored the generality of behavioral immunization by examining the impact of prior escapable tailshock on the behavioral consequences of cold swim stress. Exposure to a 5min cold-water (19°C) swim caused an anxiety-like reduction in social interaction that was dependent upon 5-HT2C receptor activation. Rats with prior exposure to escapable tailshock did not develop the swim-induced anxiety. Plasticity in the medial prefrontal cortex, a hypothetical neural mechanism underlying behavioral immunization, is discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

Depression of Excitatory Synapses onto Parvalbumin Interneurons in the Medial Prefrontal Cortex in Susceptibility to Stress

PubMed Central

Delevich, Kristen

2015-01-01

In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events. PMID:25698754

In a rat model of panic, corticotropin responses to dorsal periaqueductal gray stimulation depend on physical exertion.

PubMed

de Souza Armini, Rubia; Bernabé, Cristian Setúbal; Rosa, Caroline Azevedo; Siller, Carlos Antônio; Schimitel, Fagna Giacomin; Tufik, Sérgio; Klein, Donald Franklin; Schenberg, Luiz Carlos

2015-03-01

Panic disorder patients are exquisitely and specifically sensitive to hypercapnia. The demonstration that carbon dioxide provokes panic in fear-unresponsive amygdala-calcified Urbach-Wiethe patients emphasizes that panic is not fear nor does it require the activation of the amygdala. This is consonant with increasing evidence suggesting that panic is mediated caudally at midbrain's dorsal periaqueductal gray matter (DPAG). Another startling feature of the apparently spontaneous clinical panic is the counterintuitive lack of increments in corticotropin, cortisol and prolactin, generally considered 'stress hormones'. Here we show that the stress hormones are not changed during DPAG-evoked panic when escape is prevented by stimulating the rat in a small compartment. Neither did the corticotropin increase when physical exertion was statistically adjusted to the same degree as non-stimulated controls, as measured by lactate plasma levels. Conversely, neuroendocrine responses to foot-shocks were independent from muscular effort. Data are consonant with DPAG mediation of panic attacks. Copyright © 2015 Elsevier Ltd. All rights reserved.

Not all stressors are equal: behavioral and endocrine evidence for development of contextual fear conditioning after a single session of footshocks but not of immobilization.

PubMed

Daviu, Núria; Delgado-Morales, Raúl; Nadal, Roser; Armario, Antonio

2012-01-01

Exposure of animals to footshocks (FS) in absence of any specific cue results in the development of fear to the compartment where shocks were given (contextual fear conditioning), and this is usually evaluated by time spent freezing. However, the extent to which contextual fear conditioning always develops when animals are exposed to other stressors is not known. In the present work we firstly demonstrated, using freezing, that exposure of adult rats to a single session of FS resulted in short-term and long-term contextual fear conditioning (freezing) that was paralleled by increased hypothalamic-pituitary-adrenal (HPA) activation. In contrast, using a similar design, no HPA or behavioral evidence for such conditioning was found after exposure to immobilization on boards (IMO), despite this stressor being of similar severity as FS on the basis of standard physiological measures of stress, including HPA activation. In a final experiment we directly compared the exposure to the two stressors in the same type of context and tested for the development of conditioning to the context and to a specific cue for IMO (the board). We observed the expected high levels of freezing and the conditioned HPA activation after FS, but not after IMO, regardless of the presence of the board during testing. Therefore, it can be concluded that development of fear conditioning to context or particular cues, as evaluated by either behavioral or endocrine measures, appears to be dependent on the nature of the aversive stimuli, likely to be related to biologically preparedness to establish specific associations.

Verapamil enhances acute stress or glucocorticoid-induced deficits in retrieval of long-term memory in rats.

PubMed

Rashidy-Pour, Ali; Vafaei, Abbas Ali; Taherian, Abbas Ali; Miladi-Gorji, Hossein; Sadeghi, Hassan; Fathollahi, Yaghoub; Bandegi, Ahmad Reza

2009-10-12

This study was designed to investigate an interaction between acute restraint stress and corticosterone with verapamil, a blocker of L-type voltage-dependent calcium (VDC) channels on retrieval of long-term memory. Young adult male rats were trained in one trial inhibitory avoidance task (0.5 mA, 3 s footshock). On retention test given 48 h after training, the latency to re-enter dark compartment of the apparatus was recorded. In Experiment 1, verapamil pretreatment (5, 10, or 20 mg/kg) enhanced the impairing effects of acute stress (which was applied for 10 min in a Plexiglass tube 30 min before the retention test) on memory retrieval. The applied stress increased circulating corticosterone levels as assessed immediately after the retention test, indicating that stress-induced impairment of memory retrieval is mediated, in part, by increased plasma levels of glucocorticoids. Verapamil did not change this response. In Experiment 2, pretreatment of an intermediate dose of verapamil also enhanced corticosterone-induced impairment of memory retrieval. In Experiments 3 and 4, acute stress or corticosterone did not change motor activity with or without prior treatment of verapamil, suggesting that stress or glucocorticoid-induced impairment of memory retrieval is not due to any gross disturbances in motor performance of animals. These findings indicate that blockade of L-type VDC channels enhances stress or glucocorticoid-induced impairment of memory retrieval, and provide evidence for the existence of an interaction between glucocorticoids and L-type VDC channels on memory retrieval.

Metyrapone Reveals That Previous Chronic Stress Differentially Impairs Hippocampal-dependent Memory

PubMed Central

CONRAD, CHERYL D.; MAULDIN-JOURDAIN, MELISSA L.; HOBBS, REBECCA J.

2007-01-01

Chronic stress facilitates fear conditioning in rats with hippocampal neuronal atrophy and in rats in which the atrophy is prevented with tianeptine, a serotonin re-uptake enhancer. The purpose of this study was to determine whether the lack of dissociation between fear conditioning performance and hippocampal integrity was masked by the presence of endogenous corticosteroids during training. As in previous studies, rats were stressed by daily restraint (6 h/day for 21 days), trained in the conditioning chamber (day 23), and then assessed for conditioned fear (day 25) at a time when hippocampal dendritic atrophy persists. On the training day, half of the control and stressed rats were injected with metyrapone to reduce corticosterone release. Two hours later, two paired or unpaired presentations of tone and footshock were delivered. Although metyrapone reduced conditioned fear in all rats, only stressed rats showed dissociated fear conditioning (i.e. tone conditioning was reduced while contextual conditioning was eliminated). Chronically stressed rats, regardless of metyrapone treatment displayed more rearing in the open field when tested immediately after the completion of fear conditioning. These data support the hypothesis that increased emotionality and enhanced fear conditioning exhibited by chronically stressed rats may be due to endogenous corticosterone secretion at the time of fear conditioned training. Moreover, these data suggest that chronic stress impairs hippocampal-dependent processes more robustly than hippocampal-independent processes after metyrapone to reduce corticosterone secretion during aversive training. PMID:18301732

Behavioral and neuroendocrine consequences of juvenile stress combined with adult immobilization in male rats.

PubMed

Fuentes, Silvia; Carrasco, Javier; Armario, Antonio; Nadal, Roser

2014-08-01

Exposure to stress during childhood and adolescence increases vulnerability to developing several psychopathologies in adulthood and alters the activity of the hypothalamic-pituitary-adrenal (HPA) axis, the prototypical stress system. Rodent models of juvenile stress appear to support this hypothesis because juvenile stress can result in reduced activity/exploration and enhanced anxiety, although results are not always consistent. Moreover, an in-depth characterization of changes in the HPA axis is lacking. In the present study, the long-lasting effects of juvenile stress on adult behavior and HPA function were evaluated in male rats. The juvenile stress consisted of a combination of stressors (cat odor, forced swim and footshock) during postnatal days 23-28. Juvenile stress reduced the maximum amplitude of the adrenocorticotropic hormone (ACTH) levels (reduced peak at lights off), without affecting the circadian corticosterone rhythm, but other aspects of the HPA function (negative glucocorticoid feedback, responsiveness to further stressors and brain gene expression of corticotrophin-releasing hormone and corticosteroid receptors) remained unaltered. The behavioral effects of juvenile stress itself at adulthood were modest (decreased activity in the circular corridor) with no evidence of enhanced anxiety. Imposition of an acute severe stressor (immobilization on boards, IMO) did not increase anxiety in control animals, as evaluated one week later in the elevated-plus maze (EPM), but it potentiated the acoustic startle response (ASR). However, acute IMO did enhance anxiety in the EPM, in juvenile stressed rats, thereby suggesting that juvenile stress sensitizes rats to the effects of additional stressors. Copyright © 2014 Elsevier Inc. All rights reserved.

Reinstatement in a Cocaine vs. Food Choice Situation: Reversal of Preference between Drug and Non-Drug Rewards

PubMed Central

Tunstall, Brendan J.; Kearns, David N.

2013-01-01

Recent studies (for review see Ahmed, 2010; 2012) show that when given a mutually exclusive choice between cocaine and food, rats almost exclusively choose food. The present experiment investigated potential shifts in preference between levers associated with either food or cocaine which might occur during extinction (food and cocaine no longer available) and during footshock-induced, cocaine-primed, and food-primed reinstatement. During self-administration sessions where food and cocaine were simultaneously available, rats demonstrated a stable food preference, choosing food over cocaine on 83% of trials. During extinction when neither reinforcer was available, no preference between levers was evident and responding decreased until rats responded on the previously food- and cocaine-associated levers at equally low rates. Footshock resulted in a non-specific reinstatement of responding upon both levers, while cocaine priming resulted in a significant preference for cocaine seeking over food seeking. This suggests that the mechanism underlying footshock-induced reinstatement is distinct from that of cocaine-primed reinstatement. Food priming engendered a mild, non-specific increase in responding on both levers. Although rats generally prefer food over cocaine when presented with a choice between these primary reinforcers, the present results suggest that in certain situations cocaine-seeking behavior prevails over food-seeking behavior. PMID:23551949

Galanin Mediates Features of Neural and Behavioral Stress Resilience Afforded by Exercise

PubMed Central

Sciolino, N. R.; Smith, J.M.; Stranahan, A.M.; Freeman, K.G.; Edwards, G. L.; Weinshenker, D.; Holmes, P.V.

2014-01-01

Exercise promotes resilience to stress and increases galanin in the locus coeruleus (LC), but the question of whether changes in galanin signaling mediate the stress-buffering effects of exercise has never been addressed. To test the contributions of galanin to stress resilience, male Sprague Dawley rats received intracerebroventricular (ICV) cannulation for drug delivery and frontocortical cannulation for microdialysis, and were housed with or without a running wheel for 21d. Rats were acutely injected with vehicle or the galanin receptor antagonist M40 and exposed to a single session of either footshock or no stress. Other groups received galanin, the galanin receptor antagonist M40, or vehicle chronically for 21d prior to the stress session. Microdialysis sampling occurred during stress exposure and anxiety-related behavior was measured on the following day in the elevated plus maze. Dendritic spines were visualized by Golgi impregnation in medial prefrontal cortex (mPFC) pyramidal neurons and quantified. Exercise increased galanin levels in the LC. Under non-stressed conditions, anxiety-related behavior and dopamine levels were comparable between exercised and sedentary rats. In contrast, exposure to stress reduced open arm exploration in sedentary rats but not in exercise rats or those treated chronically with ICV galanin, indicating improved resilience. Both exercise and chronic, ICV galanin prevented the increased dopamine overflow and loss of dendritic spines observed after stress in sedentary rats. Chronic, but not acute M40 administration blocked the resilience-promoting effects of exercise. The results indicate that increased galanin levels promote features of resilience at both behavioral and neural levels. PMID:25301278

Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress

PubMed Central

Mantsch, John R; Baker, David A; Funk, Douglas; Lê, Anh D; Shaham, Yavin

2016-01-01

In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse. PMID:25976297

Stress enables reinforcement-elicited serotonergic consolidation of fear memory

PubMed Central

Baratta, Michael V.; Kodandaramaiah, Suhasa B.; Monahan, Patrick E.; Yao, Junmei; Weber, Michael D.; Lin, Pei-Ann; Gisabella, Barbara; Petrossian, Natalie; Amat, Jose; Kim, Kyungman; Yang, Aimei; Forest, Craig R.; Boyden, Edward S.; Goosens, Ki A.

2015-01-01

Background Prior exposure to stress is a risk factor for developing post-traumatic stress disorder (PTSD) in response to trauma, yet the mechanisms by which this occurs are unclear. Using a rodent model of stress-based susceptibility to PTSD, we investigated the role of serotonin in this phenomenon. Methods Adult mice were exposed to repeated immobilization stress or handling, and the role of serotonin in subsequent fear learning was assessed using pharmacological manipulation and western blot detection of serotonin receptors, measurements of serotonin, high-speed optogenetic silencing, and behavior. Results Both dorsal raphe serotonergic activity during aversive reinforcement and amygdala serotonin 2c receptor (5-HT2CR) activity during memory consolidation are necessary for stress enhancement of fear memory, but neither process affects fear memory in unstressed mice. Additionally, prior stress increases amygdala sensitivity to serotonin by promoting surface expression of 5-HT2CR without affecting tissue levels of serotonin in the amygdala. We also show that the serotonin that drives stress enhancement of associative cued fear memory can arise from paired or unpaired footshock, an effect not predicted by theoretical models of associative learning. Conclusion Stress bolsters the consequences of aversive reinforcement, not by simply enhancing the neurobiological signals used to encode fear in unstressed animals, but rather by engaging distinct mechanistic pathways. These results reveal that predictions from classical associative learning models do not always hold for stressed animals, and suggest that 5-HT2CR blockade may represent a promising therapeutic target for psychiatric disorders characterized by excessive fear responses such as that observed in PTSD. PMID:26248536

Role of relaxin-3/RXFP3 system in stress-induced binge-like eating in female rats.

PubMed

Calvez, Juliane; de Ávila, Camila; Matte, Louis-Olivier; Guèvremont, Geneviève; Gundlach, Andrew L; Timofeeva, Elena

2016-03-01

Binge eating is frequently stimulated by stress. The neuropeptide relaxin-3 (RLN3) and its native receptor RXFP3 are implicated in stress and appetitive behaviors. We investigated the dynamics of the central RLN3/RXFP3 system in a newly established model of stress-induced binge eating. Female Sprague-Dawley rats were subjected to unpredictable intermittent 1-h access to 10% sucrose. When sucrose intake stabilized, rats were assessed for consistency of higher or lower sucrose intake in response to three unpredictable episodes of foot-shock stress; and assigned as binge-like eating prone (BEP) or binge-like eating resistant (BER). BEP rats displayed elevated consumption of sucrose under non-stressful conditions (30% > BER) and an additional marked increase in sucrose intake (60% > BER) in response to stress. Conversely, sucrose intake in BER rats was unaltered by stress. Chow intake was similar in both phenotypes on 'non-stress' days, but was significantly reduced by stress in BER, but not BEP, rats. After stress, BEP, but not BER, rats displayed a significant increase in RLN3 mRNA levels in the nucleus incertus. In addition, in response to stress, BEP, but not BER, rats had increased RXFP3 mRNA levels in the paraventricular and supraoptic nuclei of the hypothalamus. Intracerebroventricular administration of a selective RXFP3 antagonist, R3(B1-22)R, blocked the stress-induced increase in sucrose intake in BEP rats and had no effect on sucrose intake in BER rats. These results provide important evidence for a role of the central RLN3/RXFP3 system in the regulation of stress-induced binge eating in rats, and have therapeutic implications for eating disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

Chronic Vortioxetine Treatment Reduces Exaggerated Expression of Conditioned Fear Memory and Restores Active Coping Behavior in Chronically Stressed Rats.

PubMed

Hatherall, Lauren; Sánchez, Connie; Morilak, David A

2017-04-01

Stress is a risk factor for depression and anxiety disorders, disrupting neuronal processes leading to exaggerated fear and compromised coping behaviors. Current antidepressants are only partially effective. Vortioxetine, a novel multimodal antidepressant, is a serotonin transporter inhibitor; 5-HT3, 5-HT7, and 5-HT1D receptor antagonist; 5-HT1B partial agonist; and 5-HT1A agonist. We have shown that chronic dietary vortioxetine administration reversed stress-induced deficits in cognitive flexibility. In the present studies, we investigated the generality of vortioxetine's effects on other stress-related behavioral changes after different types of chronic stress. In experiment 1, rats were fear-conditioned by pairing a tone with footshock, then exposed to chronic plus acute prolonged stress. In experiment 2, rats were exposed to chronic unpredictable stress. In both experiments, beginning on day 4 of chronic stress, vortioxetine was given in the diet (24 mg/kg/d). In experiment 1, effects of vortioxetine were tested on stress-induced changes in retention and extinction of cue-conditioned fear, and in experiment 2, on coping behavior on the shock probe defensive burying test after chronic stress. Chronic stress exaggerated the expression of conditioned fear memory. Vortioxetine restored fear memory to control levels and rendered extinction in stressed rats comparable with that in controls. In experiment 2, chronic unpredictable stress caused a shift from active to passive coping behavior, and vortioxetine restored active coping. Vortioxetine reduced exaggerated expression of conditioned fear and restored adaptive coping behavior following 2 different types of chronic stress, adding to the evidence of its therapeutic potential in the management of depression and anxiety disorders. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Depression of excitatory synapses onto parvalbumin interneurons in the medial prefrontal cortex in susceptibility to stress.

PubMed

Perova, Zinaida; Delevich, Kristen; Li, Bo

2015-02-18

In response to extreme stress, individuals either show resilience or succumb to despair. The prefrontal cortex (PFC) is required for coping with stress, and PFC dysfunction has been implicated in stress-related mental disorders, including depression. Nevertheless, the mechanisms by which the PFC participates in stress responses remain unclear. Here, we investigate the role of parvalbumin (PV) interneurons in the medial PFC (mPFC) in shaping behavioral responses to stress induced by the learned helplessness procedure, in which animals are subjected to an unpredictable and inescapable stressor. PV interneurons in the mPFC were probed and manipulated in knock-in mice expressing the Cre recombinase under the endogenous parvalbumin promoter. Notably, we found that excitatory synaptic transmission onto these neurons was decreased in mice showing helplessness, a behavioral state that is thought to resemble features of human depression. Furthermore, selective suppression of PV interneurons in the mPFC using hM4Di, a DREADD (designer receptor exclusively activated by designer drug), promoted helplessness, indicating that activation of these neurons during stress promotes the establishment of resilient behavior. Our results reveal a cellular mechanism of mPFC dysfunction that may contribute to the emergence of maladaptive behavioral responses in the face of adverse life events. Copyright © 2015 the authors 0270-6474/15/353201-06$15.00/0.

Females do not express learned helplessness like males do.

PubMed

Dalla, Christina; Edgecomb, Carol; Whetstone, Abigail S; Shors, Tracey J

2008-06-01

Women are more likely than men to suffer from stress-related mental disorders, such as depression. In the present experiments, we identified sex differences in one of the most common animal models of depression, that of learned helplessness. Male and female rats were trained to escape a mild footshock each day for 7 days (controllable stress). Each rat was yoked to another rat that could not escape (uncontrollable stress), but was exposed to the same amount of shock. One day later, all stressed rats and unstressed controls were tested on a more difficult escape task in a different context. Most males exposed to uncontrollable stress did not learn to escape and were therefore helpless. In contrast, most females did learn to escape on the more difficult escape task, irrespective of whether they had been exposed to controllable or uncontrollable stress. The sex differences in helplessness behavior were not dependent on the presence of sex hormones in adulthood, because neither ovariectomy of females nor castration of males abolished them. The absence of helplessness in females was neither dependent on organizational effects of testosterone during the day of birth, because masculinized females did not express helplessness as adults. Thus, sex differences in helplessness behavior are independent of gonadal hormones in adulthood and testosterone exposure during perinatal development. Learned helplessness may not constitute a valid model for depressive behavior in women, at least as reflected by the response of female rats to operant conditioning procedures after stressful experience.

Onset and severity of inflammation in rats exposed to the learned helplessness paradigm.

PubMed

Chover-Gonzalez, A J; Jessop, D S; Tejedor-Real, P; Gibert-Rahola, J; Harbuz, M S

2000-07-01

To test the hypothesis that there is an association between susceptibility to inflammation and a hyporesponsive hypothalamo-pituitary-adrenal (HPA) axis. Animals were separated on the basis of behaviour in the learned helplessness (LH) paradigm into groups of LH(+) (i.e. animals which did not escape footshock) and LH(-) animals. Adjuvant-induced arthritis (AA) was subsequently induced in the LH(+) and LH(-) animals. Plasma corticosterone was significantly increased in response to the LH test in the LH(-) compared with the LH(+) rats. We observed an earlier onset and increased inflammation in the LH(-) rats in spite of the greater corticosterone response to the acute stress. We noted lower levels of plasma testosterone in the LH(-) animals suggesting a possible influence for this protective factor in AA. These data suggest that increased onset and severity of inflammation in AA is not a simple consequence of an attenuated HPA axis response to stress as proposed in the Lewis rat. Indeed we have observed the converse. Together these data suggest that the balance of pro- and anti-inflammatory factors released in response to stress may influence the progress of AA.

Acute episodes of predator exposure in conjunction with chronic social instability as an animal model of post-traumatic stress disorder

PubMed Central

Zoladz, Phillip R.; Conrad, Cheryl D.; Fleshner, Monika; Diamond, David M.

2008-01-01

People who are exposed to horrific, life-threatening experiences are at risk for developing post-traumatic stress disorder (PTSD). Some of the symptoms of PTSD include persistent anxiety, exaggerated startle, cognitive impairments and increased sensitivity to yohimbine, an α2-adrenergic receptor antagonist. We have taken into account the conditions known to induce PTSD, as well as factors responsible for long-term maintenance of the disorder, to develop an animal model of PTSD. Adult male Sprague–Dawley rats were administered a total of 31 days of psychosocial stress, composed of acute and chronic components. The acute component was a 1-h stress session (immobilization during cat exposure), which occurred on Days 1 and 11. The chronic component was that on all 31 days the rats were given unstable housing conditions. We found that psychosocially stressed rats had reduced growth rate, reduced thymus weight, increased adrenal gland weight, increased anxiety, an exaggerated startle response, cognitive impairments, greater cardiovascular and corticosterone reactivity to an acute stressor and heightened responsivity to yohimbine. This work demonstrates the effectiveness of acute inescapable episodes of predator exposure administered in conjunction with daily social instability as an animal model of PTSD. PMID:18574787

Neurogenesis and Helplessness are Mediated by Controllability in Males but not in Females

PubMed Central

Shors, Tracey J.; Mathew, Jason; Sisti, Helene M.; Edgecomb, Carol; Beckoff, Steven; Dalla, Christina

2009-01-01

Background Numerous studies have implicated neurogenesis in the hippocampus in animal models of depression, especially those related to controllability and learned helplessness. Here, we tested the hypothesis that uncontrollable, but not controllable stress would reduce cell proliferation in the hippocampus of male and female rats, and would relate to the expression of helplessness behavior. Methods To manipulate controllability, groups of male and female rats were trained in one session (acute stress) or over seven sessions (repeated stress) to escape a footshock, while yoked controls could not escape, but were exposed to the same amount of stress. Cell proliferation was assessed with immunohistochemistry of BrdU and immunofluorescence of BrdU and NeuN. Separate groups were exposed to either controllable or uncontrollable stress and their ability to learn to escape during training on a more difficult task was used as a behavioral measure of helplessness. Results Acute stress reduced cell proliferation in males, but did not affect proliferation in the female hippocampus. When animals were given the opportunity to learn to control the stress over days, males produced more cells than the yoked males without control. Repeated training with controllable stress did not influence proliferation in females. Under all conditions, males were more likely than females to express helplessness behavior, even males that were not previously stressed. Conclusions The modulation of neurogenesis by controllability was evident in males but not in females, as was the expression of helplessness behavior, despite the fact that men are less likely than women to experience depression. PMID:17306770

Neurogenesis and helplessness are mediated by controllability in males but not in females.

PubMed

Shors, Tracey J; Mathew, Jason; Sisti, Helene M; Edgecomb, Carol; Beckoff, Steven; Dalla, Christina

2007-09-01

Numerous studies have implicated neurogenesis in the hippocampus in animal models of depression, especially those related to controllability and learned helplessness. Here, we tested the hypothesis that uncontrollable but not controllable stress would reduce cell proliferation in the hippocampus of male and female rats and would relate to the expression of helplessness behavior. To manipulate controllability, groups of male and female rats were trained in one session (acute stress) or over seven sessions (repeated stress) to escape a footshock, whereas yoked control subjects could not escape but were exposed to the same amount of stress. Cell proliferation was assessed with immunohistochemistry of bromodeoxyuridine (BrdU) and immunofluorescence of BrdU and neuronal nuclei (NeuN). Separate groups were exposed to either controllable or uncontrollable stress, and their ability to learn to escape during training on a more difficult task was used as a behavioral measure of helplessness. Acute stress reduced cell proliferation in males but did not affect proliferation in the female hippocampus. When animals were given the opportunity to learn to control the stress over seven days, males produced more cells than the yoked males without control. Repeated training with controllable stress did not influence proliferation in females. Under all conditions, males were more likely than females to express helplessness behavior, even males that were not previously stressed. The modulation of neurogenesis by controllability was evident in males but not in females, as was the expression of helplessness behavior, despite the fact that men are less likely than women to experience depression.

Differential regulation of serotonin (5HT)2A receptor mRNA and protein levels after single and repeated stress in rat brain: role in learned helplessness behavior.

PubMed

Dwivedi, Yogesh; Mondal, Amal C; Payappagoudar, Gurubasanagouda V; Rizavi, Hooriyah S

2005-02-01

Stress-induced learned helplessness in animals serves as a model of behavioral depression and other stress-related disorders. Our recent report that repeated stress prolongs the duration of learned helplessness behavior in rats may be important since acute and recurrent disorders may have different responsive mechanisms. To examine the role of serotonergic (5HT) mechanisms in such behavior, we studied the expression of 5HT2A receptors in different brain areas of rats, and further investigated whether the alterations in expression of 5HT2A receptors are similar after single versus repeated stress. Rats exposed to inescapable shock once on day 1, or twice, on day 1 and day 7, were tested for escape latency on days 2 and 4, or day 14, respectively. Higher escape latencies were observed on day 2 after single, and on day 14 after repeated shock. Whereas the single-stress paradigm produced a significant decrease of 5HT2A receptor mRNA and protein expression in hippocampus of non-learned helpless and learned helpless rats as compared with tested controls, repeated stress resulted in increase in frontal cortex but decrease in hippocampus and hypothalamus of learned helpless rats only, as compared with tested control rats. These results demonstrate differential regulation of 5HT2A receptors in LH rats after single and repeated stress, which may be critical in the pathophysiology of depression/other stress-related disorders.

A matter of timing: harm reduction in learned helplessness.

PubMed

Richter, Sophie Helene; Sartorius, Alexander; Gass, Peter; Vollmayr, Barbara

2014-11-03

Learned helplessness has excellent validity as an animal model for depression, but problems in reproducibility limit its use and the high degree of stress involved in the paradigm raises ethical concerns. We therefore aimed to identify which and how many trials of the learned helplessness paradigm are necessary to distinguish between helpless and non-helpless rats. A trial-by-trial reanalysis of tests from 163 rats with congenital learned helplessness or congenital non-learned helplessness and comparison of 82 rats exposed to inescapable shock with 38 shock-controls revealed that neither the first test trials, when rats showed unspecific hyperlocomotion, nor trials of the last third of the test, when almost all animals responded quickly to the stressor, contributed to sensitivity and specificity of the test. Considering only trials 3-10 improved the classification of helpless and non-helpless rats. The refined analysis allows abbreviation of the test for learned helplessness from 15 trials to 10 trials thereby reducing pain and stress of the experimental animals without losing statistical power.

Role of dopamine receptors in the ventral tegmental area in conditioned fear.

PubMed

de Oliveira, Amanda Ribeiro; Reimer, Adriano Edgar; Brandão, Marcus Lira

2009-05-16

The increased startle reflex in the presence of a stimulus that has been previously paired with footshock has been termed fear-potentiated startle (FPS) and is considered a reliable index of anxiety. Some studies have suggested an association between stressful situations and alterations in dopaminergic (DA) transmission. Many studies converge on the hypothesis that the mesocorticolimbic pathway, originating from DA neurons in the ventral tegmental area (VTA), is particularly sensitive to fear-arousing stimuli. The present study explored the involvement of VTA DA receptors in the acquisition and expression of conditioned fear to a light conditioned stimulus (CS). We evaluated the effects of intra-VTA administration of SKF 38393 (D(1) agonist), SCH 23390 (D(1) antagonist), quinpirole (D(2) agonist), and sulpiride (D(2) antagonist) on FPS. All drugs were administered bilaterally into the VTA (1.0 microg/0.2 microl/site). Locomotor activity/exploration and motor coordination were evaluated in the open-field and rotarod tests. None of the drugs produced significant effects on FPS when injected before conditioning, indicating that VTA DA receptors are not involved in the acquisition of conditioned fear to a light-CS. In contrast, when injected before the test session, quinpirole significantly reduced FPS, whereas the other drugs had no effect. Quinpirole's ability to decrease FPS may be the result of an action on VTA D(2) presynaptic autoreceptors that decrease dopamine levels in terminal fields of the mesocorticolimbic pathway. Altogether, the present results suggest the importance of VTA DA neurons in the fear-activating effects of Pavlovian conditioning. In addition to demonstrating the importance of dopaminergic mechanisms in the motivational consequences of footshock, the present findings also indicate that these neural circuits are mainly involved in the expression, rather than acquisition, of conditioned fear.

The effects of acute nicotine on contextual safety discrimination.

PubMed

Kutlu, Munir G; Oliver, Chicora; Gould, Thomas J

2014-11-01

Anxiety disorders, such as post-traumatic stress disorder (PTSD), may be related to an inability to distinguish safe versus threatening environments and to extinguish fear memories. Given the high rate of cigarette smoking in patients with PTSD, as well as the recent finding that an acute dose of nicotine impairs extinction of contextual fear memory, we conducted a series of experiments to investigate the effect of acute nicotine in an animal model of contextual safety discrimination. Following saline or nicotine (at 0.0275, 0.045, 0.09 and 0.18 mg/kg) administration, C57BL/6J mice were trained in a contextual discrimination paradigm, in which the subjects received presentations of conditioned stimuli (CS) that co-terminated with a foot-shock in one context (context A (CXA)) and only CS presentations without foot-shock in a different context (context B (CXB)). Therefore, CXA was designated as the 'dangerous context', whereas CXB was designated as the 'safe context'. Our results suggested that saline-treated animals showed a strong discrimination between dangerous and safe contexts, while acute nicotine dose-dependently impaired contextual safety discrimination (Experiment 1). Furthermore, our results demonstrate that nicotine-induced impairment of contextual safety discrimination learning was not a result of increased generalized freezing (Experiment 2) or contingent on the common CS presentations in both contexts (Experiment 3). Finally, our results show that increasing the temporal gap between CXA and CXB during training abolished the impairing effects of nicotine (Experiment 4). The findings of this study may help link nicotine exposure to the safety learning deficits seen in anxiety disorder and PTSD patients. © The Author(s) 2014.

Not all stressors are equal: behavioral and endocrine evidence for development of contextual fear conditioning after a single session of footshocks but not of immobilization

PubMed Central

Daviu, Núria; Delgado-Morales, Raúl; Nadal, Roser; Armario, Antonio

2012-01-01

Exposure of animals to footshocks (FS) in absence of any specific cue results in the development of fear to the compartment where shocks were given (contextual fear conditioning), and this is usually evaluated by time spent freezing. However, the extent to which contextual fear conditioning always develops when animals are exposed to other stressors is not known. In the present work we firstly demonstrated, using freezing, that exposure of adult rats to a single session of FS resulted in short-term and long-term contextual fear conditioning (freezing) that was paralleled by increased hypothalamic-pituitary-adrenal (HPA) activation. In contrast, using a similar design, no HPA or behavioral evidence for such conditioning was found after exposure to immobilization on boards (IMO), despite this stressor being of similar severity as FS on the basis of standard physiological measures of stress, including HPA activation. In a final experiment we directly compared the exposure to the two stressors in the same type of context and tested for the development of conditioning to the context and to a specific cue for IMO (the board). We observed the expected high levels of freezing and the conditioned HPA activation after FS, but not after IMO, regardless of the presence of the board during testing. Therefore, it can be concluded that development of fear conditioning to context or particular cues, as evaluated by either behavioral or endocrine measures, appears to be dependent on the nature of the aversive stimuli, likely to be related to biologically preparedness to establish specific associations. PMID:23112767

A Comparison of Objective and Subjective Stress in Homogeneous Male and Female Teams in a Mars Simulation

NASA Astrophysics Data System (ADS)

Bishop, S.; Sundaresan, A.

Introduction The role of stress and its impact on coping performance motivation behavior cognitive functioning and psychological well-being has become a key focus for long duration missions Since all extreme environments are characterized by significant physical demands e g skiing climbing EVAs as well as inescapable environmental characteristics e g imminent danger noise isolation confinement loss of normal sensory stimuli an examination of the impact of prolong stress in analogue environments should provide insight into developing effective support and countermeasures for long duration space crews The presence of even low levels of chronic stressors if not met with functional adaptation and or countermeasures has been shown to produce subjective symptoms of stress persistent performance incompetence accelerated fatiguability altered mood states increased rate of infections and decrements in attention and cognitive Gender has been shown to cut across both individual factors and group factors including response to stress and ways of coping Generally men and women differ in many arenas such as interaction and communication styles need for affiliation responses to crowding privacy and confined spaces Men and women in homogeneous groups interact in significantly different ways than those in mixed groups Therefore differences between genders on subjective and objective responses to stress are of interest The Mars Society Utah Desert Simulation MDRS facility provides a unique opportunity to examine the interaction of

The Vasopressin 1b Receptor Antagonist A-988315 Blocks Stress Effects on the Retrieval of Object-Recognition Memory

PubMed Central

Barsegyan, Areg; Atsak, Piray; Hornberger, Wilfried B; Jacobson, Peer B; van Gaalen, Marcel M; Roozendaal, Benno

2015-01-01

Stress-induced activation of the hypothalamo–pituitary–adrenocortical (HPA) axis and high circulating glucocorticoid levels are well known to impair the retrieval of memory. Vasopressin can activate the HPA axis by stimulating vasopressin 1b (V1b) receptors located on the pituitary. In the present study, we investigated the effect of A-988315, a selective and highly potent non-peptidergic V1b-receptor antagonist with good pharmacokinetic properties, in blocking stress effects on HPA-axis activity and memory retrieval. To study cognitive performance, male Sprague-Dawley rats were trained on an object-discrimination task during which they could freely explore two identical objects. Memory for the objects and their location was tested 24 h later. A-988315 (20 or 60 mg/kg) or water was administered orally 90 min before retention testing, followed 60 min later by stress of footshock exposure. A-988315 dose-dependently dampened stress-induced increases in corticosterone plasma levels, but did not significantly alter HPA-axis activity of non-stressed control rats. Most importantly, A-988315 administration prevented stress-induced impairment of memory retrieval on both the object-recognition and the object-location tasks. A-988315 did not alter the retention of non-stressed rats and did not influence the total time spent exploring the objects or experimental context in either stressed or non-stressed rats. Thus, these findings indicate that direct antagonism of V1b receptors is an effective treatment to block stress-induced activation of the HPA axis and the consequent impairment of retrieval of different aspects of recognition memory. PMID:25669604

The expression of plasticity-related genes in an acute model of stress is modulated by chronic desipramine in a time-dependent manner within medial prefrontal cortex.

PubMed

Nava, Nicoletta; Treccani, Giulia; Müller, Heidi Kaastrup; Popoli, Maurizio; Wegener, Gregers; Elfving, Betina

2017-01-01

It is well established that stress plays a major role in the pathogenesis of neuropsychiatric diseases. Stress-induced alteration of synaptic plasticity has been hypothesized to underlie the morphological changes observed by neuroimaging in psychiatric patients in key regions such as hippocampus and prefrontal cortex (PFC). We have recently shown that a single acute stress exposure produces significant short-term alterations of structural plasticity within medial PFC. These alterations were partially prevented by previous treatment with chronic desipramine (DMI). In the present study we evaluated the effects of acute Foot-shock (FS)-stress and pre-treatment with the traditional antidepressant DMI on the gene expression of key regulators of synaptic plasticity and structure. Expression of Homer, Shank, Spinophilin, Densin-180, and the small RhoGTPase related gene Rac1 and downstream target genes, Limk1, Cofilin1 and Rock1 were investigated 1 day (1d), 7 d and 14d after FS-stress exposure. We found that DMI specifically increases the short-term expression of Spinophilin, as well as Homer and Shank family genes, and that both acute stress and DMI exert significant long-term effects on mRNA levels of genes involved in spine plasticity. These findings support the knowledge that acute FS stress and antidepressant treatment induce both rapid and sustained time-dependent alterations in structural components of synaptic plasticity in rodent medial PFC. Copyright © 2016 Elsevier B.V. and ECNP. All rights reserved.

Unconditioned stimulus pathways to the amygdala: effects of lesions of the posterior intralaminar thalamus on foot-shock-induced c-Fos expression in the subdivisions of the lateral amygdala.

PubMed

Lanuza, E; Moncho-Bogani, J; Ledoux, J E

2008-08-26

The lateral nucleus of the amygdala (LA) is a site of convergence for auditory (conditioned stimulus) and foot-shock (unconditioned stimulus) inputs during fear conditioning. The auditory pathways to LA are well characterized, but less is known about the pathways through which foot shock is transmitted. Anatomical tracing and physiological recording studies suggest that the posterior intralaminar thalamic nucleus, which projects to LA, receives both auditory and somatosensory inputs. In the present study we examined the expression of the immediate-early gene c-fos in the LA in rats in response to foot-shock stimulation. We then determined the effects of posterior intralaminar thalamic lesions on foot-shock-induced c-Fos expression in the LA. Foot-shock stimulation led to an increase in the density of c-Fos-positive cells in all LA subnuclei in comparison to controls exposed to the conditioning box but not shocked. However, some differences among the dorsolateral, ventrolateral and ventromedial subnuclei were observed. The ventrolateral subnucleus showed a homogeneous activation throughout its antero-posterior extension. In contrast, only the rostral aspect of the ventromedial subnucleus and the central aspect of the dorsolateral subnucleus showed a significant increment in c-Fos expression. The density of c-Fos-labeled cells in all LA subnuclei was also increased in animals placed in the box in comparison to untreated animals. Unilateral electrolytic lesions of the posterior intralaminar thalamic nucleus and the medial division of the medial geniculate body reduced foot-shock-induced c-Fos activation in the LA ipsilateral to the lesion. The number of c-Fos labeled cells on the lesioned side was reduced to the levels observed in the animals exposed only to the box. These results indicate that the LA is involved in processing information about the foot-shock unconditioned stimulus and receives this kind of somatosensory information from the posterior intralaminar thalamic nucleus and the medial division of the medial geniculate body.

History of chronic stress modifies acute stress-evoked fear memory and acoustic startle in male rats.

PubMed

Schmeltzer, Sarah N; Vollmer, Lauren L; Rush, Jennifer E; Weinert, Mychal; Dolgas, Charles M; Sah, Renu

2015-01-01

Chronicity of trauma exposure plays an important role in the pathophysiology of posttraumatic stress disorder (PTSD). Thus, exposure to multiple traumas on a chronic scale leads to worse outcomes than acute events. The rationale for the current study was to investigate the effects of a single adverse event versus the same event on a background of chronic stress. We hypothesized that a history of chronic stress would lead to worse behavioral outcomes than a single event alone. Male rats (n = 14/group) were exposed to either a single traumatic event in the form of electric foot shocks (acute shock, AS), or to footshocks on a background of chronic stress (chronic variable stress-shock, CVS-S). PTSD-relevant behaviors (fear memory and acoustic startle responses) were measured following 7 d recovery. In line with our hypothesis, CVS-S elicited significant increases in fear acquisition and conditioning versus the AS group. Unexpectedly, CVS-S elicited reduced startle reactivity to an acoustic stimulus in comparison with the AS group. Significant increase in FosB/ΔFosB-like immunostaining was observed in the dentate gyrus, basolateral amygdala and medial prefrontal cortex of CVS-S rats. Assessments of neuropeptide Y (NPY), a stress-regulatory transmitter associated with chronic PTSD, revealed selective reduction in the hippocampus of CVS-S rats. Collectively, our data show that cumulative stress potentiates delayed fear memory and impacts defensive responding. Altered neuronal activation in forebrain limbic regions and reduced NPY may contribute to these phenomena. Our preclinical studies support clinical findings reporting worse PTSD outcomes stemming from cumulative traumatization in contrast to acute trauma.

Experimental occlusal disharmony - A promoting factor for anxiety in rats under chronic psychological stress.

PubMed

Tang, Xuan; Li, Jian; Jiang, Ting; Han, Shu-Hui; Yao, Dong-Yuan

2017-04-03

Clinically, patients under chronic psychological stress (PS) appear to be more susceptible to occlusal disharmony (OD) compared with those without PS. OD was proved to introduce anxiety-like stress. Therefore, the purpose of the study was to investigate whether OD would affect psychological stress-induced anxiety and its underlying mechanisms. Chronic PS was induced by a communication box, and OD was produced by bonding a 0.3mm-thick crown on the right maxillary first molar of male Sprague-Dawley rats. Sixty-seven rats were randomly divided into 8 groups: (A) chronic PS plus OD group (n=6); (B) chronic PS plus sham OD group (n=6); (C) chronic PS only group (n=6); (D) OD group (n=6); (E) sham OD group (n=6); (F) control group (n=6); (G) naive group (n=6); (H) foot-shock group (n=25). Open-field test (OFT) and elevated plus maze test (EPM) were conducted on the 7th, 21th, 35th day to measure the anxiety level of each group except naive and foot-shock group. In addition, corticosterone (CORT) level in serum, 5-hydroxytryptamine (5-HT) and 5-HT 2A receptor (5-HT 2A R) expressions in prefrontal cortex (PFC), hippocampal CA1 and dentate gyrus (DG) areas were measured on the 35th day to elucidate the mechanism(s) by which the exacerbation occurred. The significant differences in OFT and EPM tests on day 21 or day 35 between groups (p<0.01) indicated the successful establishment of animal model of PS or OD. And there was a significant increase in CORT concentration in serum (p<0.01), 5-HT expressions in PFC, hippocampal DG areas and 5-HT 2A R expressions in PFC, hippocampal CA1 areas (p<0.05) in group A, B, C, D compared with group F. Similar results were also found in group A, B, C, D when compared with group G (p<0.05) except 5-HT expression in DG area in group C and D (p>0.05), together with a gradual decrease in values of all the parameters mentioned above from group A to group G. The significant changes in exploratory behaviors, serum CORT concentration, 5-HT and 5-HT 2A R expressions induced by OD in rats with or without chronic PS, and more obvious alterations in rats with chronic PS, may indicate that OD may be a promoting factor for anxiety through both peripheral and central pathways via the hypothalamus-pituitary-adrenal (HPA) axis and 5-HT system. Copyright © 2017 Elsevier Inc. All rights reserved.

Fluoxetine reverses the behavioral despair induced by neurogenic stress in mice: role of N-methyl-d-aspartate and opioid receptors.

PubMed

Haj-Mirzaian, Arya; Kordjazy, Nastaran; Ostadhadi, Sattar; Amiri, Shayan; Haj-Mirzaian, Arvin; Dehpour, AhmadReza

2016-06-01

Opioid and N-methyl-d-aspartate (NMDA) receptors mediate different effects of fluoxetine. We investigated whether opioid and NMDA receptors are involved in the protective effect of fluoxetine against the behavioral despair induced by acute physical stress in male mice. We used the forced swimming test (FST), tail suspension test (TST), and open-field test (OFT) for behavioral evaluation. We used fluoxetine, naltrexone (opioid receptor antagonist), MK-801 (NMDA receptor antagonist), morphine (opioid receptor agonist), and NMDA (NMDA receptor agonist). Acute foot-shock stress (FSS) significantly induced behavioral despair (depressive-like) and anxiety-like behaviors in tests. Fluoxetine (5 mg/kg) reversed the depressant-like effect of FSS, but it did not alter the locomotion and anxiety-like behavior in animals. Acute administration of subeffective doses of naltrexone (0.3 mg/kg) or MK-801 (0.01 mg/kg) potentiated the antidepressant-like effect of fluoxetine, while subeffective doses of morphine (1 mg/kg) and NMDA (75 mg/kg) abolished this effect of fluoxetine. Also, co-administration of subeffective doses of naltrexone (0.05 mg/kg) and MK-801 (0.003 mg/kg) with fluoxetine (1 mg/kg) induced a significant decrease in the immobility time in FST and TST. Our results showed that opioid and NMDA receptors (alone or in combination) are involved in the antidepressant-like effect of fluoxetine against physical stress.

Peritraumatic startle response predicts the vulnerability to develop PTSD-like behaviors in rats: a model for peritraumatic dissociation

PubMed Central

Dong, Xinwen; Li, Yonghui

2014-01-01

Peritraumatic dissociation, a state characterized by alteration in perception and reduced awareness of surroundings, is considered to be a risk factor for the development of post-traumatic stress disorder (PTSD). However, the predictive ability of peritraumatic dissociation is questioned for the inconsistent results in different time points of assessment. The startle reflex is an objective behavioral measurement of defensive response to abrupt and intense sensory stimulus of surroundings, with potential to be used as an assessment on the dissociative status in both humans and rodents. The present study examined the predictive effect of acoustic startle response (ASR) in different time points around the traumatic event in an animal model of PTSD. The PTSD-like symptoms, including hyperarousal, avoidance, and contextual fear, were assessed 2–3 weeks post-trauma. The results showed that (1) the startle amplitude attenuated immediate after intense footshock in almost half of the stress animals, and (2) the attenuated startle responses at 1 h but not 24 h after stress predicted the development of severe PTSD-like symptoms. These data indicate that the startle alteration at the immediate period after trauma, including 1 h, is more important in PTSD prediction than 24 h after trauma. Our study also suggests that the startle attenuation immediate after intense stress may serve as an objective measurement of peritraumatic dissociation in rats. PMID:24478660

Microarray analyses reveal novel targets of exercise-induced stress resistance in the dorsal raphe nucleus

PubMed Central

Loughridge, Alice B.; Greenwood, Benjamin N.; Day, Heidi E. W.; McQueen, Matthew B.; Fleshner, Monika

2013-01-01

Serotonin (5-HT) is implicated in the development of stress-related mood disorders in humans. Physical activity reduces the risk of developing stress-related mood disorders, such as depression and anxiety. In rats, 6 weeks of wheel running protects against stress-induced behaviors thought to resemble symptoms of human anxiety and depression. The mechanisms by which exercise confers protection against stress-induced behaviors, however, remain unknown. One way by which exercise could generate stress resistance is by producing plastic changes in gene expression in the dorsal raphe nucleus (DRN). The DRN has a high concentration of 5-HT neurons and is implicated in stress-related mood disorders. The goal of the current experiment was to identify changes in the expression of genes that could be novel targets of exercise-induced stress resistance in the DRN. Adult, male F344 rats were allowed voluntary access to running wheels for 6 weeks; exposed to inescapable stress or no stress; and sacrificed immediately and 2 h after stressor termination. Laser capture micro dissection selectively sampled the DRN. mRNA expression was measured using the whole genome Affymetrix microarray. Comprehensive data analyses of gene expression included differential gene expression, log fold change (LFC) contrast analyses with False Discovery Rate correction, KEGG and Wiki Web Gestalt pathway enrichment analyses, and Weighted Gene Correlational Network Analysis (WGCNA). Our results suggest that physically active rats exposed to stress modulate expression of twice the number of genes, and display a more rapid and strongly coordinated response, than sedentary rats. Bioinformatics analyses revealed several potential targets of stress resistance including genes that are related to immune processes, tryptophan metabolism, and circadian/diurnal rhythms. PMID:23717271

Stress, chemical defense agents, and cholinergic receptors. Midterm report, 1 November 1987-31 July 1989

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lane, J.D.

1989-11-30

This project is assessing the affects of exposure to a chemical defense agent on anxiety and stress, by using rat models of anxiety (conditioned emotional response (CER); conditioned suppression) and unconditioned non-specific stres (exposure to footshock). The specific experiments determined the plasticity of muscarinic cholinergic binding sites in the central nervous system. The neuroanatomical locus and neuropharmacological profile of changes in binding sites were assessed in brain areas enriched in cholinergic markers. Acetylcholine turnover was measured to determine if the receptor response is compensatory or independent. The effects of acute exposure to doses of a chemical defense agent (soman--XGD) onmore » lethality and behaviors were examined. The experiments involved training and conditioning adult rats to CER using standard operant/respondent techniques. The binding of radiolabelled ligand was studied in vitro using brain membranes and tissue sections (autoradiography). The major findings are that CER produces increases in acetylcholine turnover in brain areas involved in anxiety, and that primarily post-synaptic M1 receptors compensatorly decrease in response. These neurochemical phenomena are directly correlated with several behaviors, including onset and extinction of CER and non-specific stress. Followup experiments have been designed to test the interaction of CER, XGD and neurochemistry.« less

[Changes in glutamate release in the rat nucleus accumbens during food and pain reinforcement].

PubMed

Saul'skaia, N B; Mikhaĭlova, M O; Pudovkina, O L; Gorbachevskaia, A I

2000-01-01

In vivo microdialysis combined with HPLC-EC analysis was used to monitor extracellular glutamate in the n. accumbens of Sprague-Dawley rats during footshock and food delivery. The footshock presentation resulted in a delayed increase in extracellular glutamate level, whereas the food intake caused its decrease. The intra-accumbens infusion of glutamate reuptake blocker D,L-threo-beta-hydroxiaspartate (1 mM) completely prevented the food-induced decrease in glutamate level. The intra-accumbens infusion of sodium channel blocker tetrodotoxin (1 microM) led to an increase in glutamate extracellular level in the n. accumbens in response to food intake. The results suggest that the food-induced decrease in glutamate extracellular level in the n. accumbens occurs due to an enhancement of high-affinity glutamate uptake that is probably under the neuronal control during feeding.

The CRF₁ receptor antagonist SSR125543 prevents stress-induced long-lasting sleep disturbances in a mouse model of PTSD: comparison with paroxetine and d-cycloserine.

PubMed

Philbert, Julie; Beeské, Sandra; Belzung, Catherine; Griebel, Guy

2015-02-15

The selective CRF₁ (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term behavioral and electrophysiological effects produced by traumatic stress exposure in mice. Sleep disturbances are one of the most commonly reported symptoms by people with post-traumatic stress disorder (PTSD). The present study aims at investigating whether SSR125543 (10 mg/kg/day/i.p. for 2 weeks) is able to attenuate sleep/wakefulness impairment induced by traumatic stress exposure in a model of PTSD in mice using electroencephalographic (EEG) analysis. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day/i.p.), and the partial N-methyl-d-aspartate (NMDA) receptor agonist, d-cycloserine (10 mg/kg/day/i.p.), two compounds which have demonstrated clinical efficacy against PTSD. Baseline EEG recording was performed in the home cage for 6h prior to the application of two electric foot-shocks of 1.5 mA. Drugs were administered from day 1 post-stress to the day preceding the second EEG recording session, performed 14 days later. Results showed that at day 14 post-stress, shocked mice displayed sleep fragmentation as shown by an increase in the occurrence of both non-rapid eye movement (NREM) sleep and wakefulness bouts. The duration of wakefulness, NREM and REM sleep were not significantly affected. The stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine. These findings confirm further that the CRF₁ receptor antagonist SSR125543 is able to attenuate the deleterious effects of traumatic stress exposure. Copyright © 2014 Elsevier B.V. All rights reserved.

Stress modulation of the memory retrograde-enhancing effects of the awakening drug modafinil in mice.

PubMed

Béracochéa, Daniel; Liscia, Pierrette; Tronche, Christophe; Chauveau, Frédéric; Jouanin, Jean-Claude; Piérard, Christophe

2008-01-01

This study investigated the dose-effect relationship of modafinil administration on contextual memory processes, in parallel with the measurements of plasma corticosterone levels in acutely stressed mice. Memory was first evaluated in normal (nonstressed) mice either in contextual (CSD) or spatial (SSD) tasks. Thus, C57 Bl/6 Jico mice learned two consecutive discriminations (D1 and D2) in a four-hole board. The discriminations occurred on either distinct (CSD) or identical (SSD) floors (internal contextual cues). All mice received a vehicle intraperitoneal injection before learning and were injected 24 h later (20 min before the test session) either with vehicle or modafinil. Results showed that modafinil-treated mice behaved similarly as vehicles in the spatial SSD task, whereas in contrast, memory of the first-learned discrimination (D1) in the CSD task was enhanced by a 32- but not a 16-mg/kg modafinil dose. Hence, we studied the effect of a pretest acute stress (electric footshocks) specifically on D1 performance in modafinil-treated subjects. Immediately after behavioral testing, blood was sampled to measure plasma corticosterone levels. Results showed that: (1) stress significantly improved performance in vehicles, (2) stress decreased the efficiency threshold of modafinil, as performance was enhanced at the low dose (16 mg/kg), whereas this enhancement was obtained for the high dose (32 mg/kg) under nonstress conditions, (3) the performance was impaired at the high (32 mg/kg) dose, and (4) modafinil significantly reduced the magnitude of the stress-induced corticosterone secretion, mainly at the dose of 32 mg/kg.

Running Reduces Uncontrollable Stress-Evoked Serotonin and Potentiates Stress-Evoked Dopamine Concentrations in the Rat Dorsal Striatum

PubMed Central

Clark, Peter J.; Amat, Jose; McConnell, Sara O.; Ghasem, Parsa R.; Greenwood, Benjamin N.; Maier, Steven F.; Fleshner, Monika

2015-01-01

Accumulating evidence from both the human and animal literature indicates that exercise reduces the negative consequences of stress. The neurobiological etiology for this stress protection, however, is not completely understood. Our lab reported that voluntary wheel running protects rats from expressing depression-like instrumental learning deficits on the shuttle box escape task after exposure to unpredictable and inescapable tail shocks (uncontrollable stress). Impaired escape behavior is a result of stress-sensitized serotonin (5-HT) neuron activity in the dorsal raphe (DRN) and subsequent excessive release of 5-HT into the dorsal striatum following exposure to a comparatively mild stressor. However, the possible mechanisms by which exercise prevents stress-induced escape deficits are not well characterized. The purpose of this experiment was to test the hypothesis that exercise blunts the stress-evoked release of 5-HT in the dorsal striatum. Changes to dopamine (DA) levels were also examined, since striatal DA signaling is critical for instrumental learning and can be influenced by changes to 5-HT activity. Adult male F344 rats, housed with or without running wheels for 6 weeks, were either exposed to tail shock or remained undisturbed in laboratory cages. Twenty-four hours later, microdialysis was performed in the medial (DMS) and lateral (DLS) dorsal striatum to collect extracellular 5-HT and DA before, during, and following 2 mild foot shocks. We report wheel running prevents foot shock-induced elevation of extracellular 5-HT and potentiates DA concentrations in both the DMS and DLS approximately 24 h following exposure to uncontrollable stress. These data may provide a possible mechanism by which exercise prevents depression-like instrumental learning deficits following exposure to acute stress. PMID:26555633

Against the Very Idea of the Politicization of Public Health Policy

PubMed Central

2012-01-01

I criticize the concern over the politicization of public health policy as a justification for preferring a narrow to a broad model of public health. My critique proceeds along 2 lines. First, the fact that administrative structures and actors are primary sources of public health policy demonstrates its inescapably political and politicized nature. Second, historical evidence shows that public health in Great Britain and the United States has from its very inception been political and politicized. I conclude by noting legitimate ethical concerns regarding the political nature of public health policy and argue that open deliberation in a democratic social order is best served by acknowledging the constraints of the inescapably politicized process of public health policymaking. PMID:22095345

Delayed suppression of hippocampal cell proliferation in rats following inescapable shocks.

PubMed

Fornal, Casimir A; Stevens, Joanne; Barson, Jessica R; Blakley, Gregory G; Patterson-Buckendahl, Patricia; Jacobs, Barry L

2007-01-26

Adult Sprague-Dawley rats were exposed to a single session of 100 inescapable tail shocks (IS). Bromodeoxyuridine (BrdU) was administered 1 h, 2 days or 7 days later and hippocampal cell proliferation (CP) was assessed after a 2-h survival period. Measures of plasma corticosterone (CORT) levels were also obtained. Despite a large increase in CORT immediately following IS, no associated change in CP was observed. In fact, the only significant change in CP was seen 7 days after IS, at a time when CORT was unchanged from control levels. These data raise questions about the general nature of the relationship between CORT and CP. They also suggest that, under some conditions, changes in hippocampal CP may emerge only after an "incubation period".

The fossil record of evolution: Analysis of extinction

NASA Technical Reports Server (NTRS)

Raup, D. M.

1986-01-01

There is increasing evidence that events in space have had direct effects on Earth history and on the history of life on Earth. Nowhere is this more evident than in mass extinction. The biosphere has undergone repeated devastation caused by relatively short-lived environmental stress, with species kill rates up to 80 and 95%. For five of the mass extinctions, geochemical or other evidence was reported suggesting large body impact as the cause of the environmental stress producing the extinctions. It was argued on statistical ground that the major extinction events are uniformly periodic in geological time. If it is true that large body impact is a principal cause of mass extinctions and if the periodicity is real, than a cosmic driving mechanism is inescapable. Paleontological data sets were developed which detail the ranges in geological time of about 4,000 families and 25,000 genera of fossil marine organisms. Analyses to date have concentrated on the most recent 250 million years. Associated with these studies are analyses of other aspects of Earth history which may have signatures indicative of extraterrestrial effects.

[GABA-NO interaction in the N. Accumbens during danger-induced inhibition of exploratory behavior].

PubMed

Saul'skaia, N V; Terekhova, E A

2013-01-01

In Sprague-Dawley rats by means of in vivo microdialysis combined with HPLC analysis, it was shown that presentation to rats during exploratory activity of a tone previously pared with footshock inhibited the exploration and prevented the exploration-induced increase in extracellular levels of citrulline (an NO co-product) in the medial n. accumbens. Intra-accumbal infusions of 20 μM bicuculline, a GABA(A)-receptor antagonist, firstly, partially restored the exploration-induced increase of extracellular citrulline levels in this brain area, which was inhibited by presentation of the tone, previously paired with foot-shock and, secondly, prevented the inhibition of exploratory behavior produced by this sound signal of danger. The data obtained indicate for the first time that signals of danger inhibit exploratory behavior and exploration-induced activation of the accumbal nitrergic system via GABA(A)-receptor mechanisms.

Neuropharmacology of memory consolidation and reconsolidation: Insights on central cholinergic mechanisms.

PubMed

Blake, M G; Krawczyk, M C; Baratti, C M; Boccia, M M

2014-01-01

Central cholinergic system is critically involved in all known memory processes. Endogenous acetylcholine release by cholinergic neurons is necessary for modulation of acquisition, encoding, consolidation, reconsolidation, extinction, retrieval and expression. Experiments from our laboratory are mainly focused on elucidating the mechanisms by which acetylcholine modulates memory processes. Blockade of hippocampal alpha-7-nicotinic receptors (α7-nAChRs) with the antagonist methyllycaconitine impairs memory reconsolidation. However, the administration of a α7-nAChR agonist (choline) produce a paradoxical modulation, causing memory enhancement in mice trained with a weak footshock, but memory impairment in animals trained with a strong footshock. All these effects are long-lasting, and depend on the age of the memory trace. This review summarizes and discusses some of our recent findings, particularly regarding the involvement of α7-nAChRs on memory reconsolidation. Copyright © 2014 Elsevier Ltd. All rights reserved.

Protective effects of Andrographis paniculata extract and pure andrographolide against chronic stress-triggered pathologies in rats.

PubMed

Thakur, Ajit Kumar; Soni, Upendra Kumar; Rai, Geeta; Chatterjee, Shyam Sunder; Kumar, Vikas

2014-11-01

This study was designed to experimentally verify the possibility that Andrographis paniculata could be another medicinal herb potentially useful for prevention of diverse spectrums of pathologies commonly associated with chronic unavoidable environmental stress, and whether andrographolide could as well be its quantitatively major bioactive secondary metabolite. Preventive effects of 21 daily oral 50, 100 and 200 mg/kg doses of a therapeutically used extract of the plant (AP) and 30 and 60 mg/kg/day of pure andrographolide were compared in rats subjected to 1-h daily unavoidable foot-shocks. A pharmaceutically well-standardized Withania somnifera (WS) root extract was used as a reference herbal anti-stress agent in all experiments. Effects of the treatments on stress-induced alterations in body weight, gastric ulcer, adrenal and spleen weights, and depressive state and sexual behavior in male rats were quantified. Other parameters quantified were plasma cortisol levels, and expressions of the cytokines TNF-α, IL-10 and IL-1β in blood and brain. All observed stress-induced pathological changes were less pronounced or completely prevented by both AP and pure andrographolide. Even the lowest tested doses of AP (50 mg/kg/day) or of andrographolide (30 mg/kg/day) suppressed almost maximally the blood IL-1β and IL-10 as well as brain TNF-α and IL-10 expressions induced by chronic stress. Qualitatively, the observed activity profiles of both of them were similar to those of WS dose tested. These results reveal that both AP and andrographolide are pharmacologically polyvalent anti-stress agents, and that biological processes regulating corticosterone and cytokine homeostasis are involved in their modes of actions.

Chronic stress disrupts fear extinction and enhances amygdala and hippocampal Fos expression in an animal model of post-traumatic stress disorder.

PubMed

Hoffman, Ann N; Lorson, Nickolaus G; Sanabria, Federico; Foster Olive, M; Conrad, Cheryl D

2014-07-01

Chronic stress may impose a vulnerability to develop maladaptive fear-related behaviors after a traumatic event. Whereas previous work found that chronic stress impairs the acquisition and recall of extinguished fear, it is unknown how chronic stress impacts nonassociative fear, such as in the absence of the conditioned stimulus (CS) or in a novel context. Male rats were subjected to chronic stress (STR; wire mesh restraint 6 h/d/21d) or undisturbed (CON), then tested on fear acquisition (3 tone-footshock pairings), and two extinction sessions (15 tones/session) within the same context. Then each group was tested (6 tones) in the same context (SAME) or a novel context (NOVEL), and brains were processed for functional activation using Fos immunohistochemistry. Compared to CON, STR showed facilitated fear acquisition, resistance to CS extinction on the first extinction day, and robust recovery of fear responses on the second extinction day. STR also showed robust freezing to the context alone during the first extinction day compared to CON. When tested in the same or a novel context, STR exhibited higher freezing to context than did CON, suggesting that STR-induced fear was independent of context. In support of this, STR showed increased Fos-like expression in the basolateral amygdala and CA1 region of the hippocampus in both the SAME and NOVEL contexts. Increased Fos-like expression was also observed in the central amygdala in STR-NOVEL vs. CON-NOVEL. These data demonstrate that chronic stress enhances fear learning and impairs extinction, and affects nonassociative processes as demonstrated by enhanced fear in a novel context. Copyright © 2014 Elsevier Inc. All rights reserved.

Predator-based psychosocial stress animal model of PTSD: Preclinical assessment of traumatic stress at cognitive, hormonal, pharmacological, cardiovascular and epigenetic levels of analysis.

PubMed

Zoladz, Phillip R; Diamond, David M

2016-10-01

Research on post-traumatic stress disorder (PTSD) is faced with the challenge of understanding how a traumatic experience produces long-lasting detrimental effects on behavior and brain functioning, and more globally, how stress exacerbates somatic disorders, including cardiovascular disease. Moreover, the design of translational research needs to link animal models of PTSD to clinically relevant risk factors which address why only a subset of traumatized individuals develop persistent psychopathology. In this review, we have summarized our psychosocial stress rodent model of PTSD which is based on well-described PTSD-inducing risk factors, including a life-threatening experience, a sense of horror and uncontrollability, and insufficient social support. Specifically, our animal model of PTSD integrates acute episodes of inescapable exposure of immobilized rats to a predator with chronic daily social instability. This stress regimen produces PTSD-like effects in rats at behavioral, cognitive, physiological, pharmacological and epigenetic levels of analysis. We have discussed a recent extension of our animal model of PTSD in which stress exacerbated coronary pathology following an ischemic event, assessed in vitro. In addition, we have reviewed our research investigating pharmacological and non-pharmacological therapeutic strategies which may have value in clinical approaches toward the treatment of traumatized people. Overall, our translational approach bridges the gap between human and animal PTSD research to create a framework with which to enhance our understanding of the biological basis of trauma-induced pathology and to assess therapeutic approaches in the treatment of psychopathology. Copyright © 2016 Elsevier Inc. All rights reserved.

The Mouse Forced Swim Test

PubMed Central

Can, Adem; Dao, David T.; Arad, Michal; Terrillion, Chantelle E.; Piantadosi, Sean C.; Gould, Todd D.

2012-01-01

The forced swim test is a rodent behavioral test used for evaluation of antidepressant drugs, antidepressant efficacy of new compounds, and experimental manipulations that are aimed at rendering or preventing depressive-like states. Mice are placed in an inescapable transparent tank that is filled with water and their escape related mobility behavior is measured. The forced swim test is straightforward to conduct reliably and it requires minimal specialized equipment. Successful implementation of the forced swim test requires adherence to certain procedural details and minimization of unwarranted stress to the mice. In the protocol description and the accompanying video, we explain how to conduct the mouse version of this test with emphasis on potential pitfalls that may be detrimental to interpretation of results and how to avoid them. Additionally, we explain how the behaviors manifested in the test are assessed. PMID:22314943

Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior

PubMed Central

Cheng, Yuyan; Pardo, Marta; de Souza Armini, Rubia; Martinez, Ana; Mouhsine, Hadley; Zagury, Jean-Francois; Jope, Richard S.; Beurel, Eleonore

2016-01-01

Most psychiatric and neurological diseases are exacerbated by stress. Because this may partially result from stress-induced inflammation, we examined factors involved in this stress response. After a paradigm of inescapable foot shock stress that causes learned helplessness depression-like behavior, eighteen cytokines and chemokines increased in mouse hippocampus, peaking 6 to 12 hr after stress. A 24 hr prior pre-conditioning stress accelerated the rate of stress-induced hippocampal cytokine and chemokine increases, with most reaching peak levels after 1 to 3 hr, often without altering the maximal levels. Toll-like receptor 4 (TLR4) was involved in this response because most stress-induced hippocampal cytokines and chemokines were attenuated in TLR4 knockout mice. Stress activated glycogen synthase kinase-3 (GSK3) in wild-type mouse hippocampus, but not in TLR4 knockout mice. Administration of the antidepressant fluoxetine or the GSK3 inhibitor TDZD-8 reduced the stress-induced increases of most hippocampal cytokines and chemokines. Stress increased hippocampal levels of the danger-associated molecular pattern (DAMP) protein high mobility group box 1 (HMGB1), activated the inflammatory transcription factor NF-κB, and the NLRP3 inflammasome. Knockdown of HMGB1 blocked the acceleration of cytokine and chemokine increases in the hippocampus caused by two successive stresses. Fluoxetine treatment blocked stress-induced up-regulation of HMGB1 and subsequent NF-κB activation, whereas TDZD-8 administration attenuated NF-κB activation downstream of HMGB1. To test if stress-induced cytokines and chemokines contribute to depression-like behavior, the learned helplessness model was assessed. Antagonism of TNFα modestly reduced susceptibility to learned helplessness induction, whereas TLR4 knockout mice were resistant to learned helplessness. Thus, stress-induces a broad inflammatory response in mouse hippocampus that involves TLR4, GSK3, and downstream inflammatory signaling, and these stress responses contribute to susceptibility to depression-like behavior in mice. PMID:26772151

Stress-induced neuroinflammation is mediated by GSK3-dependent TLR4 signaling that promotes susceptibility to depression-like behavior.

PubMed

Cheng, Yuyan; Pardo, Marta; Armini, Rubia de Souza; Martinez, Ana; Mouhsine, Hadley; Zagury, Jean-Francois; Jope, Richard S; Beurel, Eleonore

2016-03-01

Most psychiatric and neurological diseases are exacerbated by stress. Because this may partially result from stress-induced inflammation, we examined factors involved in this stress response. After a paradigm of inescapable foot shock stress that causes learned helplessness depression-like behavior, eighteen cytokines and chemokines increased in mouse hippocampus, peaking 6-12h after stress. A 24h prior pre-conditioning stress accelerated the rate of stress-induced hippocampal cytokine and chemokine increases, with most reaching peak levels after 1-3h, often without altering the maximal levels. Toll-like receptor 4 (TLR4) was involved in this response because most stress-induced hippocampal cytokines and chemokines were attenuated in TLR4 knockout mice. Stress activated glycogen synthase kinase-3 (GSK3) in wild-type mouse hippocampus, but not in TLR4 knockout mice. Administration of the antidepressant fluoxetine or the GSK3 inhibitor TDZD-8 reduced the stress-induced increases of most hippocampal cytokines and chemokines. Stress increased hippocampal levels of the danger-associated molecular pattern (DAMP) protein high mobility group box 1 (HMGB1), activated the inflammatory transcription factor NF-κB, and the NLRP3 inflammasome. Knockdown of HMGB1 blocked the acceleration of cytokine and chemokine increases in the hippocampus caused by two successive stresses. Fluoxetine treatment blocked stress-induced up-regulation of HMGB1 and subsequent NF-κB activation, whereas TDZD-8 administration attenuated NF-κB activation downstream of HMGB1. To test if stress-induced cytokines and chemokines contribute to depression-like behavior, the learned helplessness model was assessed. Antagonism of TNFα modestly reduced susceptibility to learned helplessness induction, whereas TLR4 knockout mice were resistant to learned helplessness. Thus, stress-induces a broad inflammatory response in mouse hippocampus that involves TLR4, GSK3, and downstream inflammatory signaling, and these stress responses contribute to susceptibility to depression-like behavior in mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Using conditioned suppression to investigate compulsive drug seeking in rats.

PubMed

Limpens, Jules H W; Schut, Evelien H S; Voorn, Pieter; Vanderschuren, Louk J M J

2014-09-01

Persistent drug seeking despite harmful consequences is a defining characteristic of addiction. Recent preclinical studies have demonstrated the occurrence of this hallmark feature of addictive behaviour in rodents. For example, it has been shown that the ability of an aversive conditioned stimulus (CS) to suppress cocaine seeking was diminished after an extended self-administration history. The present study aimed to optimize the experimental conditions to examine conditioned suppression of sucrose and cocaine seeking in rats, and its dependence on the longevity of self-administration experience. We investigated whether conditioned suppression depends on the intensity and quantity of footshocks during conditioning. In addition, the effects of CS omission, extinction and reconditioning were investigated, as well as the influence of the CS interval sequence on conditioned suppression. We also compared conditioned suppression after a limited and extended sucrose or cocaine self-administration history. We found that conditioned suppression depended on the intensity rather than the quantity of footshocks, whereby a higher footshock intensity was necessary to induce suppression of cocaine seeking compared to sucrose seeking. Conditioned suppression was most pronounced when the test started with presentation of the aversive CS, and conditioned suppression could be extinguished and reacquired. In addition, conditioned suppression of cocaine, but not sucrose seeking was reduced after extended self-administration experience. These data provide a detailed analysis of conditioned suppression of cocaine and sucrose seeking. Importantly, we confirm the usefulness of conditioned suppression to study persistent drug seeking after prolonged drug self-administration. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Altered protein kinase a in brain of learned helpless rats: effects of acute and repeated stress.

PubMed

Dwivedi, Yogesh; Mondal, Amal C; Shukla, Pradeep K; Rizavi, Hooriyah S; Lyons, Jennifer

2004-07-01

Stress-induced learned helplessness (LH) in animals serves as a model of behavioral depression and some aspects of posttraumatic stress disorder. We examined whether LH behavior is associated with alterations in protein kinase A (PKA), a critical phosphorylating enzyme, how long these alterations persist after inescapable shock (IS), and whether repetition of IS prolongs the duration of LH behavior and changes in PKA. Rats were exposed to IS either on day 1 or twice, on day 1 and day 7. Rats were tested for escape latency on days 2 and 4 after day 1 IS or days 2, 8, and 14 after day 1 and day 7 IS. [(3)H]cAMP (cyclic adenosine monophosphate) binding, catalytic activity and expression of PKA subunits were determined in frontal cortex and hippocampus. Higher escape latencies were observed in rats tested on day 2 after single IS and on day 14 after repeated IS. Concurrently, reduced [(3)H]cAMP binding, PKA activity, and expression of selective PKA RIIbeta and Calpha and Cbeta subunits were observed in the brains of these rats. Repeated IS prolongs the duration of LH behavior, and LH behavior is associated with reductions in apparent activity and expression of PKA. These reductions in PKA may be critical in the pathophysiology of depression and other stress-related disorders.

The antioxidants alpha-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice.

PubMed

Farr, Susan A; Poon, H Fai; Dogrukol-Ak, Dilek; Drake, Jeniffer; Banks, William A; Eyerman, Edward; Butterfield, D Allan; Morley, John E

2003-03-01

Oxidative stress may play a crucial role in age-related neurodegenerative disorders. Here, we examined the ability of two antioxidants, alpha-lipoic acid (LA) and N-acetylcysteine (NAC), to reverse the cognitive deficits found in the SAMP8 mouse. By 12 months of age, this strain develops elevated levels of Abeta and severe deficits in learning and memory. We found that 12-month-old SAMP8 mice, in comparison with 4-month-old mice, had increased levels of protein carbonyls (an index of protein oxidation), increased TBARS (an index of lipid peroxidation) and a decrease in the weakly immobilized/strongly immobilized (W/S) ratio of the protein-specific spin label MAL-6 (an index of oxidation-induced conformational changes in synaptosomal membrane proteins). Chronic administration of either LA or NAC improved cognition of 12-month-old SAMP8 mice in both the T-maze footshock avoidance paradigm and the lever press appetitive task without inducing non-specific effects on motor activity, motivation to avoid shock, or body weight. These effects probably occurred directly within the brain, as NAC crossed the blood-brain barrier and accumulated in the brain. Furthermore, treatment of 12-month-old SAMP8 mice with LA reversed all three indexes of oxidative stress. These results support the hypothesis that oxidative stress can lead to cognitive dysfunction and provide evidence for a therapeutic role for antioxidants.

Brain prolactin is involved in stress-induced REM sleep rebound.

PubMed

Machado, Ricardo Borges; Rocha, Murilo Ramos; Suchecki, Deborah

2017-03-01

REM sleep rebound is a common behavioural response to some stressors and represents an adaptive coping strategy. Animals submitted to multiple, intermittent, footshock stress (FS) sessions during 96h of REM sleep deprivation (REMSD) display increased REM sleep rebound (when compared to the only REMSD ones, without FS), which is correlated to high plasma prolactin levels. To investigate whether brain prolactin plays a role in stress-induced REM sleep rebound two experiments were carried out. In experiment 1, rats were either not sleep-deprived (NSD) or submitted to 96h of REMSD associated or not to FS and brains were evaluated for PRL immunoreactivity (PRL-ir) and determination of PRL concentrations in the lateral hypothalamus and dorsal raphe nucleus. In experiment 2, rats were implanted with cannulas in the dorsal raphe nucleus for prolactin infusion and were sleep-recorded. REMSD associated with FS increased PRL-ir and content in the lateral hypothalamus and all manipulations increased prolactin content in the dorsal raphe nucleus compared to the NSD group. Prolactin infusion in the dorsal raphe nucleus increased the time and length of REM sleep episodes 3h after the infusion until the end of the light phase of the day cycle. Based on these results we concluded that brain prolactin is a major mediator of stress-induced REMS. The effect of PRL infusion in the dorsal raphe nucleus is discussed in light of the existence of a bidirectional relationship between this hormone and serotonin as regulators of stress-induced REM sleep rebound. Copyright © 2016 Elsevier Inc. All rights reserved.

Cardiovascular and metabolic consequences of the association between chronic stress and high-fat diet in rats.

PubMed

Simas, Bruna B; Nunes, Everson A; Crestani, Carlos C; Speretta, Guilherme F

2018-05-01

Obesity and chronic stress are considered independent risk factors for the development of cardiovascular diseases and changes in autonomic system activity. However, the cardiovascular consequences induced by the association between high-fat diet (HFD) and chronic stress are not fully understood. We hypothesized that the association between HFD and exposure to a chronic variable stress (CVS) protocol for four weeks might exacerbate the cardiovascular and metabolic disturbances in rats when compared to these factors singly. To test this hypothesis, male Wistar rats were divided into four groups: control-standard chow diet (SD; n = 8); control-HFD (n = 8); CVS-SD (n = 8); and CVS-HFD (n = 8). The CVS consisted of repeated exposure of the rats to different inescapable and unpredictable stressors (restraint tress; damp sawdust, cold, swim stress and light cycle inversion). We evaluated cardiovascular function, autonomic activity, dietary intake, adiposity and metabolism. The HFD increased body weight, adiposity and blood glucose concentration (∼15%) in both control and CVS rats. The CVS-HFD rats showed decreased insulin sensitivity (25%) compared to CVS-SD rats. The control-HFD and CVS-HFD rats presented increased intrinsic heart rate (HR) values (∼8%). CVS increased cardiac sympathetic activity (∼65%) in both SD- and HFD-fed rats. The HFD increased basal HR (∼10%). Blood pressure and baroreflex analyzes showed no differences among the experimental groups. In conclusion, the present data indicate absence of interaction on autonomic imbalance evoked by either CVS or HFD. Additionally, HFD increased HR and evoked metabolic disruptions which are independent of stress exposure.

The stressed female brain: neuronal activity in the prelimbic but not infralimbic region of the medial prefrontal cortex suppresses learning after acute stress.

PubMed

Maeng, Lisa Y; Shors, Tracey J

2013-01-01

Women are nearly twice as likely as men to suffer from anxiety and post-traumatic stress disorder (PTSD), indicating that many females are especially vulnerable to stressful life experience. A profound sex difference in the response to stress is also observed in laboratory animals. Acute exposure to an uncontrollable stressful event disrupts associative learning during classical eyeblink conditioning in female rats but enhances this same type of learning process in males. These sex differences in response to stress are dependent on neuronal activity in similar but also different brain regions. Neuronal activity in the basolateral nucleus of the amygdala (BLA) is necessary in both males and females. However, neuronal activity in the medial prefrontal cortex (mPFC) during the stressor is necessary to modify learning in females but not in males. The mPFC is often divided into its prelimbic (PL) and infralimbic (IL) subregions, which differ both in structure and function. Through its connections to the BLA, we hypothesized that neuronal activity within the PL, but not IL, during the stressor is necessary to suppress learning in females. To test this hypothesis, either the PL or IL of adult female rats was bilaterally inactivated with GABAA agonist muscimol during acute inescapable swim stress. About 24 h later, all subjects were trained with classical eyeblink conditioning. Though stressed, females without neuronal activity in the PL learned well. In contrast, females with IL inactivation during the stressor did not learn well, behaving similarly to stressed vehicle-treated females. These data suggest that exposure to a stressful event critically engages the PL, but not IL, to disrupt associative learning in females. Together with previous studies, these data indicate that the PL communicates with the BLA to suppress learning after a stressful experience in females. This circuit may be similarly engaged in women who become cognitively impaired after stressful life events.

Forensic historiography: narratives and science.

PubMed

Drukteinis, Albert M

2014-01-01

Psychiatrists function, in part, as historians who rely on patient narratives to help them understand presenting mental disorders and explain their causes. Forensic psychiatrists have been skeptical of using narratives, raising concerns about their lack of objectivity and potential for bias. They also have criticized narratives as being more performative than scientific. Recent authors, however, have pointed out that narratives may be helpful in forming forensic opinions and supporting oral testimony, while stressing that their use must be consistent with the ethics espoused by forensic psychiatry. This article reviews the role of narratives in understanding human events and the ubiquitous presence of narratives in the judicial process. It delves into the inescapability of using explicit or implicit narratives in the course of forensic practice, as well as how they may be meaningfully incorporated into evaluations and find expression alongside scientific principles. © 2014 American Academy of Psychiatry and the Law.

[Military psychiatry in Israel: a 50-year perspective].

PubMed

Bleich, A

2000-05-01

The history of military psychiatry in Israel may be divided into 2 main periods. The first extended from the War of Independence in 1948, through the Sinai, Six Day and Yom Kippur Wars. Its outstanding feature was avoidance of the issue of combat stress reaction (CSR). The Yom Kippur War made the recognition of CSR inescapable, assisted in breaking up denial, and served as a stimulus for development of the next phase of the system. This second phase was characterized by impressive progress in all areas of military psychiatry. The rich experience accumulated during the wars, together with the assimilation of a research culture which began blooming, especially in the wake of the Lebanon War, aided the development and crystallization of concepts related to combat and non-combat military psychiatry alike. The build-up of the mental health organization overlapped field deployment of the Medical Corps.

Inescapable Stress Changes Walking Behavior in Flies - Learned Helplessness Revisited.

PubMed

Batsching, Sophie; Wolf, Reinhard; Heisenberg, Martin

2016-01-01

Like other animals flies develop a state of learned helplessness in response to unescapable aversive events. To show this, two flies, one 'master', one 'yoked', are each confined to a dark, small chamber and exposed to the same sequence of mild electric shocks. Both receive these shocks when the master fly stops walking for more than a second. Behavior in the two animals is differently affected by the shocks. Yoked flies are transiently impaired in place learning and take longer than master flies to exit from the chamber towards light. After the treatment they walk more slowly and take fewer and shorter walking bouts. The low activity is attributed to the fly's experience that its escape response, an innate behavior to terminate the electric shocks, does not help anymore. Earlier studies using heat pulses instead of electric shocks had shown similar effects. This parallel supports the interpretation that it is the uncontrollability that induces the state.

Individual Differences in Animal Stress Models: Considering Resilience, Vulnerability, and the Amygdala in Mediating the Effects of Stress and Conditioned Fear on Sleep.

PubMed

Wellman, Laurie L; Fitzpatrick, Mairen E; Hallum, Olga Y; Sutton, Amy M; Williams, Brook L; Sanford, Larry D

2016-06-01

To examine the REM sleep response to stress and fearful memories as a potential marker of stress resilience and vulnerability and to assess the role of the basolateral amygdala (BLA) in mediating the effects of fear memory on sleep. Outbred Wistar rats were surgically implanted with electrodes for recording EEG and EMG and with bilateral guide cannulae directed at the BLA. Data loggers were placed intraperitoneally to record core body temperature. After recovery from surgery, the rats received shock training (ST: 20 footshocks, 0.8 mA, 0.5-s duration, 60-s interstimulus interval) and afterwards received microinjections of the GABAA agonist muscimol (MUS; 1.0 μM) to inactivate BLA or microinjections of vehicle (VEH) alone. Subsequently, the rats were separated into 4 groups (VEH-vulnerable (VEH-Vul; n = 14), VEH-resilient (VEH-Res; n = 13), MUS-vulnerable (MUS-Vul; n = 8), and MUS-resilient (MUS-Res; n = 11) based on whether or not REM was decreased, compared to baseline, during the first 4 h following ST. We then compared sleep, freezing, and the stress response (stress-induced hyperthermia, SIH) across groups to determine the effects of ST and fearful context re-exposure alone (CTX). REM was significantly reduced on the ST day in both VEH-Vul and MUS-Vul rats; however, post-ST MUS blocked the reduction in REM on the CTX day in the MUS-Vul group. The VEH-Res and MUS-Res rats showed similar levels of REM on both ST and CTX days. The effects of post-ST inactivation of BLA on freezing and SIH were minimal. Outbred Wistar rats can show significant individual differences in the effects of stress on REM that are mediated by BLA. These differences in REM can be independent of behavioral fear and the peripheral stress response, and may be an important biomarker of stress resilience and vulnerability. © 2016 Associated Professional Sleep Societies, LLC.

A Conditioned Behavioral Paradigm for Assessing Onset and Lasting Tinnitus in Rats

PubMed Central

Pace, Edward; Luo, Hao; Bobian, Michael; Panekkad, Ajay; Zhang, Xueguo; Zhang, Huiming; Zhang, Jinsheng

2016-01-01

Numerous behavioral paradigms have been developed to assess tinnitus-like behavior in animals. Nevertheless, they are often limited by prolonged training requirements, as well as an inability to simultaneously assess onset and lasting tinnitus behavior, tinnitus pitch or duration, or tinnitus presence without grouping data from multiple animals or testing sessions. To enhance behavioral testing of tinnitus, we developed a conditioned licking suppression paradigm to determine the pitch(s) of both onset and lasting tinnitus-like behavior within individual animals. Rats learned to lick water during broadband or narrowband noises, and to suppress licking to avoid footshocks during silence. After noise exposure, rats significantly increased licking during silent trials, suggesting onset tinnitus-like behavior. Lasting tinnitus-behavior, however, was exhibited in about half of noise-exposed rats through 7 weeks post-exposure tested. Licking activity during narrowband sound trials remained unchanged following noise exposure, while ABR hearing thresholds fully recovered and were comparable between tinnitus(+) and tinnitus(-) rats. To assess another tinnitus inducer, rats were injected with sodium salicylate. They demonstrated high pitch tinnitus-like behavior, but later recovered by 5 days post-injection. Further control studies showed that 1): sham noise-exposed rats tested with footshock did not exhibit tinnitus-like behavior, and 2): noise-exposed or sham rats tested without footshocks showed no fundamental changes in behavior compared to those tested with shocks. Together, these results demonstrate that this paradigm can efficiently test the development of noise- and salicylate-induced tinnitus behavior. The ability to assess tinnitus individually, over time, and without averaging data enables us to realistically address tinnitus in a clinically relevant way. Thus, we believe that this optimized behavioral paradigm will facilitate investigations into the mechanisms of tinnitus and development of effective treatments. PMID:27835697

Targeted deletion of the GABRA2 gene encoding alpha2-subunits of GABA(A) receptors facilitates performance of a conditioned emotional response, and abolishes anxiolytic effects of benzodiazepines and barbiturates.

PubMed

Dixon, C I; Rosahl, T W; Stephens, D N

2008-07-01

Mice with point-mutated alpha2 GABA(A) receptor subunits (rendering them diazepam insensitive) are resistant to the anxiolytic-like effects of benzodiazepines (BZs) in the conditioned emotional response (CER) test, but show normal anxiolytic effects of a barbiturate. We investigated the consequence of deleting the alpha2-subunit on acquisition of the CER with increasing intensity of footshock, and on the anxiolytic efficacy of a benzodiazepine, diazepam, and a barbiturate, pentobarbital. alpha2 knockout (KO) and wildtype (WT) mice were trained in a conditioned emotional response (CER) task, in which lever pressing for food on a variable interval (VI) schedule was suppressed during the presentation of a compound light/tone conditioned stimulus (CS+) that predicted footshock. The ability of diazepam and of pentobarbital to reduce suppression during the CS+ was interpreted as an anxiolytic response. There were no differences between the genotypes in shock sensitivity, as assessed by their flinch responses to increasing levels of shock. However, alpha2 KO mice showed a greater suppression of lever pressing than WT littermates in the presence of a compound cue signalling footshock. Diazepam (0, 0.5, 1 and 2 mg/kg) induced a dose-dependent anxiolytic-like effect in WT mice but no such effect was seen in KO mice. Similarly, although pentobarbital (20 mg/kg) reduced the ability of the CS+ to reduce lever pressing rates in WT mice, this effect was not seen in the KO. These findings suggest that alpha2-containing GABA(A) receptors mediate the anxiolytic effects of barbiturates, as well as benzodiazepines, and that they may be involved in neuronal circuits underlying conditioned anxiety.

Temporal parameters of post-stress prophylactic glucose treatment in rats.

PubMed

Conoscenti, M A; Hart, E E; Smith, N J; Minor, T R

2017-05-01

Acute trauma can lead to life-long changes in susceptibility to psychiatric disease, such as post-traumatic stress disorder (PTSD). Rats given free access to a concentrated glucose solution for 24 h beginning immediately after trauma failed to show stress-related pathology in the learned helplessness model of PTSD and comorbid major depression. We assessed effective dosing and temporal constraints of the glucose intervention in three experiments. We exposed 120 male Sprague-Dawley rats to 100, 1 mA, 3-15 s, inescapable and unpredictable electric tail shocks (over a 110-min period) or simple restraint in the learned helplessness procedure. Rats in each stress condition had access to a 40% glucose solution or water. We measured fluid consumption under 18-h free access conditions, or limited access (1, 3, 6, 18 h) beginning immediately after trauma, or 3-h access with delayed availability of the glucose solution (0, 1, 3, 6 h). We hypothesized that longer and earlier access following acute stress would improve shuttle-escape performance. Rats exposed to traumatic shock and given 18-h access to glucose failed to show exaggerated fearfulness and showed normal reactivity to foot shock during testing as compared to their water-treated counterparts. At least 3 h of immediate post-stress access to glucose were necessary to see these improvements in test performance. Moreover, delaying access to glucose for more than 3 h post-trauma yielded no beneficial effects. These data clearly identify limits on the post-stress glucose intervention. In conclusion, glucose should be administered almost immediately and at the highest dose after trauma.

Interleukin-1 may link helplessness-hopelessness with cancer progression: a proposed model.

PubMed

Argaman, Miriam; Gidron, Yori; Ariad, Shmuel

2005-01-01

A model of the relations between psychological factors and cancer progression should include brain and systemic components and their link with critical cellular stages in cancer progression. We present a psychoneuroimmunological (PNI) model that links helplessness-hopelessness (HH) with cancer progression via interleukin-1beta (IL-1beta). IL-1beta was elevated in the brain following exposure to inescapable shock, and HH was minimized by antagonizing cerebral IL-1beta. Elevated cerebral IL-1beta increased cancer metastasis in animals. Inescapable shock was associated with systemic elevations of IL-1beta and peripheral IL-1beta was associated with escape from apoptosis, angiogenesis, and metastasis. Involvement of the sympathetic nervous system and the hypothalamic-pituitary-adrenal axis are discussed. Future studies need to identify the role of additional factors in this PNI pathway.

Motivation for palatable food despite consequences in an animal model of binge eating.

PubMed

Oswald, Kimberly D; Murdaugh, Donna L; King, Vinetra L; Boggiano, Mary M

2011-04-01

Binge eating involves an abnormal motivation for highly palatable food in that these foods are repeatedly consumed despite their binge-triggering effects and life-affecting consequences associated with binge eating. We determined if rats identified as binge-eating prone (BEP) similarly display abnormal motivation for palatable food. Food-sated BEP and binge-eating resistant (BER) rats were given voluntary access to palatable food paired with increasing intensity of footshock. Later, they were exposed to a period of cyclic caloric restriction-refeeding. BEPs consumed significantly more and tolerated higher levels of footshock for palatable food than BERs. Cyclic restriction-refeeding increased BERs' tolerance of shock for palatable food. Previously observed parallels of the rat BEP model to human binge eating can now be extended to include an abnormal motivation for palatable food. This model should prove useful in identifying specific genes that interact with the nutritional environment to mediate binge eating and may point to novel physiological targets to treat compulsive overeating. Copyright © 2010 Wiley Periodicals, Inc.

Motivation for Palatable Food Despite Consequences in an Animal Model of Binge-Eating

PubMed Central

Oswald, Kimberly D.; Murdaugh, Donna L.; King, Vinetra L.; Boggiano, Mary M.

2010-01-01

Objective Binge-eating involves an abnormal motivation for highly palatable food in that these foods are repeatedly consumed despite their binge-triggering effects and life-affecting consequences associated with binge-eating. We determined if rats identified as binge-eating prone (BEP) similarly display abnormal motivation for palatable food. Method Food-sated BEP and binge-eating resistant (BER) rats were given voluntary access to palatable food paired with increasing intensity of footshock. Later, they were exposed to a period of cyclic caloric restriction-refeeding. Results BEPs consumed significantly more and tolerated higher levels of footshock for palatable food than BERs. Cyclic restriction-refeeding increased BERs' tolerance of shock for palatable food. Discussion Previously observed parallels of the rat BEP model to human binge-eating can now be extended to include an abnormal motivation for palatable food. This model should prove useful in identifying specific genes that interact with the nutritional environment to mediate binge-eating and may point to novel physiological targets to treat compulsive overeating. PMID:20186718

A dissociation between renewal and contextual fear conditioning in juvenile rats.

PubMed

Park, Chun Hui J; Ganella, Despina E; Kim, Jee Hyun

2017-05-01

We investigated whether juvenile rats do not express renewal following extinction of conditioned fear due to their inability to form a long-term contextual fear memory. In experiment 1, postnatal day (P) 18 and 25 rats received 3 white-noise and footshock pairings, followed by 60 white-noise alone presentations the next day. When tested in a different context to extinction, P25 rats displayed renewal whereas P18 rats did not. Experiments 2A and 2B surprisingly showed that P18 and P25 rats do not show differences in contextual and cued fear, regardless of the conditioning-test intervals and the number of white-noise-footshock pairings received. Finally, we observed age differences in contextual fear when P25 rats were weaned at P21 in experiment 3. These results indicate that the developmental dissociation observed in renewal of extinguished fear is not related to the widely believed late emergence of contextual fear learning. © 2017 Wiley Periodicals, Inc.

A Single Bout of Fasting (24 h) Reduces Basal Cytokine Expression and Minimally Impacts the Sterile Inflammatory Response in the White Adipose Tissue of Normal Weight F344 Rats

PubMed Central

Paton, Madeline M.; Cox, Stewart S.

2016-01-01

Sterile inflammation occurs when inflammatory proteins are increased in blood and tissues by nonpathogenic states and is a double-edged sword depending on its cause (stress, injury, or disease), duration (transient versus chronic), and inflammatory milieu. Short-term fasting can exert a host of health benefits through unknown mechanisms. The following experiment tested if a 24 h fast would modulate basal and stress-evoked sterile inflammation in plasma and adipose. Adult male F344 rats were either randomized to ad libitum access to food or fasted for 24 h prior to 0 (control), 10, or 100, 1.5 mA-5 s intermittent, inescapable tail shocks (IS). Glucose, nonesterified free fatty acids (NEFAs), insulin, leptin, and corticosterone were measured in plasma and tumor necrosis factor- (TNF-) α, interleukin- (IL-) 1β, IL-6, and IL-10 in plasma, and subcutaneous, intraperitoneal, and visceral compartments of white adipose tissue (WAT). In control rats, a 24 h fast reduced all measured basal cytokines in plasma and visceral WAT, IL-1β and IL-6 in subcutaneous WAT, and IL-6 in intraperitoneal WAT. In stressed rats (IS), fasting reduced visceral WAT TNF-α, subcutaneous WAT IL-1β, and plasma insulin and leptin. Short-term fasting may thus prove to be a useful dietary strategy for reducing peripheral inflammatory states associated with visceral obesity and chronic stress. PMID:28077915

A Single Bout of Fasting (24 h) Reduces Basal Cytokine Expression and Minimally Impacts the Sterile Inflammatory Response in the White Adipose Tissue of Normal Weight F344 Rats.

PubMed

Speaker, Kristin J; Paton, Madeline M; Cox, Stewart S; Fleshner, Monika

2016-01-01

Sterile inflammation occurs when inflammatory proteins are increased in blood and tissues by nonpathogenic states and is a double-edged sword depending on its cause (stress, injury, or disease), duration (transient versus chronic), and inflammatory milieu. Short-term fasting can exert a host of health benefits through unknown mechanisms. The following experiment tested if a 24 h fast would modulate basal and stress-evoked sterile inflammation in plasma and adipose. Adult male F344 rats were either randomized to ad libitum access to food or fasted for 24 h prior to 0 (control), 10, or 100, 1.5 mA-5 s intermittent, inescapable tail shocks (IS). Glucose, nonesterified free fatty acids (NEFAs), insulin, leptin, and corticosterone were measured in plasma and tumor necrosis factor- (TNF-) α , interleukin- (IL-) 1 β , IL-6, and IL-10 in plasma, and subcutaneous, intraperitoneal, and visceral compartments of white adipose tissue (WAT). In control rats, a 24 h fast reduced all measured basal cytokines in plasma and visceral WAT, IL-1 β and IL-6 in subcutaneous WAT, and IL-6 in intraperitoneal WAT. In stressed rats (IS), fasting reduced visceral WAT TNF- α , subcutaneous WAT IL-1 β , and plasma insulin and leptin. Short-term fasting may thus prove to be a useful dietary strategy for reducing peripheral inflammatory states associated with visceral obesity and chronic stress.

Using feminist, emotion-focused, and developmental approaches to enhance cognitive-behavioral therapies for posttraumatic stress disorder related to childhood sexual abuse.

PubMed

Cohen, Jacqueline N

2008-06-01

A body of research indicates the efficacy of cognitive-behavioral interventions for the treatment of posttraumatic stress disorder (PTSD) subsequent to sexual assault in adulthood. The generalizability of these treatments to women who present with trauma symptoms associated with childhood sexual abuse (CSA) has yet to be shown, however. A number of characteristics and dynamics of CSA that make it unique from sexual assault in adulthood are described, specifically its disruption of normal childhood development, its impact on attachment style and interpersonal relationships, its inescapability, and the stigma attached to it. Then, drawing on the developmental, emotion-focused, and feminist literatures, a number of considerations that would enhance the application of cognitive- behavioral trauma therapies to the treatment of women with PTSD related to CSA are delineated. These considerations relate to providing clients with corrective interpersonal experiences, creating new relationship events, enhancing affect regulation skills before initiating exposure therapy, considering the time elapsed since the abuse, addressing themes of power, betrayal, self-blame, stigma, and sex-related cognitions and emotions, and helping clients develop a feminist consciousness. (PsycINFO Database Record (c) 2010 APA, all rights reserved).

Therapeutic Effects of Extinction Learning as a Model of Exposure Therapy in Rats.

PubMed

Fucich, Elizabeth A; Paredes, Denisse; Morilak, David A

2016-12-01

Current treatments for stress-related psychiatric disorders, such as depression and posttraumatic stress disorder (PTSD), are inadequate. Cognitive behavioral psychotherapies, including exposure therapy, are an alternative to pharmacotherapy, but the neurobiological mechanisms are unknown. Preclinical models demonstrating therapeutic effects of behavioral interventions are required to investigate such mechanisms. Exposure therapy bears similarity to extinction learning. Thus, we investigated the therapeutic effects of extinction learning as a behavioral intervention to model exposure therapy in rats, testing its effectiveness in reversing chronic stress-induced deficits in cognitive flexibility and coping behavior that resemble dimensions of depression and PTSD. Rats were fear-conditioned by pairing a tone with footshock, and then exposed to chronic unpredictable stress (CUS) that induces deficits in cognitive set-shifting and active coping behavior. They then received an extinction learning session as a therapeutic intervention by repeated exposure to the tone with no shock. Effects on cognitive flexibility and coping behavior were assessed 24 h later on the attentional set-shifting test or shock-probe defensive burying test, respectively. Extinction reversed the CUS-induced deficits in cognitive flexibility and coping behavior, and increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex (mPFC) of stress-compromised rats, suggesting a role for activity-dependent protein synthesis in the therapeutic effect. Inhibiting protein synthesis by microinjecting anisomycin into mPFC blocked the therapeutic effect of extinction on cognitive flexibility. These results demonstrate the utility of extinction as a model by which to study mechanisms underlying exposure therapy, and suggest these mechanisms involve protein synthesis in the mPFC, the further study of which may identify novel therapeutic targets.

Therapeutic Effects of Extinction Learning as a Model of Exposure Therapy in Rats

PubMed Central

Fucich, Elizabeth A; Paredes, Denisse; Morilak, David A

2016-01-01

Current treatments for stress-related psychiatric disorders, such as depression and posttraumatic stress disorder (PTSD), are inadequate. Cognitive behavioral psychotherapies, including exposure therapy, are an alternative to pharmacotherapy, but the neurobiological mechanisms are unknown. Preclinical models demonstrating therapeutic effects of behavioral interventions are required to investigate such mechanisms. Exposure therapy bears similarity to extinction learning. Thus, we investigated the therapeutic effects of extinction learning as a behavioral intervention to model exposure therapy in rats, testing its effectiveness in reversing chronic stress-induced deficits in cognitive flexibility and coping behavior that resemble dimensions of depression and PTSD. Rats were fear-conditioned by pairing a tone with footshock, and then exposed to chronic unpredictable stress (CUS) that induces deficits in cognitive set-shifting and active coping behavior. They then received an extinction learning session as a therapeutic intervention by repeated exposure to the tone with no shock. Effects on cognitive flexibility and coping behavior were assessed 24 h later on the attentional set-shifting test or shock-probe defensive burying test, respectively. Extinction reversed the CUS-induced deficits in cognitive flexibility and coping behavior, and increased phosphorylation of ribosomal protein S6 in the medial prefrontal cortex (mPFC) of stress-compromised rats, suggesting a role for activity-dependent protein synthesis in the therapeutic effect. Inhibiting protein synthesis by microinjecting anisomycin into mPFC blocked the therapeutic effect of extinction on cognitive flexibility. These results demonstrate the utility of extinction as a model by which to study mechanisms underlying exposure therapy, and suggest these mechanisms involve protein synthesis in the mPFC, the further study of which may identify novel therapeutic targets. PMID:27417516

Amelioration of oxidative stress-induced phenotype loss of parvalbumin interneurons might contribute to the beneficial effects of environmental enrichment in a rat model of post-traumatic stress disorder.

PubMed

Sun, Xiao R; Zhang, Hui; Zhao, Hong T; Ji, Mu H; Li, Hui H; Wu, Jing; Li, Kuan Y; Yang, Jian J

2016-10-01

Post-traumatic stress disorder (PTSD) is a common psychiatric disease following exposure to a severe traumatic event or physiological stress, which is characterized by anxiety- and depression-like behaviors and cognitive impairment. However, the underlying mechanisms remain elusive. Parvalbumin (PV) interneurons that are susceptible to oxidative stress are a subset of inhibitory GABAergic neurons regulating the excitability of pyramidal neurons, while dysfunction of PV interneurons is casually linked to many mental disorders including PTSD. We therefore hypothesized that environmental enrichment (EE), a method of enhanced cognitive, sensory and motor stimulation, can reverse the behavioral impairments by normalizing PV interneurons in a rat model of PTSD induced by inescapable foot shocks (IFS). Behavioral changes were determined by the open field, elevated plus maze, fear conditioning, and Morris water maze tests. The levels of nicotinamide adenosine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), NOX4, PV, glutamic acid decarboxylase 67 (GAD-67), and 8-hydroxy-2-deoxyguanosine (8-OH-dG) in the hippocampus and prefrontal cortex were determined. Our results showed that in this PTSD model, rats displayed the anxiety-like behavior, enhanced fear learning behavior, and hippocampus- dependent spatial memory deficit, which were accompanied by the up-regulation of NOX2, 8-OH-dG, and down-regulation of PV and GAD-67. Notably, EE reversed all these abnormalities. These results suggest that restoration of PV interneurons by inhibiting oxidative stress in the hippocampus and prefrontal cortex might represent a mechanism through which EE reverses the behavioral impairments in a rat model of PTSD induced by IFS. Copyright © 2016 Elsevier B.V. All rights reserved.

Differential expression of molecular markers of synaptic plasticity in the hippocampus, prefrontal cortex, and amygdala in response to spatial learning, predator exposure, and stress-induced amnesia.

PubMed

Zoladz, Phillip R; Park, Collin R; Halonen, Joshua D; Salim, Samina; Alzoubi, Karem H; Srivareerat, Marisa; Fleshner, Monika; Alkadhi, Karim A; Diamond, David M

2012-03-01

We have studied the effects of spatial learning and predator stress-induced amnesia on the expression of calcium/calmodulin-dependent protein kinase II (CaMKII), brain-derived neurotrophic factor (BDNF) and calcineurin in the hippocampus, basolateral amygdala (BLA), and medial prefrontal cortex (mPFC). Adult male rats were given a single training session in the radial-arm water maze (RAWM) composed of 12 trials followed by a 30-min delay period, during which rats were either returned to their home cages or given inescapable exposure to a cat. Immediately following the 30-min delay period, the rats were given a single test trial in the RAWM to assess their memory for the hidden platform location. Under control (no stress) conditions, rats exhibited intact spatial memory and an increase in phosphorylated CaMKII (p-CaMKII), total CaMKII, and BDNF in dorsal CA1. Under stress conditions, rats exhibited impaired spatial memory and a suppression of all measured markers of molecular plasticity in dorsal CA1. The molecular profiles observed in the BLA, mPFC, and ventral CA1 were markedly different from those observed in dorsal CA1. Stress exposure increased p-CaMKII in the BLA, decreased p-CaMKII in the mPFC, and had no effect on any of the markers of molecular plasticity in ventral CA1. These findings provide novel observations regarding rapidly induced changes in the expression of molecular plasticity in response to spatial learning, predator exposure, and stress-induced amnesia in brainregions involved in different aspects of memory processing. Copyright © 2011 Wiley Periodicals, Inc.

Overexpression of 5-HT1B receptor in dorsal raphe nucleus using Herpes Simplex Virus gene transfer increases anxiety behavior after inescapable stress.

PubMed

Clark, Michael S; Sexton, Timothy J; McClain, Molly; Root, Daniel; Kohen, Ruth; Neumaier, John F

2002-06-01

5-HT(1B) autoreceptors have been implicated in animal models of stress and are regulated selectively by serotonin-selective reuptake inhibitors such as fluoxetine. These terminal autoreceptors regulate serotonin release from dorsal raphe nucleus (DRN) projections throughout rat forebrain. However, it has not been previously possible to manipulate 5-HT(1B) autoreceptor activity selectively without also changing 5-HT(1B) activity in other neurons mediating different behavioral responses. Therefore, we have developed a viral-mediated gene transfer strategy to express hemagglutinin-tagged 5-HT(1B) and manipulate these autoreceptors in DRN. Green fluorescent protein (GFP) was coexpressed from a separate transcriptional unit on the same amplicon to assist in monitoring infection and expression. We confirmed the expression and biological activity of both transgenic proteins in vitro. When injected directly into DRN using stereotaxic procedure, HA-5-HT(1B) receptors were expressed in serotonergic neurons and translocated to the forebrain. The effect of DRN expression of HA-5-HT(1B) on stress-induced behaviors was compared with control rats that received GFP-only amplicons. There was no change in immobility in the forced swim test. However, HA-5-HT(1B) expression significantly reduced entrances into the central region of an open-field arena after water-restraint stress without altering overall locomotor activity, but not in the absence of stress exposure. HA-5-HT(1B) expression also reduced entries into the open arms of the elevated plus maze after water restraint. Because these tests are sensitive to increases in anxiety-like behavior, our results suggest that overactivity of 5-HT(1B) autoreceptors in DRN neurons may be an important mediator of pathological responses to stressful events.

Stress-induced facilitation of host response to bacterial challenge in F344 rats is dependent on extracellular heat shock protein 72 and independent of alpha beta T cells.

PubMed

Campisi, Jay; Sharkey, Craig; Johnson, John D; Asea, Alexzander; Maslanik, Thomas; Bernstein-Hanley, Isaac; Fleshner, Monika

2012-11-01

Activation of the in vivo stress response can facilitate antibacterial host defenses. One possible mechanism for this effect is stress-induced release of heat shock protein 72 (Hsp72) into the extracellular environment. Hsp72 is a ubiquitous cellular protein that is up-regulated in response to cellular stress, and modulates various aspects of immune function including macrophage inflammatory/bactericidal responses and T-cell function when found in the extracellular environment. The current study tested the hypothesis that in vivo extracellular Hsp72 (eHsp72) at the site of inflammation contributes to stress-induced restricted development of bacteria, and facilitated recovery from bacteria-induced inflammation, and that this effect is independent of alpha beta (αβ) T cells. Male F344 rats were exposed to either inescapable electrical tail-shocks or no stress, and subcutaneously injected with Escherichia coli (ATCC 15746). The role of eHsp72 was investigated by Hsp72-immunoneutralization at the inflammatory site. The potential contribution of T cells was examined by testing male athymic (rnu/rnu) nude rats lacking mature αβ T cells and heterozygous thymic intact control (rnu/+) rats. The results were that stressor exposure increased plasma concentrations of eHsp72 and facilitated recovery from bacterial inflammation. Immunoneutralization of eHsp72 at the inflammatory site attenuated this effect. Stressor exposure impacted bacterial inflammation and eHsp72 equally in both athymic and intact control rats. These results support the hypothesis that eHsp72 at the site of inflammation, and not αβ T cells, contributes to the effect of stressor exposure on subcutaneous bacterial inflammation.

Serotonin 2C receptor antagonist improves fear discrimination and subsequent safety signal recall

PubMed Central

Foilb, Allison R.; Christianson, John P.

2015-01-01

The capacity to discriminate between safety and danger is fundamental for survival, but is disrupted in individuals with posttraumatic stress disorder (PTSD). Acute stressors cause a release of serotonin (5-HT) in the forebrain, which is one mechanism for enhanced fear and anxiety; these effects are mediated by the 5-HT2C receptor. Using a fear discrimination paradigm where a danger signal conditioned stimulus (CS+) coterminates with a mild footshock and a safety signal (CS-) indicates the absence of shock, we demonstrate that danger/safety discrimination and fear inhibition develops over the course of 4 daily conditioning sessions. Systemic administration of the 5-HT2C receptor antagonist SB 242084 (0.25 or 1.0 mg/kg) prior to conditioning reduced behavioral freezing during conditioning, improved learning and subsequent inhibition of fear by the safety signal. Discrimination was apparent in the first recall test, and discrimination during training was evident after 3 days of conditioning versus 5 days in the vehicle treated controls. These results suggest a novel therapeutic use for 5-HT2C receptor antagonists to improve learning under stressful circumstances. Potential anatomical loci for 5-HT2C receptor modulation of fear discrimination learning and cognitive performance enhancement are discussed. PMID:26344640

Studies of learned helplessness in honey bees (Apis mellifera ligustica).

PubMed

Dinges, Christopher W; Varnon, Christopher A; Cota, Lisa D; Slykerman, Stephen; Abramson, Charles I

2017-04-01

The current study reports 2 experiments investigating learned helplessness in the honey bee (Apis mellifera ligustica). In Experiment 1, we used a traditional escape method but found the bees' activity levels too high to observe changes due to treatment conditions. The bees were not able to learn in this traditional escape procedure; thus, such procedures may be inappropriate to study learned helplessness in honey bees. In Experiment 2, we used an alternative punishment, or passive avoidance, method to investigate learned helplessness. Using a master and yoked design where bees were trained as either master or yoked and tested as either master or yoked, we found that prior training with unavoidable and inescapable shock in the yoked condition interfered with avoidance and escape behavior in the later master condition. Unlike control bees, learned helplessness bees failed to restrict their movement to the safe compartment following inescapable shock. Unlike learned helplessness studies in other animals, no decrease in general activity was observed. Furthermore, we did not observe a "freezing" response to inescapable aversive stimuli-a phenomenon, thus far, consistently observed in learned helplessness tests with other species. The bees, instead, continued to move back and forth between compartments despite punishment in the incorrect compartment. These findings suggest that, although traditional escape methods may not be suitable, honey bees display learned helplessness in passive avoidance procedures. Thus, regardless of behavioral differences from other species, honey bees can be a unique invertebrate model organism for the study of learned helplessness. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

78 FR 5247 - Martin Luther King, Jr., Federal Holiday, 2013

Federal Register 2010, 2011, 2012, 2013, 2014

2013-01-24

... continuous struggle.'' Throughout the 1950s and 1960s, he mobilized multitudes of men and women to take on a... that ``we are caught in an inescapable network of mutuality, tied in a single garment of destiny...

Cooperation South, 2002.

ERIC Educational Resources Information Center

Gitta, Cosmas, Ed.

2002-01-01

The current international debate over patient rights to essential drugs versus intellectual property rights is inescapable. Across fields such as pharmaceuticals, electronics, and biotechnology, southern hemisphere countries appear to be finding it increasingly difficult to afford and benefit from technologies and ideas produced by big…

Learned Together, Extinguished Apart: Reducing Fear to Complex Stimuli

ERIC Educational Resources Information Center

Jones, Carolyn E.; Ringuet, Stephanie; Monfils, Marie-H.

2013-01-01

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a footshock) leads to associative learning such that the tone alone comes to elicit a conditioned response (e.g., freezing). We have previously shown that an extinction session that occurs within the reconsolidation window…

Neural Correlates of Appetitive-Aversive Interactions in Pavlovian Fear Conditioning

ERIC Educational Resources Information Center

Nasser, Helen M.; McNally, Gavan P.

2013-01-01

We used Pavlovian counterconditioning in rats to identify the neural mechanisms for appetitive-aversive motivational interactions. In Stage I, rats were trained on conditioned stimulus (CS)-food (unconditioned stimulus [US]) pairings. In Stage II, this appetitive CS was transformed into a fear CS via pairings with footshock. The development of…

Context Memory Formation Requires Activity-Dependent Protein Degradation in the Hippocampus

ERIC Educational Resources Information Center

Cullen, Patrick K.; Ferrara, Nicole C.; Pullins, Shane E.; Helmstetter, Fred J.

2017-01-01

Numerous studies have indicated that the consolidation of contextual fear memories supported by an aversive outcome like footshock requires de novo protein synthesis as well as protein degradation mediated by the ubiquitin-proteasome system (UPS). Context memory formed in the absence of an aversive stimulus by simple exposure to a novel…

Amygdala kindling-resistant (SLOW) or -prone (FAST) rat strains show differential fear responses.

PubMed

Mohapel, P; McIntyre, D C

1998-12-01

The authors compared two rat strains, selectively bred for their susceptibility to amygdala kindling, with respect to their performance on various behavioral and learning tasks that are associated with fear and anxiety. The two rat strains differed significantly in measurements of exploration of novel and familiar environments, as well as in reactivity to footshock and fear-based learning. The kindling-resistant (SLOW) strain exhibited a lower ratio of open- to closed-arm entries in the elevated plus-maze, less activity over days in the open field, greater behavioral suppression in the open-field if previously footshocked, greater freezing in the inhibitory avoidance task, and slower acquisition and poorer retention in the one-way avoidance task than did the kindling-prone (FAST) strain. These experiments suggest that the SLOW rats are more expressively fearful than the FAST rats, particularly with respect to environmentally triggered freezing or immobility. Further, these observations imply that the relatively constrained excitability of the amygdala network in the SLOW rats might mediate their relatively greater expression of fear and anxiety compared with the FAST rats.

Involvement of the basolateral amygdala in muscarinic cholinergic modulation of extinction memory consolidation

PubMed Central

Boccia, Mariano M.; Blake, Mariano G.; Baratti, Carlos M.; McGaugh, James L.

2009-01-01

Previous studies have reported that drugs affecting neuromodulatory systems within the basolateral amygdala (BLA), including drugs affecting muscarinic cholinergic receptors, modulate the consolidation of many kinds of training, including contextual fear conditioning (CFC). The present experiments investigated the involvement of muscarinic cholinergic influences within the BLA in modulating the consolidation of CFC extinction memory. Male Sprague Dawley rats implanted with unilateral cannula aimed at the BLA were trained on a CFC task, using footshock stimulation, and 24 and 48 h later were given extinction training by replacing them in the apparatus without footshock. Following each extinction session they received intra-BLA infusions of the cholinergic agonist oxotremorine (10 ng). Immediate post-extinction BLA infusions significantly enhanced extinction but infusions administered 180 min after extinction training did not influence extinction. Thus the oxotremorine effects were time-dependent and not attributable to non-specific effects on retention performance. These findings provide evidence that, as previously found with original CFC learning, cholinergic activation within the BLA modulates the consolidation of CFC extinction. PMID:18706510

(+/-)-3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') increases social interaction in rats.

PubMed

Morley, K C; McGregor, I S

2000-11-10

A series of experiments administered a low dose range (0, 1.25, 2.5 and 5 mg/kg) of (+/-)-3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') to rats and assessed them in a variety of standard tests of anxiety. These tests included the emergence and elevated plus-maze tests, social interaction, cat odor avoidance and footshock-induced ultrasonic vocalizations. MDMA increased anxiety-related behaviours in the emergence and elevated plus-maze tests at all dose levels. A 5 mg/kg dose of MDMA also significantly reduced the time spent in close proximity to an anxiogenic cat odor stimulus. The 5 mg/kg dose also significantly reduced footshock-induced ultrasonic vocalizations. In the social interaction test, MDMA decreased aggressive behaviours at all doses tested, while the highest dose (5 mg/kg) also significantly increased the duration of social interaction. These results indicate that MDMA has both anxiogenic and anxiolytic effects depending upon the test situation employed. The facilitation of social interaction produced by MDMA in rats concurs with human experience of MDMA as a uniquely prosocial drug.

Glutamatergic transmission in the nucleus of the solitary tract modulates memory through influences on amygdala noradrenergic systems.

PubMed

Miyashita, Teiko; Williams, Cedric L

2002-02-01

The authors examined whether glutamate release from the vagus nerve onto the nucleus of the solitary tract (NTS) is one mechanism by which the vagus influences memory and neural activity in limbic structures. Rats trained to drink from a spout were given a footshock (0.35 mA) on Day 5 after approaching the spout. Phosphate-buffered saline or 5.0, 50.0, or 100.0 nmol/0.5 microl glutamate was then infused into the NTS. Glutamate (5.0 or 50.0 nmol) significantly enhanced memory on the retention test. In Experiment 2, this effect was attenuated by blocking noradrenergic receptors in the amygdala with propranolol (0.3 microg/0.5 microl). Experiment 3 used in vivo microdialysis to determine whether footshock plus glutamate (50.0 nmol) alters noradrenergic output in the amygdala. These treatments caused a significant and long-lasting increase in amygdala noradrenergic concentrations. The results indicate that glutamate may be one transmitter that conveys the effects of vagal activation on brain systems that process memory.

Medial prefrontal cortex circuit function during retrieval and extinction of associative learning under anesthesia.

PubMed

Fenton, G E; Halliday, D M; Mason, R; Stevenson, C W

2014-04-18

Associative learning is encoded under anesthesia and involves the medial prefrontal cortex (mPFC). Neuronal activity in mPFC increases in response to a conditioned stimulus (CS+) previously paired with an unconditioned stimulus (US) but not during presentation of an unpaired stimulus (CS-) in anesthetized animals. Studies in conscious animals have shown dissociable roles for different mPFC subregions in mediating various memory processes, with the prelimbic (PL) and infralimbic (IL) cortex involved in the retrieval and extinction of conditioned responding, respectively. Therefore PL and IL may also play different roles in mediating the retrieval and extinction of discrimination learning under anesthesia. Here we used in vivo electrophysiology to examine unit and local field potential (LFP) activity in PL and IL before and after auditory discrimination learning and during later retrieval and extinction testing in anesthetized rats. Animals received repeated presentations of two distinct sounds, one of which was paired with footshock (US). In separate control experiments animals received footshocks without sounds. After discrimination learning the paired (CS+) and unpaired (CS-) sounds were repeatedly presented alone. We found increased unit firing and LFP power in PL and, to a lesser extent, IL after discrimination learning but not after footshocks alone. After discrimination learning, unit firing and LFP power increased in PL and IL in response to presentation of the first CS+, compared to the first CS-. However, PL and IL activity increased during the last CS- presentation, such that activity during presentation of the last CS+ and CS- did not differ. These results confirm previous findings and extend them by showing that increased PL and IL activity result from encoding of the CS+/US association rather than US presentation. They also suggest that extinction may occur under anesthesia and might be represented at the neural level in PL and IL. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Social transmission of Pavlovian fear: fear-conditioning by-proxy in related female rats.

PubMed

Jones, Carolyn E; Riha, Penny D; Gore, Andrea C; Monfils, Marie-H

2014-05-01

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a foot-shock) leads to associative learning such that the tone alone will elicit a conditioned response (e.g., freezing). Individuals can also acquire fear from a social context, such as through observing the fear expression of a conspecific. In the current study, we examined the influence of kinship/familiarity on social transmission of fear in female rats. Rats were housed in triads with either sisters or non-related females. One rat from each cage was fear conditioned to a tone CS+ shock US. On day two, the conditioned rat was returned to the chamber accompanied by one of her cage mates. Both rats were allowed to behave freely, while the tone was played in the absence of the foot-shock. The previously untrained rat is referred to as the fear-conditioned by-proxy (FCbP) animal, as she would freeze based on observations of her cage-mate's response rather than due to direct personal experience with the foot-shock. The third rat served as a cage-mate control. The third day, long-term memory tests to the CS were performed. Consistent with our previous application of this paradigm in male rats (Bruchey et al. in Behav Brain Res 214(1):80-84, 2010), our results revealed that social interactions between the fear conditioned and FCbP rats on day two contribute to freezing displayed by the FCbP rats on day three. In this experiment, prosocial behavior occurring at the termination of the cue on day two was significantly greater between sisters than their non-sister counterparts, and this behavior resulted in increased freezing on day three. Our results suggest that familiarity and/or kinship influences the social transmission of fear in female rats.

Giving High Schools an Occupational Focus.

ERIC Educational Resources Information Center

Grubb, W. Norton

1992-01-01

High school is an inescapably vocational institution whose occupational focus is largely hidden. Integration of vocational and academic education through academies, occupationally focused schools, and occupational clusters may eliminate "shopping mall" course selections, improve teaching of all subjects, enhance student engagement with learning,…

Alpha1-adrenergic receptor blockade in the VTA modulates fear memories and stress responses.

PubMed

Solecki, Wojciech B; Szklarczyk, Klaudia; Klasa, Adam; Pradel, Kamil; Dobrzański, Grzegorz; Przewłocki, Ryszard

2017-08-01

Activity of the ventral tegmental area (VTA) and its terminals has been implicated in the Pavlovian associative learning of both stressful and rewarding stimuli. However, the role of the VTA noradrenergic signaling in fear responses remains unclear. We aimed to examine how alpha 1 -adrenergic receptor (α 1 -AR) signaling in the VTA affects conditioned fear. The role of α 1 -AR was assessed using the micro-infusions into the VTA of the selective antagonists (0.1-1µg/0.5µl prazosin and 1µg/0.5µl terazosin) in acquisition and expression of fear memory. In addition, we performed control experiments with α 1 -AR blockade in the mammillary bodies (MB) - a brain region with α 1 -AR expression adjacent to the VTA. Intra-VTA but not intra-MB α 1 -AR blockade prevented formation and retrieval of fear memories. Importantly, local administration of α 1 -AR antagonists did not influence footshock sensitivity, locomotion or anxiety-like behaviors. Similarly, α 1 -AR blockade in the VTA had no effects on negative affect measured as number of 22kHz ultrasonic vocalizations during fear conditioning training. We propose that noradrenergic signaling in the VTA via α 1 -AR regulates formation and retrieval of fear memories but not other behavioral responses to stressful environmental stimuli. It enhances the encoding of environmental stimuli by the VTA to form and retrieve conditioned fear memories and to predict future behavioral outcomes. Our results provide novel insight into the role of the VTA α 1 -AR signaling in the regulation of stress responsiveness and fear memory. Copyright © 2017 Elsevier B.V. and ECNP. All rights reserved.

Early life stress in rats sex-dependently affects remote endocrine rather than behavioral consequences of adult exposure to contextual fear conditioning.

PubMed

Fuentes, Sílvia; Daviu, Núria; Gagliano, Humberto; Belda, Xavier; Armario, Antonio; Nadal, Roser

2018-05-30

Exposure to electric foot-shocks can induce in rodents contextual fear conditioning, generalization of fear to other contexts and sensitization of the hypothalamic-pituitary-adrenal (HPA) axis to further stressors. All these aspects are relevant for the study of post-traumatic stress disorder. In the present work we evaluated in rats the sex differences and the role of early life stress (ELS) in fear memories, generalization and sensitization. During the first postnatal days subjects were exposed to restriction of nesting material along with exposure to a "substitute" mother. In the adulthood they were exposed to (i) a contextual fear conditioning to evaluate long-term memory and extinction and (ii) to a novel environment to study cognitive fear generalization and HPA axis heterotypic sensitization. ELS did not alter acquisition, expression or extinction of context fear conditioned behavior (freezing) in either sex, but reduced activity in novel environments only in males. Fear conditioning associated hypoactivity in novel environments (cognitive generalization) was greater in males than females but was not specifically affected by ELS. Although overall females showed greater basal and stress-induced levels of ACTH and corticosterone, an interaction between ELS, shock exposure and sex was found regarding HPA hormones. In males, ELS did not affect ACTH response in any situation, whereas in females, ELS reduced both shock-induced sensitization of ACTH and its conditioned response to the shock context. Also, shock-induced sensitization of corticosterone was only observed in males and ELS specifically reduced corticosterone response to stressors in males but not females. In conclusion, ELS seems to have only a minor impact on shock-induced behavioral conditioning, while affecting the unconditioned and conditioned responses of HPA hormones in a sex-dependent manner. Copyright © 2018. Published by Elsevier Inc.

MicroRNA expression in rat brain exposed to repeated inescapable shock: differential alterations in learned helplessness vs. non-learned helplessness.

PubMed

Smalheiser, Neil R; Lugli, Giovanni; Rizavi, Hooriyah S; Zhang, Hui; Torvik, Vetle I; Pandey, Ghanshyam N; Davis, John M; Dwivedi, Yogesh

2011-11-01

MicroRNA (miRNA) expression was measured within frontal cortex of male Holtzman rats subjected to repeated inescapable shocks at days 1 and 7, tested for learned helplessness (LH) at days 2 and 8, and sacrificed at day 15. We compared rats that did vs. did not exhibit LH, as well as rats that were placed in the apparatus and tested for avoidance but not given shocks (tested controls, TC). Non-learned helpless (NLH) rats showed a robust adaptive miRNA response to inescapable shock whereas LH rats showed a markedly blunted response. One set of 12 miRNAs showed particularly large, significant down-regulation in NLH rats relative to tested controls (mir-96, 141, 182, 183, 183*, 298, 200a, 200a*, 200b, 200b*, 200c, 429). These were encoded at a few shared polycistronic loci, suggesting that the down-regulation was coordinately controlled at the level of transcription. Most of these miRNAs are enriched in synaptic fractions. Moreover, almost all of these share 5'-seed motifs with other members of the same set, suggesting that they will hit similar or overlapping sets of target mRNAs. Finally, half of this set is predicted to hit Creb1 as a target. We also identified a core miRNA co-expression module consisting of 36 miRNAs that are highly correlated with each other across individuals of the LH group (but not in the NLH or TC groups). Thus, miRNAs participate in the alterations of gene expression networks that underlie the normal (NLH) as well as aberrant (LH) response to repeated shocks.

Inescapable Stress Changes Walking Behavior in Flies - Learned Helplessness Revisited

PubMed Central

Batsching, Sophie; Wolf, Reinhard; Heisenberg, Martin

2016-01-01

Like other animals flies develop a state of learned helplessness in response to unescapable aversive events. To show this, two flies, one 'master', one 'yoked', are each confined to a dark, small chamber and exposed to the same sequence of mild electric shocks. Both receive these shocks when the master fly stops walking for more than a second. Behavior in the two animals is differently affected by the shocks. Yoked flies are transiently impaired in place learning and take longer than master flies to exit from the chamber towards light. After the treatment they walk more slowly and take fewer and shorter walking bouts. The low activity is attributed to the fly's experience that its escape response, an innate behavior to terminate the electric shocks, does not help anymore. Earlier studies using heat pulses instead of electric shocks had shown similar effects. This parallel supports the interpretation that it is the uncontrollability that induces the state. PMID:27875580

Prefrontal Cortex Lesions and Sex Differences in Fear Extinction and Perseveration

ERIC Educational Resources Information Center

Baran, Sarah E.; Armstrong, Charles E.; Niren, Danielle C.; Conrad, Cheryl D.

2010-01-01

Electrolytic lesions of the medial prefrontal cortex (PFCX) were examined using fear conditioning to assess the recall of fear extinction and performance in the Y-maze, open field, and object location/recognition in male and female Sprague-Dawley rats. Rats were conditioned to seven tone/footshocks, followed by extinction after 1-h and 24-h…

Dissociation between Complete Hippocampal Context Memory Formation and Context Fear Acquisition

ERIC Educational Resources Information Center

Leake, Jessica; Zinn, Raphael; Corbit, Laura; Vissel, Bryce

2017-01-01

Rodents require a minimal time period to explore a context prior to footshock to display plateau-level context fear at test. To investigate whether this rapid fear plateau reflects complete memory formation within that short time-frame, we used the immediate-early gene product Arc as an indicator of hippocampal context memory formation-related…

Uncertainty, risk, and the role of epidemiology in public policy development.

PubMed

Dinman, B D; Sussman, N B

1983-07-01

Risk taking is a concommitant of life--inescapable beyond the inert, sessile state. Accordingly, risk assessment is implicit for almost all human activities, from daily actions, such as crossing a trafficked street to esoteric ones such as landing on the moon.

Violence in Children's Literature Today.

ERIC Educational Resources Information Center

Nimon, Maureen

Because violence is an inescapable reality of the world, this paper asks the question, "Does violence have any place in children's literature?" For centuries, children's literature has encompassed stories in which the virtuous were rewarded and evildoers suffered retribution. Historically, violence was frequently part of punishment.…

"Language," "Communication," and the Longing for the Authentic in LSP Testing

ERIC Educational Resources Information Center

Hoekje, Barbara

2016-01-01

This commentary argues that the OET research raises inescapable contradictions in trying to separate "language" from "communication" within a weak performance test and advocates for reconceptualizing the legitimate domain of "language" more widely, reclaiming the full potential of the communicative competence…

Long-Term Interference Effect: An Alternative to "Learned Helplessness"

ERIC Educational Resources Information Center

Glazer, Howard I.; Weiss, Jay M.

1976-01-01

Presents three experiments that explore whether inescapable shock of long duration and moderate intensity (LoShk) produces an avoidance-escape deficit (called an interference effect) by causing animals to learn to respond less actively or by causing them to learn to be "helpless". (Editor)

Decreased sexual motivation and heightened anxiety in male Long-Evans rats are correlated with the memory for a traumatic event.

PubMed

Hawley, Wayne R; Grissom, Elin M; Belkin, Mark N; James, Thomas F; Dohanich, Gary P

2013-05-01

Individuals suffering from posttraumatic stress disorder (PTSD) frequently report disturbances in sexual functioning in addition to alterations in their affective behaviors. Notably, maladaptive cognitions and dysfunctional behaviors are perpetuated by the emergence of the intrusive thoughts that characterize the disorder. In rats, reminders of a traumatic event designed to simulate intrusive thoughts are associated with impairments in affective, social, and sexual behaviors. The current study examined the relationship between the memory for a traumatic event and changes in sexual and affective behaviors in male Long-Evans rats (N = 36). The trauma featured a combination stressor consisting of simultaneous exposure to a footshock and the odor of soiled cat litter. Memory for the trauma was reactivated by re-exposures to the context of the trauma in the absence of stressors and confirmed by assessing the percentage of time spent freezing. Following the second and final reminder, traumatized males exhibited reduced sexual motivation and increased anxiety, signified by longer latencies to achieve their first mount on a post-stress test of sexual behavior, and longer latencies to begin feeding in a novel environment, respectively. Correlational analyses revealed that decreased sexual motivation and heightened anxiety were predicted by the memory for the trauma as indicated by the time spent freezing during the re-exposures. The findings from the current study have implications for understanding the relationship between stress and sexual functioning and indicate that the impairments in sexual behavior that often occur in individuals with PTSD may be impacted by their memory for the trauma.

Autonomy and the Working-Class Freelance

ERIC Educational Resources Information Center

Medway, Peter

2015-01-01

In taking into account the realities of the writing process in the ways teachers organize their classrooms, they inescapably find themselves involved with the notion of student autonomy. Some guidelines for supporting independent-minded adolescents in the classroom suggest themselves, and this article provides other suggestions for planning…

Basolateral Amygdala Projections to Ventral Hippocampus Modulate the Consolidation of Footshock, but Not Contextual, Learning in Rats

ERIC Educational Resources Information Center

Huff, Mary L.; Emmons, Eric B.; Narayanan, Nandakumar S.; LaLumiere, Ryan T.

2016-01-01

The basolateral amygdala (BLA) modulates memory consolidation for a variety of types of learning, whereas other brain regions play more selective roles in specific kinds of learning suggesting a role for differential consolidation via distinct BLA pathways. The ventral hippocampus (VH), an efferent target of the BLA, has been suggested to…

Spermidine-Induced Improvement of Reconsolidation of Memory Involves Calcium-Dependent Protein Kinase in Rats

ERIC Educational Resources Information Center

Girardi, Bruna Amanda; Ribeiro, Daniela Aymone; Signor, Cristiane; Muller, Michele; Gais, Mayara Ana; Mello, Carlos Fernando; Rubin, Maribel Antonello

2016-01-01

In this study, we determined whether the calcium-dependent protein kinase (PKC) signaling pathway is involved in the improvement of fear memory reconsolidation induced by the intrahippocampal administration of spermidine in rats. Male Wistar rats were trained in a fear conditioning apparatus using a 0.4-mA footshock as an unconditioned stimulus.…

Sustainability: Why the Language and Ethics of Sustainability Matter in the Geoscience Classroom

ERIC Educational Resources Information Center

Metzger, Ellen P.; Curren, Randall R.

2017-01-01

Because challenges to sustainability arise at the intersection of human and biophysical systems they are inescapably embedded in social contexts and involve multiple stakeholders with diverse and often conflicting needs and value systems. Addressing complex and solution-resistant problems such as climate change, biodiversity loss, and…

Campus Unrest and Exhausted Administrators.

ERIC Educational Resources Information Center

Schaefer, Robert J.

No precise explanation can be offered for student uprisings at colleges and universities, but a sense of social purpose seems to pervade these disruptive activities. A college education, once a matter of free choice, is now a twentieth-century imperative for social and economic mobility. Modern students, frustrated by the inescapability of the…

PREFACE TO: "PHARMACEUTICALS AND PERSONAL CARE PRODUCTS IN THE ENVIRONMENT: SCIENTIFIC AND REGULATORY ISSUES"

EPA Science Inventory

Often overlooked in our daily lives are the inescapable, intimate, and immediate connections between our personal activities and the environment in which we live. This is especially true with regard to the use and disposal of consumer chemicals. A significant aspect of our global...

India, Europe, America: A Geocultural Triangle

ERIC Educational Resources Information Center

Pells, Richard

2006-01-01

America's reputation abroad has never been so abysmal. That is the inescapable conclusion of countless books, newspaper and magazine articles, and public-opinion polls that have documented the growth of anti-Americanism during the Bush administration. Yet outside Europe and the Middle East, the loathing for Bush and the bitterness toward America…

Community College Leadership Transition through the Framework of Appreciative Inquiry

ERIC Educational Resources Information Center

Royer, Dan W.; Latz, Amanda O.

2016-01-01

Our paper considers a critical juncture in community college leadership as many community college leaders approach retirement. These transitions are inescapable. How will institutional memory (Parker, 2011) be preserved with the passing of the leadership mantel to a new generation? These transitions also impact ways in which leaders influence…

The Learning Disability Phenomenon in Pursuit of Axioms

ERIC Educational Resources Information Center

Healey, William C.

2005-01-01

The social epistemologist studies the basic nature of knowledge and defines axioms as statements of absolute truths that are undeniable, inescapable, and devoid of most uncertainties (Machan, 1985). The accidental phenomenon of learning disabilities (LD) has pursued the scientific truths in axioms for 42 years. Writing facts and perceptions…

Leveraging Early Childhood Data for Better Decision Making

ERIC Educational Resources Information Center

Sirinides, Philip; Coffey, Missy

2018-01-01

Americans share an expectation that government will serve the common good, creating inescapable pressure for public agencies--especially those that serve young children--to perform well. Yet education and human services agencies continually struggle to respond to the complex conditions in which children are born. How can they address the practical…

Aesthetics of Surrender: Levinas and the Disruption of Agency in Moral Education.

ERIC Educational Resources Information Center

Chinnery, Ann

2003-01-01

Uses jazz improvisation as a metaphor to focus on three interrelated aspects of ethical responsibility according to Emmanuel Lavinas's theories: (1) passivity; (2) heteronomy; and (3) inescapability. Discusses some ways in which reframing responsibility and subjectivity along this line might offer new possibilities for conceiving subjectivity and…

Thinking on Good Things.

ERIC Educational Resources Information Center

Hysten, Franklin T.

1998-01-01

A college junior's personal narrative tells how, with the help of a handful of caring adults, he managed to overcome a life of poverty with no parental support. He states that adults can help troubled adolescents by emphasizing their creativity and intellect, not their bad habits or inescapable backgrounds and history. (Author/MKA)

Individual Differences in Animal Stress Models: Considering Resilience, Vulnerability, and the Amygdala in Mediating the Effects of Stress and Conditioned Fear on Sleep

PubMed Central

Wellman, Laurie L.; Fitzpatrick, Mairen E.; Hallum, Olga Y.; Sutton, Amy M.; Williams, Brook L.; Sanford, Larry D.

2016-01-01

Study Objectives: To examine the REM sleep response to stress and fearful memories as a potential marker of stress resilience and vulnerability and to assess the role of the basolateral amygdala (BLA) in mediating the effects of fear memory on sleep. Methods: Outbred Wistar rats were surgically implanted with electrodes for recording EEG and EMG and with bilateral guide cannulae directed at the BLA. Data loggers were placed intraperitoneally to record core body temperature. After recovery from surgery, the rats received shock training (ST: 20 footshocks, 0.8 mA, 0.5-s duration, 60-s interstimulus interval) and afterwards received microinjections of the GABAA agonist muscimol (MUS; 1.0 μM) to inactivate BLA or microinjections of vehicle (VEH) alone. Subsequently, the rats were separated into 4 groups (VEH-vulnerable (VEH-Vul; n = 14), VEH-resilient (VEH-Res; n = 13), MUS-vulnerable (MUS-Vul; n = 8), and MUS-resilient (MUS-Res; n = 11) based on whether or not REM was decreased, compared to baseline, during the first 4 h following ST. We then compared sleep, freezing, and the stress response (stress-induced hyperthermia, SIH) across groups to determine the effects of ST and fearful context re-exposure alone (CTX). Results: REM was significantly reduced on the ST day in both VEH-Vul and MUS-Vul rats; however, post-ST MUS blocked the reduction in REM on the CTX day in the MUS-Vul group. The VEH-Res and MUS-Res rats showed similar levels of REM on both ST and CTX days. The effects of post-ST inactivation of BLA on freezing and SIH were minimal. Conclusions: Outbred Wistar rats can show significant individual differences in the effects of stress on REM that are mediated by BLA. These differences in REM can be independent of behavioral fear and the peripheral stress response, and may be an important biomarker of stress resilience and vulnerability. Citation: Wellman LL, Fitzpatrick ME, Hallum OY, Sutton AM, Williams BL, Sanford LD. Individual differences in animal stress models: considering resilience, vulnerability, and the amygdala in mediating the effects of stress and conditioned fear on sleep. SLEEP 2016;39(6):1293–1303. PMID:27091518

Impact of oxidative stress defense on bacterial survival and morphological change in Campylobacter jejuni under aerobic conditions.

PubMed

Oh, Euna; McMullen, Lynn; Jeon, Byeonghwa

2015-01-01

Campylobacter jejuni, a microaerophilic foodborne pathogen, inescapably faces high oxygen tension during its transmission to humans. Thus, the ability of C. jejuni to survive under oxygen-rich conditions may significantly impact C. jejuni viability in food and food safety as well. In this study, we investigated the impact of oxidative stress resistance on the survival of C. jejuni under aerobic conditions by examining three mutants defective in key antioxidant genes, including ahpC, katA, and sodB. All the three mutants exhibited growth reduction under aerobic conditions compared to the wild-type (WT), and the ahpC mutant showed the most significant growth defect. The CFU reduction in the mutants was recovered to the WT level by complementation. Higher levels of reactive oxygen species were accumulated in C. jejuni under aerobic conditions than microaerobic conditions, and supplementation of culture media with an antioxidant recovered the growth of C. jejuni. The levels of lipid peroxidation and protein oxidation were significantly increased in the mutants compared to WT. Additionally, the mutants exhibited different morphological changes under aerobic conditions. The ahpC and katA mutants developed coccoid morphology by aeration, whereas the sodB mutant established elongated cellular morphology. Compared to microaerobic conditions, interestingly, aerobic culture conditions substantially induced the formation of coccoidal cells, and antioxidant treatment reduced the emergence of coccoid forms under aerobic conditions. The ATP concentrations and PMA-qPCR analysis supported that oxidative stress is a factor that induces the development of a viable-but-non-culturable state in C. jejuni. The findings in this study clearly demonstrated that oxidative stress resistance plays an important role in the survival and morphological changes of C. jejuni under aerobic conditions.

17β Estradiol increases resilience and improves hippocampal synaptic function in helpless ovariectomized rats

PubMed Central

Bredemann, Teruko M.; McMahon, Lori L.

2014-01-01

Summary Memory impairment is the most commonly reported cognitive symptom associated with major depressive disorder. Decreased hippocampal volume and neurogenesis in depression link hippocampal dysfunction with deficits in memory. Stress decreases hippocampal dendritic spine density and long-term potentiation (LTP) at glutamate synapses, a cellular correlate of learning and memory. However, elevated plasma levels of 17β estradiol (E2) during proestrus increase hippocampal structure and function, directly opposing the negative consequences of stress. In women, significant fluctuations in ovarian hormones likely increase vulnerability of hippocampal circuits to stress, potentially contributing to the greater incidence of depression compared to men. Using the learned helplessness model of depression and ovariectomized female rats, we investigated whether acquisition of helplessness and hippocampal synaptic dysfunction is differentially impacted by the presence or absence of plasma E2. We find that inescapable shock induces a greater incidence of helplessness in vehicle- versus E2-treated OVX rats. In the vehicle-treated group, LTP was absent at CA3-CA1 synapses in slices only from helpless rats, and CA1 spine density was decreased compared to resilient rats. In contrast, significant LTP was observed in slices from E2-treated helpless rats; importantly, spine density was not different between E2-treated helpless and resilient rats, dissociating spine density from the LTP magnitude. We also find that E2 replacement can reverse previously established helpless behavior. Thus, our results show that E2 replacement in OVX rats increases resilience and improves hippocampal plasticity, suggesting that E2 therapy may increase resilience to stress and preserve hippocampal function in women experiencing large fluctuations in plasma estrogen levels. PMID:24636504

Behavioral and hormonal responses to stress in binge-like eating prone female rats.

PubMed

Calvez, Juliane; Timofeeva, Elena

2016-04-01

Binge eating episodes are frequently stimulated by stress. We developed a model of binge eating proneness based on individual sensitivity of young female Sprague Dawley rats to significantly increase sucrose consumption in response to stress. The rats were subjected to unpredictable intermittent 1-h access to 10% sucrose. After the stabilization of sucrose intake, rats were assessed for consistency of higher (for binge-like eating prone, BEP) or lower (for binge-like eating resistant, BER) sucrose intake in response to unpredictable episodes of foot-shock stress. The objectives of this study included demonstrating face validity of the BEP model and determining if some of the features of this model were pre-existing before exposure to intermittent access to sucrose and repeated stress. The BEP rats consumed a larger (20%>BER) amount of sucrose in a discrete (1-h) period of time compared to the BER phenotype in non-stressful conditions and significantly increased sucrose intake (50%>BER) under stress. Conversely, stress did not affect sucrose intake in BER rats. BEP rats showed higher sucrose intake compared to BER rats at the beginning of darkness as well as during the light period when they were sated and not physically hungry. Analyses of the sucrose licking microstructure revealed that BEP rats had a high motivational drive to consume sucrose in non-stressful condition and an increased hedonic value of sucrose when they were exposed to stressful conditions. BEP rats consumed sucrose much more rapidly under stressful conditions compared to BER rats. Finally, BEP rats demonstrated compulsive-like intake of sucrose (assessed in the light-dark box) and a blunted stress-induced increase in plasma corticosterone levels. Body weight and chow intake were not different between the phenotypes. Before exposure to intermittent access to sucrose and repeated stress, the BEP rats showed no clear evidence for compulsive sucrose intake. However, from the first 1-h access to sucrose, the BEP rats exhibited sucrose overeating; and from the first exposure to stress before intermittent access to sucrose, the BEP rats showed a blunted increase in corticosterone plasma levels. Innate sucrose hyperconsumption and altered reactivity of the hypothalamo-pituitary adrenal (HPA) axis to stress may be involved in the development of binge-like eating. Increased perceived hedonic value of palatable food and an increased motivation to consume this food despite aversive conditions as well as deregulated reactivity of the HPA axis may contribute to stress-induced bingeing on sucrose in BEP rats. Copyright © 2016 Elsevier Inc. All rights reserved.

The Knight of Faith: Ethics in Special Needs Education

ERIC Educational Resources Information Center

Steinnes, Jenny

2011-01-01

This article attempts to contribute to the understanding of the particularly important and inescapable role that ethics must play in the context of special needs education. Perspectives from Kierkegaard and Derrida are presented and used in order to explore the complexity of the context and to show the importance and responsibility of the agency…

South-South Universities Curriculum Characteristics and Global Collaboration in the 21st Century

ERIC Educational Resources Information Center

Obiekezie, Eucharia Obiageli; Essien, Margaret; Essien, Alexander Timothy

2013-01-01

Globalization imposes certain inescapable requirements on a university's curriculum. One such requirement is the elasticity of the curriculum to sustain local demands and accommodate global concerns. Using the ex post facto design, this paper examines the impact of global collaboration on the curriculum characteristics of selected universities in…

Reduction in Force: The Legal Aspects.

ERIC Educational Resources Information Center

Ware, Martha L.

Six legal issues surrounding a school district's reduction in force are described in this twelfth chapter in a book on school law. First, the courts generally hold that the school board must prove that a reduction in force (RIF) is inescapable. The second issue revolves around which positions and employees are being eliminated. In deciding such…

The long darkness: Psychological and moral perspectives on nuclear winter

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grinspoon, L.

1986-01-01

This book presents papers on the risks of nuclear weapons. Topics considered include nuclear war and climatic catastrophe, evolutionary and developmental considerations, a biological comment on Erikson's notion of pseudospeciation, national security, unexamined assumptions and inescapable consequences, opposing the nuclear threat (the convergence of moral analysis and empirical data), and nuclear winter.

The Repression of the Sublime

ERIC Educational Resources Information Center

Haronian, Frank

1977-01-01

Psychosynthesis is one approach that strives to reach from the lower unconscious to the self, helping man to recognize his higher as well as his lower impulses, to accept the responsibility of deciding which to express and which to renounce, and to deal with the anxiety that is an inescapable aspect of the process of self-actualization. (Author)

Building a More Sustainable Future for Senior Living

ERIC Educational Resources Information Center

Scarfo, Bob

2011-01-01

The aging of society is an inescapable trend that some neighborhoods, municipalities, and counties are admitting needs their attention. As the extent of the changes required to become senior friendly, let alone sustainable, are being realized, many communities are experiencing pushback from voters, old-guard city and county staff, and even elected…

The Electronic Library and the Online Classroom: A Technical, Legal, Ethical, and Moral Perspective.

ERIC Educational Resources Information Center

Latimore, Ritchie R.

This paper addresses online classroom and electronic library issues which include the myriad of technical difficulties encountered, along with physical and intellectual property rights. It also makes a statistical comparison of two proportions of Internet access between city and rural schools. An inescapable time lag between the introduction of…

Race and TESOL: Introduction to Concepts and Theories

ERIC Educational Resources Information Center

Kubota, Ryuko; Lin, Angel

2006-01-01

The field of teaching English to speakers of other languages (TESOL) brings people from various racialized backgrounds together in teaching, learning, and research. The idea of race, racialization, and racism are inescapable topics that arise in the contact zones created by teaching English worldwide and thus are valid topics to explore in the…

Regimes of Performance: Practices of the Normalised Self in the Neoliberal University

ERIC Educational Resources Information Center

Morrissey, John

2015-01-01

Universities today inescapably find themselves part of nationally and globally competitive networks that appear firmly inflected by neoliberal concerns of rankings, benchmarking and productivity. This, of course, has in turn led to progressively anticipated and regulated forms of academic subjectivity that many fear are overly econo-centric in…

Previous Ketamine Produces an Enduring Blockade of Neurochemical and Behavioral Effects of Uncontrollable Stress

PubMed Central

Dolzani, Samuel D.; Tilden, Scott; Christianson, John P.; Kubala, Kenneth H.; Bartholomay, Kristi; Sperr, Katherine; Ciancio, Nicholas; Watkins, Linda R.; Maier, Steven F.

2016-01-01

Recent interest in the antidepressant and anti-stress effects of subanesthetic doses of ketamine, an NMDA receptor antagonist, has identified mechanisms whereby ketamine reverses the effect of stress, but little is known regarding the prophylactic effect ketamine might have on future stressors. Here we investigate the prophylactic effect of ketamine against neurochemical and behavioral changes that follow inescapable, uncontrollable tail shocks (ISs) in Sprague Dawley rats. IS induces increased anxiety, which is dependent on activation of serotonergic (5-HT) dorsal raphe nucleus (DRN) neurons that project to the basolateral amygdala (BLA). Ketamine (10 mg/kg, i.p.) administered 2 h, 1 week, or 2 weeks before IS prevented the increased extracellular levels of 5-HT in the BLA typically produced by IS. In addition, ketamine administered at these time points blocked the decreased juvenile social investigation produced by IS. Microinjection of ketamine into the prelimbic (PL) region of the medial prefrontal cortex duplicated the effects of systemic ketamine, and, conversely, systemic ketamine effects were prevented by pharmacological inhibition of the PL. Although IS does not activate DRN-projecting neurons from the PL, IS did so after ketamine, suggesting that the prophylactic effect of ketamine is a result of altered functioning of this projection. SIGNIFICANCE STATEMENT The reported data show that systemic ketamine, given up to 2 weeks before a stressor, blunts behavioral and neurochemical effects of the stressor. The study also advances understanding of the mechanisms involved and suggests that ketamine acts at the prelimbic cortex to sensitize neurons that project to and inhibit the DRN. PMID:26740657

Anxiety, cognition, and habit: a multiple memory systems perspective.

PubMed

Packard, Mark G

2009-10-13

Consistent with a multiple systems approach to memory organization in the mammalian brain, numerous studies have differentiated the roles of the hippocampus and dorsal striatum in "cognitive" and "habit" learning and memory, respectively. Additional research indicates that activation of efferent projections of the basolateral amygdala (BLA), a brain region implicated in mammalian emotion, modulates memory processes occurring in other brain structures. The present brief review describes research designed to link these general concepts by examining the manner in which emotional state may influence the relative use of multiple memory systems. In a dual-solution plus-maze task that can be acquired using either hippocampus-dependent or dorsal striatal-dependent learning, acute pre-training or pre-retrieval emotional arousal (restraint stress/inescapable foot shock, exposure to the predator odor TMT, or peripheral injection of anixogenic drugs) biases rats towards the use of habit memory. Moreover, intra-BLA injection of anxiogenic drugs is sufficient to bias rats towards the use of dorsal striatal-dependent habit memory. In single-solution plus-maze tasks that require the use of either cognitive or habit learning, intra-BLA infusions of anxiogenic drugs result in a behavioral profile indicating an impairing effect on hippocampus-dependent memory that effectively produces enhanced habit learning by eliminating competitive interference between cognitive and habit memory systems. It is speculated that the predominant use of habit memory that can be produced by anxious and/or stressful emotional states may have implications for understanding the role of learning and memory processes in various human psychopathologies, including for example post-traumatic stress disorder and drug addiction.

Resveratrol ameliorated the behavioral deficits in a mouse model of post-traumatic stress disorder.

PubMed

Zhang, Ze-Shun; Qiu, Zhi-Kun; He, Jia-Li; Liu, Xu; Chen, Ji-Sheng; Wang, Yu-Lu

2017-10-01

Post-traumatic stress disorder (PTSD) has become a major psychiatric and neurological issue. Resveratrol is shown to be effective on depression and anxiety. However, the mechanism of anti-PTSD-like effects of resveratrol remains unknown. The present study aimed to explore the possible molecular and cellular mechanisms underlying the anti-PTSD-like effects of resveratrol. Following a 2-day exposure to inescapable electric foot shocks, animals were administered resveratrol (10, 20, and 40mg/kg, i.g.) during the behavioral tests, which included contextual freezing measurement, elevated plus maze test, staircase test, and open field test. Similar to the positive control drug sertraline (15mg/kg, i.g.), the behavioral deficits of stressed mice were blocked by resveratrol (20 and 40mg/kg, i.g.), which reversed the increased freezing time in contextual freezing measurement and the number of rears in the staircase test and blocked the decrease in time and number of entries in open arms in the elevated plus maze test without affecting the locomotor activity in the open field test. In addition, resveratrol (20 and 40mg/kg, i.g.) antagonized the decrease in the levels of progesterone and allopregnanolone in the prefrontal cortex and hippocampus. Furthermore, long-term resveratrol attenuated the dysfunctions of hypothalamic-pituitary-adrenal axis simultaneously. Collectively, the evidence indicated that the anti-PTSD-like effects of resveratrol were associated with the normalization of biosynthesis of neurosteroids in the brain and prevention of the hypothalamic-pituitary-adrenal axis dysfunction. Copyright © 2017. Published by Elsevier Inc.

Repeated electroacupuncture attenuating of apelin expression and function in the rostral ventrolateral medulla in stress-induced hypertensive rats.

PubMed

Zhang, Cheng-Rong; Xia, Chun-Mei; Jiang, Mei-Yan; Zhu, Min-Xia; Zhu, Ji-Min; Du, Dong-Shu; Liu, Min; Wang, Jin; Zhu, Da-Nian

2013-08-01

Studies have revealed that apelin is a novel multifunctional peptide implicated both in blood pressure (BP) regulation and cardiac function control. Evidence shows that apelin and its receptor (APJ) in the rostral ventrolateral medulla (RVLM) may play an important role in central BP regulation; however, its role is controversial and very few reports have shown the relationship between acupuncture and apelin. Our study aims to both investigate the apelinergic system role in stress-induced hypertension (SIH) and determine whether acupuncture therapy effects on hypertension involve the apelinergic system in the RVLM. We established the stress-induced hypertensive rat (SIHR) model using electric foot-shock stressors with noise interventions. The expression of both apelin and the APJ receptor in the RVLM neurons was examined by immunohistochemical staining and Western blots. The results showed apelin expression increased remarkably in SIHR while APJ receptor expression showed no significant difference between control and SIHR groups. Microinjection of apelin-13 into the RVLM of control rats or SIHR produced pressor and tachycardic effects. Furthermore, effects induced by apelin-13 in SIHR were significantly greater than those of control rats. In addition, repetitive electroacupuncture (EA) stimulation at the Zusanli (ST-36) acupoint attenuated hypertension and apelin expression in the RVLM in SIHR; it also attenuated the pressor effect elicited by exogenous apelin-13 microinjection in SIHR. The results suggest that augmented apelin in the RVLM was part of the manifestations of SIH; the antihypertensive effects of EA might be associated with the attenuation of apelin expression and function in the RVLM, which might be a novel role for EA in SIH setting. Copyright © 2013 Elsevier Inc. All rights reserved.

Effects of neuropeptide Y and ethanol on arousal and anxiety-like behavior in alcohol-preferring rats.

PubMed

Gilpin, Nicholas W; Henderson, Angela N; Badia-Elder, Nancy E; Stewart, Robert B

2011-03-01

Neuropeptide Y (NPY) is abundant in the mammalian brain and plays a prominent role in behaviors related to negative affect and alcohol. NPY suppresses anxiety-like behavior and alcohol-drinking behaviors in a wide array of rodent models and also affects changes in these behaviors produced by fearful and stressful stimuli. Rats selectively bred for high alcohol preference (P rats) appear to be particularly sensitive to the behavioral effects of NPY. The dual purpose of the present investigation was to determine the effects of intraventricular NPY on (1) the acoustic startle response (ASR) of P rats in a high-anxiety setting and (2) social interaction behavior of P rats. In experiment 1, P rats were either cycled through periods of long-term ethanol access and abstinence or they remained ethanol naive. Rats were injected with one of four NPY doses and tested for ASR before and after footshock stress. NPY suppressed ASR in all P rats regardless of shock condition or drinking history. In experiment 2, rats received intraventricular infusion of one of four NPY doses and were then injected with either ethanol (0.75 g/kg) or saline and tested for social interaction. NPY increased social interaction in P rats even at doses that suppressed locomotor activity, regardless of ethanol dose. Suppression of anxiety-like and arousal behaviors by NPY in the present study confirm a role for NPY in alcohol-related behaviors in alcohol-preferring P rats. Copyright © 2011 Elsevier Inc. All rights reserved.

Latent Inhibition as a Function of US Intensity in a Two-Stage CER Procedure

ERIC Educational Resources Information Center

Rodriguez, Gabriel; Alonso, Gumersinda

2004-01-01

An experiment is reported in which the effect of unconditioned stimulus (US) intensity on latent inhibition (LI) was examined, using a two-stage conditioned emotional response (CER) procedure in rats. A tone was used as the pre-exposed and conditioned stimulus (CS), and a foot-shock of either a low (0.3 mA) or high (0.7 mA) intensity was used as…

Juvenile female rats, but not male rats, show renewal, reinstatement, and spontaneous recovery following extinction of conditioned fear.

PubMed

Park, Chun Hui J; Ganella, Despina E; Kim, Jee Hyun

2017-12-01

Anxiety disorders emerge early, and girls are significantly more likely to develop anxiety compared to boys. However, sex differences in fear during development are poorly understood. Therefore, we investigated juvenile male and female rats in the relapse behaviors following extinction of conditioned fear. In all experiments, 18-d-old rats first received three white-noise-footshock pairings on day 1. On day 2, extinction involved 60 white-noise alone trials. In experiment 1, we examined renewal by testing the rats in either the same or different context as extinction on day 3. Male rats did not show renewal, however, female rats showed renewal. Experiment 2 investigated reinstatement by giving rats either a mild reminder footshock or context exposure on day 3. When tested the next day, male rats did not show reinstatement, whereas female rats showed reinstatement. Experiment 3 investigated spontaneous recovery by testing the rats either 1 or 5 d following extinction. Male rats did not show any spontaneous recovery whereas female rats did. Taken together, fear regulation appear to be different in males versus females from early in development, which may explain why girls are more prone to suffer from anxiety disorders compared to boys. © 2017 Park et al.; Published by Cold Spring Harbor Laboratory Press.

Effect of Dorsal and Ventral Hippocampal Lesions on Contextual Fear Conditioning and Unconditioned Defensive Behavior Induced by Electrical Stimulation of the Dorsal Periaqueductal Gray

PubMed Central

Ballesteros, Carolina Irurita; de Oliveira Galvão, Bruno; Maisonette, Silvia; Landeira-Fernandez, J.

2014-01-01

The dorsal (DH) and ventral (VH) subregions of the hippocampus are involved in contextual fear conditioning. However, it is still unknown whether these two brain areas also play a role in defensive behavior induced by electrical stimulation of the dorsal periaqueductal gray (dPAG). In the present study, rats were implanted with electrodes into the dPAG to determine freezing and escape response thresholds after sham or bilateral electrolytic lesions of the DH or VH. The duration of freezing behavior that outlasted electrical stimulation of the dPAG was also measured. The next day, these animals were subjected to contextual fear conditioning using footshock as an unconditioned stimulus. Electrolytic lesions of the DH and VH impaired contextual fear conditioning. Only VH lesions disrupted conditioned freezing immediately after footshock and increased the thresholds of aversive freezing and escape responses to dPAG electrical stimulation. Neither DH nor VH lesions disrupted post-dPAG stimulation freezing. These results indicate that the VH but not DH plays an important role in aversively defensive behavior induced by dPAG electrical stimulation. Interpretations of these findings should be made with caution because of the fact that a non-fiber-sparing lesion method was employed. PMID:24404134

Inescapable Bodies, Disquieting Perception: Why Adults Seek to Tame and Harness Swift's Excremental Satire in "Gulliver's Travels"

ERIC Educational Resources Information Center

Stallcup, Jackie E.

2004-01-01

Jonathan Swift's "Gulliver's Travels" is a complex, uninhibited, savage satire that concludes with the narrator's descent into madness--hardly a likely candidate for children's reading. In the nearly three hundred years since it was first published, however, "Gulliver's Travels" has become associated with children's literature, though it is…

The Inescapability of Your Past

ERIC Educational Resources Information Center

Pannapacker, W. A.

2007-01-01

The memory of the academy is long, and its scope is national. Disagreements of no real consequence are remembered for entire careers, mutating and multiplying among allies and advisees into a kind of poisonous gas that can sour the air of an entire sector of the profession for generations. The author maintains that there is no other profession,…

JPRS Report, China.

DTIC Science & Technology

1991-11-04

inthe lfinalie aalysis, nonommity economyc eand inescapable burdens, equalitarian distribution ten-ciency are, in the final analysis, noncommodity...conforms to the heavy industrial enterprise national economy onto an orderly course of operation. characteristic of a long production-results cycle , but...into a benign cycle of autonomy political indoctrination, and assure and supervise imple- in operation, responsibility for their own profits and

The Essential Uncertainty of Thinking: Education and Subject in John Dewey

ERIC Educational Resources Information Center

D'Agnese, Vasco

2017-01-01

In this paper, I analyse the Deweyan account of thinking and subject and discuss the educational consequences that follow from such an account. I argue that despite the grouping of thinking and reflective thought that has largely appeared in the interpretation of Deweyan work, Dewey discloses an inescapable uncertainty at the core of human…

Inclusive Education and Social Inequality: An Update of the Question and Some Geographical Considerations

ERIC Educational Resources Information Center

Rambla, Xavier; Ferrer, Ferran; Tarabini, Aina; Verger, Antoni

2008-01-01

The aim of this article is to review the current state of inclusive education in the world and to suggest a few relevant considerations. The first section "Two parallel concerns" retraces the inescapable connections between the educational aspects of inclusive education and more general concerns regarding inequality. The second section "Inclusive…

Ameliorating Impact of Prophylactic Intranasal Oxytocin on Signs of Fear in a Rat Model of Traumatic Stress

PubMed Central

Renicker, Micah D.; Cysewski, Nicholas; Palmer, Samuel; Nakonechnyy, Dmytro; Keef, Andrew; Thomas, Morgan; Magori, Krisztian; Daberkow, David P.

2018-01-01

Oxytocin treatment reduces signs of long-term emotional stress after exposure to trauma; however, little is known about the potential protective effects of oxytocin treatment on behavioral and physiological changes associated with extreme stress exposure. The objective of this study was to investigate oxytocin treatment as a prophylactic measure against rat signs of fear. Two separate experiments were conducted in which the time of intranasal oxytocin administration differed. Intranasal oxytocin (1.0 μg/kg) was administered 5 min after daily exposure to foot shock in Experiment #1 and 1 h before foot shock in Experiment #2. In Experiment #1, possible massage-evoked oxytocin release (5 min after foot shock) was also investigated. In both experiments, a contextual fear conditioning procedure was employed in which stress was induced via inescapable foot shock (3 days, 40 shocks/day, 8 mA/shock) in a fear conditioning chamber. Male Sprague-Dawley rats (n = 24) were divided into four groups (n = 6, per group) for each experiment. Experiment #1 groups: Control Exp#1 (intranasal saline and no foot shock); Stress Exp#1 (intranasal saline 5 min after foot shock); Massage+Stress Exp#1 (massage-like stroking and intranasal saline 5 min after foot shock); Oxytocin+Stress Exp#1 (intranasal oxytocin 5 min after foot shock). Experiment #2 groups: Control Exp#2 (intranasal saline and no foot shock); Stress Exp#2 (intranasal saline 1 h before foot shock); Oxytocin Exp#2 (intranasal oxytocin and no foot shock); Oxytocin+Stress Exp#2 (intranasal oxytocin 1 h before foot shock). One week after fear conditioning (and other treatments), rats were independently evaluated for behavioral signs of fear. Two weeks after conditioning, physiological signs of fear were also assessed (Experiment #1). Relative to controls, rats treated with intranasal oxytocin 5 min after daily foot shock sessions exhibited significantly less immobility upon re-exposure to the shock chamber and attenuated physiological responses related to fear (e.g., elevated heart rate and blood pressure). Furthermore, intranasal oxytocin treatment given 1 h before daily foot shock sessions significantly decreased immobility and defecation upon re-exposure to the shock chamber, relative to controls. The results of this study suggest that prophylactic intranasal oxytocin, administered contemporaneously with aversive stimuli, mitigates behavioral and physiological responses associated with traumatic stress. PMID:29892216

Post-Retrieval Effects of ICV Infusions of Hemicholinium in Mice Are Dependent on the Age of the Original Memory

ERIC Educational Resources Information Center

Boccia, Mariano M.; Blake, Mariano G.; Acosta, Gabriela B.; Baratti, Carlos M.

2006-01-01

CF-1 male mice were trained in an inhibitory avoidance task using a high footshock (1,2 mA, 50 Hz, 1 sec) in order to reduce the influence of extinction on retention performance. At 2, 7, 14, or 30 d after training, the first retention test was performed and hemicholinium (HC-3, 1.0 microgram/mice), a specific inhibitor of high-affinity choline…

A Situationist Lesson for Character Education: Re-Conceptualising the Inculcation of Virtues by Converting Local Virtues to More Global Ones

ERIC Educational Resources Information Center

Chen, Yi-Lin

2015-01-01

Inspired by the debate about character between situationism and virtue ethics, I argue that John Doris's idea, "local trait", offers a fresh insight into contemporary character education. Its positive variant, "local virtue", signals an inescapable relay station of the gradual development of virtue, and serves as a promising…

Dying To Teach: The Educator's Search for Immortality. Advances in Contemporary Educational Thought Series, Volume 18.

ERIC Educational Resources Information Center

Blacker, David J.

This book offers both an intellectual history and a sustained argument for the inescapability of education's immortality agenda. It seeks a Hegelian synthesis of common ideas about living in one's students by giving them something of oneself, developing the image of immortality as an a-temporal, mythic, meaning-making, relational enterprise.…

The Healthy K Club: Promoting a Healthy Start for Kindergartners

ERIC Educational Resources Information Center

Phillips, Chip; Kreiling, Rich

2005-01-01

It's no secret that America's youth are now more out of shape than ever before. Study after study documents the sad saga of childhood obesity. Quick-fix remedies such as "Atkins for Kids" and child-friendly aerobics classes are proliferating. There are fat camps for kids and low-fat "candy." Still, an inescapable fact remains: As a nation, and…

Risk management: Core principles and practices, and their relevance to wildland fire

Treesearch

Matthew P. Thompson; Donald G. MacGregor; Dave Calkin

2016-01-01

The Forest Service, U.S. Department of Agriculture faces a future of increasing complexity and risk, pressing financial issues, and the inescapable possibility of loss of human life. These issues are perhaps most acute for wildland fire management, the highest risk activity in which the Forest Service engages. Risk management (RM) has long been put forth as an...

Invisible Higher Education: Higher Education Institutions from Central and Eastern Europe in Global Rankings

ERIC Educational Resources Information Center

Boyadjieva, Pepka

2017-01-01

The starting point of this study is the argument that not only rankings of higher education institutions (HEIs) are inescapable, but so is the constant criticism to which they are subjected. Against this background, the paper discusses how HEIs from Central and Eastern Europe countries (CEECs) are (non)represented in the main global university…

Massification and the Large Lecture Theatre: From Panic to Excitement

ERIC Educational Resources Information Center

Arvanitakis, James

2014-01-01

In this article I examine the role of the contemporary university in light of the mass increase in class sizes that has occurred on an international scale. While we may look nostalgically back to a time when lectures numbered a few hundred students and tutorials had as few as ten, massification at undergraduate level is an inescapable fact of…

Guided Portfolio Writing as a Scaffold for Reflective Learning in In-Service Contexts: A Case Study

ERIC Educational Resources Information Center

Pires Pereira, Íris Susana; Cristo Parente, Maria Cristina; Vieira da Silva, Cristina

2016-01-01

Language is widely recognized as an inescapable mediating tool for professional learning, and with this text we want to contribute to a better understanding of the particular role that guided writing can play in in-service professional reflective learning. We analysed one pre-school teacher's written portfolio, the construction of which was guided…

Learned helplessness in the rat: effect of response topography in a within-subject design.

PubMed

dos Santos, Cristiano Valerio; Gehm, Tauane; Hunziker, Maria Helena Leite

2011-02-01

Three experiments investigated learned helplessness in rats manipulating response topography within-subject and different intervals between treatment and tests among groups. In Experiment 1, rats previously exposed to inescapable shocks were tested under an escape contingency where either jumping or nose poking was required to terminate shocks; tests were run either 1, 14 or 28 days after treatment. Most rats failed to jump, as expected, but learned to nose poke, regardless of the interval between treatment and tests and order of testing. The same results were observed in male and female rats from a different laboratory (Experiment 2) and despite increased exposure to the escape contingencies using a within-subject design (Experiment 3). Furthermore, no evidence of helplessness reversal was observed, since animals failed to jump even after having learned to nose-poke in a previous test session. These results are not consistent with a learned helplessness hypothesis, which claims that shock (un)controllability is the key variable responsible for the effect. They are nonetheless consistent with the view that inescapable shocks enhance control by irrelevant features of the relationship between the environment and behavior. Copyright © 2010 Elsevier B.V. All rights reserved.

The Inescapable Influence of Noncoding RNAs in Cancer

PubMed Central

Adams, Brian D.; Anastasiadou, Eleni; Esteller, Manel; He, Lin; Slack, Frank J.

2015-01-01

This report summarizes information presented at the 2015 Keystone Symposium on “MicroRNAs and Noncoding RNAs in Cancer”. Nearly two decades after the discovery of the first microRNA (miRNA), the role of noncoding RNAs in developmental processes and the mechanisms behind their dysregulation in cancer has been steadily elucidated. Excitingly, miRNAs have begun making their way into the clinic to combat disease such a hepatitis C, and various forms of cancer. Therefore, at this Keystone meeting novel findings were presented that enhance our view on how small and long noncoding RNAs control developmental timing and oncogenic processes. Recurring themes included, 1) how miRNAs can be differentially processed, degraded, and regulated by ribonucleoprotein (RNP) complexes, 2) how particular miRNA genetic networks that control developmental process, when disrupted, can result in cancer disease, 3) the technologies available to therapeutically deliver RNA to combat diseases such as cancer, and 4) the elucidation of the mechanism of actions for long noncoding RNAs, currently a poorly understood class of noncoding RNA. During the meeting there was an emphasis on presenting unpublished findings, and the breadth of topics covered reflected how inescapable the influence of noncoding RNAs are in development and cancer. PMID:26567137

Food restriction does not relieve PTSD-like anxiety.

PubMed

Hendriksen, Hendrikus; Bink, Diewertje I; Vergoossen, Dana L E; Suzet van Slobbe, E; Olivier, Berend; Oosting, Ronald S

2015-04-15

We used the inescapable foot shock paradigm (IFS) in rats as an animal model for post-traumatic stress disorder (PTSD). Previously we showed that exercise reversed the enhanced stress sensitivity induced by IFS. From literature it is known that food restriction has antidepressant and anxiolytic effects. Since both treatments influence energy expenditure, we questioned whether food restriction reduces anxiety in the IFS model via a comparable, NPY dependent mechanism as enrichment. Anxiety of IFS-exposed animals was measured as change in locomotion and freezing after sudden silence in an open field test, before and after two weeks of food restriction. In addition a forced swim test (FST) was performed. Next, using qPCR, the expression of neuropeptide Y (NPY) and the neuropeptide Y1 receptor (Y1 receptor) was measured in the amygdala. Food restriction increased locomotion and decreased freezing behavior both in control and IFS animals. These effects were small. IFS-induced anxiety was not abolished after two weeks of food restriction. IFS did not influence immobility or the duration of swimming in the FST of animals fed ad libitum. However, food restriction increased swimming and decreased the duration of immobility in IFS-exposed animals. Y1 receptor expression in the basolateral amygdala decreased after both IFS and food restriction. Although food restriction seems to induce a general anxiolytic effect, it does not operate via enhanced Y1 receptor expression and has no effect on the more pathogenic anxiety induced by IFS. Copyright © 2014 Elsevier B.V. All rights reserved.

Adult neurogenesis is reduced in the dorsal hippocampus of rats displaying learned helplessness behavior.

PubMed

Ho, Y C; Wang, S

2010-11-24

Clinical and preclinical studies suggest that the hippocampus has a role in the pathophysiology of major depression. In the learned helplessness (LH) animal model of depression after inescapable shocks (ISs) animals that display LH behavior have reduced cell proliferation in the hippocampus; this effect can be reversed by antidepressant treatment. Using this model, we compared rats that displayed LH behavior and rats that did not show LH behavior (NoLH) after ISs to determine whether reduced hippocampal cell proliferation is associated with the manifestation of LH behavior or is a general response to stress. Specifically, we examined cell proliferation, neurogenesis, and synaptic function in dorsal and ventral hippocampus of LH and NoLH animals and control rats that were not shocked. The LH rats had showed reduced cell proliferation, neurogenesis, and synaptic transmission in the dorsal hippocampus, whereas no changes were seen in the ventral hippocampus. These changes were not observed in the NoLH animals. In a group of NoLH rats that received the same amount of electrical shock as the LH rats to control for the unequal shocks received in these two groups, we observed changes in Ki-67(+) cells associated with acute stress. We conclude that reduced hippocampal cell proliferation and neurogenesis are associated with the manifestation of LH behavior and that the dorsal hippocampus is the most affected area. Copyright © 2010 IBRO. Published by Elsevier Ltd. All rights reserved.

Sonic hedgehog signaling regulates amygdalar neurogenesis and extinction of fear memory.

PubMed

Hung, Hui-Chi; Hsiao, Ya-Hsin; Gean, Po-Wu

2015-10-01

It is now recognized that neurogenesis occurs throughout life predominantly in the subgranular zone (SGZ) of the hippocampus and the subventricular zone (SVZ) of the lateral ventricle. In the present study, we investigated the relationship between neurogenesis in the amygdala and extinction of fear memory. Mice received 15 tone-footshock pairings. Twenty-four hours after training, the mice were given 15 tone-alone trials (extinction training) once per day for 7 days. Two hours before extinction training, the mice were injected intraperitoneally with 5-bromo-3-deoxyuridine (BrdU). BrdU-positive and NeuN-positive cells were analyzed 52 days after the training. A group of mice that received tone-footshock pairings but no extinction training served as controls (FC+No-Ext). The number of BrdU(+)/NeuN(+) cells was significantly higher in the extinction (FC+Ext) than in the FC+No-Ext mice. Proliferation inhibitor methylazoxymethanol acetate (MAM) or DNA synthesis inhibitor cytosine arabinoside (Ara-C) reduced neurogenesis and retarded extinction. Silencing Sonic hedgehog (Shh) gene with short hairpin interfering RNA (shRNA) by means of a retrovirus expression system to knockdown Shh specifically in the mitotic neurons reduced neurogenesis and retarded extinction. By contrast, over-expression of Shh increased neurogenesis and facilitated extinction. These results suggest that amygdala neurogenesis and Shh signaling are involved in the extinction of fear memory. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Increased expression of proenkephalin and prodynorphin mRNAs in the nucleus accumbens of compulsive methamphetamine taking rats.

PubMed

Cadet, Jean Lud; Krasnova, Irina N; Walther, Donna; Brannock, Christie; Ladenheim, Bruce; McCoy, Michael T; Collector, Daniel; Torres, Oscar V; Terry, Ndeah; Jayanthi, Subramaniam

2016-11-14

Addiction is associated with neuroadaptive changes in the brain. In the present paper, we used a model of methamphetamine self-administration during which we used footshocks to divide rats into animals that continue to press a lever to get methamphetamine (shock-resistant) and those that significantly reduce pressing the lever (shock-sensitive) despite the shocks. We trained male Sprague-Dawley rats to self-administer methamphetamine (0.1 mg/kg/infusion) for 9 hours daily for 20 days. Control group self-administered saline. Subsequently, methamphetamine self-administration rats were punished by mild electric footshocks for 10 days with gradual increases in shock intensity. Two hours after stopping behavioral experiments, we euthanized rats and isolated nucleus accumbens (NAc) samples. Affymetrix Array experiments revealed 24 differentially expressed genes between the shock-resistant and shock-sensitive rats, with 15 up- and 9 downregulated transcripts. Ingenuity pathway analysis showed that these transcripts belong to classes of genes involved in nervous system function, behavior, and disorders of the basal ganglia. These genes included prodynorphin (PDYN) and proenkephalin (PENK), among others. Because PDYN and PENK are expressed in dopamine D1- and D2-containing NAc neurons, respectively, these findings suggest that mechanisms, which impact both cell types may play a role in the regulation of compulsive methamphetamine taking by rats.

The Rise and Fall of Human Rights in English Education Policy? Inescapable National Interests and PREVENT

ERIC Educational Resources Information Center

Bowie, Robert A.

2017-01-01

The article interprets changes in human rights education in English school policy on values which have increasingly been framed by PREVENT and a move from international to national expressions of values. It reveals the extent of the impact and nature of this change on human rights education in school policy for the first time. It reports changes…

Translations on Environmental Quality, Number 128

DTIC Science & Technology

1977-01-17

filters. The mechanical filter has a 5 cubic meter filtering material operational volume and is charged with activized BAU charcoal . The cationite...cubic meter activized BAU charcoal . The cationite and anionite filters are charged with strong acid cationite and strong alkali anionite in their N and...Extensive Reprocessing of Slags. In ferrous metallurgy , pig and steel pro- duction is inescapably connected with the production of large amounts of

Examining Parent-Teacher Communication in School Systems through the Use of Emergent Technologies

ERIC Educational Resources Information Center

Trevino, Rodrigo

2012-01-01

Technology has become a part of the fabric of the lives of people, whether it be communicating with a loved one on the other side of the world or paying a utility bill via the Internet. Most people have experienced some level of technology integration into their life. An inescapable rite of passage for most people in developed countries is the…

Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats

DTIC Science & Technology

2009-09-01

startle amplitude. They then received Pavlovian fear conditioning of five pairings of a 3 s light co-terminating with a 500 ms, 0.6mA footshock. Four...Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats PRINCIPAL INVESTIGATOR: Jeffrey B. Rosen, Ph.D...NUMBER Oxytocin and Social Support as Synergistic Inhibitors of Aversive Fear Conditioning and Fear-Potentiated Startle in Male Rats 5b. GRANT

Combat Exclusion: An Equal Protection Analysis

DTIC Science & Technology

1997-04-01

state had an important interest in preventing teenage pregnancy.236 It also found that because "young men and young women are not similarly situated...the opinion that a gender-neutral law would be a greater deterrent to teenage pregnancy because subjecting both parties to the intercourse to...and inescapably identifiable consequences of teenage pregnancy fall on the young female, a legislature acts well within its authority when it elects

Google Is Not the Net: Social Networks Are Surging and Present the Real Service Challenge--And Opportunity--For Libraries

ERIC Educational Resources Information Center

Albanese, Andrew Richard

2006-01-01

This article observes that it's not hard to understand why Google creates such unease among librarians. The profession, however, can't afford to be myopic when it comes to Google. As inescapable as it is, Google is not the Internet. And as the web evolves, new opportunities and challenges loom larger for libraries than who's capturing the bulk of…

Nicotine disrupts safety learning by enhancing fear associated with a safety cue via the dorsal hippocampus.

PubMed

Connor, David A; Kutlu, Munir G; Gould, Thomas J

2017-07-01

Learned safety, a learning process in which a cue becomes associated with the absence of threat, is disrupted in individuals with post-traumatic stress disorder (PTSD). A bi-directional relationship exists between smoking and PTSD and one potential explanation is that nicotine-associated changes in cognition facilitate PTSD emotional dysregulation by disrupting safety associations. Therefore, we investigated whether nicotine would disrupt learned safety by enhancing fear associated with a safety cue. In the present study, C57BL/6 mice were administered acute or chronic nicotine and trained over three days in a differential backward trace conditioning paradigm consisting of five trials of a forward conditioned stimulus (CS)+ (Light) co-terminating with a footshock unconditioned stimulus followed by a backward CS- (Tone) presented 20 s after cessation of the unconditioned stimulus. Summation testing found that acute nicotine disrupted learned safety, but chronic nicotine had no effect. Another group of animals administered acute nicotine showed fear when presented with the backward CS (Light) alone, indicating the formation of a maladaptive fear association with the backward CS. Finally, we investigated the brain regions involved by administering nicotine directly into the dorsal hippocampus, ventral hippocampus, and prelimbic cortex. Infusion of nicotine into the dorsal hippocampus disrupted safety learning.

Requirement of NF-kappa B Activation in Different Mice Brain Areas during Long-Term Memory Consolidation in Two Contextual One-Trial Tasks with Opposing Valences

PubMed Central

Salles, Angeles; Krawczyk, Maria del C.; Blake, Mariano; Romano, Arturo; Boccia, Mariano M.; Freudenthal, Ramiro

2017-01-01

NF-kappa B is a transcription factor whose activation has been shown to be necessary for long-term memory consolidation in several species. NF-kappa B is activated and translocates to the nucleus of cells in a specific temporal window during consolidation. Our work focuses on a one trial learning tasks associated to the inhibitory avoidance (IA) setting. Mice were trained either receiving or not a footshock when entering a dark compartment (aversive vs. appetitive learning). Regardless of training condition (appetitive or aversive), latencies to step-through during testing were significantly different to those measured during training. Additionally, these testing latencies were also different from those of a control group that only received a shock unrelated to context. Moreover, nuclear NF-kappa B DNA-binding activity was augmented in the aversive and the appetitive tasks when compared with control and naïve animals. NF-kappa B inhibition by Sulfasalazine injected either in the Hippocampus, Amygdala or Nucleus accumbens immediately after training was able to impair retention in both training versions. Our results suggest that NF-kappa B is a critical molecular step, in different brain areas on memory consolidation. This was the case for both the IA task and also the modified version of the same task where the footshock was omitted during training. This work aims to further investigate how appetitive and aversive memories are consolidated. PMID:28439227

Opposite effects of fear conditioning and extinction on dendritic spine remodelling.

PubMed

Lai, Cora Sau Wan; Franke, Thomas F; Gan, Wen-Biao

2012-02-19

It is generally believed that fear extinction is a form of new learning that inhibits rather than erases previously acquired fear memories. Although this view has gained much support from behavioural and electrophysiological studies, the hypothesis that extinction causes the partial erasure of fear memories remains viable. Using transcranial two-photon microscopy, we investigated how neural circuits are modified by fear learning and extinction by examining the formation and elimination of postsynaptic dendritic spines of layer-V pyramidal neurons in the mouse frontal association cortex. Here we show that fear conditioning by pairing an auditory cue with a footshock increases the rate of spine elimination. By contrast, fear extinction by repeated presentation of the same auditory cue without a footshock increases the rate of spine formation. The degrees of spine remodelling induced by fear conditioning and extinction strongly correlate with the expression and extinction of conditioned fear responses, respectively. Notably, spine elimination and formation induced by fear conditioning and extinction occur on the same dendritic branches in a cue- and location-specific manner: cue-specific extinction causes formation of dendritic spines within a distance of two micrometres from spines that were eliminated after fear conditioning. Furthermore, reconditioning preferentially induces elimination of dendritic spines that were formed after extinction. Thus, within vastly complex neuronal networks, fear conditioning, extinction and reconditioning lead to opposing changes at the level of individual synapses. These findings also suggest that fear memory traces are partially erased after extinction.

Renewal after the punishment of free operant behavior.

PubMed

Bouton, Mark E; Schepers, Scott T

2015-01-01

Three experiments examined the role of context in punishment learning. In Experiment 1, rats were trained to lever press for food in Context A and then punished for responding in Context B (by presenting response-contingent footshock). Punishment led to complete suppression of the response. However, when responding was tested (in extinction) in Contexts A and B, a strong renewal of responding occurred in Context A. In Experiment 2, renewal also occurred when initial reinforcement occurred in Context A, punishment occurred in Context B, and testing occurred in a new context (Context C). In both experiments, behavioral suppression and renewal were not observed in groups that received noncontingent (yoked) footshocks in Context B. In Experiment 3, 2 responses (lever press and chain pull) were separately reinforced in Contexts A and B and then punished in the opposite context. Although the procedure equated the contexts on their association with reinforcement and punishment, renewal of each response was observed when it was tested in its nonpunished context. The contexts also influenced response choice. Overall, the results suggest that punishment is specific to the context in which it is learned, and establish that its context-specificity does not depend on a simple association between the context and shock. Like extinction, punishment may involve learning to inhibit a specific response in a specific context. Implications for theories of punishment and for understanding the cessation of problematic operant behavior (e.g., drug abuse) are discussed. PsycINFO Database Record (c) 2015 APA, all rights reserved.

Metaphor: An Inescapable Phenomenon in Natural Language Comprehension.

DTIC Science & Technology

1981-05-04

Two Metaphors are Better Than One 11 2.2 Why Metaphor? 12 2.3 How Metaphors Structure Inference Processes 14 2.4 Analogical Mappings in Problem Solving...understanding process by taking advantage o( the reasons why the writer may have chosen the particular metaphor (rather than a different metaphor or a literal...quantifiable feature of the part of the input that undergoes the upward movement. * The Imolicit-Intention Component encodes the reasons why this metaphor

Effect of yohimbine on reinstatement of operant responding in rats is dependent on cue contingency but not food reward history.

PubMed

Chen, Yu-Wei; Fiscella, Kimberly A; Bacharach, Samuel Z; Tanda, Gianluigi; Shaham, Yavin; Calu, Donna J

2015-07-01

Yohimbine is an alpha-2 adrenoceptor antagonist that has been used in numerous studies as a pharmacological stressor in rodents, monkeys and humans. Recently, yohimbine has become the most common stress manipulation in studies on reinstatement of drug and food seeking. However, the wide range of conditions under which yohimbine promotes reward seeking is significantly greater than that of stressors like intermittent footshock. Here, we addressed two fundamental questions regarding yohimbine's effect on reinstatement of reward seeking: (1) whether the drug's effect on operant responding is dependent on previous reward history or cue contingency, and (2) whether yohimbine is aversive or rewarding under conditions typically used in reinstatement studies. We also used in vivo microdialysis to determine yohimbine's effect on dopamine levels in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). We found that the magnitude of yohimbine-induced (0.5, 1.0, 2.0 mg/kg) operant responding during the reinstatement tests was critically dependent on the contingency between lever pressing and discrete tone-light cue delivery but not the previous history with food reward during training. We also found that yohimbine (2 mg/kg) did not cause conditioned place aversion. Finally, we found that yohimbine modestly increased dopamine levels in mPFC but not NAc. Results suggest that yohimbine's effects on operant responding in reinstatement studies are likely independent of the history of contingent self-administration of food or drug rewards and may not be related to the commonly assumed stress-like effects of yohimbine. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Serotonin 2C receptor antagonist improves fear discrimination and subsequent safety signal recall.

PubMed

Foilb, Allison R; Christianson, John P

2016-02-04

The capacity to discriminate between safety and danger is fundamental for survival, but is disrupted in individuals with posttraumatic stress disorder (PTSD). Acute stressors cause a release of serotonin (5-HT) in the forebrain, which is one mechanism for enhanced fear and anxiety; these effects are mediated by the 5-HT2Creceptor. Using a fear discrimination paradigm where a danger signal conditioned stimulus (CS+) co-terminates with a mild footshock and a safety signal (CS-) indicates the absence of shock, we demonstrate that danger/safety discrimination and fear inhibition develop over the course of 4 daily conditioning sessions. Systemic administration of the 5-HT2Creceptor antagonist SB 242084 (0.25 or 1.0mg/kg) prior to conditioning reduced behavioral freezing during conditioning, and improved learning and subsequent inhibition of fear by the safety signal. Discrimination was apparent in the first recall test, and discrimination during training was evident after 3days of conditioning versus 5days in the vehicle treated controls. These results suggest a novel therapeutic use for 5-HT2Creceptor antagonists to improve learning under stressful circumstances. Potential anatomical loci for 5-HT2Creceptor modulation of fear discrimination learning and cognitive performance enhancement are discussed. John P. Christianson and Allison R. Foilb, the authors, verify that animal research was carried out in accordance with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 80-23) and all procedures involving animals were reviewed and approved by the Boston College Animal Care and Use Committee. All efforts were made to limit the number of animals used and their suffering. Copyright © 2015 Elsevier Inc. All rights reserved.

Oral administration of levo-tetrahydropalmatine attenuates reinstatement of extinguished cocaine seeking by cocaine, stress or drug-associated cues in rats.

PubMed

Figueroa-Guzman, Yazmin; Mueller, Christopher; Vranjkovic, Oliver; Wisniewski, Samantha; Yang, Zheng; Li, Shi-Jiang; Bohr, Colin; Graf, Evan N; Baker, David A; Mantsch, John R

2011-07-01

Cocaine addiction is characterized by a persistently heightened susceptibility to drug relapse. For this reason, the identification of medications that prevent drug relapse is a critical goal of drug abuse research. Drug re-exposure, the onset of stressful life events, and exposure to cues previously associated with drug use have been identified as determinants of relapse in humans and have been found to reinstate extinguished cocaine seeking in rats. This study examined the effects of acute oral (gavage) administration of levo-tetrahydropalmatine (l-THP), a tetrahydroprotoberberine isoquinoline with a pharmacological profile that includes antagonism of D1, D2 and D3 dopamine receptors, on the reinstatement of extinguished cocaine seeking by a cocaine challenge (10mg/kg, ip), a stressor (uncontrollable electric footshock [EFS]) or response-contingent exposure to a stimulus (tone and light complex) previously associated with drug delivery in male Sprague-Dawley rats. Extinguished drug seeking was reinstated by ip cocaine, EFS, or response-contingent presentation of drug-associated cues in vehicle-pretreated rats following extinction of iv cocaine self-adminisration. Oral administration of either 3.0 or 10.0mg/kg l-THP 1h prior to reinstatement testing significantly attenuated reinstatement by each of the stimuli. Food-reinforced responding and baseline post-extinction responding were significantly attenuated at the 10.0, but not the 3.0mg/kg, l-THP dose, indicating that the effects of 3mg/kg l-THP on reinstatement were likely independent of non-specific motor impairment. These findings further suggest that l-THP may have utility for the treatment of cocaine addiction. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Differential response to gepirone but not to chlordiazepoxide in malnourished rats subjected to learned helplessness.

PubMed

Camargo, L M M; Nascimento, A B; Almeida, S S

2008-01-01

The learned helplessness (LH) paradigm is characterized by learning deficits resulting from inescapable events. The aims of the present study were to determine if protein-calorie malnutrition (PCM) alters learning deficits induced by LH and if the neurochemical changes induced by malnutrition alter the reactivity to treatment with GABA-ergic and serotonergic drugs during LH. Well-nourished (W) and PCM Wistar rats (61 days old) were exposed or not to inescapable shocks (IS) and treated with gepirone (GEP, 0.0-7.5 mg/kg, intraperitoneally, N = 128) or chlordiazepoxide (0.0-7.5 mg/kg, intraperitoneally, N = 128) 72 h later, 30 min before the test session (30 trials of escape learning). The results showed that rats exposed to IS had higher escape latency than non-exposed rats (12.6 +/- 2.2 vs 4.4 +/- 0.8 s) and that malnutrition increased learning impairment produced by LH. GEP increased the escape latency of W animals exposed or non-exposed to IS, but did not affect the response of PCM animals, while chlordiazepoxide reduced the escape deficit of both W and PCM rats. The data suggest that PCM animals were more sensitive to the impairment produced by LH and that PCM led to neurochemical changes in the serotonergic system, resulting in hyporeactivity to the anxiogenic effects of GEP in the LH paradigm.

Sex-dependent effects of an early life treatment in rats that increases maternal care: vulnerability or resilience?

PubMed Central

Fuentes, Sílvia; Daviu, Núria; Gagliano, Humberto; Garrido, Pedro; Zelena, Dóra; Monasterio, Nela; Armario, Antonio; Nadal, Roser

2014-01-01

Early life stress (ELS) in rodents has profound long-term effects that are partially mediated by changes in maternal care. ELS not only induces “detrimental” effects in adulthood, increasing psychopathology, but also promotes resilience to further stressors. In Long-Evans rats, we evaluated a combination of two procedures as a model of ELS: restriction of bedding during the first post-natal days and exposure to a “substitute” mother. The maternal care of biological and “substitute” mothers was measured. The male and female offspring were evaluated during adulthood in several contexts. Anxiety was measured by the elevated plus-maze (EPM), acoustic startle response (ASR) and forced swim test (FST). In other group of animals, novelty-seeking was measured (activity in an inescapable novel environment, preference for novel environments and exploration of novel objects). Plasmatic ACTH and corticosterone in basal conditions and in response to stress were also measured. Cognitive impulsivity was assessed by a delay-discounting paradigm, and impulsive action, attention and compulsive-like behavior by a five choice serial reaction time task (5CSRTT). ELS decreased pup body weight and increased the care of the biological mother; however, the “substitute” mother did not exhibit overt maltreatment. A mixture of “detrimental” and “beneficial” effects was shown. In the 5CSRTT, attention was impaired in both genders, and in females, ELS increased compulsive-like behavior. Novel object exploration was only increased by ELS in males, but the preference for novel spaces decreased in both genders. Baseline anxiety (EPM and ASR) and recognition memory were not affected. Unexpectedly, ELS decreased the ACTH response to novelty and swim stress and increased active coping in the FST in both genders. Cognitive impulsivity was decreased only in females, but impulsive action was not affected. The enhancement in maternal care may “buffer” the effects of ELS in a context-dependent manner. PMID:24616673

Sex-dependent effects of an early life treatment in rats that increases maternal care: vulnerability or resilience?

PubMed

Fuentes, Sílvia; Daviu, Núria; Gagliano, Humberto; Garrido, Pedro; Zelena, Dóra; Monasterio, Nela; Armario, Antonio; Nadal, Roser

2014-01-01

Early life stress (ELS) in rodents has profound long-term effects that are partially mediated by changes in maternal care. ELS not only induces "detrimental" effects in adulthood, increasing psychopathology, but also promotes resilience to further stressors. In Long-Evans rats, we evaluated a combination of two procedures as a model of ELS: restriction of bedding during the first post-natal days and exposure to a "substitute" mother. The maternal care of biological and "substitute" mothers was measured. The male and female offspring were evaluated during adulthood in several contexts. Anxiety was measured by the elevated plus-maze (EPM), acoustic startle response (ASR) and forced swim test (FST). In other group of animals, novelty-seeking was measured (activity in an inescapable novel environment, preference for novel environments and exploration of novel objects). Plasmatic ACTH and corticosterone in basal conditions and in response to stress were also measured. Cognitive impulsivity was assessed by a delay-discounting paradigm, and impulsive action, attention and compulsive-like behavior by a five choice serial reaction time task (5CSRTT). ELS decreased pup body weight and increased the care of the biological mother; however, the "substitute" mother did not exhibit overt maltreatment. A mixture of "detrimental" and "beneficial" effects was shown. In the 5CSRTT, attention was impaired in both genders, and in females, ELS increased compulsive-like behavior. Novel object exploration was only increased by ELS in males, but the preference for novel spaces decreased in both genders. Baseline anxiety (EPM and ASR) and recognition memory were not affected. Unexpectedly, ELS decreased the ACTH response to novelty and swim stress and increased active coping in the FST in both genders. Cognitive impulsivity was decreased only in females, but impulsive action was not affected. The enhancement in maternal care may "buffer" the effects of ELS in a context-dependent manner.

Behavioural analysis of four mouse strains in an anxiety test battery.

PubMed

van Gaalen, M M; Steckler, T

2000-10-01

Differences in locomotor activity, exploratory activity and anxiety-like behaviour of C57BL/6ChR,C57BL/6J, Swiss Webster/J and A/J strain were investigated in an anxiety battery. The battery consisted of paradigms studying spontaneous behaviour after a mild stressor, tasks of innate anxiety (light-dark box, elevated plus maze, novel object exploration), response to a conflict situation (Vogel conflict), conditioned fear and response to inescapable swim stress. Locomotor activity was studied in an open field and compared with locomotion in the other tests. Exploratory behaviour was studied in a 16-hole board task. The data confirm previous studies suggesting that A/J mice are a relatively anxious strain. Also, the data indicated that locomotor activity was independent of the paradigm employed, while the rank order of strain-dependent effects on anxiety-related behaviour changed as a function of the task under study. Our data provide further support for the notion that choice of strain is essential in studies of anxiety-related behaviour. Influence of strain should be considered in pharmacological and lesion studies, as well as in studies with mutant mice. In addition, the data indicate that different anxiety paradigms tax different aspects of anxiety, suggesting that a battery of different tests should be used in studies of anxiety-related behaviour.

Learned helplessness: validity and reliability of depressive-like states in mice.

PubMed

Chourbaji, S; Zacher, C; Sanchis-Segura, C; Dormann, C; Vollmayr, B; Gass, P

2005-12-01

The learned helplessness paradigm is a depression model in which animals are exposed to unpredictable and uncontrollable stress, e.g. electroshocks, and subsequently develop coping deficits for aversive but escapable situations (J.B. Overmier, M.E. Seligman, Effects of inescapable shock upon subsequent escape and avoidance responding, J. Comp. Physiol. Psychol. 63 (1967) 28-33 ). It represents a model with good similarity to the symptoms of depression, construct, and predictive validity in rats. Despite an increased need to investigate emotional, in particular depression-like behaviors in transgenic mice, so far only a few studies have been published using the learned helplessness paradigm. One reason may be the fact that-in contrast to rats (B. Vollmayr, F.A. Henn, Learned helplessness in the rat: improvements in validity and reliability, Brain Res. Brain Res. Protoc. 8 (2001) 1-7)--there is no generally accepted learned helplessness protocol available for mice. This prompted us to develop a reliable helplessness procedure in C57BL/6N mice, to exclude possible artifacts, and to establish a protocol, which yields a consistent fraction of helpless mice following the shock exposure. Furthermore, we validated this protocol pharmacologically using the tricyclic antidepressant imipramine. Here, we present a mouse model with good face and predictive validity that can be used for transgenic, behavioral, and pharmacological studies.

Emotional response in dopamine D2L receptor-deficient mice

PubMed Central

Hranilovic, Dubravka; Bucan, Maja; Wang, Yanyan

2008-01-01

The dopamine D2 receptor (D2R) system has been implicated in emotional processing which is often impaired in neuropsychiatric disorders. The long (D2L) and the short (D2S) isoforms of D2R are generated by alternative splicing of the same gene. To study differential roles of the two D2R isoforms, D2L-deficient mice (D2L−/−) expressing functional D2S were previously generated. In this study the contribution of D2L isoform to emotional response was investigated by examining behaviors that reflect emotionality (exploratory behavior, anxiety-like behavior and learned helplessness) in D2L−/− and (wild-type) WT mice. While the thigmotactic, locomotor and general components of anxiety in zero maze did not differ among the genotypes, D2L−/− mice displayed significantly lower level of exploration in a hole board and zero maze, and significantly higher increase in latency to escape from a foot shock after the learned helplessness training, compared with WT mice. These results suggest that D2L may play a more prominent role than D2S in mediating emotional response, such as behavioral reactions to novelty and inescapable stress. Our findings contribute to a better understanding of the molecular and cellular mechanisms underlying emotional responses. PMID:18835570

Dopamine D1 receptor-dependent regulation of extracellular citrulline level in the rat nucleus accumbens during conditioned fear response.

PubMed

Saulskaya, Natalia B; Fofonova, Nellia V; Sudorghina, Polina V; Saveliev, Sergey A

2008-08-01

Nucleus accumbens (N.Acc) contains a subclass of nitric oxide (NO)-generating interneurons that are presumably regulated by the dopamine input. Receptor mechanisms underlying dopamine-NO interaction in the N.Acc are poorly understood. In the current study, we used in vivo microdialysis combined with high-performance liquid chromatography to examine participation of dopamine D1 receptors in regulation of extracellular levels of citrulline (an NO co-product) in the medial N.Acc of Sprague-Dawley rats during both pharmacological challenge and a conditioned fear response. The intraaccumbal infusion of the D1 receptor agonist SKF-38393 (100-500 microM) increased dose-dependently the local dialysate citrulline levels. The SKF-38393-induced increase in extracellular citrulline was prevented by intraaccumbal infusions of 500 microM 7-nitroindazole, a neuronal NO synthase inhibitor. In behavioral microdialysis experiment, the accumbal levels of extracellular citrulline markedly increased in rats given a mild footshock paired with tone. The presentation of the tone previously paired with footshock (the conditioned fear response) produced a "conditioned" rise of extracellular citrulline levels in the N.Acc which was attenuated by intraaccumbal infusion of 100 microM SCH-23390, a dopamine D1 receptor antagonist, and prevented by intraaccumbal infusion of 500 microM 7-nitroindazole. The results suggest that in the N.Acc, the dopamine D1 receptors might regulate the neuronal NO synthase activity; this dopamine-dependent mechanism seems to participate in activation of the neuronal NO synthase and probably NO formation in this brain area during the conditioned fear response.

Spontaneous Recovery But Not Reinstatement of the Extinguished Conditioned Eyeblink Response in the Rat

PubMed Central

Thanellou, Alexandra; Green, John T.

2011-01-01

Reinstatement, the return of an extinguished conditioned response (CR) after reexposure to the unconditioned stimulus (US), and spontaneous recovery, the return of an extinguished CR with the passage of time, are two of four well-established phenomena which demonstrate that extinction does not erase the conditioned stimulus (CS)-US association. However, reinstatement of extinguished eyeblink CRs has never been demonstrated and spontaneous recovery of extinguished eyeblink CRs has not been systematically demonstrated in rodent eyeblink conditioning. In Experiment 1, US reexposure was administered 24 hours prior to a reinstatement test. In Experiment 2, US reexposure was administered 5 min prior to a reinstatement test. In Experiment 3, a long, discrete cue (a houselight), present in all phases of training and testing, served as a context within which each trial occurred to maximize context processing, which in other preparations has been shown to be required for reinstatement. In Experiment 4, an additional group was included that received footshock exposure, rather than US reexposure, between extinction and test, and contextual freezing was measured prior to test. Spontaneous recovery was robust in Experiments 3 and 4. In Experiment 4, context freezing was strong in a group given footshock exposure but not in a group given eyeshock US reexposure. There was no reinstatement observed in any experiment. With stimulus conditions that produce eyeblink conditioning and research designs that produce reinstatement in other forms of classical conditioning, we observed spontaneous recovery but not reinstatement of extinguished eyeblink CRs. This suggests that reinstatement, but not spontaneous recovery, is a preparation- or substrate-dependent phenomenon. PMID:21517145

A Transient Dopamine Signal Represents Avoidance Value and Causally Influences the Demand to Avoid

PubMed Central

Pultorak, Katherine J.; Schelp, Scott A.; Isaacs, Dominic P.; Krzystyniak, Gregory

2018-01-01

Abstract While an extensive literature supports the notion that mesocorticolimbic dopamine plays a role in negative reinforcement, recent evidence suggests that dopamine exclusively encodes the value of positive reinforcement. In the present study, we employed a behavioral economics approach to investigate whether dopamine plays a role in the valuation of negative reinforcement. Using rats as subjects, we first applied fast-scan cyclic voltammetry (FSCV) to determine that dopamine concentration decreases with the number of lever presses required to avoid electrical footshock (i.e., the economic price of avoidance). Analysis of the rate of decay of avoidance demand curves, which depict an inverse relationship between avoidance and increasing price, allows for inference of the worth an animal places on avoidance outcomes. Rapidly decaying demand curves indicate increased price sensitivity, or low worth placed on avoidance outcomes, while slow rates of decay indicate reduced price sensitivity, or greater worth placed on avoidance outcomes. We therefore used optogenetics to assess how inducing dopamine release causally modifies the demand to avoid electrical footshock in an economic setting. Increasing release at an avoidance predictive cue made animals more sensitive to price, consistent with a negative reward prediction error (i.e., the animal perceives they received a worse outcome than expected). Increasing release at avoidance made animals less sensitive to price, consistent with a positive reward prediction error (i.e., the animal perceives they received a better outcome than expected). These data demonstrate that transient dopamine release events represent the value of avoidance outcomes and can predictably modify the demand to avoid. PMID:29766047

Hemodynamic responses in amygdala and hippocampus distinguish between aversive and neutral cues during Pavlovian fear conditioning in behaving rats

PubMed Central

McHugh, Stephen B; Marques-Smith, Andre; Li, Jennifer; Rawlins, J N P; Lowry, John; Conway, Michael; Gilmour, Gary; Tricklebank, Mark; Bannerman, David M

2013-01-01

Lesion and electrophysiological studies in rodents have identified the amygdala and hippocampus (HPC) as key structures for Pavlovian fear conditioning, but human functional neuroimaging studies have not consistently found activation of these structures. This could be because hemodynamic responses cannot detect the sparse neuronal activity proposed to underlie conditioned fear. Alternatively, differences in experimental design or fear levels could account for the discrepant findings between rodents and humans. To help distinguish between these alternatives, we used tissue oxygen amperometry to record hemodynamic responses from the basolateral amygdala (BLA), dorsal HPC (dHPC) and ventral HPC (vHPC) in freely-moving rats during the acquisition and extinction of conditioned fear. To enable specific comparison with human studies we used a discriminative paradigm, with one auditory cue [conditioned stimulus (CS)+] that was always followed by footshock, and another auditory cue (CS−) that was never followed by footshock. BLA tissue oxygen signals were significantly higher during CS+ than CS− trials during training and early extinction. In contrast, they were lower during CS+ than CS− trials by the end of extinction. dHPC and vHPC tissue oxygen signals were significantly lower during CS+ than CS− trials throughout extinction. Thus, hemodynamic signals in the amygdala and HPC can detect the different patterns of neuronal activity evoked by threatening vs. neutral stimuli during fear conditioning. Discrepant neuroimaging findings may be due to differences in experimental design and/or fear levels evoked in participants. Our methodology offers a way to improve translation between rodent models and human neuroimaging. PMID:23173719

The Role of the Lateral Habenula in Punishment

PubMed Central

Jean-Richard Dit Bressel, Philip; McNally, Gavan P.

2014-01-01

The lateral habenula (LHb) is a small epithalamic structure that projects via the fasciculus retroflexus to the midbrain. The LHb is known to modulate midbrain dopamine (DA) neurons, including inhibition of ventral tegmental area (VTA) neurons via glutamatergic excitation of the GABAergic rostromedial tegmental nucleus (RMTg). A variety of lines of evidence show activity in LHb and the LHb-RMTg pathway is correlated with, and is sufficient to support, punishment learning. However, it is not immediately clear whether LHb is necessary for punishment. Here we used a within-subjects punishment task to assess the role of LHb in the acquisition and expression of punishment as well as in aversive choice. Rats that pressed two individually presented levers for pellet rewards rapidly suppressed responding to one lever if it also caused footshock deliveries (punished lever) but continued pressing a second lever that did not cause footshock (unpunished lever). Infusions of an AMPA receptor antagonist (NBQX) into LHb had no effect on the acquisition or expression of this punishment, or on aversive choice, but did increase locomotion. Infusion of the sodium channel blocker bupivacaine likewise had no effect on expression of punishment. However, infusion of the calcium channel blocker mibefradil did affect expression of punishment by significantly decreasing the latency with which rats responded on the punished lever and significantly increasing unpunished lever-pressing. Taken together, these findings indicate that the LHb plays a limited role in punishment, influencing only latency to respond. This role is linked to calcium channel permeability and not AMPA receptor or sodium channel permeability. PMID:25365401

Learning Induces Sonic Hedgehog Signaling in the Amygdala which Promotes Neurogenesis and Long-Term Memory Formation

PubMed Central

Hung, Hui-Chi; Hsiao, Ya-Hsin

2015-01-01

Background: It is known that neurogenesis occurs throughout the life mostly in the subgranular zone of the hippocampus and the subventricular zone of the lateral ventricle. We investigated whether neurogenesis occurred in the amygdala and its function in fear memory formation. Methods: For detection of newborn neurons, mice were injected intraperitoneally with 5-bromo-2’-deoxyuridine (BrdU) 2h before receiving 15 tone–footshock pairings, and newborn neurons were analyzed 14 and 42 days after training. To determine the relationship between neurogenesis and memory formation, mice were given a proliferation inhibitor methylazoxymethanol (MAM) or a DNA synthesis inhibitor cytosine arabinoside (Ara-C). To test whether sonic hedgehog (Shh) signaling was required for neurogenesis, Shh-small hairpin–interfering RNA (shRNA) was inserted into a retroviral vector (Retro-Shh-shRNA). Results: The number of BrdU+/Neuronal nuclei (NeuN)+ cells was significantly higher in the conditioned mice, suggesting that association of tone with footshock induced neurogenesis. MAM and Ara-C markedly reduced neurogenesis and impaired fear memory formation. Shh, its receptor patched 1 (Ptc1), and transcription factor Gli1 protein levels increased at 1 day and returned to baseline at 7 days after fear conditioning. Retro-Shh-shRNA, which knocked down Shh specifically in the mitotic neurons, reduced the number of BrdU+/NeuN+ cells and decreased freezing responses. Conclusions: These results suggest that fear learning induces Shh signaling activation in the amygdala, which promotes neurogenesis and fear memory formation. PMID:25522410

A critical role of nucleus accumbens dopamine D1-family receptors in renewal of alcohol seeking after punishment-imposed abstinence.

PubMed

Marchant, Nathan J; Kaganovsky, Konstantin

2015-06-01

In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, in which extinction training in context (B) suppresses alcohol seeking, and renewal of this seeking occurs when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence in response to the negative consequences of excessive use. We recently developed a procedure to study renewal in laboratory rats after abstinence imposed by negative consequences (footshock punishment). The mechanisms of renewal of punished alcohol seeking are largely unknown. Here, we used the D1-family receptor antagonist SCH 23390 to examine the role of nucleus accumbens (NAc) shell and core dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We trained alcohol-preferring "P rats" to self-administer 20% alcohol in Context A and subsequently suppressed alcohol taking via response-contingent footshock punishment in Context B. We tested the effects of systemic, NAc shell, or NAc core injections of SCH 23390 on renewal of alcohol seeking after punishment-imposed abstinence. We found that both systemic and NAc shell and core injections of SCH 23390 decreased renewal of punished alcohol seeking. Our results demonstrate a critical role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We discuss these results in reference to the brain mechanisms of renewal of alcohol seeking after extinction versus punishment. (c) 2015 APA, all rights reserved).

The role of the basolateral amygdala in punishment

PubMed Central

Jean-Richard-Dit-Bressel, Philip

2015-01-01

Aversive stimuli not only support fear conditioning to their environmental antecedents, they also punish behaviors that cause their occurrence. The amygdala, especially the basolateral nucleus (BLA), has been critically implicated in Pavlovian fear learning but its role in punishment remains poorly understood. Here, we used a within-subjects punishment task to assess the role of the BLA in the acquisition and expression of punishment as well as aversive choice. Rats that pressed two individually presented levers for pellet rewards rapidly suppressed responding to one lever if it also caused footshock deliveries (punished lever) but continued pressing a second lever that did not cause footshock (unpunished lever). Infusions of GABA agonists baclofen and muscimol (BM) into the BLA significantly impaired the acquisition of this suppression. BLA inactivations using BM also reduced the expression of well-trained punishment. There was anatomical segregation within the BLA so that caudal, not rostral, BLA was implicated in punishment. However, when presented with punished and unpunished levers simultaneously in a choice test without deliveries of shock punisher, rats expressed a preference for unpunished over the punished lever and BLA inactivations had no effect on this preference. Taken together, these findings indicate that the BLA is important for both the acquisition and expression of punishment but not for aversive choice. This role appears to be linked to neurons in the caudal BLA, rather than rostral BLA, although the circuitry that contributes to this functional segregation is currently unknown, and is most parsimoniously interpreted as a role for caudal BLA in determining the aversive value of the shock punisher. PMID:25593299

The role of the lateral habenula in punishment.

PubMed

Jean-Richard Dit Bressel, Philip; McNally, Gavan P

2014-01-01

The lateral habenula (LHb) is a small epithalamic structure that projects via the fasciculus retroflexus to the midbrain. The LHb is known to modulate midbrain dopamine (DA) neurons, including inhibition of ventral tegmental area (VTA) neurons via glutamatergic excitation of the GABAergic rostromedial tegmental nucleus (RMTg). A variety of lines of evidence show activity in LHb and the LHb-RMTg pathway is correlated with, and is sufficient to support, punishment learning. However, it is not immediately clear whether LHb is necessary for punishment. Here we used a within-subjects punishment task to assess the role of LHb in the acquisition and expression of punishment as well as in aversive choice. Rats that pressed two individually presented levers for pellet rewards rapidly suppressed responding to one lever if it also caused footshock deliveries (punished lever) but continued pressing a second lever that did not cause footshock (unpunished lever). Infusions of an AMPA receptor antagonist (NBQX) into LHb had no effect on the acquisition or expression of this punishment, or on aversive choice, but did increase locomotion. Infusion of the sodium channel blocker bupivacaine likewise had no effect on expression of punishment. However, infusion of the calcium channel blocker mibefradil did affect expression of punishment by significantly decreasing the latency with which rats responded on the punished lever and significantly increasing unpunished lever-pressing. Taken together, these findings indicate that the LHb plays a limited role in punishment, influencing only latency to respond. This role is linked to calcium channel permeability and not AMPA receptor or sodium channel permeability.

Enhanced noradrenergic activity in the amygdala contributes to hyperarousal in an animal model of PTSD.

PubMed

Ronzoni, Giacomo; Del Arco, Alberto; Mora, Francisco; Segovia, Gregorio

2016-08-01

Increased activity of the noradrenergic system in the amygdala has been suggested to contribute to the hyperarousal symptoms associated with post-traumatic stress disorder (PTSD). However, only two studies have examined the content of noradrenaline or its metabolites in the amygdala of rats previously exposed to traumatic stress showing inconsistent results. The aim of this study was to investigate the effects of an inescapable foot shock (IFS) procedure (1) on reactivity to novelty in an open-field (as an index of hyperarousal), and (2) on noradrenaline release in the amygdala during an acute stress. To test the role of noradrenaline in amygdala, we also investigated the effects of microinjections of propranolol, a β-adrenoreceptor antagonist, and clenbuterol, a β-adrenoreceptor agonist, into the amygdala of IFS and control animals. Finally, we evaluated the expression of mRNA levels of β-adrenoreceptors (β1 and β2) in the amygdala, the hippocampus and the prefrontal cortex. Male Wistar rats (3 months) were stereotaxically implanted with bilateral guide cannulae. After recovering from surgery, animals were exposed to IFS (10 shocks, 0.86mA, and 6s per shock) and seven days later either microdialysis or microinjections were performed in amygdala. Animals exposed to IFS showed a reduced locomotion compared to non-shocked animals during the first 5min in the open-field. In the amygdala, IFS animals showed an enhanced increase of noradrenaline induced by stress compared to control animals. Bilateral microinjections of propranolol (0.5μg) into the amygdala one hour before testing in the open-field normalized the decreased locomotion observed in IFS animals. On the other hand, bilateral microinjections of clenbuterol (30ng) into the amygdala of control animals did not change the exploratory activity induced by novelty in the open field. IFS modified the mRNA expression of β1 and β2 adrenoreceptors in the prefrontal cortex and the hippocampus. These results suggest that an increased noradrenergic activity in the amygdala contributes to the expression of hyperarousal in an animal model of PTSD. Copyright © 2016 Elsevier Ltd. All rights reserved.

A robust animal model of state anxiety: fear-potentiated behaviour in the elevated plus-maze.

PubMed

Korte, S Mechiel; De Boer, Sietse F

2003-02-28

Fear (i.e., decreased percentage time spent on open-arm exploration) in the elevated plus-maze can be potentiated by prior inescapable stressor exposure, but not by escapable stress. The use of fear-potentiated plus-maze behaviour has several advantages as compared to more traditional animal models of anxiety. (a) In contrast to the traditional (spontaneous) elevated plus-maze, which measures innate fear of open spaces, fear-potentiated plus-maze behaviour reflects an enhanced anxiety state (allostatic state). This "state anxiety" can be defined as an unpleasant emotional arousal in face of threatening demands or dangers. A cognitive appraisal of threat is a prerequisite for the experience of this type of emotion. (b) Depending on the stressor used (e.g., fear of shock, predator odour, swim stress, restraint, social defeat, predator stress (cat)), this enhanced anxiety state can last from 90 min to 3 weeks. Stress effects are more severe when rats are isolated in comparison to group housing. (c) Drugs can be administered in the absence of the original stressor and after stressor exposure. As a consequence, retrieval mechanisms are not affected by drug treatment. (d) Fear-potentiated plus-maze behaviour is sensitive to proven/putative anxiolytics and anxiogenics which act via mechanisms related to the benzodiazepine-gamma-aminobutyric acid receptor, but it is also sensitive to corticotropin-releasing receptor antagonists and glucocorticoid receptor antagonists and serotonin receptor agonists/antagonists complex (high predictive validity). (e) Fear-potentiated plus-maze behaviour is very robust, and experiments can easily be replicated in other labs. (f) Fear-potentiated plus-maze behaviour can be measured both in males and females. (g) Neural mechanisms involved in contextual fear conditioning, fear potentiation and state anxiety can be studied.Thus, fear-potentiated plus-maze behaviour may be a valuable measure in the understanding of neural mechanisms involved in the development of anxiety disorders and in the search for novel anxiolytics. Finally, the involvement of corticotropin-releasing factor and corticosteroid-corticotropin-releasing factor interactions in the production of fear-potentiated plus-maze behaviour are discussed.

Influence of Pre-reproductive Maternal Enrichment on Coping Response to Stress and Expression of c-Fos and Glucocorticoid Receptors in Adolescent Offspring

PubMed Central

Cutuli, Debora; Berretta, Erica; Pasqualini, Greta; De Bartolo, Paola; Caporali, Paola; Laricchiuta, Daniela; Sampedro-Piquero, Patricia; Gelfo, Francesca; Pesoli, Matteo; Foti, Francesca; Begega, Azucena; Petrosini, Laura

2017-01-01

Environmental enrichment (EE) is an experimental setting broadly used for investigating the effects of complex social, cognitive, and sensorimotor stimulations on brain structure and function. Recent studies point out that parental EE experience, even occurring in the pre-reproductive phase, affects neural development and behavioral trajectories of the offspring. In the present study we investigated the influences of pre-reproductive EE of female rats on maternal behavior and adolescent male offspring's coping response to an inescapable stressful situation after chronic social isolation. For this purpose female Wistar rats were housed from weaning to breeding age in enriched or standard environments. Subsequently, all females were mated and housed in standard conditions until offspring weaning. On the first post partum day (ppd 1), mother-pup interactions in undisturbed conditions were recorded. Further, after weaning the male pups were reared for 2 weeks under social isolation or in standard conditions, and then submitted or not to a single-session Forced Swim Test (FST). Offspring's neuronal activation and plastic changes were identified by immunohistochemistry for c-Fos and glucocorticoid receptors (GRs), and assessed by using stereological analysis. The biochemical correlates were measured in the hippocampus, amygdala and cingulate cortex, structures involved in hypothalamic-pituitary-adrenocortical axis regulation. Enriched dams exhibited increased Crouching levels in comparison to standard reared dams. In the offspring of both kinds of dams, social isolation reduced body weight, decreased Immobility, and increased Swimming during FST. Moreover, isolated offspring of enriched dams exhibited higher levels of Climbing in comparison to controls. Interestingly, in the amygdala of both isolated and control offspring of enriched dams we found a lower number of c-Fos immunopositive cells in response to FST and a higher number of GRs in comparison to the offspring of standard dams. These results highlight the profound influence of a stressful condition, such as the social isolation, on the brain of adolescent rats, and underline intergenerational effects of maternal experiences in regulating the offspring response to stress. PMID:28536510

Uses of duckweed

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hillman, W.S.; Culley, D.D. Jr.

1978-07-01

Among the various approaches to improving present technologies for waste-water treatment, several involve the use of plants, which can remove pollutants and provide materials useful as animal feeds or energy sources. Various aquatic plants are being proposed in such approaches, and the duckweeds in particular, an essentially unique group of higher aquatic plants, might be especially advantageous in such systems. Although this article focuses on only this one group of plants, it can nevertheless provide an introduction to issues that are both scientifically challenging and existentially inescapable.

Gravitation: Foundations and Frontiers

NASA Astrophysics Data System (ADS)

Padmanabhan, T.

2010-01-01

1. Special relativity; 2. Scalar and electromagnetic fields in special relativity; 3. Gravity and spacetime geometry: the inescapable connection; 4. Metric tensor, geodesics and covariant derivative; 5. Curvature of spacetime; 6. Einstein's field equations and gravitational dynamics; 7. Spherically symmetric geometry; 8. Black holes; 9. Gravitational waves; 10. Relativistic cosmology; 11. Differential forms and exterior calculus; 12. Hamiltonian structure of general relativity; 13. Evolution of cosmological perturbations; 14. Quantum field theory in curved spacetime; 15. Gravity in higher and lower dimensions; 16. Gravity as an emergent phenomenon; Notes; Index.

An anxiogenic benzodiazepine receptor ligand induces learned helplessness.

PubMed

Drugan, R C; Maier, S F; Skolnick, P; Paul, S M; Crawley, J N

1985-07-31

Rats treated with the anxiogenic beta-carboline, N-methyl-beta-carboline-3-carboxamide (FG-7142), failed to acquire an escape response 24 h after treatment. Administration of FG-7142 resulted in a behavioral effect equivalent to a session of inescapable tailshock in this paradigm of learned helplessness. Pretreatment of rats with the selective benzodiazepine receptor antagonist Ro15-1788 blocked the development of learned helplessness elicited by FG-7142. These findings suggest that 'anxiety' may be a major factor in the development of learned helplessness.

Tandospirone, a 5-HT1A partial agonist, ameliorates aberrant lactate production in the prefrontal cortex of rats exposed to blockade of N-methy-D-aspartate receptors; Toward the therapeutics of cognitive impairment of schizophrenia.

PubMed

Uehara, Takashi; Matsuoka, Tadasu; Sumiyoshi, Tomiki

2014-01-01

Augmentation therapy with serotonin-1A (5-HT1A) receptor partial agonists has been suggested to improve cognitive impairment in patients with schizophrenia. Decreased activity of prefrontal cortex may provide a basis for cognitive deficits of the disease. Lactate plays a significant role in the supply of energy to the brain, and glutamatergic neurotransmission contributes to lactate production. The purposes of this study were to examine the effect of repeated administration (once a daily for 4 days) of tandospirone (0.05 or 5 mg/kg) on brain energy metabolism, as represented by extracellular lactate concentration (eLAC) in the medial prefrontal cortex (mPFC) of a rat model of schizophrenia. Four-day treatment with MK-801, an NMDA-R antagonist, prolonged eLAC elevation induced by foot-shock stress (FS). Co-administration with the high-dose tandospirone suppressed prolonged FS-induced eLAC elevation in rats receiving MK-801, whereas tandospirone by itself did not affected eLAC increment. These results suggest that stimulation of 5-HT1A receptors ameliorates abnormalities of energy metabolism in the mPFC due to blockade of NMDA receptors. These findings provide a possible mechanism, based on brain energy metabolism, by which 5-HT1A agonism improve cognitive impairment of schizophrenia and related disorders.

Neurobiology of anxiety disorders and implications for treatment.

PubMed

Garakani, Amir; Mathew, Sanjay J; Charney, Dennis S

2006-11-01

The neurobiology of the anxiety disorders, which include panic disorder, post-traumatic stress disorder (PTSD), and specific phobias, among others, has been clarified by advances in the field of classical or Pavlovian conditioning, and in our understanding of basic mechanisms of memory and learning. Fear conditioning occurs when a neutral conditioned stimulus (such as a tone) is paired with an aversive, or unconditioned stimulus (such as a footshock), and then in the absence of the unconditioned stimulus, causes a conditioned fear response. Preclinical studies have shown that the amygdala plays a key role in fear circuitry, and that abnormalities in amygdala pathways can affect the acquisition and expression of fear conditioning. Drugs such as glutamate N-methyl-D-aspartate (NMDA) antagonists, and blockers of voltage-gated calcium channels, in the amygdala, may block these effects. There is also preliminary evidence for the use of centrally acting beta-adrenergic antagonists, like propranolol, to inhibit consolidation of traumatic memories in PTSD. Finally, fear extinction, which entails new learning of fear inhibition, is central to the mechanism of effective anti-anxiety treatments. Several pharmacological manipulations, such as D-cycloserine, a partial NMDA agonist, have been found to facilitate extinction. Combining these medication approaches with psychotherapies that promote extinction, such as cognitive behavioral therapy (CBT), may offer patients with anxiety disorders a rapid and robust treatment with good durability of effect.

Behavioural studies on BR-16A (Mentat), a herbal psychotropic formulation.

PubMed

Bhattacharya, S K

1994-01-01

The anxiolytic, antidepressant and anti-aggression activities of Mentat were investigated in rats and mice, using standard behavioural paradigms. Single acute administration of Mentat, up to a dose of 200 mg/kg, ip, induced insignificant behavioural effects on the test parameters. However, when Mentat was administered subchronically for 7 days at two dose levels (50 and 100 mg/kg, intragastrically), the drug induced dose-related behavioural effects. Thus, it exhibited anxiolytic effect, as assessed by paradigms like the open-field test and elevated plus-maze tests in mice, and the social interaction test and Vogel's drink conflict test in rats. Furthermore, Mentat attenuated the increase in rat brain tribulin, a putative endocoid marker of anxiety, levels induced by pentylenetetrazole (20 mg/kg, sc), a known anxiogenic agent. Mentat attenuated footshock-induced aggressive behaviour in paired rats but failed to affect clonidine-induced automutilative behaviour. The observed aggression-attenuating effect of Mentat may be related to its anxiolytic activity. Mentat exhibited significant antidepressant effect as indicated by its ability to reduce swim stress induced immobility in Porsolt's behavioural despair test, reduction in escape failures concomitant with an increase in avoidance response in the learned helplessness test, and attenuation of muricidal behaviour, in rats. The observed behavioural effects are consonant with the reported clinical utility of Mentat as an adjuvant in the treatment of anxiety and depression.

Maternal inexperience as a risk factor of innate fear and PTSD-like symptoms in mice.

PubMed

Siegmund, Anja; Dahlhoff, Maik; Habersetzer, Ursula; Mederer, Anna; Wolf, Eckhard; Holsboer, Florian; Wotjak, Carsten T

2009-09-01

In laboratory rats and mice, differences in maternal care during the first week of life have been shown to exert long-lasting consequences on cognitive functioning and stress processing of the offspring. Such epigenetic programming is also assumed to play an important role in the transgenerational transmission of PTSD in humans. Here we studied whether even subtle within-subject differences in maternal care - caused by increasing mothering experience from the first to the second litter - can determine subsequent vulnerability for PTSD-like behaviour. To assess the influence of maternal experience on different components of fear, we analysed the adult male offspring of two subsequent litters (offspring 1, 2) from the same parental C57BL/6NCrl (B6N) and C57BL/6JOla (B6JOla) mice for (i) their innate anxiety behaviour on a modified hole board and (ii) their vulnerability to develop long-lasting PTSD-like fear symptoms ("hyperarousal", contextually conditioned fear) following perception of an inescapable foot shock. Increasing maternal experience reduced the animals' innate fear on the modified hole board (more exploration, less inhibition), the acute stress reaction to the shock and - one month after trauma - the levels of hyperarousal-like behaviour in the PTSD-prone B6N strain. In contrast, both acquisition and extinction of contextually conditioned fear were increased in the second offspring, representing cognitive flexibility. A factor analysis showed that innate fear, "hyperarousal" and conditioned fear represent independent behavioural dimensions. In conclusion, the present study identifies maternal inexperience as a risk factor for the development of PTSD-like symptoms. This effect - occurring in inbred mice on an almost identical genetic background - emphasizes the impact of epigenetic factors in PTSD-like behaviour.

Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice.

PubMed

Landgraf, Dominic; Long, Jaimie E; Proulx, Christophe D; Barandas, Rita; Malinow, Roberto; Welsh, David K

2016-12-01

Major depressive disorder is associated with disturbed circadian rhythms. To investigate the causal relationship between mood disorders and circadian clock disruption, previous studies in animal models have employed light/dark manipulations, global mutations of clock genes, or brain area lesions. However, light can impact mood by noncircadian mechanisms; clock genes have pleiotropic, clock-independent functions; and brain lesions not only disrupt cellular circadian rhythms but also destroy cells and eliminate important neuronal connections, including light reception pathways. Thus, a definitive causal role for functioning circadian clocks in mood regulation has not been established. We stereotactically injected viral vectors encoding short hairpin RNA to knock down expression of the essential clock gene Bmal1 into the brain's master circadian pacemaker, the suprachiasmatic nucleus (SCN). In these SCN-specific Bmal1-knockdown (SCN-Bmal1-KD) mice, circadian rhythms were greatly attenuated in the SCN, while the mice were maintained in a standard light/dark cycle, SCN neurons remained intact, and neuronal connections were undisturbed, including photic inputs. In the learned helplessness paradigm, the SCN-Bmal1-KD mice were slower to escape, even before exposure to inescapable stress. They also spent more time immobile in the tail suspension test and less time in the lighted section of a light/dark box. The SCN-Bmal1-KD mice also showed greater weight gain, an abnormal circadian pattern of corticosterone, and an attenuated increase of corticosterone in response to stress. Disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioral despair, and anxiety-like behavior in mice, establishing SCN-Bmal1-KD mice as a new animal model of depression. Copyright © 2016 Society of Biological Psychiatry. All rights reserved.

Genetic Disruption of Circadian Rhythms in the Suprachiasmatic Nucleus Causes Helplessness, Behavioral Despair, and Anxiety-like Behavior in Mice

PubMed Central

Landgraf, Dominic; Long, Jaimie E.; Proulx, Christophe D.; Barandas, Rita; Malinow, Roberto; Welsh, David K.

2016-01-01

Background Major depressive disorder is associated with disturbed circadian rhythms. To investigate the causal relationship between mood disorders and circadian clock disruption, previous studies in animal models have employed light/dark manipulations, global mutations of clock genes, or brain area lesions. However, light can impact mood by noncircadian mechanisms; clock genes have pleiotropic, clock-independent functions; and brain lesions not only disrupt cellular circadian rhythms but also destroy cells and eliminate important neuronal connections, including light reception pathways. Thus, a definitive causal role for functioning circadian clocks in mood regulation has not been established. Methods We stereotactically injected viral vectors encoding short hairpin RNA to knock down expression of the essential clock gene Bmal1 into the brain's master circadian pacemaker, the suprachiasmatic nucleus (SCN). Results In these SCN-specific Bmal1-knockdown (SCN-Bmal1-KD) mice, circadian rhythms were greatly attenuated in the SCN, while the mice were maintained in a standard light/dark cycle, SCN neurons remained intact, and neuronal connections were undisturbed, including photic inputs. In the learned helplessness paradigm, the SCN-Bmal1-KD mice were slower to escape, even before exposure to inescapable stress. They also spent more time immobile in the tail suspension test and less time in the lighted section of a light/dark box. The SCN-Bmal1-KD mice also showed greater weight gain, an abnormal circadian pattern of corticosterone, and an attenuated increase of corticosterone in response to stress. Conclusions Disrupting SCN circadian rhythms is sufficient to cause helplessness, behavioral despair, and anxiety-like behavior in mice, establishing SCN-Bmal1-KD mice as a new animal model of depression. PMID:27113500

Overlapping neurobiology of learned helplessness and conditioned defeat: implications for PTSD and mood disorders.

PubMed

Hammack, Sayamwong E; Cooper, Matthew A; Lezak, Kimberly R

2012-02-01

Exposure to traumatic events can increase the risk for major depressive disorder (MDD) as well as posttraumatic stress disorder (PTSD), and pharmacological treatments for these disorders often involve the modulation of serotonergic (5-HT) systems. Several behavioral paradigms in rodents produce changes in behavior that resemble symptoms of MDD and these behavioral changes are sensitive to antidepressant treatments. Here we review two animal models in which MDD-like behavioral changes are elicited by exposure to an acute traumatic event during adulthood, learned helplessness (LH) and conditioned defeat. In LH, exposure of rats to inescapable, but not escapable, tailshock produces a constellation of behavioral changes that include deficits in fight/flight responding and enhanced anxiety-like behavior. In conditioned defeat, exposure of Syrian hamsters to a social defeat by a more aggressive animal leads to a loss of territorial aggression and an increase in submissive and defensive behaviors in subsequent encounters with non-aggressive conspecifics. Investigations into the neural substrates that control LH and conditioned defeat revealed that increased 5-HT activity in the dorsal raphe nucleus (DRN) is critical for both models. Other key brain regions that regulate the acquisition and/or expression of behavior in these two paradigms include the basolateral amygdala (BLA), central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). In this review, we compare and contrast the role of each of these neural structures in mediating LH and conditioned defeat, and discuss the relevance of these data in developing a better understanding of the mechanisms underlying trauma-related depression. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Enoxacin Elevates MicroRNA Levels in Rat Frontal Cortex and Prevents Learned Helplessness

PubMed Central

Smalheiser, Neil R.; Zhang, Hui; Dwivedi, Yogesh

2014-01-01

Major depressive disorder (MDD) is a major public health concern. Despite tremendous advancement, the pathogenic mechanisms associated with MDD are still unclear. Moreover, a significant number of MDD subjects do not respond to the currently available medication. MicroRNAs (miRNAs) are a class of small non-coding RNAs that control gene expression by modulating translation, mRNA degradation or stability of mRNA targets. The role of miRNAs in disease pathophysiology is emerging rapidly. Recently, we reported that miRNA expression is down-regulated in frontal cortex of depressed suicide subjects, and that rats exposed to repeated inescapable shock show differential miRNA changes depending on whether they exhibited normal adaptive responses or learned helpless (LH) behavior. Enoxacin, a fluoroquinolone used clinically as an anti-bacterial compound, enhances the production of miRNAs in vitro and in peripheral tissues in vivo, but has not yet been tested as an experimental tool to study the relation of miRNA expression to neural functions or behavior. Treatment of rats with 10 or 25 mg/kg enoxacin for 1 week increased the expression of miRNAs in frontal cortex and decreased the proportion of rats exhibiting LH behavior following inescapable shock. Further studies are warranted to learn whether enoxacin may ameliorate depressive behavior in other rodent paradigms and in human clinical situations, and if so whether its mechanism is due to upregulation of miRNAs. PMID:24575053

Lesion of the Ventral Periaqueductal Gray Reduces Conditioned Fear but Does Not Change Freezing Induced by Stimulation of the Dorsal Periaqueductal Gray

PubMed Central

Vianna, Daniel M.L.; Graeff, Frederico G.; Landeira-Fernandez, Jesus; Brandão, Marcus L.

2001-01-01

Previously-reported evidence showed that freezing to a context previously associated with footshock is impaired by lesion of the ventral periaqueductal gray (vPAG). It has also been shown that stepwise increase in the intensity of the electrical stimulation of the dorsal periaqueductal gray (dPAG) produces alertness, then freezing, and finally escape. These aversive responses are mimicked by microinjections of GABA receptor antagonists, such as bicuculline, or blockers of the glutamic acid decarboxylase (GAD), such as semicarbazide, into the dPAG. In this work, we examined whether the expression of these defensive responses could be the result of activation of ventral portion of the periaqueductal gray. Sham- or vPAG electrolytic–lesioned rats were implanted with an electrode in the dPAG for the determination of the thresholds of freezing and escape responses. The vPAG electrolytic lesions were behaviorally verified through a context-conditioned fear paradigm. Results indicated that lesion of the vPAG disrupted conditioned freezing response to contextual cues associated with footshocks but did not change the dPAG electrical stimulation for freezing and escape responses. In a second experiment, lesion of the vPAG also did not change the amount of freezing and escape behavior produced by microinjections of semicarbazide into the dPAG. These findings indicate that freezing and escape defensive responses induced by dPAG stimulation do not depend on the integrity of the vPAG. A discussion on different neural circuitries that might underlie different inhibitory and active defensive behavioral patterns that animals display during threatening situations is presented. PMID:11390636

Depletion of nucleus accumbens dopamine leads to impaired reward and aversion processing in mice: Relevance to motivation pathologies.

PubMed

Bergamini, Giorgio; Sigrist, Hannes; Ferger, Boris; Singewald, Nicolas; Seifritz, Erich; Pryce, Christopher R

2016-10-01

Dopamine (DA) neurotransmission, particularly the ventral tegmental area-nucleus accumbens (VTA-NAcc) projection, underlies reward and aversion processing, and deficient DA function could underlie motivational impairments in psychiatric disorders. 6-hydroxydopamine (6-OHDA) injection is an established method for chronic DA depletion, principally applied in rat to study NAcc DA regulation of reward motivation. Given the increasing focus on studying environmental and genetic regulation of DA function in mouse models, it is important to establish the effects of 6-OHDA DA depletion in mice, in terms of reward and aversion processing. This mouse study investigated effects of 6-OHDA-induced NAcc DA depletion using the operant behavioural test battery of progressive ratio schedule (PRS), learned non-reward (LNR), learned helplessness (LH), treadmill, and in addition Pavlovian fear conditioning. 6-OHDA NAcc DA depletion, confirmed by ex vivo HPLC-ED, reduced operant responding: for gustatory reward under effortful conditions in the PRS test; to a stimulus recently associated with gustatory non-reward in the LNR test; to escape footshock recently experienced as uncontrollable in the LH test; and to avoid footshock by physical effort in the treadmill test. Evidence for specificity of effects to NAcc DA was provided by lack of effect of medial prefrontal cortex DA depletion in the LNR and LH tests. These findings add significantly to the evidence that NAcc DA is a major regulator of behavioural responding, particularly at the motivational level, to both reward and aversion. They demonstrate the suitability of mouse models for translational study of causation and reversal of pathophysiological DA function underlying motivation psychopathologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Significant long-term, but not short-term, hippocampal-dependent memory impairment in adult rats exposed to alcohol in early postnatal life.

PubMed

Goodfellow, Molly J; Lindquist, Derick H

2014-09-01

In rodents, ethanol exposure in early postnatal life is known to induce structural and functional impairments throughout the brain, including the hippocampus. Herein, rat pups were administered one of three ethanol doses over postnatal days (PD) 4-9, a period of brain development comparable to the third trimester of human pregnancy. As adults, control and ethanol rats were trained and tested in a variant of hippocampal-dependent one-trial context fear conditioning. In Experiment 1, subjects were placed into a novel context and presented with an immediate footshock (i.e., within ∼8 sec). When re-exposed to the same context 24 hr later low levels of conditioned freezing were observed. Context pre-exposure 24 hr prior to the immediate shock reversed the deficit in sham-intubated and unintubated control rats, enhancing freezing behavior during the context retention test. Even with context pre-exposure, however, significant dose-dependent reductions in contextual freezing were seen in ethanol rats. In Experiment 2, the interval between context pre-exposure and the immediate shock was shortened to 2 hr, in addition to the standard 24 hr. Ethanol rats trained with the 2 hr, but not 24 hr, interval displayed retention test freezing levels roughly equal to controls. Results suggest the ethanol rats can encode a short-term context memory and associate it with the aversive footshock 2 hr later. In the 24 hr ethanol rats the short-term context memory is poorly transferred or consolidated into long-term memory, we propose, impeding the memory's subsequent retrieval and association with shock. © 2014 Wiley Periodicals, Inc.

The role of the basolateral amygdala in punishment.

PubMed

Jean-Richard-Dit-Bressel, Philip; McNally, Gavan P

2015-02-01

Aversive stimuli not only support fear conditioning to their environmental antecedents, they also punish behaviors that cause their occurrence. The amygdala, especially the basolateral nucleus (BLA), has been critically implicated in Pavlovian fear learning but its role in punishment remains poorly understood. Here, we used a within-subjects punishment task to assess the role of the BLA in the acquisition and expression of punishment as well as aversive choice. Rats that pressed two individually presented levers for pellet rewards rapidly suppressed responding to one lever if it also caused footshock deliveries (punished lever) but continued pressing a second lever that did not cause footshock (unpunished lever). Infusions of GABA agonists baclofen and muscimol (BM) into the BLA significantly impaired the acquisition of this suppression. BLA inactivations using BM also reduced the expression of well-trained punishment. There was anatomical segregation within the BLA so that caudal, not rostral, BLA was implicated in punishment. However, when presented with punished and unpunished levers simultaneously in a choice test without deliveries of shock punisher, rats expressed a preference for unpunished over the punished lever and BLA inactivations had no effect on this preference. Taken together, these findings indicate that the BLA is important for both the acquisition and expression of punishment but not for aversive choice. This role appears to be linked to neurons in the caudal BLA, rather than rostral BLA, although the circuitry that contributes to this functional segregation is currently unknown, and is most parsimoniously interpreted as a role for caudal BLA in determining the aversive value of the shock punisher. © 2015 Jean-Richard-Dit-Bressel and McNally; Published by Cold Spring Harbor Laboratory Press.

A single footshock causes long-lasting hypoactivity in unknown environments that is dependent on the development of contextual fear conditioning.

PubMed

Daviu, Núria; Fuentes, Silvia; Nadal, Roser; Armario, Antonio

2010-09-01

Exposure to a single session of footshocks induces long-lasting inhibition of activity in unknown environments that markedly differ from the shock context. Interestingly, these effects are not necessarily associated to an enhanced anxiety and interpretation of this hypoactivity remains unclear. In the present experiment we further studied this phenomenon in male Sprague-Dawley rats. In a first experiment, a session of three shocks resulted in hypoactivity during exposure, 6-12days later, to three different unknown environments. This altered behaviour was not accompanied by a greater hypothalamic-pituitary-adrenal (HPA) activation, although greater HPA activation paralleling higher levels of freezing was observed in the shock context. In a second experiment we used a single shock and two procedures, one with pre-exposure to the context before the shock and another with immediate shock that did not induce contextual fear conditioning. Hypoactivity and a certain level of generalization of fear (freezing) to the unknown environments only appeared in the group that developed fear conditioning, but no evidence for enhanced anxiety in the elevated plus-maze was found in any group. The results suggest that if animals are able to associate an aversive experience with a distinct unknown environment, they would display more cautious behaviour in any unknown environment and such strategy persists despite repeated experience with different environments. This long-lasting cautious behaviour was not associated to greater HPA response to the unknown environment that was however observed in the shock context. The present findings raised some concerns about interpretation of long-lasting behavioural changes caused by brief stressors. Copyright 2010 Elsevier Inc. All rights reserved.

Compulsive methamphetamine taking under punishment is associated with greater cue-induced drug seeking in rats.

PubMed

Torres, Oscar V; Jayanthi, Subramanian; Ladenheim, Bruce; McCoy, Michael T; Krasnova, Irina N; Cadet, Jean Lud

2017-05-30

Methamphetamine (METH) addicts lose control over drug consumption despite suffering multiple adverse medicolegal consequences. To mimic the negative events associated with drug addiction in humans, we recently introduced a rat model of self-administration (SA) with response-contingent punishment on METH intake. These procedures allowed us to distinguish between two addiction-like phenotypes in rats, those that sustained METH taking despite negative consequences (shock-resistant, SR) and rats that significantly reduced their METH intake (shock-sensitive, SS). Here, we further developed our adverse consequence model and examined incubation of METH craving by measuring cue-induced drug seeking in SR and SS rats. Male Sprague-Dawley rats were trained to self-administer METH (0.1mg/kg/injection) or saline intravenously (i.v.) during twenty-two 9-h sessions that consisted of 3 separate 3-h sessions separated by 30min. Subsequently, rats were subjected to incremental footshocks during thirteen additional 9-h METH SA sessions performed in a fashion identical to the training phase. Cue-induced drug craving was then assessed at 2 and 21days after the footshock phase. All rats escalated their intake of METH, with both phenotypes showing similar drug taking patterns during SA training. In addition, rats that continued their METH intake despite negative consequences showed even greater cue-induced drug craving following withdrawal than the rats that reduced METH intake following negative consequences. Taken together, our adverse consequence-based model highlights the possibility of identifying rats by addiction-like phenotypes and subsequent vulnerability to relapse-like behaviors. The use of similar SA models should help in the development of better therapeutic approaches to treat different stages of METH addiction. Published by Elsevier B.V.

Evidence for the involvement of extinction-associated inhibitory learning in the forced swimming test.

PubMed

Campus, P; Colelli, V; Orsini, C; Sarra, D; Cabib, S

2015-02-01

The forced swimming test (FST) remains one of the most used tools for screening antidepressants in rodent models. Nonetheless, the nature of immobility, its main behavioral measure, is still a matter of debate. The present study took advantage of our recent finding that mice of the inbred DBA/2J strain require a functioning left dorsolateral striatum (DLS) to consolidate long-term memory of FST to test whether immobility is the outcome of stress-related learning. Infusion of the GABA-A agonist muscimol in the left DLS immediately after a single experience of FST prevented and infusion in the left or the right amygdala impaired recall of the acquired levels of immobility in a probe test performed 24h later. Post-training left DLS infusion of muscimol, at a dose capable of preventing retention of FST-induced immobility, did not influence 24h retention of inhibitory avoidance training or of the escape response acquired in a water T-maze. However, this same treatment prevented 24h retention of the extinction training of the consolidated escape response. These results indicate that a left DLS-centered memory system selectively mediates memory consolidation of FST and of escape extinction and support the hypothesis that immobility is the result of extinction-like inhibitory learning involving all available escape responses due to the inescapable/unavoidable nature of FST experience. Copyright © 2014 Elsevier B.V. All rights reserved.

Body temperature as a conditional response measure for pavlovian fear conditioning.

PubMed

Godsil, B P; Quinn, J J; Fanselow, M S

2000-01-01

On six days rats were exposed to each of two contexts. They received an electric shock in one context and nothing in the other. Rats were tested later in each environment without shock. The rats froze and defecated more often in the shock-paired environment; they also exhibited a significantly larger elevation in rectal temperature in that environment. The rats discriminated between each context, and we suggest that the elevation in temperature is the consequence of associative learning. Thus, body temperature can be used as a conditional response measure in Pavlovian fear conditioning experiments that use footshock as the unconditional stimulus.

Cornering the fear engram: long-term synaptic changes in the lateral nucleus of the amygdala after fear conditioning.

PubMed

Kwon, Jeong-Tae; Choi, June-Seek

2009-08-05

Use-dependent synaptic modifications in the lateral nucleus of the amygdala (LA) have been suggested to be the cellular analog of memory trace after pavlovian fear conditioning. However, whether neurophysiological changes in the LA are produced as a direct consequence of associative learning awaits additional proof. Using microstimulation of the medial geniculate nucleus of the thalamus as the conditioned stimulus (CS), we demonstrated that contingent pairings of the brain-stimulation CS and a footshock unconditioned stimulus lead to enhanced synaptic efficacy in the thalamic input to the LA, supporting the hypothesis that localized synaptic alterations underlie fear memory formation.

Role of cannabinoidergic mechanisms in ethanol self-administration and ethanol seeking in rat adult offspring following perinatal exposure to {delta}{sup 9}-tetrahydrocannabinol

DOE Office of Scientific and Technical Information (OSTI.GOV)

Economidou, Daina; Mattioli, Laura; Ubaldi, Massimo

The present study evaluated the consequences of perinatal {delta}{sup 9}-tetrahydrocannabinol ({delta}{sup 9}-THC) treatment (5 mg/kg/day by gavage), either alone or combined with ethanol (3% v/v as the only fluid available), on ethanol self-administration and alcohol-seeking behavior in rat adult offspring. Furthermore, the effect of the selective cannabinoid CB{sub 1} receptor antagonist, SR-141716A, on ethanol self-administration and on reinstatement of ethanol-seeking behavior induced either by stress or conditioned drug-paired cues was evaluated in adult offspring of rats exposed to the same perinatal treatment. Lastly, microarray experiments were conducted to evaluate if perinatal treatment with {delta}{sup 9}-tetrahydrocannabinol, ethanol or their combination causesmore » long-term changes in brain gene expression profile in rats. The results of microarray data analysis showed that 139, 112 and 170 genes were differentially expressed in the EtOH, {delta}{sup 9}-THC, or EtOH + {delta}{sup 9}-THC group, respectively. No differences in alcohol self-administration and alcohol seeking were observed between rat groups. Intraperitoneal (IP) administration of SR-141716A (0.3-3.0 mg/kg) significantly reduced lever pressing for ethanol and blocked conditioned reinstatement of alcohol seeking. At the same doses SR-141716A failed to block foot-shock stress-induced reinstatement of alcohol seeking. The results reveal that perinatal exposure to {delta}{sup 9}-THC ethanol or their combination results in evident changes in gene expression patterns. However, these treatments do not significantly affect vulnerability to ethanol abuse in adult offspring. On the other hand, the results obtained with SR-141716A emphasize that endocannabinoid mechanisms play a major role in ethanol self-administration, as well as in the reinstatement of ethanol-seeking behavior induced by conditioned cues, supporting the idea that cannabinoid CB{sub 1} receptor antagonists may represent interesting agents for the pharmacotherapy of alcoholism.« less

A single exposure to immobilization causes long-lasting pituitary-adrenal and behavioral sensitization to mild stressors.

PubMed

Belda, Xavier; Fuentes, Silvia; Nadal, Roser; Armario, Antonio

2008-11-01

We have previously reported that a single exposure to immobilization (IMO) in rats causes a long-term desensitization of the hypothalamic-pituitary-adrenal (HPA) response to the same (homotypic) stressor. Since there are reports showing that a single exposure to other stressors causes sensitization of the HPA response to heterotypic stressors and increases anxiety-like behavior, we studied in the present work the long-term effects of IMO on behavioral and HPA response to mild superimposed stressors. In Experiments 1 and 2, adult male Sprague-Dawley rats were subjected to 2 h of IMO and then exposed for 5 min to the elevated plus-maze (EPM) at 1, 3 or 7 days after IMO. Blood samples were taken at 15 min after initial exposure to the EPM. Increases in anxiety-like behavior and HPA responsiveness to the EPM were found at all times post-IMO. Changes in the resting levels of HPA hormones did not explain the enhanced HPA responsiveness to the EPM (Experiment 3). In Experiments 4 and 5, we studied the effects of a single exposure to a shorter session of IMO (1 h) on behavioral and HPA responses to a brief and mild session of foot-shocks done 10 days after IMO. Neither previous IMO nor exposure to shocks in control rats modified behavior in the EPM. However, a brief session of shocks in previously IMO-exposed rats dramatically increased anxiety in the EPM. HPA and freezing responses to shocks were similar in control and previous IMO groups. Therefore, a single exposure to IMO appears to induce long-lasting HPA and behavioral sensitization to mild superimposed stressors, although the two responses are likely to be at least partially independent. Long-term effects of IMO on the susceptibility to stress-induced endocrine and emotional disturbances may be relevant to the characterization of animal models of post-traumatic stress.

Wuling powder prevents the depression-like behavior in learned helplessness mice model through improving the TSPO mediated-mitophagy.

PubMed

Li, Dongmei; Zheng, Ji; Wang, Mingyang; Feng, Lu; Liu, Yanyong; Yang, Nan; Zuo, Pingping

2016-06-20

Wuling powder (trade name: Wuling capsule), a traditional Chinese medicine (TCM), was extracted from mycelia of precious Xylaria Nigripes (Kl.) Sacc by modern fermentation technology, and has been claimed to be fully potent in improving the signs of insomnia and cognitive deficits. Moreover, Wuling capsule was effective in treating post-stroke and orther co-cormbid depression both in clinical and in basic research. In order to clarify the molecular mechanisms of the antidepressant effect of Wuling powder, we established learned helplessness (LH) depression animal model and focused on 18kDa translocator protein (TSPO) mediated-mitophagy pathway. Mice were exposed to the inescapable e-shock (IS) once a day for three consecutive days to establish the LH model. Then mice were orally administered Wuling powder for 2 weeks. For the behavioral assessment, Shuttle box test, novelty suppressed feeding test (NSF) and forced swimming test (FST) were performed. Following the behavioral assessment, we assessed the protein expression level that were related to TSPO-mediated mitophagy signaling pathway by Western blotting analysis. Finally, immunohistochemistry method was used to assess the neuroprotective effects of Wuling powder. Compared with mice that were subjected to inescapable e-shock, Wuling powder exhibited antidepressant effect in the multiple behavioral tests. In addition, Wuling powder altered the expression level of multiple proteins related to TSPO-mediated mitophagy signaling pathway. Our results suggested that Wuling powder exhibited an obvious antidepressant effect, which could be due to the improvement of TSPO-mediated mitophagy signaling pathway. Copyright © 2016. Published by Elsevier Ireland Ltd.

Anxiolytic-like and antidepressant-like activities of MCL0129 (1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine), a novel and potent nonpeptide antagonist of the melanocortin-4 receptor.

PubMed

Chaki, Shigeyuki; Hirota, Shiho; Funakoshi, Takeo; Suzuki, Yoshiko; Suetake, Sayoko; Okubo, Taketoshi; Ishii, Takaaki; Nakazato, Atsuro; Okuyama, Shigeru

2003-02-01

We investigated the effects of a novel melanocortin-4 (MC4) receptor antagonist,1-[(S)-2-(4-fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine (MCL0129) on anxiety and depression in various rodent models. MCL0129 inhibited [(125)I][Nle(4)-D-Phe(7)]-alpha-melanocyte-stimulating hormone (alpha-MSH) binding to MC4 receptor with a K(i) value of 7.9 nM, without showing affinity for MC1 and MC3 receptors. MCL0129 at 1 microM had no apparent affinity for other receptors, transporters, and ion channels related to anxiety and depression except for a moderate affinity for the sigma(1) receptor, serotonin transporter, and alpha(1)-adrenoceptor, which means that MCL0129 is selective for the MC4 receptor. MCL0129 attenuated the alpha-MSH-increased cAMP formation in COS-1 cells expressing the MC4 receptor, whereas MCL0129 did not affect basal cAMP levels, thereby indicating that MCL0129 acts as an antagonist at the MC4 receptor. Swim stress markedly induced anxiogenic-like effects in both the light/dark exploration task in mice and the elevated plus-maze task in rats, and MCL0129 reversed the stress-induced anxiogenic-like effects. Under nonstress conditions, MCL0129 prolonged time spent in the light area in the light/dark exploration task and suppressed marble-burying behavior. MCL0129 shortened immobility time in the forced swim test and reduced the number of escape failures in inescapable shocks in the learned helplessness test, thus indicating an antidepressant potential. In contrast, MCL0129 had negligible effects on spontaneous locomotor activity, Rotarod performance, and hexobarbital-induced anesthesia. These observations indicate that MCL0129 is a potent and selective MC4 antagonist with anxiolytic- and antidepressant-like activities in various rodent models. MC4 receptor antagonists may prove effective for treating subjects with stress-related disorders such as depression and/or anxiety.

A critique of Bernstein's beyond objectivism and relativism: science, hermeneutics, and praxis.

PubMed

Matusitz, Jonathan; Kramer, Eric

2011-06-01

This analysis comments on Bernstein's lack of clear understanding of subjectivity, based on his book, Beyond Objectivism and Relativism: Science, Hermeneutics, and Praxis. Bernstein limits his interpretation of subjectivity to thinkers such as Gadamer and Habermas. The authors analyze the ideas of classic scholars such as Edmund Husserl and Friedrich Nietzsche. Husserl put forward his notion of transcendental subjectivity and phenomenological ramifications of the relationship between subjectivity and objectivity. Nietzsche referred to subjectivity as "perspectivism," the inescapable fact that any and all consciousnesses exist in space and time. Consciousness is fundamentally constituted of cultural, linguistic, and historical dimensions.

Lunar architecture and urbanism

NASA Astrophysics Data System (ADS)

Sherwood, Brent

1992-09-01

Human civilization and architecture have defined each other for over 5000 years on Earth. Even in the novel environment of space, persistent issues of human urbanism will eclipse, within a historically short time, the technical challenges of space settlement that dominate our current view. By adding modern topics in space engineering, planetology, life support, human factors, material invention, and conservation to their already renaissance array of expertise, urban designers can responsibly apply ancient, proven standards to the exciting new opportunities afforded by space. Inescapable facts about the Moon set real boundaries within which tenable lunar urbanism and its component architecture must eventually develop.

When the analyst is ill: dimensions of self-disclosure.

PubMed

Pizer, B

1997-07-01

This article examines questions related to the "inescapable," the "inadvertent," and the "deliberate" personal disclosures by an analyst. Technical and personal considerations that influence the analyst's decision to disclose, as well as the inherent responsibilities and potential clinical consequences involved in self-disclosure, are explored, with particular attention to transference-countertransference dynamics, therapeutic goals, and the negotiation of resistance. The author describes her clinical work during a period of prolonged illness, with case vignettes that illustrate how-self-disclosure may be regarded as both an occasional authentic requirement and a regular intrinsic component of clinical technique.

". . . How narrow the strait!". The God machine and the spirit of liberty.

PubMed

Harris, John

2014-07-01

This article explores the consequences of interventions to secure moral enhancement that are at once compulsory and inescapable and of which the subject will be totally unaware. These are encapsulated in an arresting example used by Ingmar Perrson and Julian Savulescu concerning a "God machine" capable of achieving at least three of these four objectives. This article demonstrates that the first objective--namely, moral enhancement--is impossible to achieve by these means and that the remaining three are neither moral nor enhancements nor remotely desirable. Along the way the nature of morality properly so called is further explored.

Lunar architecture and urbanism

NASA Technical Reports Server (NTRS)

Sherwood, Brent

1992-01-01

Human civilization and architecture have defined each other for over 5000 years on Earth. Even in the novel environment of space, persistent issues of human urbanism will eclipse, within a historically short time, the technical challenges of space settlement that dominate our current view. By adding modern topics in space engineering, planetology, life support, human factors, material invention, and conservation to their already renaissance array of expertise, urban designers can responsibly apply ancient, proven standards to the exciting new opportunities afforded by space. Inescapable facts about the Moon set real boundaries within which tenable lunar urbanism and its component architecture must eventually develop.

The mesencephalic GCt-ICo complex and tonic immobility in pigeons (Columba livia): a c-Fos study.

PubMed

Melleu, Fernando Falkenburger; Lino-de-Oliveira, C; Marino-Neto, J

2017-04-01

Tonic immobility (TI) is a response to a predator attack, or other inescapable danger, characterized by immobility, analgesia and unresponsiveness to external stimuli. In mammals, the periaqueductal gray (PAG) and deep tectal regions control the expression of TI as well as other defensive behaviors. In birds, little is known about the mesencephalic circuitry involved in the control of TI. Here, adult pigeons (both sex, n = 4/group), randomly assigned to non-handled, handled or TI groups, were killed 90 min after manipulations and the brains processed for detection of c-Fos immunoreactive cells (c-Fos-ir, marker for neural activity) in the mesencephalic central gray (GCt) and the adjacent nucleus intercollicularis (ICo). The NADPH-diaphorase staining delineated the boundaries of the sub nuclei in the ICo-GCt complex. Compared to non-handled, TI (but not handling) induced c-Fos-ir in NADPH-diaphorase-rich and -poor regions. After TI, the number of c-Fos-ir increased in the caudal and intermediate areas of the ICo (but not in the GCt), throughout the rostrocaudal axis of the dorsal stratum griseum periventriculare (SGPd) of the optic tectum and in the n. mesencephalicus lateralis pars dorsalis (MLd), which is part of the ascending auditory pathway. These data suggest that inescapable threatening stimuli such as TI may recruit neurons in discrete areas of ICo-GCt complex, deep tectal layer and in ascending auditory circuits that may control the expression of defensive behaviors in pigeons. Additionally, data indicate that the contiguous deep tectal SCPd (but not GCt) in birds may be functionally comparable to the mammalian dorsal PAG.

Basolateral Amygdala and the Regulation of Fear-Conditioned Changes in Sleep: Role of Corticotropin-Releasing Factor

PubMed Central

Wellman, Laurie L.; Yang, Linghui; Ambrozewicz, Marta A.; Machida, Mayumi; Sanford, Larry D.

2013-01-01

Study Objective: To determine whether corticotropin-releasing factor (CRF) in the basolateral amygdala (BLA) modulated sleep and fear-conditioned alterations in sleep. Design: After 2 days of habituation to recording procedures, baseline sleep recordings were obtained. The animals were then habituated to the handling procedure necessary for microinjections over 2 consecutive days. In experiment 1, rats received microinjections of 0.5 μL antalarmin (1.61 or 4.82 mM), a CRF receptor 1 antagonist, or distilled water once a week for 3 wk. In experiment 2, rats received a microinjection of either antalarmin or vehicle prior to inescapable shock training (ST; 20 shocks; 0.8 mA, 0.5 sec; 1 min interstimulus interval). The animals were placed back in the context 7 days later for 30 min without shock (CR; context re-exposure). Sleep was recorded for 8 h after each manipulation. Setting: NA. Subjects: Outbred Wistar rats. Interventions: The rats were surgically implanted with electrodes for recording the electroencephalogram and electromyogram for determining arousal state and with bilateral guide cannulae directed at BLA. Measurements and Results: Antalarmin microinjected into BLA did not significantly alter sleep under undisturbed conditions. However, antalarmin microinjected bilaterally into BLA prior to ST blocked reductions in rapid eye movement sleep that ST normally produces. Further, the single microinjection prior to ST blocked the reduction in rapid eye movement typically seen after subsequent CR. Behavioral freezing, an indicator of fear memory, was not altered. Conclusions: CRF in BLA is involved in regulating stress-induced alterations in sleep and it plays a role in modulating how stressful memories influence sleep. Citation: Wellman LL; Yang L; Ambrozewicz MA; Machida M; Sanford LD. Basolateral amygdala and the regulation of fear-conditioned changes in sleep: role of corticotropin-releasing factor. SLEEP 2013;36(4):471-480. PMID:23564994

Chronic anthropogenic noise disrupts glucocorticoid signaling and has multiple effects on fitness in an avian community.

PubMed

Kleist, Nathan J; Guralnick, Robert P; Cruz, Alexander; Lowry, Christopher A; Francis, Clinton D

2018-01-23

Anthropogenic noise is a pervasive pollutant that decreases environmental quality by disrupting a suite of behaviors vital to perception and communication. However, even within populations of noise-sensitive species, individuals still select breeding sites located within areas exposed to high noise levels, with largely unknown physiological and fitness consequences. We use a study system in the natural gas fields of northern New Mexico to test the prediction that exposure to noise causes glucocorticoid-signaling dysfunction and decreases fitness in a community of secondary cavity-nesting birds. In accordance with these predictions, and across all species, we find strong support for noise exposure decreasing baseline corticosterone in adults and nestlings and, conversely, increasing acute stressor-induced corticosterone in nestlings. We also document fitness consequences with increased noise in the form of reduced hatching success in the western bluebird ( Sialia mexicana ), the species most likely to nest in noisiest environments. Nestlings of all three species exhibited accelerated growth of both feathers and body size at intermediate noise amplitudes compared with lower or higher amplitudes. Our results are consistent with recent experimental laboratory studies and show that noise functions as a chronic, inescapable stressor. Anthropogenic noise likely impairs environmental risk perception by species relying on acoustic cues and ultimately leads to impacts on fitness. Our work, when taken together with recent efforts to document noise across the landscape, implies potential widespread, noise-induced chronic stress coupled with reduced fitness for many species reliant on acoustic cues.

Reasons for middle-aged women in Taiwan to choose hysterectomy: a qualitative study using the bounded rationality perspective.

PubMed

Wu, Shu-Mei; Lee, Hui-Ling; Yeh, Mei-Yu; Che, Hui-Lian

2014-12-01

To explore women's perspectives on deciding to undergo hysterectomy for benign conditions based on physicians' recommendations and the women's own judgement. Hysterectomy is the second most common surgical procedure worldwide. Although most hysterectomies are elective, physicians may recommend treatment that involves a loss of sexuality or ovary removal, creating a difficult choice for women. Qualitative, in-depth interview A purposive sample of 17 women was recruited. The women had decided to undergo hysterectomy after the diagnosis of uterine fibroids. All these women had already decided not to have more children. Data were collected by in-depth interviewing, and content analysis was used to analyse the data. Our study revealed five themes: release from stress, inescapable fate, positive support, hoping for peace of mind and sense of trust. The participants felt that mental and physical health were the most important considerations, noting that when women no longer want children, a uterus is useless. The women believed that they retained their womanhood, even without a uterus, and were satisfied with the outcomes of their hysterectomy decisions. Our findings might serve as educational and counselling reference materials for healthcare providers, ensuring that women receive appropriate care quality and have their needs met. Healthcare providers can then maximise women's empowerment, deepen their awareness of body image and their concept of self-care and help them to clearly perceive their own concerns and needs so that they can make suitable decisions. © 2014 John Wiley & Sons Ltd.

Affective and cognitive mechanisms of risky decision making.

PubMed

Shimp, Kristy G; Mitchell, Marci R; Beas, B Sofia; Bizon, Jennifer L; Setlow, Barry

2015-01-01

The ability to make advantageous decisions under circumstances in which there is a risk of adverse consequences is an important component of adaptive behavior; however, extremes in risk taking (either high or low) can be maladaptive and are characteristic of a number of neuropsychiatric disorders. To better understand the contributions of various affective and cognitive factors to risky decision making, cohorts of male Long-Evans rats were trained in a "Risky Decision making Task" (RDT), in which they made discrete trial choices between a small, "safe" food reward and a large, "risky" food reward accompanied by varying probabilities of footshock. Experiment 1 evaluated the relative contributions of the affective stimuli (i.e., punishment vs. reward) to RDT performance by parametrically varying the magnitudes of the footshock and large reward. Varying the shock magnitude had a significant impact on choice of the large, "risky" reward, such that greater magnitudes were associated with reduced choice of the large reward. In contrast, varying the large, "risky" reward magnitude had minimal influence on reward choice. Experiment 2 compared individual variability in RDT performance with performance in an attentional set shifting task (assessing cognitive flexibility), a delayed response task (assessing working memory), and a delay discounting task (assessing impulsive choice). Rats characterized as risk averse in the RDT made more perseverative errors on the set shifting task than did their risk taking counterparts, whereas RDT performance was not related to working memory abilities or impulsive choice. In addition, rats that showed greater delay discounting (greater impulsive choice) showed corresponding poorer performance in the working memory task. Together, these results suggest that reward-related decision making under risk of punishment is more strongly influenced by the punishment than by the reward, and that risky and impulsive decision making are associated with distinct components of executive function. Copyright © 2014 Elsevier Inc. All rights reserved.

Bisphenol-A rapidly enhanced passive avoidance memory and phosphorylation of NMDA receptor subunits in hippocampus of young rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xu Xiaohong, E-mail: xuxh63@zjnu.cn; Li Tao; Luo Qingqing

Bisphenol-A (BPA), an endocrine disruptor, is found to influence development of brain and behaviors in rodents. The previous study indicated that perinatal exposure to BPA impaired learning-memory and inhibited N-methyl-D-aspartate receptor (NMDAR) subunits expressions in hippocampus during the postnatal development in rats; and in cultured hippocampal neurons, BPA rapidly promotes dynamic changes in dendritic morphology through estrogen receptor-mediated pathway by concomitant phosphorylation of NMDAR subunit NR2B. In the present study, we examined the rapid effect of BPA on passive avoidance memory and NMDAR in the developing hippocampus of Sprague-Dawley rats at the age of postnatal day 18. The results showedmore » that BPA or estradiol benzoate (EB) rapidly extended the latency to step down from the platform 1 h after footshock and increased the phosphorylation levels of NR1, NR2B, and mitogen-activated extracellular signal-regulated kinase (ERK) in hippocampus within 1 h. While 24 h after BPA or EB treatment, the improved memory and the increased phosphorylation levels of NR1, NR2B, ERK disappeared. Furthermore, pre-treatment with an estrogen receptors (ERs) antagonist, ICI182,780, or an ERK-activating kinase inhibitor, U0126, significantly attenuated EB- or BPA-induced phosphorylations of NR1, NR2B, and ERK within 1 h. These data suggest that BPA rapidly enhanced short-term passive avoidance memory in the developing rats. A non-genomic effect via ERs may mediate the modulation of the phosphorylation of NMDAR subunits NR1 and NR2B through ERK signaling pathway. - Highlights: > BPA rapidly extended the latency to step down from platform 1 h after footshock. > BPA rapidly increased pNR1, pNR2B, and pERK in hippocampus within 1 h. > ERs antagonist or MEK inhibitor attenuated BPA-induced pNR1, pNR2B, and pERK.« less

Pharmacogenetic excitation of dorsomedial prefrontal cortex restores fear prediction error.

PubMed

Yau, Joanna Oi-Yue; McNally, Gavan P

2015-01-07

Pavlovian conditioning involves encoding the predictive relationship between a conditioned stimulus (CS) and an unconditioned stimulus, so that synaptic plasticity and learning is instructed by prediction error. Here we used pharmacogenetic techniques to show a causal relation between activity of rat dorsomedial prefrontal cortex (dmPFC) neurons and fear prediction error. We expressed the excitatory hM3Dq designer receptor exclusively activated by a designer drug (DREADD) in dmPFC and isolated actions of prediction error by using an associative blocking design. Rats were trained to fear the visual CS (CSA) in stage I via pairings with footshock. Then in stage II, rats received compound presentations of visual CSA and auditory CS (CSB) with footshock. This prior fear conditioning of CSA reduced the prediction error during stage II to block fear learning to CSB. The group of rats that received AAV-hSYN-eYFP vector that was treated with clozapine-N-oxide (CNO; 3 mg/kg, i.p.) before stage II showed blocking when tested in the absence of CNO the next day. In contrast, the groups that received AAV-hSYN-hM3Dq and AAV-CaMKIIα-hM3Dq that were treated with CNO before stage II training did not show blocking; learning toward CSB was restored. This restoration of prediction error and fear learning was specific to the injection of CNO because groups that received AAV-hSYN-hM3Dq and AAV-CaMKIIα-hM3Dq that were injected with vehicle before stage II training did show blocking. These effects were not attributable to the DREADD manipulation enhancing learning or arousal, increasing fear memory strength or asymptotic levels of fear learning, or altering fear memory retrieval. Together, these results identify a causal role for dmPFC in a signature of adaptive behavior: using the past to predict future danger and learning from errors in these predictions. Copyright © 2015 the authors 0270-6474/15/350074-10$15.00/0.

Roles of testosterone and amygdaloid LTP induction in determining sex differences in fear memory magnitude.

PubMed

Chen, Li-Shen; Tzeng, Wen-Yu; Chuang, Jia-Ying; Cherng, Chianfang G; Gean, Po-Wu; Yu, Lung

2014-08-01

Women are thought to form fear memory more robust than men do and testosterone is suspected to play a role in determining such a sex difference. Mouse cued fear freezing was used to study the sex-related susceptibility and the role of testosterone in fear memory in humans. A 75-dB tone was found to provoke weak freezing, while 0.15-mA and 0.20-mA footshock caused strong freezing responses. No sex differences were noticed in the tone- or footshock-induced (naïve fear) freezing. Following the conditionings, female mice exhibited greater tone (cued fear)-induced freezing than did male mice. Nonetheless, female mice demonstrated indistinctive cued fear freezing across the estrous phases and ovariectomy did not affect such freezing in female mice. Orchidectomy enhanced the cued fear freezing in male mice. Systemic testosterone administrations and an intra-lateral nucleus of amygdala (LA) testosterone infusion diminished the cued fear freezing in orchidectomized male mice, while pretreatment with flutamide (Flu) eradicated these effects. Long-term potentiation (LTP) magnitude in LA has been known to correlate with the strength of the cued fear conditioning. We found that LA LTP magnitude was indeed greater in female than male mice. Orchidectomy enhanced LTP magnitude in males' LA, while ovariectomy decreased LTP magnitude in females' LA. Testosterone decreased LTP magnitude in orchidectomized males' LA and estradiol enhanced LTP magnitude in ovariectomized females' LA. Finally, male mice had lower LA GluR1 expression than female mice and orchidectomy enhanced the GluR1 expression in male mice. These findings, taken together, suggest that testosterone plays a critical role in rendering the sex differences in the cued fear freezing and LA LTP. Testosterone is negatively associated with LA LTP and the cued fear memory in male mice. However, ovarian hormones and LA LTP are loosely associated with the cued fear memory in female mice. Copyright © 2014 Elsevier Inc. All rights reserved.

Affective and cognitive mechanisms of risky decision making

PubMed Central

Shimp, Kristy G.; Mitchell, Marci R.; Beas, B. Sofia; Bizon, Jennifer L.; Setlow, Barry

2014-01-01

The ability to make advantageous decisions under circumstances in which there is a risk of adverse consequences is an important component of adaptive behavior; however, extremes in risk taking (either high or low) can be maladaptive and are characteristic of a number of neuropsychiatric disorders. To better understand the contributions of various affective and cognitive factors to risky decision making, cohorts of male Long-Evans rats were trained in a “Risky Decision making Task” (RDT), in which they made discrete trial choices between a small, “safe” food reward and a large, “risky” food reward accompanied by varying probabilities of footshock. Experiment 1 evaluated the relative contributions of the affective stimuli (i.e., punishment vs. reward) to RDT performance by parametrically varying the magnitudes of the footshock and large reward. Varying the shock magnitude had a significant impact on choice of the large, “risky” reward, such that greater magnitudes were associated with reduced choice of the large reward. In contrast, varying the large, “risky” reward magnitude had minimal influence on reward choice. Experiment 2 compared individual variability in RDT performance with performance in an attentional set shifting task (assessing cognitive flexibility), a delayed response task (assessing working memory), and a delay discounting task (assessing impulsive choice). Rats characterized as risk averse in the RDT made more perseverative errors on the set shifting task than did their risk taking counterparts, whereas RDT performance was not related to working memory abilities or impulsive choice. In addition, rats that showed greater delay discounting (greater impulsive choice) showed corresponding poorer performance in the working memory task. Together, these results suggest that reward-related decision making under risk of punishment is more strongly influenced by the punishment than by the reward, and that risky and impulsive decision making are associated with distinct components of executive function. PMID:24642448

Age and experience dependent changes in Egr-1 expression during the ontogeny of the context preexposure facilitation effect (CPFE).

PubMed

Robinson-Drummer, P A; Chakraborty, T; Heroux, N A; Rosen, J B; Stanton, M E

2018-04-01

The context preexposure facilitation effect (CPFE) is a variant of contextual fear conditioning in which acquisition of the contextual representation and association of the retrieved contextual memory with an immediate foot-shock are separated by 24 h. During the CPFE, learning- related expression patterns of the early growth response-1 gene (Egr-1) vary based on training phase and brain sub-region in adult and adolescent rats (Asok, Schreiber, Jablonski, Rosen, & Stanton, 2013; Schreiber, Asok, Jablonski, Rosen, & Stanton, 2014; Chakraborty, Asok, Stanton, & Rosen, 2016). The current experiments extended our previous findings by examining Egr-1 expression in infant (PD17) and juvenile (PD24) rats during the CPFE using preexposure protocols involving single-exposure (SE) or multiple-exposure (ME) to context. Following a 5 min preexposure to the training context (i.e. the SE protocol), Egr-1 expression in the medial prefrontal cortex (mPFC), dorsal hippocampus (dHPC) and lateral nucleus of the amygdala (LA) was differentially increased in PD24 rats relative to PD17 rats. In contrast, increased Egr-1 expression following an immediate foot-shock (2s, 1.5 mA) did not differ between PD17 and PD24 rats, and was not learning-related. Interestingly, increasing the number of exposures to the training chamber on the preexposure day (i.e. ME protocol) altered training-day expression such that a learning-related increase in expression was observed in the mPFC in PD24 but not PD17 rats. Together, these results illustrate a clear maturation of Egr-1 expression that is both age- and experience-dependent. In addition, the data suggest that regional activity and plasticity within the mPFC on the preexposure but not the training day may contribute to the ontogenetic profile of the effect. Further studies are necessary to elucidate the causal role of sub-region-specific neuroplasticity in the ontogeny of the CPFE. Copyright © 2018 Elsevier Inc. All rights reserved.

Context-induced relapse to cocaine seeking after punishment-imposed abstinence is associated with activation of cortical and subcortical brain regions.

PubMed

Pelloux, Yann; Hoots, Jennifer K; Cifani, Carlo; Adhikary, Sweta; Martin, Jennifer; Minier-Toribio, Angelica; Bossert, Jennifer M; Shaham, Yavin

2018-03-01

We recently developed a rat model of context-induced relapse to alcohol seeking after punishment-imposed abstinence to mimic relapse after self-imposed abstinence due to adverse consequences of drug use. Here, we determined the model's generality to cocaine and have begun to explore brain mechanisms of context-induced relapse to cocaine seeking after punishment-imposed abstinence, using the activity marker Fos. In exp. 1, we trained rats to self-administer cocaine (0.75 mg/kg/infusion, 6 hours/day, 12 days) in context A. Next, we transferred them to context B where for the paired group, but not unpaired group, 50 percent of cocaine-reinforced lever presses caused aversive footshock. We then tested the rats for cocaine seeking under extinction conditions in contexts A and B. We also retested them for relapse after retraining in context A and repunishment in context B. In exp. 2, we used Fos immunoreactivity to determine relapse-associated neuronal activation in brain regions of rats exposed to context A, context B or neither context. Results showed the selective shock-induced suppression of cocaine self-administration and context-induced relapse after punishment-imposed abstinence in rats exposed to paired, but not unpaired, footshock. Additionally, context-induced relapse was associated with selective activation of dorsal and ventral medial prefrontal cortex, anterior insula, dorsal striatum, basolateral amygdala, paraventricular nucleus of the thalamus, lateral habenula, substantia nigra, ventral subiculum, and dorsal raphe, but not nucleus accumbens, central amygdala, lateral hypothalamus, ventral tegmental area and other brain regions. Together, context-induced relapse after punishment-imposed abstinence generalizes to rats with a history of cocaine self-administration and is associated with selective activation of cortical and subcortical regions. Published 2017. This article is a U.S. Government work and is in the public domain in the USA.

Sex differences in discriminating between cues predicting threat and safety.

PubMed

Day, Harriet L L; Reed, Molly M; Stevenson, Carl W

2016-09-01

Post-traumatic stress disorder (PTSD) is more prevalent in women than men. PTSD is characterized by overgeneralization of fear to innocuous stimuli and involves impaired inhibition of learned fear by cues that predict safety. While evidence indicates that learned fear inhibition through extinction differs in males and females, less is known about sex differences in fear discrimination and safety learning. Here we examined auditory fear discrimination in male and female rats. In Experiment 1A, rats underwent 1-3days of discrimination training consisting of one tone predicting threat (CS+; presented with footshock) and another tone predicting safety (CS-; presented alone). Females, but not males, discriminated between the CS+ and CS- after one day of training. After 2-3days of training, however, males discriminated whereas females generalized between the CS+ and CS-. In Experiment 1B, females showed enhanced anxiety-like behaviour and locomotor activity in the open field, although these results were unlikely to explain the sex differences in fear discrimination. In Experiment 2, we found no differences in shock sensitivity between males and females. In Experiment 3, males and females again discriminated and generalized, respectively, after three days of training. Moreover, fear generalization in females resulted from impaired safety learning, as shown by a retardation test. Whereas subsequent fear conditioning to the previous CS- retarded learning in males, females showed no such retardation. These results suggest that, while females show fear discrimination with limited training, they show fear generalization with extended training due to impaired safety learning. Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.

Dendritic structural plasticity in the basolateral amygdala after fear conditioning and its extinction in mice

PubMed Central

Heinrichs, Stephen C.; Leite-Morris, Kimberly A.; Guy, Marsha D.; Goldberg, Lisa R.; Young, Angela J.; Kaplan, Gary B.

2015-01-01

Previous research suggests that morphology and arborization of dendritic spines change as a result of fear conditioning in cortical and subcortical brain regions. This study uniquely aims to delineate these structural changes in the basolateral amygdala (BLA) after both fear conditioning and fear extinction. C57BL/6 mice acquired robust conditioned fear responses (70–80% cued freezing behavior) after six pairings with a tone cue associated with footshock in comparison to unshocked controls. During fear acquisition, freezing behavior was significantly affected by both shock exposure and trial number. For fear extinction, mice were exposed to the conditioned stimulus tone in the absence of shock administration and behavioral responses significantly varied by shock treatment. In the retention tests over 3 weeks, the percentage time spent freezing varied with the factor of extinction training. In all treatment groups, alterations in dendritic plasticity were analyzed using Golgi–Cox staining of dendrites in the BLA. Spine density differed between the fear conditioned group and both the fear extinction and control groups on third order dendrites. Spine density was significantly increased in the fear conditioned group compared to the fear extinction group and controls. Similarly in Sholl analyses, fear conditioning significantly increased BLA spine numbers and dendritic intersections while subsequent extinction training reversed these effects. In summary, fear extinction produced enduring behavioral plasticity that is associated with a reversal of alterations in BLA dendritic plasticity produced by fear conditioning. These neuroplasticity findings can inform our understanding of structural mechanisms underlying stress-related pathology can inform treatment research into these disorders. PMID:23570859

Introduction to the special issue on Social Darwinism.

PubMed

Albee, G W

1996-09-01

A brief history is provided of interventions with people with emotional disorders since the 1950s. A shortage of therapists is inescapable and even successful treatment does not change incidence. But the individual defect model supports the conservative view that causes are to be found inside people, rather than in social injustice. People who are defective are to be treated as part of the medical model that is extended to cover social problems. This view is an obvious extension of Social Darwinism that has long attributed success and failure to bad genes and good genes rather than to advantaged and disadvantaged social-economic environments.

Feminism and public health ethics

PubMed Central

Rogers, W A

2006-01-01

This paper sketches an account of public health ethics drawing upon established scholarship in feminist ethics. Health inequities are one of the central problems in public health ethics; a feminist approach leads us to examine not only the connections between gender, disadvantage, and health, but also the distribution of power in the processes of public health, from policy making through to programme delivery. The complexity of public health demands investigation using multiple perspectives and an attention to detail that is capable of identifying the health issues that are important to women, and investigating ways to address these issues. Finally, a feminist account of public health ethics embraces rather than avoids the inescapable political dimensions of public health. PMID:16731735

Feminism and public health ethics.

PubMed

Rogers, W A

2006-06-01

This paper sketches an account of public health ethics drawing upon established scholarship in feminist ethics. Health inequities are one of the central problems in public health ethics; a feminist approach leads us to examine not only the connections between gender, disadvantage, and health, but also the distribution of power in the processes of public health, from policy making through to programme delivery. The complexity of public health demands investigation using multiple perspectives and an attention to detail that is capable of identifying the health issues that are important to women, and investigating ways to address these issues. Finally, a feminist account of public health ethics embraces rather than avoids the inescapable political dimensions of public health.

The application of DEA model in enterprise environmental performance auditing

NASA Astrophysics Data System (ADS)

Li, F.; Zhu, L. Y.; Zhang, J. D.; Liu, C. Y.; Qu, Z. G.; Xiao, M. S.

2017-01-01

As a part of society, enterprises have an inescapable responsibility for environmental protection and governance. This article discusses the feasibility and necessity of enterprises environmental performance auditing and uses DEA model calculate the environmental performance of Haier for example. The most of reference data are selected and sorted from Haier’s environmental reportspublished in 2008, 2009, 2011 and 2015, and some of the data from some published articles and fieldwork. All the calculation results are calculated by DEAP software andhave a high credibility. The analysis results of this article can give corporate managements an idea about using environmental performance auditing to adjust their corporate environmental investments capital quota and change their company’s environmental strategies.

Chronic orofacial pain.

PubMed

Renton, T

2017-07-01

The issues specific to trigeminal pain include the complexity of the region, the problematic impact on daily function and significant psychological impact (J Dent, 43, 2015, 1203). By nature of the geography of the pain (affecting the face, eyes, scalp, nose, mouth), it may interfere with just about every social function we take for granted and enjoy (J Orofac Pain, 25, 2011, 333). The trigeminal nerve is the largest sensory nerve in the body, protecting the essential organs that underpin our very existence (brain, eyes, nose, mouth). It is no wonder that pain within the trigeminal system in the face is often overwhelming and inescapable for the affected individual. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Nurse education and convergent information technologies.

PubMed

Howard, B

This article concerns one of the main problems facing nurse education, that of meeting individualised learner needs. This endeavour is inescapable because of current trends in the curriculum, trends towards continuous assessment and more recently, advice from the English National Board (ENB) regarding continuous theoretical assessment. Computer assisted learning, it is suggested, can be helpful in nurturing individual learner progress. Sophisticated technologies are available to educationalists which develop individual learning strategies, but the cost of producing the necessary courseware is high, both in terms of money and tutor time. Hopefully a solution has been found as a project has been funded and is being run by the ENB allowing tutors to develop skills in this area of education.

Disclosure of computerized health care information: provider privacy rights under supply side competition.

PubMed

Watson, B L

1981-01-01

This Article explores the constitutional, statutory and common law privacy rights of physicians given the inescapable role of delivery data under supply side competition. The Article begins with a general review of the federal constitutional right of privacy. It then discusses the statutory protection given to physician-specific data under current federal law, and considers the insights gained from the controversy over physician data and the federal Freedom of Information Act. The remainder of the Article analyzes the usefulness of several common law causes of action to remedy the misuse of physician data, and concludes with recommendations which may obviate the need for litigation to protect against misuse of physician-specific data.

Vampires and resurrection men: the perils and pleasures of the embodied past in 1840s sensational fiction.

PubMed

Hackenberg, Sara

2009-01-01

This essay examines embodied representations of the past in two of the most popular penny serials of the 1840s, G.W.M. Reynolds's "The Mysteries of London" and James Malcolm Rymer's "Varney the Vampyre; or, The Feast of Blood." The cadaverous "Resurrection man" of "The Mysteries" and Sir Francis Varney the Vampire -- both villains figured as irrepressible, resurrected corpses -- corporealize the inescapable return of personal and political history. Functioning as shadowy doubles of their serials' virtuous heroes, these corpse-villains trouble melodramatic distinctions between virtue and vice, and their own deeply contradictory histories disrupt their novels' engagements with historical presence and historical agency.

The Breivik controversy: politics, terrorism and psychiatry.

PubMed

Tietze, Tad

2014-08-01

To examine and analyse the controversy over psychiatric aspects of the case of Norwegian far right mass murderer Anders Behring Breivik. Because of a basic acceptance of methodological individualism and scientific positivism, mainstream psychiatry is currently ill suited to being broadly applied to the spheres of politics and political violence. Rather than jettison psychiatric insights in such cases, the choices facing the profession are either to accept the narrowness of its utility or to work towards a theoretical framework that sees the individual psyche as socially embedded rather than as socially constitutive, and psychiatric science itself as socially constructed and hence inescapably value-laden. © The Royal Australian and New Zealand College of Psychiatrists 2014.

MANAGEMENT OF ENDOCRINE DISEASE: Can we cure Cushing's disease? A personal view.

PubMed

Bertagna, X

2018-05-01

One of today's challenges in endocrinology is the treatment of Cushing's disease: Although pituitary surgery has the potential to 'cure' the patient and restore a completely normal pituitary adrenal axis, there are immediate failures and late recurrences that will ultimately require alternate therapeutic approaches. Their high number is in direct correlation with their serious limitations and they all appear to be 'default options'. This 'personal view' tries to shed some light on the inescapable difficulties of the current treatments of Cushing's disease and to provide some optimistic view for the future where the pituitary adenoma should be the 'reasonable obsession' of a successful therapeutist. © 2018 European Society of Endocrinology.

Overlapping neurobiology of learned helplessness and conditioned defeat: Implications for PTSD and mood disorders

PubMed Central

Hammack, Sayamwong E.; Cooper, Matthew A.; Lezak, Kimberly R.

2012-01-01

Exposure to traumatic events can increase the risk for major depressive disorder (MDD) as well as posttraumatic stress disorder (PTSD), and pharmacological treatments for these disorders often involve the modulation of serotonergic (5-HT) systems. Several behavioral paradigms in rodents produce changes in behavior that resemble symptoms of MDD and these behavioral changes are sensitive to antidepressant treatments. Here we review two animal models in which MDD-like behavioral changes are elicited by exposure to an acute traumatic event during adulthood, learned helplessness (LH) and conditioned defeat. In LH, exposure of rats to inescapable, but not escapable, tailshock produces a constellation of behavioral changes that include deficits in fight/flight responding and enhanced anxiety-like behavior. In conditioned defeat, exposure of Syrian hamsters to a social defeat by a more aggressive animal leads to a loss of territorial aggression and an increase in submissive and defensive behaviors in subsequent encounters with non-aggressive conspecifics. Investigations into the neural substrates that control LH and conditioned defeat revealed that increased 5-HT activity in the dorsal raphe nucleus (DRN) is critical for both models. Other key brain regions that regulate the acquisition and/or expression of behavior in these two paradigms include the basolateral amygdala (BLA), central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST). In this review, we compare and contrast the role of each of these neural structures in mediating LH and conditioned defeat, and discuss the relevance of these data in developing a better understanding of the mechanisms underlying trauma-related depression. PMID:21396383

Treatment with escitalopram but not desipramine decreases escape latency times in a learned helplessness model using juvenile rats.

PubMed

Reed, Abbey L; Anderson, Jeffrey C; Bylund, David B; Petty, Frederick; El Refaey, Hesham; Happe, H Kevin

2009-08-01

The pharmacological treatment of depression in children and adolescents is different from that of adults due to the lack of efficacy of certain antidepressants in the pediatric age group. Our current understanding of why these differences occur is very limited. To develop more effective treatments, a juvenile animal model of depression was tested to validate it as a possible model to specifically study pediatric depression. Procedures for use with juvenile rats at postnatal day (PND) 21 and 28 were adapted from the adult learned helplessness model in which, 24 h after exposure to inescapable stress, animals are unable to remove themselves from an easily escapable stressor. Rats were treated for 7 days with either the selective serotonin reuptake inhibitor escitalopram at 10 mg/kg or the tricyclic antidepressant desipramine at 3, 10, or 15 mg/kg to determine if treatment could decrease escape latency times. Escitalopram treatment was effective at decreasing escape latency times in all ages tested. Desipramine treatment did not decrease escape latency times for PND 21 rats, but did decrease times for PND 28 and adult animals. The learned helplessness model with PND 21 rats predicts the efficacy of escitalopram and the lack of efficacy of desipramine seen in the treatment of pediatric depression. These findings suggest that the use of PND 21 rats in a modified learned helplessness procedure may be a valuable model of human pediatric depression that can predict pediatric antidepressant efficacy and be used to study antidepressant mechanisms involved in pediatric depression.

The role of the dorsomedial part of the prefrontal cortex serotonergic innervation in rat responses to the aversively conditioned context: behavioral, biochemical and immunocytochemical studies.

PubMed

Lehner, Małgorzata; Taracha, Ewa; Turzyńska, Danuta; Sobolewska, Alicja; Hamed, Adam; Kołomańska, Paulina; Skórzewska, Anna; Maciejak, Piotr; Szyndler, Janusz; Bidziński, Andrzej; Płaźnik, Adam

2008-10-10

In this study we have explored differences in animal reactivity to conditioned aversive stimuli using the conditioned fear test (a contextual fear-freezing response), in rats subjected to the selective lesion of the prefrontal cortex serotonergic innervation, and differing in their response to the acute painful stimulation, a footshock (HS--high sensitivity rats, and LS--low sensitivity rats, selected arbitrarily according to their behavior in the 'flinch-jump' pre-test). Local administration of serotonergic neurotoxin (5,7-dihydroxytryptamine) to the dorsomedial part of the prefrontal cortex caused a very strong, structure and neurotransmitter selective depletion of serotonin concentration. In HS rats, the serotonergic lesion significantly disinhibited rat behavior controlled by fear, enhanced c-Fos expression in the dorsomedial prefrontal area, and increased the concentration of GABA in the basolateral amygdala, measured in vivo after the testing session of the conditioned fear test. The LS animals revealed an opposite pattern of behavioral and biochemical changes after serotonergic lesion: an increase in the duration of a freezing response, and expression of c-Fos in the basolateral and central nuclei of amygdala, and a lower GABA concentration in the basolateral amygdala. In control conditions, c-Fos expression did not differ in LS and HS, naïve, not conditioned and not exposed to the test cage animals. The present study adds more arguments for the controlling role of serotonergic innervation of the dorsomedial part of the prefrontal cortex in processing emotional input by other brain centers. Moreover, it provides experimental data, which may help to better explain the anatomical and biochemical basis of differences in individual reactivity to stressful stimulation, and, possibly, to anxiolytic drugs with serotonergic or GABAergic profiles of action.

Postnatal LPS Challenge Impacts Escape Learning and Expression of Plasticity Factors Mmp9 and Timp1 in Rats: Effects of Repeated Training.

PubMed

Trofimov, Alexander; Strekalova, Tatyana; Mortimer, Niall; Zubareva, Olga; Schwarz, Alexander; Svirin, Evgeniy; Umriukhin, Aleksei; Svistunov, Andrei; Lesch, Klaus-Peter; Klimenko, Victor

2017-08-01

Bacterial intoxication associated with inflammatory conditions during development can impair brain functions, in particular evolutionarily novel forms of memory, such as explicit learning. Little is known about the dangers of early-life inflammation on more basic forms of learning, for example, the acquisition of motor escape abilities, which are generally better preserved under pathological conditions. To address this limitation in knowledge, an inflammatory response was elicited in Wistar pups by lipopolysaccharide (LPS) injections (25 μg/kg) on postnatal days P15, P18 and P21. The acquisition of escape behaviour was tested from P77 by active avoidance footshock model and water maze. Open-field behaviour and blood corticosterone levels were also measured. Rat brain tissue was collected from pups 2 h post-injection and from adult rats which either underwent escape training on P77-P81 or remained untrained. mRNA levels of developmental brain plasticity factors MMP-9 and TIMP-1 were investigated in the medial prefrontal cortex and ventral/dorsal hippocampus. LPS-challenged rats displayed moderately deficient escape responses in both memory tests, increased freezing behaviour and, surprisingly, reduced blood cortisol levels. Mmp9 and Timp1, and their ratio to one another, were differentially altered in pups versus adult untrained rats but remained unchanged overall in rats trained in either learning task. Together, our data indicate that systemic pro-inflammatory response during early postnatal development has long-lasting effects, including on the acquisition of motor escape abilities and plasticity factor expression, into adulthood. Our data suggest that altered stress response could possibly mediate these deviations and repeated training might generate positive effects on plasticity under the employed conditions.

Behavioral responses of deafened guinea pigs to intracochlear electrical stimulation: a new rapid psychophysical procedure.

PubMed

Agterberg, Martijn J H; Versnel, Huib

2014-07-01

In auditory research the guinea pig is often preferred above rats and mice because of the easily accessible cochlea and because the frequency range of its hearing is more comparable to that of humans. Studies of the guinea-pig auditory system primarily apply histological and electrophysiological measures. Behavioral animal paradigms, in particular in combination with these histological and electrophysiological methods, are necessary in the development of new therapeutic interventions. However, the guinea pig is not considered an attractive animal for behavioral experiments. Therefore, the purpose of this study was to develop a behavioral task suitable for guinea pigs, that can be utilized in cochlear-implant related research. Guinea pigs were trained in a modified shuttle-box in which a stream of air was used as unconditioned stimulus (UCS). A stream of air was preferred over conventionally used methods as electric foot-shocks since it produces less stress, which is a confounding factor in behavioral experiments. Hearing guinea pigs were trained to respond to acoustic stimuli. They responded correctly within only five sessions of ten minutes. The animals maintained their performance four weeks after the right cochlea was implanted with an electrode array. After systemic deafening, the animals responded in the first session immediately to intracochlear electrical stimulation. These responses were not affected by daily chronic electrical stimulation (CES). In conclusion, the present study demonstrates that guinea pigs can be trained relatively fast to respond to acoustic stimuli, and that the training has a lasting effect, which generalizes to intracochlear electrical stimulation after deafening. Furthermore, it demonstrates that bilaterally deafened guinea pigs with substantial (∼50%) loss of spiral ganglion cells (SGCs), detect intracochlear electrical stimulation. Copyright © 2014 Elsevier B.V. All rights reserved.

Augmentation of the noradrenergic system in alpha-2 adrenergic receptor deficient mice: anatomical changes associated with enhanced fear memory.

PubMed

Davies, M Frances; Tsui, Janet Y; Flannery, Judy A; Li, Xiangqi; DeLorey, Timothy M; Hoffman, Brian B

2003-10-03

We have investigated sensitivity to the conditioned fear procedure of mice is influenced by the genetic deletion of alpha2A adrenoceptors (ARs). We observed a heightened freezing response in the discrete cue memory test in alpha2A AR knockout (alpha2A AR KO) mice and in D79N mice, a transgenic mouse strain with functionally impaired alpha2A ARs. No significant differences in contextual memory were observed between control and alpha2A AR KO or D79N mice suggesting a minimal role for the noradrenergic system in contextual memory. We speculated that the increased freezing response of the alpha2A AR KO and D79N mice in the discrete cue setting was due to increased release of norepinephrine evoked by the unconditioned footshock stimulus. In alpha2A AR KO mice we measured a doubling in the number of noradrenergic neurons in the locus coeruleus (LC) and a large increase in the cell volume of tyrosine hydroxylase positive neurons, likely due to selective preservation of large, multipolar neurons in the subcoeruleus. Hyperplasia of the noradrenergic neurons in the nucleus tractus solitarius, A5 and A7, was also observed. Alpha2A AR KO mice exhibit greater c-Fos expression in the LC compared to wild type mice suggesting that the LC neurons in the alpha2A AR KO mice were spontaneously more active. This study suggests that alpha2A ARs are involved in the development of the central noradrenergic system and raises the possibility that alterations in alpha2A AR expression may contribute to variations in fear and stress responses.

A Rodent “Self-Report” Measure of Methamphetamine Craving? Rat Ultrasonic Vocalizations During Methamphetamine Self-Administration, Extinction, and Reinstatement

PubMed Central

Mahler, Stephen V.; Moorman, David E.; Feltenstein, Matthew W.; Cox, Brittney M.; Ogburn, Katelyn B.; Bachar, Michal; McGonigal, Justin T.; Ghee, Shannon M.; See, Ronald E.

2012-01-01

Rats emit ultrasonic vocalizations (USVs) in a variety of contexts, and it is increasingly clear that USVs reflect more complex information than mere positive and negative affect states. We sought to examine USVs in a common model of addiction and relapse, the self-administration/reinstatement paradigm, in order to gain insight into subjective states experienced by rats during various types of methamphetamine seeking. We measured three subtypes of “50kHz” USVs [flats, trills, and non-trill frequency modulated USVs (FMs)], as well as long and short duration “22kHz” USVs, during self-administration and extinction training, and during reinstatement elicited by cues, a methamphetamine prime, cues + prime, or the pharmacological stressor yohimbine. During self-administration and extinction, rats emitted many flats and FMs, (and short duration “22kHz” USVs on day 1 of self-administration), but few trills. In contrast, methamphetamine priming injections potently enhanced FMs and trills, and trill production was correlated with the degree of methamphetamine + cue-elicited reinstatement. Cues alone yielded increases only in flat USVs during reinstatement, though a subset of rats displaying strong cue-induced reinstatement also emitted long duration, aversion-related “22kHz” USVs. Although yohimbine administration caused reinstatement, it did not induce “22kHz” USVs in methamphetamine-experienced or methamphetamine-naïve rats (unlike footshock stress, which did induce long duration “22kHz” USVs). These findings demonstrate heterogeneity of rat USVs emitted during different types of methamphetamine seeking, and highlight their potential usefulness for gaining insight into the subjective states of rats in rodent models of drug addiction and relapse. PMID:22940018

Impairment of contextual conditioned fear extinction after microinjection of alpha-1-adrenergic blocker prazosin into the medial prefrontal cortex.

PubMed

Do-Monte, Fabrício H M; Allensworth, Melody; Carobrez, Antônio P

2010-07-29

Long-lasting memories of aversive or stressful events have been associated with the noradrenergic system activation. Alpha-1-adrenergic antagonist prazosin has successfully been used in the last years to treat anxiety disorders related to aversive memories recurrence in humans. Contextual conditioned fear extinction paradigm in rats has been used to better understand the mechanisms involved in the attenuation of defensive behaviour after a traumatic situation. Here we investigated the effects of systemic administration of prazosin in the fear extinction processes. Rats were previously paired in a contextual fear conditioning box (1 footshock, 1 mA, 2s duration), further returning to the same box during three consecutive days receiving an intraperitoneal injection of vehicle or prazosin 30 min before (acquisition of extinction; 0.1 or 0.5mg/kg) or immediately after (consolidation of extinction, 0.5 or 1.5mg/kg) each extinction session (10 min). On the last day, all animals were re-exposed undrugged to the apparatus. Since the medial prefrontal cortex (mPFC) has been described as a key structure in the modulation of conditioned fear extinction, the effects of intra-mPFC microinjection (0.2 microl per side) of vehicle (PBS) or prazosin (0.75 or 2.5 nmol) in the acquisition of fear extinction (10 min before extinction session 1) were further evaluated. Subjects were drug-free re-exposed to the same box in the next day (extinction session 2). The percentage of freezing time was used as the memory retention parameter. The results showed that either systemic or intra-mPFC-alpha-1-adrenergic blockade increased the freezing time in the last extinction sessions, suggesting impairment of the extinction of contextual conditioned fear in rats. Copyright 2010 Elsevier B.V. All rights reserved.

Overexpression of CREB in the nucleus accumbens shell increases cocaine reinforcement in self-administering rats.

PubMed

Larson, Erin B; Graham, Danielle L; Arzaga, Rose R; Buzin, Nicole; Webb, Joseph; Green, Thomas A; Bass, Caroline E; Neve, Rachael L; Terwilliger, Ernest F; Nestler, Eric J; Self, David W

2011-11-09

Chronic exposure to addictive drugs enhances cAMP response element binding protein (CREB)-regulated gene expression in nucleus accumbens (NAc), and these effects are thought to reduce the positive hedonic effects of passive cocaine administration. Here, we used viral-mediated gene transfer to produce short- and long-term regulation of CREB activity in NAc shell of rats engaging in volitional cocaine self-administration. Increasing CREB expression in NAc shell markedly enhanced cocaine reinforcement of self-administration behavior, as indicated by leftward (long-term) and upward (short-term) shifts in fixed ratio dose-response curves. CREB also increased the effort exerted by rats to obtain cocaine on more demanding progressive ratio schedules, an effect highly correlated with viral-induced modulation of BDNF protein in the NAc shell. CREB enhanced cocaine reinforcement when expressed either throughout acquisition of self-administration or when expression was limited to postacquisition tests, indicating a direct effect of CREB independent of reinforcement-related learning. Downregulating endogenous CREB in NAc shell by expressing a short hairpin RNA reduced cocaine reinforcement in similar tests, while overexpression of a dominant-negative CREB(S133A) mutant had no significant effect on cocaine self-administration. Finally, increasing CREB expression after withdrawal from self-administration enhanced cocaine-primed relapse, while reducing CREB levels facilitated extinction of cocaine seeking, but neither altered relapse induced by cocaine cues or footshock stress. Together, these findings indicate that CREB activity in NAc shell increases the motivation for cocaine during active self-administration or after withdrawal from cocaine. Our results also highlight that volitional and passive drug administration can lead to substantially different behavioral outcomes.

The just provision of health care: a reply to Elizabeth Telfer.

PubMed Central

Steiner, H

1976-01-01

Dr Hillel Steiner in this reply to Elizabeth Telfer takes each of her arguments for different arrangements of a health service and examines them--'four positions which can be located on a linear ideological spectrum'--and adds a fifth which could have the effect of 'turning the alleged linear spectrum into a circle'. Underlying both Elizabeth Telfer's article and Dr Steiner's reply, the base is inescapably a 'political' one, but cannot be abandoned in favour of purely philosophical concepts. Whatever the attitude of mind of the reader of these two papers to the provision of a health service, the stimulus to more careful assessments of our own National Health Service and its problems can only be good. PMID:1003436

Magnetic fusion commercial power plants

NASA Astrophysics Data System (ADS)

Sheffield, J.

Toroidal magnetic systems present the best opportunity to make a commercial fusion power plant. They offer potential solutions to the main requirements that confront a power plant designer. An ideal system may be postulated in which the coils are a very small part of the cost, and the cost stems primarily from the inescapable components: minimal plasma heating (and sustaining system), tritium breeding blanket, shield, particle input, removal and treatment system, heat transfer system, generators, buildings, and balance of plant. No present system meets the ideal standards; however, toroidal systems contain among them the elements required. Consequently, a logical program may be based upon an evolutionary development, building on the contributions of the tokamak, which has been the mainline of research for a number of years.

Contributions of Behavioral Systems Science to Leadership for a New Progressive Movement.

PubMed

Mattaini, Mark A; Aspholm, Roberto

2016-05-01

We argue in this paper that we are in the midst of a period in which fundamental global change will be required if societies and many species, perhaps even our own, are to survive. The realities are inescapable, and the potential implications are likely to affect nearly every dimension of human life in the USA and globally. Current trends are discouraging and will be extraordinarily difficult to shift, given global structural realities. It is hard to imagine a time when effective leadership is more necessary or will be more challenging. Our thesis here is that behavioral systems science can contribute in meaningful ways to shaping and sustaining such leadership, leadership required to advance a new progressive movement.

Differential effects of adding and removing components of a context on the generalization of conditional freezing.

PubMed

González, Felisa; Quinn, Jennifer J; Fanselow, Michael S

2003-01-01

Rats were conditioned across 2 consecutive days where a single unsignaled footshock was presented in the presence of specific contextual cues. Rats were tested with contexts that had additional stimulus components either added or subtracted. Using freezing as a measure of conditioning, removal but not addition of a cue from the training context produced significant generalization decrement. The results are discussed in relation to the R. A. Rescorla and A. R. Wagner (1972), J. M. Pearce (1994), and A. R. Wagner and S. E. Brandon (2001) accounts of generalization. Although the present data are most consistent with elemental models such as Rescorla and Wagner, a slight modification of the Wagner-Brandon replaced-elements model that can account for differences in the pattern of generalization obtained with contexts and discrete conditional stimuli is proposed.

Attacking Heterogeneity in Schizophrenia by Deriving Clinical Subgroups From Widely Available Symptom Data.

PubMed

Dickinson, Dwight; Pratt, Danielle N; Giangrande, Evan J; Grunnagle, MeiLin; Orel, Jennifer; Weinberger, Daniel R; Callicott, Joseph H; Berman, Karen F

2018-01-13

Previous research has identified (1) a "deficit" subtype of schizophrenia characterized by enduring negative symptoms and diminished emotionality and (2) a "distress" subtype associated with high emotionality-including anxiety, depression, and stress sensitivity. Individuals in deficit and distress categories differ sharply in development, clinical course and behavior, and show distinct biological markers, perhaps signaling different etiologies. We tested whether deficit and distress subtypes would emerge from a simple but novel data-driven subgrouping analysis, based on Positive and Negative Syndrome Scale (PANSS) negative and distress symptom dimensions, and whether subgrouping was informative regarding other facets of behavior and brain function. PANSS data, and other assessments, were available for 549 people with schizophrenia diagnoses. Negative and distress symptom composite scores were used as indicators in 2-step cluster analyses, which divided the sample into low symptom (n = 301), distress (n = 121), and deficit (n = 127) subgroups. Relative to the low-symptom group, the deficit and distress subgroups had comparably higher total PANSS symptoms (Ps < .001) and were similarly functionally impaired (eg, global functioning [GAF] Ps < .001), but showed markedly different patterns on symptom, cognitive and personality variables, among others. Initial analyses of functional magnetic resonance imaging (fMRI) data from a 182-participant subset of the full sample also suggested distinct patterns of neural recruitment during working memory. The field seeks more neuroscience-based systems for classifying psychiatric conditions, but these are inescapably behavioral disorders. More effective parsing of clinical and behavioral traits could identify homogeneous target groups for further neural system and molecular studies, helping to integrate clinical and neuroscience approaches. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center 2017.

Epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression.

PubMed

Su, Chun-Lin; Su, Chun-Wei; Hsiao, Ya-Hsin; Gean, Po-Wu

2016-05-01

Major depressive disorder (MDD), one of the most common mental disorders, is a significant risk factor for suicide and causes a low quality of life for many people. However, the causes and underlying mechanism of depression remain elusive. In the current work, we investigated epigenetic regulation of BDNF in the learned helplessness-induced animal model of depression. Mice were exposed to inescapable stress and divided into learned helplessness (LH) and resilient (LH-R) groups depending on the number they failed to escape. We found that the LH group had longer immobility duration in the forced swimming test (FST) and tail suspension tests (TST), which is consistent with a depression-related phenotype. Western blotting analysis and enzyme-linked immunosorbent assay (ELISA) revealed that the LH group had lower BDNF expression than that of the LH-R group. The LH group consistently had lower BDNF mRNA levels, as detected by qPCR assay. In addition, we found BDNF exon IV was down-regulated in the LH group. Intraperitoneal injection of imipramine or histone deacetylase inhibitors (HDACi) to the LH mice for 14 consecutive days ameliorated depression-like behaviors and reversed the decrease in BDNF. The expression of HDAC5 was up-regulated in the LH mice, and a ChIP assay revealed that the level of HDAC5 binding to the promoter region of BDNF exon IV was higher than that seen in other groups. Knockdown of HDAC5 reduced depression-like behaviors in the LH mice. Taken together, these results suggest that epigenetic regulation of BDNF by HDAC5 plays an important role in the learned helplessness model of depression. Copyright © 2016 Elsevier Ltd. All rights reserved.

‘To do or not to do’? The neurobiology of decision-making in daily life: I. Getting the basics

PubMed Central

Palmini, André; Haase, Victor Geraldi

2007-01-01

The constant conflict between decisions leading to immediate pleasurable consequences versus behaviors aiming at long-term social advantages is reviewed here in the framework of the evolutionary systems regulating behavior. The inescapable temporal perspective in decision-making in everyday life is highlighted and integrated with the role of the executive functions in the modulation of subcortical systems. In particular, the representations of the ‘non-existent’ future in the prefrontal cortical regions and how these representations can bridge theory and practice in everyday life are addressed. Relevant discussions regarding the battle between emotions and reasons in the determination of more complex decisions in the realm of neuroeconomics and in moral issues have been reserved for a second essay. PMID:29213362

Virtual Violence.

PubMed

2016-08-01

In the United States, exposure to media violence is becoming an inescapable component of children's lives. With the rise in new technologies, such as tablets and new gaming platforms, children and adolescents increasingly are exposed to what is known as "virtual violence." This form of violence is not experienced physically; rather, it is experienced in realistic ways via new technology and ever more intense and realistic games. The American Academy of Pediatrics continues to be concerned about children's exposure to virtual violence and the effect it has on their overall health and well-being. This policy statement aims to summarize the current state of scientific knowledge regarding the effects of virtual violence on children's attitudes and behaviors and to make specific recommendations for pediatricians, parents, industry, and policy makers. Copyright © 2016 by the American Academy of Pediatrics.

Hippocampal awake replay in fear memory retrieval

PubMed Central

Wu, Chun-Ting; Haggerty, Daniel; Kemere, Caleb; Ji, Daoyun

2017-01-01

Hippocampal place cells are key to episodic memories. How these cells participate in memory retrieval remains unclear. Here, after rats acquired a fear memory by receiving mild foot-shocks at a shock zone of a track, we analyzed place cells when the animals were placed back to the track and displayed an apparent memory retrieval behavior: avoidance of the shock zone. We found that place cells representing the shock zone were reactivated, despite the fact that the animals did not enter the shock zone. This reactivation occurred in ripple-associated awake replay of place cell sequences encoding the paths from the animal’s current positions to the shock zone, but not in place cell sequences within individual cycles of theta oscillation. The result reveals a specific place cell pattern underlying the inhibitory avoidance behavior and provides strong evidence for the involvement of awake replay in fear memory retrieval. PMID:28218916

Sex-specific effect of the anabolic steroid, 17α-methyltestosterone, on inhibitory avoidance learning in periadolescent rats

PubMed Central

Ramos-Pratts, Keyla; Rosa-González, Dariana; Pérez-Acevedo, Nivia L.; Cintrón-López, Dahima; Barreto-Estrada, Jennifer L.

2013-01-01

The illicit use of anabolic androgenic steroids (AAS) has gained popularity among adolescents in the last decade. However, although it is known that exposure to AAS impairs cognition in adult animal models, the cognitive effects during adolescence remain undetermined. An inhibitory avoidance task (IAT) was used to assess the effect of AAS (17α-methyltestosterone; 17α-meT-7.5 mg/kg) in male and female periadolescent rats. A single injection of 17α-meT immediately before the footshock produced significant impairment of inhibitory avoidance learning in males but not females. Generalized anxiety, locomotion, and risk assessment behaviors (RAB) were not affected. Our results show that exposure to a single pharmacological dose of 17α-meT during periadolescence exerts sex-specific cognitive effects without affecting anxiety. Thus, disruption of the hormonal milieu during this early developmental period might have negative impact on learning and memory. PMID:23792034

Successful Beam-Beam Tuneshift Compensation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bishofberger, Kip Aaron

2005-01-01

The performance of synchrotron colliders has been limited by the beam-beam limit, a maximum tuneshift that colliding bunches could sustain. Due to bunch-to-bunch tune variation and intra-bunch tune spread, larger tuneshifts produce severe emittance growth. Breaking through this constraint has been viewed as impossible for several decades. This dissertation introduces the physics of ultra-relativistic synchrotrons and low-energy electron beams, with emphasis placed on the limits of the Tevatron and the needs of a tuneshift-compensation device. A detailed analysis of the Tevatron Electron Lens (T EL) is given, comparing theoretical models to experimental data whenever possible. Finally, results of Tevatron operationsmore » with inclusion of the T EL are presented and analyzed. It is shown that the T EL provides a way to shatter the previously inescapable beam-beam limit.« less

Einstein and Time in Physics and Philosophy

NASA Astrophysics Data System (ADS)

Canales, Jimena

Current debates about time have left ``a hole at the heart of physics'' (Scientific American, Sept 2002). The main problem with contemporary explanations is usually traced to Einstein's theory of relativity, to the notion of a ``block universe,'' and to his famous claim that ``the distinction between the past, present and future is only a stubbornly persistent illusion.'' While some scientist have tried to incorporate elements of our experience of time into our explanations of the universe, others continue to claim that our sense of time is simply illusory. Can these debates be solved by science alone or are they inescapably philosophical, historical and cultural? My talk will explore the origins of this persistent quandary by focusing on the relation of physics to philosophy, history and the humanities. Can we solve the problem of time without engaging in ``Science Wars''?

The physics four-year degree as passport to the workplace

NASA Astrophysics Data System (ADS)

Holcomb, D. F.

1997-03-01

A small fraction of our physics major students (about 7%) will be our descendants in the university. Another 7% will take up careers in physics or cognate areas based on their Ph.D. degrees. Most of the remaining graduates will go on to non-physics careers. What is a proper physics education for these varied career paths? Presenters at the ICUPE concentrated on the first of the conference themes, namely, "In the light of changes in the workplace, what should be new educational goals for the physics major program?" Efforts of a rapporteur to synthesize lead inescapably to a personal viewpoint. I'll describe the common themes and conclusions which I heard, and add a few related comments from my own experience. ICUPE participants also heard the talks and can footnote my remarks according to their own hearing.

Activation of type 4 dopaminergic receptors in the prelimbic area of medial prefrontal cortex is necessary for the expression of innate fear behavior.

PubMed

Vergara, Macarena D; Keller, Victor N; Fuentealba, José A; Gysling, Katia

2017-05-01

The prelimbic area (PL) of the medial Prefrontal cortex (mPFC) is involved in the acquisition and expression of conditioned and innate fear. Both types of fear share several neuronal pathways. It has been documented that dopamine (DA) plays an important role in the regulation of aversive memories in the mPFC. The exposure to an aversive stimulus, such as the smell of a predator odor or the exposure to footshock stress is accompanied by an increase in mPFC DA release. Evidence suggests that the type 4 dopaminergic receptor (D4R) is the molecular target through which DA modulates fear expression. In fact, the mPFC is the brain region with the highest expression of D4R; however, the role of D4R in the expression of innate fear has not been fully elucidated. Therefore, the principal objective of this work was to evaluate the participation of mPFC D4R in the expression of innate fear. Rats were exposed to the elevated plus-maze (EPM) and to the cat odor paradigm after the intra PL injection of L-745,870, selective D4R antagonist, to measure the expression of fear-related behaviors. Intra PL injection of L-745,870 increased the time spent in the EPM open arms and decreased freezing behavior in the cat odor paradigm. Our results also showed that D4R is expressed in GABAergic and pyramidal neurons in the PL region of PFC. Thus, D4R antagonism in the PL decreases the expression of innate fear-behavior indicating that the activation of D4R in the PL is necessary for the expression of innate fear-behavior. Copyright © 2017 Elsevier B.V. All rights reserved.

Postseismic Deformation: Different mechanisms in different times and places.

NASA Astrophysics Data System (ADS)

Segall, P.

2004-12-01

Improved understanding of postseismic deformation may elucidate time dependent stress transfer and triggered seismicity following large earthquakes. Afterslip, distributed viscoelastic flow, and poroelastic relaxation alter crustal stress and pore pressure distributions and in many cases lead to distinctive surface deformation patterns. Delayed triggering, due to rate and state dependent friction, on the other hand need not lead to detectable surface deformation. Postseismic deformation recorded following the 1999 ChiChi, Taiwan, 2003 Tokachi-Oki, Japan, and 2000 south Iceland earthquakes can be used to test for the effects of these processes. Horizontal displacements of 10 cm accumulated in the first year following the Chi-Chi quake. These are best explained with continued slip on the Chelungpu fault (Hsu et al, G.R.L. 2002). Inversions indicate the afterslip was roughly localized in a ring around the locus of maximum coseismic slip. The observed displacement pattern is inconsistent with predictions from viscoelastic and poroelastic models. Viscoelastic relaxation of the lower crust produces shortening of the hanging wall instead of the observed extension. The fully drained poroelastic response predicts deformation concentrated near the fault ends, which was not observed. Fully time dependent calculations, however, are still required because poroelastic displacements need not be monotonic. Afterslip following the M 8 Tokachi Oki earthquake is also localized around the area of high mainshock slip (Miyazaki et al, GRL, 2004). Surprisingly, the slip is not located downdip of the mainshock, but along strike of the source region. This indicates that the transient deformation is not caused by deceleration of the earthquake instability, but rather by stress increases due to the mainshock. A major question is whether intermediate depth afterslip following the Tokachi Oki and ChiChi earthquakes occurs in stable (steady state velocity strengthening) areas which will never initiate fast earthquake slip, or on unstable (velocity weakening) parts of the fault that slipped in a stable fashion following the earthquakes due to the pre-earthquake fault state and stress. Resolution of this question has important implications for future earthquakes in these areas. Postseismic deformation in the month following the South Iceland earthquakes was clearly detected by InSAR. The spatial and temporal patterns are inconsistent with both afterslip and viscoelastic deformation. The InSAR data are, however, well explained by a rapid poroelastic response. This was confirmed by water level changes with the same spatial and temporal scales as the deformation (Jónsson et al, Nature, 2003). The decay of aftershocks is substantially longer that the poroelastic relaxation, suggesting that poroelastic effects do not control the timing of triggered earthquakes. The InsAR data, however, are insensitive to pore pressure changes at the depths of most aftershocks. At longer time scales, other processes dominate the observed deformation (Arnadottir, this meeting). An inescapable conclusion of these studies is that different physical processes dominate postseismic deformation in different geologic environments at different time scales.

Bed bugs, public health, and social justice: Part 2, An opinion survey.

PubMed

Eddy, Christopher; Jones, Susan C

2011-04-01

Bed bug infestations have resurged globally, nationally, and locally, yet the public health community in the U.S. has yet to mount a coordinated response to the escalating bed bug problem. Surveys of attendees at the 2009 National Environmental Health Association Annual Educational Conference & Exhibition, 2009 Ohio Association of Health Commissioners Fall Conference, 2009 Central Ohio Bed Bug Summit, and 2010 Hamilton County Council on Aging Annual Conference were conducted to gauge opinions about bed bugs. Survey results revealed that 90% of all respondents considered bed bugs to be a public health concern, and 73% indicated that bed bugs pose an environmental justice concern. These findings, which indicate that bed bugs are an inescapable public health mandate with environmental justice undertones, should rally public health agencies at federal, state, and local levels to respond with authority of agency to the escalating bed bug problem.

The speed-accuracy tradeoff: history, physiology, methodology, and behavior

PubMed Central

Heitz, Richard P.

2014-01-01

There are few behavioral effects as ubiquitous as the speed-accuracy tradeoff (SAT). From insects to rodents to primates, the tendency for decision speed to covary with decision accuracy seems an inescapable property of choice behavior. Recently, the SAT has received renewed interest, as neuroscience approaches begin to uncover its neural underpinnings and computational models are compelled to incorporate it as a necessary benchmark. The present work provides a comprehensive overview of SAT. First, I trace its history as a tractable behavioral phenomenon and the role it has played in shaping mathematical descriptions of the decision process. Second, I present a “users guide” of SAT methodology, including a critical review of common experimental manipulations and analysis techniques and a treatment of the typical behavioral patterns that emerge when SAT is manipulated directly. Finally, I review applications of this methodology in several domains. PMID:24966810

Interplay between defects, disorder and flexibility in metal-organic frameworks

NASA Astrophysics Data System (ADS)

Bennett, Thomas D.; Cheetham, Anthony K.; Fuchs, Alain H.; Coudert, François-Xavier

2017-01-01

Metal-organic frameworks are a novel family of chemically diverse materials, which are of interest across engineering, physics, chemistry, biology and medicine-based disciplines. Since the development of the field in its current form more than two decades ago, priority has been placed on the synthesis of new structures. However, more recently, a clear trend has emerged in shifting the emphasis from material design to exploring the chemical and physical properties of structures already known. In particular, although such nanoporous materials were traditionally seen as rigid crystalline structures, there is growing evidence that large-scale flexibility, the presence of defects and long-range disorder are not the exception in metal-organic frameworks, but the rule. Here we offer some perspective into how these concepts are perhaps inescapably intertwined, highlight recent advances in our understanding and discuss how a consideration of the interfaces between them may lead to enhancements of the materials' functionalities.

The birth of tragedy in pediatrics: a phronetic conception of bioethics.

PubMed

Carnevale, Franco A

2007-09-01

Accepted standards of parental decisional autonomy and child best interests do not address adequately the complex moral problems involved in the care of critically ill children. A growing body of moral discourse is calling for the recognition of ;tragedy' in selected human problems. A tragic dilemma is an irresolvable dilemma with forced terrible alternatives, where even the virtuous agent inescapably emerges with ;dirty hands'. The shift in moral framework described here recognizes that the form of conduct called for by tragic dilemmas is the practice of phronesis. The phronetic agent has acquired a capacity to discern good agency in tragic circumstances. This discernment is practiced through the artful creation of moral narratives: stories that convey that which is morally meaningful in a particular situation; that is, stories that are ;meaning making'. The phronetic agent addresses tragic dilemmas involving children as a narrator of contextualized temporal embodied human (counter)stories.

Evolutionary inevitability of sexual antagonism.

PubMed

Connallon, Tim; Clark, Andrew G

2014-02-07

Sexual antagonism, whereby mutations are favourable in one sex and disfavourable in the other, is common in natural populations, yet the root causes of sexual antagonism are rarely considered in evolutionary theories of adaptation. Here, we explore the evolutionary consequences of sex-differential selection and genotype-by-sex interactions for adaptation in species with separate sexes. We show that sexual antagonism emerges naturally from sex differences in the direction of selection on phenotypes expressed by both sexes or from sex-by-genotype interactions affecting the expression of such phenotypes. Moreover, modest sex differences in selection or genotype-by-sex effects profoundly influence the long-term evolutionary trajectories of populations with separate sexes, as these conditions trigger the evolution of strong sexual antagonism as a by-product of adaptively driven evolutionary change. The theory demonstrates that sexual antagonism is an inescapable by-product of adaptation in species with separate sexes, whether or not selection favours evolutionary divergence between males and females.

A Science Superior to Music: Joseph Sauveur and the Estrangement between Music and Acoustics

NASA Astrophysics Data System (ADS)

Fix, Adam

2015-09-01

The scientific revolution saw a shift from the natural philosophy of music to the science of acoustics. Joseph Sauveur (1653-1716), an early pioneer in acoustics, determined that science as understood in the eighteenth century could not address the fundamental problems of music, particularly the problem of consonance. Building on Descartes, Mersenne, and Huygens especially, Sauveur drew a sharp divide between sound and music, recognizing the former as a physical phenomenon obeying mechanical and mathematical principles and the latter as an inescapably subjective and unquantifiable perception. While acoustics grew prominent in the Académie des sciences, music largely fell out of the scientific discourse, becoming primarily practiced art rather than natural philosophy. This study illuminates what was considered proper science at the dawn of the Enlightenment and why one particular branch of natural philosophy—music—did not make the cut.

Designing the Balloon Experimental Twin Telescope for Infrared Interferometry

NASA Technical Reports Server (NTRS)

Rinehart, Stephen

2011-01-01

While infrared astronomy has revolutionized our understanding of galaxies, stars, and planets, further progress on major questions is stymied by the inescapable fact that the spatial resolution of single-aperture telescopes degrades at long wavelengths. The Balloon Experimental Twin Telescope for Infrared Interferometry (BETTII) is an 8-meter boom interferometer to operate in the FIR (30-90 micron) on a high altitude balloon. The long baseline will provide unprecedented angular resolution (approx. 5") in this band. In order for BETTII to be successful, the gondola must be designed carefully to provide a high level of stability with optics designed to send a collimated beam into the cryogenic instrument. We present results from the first 5 months of design effort for BETTII. Over this short period of time, we have made significant progress and are on track to complete the design of BETTII during this year.

The inescapable smart impact detection system (ISIS): An ubiquitous and personalized fall detector based on a distributed 'divide and conquer strategy'.

PubMed

Prado-Velasco, Manuel; del Rio-Cidoncha, Maria Gloria; Ortiz-Marin, Rafael

2008-01-01

Despite the intense research in the last decade with the aim of developing a reliable solution for fall detection in the elderly and other risk populations, it can be asserted that the diffusion of fall detectors in the geriatric practice is near null. This scenario is similar to the very scarce use of telemedicine in healthcare. The present work begins analyzing why fall detectors have not achieved to permeate the industry. That road is used to know the drawbacks of current devices and systems, besides to allow studying several important concepts underlying the principles of fall detection. A novel smart detection system based on that survey is finally briefly presented. The design of this device is founded on the experience and results obtained by an earlier device that was designed in the framework of the thesis of one of the authors.

Changes of Protein Turnover in Aging Caenorhabditis elegans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dhondt, Ineke; Petyuk, Vladislav A.; Bauer, Sophie

Protein turnover rates severely decline in aging organisms, including C. elegans. However, limited information is available on turnover dynamics at the individual protein level during aging. We followed changes in protein turnover at one-day resolution using a multiple-pulse 15Nlabeling and accurate mass spectrometry approach. Forty percent of the proteome shows gradual slowdown in turnover with age, whereas only few proteins show increased turnover. Decrease in protein turnover was consistent for only a minority of functionally related protein subsets, including tubulins and vitellogenins, whereas randomly diverging turnover patterns with age were the norm. Our data suggests increased heterogeneity of protein turnovermore » of the translation machinery, whereas protein turnover of ubiquitin-proteasome and antioxidant systems are well-preserved over time. Hence, we presume that maintenance of quality control mechanisms is a protective strategy in aging worms, although the ultimate proteome collapse is inescapable.« less

Retrograde Accretion Discs in High-Mass Be/X-Ray Binaries

NASA Technical Reports Server (NTRS)

Christodoulou, D. M.; Laycock, S. G. T.; Kazanas, D.

2017-01-01

We have compiled a comprehensive library of all X-ray observations of Magellanic pulsars carried out by XMM-Newton, Chandra and RXTE in the period 1997-2014. In this work, we use the data from 53 high-mass Be/X-ray binaries in the Small Magellanic Cloud to demonstrate that the distribution of spin-period derivatives versus spin periods of spinning-down pulsars is not at all different from that of the accreting spinning-up pulsars. The inescapable conclusion is that the up and down samples were drawn from the same continuous parent population; therefore, Be/X-ray pulsars that are spinning down over periods spanning 18 yr are, in fact, accreting from retrograde discs. The presence of prograde and retrograde discs in roughly equal numbers supports a new evolutionary scenario for Be/X-ray pulsars in their spin period-period derivative diagram.

Novel monoamine oxidase A knock out mice with human-like spontaneous mutation.

PubMed

Scott, Anna L; Bortolato, Marco; Chen, Kevin; Shih, Jean C

2008-05-07

A novel line of mutant mice [monoamine oxidase A knockout (MAOA KO)] harboring a spontaneous point nonsense mutation in exon 8 of the MAO A gene was serendipitously identified in a 129/SvEvTac colony. This mutation is analogous to the cause of a rare human disorder, Brunner syndrome, characterized by complete MAO A deficiency and impulsive aggressiveness. Concurrent with previous studies of MAO A KO mice generated by insertional mutagenesis ('Tg8'), MAOA(A863T) KO lack MAO A enzyme activity and display enhanced aggression toward intruder mice. MAOA(A863T) KO, however, exhibited lower locomotor activity in a novel, inescapable open field and similar immobility during tail suspension compared with wild type, observations which differ from reports of Tg8. These findings consolidate evidence linking MAO A to aggression and highlight subtle yet distinctive phenotypical characteristics.

Novel monoamine oxidase A knock out mice with human-like spontaneous mutation

PubMed Central

Scott, Anna L.; Bortolato, Marco; Chen, Kevin; Shih, Jean C.

2012-01-01

A novel line of mutant mice [monoamine oxidase A knockout (MAOAA863T KO)] harboring a spontaneous point nonsense mutation in exon 8 of the MAO A gene was serendipitously identified in a 129/SvEvTac colony. This mutation is analogous to the cause of a rare human disorder, Brunner syndrome, characterized by complete MAO A deficiency and impulsive aggressiveness. Concurrent with previous studies of MAO A KO mice generated by insertional mutagenesis (‘Tg8’), MAOAA863T KO lack MAO A enzyme activity and display enhanced aggression toward intruder mice. MAOAA863T KO, however, exhibited lower locomotor activity in a novel, inescapable open field and similar immobility during tail suspension compared with wild type, observations which differ from reports of Tg8. These findings consolidate evidence linking MAO A to aggression and highlight subtle yet distinctive phenotypical characteristics. PMID:18418249

Medicine and Mind-Body Dualism: A Reply to Mehta's Critique.

PubMed

Joubert, Callie

2014-01-01

Neeta Mehta recently advanced the thesis that medical practice is facing a crisis today. In her paper "Mind-body dualism: a critique from a health perspective" she attributes the crisis to the philosophy of Descartes and set out to understand why this dualism is still alive despite its disavowal from philosophers, health practitioners and lay people. The aim of my reply to her critique is three-fold. First, I draw attention to a more fundamental problem and show that dualism is inescapable-scientifically and commonsensically. I then focus on the self-conscious emotions of shame, guilt and remorse, and argue that the self is not identical with a brain. The third section draws attention to the crisis in psychiatry and stipulates some of the main reasons why this is so. Contrary to Mehta's thesis, the health profession faces a crisis because of physicalism and biological reductionism.

Pulmonary Metastasectomy: A Common Practice Based on Weak Evidence

PubMed Central

Treasure, Tom

2007-01-01

The resection of secondary metastases from the lungs is a wide-spread surgical practice. Patients are referred from coloproctology teams to thoracic surgeons specifically for this surgery. What is the expected benefit? I have explored the rationale and searched the literature in order to present these patients with a well-informed opinion for their consideration. I find only weak evidence based on uncontrolled retrospective series which have been interpreted as showing a survival benefit. This has been extrapolated to policy and practice that do not stand up to scrutiny. The practice has never been subjected to randomised trial and I will argue that the present evidence is insufficient to justify the uncontrolled use of an intervention with inescapable short-term morbidity, permanent loss of function, and major cost implications. I propose ways in which the evidence may be improved, including a trial in the areas of most uncertainty. PMID:17999813

A comparative approach to closed-loop computation.

PubMed

Roth, E; Sponberg, S; Cowan, N J

2014-04-01

Neural computation is inescapably closed-loop: the nervous system processes sensory signals to shape motor output, and motor output consequently shapes sensory input. Technological advances have enabled neuroscientists to close, open, and alter feedback loops in a wide range of experimental preparations. The experimental capability of manipulating the topology-that is, how information can flow between subsystems-provides new opportunities to understand the mechanisms and computations underlying behavior. These experiments encompass a spectrum of approaches from fully open-loop, restrained preparations to the fully closed-loop character of free behavior. Control theory and system identification provide a clear computational framework for relating these experimental approaches. We describe recent progress and new directions for translating experiments at one level in this spectrum to predictions at another level. Operating across this spectrum can reveal new understanding of how low-level neural mechanisms relate to high-level function during closed-loop behavior. Copyright © 2013 Elsevier Ltd. All rights reserved.

Evidence that shock-induced immune suppression is mediated by adrenal hormones and peripheral beta-adrenergic receptors.

PubMed

Cunnick, J E; Lysle, D T; Kucinski, B J; Rabin, B S

1990-07-01

Our previous work has demonstrated that presentations of mild foot-shock to Lewis rats induces a suppression of splenic and peripheral blood lymphocyte responses to nonspecific T-cell mitogens. The present study demonstrated that adrenalectomy prevented the shock-induced suppression of the mitogenic response of peripheral blood T-cells but did not attenuate the suppression of splenic T-cells. Conversely, the beta-adrenergic receptor antagonists, propranolol and nadolol, attenuated the shock-induced suppression of splenic T-cells in a dose-dependent manner but did not attenuate suppression of the blood mitogen response. These data indicate that distinct mechanisms mediate the shock-induced suppression of T-cell responsiveness to mitogens in the spleen and the peripheral blood. The results indicate that the peripheral release of catecholamines is responsible for splenic immune suppression and that adrenal hormones, which do not interact with beta-adrenergic receptors, are responsible for shock-induced suppression of blood mitogenic responses.

Treadmill performance of mice with cerebellar lesions: 1. Purkinje cell degeneration mutant mice.

PubMed

Le Marec, N; Lalonde, R

1998-02-01

The purpose of this study was to evaluate the sensorimotor skills of a spontaneous mouse mutant, Purkinje cell degeneration (PCD), marked by selective cerebellar cortical atrophy on a treadmill activated at 1 of 2 speeds and at 1 of 3 slopes, requiring forward movements to avoid footshocks. There was no difference in latencies before falling from the belt between PCD mutants and controls during acquisition. However, PCD mutants were impaired on the fast treadmill during retention, implicating the cerebellum in the memory of a motor skill. During acquisition of the slow treadmill task at the 2 lowest slopes of inclination, PCD mutants spent more time walking than controls, an indication of a decreased ability of coordinating whole body movements. The same pattern of higher walking time on the slow treadmill in PCD mutants was evident during retention. These results indicate that the cerebellar cortex is involved in the acquisition and the retention of a task requiring equilibrium.

Cholinergic transmission in the dorsal hippocampus modulates trace but not delay fear conditioning.

PubMed

Pang, Min-Hee; Kim, Nam-Soo; Kim, Il-Hwan; Kim, Hyun; Kim, Hyun-Taek; Choi, June-Seek

2010-09-01

Although cholinergic mechanisms have been widely implicated in learning and memory processes, few studies have investigated the specific contribution of hippocampal cholinergic transmission during trace fear conditioning, a form of associative learning involving a temporal gap between two stimuli. Microinfusions of scopolamine, a muscarinic receptor antagonist, into the dorsal hippocampus (DH) produced dose-dependent impairment in the acquisition and expression of a conditioned response (CR) following trace fear conditioning with a tone conditioned stimulus (CS) and a footshock unconditioned stimulus (US) in rats. The same infusions, however, had no effect on delay conditioning, general activity, pain sensitivity or attentional modulation. Moreover, scopolamine infusions attenuated phosphorylation of extracellular signal-regulated kinase (ERK) in the amygdala, indicating that cholinergic signals in the DH are important for trace fear conditioning. Taken together, the current study provides evidence that cholinergic neurotransmission in the DH is essential for the cellular processing of CS-US association in the amygdala when the two stimuli are temporally disconnected. Copyright 2010 Elsevier Inc. All rights reserved.

The rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons, selectively encodes aversive stimuli and promotes behavioral inhibition

PubMed Central

Jhou, Thomas C.; Fields, Howard L.; Baxter, Mark G.; Saper, Clifford B.; Holland, Peter C.

2009-01-01

Summary Separate studies have implicated the lateral habenula (LHb) or amygdala-related regions in processing aversive stimuli, but their relationships to each other and to appetitive motivational systems are poorly understood. We show that neurons in the recently identified GABAergic rostromedial tegmental nucleus (RMTg), which receive a major LHb input, project heavily to midbrain dopamine neurons, and show phasic activations and/or Fos induction after aversive stimuli (footshocks, shock-predictive cues, food deprivation, or reward omission) and inhibitions after rewards or reward-predictive stimuli. RMTg lesions markedly reduce passive fear behaviors (freezing, open-arm avoidance) dependent on the extended amygdala, periaqueductal gray, or septum, all regions that project directly to the RMTg. In contrast, RMTg lesions spare or enhance active fear responses (treading, escape) in these same paradigms. These findings suggest that aversive inputs from widespread brain regions and stimulus modalities converge onto the RMTg, which opposes reward and motor-activating functions of midbrain dopamine neurons PMID:19285474

Sex-specific effect of the anabolic steroid, 17α-methyltestosterone, on inhibitory avoidance learning in periadolescent rats.

PubMed

Ramos-Pratts, Keyla; Rosa-González, Dariana; Pérez-Acevedo, Nivia L; Cintrón-López, Dahima; Barreto-Estrada, Jennifer L

2013-10-01

The illicit use of anabolic androgenic steroids (AAS) has gained popularity among adolescents in the last decade. However, although it is known that exposure to AAS impairs cognition in adult animal models, the cognitive effects during adolescence remain undetermined. An inhibitory avoidance task (IAT) was used to assess the effect of AAS (17α-methyltestosterone; 17α-meT--7.5 mg/kg) in male and female periadolescent rats. A single injection of 17α-meT immediately before the footshock produced significant impairment of inhibitory avoidance learning in males but not females. Generalized anxiety, locomotion, and risk assessment behaviors (RAB) were not affected. Our results show that exposure to a single pharmacological dose of 17α-meT during periadolescence exerts sex-specific cognitive effects without affecting anxiety. Thus, disruption of the hormonal milieu during this early developmental period might have negative impact on learning and memory. Copyright © 2013 Elsevier B.V. All rights reserved.

Factors affecting graded and ungraded memory loss following hippocampal lesions.

PubMed

Winocur, Gordon; Moscovitch, Morris; Sekeres, Melanie J

2013-11-01

This review evaluates three current theories--Standard Consolidation (Squire & Wixted, 2011), Overshadowing (Sutherland, Sparks, & Lehmann, 2010), and Multiple Trace-Transformation (Winocur, Moscovitch, & Bontempi, 2010)--in terms of their ability to account for the role of the hippocampus in recent and remote memory in animals. Evidence, based on consistent findings from tests of spatial memory and memory for acquired food preferences, favours the transformation account, but this conclusion is undermined by inconsistent results from studies that measured contextual fear memory, probably the most commonly used test of hippocampal involvement in anterograde and retrograde memory. Resolution of this issue may depend on exercising greater control over critical factors (e.g., contextual environment, amount of pre-exposure to the conditioning chamber, the number and distribution of foot-shocks) that can affect the representation of the memory shortly after learning and over the long-term. Research strategies aimed at characterizing the neural basis of long-term consolidation/transformation, as well as other outstanding issues are discussed. Copyright © 2013 Elsevier Inc. All rights reserved.

Paired-housing selectively facilitates within-session extinction of avoidance behavior, and increases c-Fos expression in the medial prefrontal cortex, in anxiety vulnerable Wistar-Kyoto rats.

PubMed

Smith, Ian M; Pang, Kevin C H; Servatius, Richard J; Jiao, Xilu; Beck, Kevin D

2016-10-01

The perseveration of avoidance behavior, even in the absence of once threatening stimuli, is a key feature of anxiety and related psychiatric conditions. This phenomenon can be observed in the Wistar-Kyoto (WKY) rat which, in comparison to outbred controls, demonstrates impaired extinction of avoidance behavior. Also characteristic of the WKY rat is abnormalities of the neurocircuitry and neuroplasticity of the medial prefrontal cortex (mPFC). One means of reducing physiological responses to anxiety, and conditioned fear, in social species is the presence of a conspecific animal. The current study investigates whether or not pair-housed WKY rats would show facilitated extinction of avoidance in comparison to individual-housed WKY rats, and whether or not pair-housing influences mPFC activation during lever-press avoidance. Male WKY rats were assigned to individual-housed and pair-housed conditions. Rats were trained in lever-press avoidance. Each session of lever-press avoidance consisted of 20 trials, where pressing a lever in response to a warning tone prevented foot-shocks. Rats received 12 acquisition sessions over 4weeks; followed by 6 extinction sessions over 2weeks, where foot-shocks ceased to be delivered. Brains were harvested 90min after trials 1 and 10 of extinction sessions 1 and 6, and mPFC sections underwent c-Fos staining as a measure of activation. Pair-housed rats showed facilitated lever-press avoidance extinction rates, but the main cause for this overall difference was a selective facilitation of within-session extinction. Similar to individual-housed rats, pair-housed rats continued to avoid during trial 1 of extinction even when the avoidance responding had been significantly reduced by the end of the previous session. Pair-housed rats sacrificed on trial 1 showed greater c-Fos expression in the anterior cingulate cortex and prelimbic cortex subregions of the mPFC compared individual-housed rats sacrificed on trial 1. This data shows pair-housing to facilitate the extinction of avoidance, and to influence activity of the mPFC, in WKY rats. Despite this environmental manipulation, the pair-housed WKY rats continued to show avoidance responding on trial 1 of extinction sessions. This demonstrates that within-session extinction can be dissociated from between-session extinction-resistance in WKY rats. Furthermore, it suggests the individual-housing of WKY rats selectively slows within-session extinction, possibly by reducing neuronal activity of the mPFC during the testing situation. Published by Elsevier Inc.

Ameliorating replicative senescence of human bone marrow stromal cells by PSMB5 overexpression

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lu, Li, E-mail: luli7300@126.com; Song, Hui-Fang; Wei, Jiao-Long

2014-01-24

Highlights: • PSMB5 overexpression restores the differentiation potential of aged hBMSCs. • PSMB5 overexpression enhances the proteasomal activity of late-stage hBMSCs. • PSMB5 overexpression inhibits replicative senescence and improved cell viability. • PSMB5 overexpression promotes cell growth by upregulating the Cyclin D1/CDK4 complex. - Abstract: Multipotent human bone marrow stromal cells (hBMSCs) potentially serve as a source for cell-based therapy in regenerative medicine. However, in vitro expansion was inescapably accompanied with cell senescence, characterized by inhibited proliferation and compromised pluripotency. We have previously demonstrated that this aging process is closely associated with reduced 20S proteasomal activity, with down-regulation of rate-limitingmore » catalytic β-subunits particularly evident. In the present study, we confirmed that proteasomal activity directly contributes to senescence of hBMSCs, which could be reversed by overexpression of the β5-subunit (PSMB5). Knocking down PSMB5 led to decreased proteasomal activity concurrent with reduced cell proliferation in early-stage hBMSCs, which is similar to the senescent phenotype observed in late-stage cells. In contrast, overexpressing PSMB5 in late-stage cells efficiently restored the normal activity of 20S proteasomes and promoted cell growth, possibly via upregulating the Cyclin D1/CDK4 complex. Additionally, PSMB5 could enhance cell resistance to oxidative stress, as evidenced by the increased cell survival upon exposing senescent hBMSCs to hydrogen peroxide. Furthermore, PSMB5 overexpression retained the pluripotency of late-stage hBMSCs by facilitating their neural differentiation both in vitro and in vivo. Collectively, our work reveals a critical role of PSMB5 in 20S proteasome-mediated protection against replicative senescence, pointing to a possible strategy for maintaining the integrity of culture-expanded hBMSCs by manipulating the expression of PSMB5.« less

Continuous place avoidance task reveals differences in spatial navigation in male and female rats.

PubMed

Cimadevilla, J M; Fenton, A A; Bures, J

2000-01-01

A new place navigation test was used to estimate the spatial orientation abilities of male and female rats. Animals had to avoid a room frame defined area on a rotating arena, entering of which was punished by mild footshock, i.e. rats had to avoid the same place in the room but different parts of the floor, which was rotated through the punished zone. Because of the rotation of the arena (one revolution per min), animals could not rely on intramaze cues and only extramaze landmarks could be used for accurate navigation. During 8 consecutive days rats were exposed to daily 40-min sessions, consisting of 20-min acquisition and 20-min extinction (shock discontinued). The position of the punished sector centered around one of the four mutually perpendicular azimuths was daily changed in a predetermined sequence. The results showed no male female differences during acquisition and better performance of males during extinction. The performance of females was not affected by estral cycle-related hormonal changes. The findings are discussed in the light of controversial results of research into sex differences in spatial abilities.

Immediate Extinction Attenuates Spontaneous Recovery and Reinstatement in a Passive Avoidance Paradigm.

PubMed

Briggs, James F; Fava, Devin A

2016-08-01

Recent research suggests that extinction occurring shortly after fear conditioning attenuates spontaneous recovery and reinstatement of fear. Two experiments investigated whether immediate extinction would prevent spontaneous recovery and reinstatement of fear using a passive avoidance paradigm. In Experiment 1, naive female adult rats (N = 40) received extinction training either immediately or 24 hours (delayed) after fear conditioning. Both extinction groups showed a significant reduction in fear at a 1-day test. At a 15-day test, spontaneous recovery was observed in the delayed extinction group while the immediate extinction group continued to show significant extinction. In Experiment 2, using a naive group of adult female rats (N = 16), the extinction result was replicated in both the immediate and delayed extinction groups at the 1-day interval. Reinstatement of fear, elicited by foot-shock in a neutral environment, was observed for the delayed group but not for the immediate group. By utilizing the passive-avoidance paradigm, these experiments replicate and extend previous findings that immediate extinction attenuates spontaneous recovery and reinstatement of fear. © The Author(s) 2016.

Effects of prior aversive experience upon retrograde amnesia induced by hypothermia.

PubMed

Jensen, R A; Riccio, D C; Gehres, L

1975-08-01

Two experiments examined the extent to which retrograde amnesia (RA) is attenuated by prior learning experiences. In Experiment 1, rats initially received either passive avoidance training in a step-through apparatus, exposure to the apparatus, or noncontingent footshock. When training on a second but different passive avoidance task was followed by hypothermia treatment, RA was obtained only in the latter two groups. In Experiment 2, one-way active avoidance training, yoked noncontingent shocks, or apparatus exposure constituted the initial experience. Subsequent step-down passive avoidance training and amnestic treatment resulted in memory loss for the prior apparatus exposure group, but not for either of the preshocked conditions. These experiments demonstrate that certain types of prior aversive experience can substantially modify the magnitude of RA, and, in conjunction with other familiarization studies, emphasize a paradox for interpretations of RA based solely upon CNS disruption. The possibility that hypothermia treatment serves as an important contextual or encoding cue necessary for memory retrieval was considered. It was suggested that prior experience may block RA by enabling rats to differentiate training and treatment conditions.

Inhibition of the mesoamygdala dopaminergic pathway impairs the retrieval of conditioned fear associations.

PubMed

Nader, K; LeDoux, J E

1999-10-01

Previous findings have demonstrated that systemic dopaminergic manipulations impair the retrieval of Pavlovian conditioned fear. A second-order fear-conditioning paradigm was used to test whether the dopaminergic projection from the ventral tegmental area (VTA) to the lateral and basal amygdala (LBA) can affect conditioned fear. Phase 1 entailed conditioned stimulus-unconditioned stimulus (CS1-US) pairings. In Phase 2, drugs were infused in either the LBA or VTA prior to pairings of CS2 (a second cue) with CS1. In Phase 3, freezing behavior elicited by CS2 was tested without drugs. Infusions of the D2 agonist quinpirole into the VTA or of the D1 antagonist SCH 23390 into the LBA caused a decrease in freezing to CS2. Both manipulations decrease D1 receptor activation in the LBA. Infusions of the D1 agonist SKF 38393 into the LBA had no effect. This pattern of results is consistent with the hypothesis that the VTA-LBA dopaminergic projection modulates the retrieval of an association between a CS and footshock US.

Object-location training elicits an overlapping but temporally distinct transcriptional profile from contextual fear conditioning.

PubMed

Poplawski, Shane G; Schoch, Hannah; Wimmer, Mathieu; Hawk, Joshua D; Walsh, Jennifer L; Giese, Karl P; Abel, Ted

2014-12-01

Hippocampus-dependent learning is known to induce changes in gene expression, but information on gene expression differences between different learning paradigms that require the hippocampus is limited. The bulk of studies investigating RNA expression after learning use the contextual fear conditioning task, which couples a novel environment with a footshock. Although contextual fear conditioning has been useful in discovering gene targets, gene expression after spatial memory tasks has received less attention. In this study, we used the object-location memory task and studied gene expression at two time points after learning in a high-throughput manner using a microfluidic qPCR approach. We found that expression of the classic immediate-early genes changes after object-location training in a fashion similar to that observed after contextual fear conditioning. However, the temporal dynamics of gene expression are different between the two tasks, with object-location memory producing gene expression changes that last at least 2 hours. Our findings indicate that different training paradigms may give rise to distinct temporal dynamics of gene expression after learning. Copyright © 2014 Elsevier Inc. All rights reserved.

Object-Location Training Elicits an Overlapping but Temporally Distinct Transcriptional Profile from Contextual Fear Conditioning

PubMed Central

Wimmer, Mathieu; Hawk, Joshua D.; Walsh, Jennifer L.; Giese, Karl P.; Abel, Ted

2014-01-01

Hippocampus-dependent learning is known to induce changes in gene expression, but information on gene expression differences between different learning paradigms that require the hippocampus is limited. The bulk of studies investigating RNA expression after learning use the contextual fear conditioning task, which couples a novel environment with a footshock. Although contextual fear conditioning has been useful in discovering gene targets, gene expression after spatial memory tasks has received less attention. In this study, we used the object-location memory task and studied gene expression at two time points after learning in a high-throughput manner using a microfluidic qPCR approach. We found that expression of the classic immediate-early genes changes after object-location training in a fashion similar to that observed after contextual fear conditioning. However, the temporal dynamics of gene expression are different between the two tasks, with object-location memory producing gene expression changes that last at least 2 hours. Our findings indicate that different training paradigms may give rise to distinct temporal dynamics of gene expression after learning. PMID:25242102

Nucleus accumbens carbachol disrupts olfactory and contextual fear-potentiated startle and attenuates baseline startle reactivity.

PubMed

Cousens, Graham A; Skrobacz, Cheryl G; Blumenthal, Anna

2011-01-20

Although the nucleus accumbens (NAc) typically is not considered a primary component of the circuitry underlying either the acquisition or retrieval of conditioned fear, evidence suggests that this region may play some role in modulating fear-related behaviors. The goal of the present study was to explore a potential role for NAc cholinergic receptors in the expression of fear-potentiated startle (FPS) and baseline startle reactivity. Intra-NAc infusion of the broad-acting cholinergic receptor agonist, carbachol, suppressed FPS elicited by re-exposure to both a discrete odor previously paired with footshock and the conditioning context. Although carbachol elevated spontaneous motor activity, activity bouts did not account for startle suppression in carbachol-treated Ss. In addition, intra-NAc carbachol suppressed baseline startle over a range of acoustic pulse intensities in the absence of explicit fear conditioning. Collectively, these findings suggest that NAc cholinergic receptors play a role in the modulation of baseline startle reactivity, rather than in the retrieval of learned fear, and that this role is independent of overt motor activity. Copyright © 2010 Elsevier B.V. All rights reserved.

Learned together, extinguished apart: reducing fear to complex stimuli

PubMed Central

Jones, Carolyn E.; Ringuet, Stephanie; Monfils, Marie-H.

2013-01-01

Pairing a previously neutral conditioned stimulus (CS; e.g., a tone) to an aversive unconditioned stimulus (US; e.g., a footshock) leads to associative learning such that the tone alone comes to elicit a conditioned response (e.g., freezing). We have previously shown that an extinction session that occurs within the reconsolidation window attenuates fear responding and prevents the return of fear in pure tone Pavlovian fear conditioning. Here we sought to examine whether this effect also applies to a more complex fear memory. First, we show that after fear conditioning to the simultaneous presentation of a tone and a light (T+L) coterminating with a shock, the compound memory that ensues is more resistant to fear extinction than simple tone-shock pairings. Next, we demonstrate that the compound memory can be disrupted by interrupting the reconsolidation of the two individual components using a sequential retrieval+extinction paradigm, provided the stronger compound component is retrieved first. These findings provide insight into how compound memories are encoded, and could have important implications for PTSD treatment. PMID:24241750

Tinnitus and hyperacusis involve hyperactivity and enhanced connectivity in auditory-limbic-arousal-cerebellar network

PubMed Central

Chen, Yu-Chen; Li, Xiaowei; Liu, Lijie; Wang, Jian; Lu, Chun-Qiang; Yang, Ming; Jiao, Yun; Zang, Feng-Chao; Radziwon, Kelly; Chen, Guang-Di; Sun, Wei; Krishnan Muthaiah, Vijaya Prakash; Salvi, Richard; Teng, Gao-Jun

2015-01-01

Hearing loss often triggers an inescapable buzz (tinnitus) and causes everyday sounds to become intolerably loud (hyperacusis), but exactly where and how this occurs in the brain is unknown. To identify the neural substrate for these debilitating disorders, we induced both tinnitus and hyperacusis with an ototoxic drug (salicylate) and used behavioral, electrophysiological, and functional magnetic resonance imaging (fMRI) techniques to identify the tinnitus–hyperacusis network. Salicylate depressed the neural output of the cochlea, but vigorously amplified sound-evoked neural responses in the amygdala, medial geniculate, and auditory cortex. Resting-state fMRI revealed hyperactivity in an auditory network composed of inferior colliculus, medial geniculate, and auditory cortex with side branches to cerebellum, amygdala, and reticular formation. Functional connectivity revealed enhanced coupling within the auditory network and segments of the auditory network and cerebellum, reticular formation, amygdala, and hippocampus. A testable model accounting for distress, arousal, and gating of tinnitus and hyperacusis is proposed. DOI: http://dx.doi.org/10.7554/eLife.06576.001 PMID:25962854

[Antiandrogen gynecomastia: an inescapable harm? Radiotherapy: a simple and efficient solution!].

PubMed

Couke, Philippe A; Jichliski, Patrice; Matzinger, Oscar; Ozsahin, Mahmut; Bulling, Shelley M; Zouhair, Abderrahim

2004-01-01

Anti-androgen induced gynecomastia, resulting from a treatment induced imbalance between oestrogens and androgens, is a frequently encountered side effect in the hormonal treatment of patients with prostatic cancer. One might expect to face an increase in the overall incidence of this side effect in the next-coming years as randomized trials clearly point to the evidence of the therapeutic benefit of anti-androgenic treatment for this prostatic cancer. Gynecomastia is often accompanied by mastodynia and does hamper quality of life. Surgery should be considered for established irreversible gynecomastia characterized by hyalinization and extensive fibrosis. However, radiotherapy is the treatment of choice for gynecomastia at it's early stage, or could eventually be considered as a prophylactic treatment in high risk patients. It is a safe and extremely well tolerated treatment resulting in a high degree of therapeutic success with a demonstrated effect on quality of life as reported in randomized trials. To date no medical treatment is proven effective nor devoid from deleterious effects and licenced for this indication.

Cannabidiol Reduces Aβ-Induced Neuroinflammation and Promotes Hippocampal Neurogenesis through PPARγ Involvement

PubMed Central

Valenza, Marta; Togna, Giuseppina Ines; Latina, Valentina; De Filippis, Daniele; Cipriano, Mariateresa; Carratù, Maria Rosaria; Iuvone, Teresa; Steardo, Luca

2011-01-01

Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported. PMID:22163051

Moral Conflicts and Religious Convictions: What Role for Clinical Ethics Consultants?

PubMed

Moskop, John C

2018-05-03

Moral conflicts over medical treatment that are the result of differences in fundamental moral commitments of the stakeholders, including religiously grounded commitments, can present difficult challenges for clinical ethics consultants. This article begins with a case example that poses such a conflict, then examines how consultants might use different approaches to clinical ethics consultation in an effort to facilitate the resolution of conflicts of this kind. Among the approaches considered are the authoritarian approach, the pure consensus approach, and the ethics facilitation approach described in the Core Competencies for Healthcare Ethics Consultation report of the American Society for Bioethics and Humanities, as well as a patient advocate approach, a clinician advocate approach, and an institutional advocate approach. The article identifies clear limitations to each of these approaches. An analysis of the introductory case illustrates those limitations, and the article concludes that deep-seated conflicts of this kind may reveal inescapable limits of current approaches to clinical ethics consultation.

The Cacophony of Space and the Clink Clunk Clang in Architecture The mall corridor redux

NASA Astrophysics Data System (ADS)

Cipriano, Nolan

The element of sound is nearly inescapable. The various ways in which sound is generated, perceived, represented, and hindered resonates not only within the realm of the auditory sense, but as well as the visual and tactile. Through investigating the representation of sound, both in the aural and visual worlds, a deeper understanding of its profound effects can be observed. In the world of architectural space it is the element of sound that is often forgotten, whereas the sonic nature of a space is not designed. This thesis endeavours to examine how, through a comprehensive understanding of the various facets of sound representations, effects, and history, it can inform specifically designed sonorously beneficial spaces that directly reflect and support their purpose. This notion will be explored through the redesign of the shopping-mall corridor within the heritage structure of the Ogilvy Building in Ottawa, Ontario. Through adaptive architecture, the possibility exists to create a subjective aural space.

The Scaling of Water Governance Tasks: A Comparative Federal Analysis of the European Union and Australia

NASA Astrophysics Data System (ADS)

Benson, David; Jordan, Andrew

2010-07-01

Conflicts over how to “scale” policy-making tasks have characterized environmental governance since time immemorial. They are particularly evident in the area of water policy and raise important questions over the democratic legitimacy, economic efficiency and effectiveness of allocating (or “scaling”) tasks to some administrative levels as opposed to others. This article adopts a comparative federalism perspective to assess the “optimality” of scaling—either upward or downward—in one issue area, namely coastal recreational water quality. It does so by comparing the scaling of recreational water quality tasks in the European Union (EU) and Australia. It reveals that the two systems have adopted rather different approaches to scaling and that this difference can partly be accounted for in federal theoretical terms. However, a much greater awareness of the inescapably political nature of scaling processes is nonetheless required. Finally, some words of caution are offered with regard to transferring policy lessons between these two jurisdictions.

Highly improved photo-induced bias stability of sandwiched triple layer structure in sol-gel processed fluorine-doped indium zinc oxide thin film transistor

NASA Astrophysics Data System (ADS)

Kim, Dongha; Park, Hyungjin; Bae, Byeong-Soo

2016-03-01

In order to improve the reliability of TFT, an Al2O3 insulating layer is inserted between active fluorine doped indium zinc oxide (IZO:F) thin films to form a sandwiched triple layer. All the thin films were fabricated via low-cost sol-gel process. Due to its large energy bandgap and high bonding energy with oxygen atoms, the Al2O3 layer acts as a photo-induced positive charge blocking layer that effectively blocks the migration of both holes and V o2+ toward the interface between the gate insulator and the semiconductor. The inserted Al2O3 triple layer exhibits a noticeably low turn on voltage shift of -0.7 V under NBIS as well as the good TFT performance with a mobility of 10.9 cm2/V ṡ s. We anticipate that this approach can be used to solve the stability issues such as NBIS, which is caused by inescapable oxygen vacancies.

Authenticity, Best Interest, and Clinical Nudging.

PubMed

Holm, Søren

2017-03-01

In this issue of the Hastings Center Report, Moti Gorin, Steven Joffe, Neal Dickert, and Scott Halpern offer a comprehensive defense of the use of nudging techniques in the clinical context, with the aim of promoting the best interests of patients. Their argument is built on three important claims: Nudging is ubiquitous and inescapable in clinical choice situations, and there is no neutral way of informing patients about their treatment choices; many patients do not have authentic (preexisting) preferences concerning their treatment choices, and those that do can easily resist nudging; and, finally, since many people lack authentic preferences and those that do can still act on their preferences, nudging in the patients' best interest is justified. I agree with the authors that if these three claims stand up to scrutiny, then they will provide a justification for many types of clinical nudging. I am, however, skeptical as to whether the claims can be sustained, despite the valiant efforts of Gorin and colleagues. © 2017 The Hastings Center.

When Foreign Domestic Helpers Care for and About Older People in Their Homes: I Am a Maid or a Friend

PubMed Central

Chiang, Vico C. L.; Leung, Doris; Ku, Ben H. B.

2018-01-01

We examine the lived experiences of foreign domestic helpers (FDH) working with community-dwelling older people in Hong Kong. Unstructured interviews were conducted with 11 female FDHs, and thematically analyzed. The theme inescapable functioning commodity represented the embodied commodification of FDHs to be functional for older people in home care. Another theme, destined reciprocity of companionship, highlighted the FDHs’ capacity to commit to home care and be concerned about older people. The waxing and waning of the possibilities of commodified companionship indicated the intermittent capacity of FDHs to find meaning in their care, in which performative nature for functional purposes and emotional engagement took turns to be the foci in migrant home care. This study addresses the transition of FDHs from task-oriented relation to companions of older people through care work. Discussion draws on the development of a kin-like relationship between FDHs and older people with emotional reciprocity grounded in moral values. PMID:29404382

Augmenting Austrian flood management practices through geospatial predictive analytics: a study in Carinthia

NASA Astrophysics Data System (ADS)

Ward, S. M.; Paulus, G.

2013-06-01

The Danube River basin has long been the location of significant flooding problems across central Europe. The last decade has seen a sharp increase in the frequency, duration and intensity of these flood events, unveiling a dire need for enhanced flood management policy and tools in the region. Located in the southern portion of Austria, the state of Carinthia has experienced a significant volume of intense flood impacts over the last decade. Although the Austrian government has acknowledged these issues, their remedial actions have been primarily structural to date. Continued focus on controlling the natural environment through infrastructure while disregarding the need to consider alternative forms of assessing flood exposure will only act as a provisional solution to this inescapable risk. In an attempt to remedy this flaw, this paper highlights the application of geospatial predictive analytics and spatial recovery index as a proxy for community resilience, as well as the cultural challenges associated with the application of foreign models within an Austrian environment.

On the importance of electroweak corrections for B anomalies

NASA Astrophysics Data System (ADS)

Feruglio, Ferruccio; Paradisi, Paride; Pattori, Andrea

2017-09-01

The growing experimental indication of Lepton Flavour Universality Violation (LFUV) both in charged- and neutral-current semileptonic B-decays, has triggered many theoretical interpretations of such non-standard phenomena. Focusing on popular scenarios where the explanation of these anomalies requires New Physics at the TeV scale, we emphasise the importance of including electroweak corrections to obtain trustable predictions for the models in question. We find that the most important quantum effects are the modifications of the leptonic couplings of the W and Z vector bosons and the generation of a purely leptonic effective Lagrangian. Although our results do not provide an inescapable no-go theorem for the explanation of the B anomalies, the tight experimental bounds on Z-pole observables and τ decays challenge an explanation of the current non-standard data. We illustrate how these effects arise, by providing a detailed discussion of the running and matching procedure which is necessary to derive the low-energy effective Lagrangian.

Entropy of the information retrieved from black holes

NASA Astrophysics Data System (ADS)

Mersini-Houghton, Laura

2016-07-01

The retrieval of black hole information was recently presented in two interesting proposals in the ‘Hawking Radiation’ conference: a revised version by Hooft of a proposal he initially suggested 20 years ago and, a new proposal by Hawking. Both proposals address the problem of black hole information loss at the classical level and derive an expression for the scattering matrix. The former uses gravitation back reaction of incoming particles that imprints its information on the outgoing modes. The latter uses supertranslation symmetry of horizons to relate a phase delay of the outgoing wave packet compared to their incoming wave partners. The difficulty in both proposals is that the entropy obtained from them appears to be infinite. By including quantum effects into the Hawking and Hooft’s proposals, I show that a subtlety arising from the inescapable measurement process, the quantum Zeno effect, not only tames divergences but it actually recovers the correct 1/4 of the area Bekenstein-Hawking entropy law of black holes.

Work Done by Titin Protein Folding Assists Muscle Contraction.

PubMed

Rivas-Pardo, Jaime Andrés; Eckels, Edward C; Popa, Ionel; Kosuri, Pallav; Linke, Wolfgang A; Fernández, Julio M

2016-02-16

Current theories of muscle contraction propose that the power stroke of a myosin motor is the sole source of mechanical energy driving the sliding filaments of a contracting muscle. These models exclude titin, the largest protein in the human body, which determines the passive elasticity of muscles. Here, we show that stepwise unfolding/folding of titin immunoglobulin (Ig) domains occurs in the elastic I band region of intact myofibrils at physiological sarcomere lengths and forces of 6-8 pN. We use single-molecule techniques to demonstrate that unfolded titin Ig domains undergo a spontaneous stepwise folding contraction at forces below 10 pN, delivering up to 105 zJ of additional contractile energy, which is larger than the mechanical energy delivered by the power stroke of a myosin motor. Thus, it appears inescapable that folding of titin Ig domains is an important, but as yet unrecognized, contributor to the force generated by a contracting muscle. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Is there evidence of learned helplessness in horses?

PubMed

Hall, Carol; Goodwin, Deborah; Heleski, Camie; Randle, Hayley; Waran, Natalie

2008-01-01

Learned helplessness is a psychological condition whereby individuals learn that they have no control over unpleasant or harmful conditions, that their actions are futile, and that they are helpless. In a series of experiments in which dogs were exposed to inescapable shocks, this lack of control subsequently interfered with the ability to learn an avoidance task. There is evidence that both neural adaptations and behavioral despair occur in response to uncontrollable aversive experiences in rodents, although this has yet to be demonstrated in other species such as horses. However, certain traditional methods of horse training and some behavioral modification techniques--it has been suggested--may involve aversive conditions over which the horse has little or no control. When training and management procedures are repeatedly unpleasant for the horse and there is no clear association between behavior and outcome, this is likely to interfere with learning and performance-in addition to compromising welfare. This article reviews published literature and anecdotal evidence to explore the possibility that the phenomenon, learned helplessness, occurs in the horse.

Creation of the BMA ensemble for SST using a parallel processing technique

NASA Astrophysics Data System (ADS)

Kim, Kwangjin; Lee, Yang Won

2013-10-01

Despite the same purpose, each satellite product has different value because of its inescapable uncertainty. Also the satellite products have been calculated for a long time, and the kinds of the products are various and enormous. So the efforts for reducing the uncertainty and dealing with enormous data will be necessary. In this paper, we create an ensemble Sea Surface Temperature (SST) using MODIS Aqua, MODIS Terra and COMS (Communication Ocean and Meteorological Satellite). We used Bayesian Model Averaging (BMA) as ensemble method. The principle of the BMA is synthesizing the conditional probability density function (PDF) using posterior probability as weight. The posterior probability is estimated using EM algorithm. The BMA PDF is obtained by weighted average. As the result, the ensemble SST showed the lowest RMSE and MAE, which proves the applicability of BMA for satellite data ensemble. As future work, parallel processing techniques using Hadoop framework will be adopted for more efficient computation of very big satellite data.

When Fathering Fails: Violence, Narcissism, and the Father Function in Ancient Tales and Clinical Analysis.

PubMed

Diamond, Michael J

2018-02-01

Manifestations of failures in both symbolic and actual flesh-and-blood fathering reveal the inescapable role played by the father's unconscious transmissions in the ever present triadic matrix. Perelberg's crucial distinction between the murdered narcissistic father and the dead symbolic father suggests the problematic internalizations that fail to uphold the paternal law required for oedipal resolution. Three father-child narratives derived from classical literature and mythology are presented in order to elucidate significant unconscious paternal fantasies pertaining to lethal rivalry and neglect of the child's otherness. These narratives suggest how the father's insufficient management of rivalrous, envious, and murderously aggressive impulses-as well as narcissistic needs that fail to take into account the child's alterity-combine with the child's intrapsychic propensities to constrict triangular space and restrict development. Consequently, unavoidable father-child rivalries, absences, neglect, and desires often make it vital to recover the "missing" paternal function in analytic space. A clinical example illustrates the impact of this absence on the analyst's countertransference.

Model Averaging for Predicting the Exposure to Aflatoxin B1 Using DNA Methylation in White Blood Cells of Infants

NASA Astrophysics Data System (ADS)

Rahardiantoro, S.; Sartono, B.; Kurnia, A.

2017-03-01

In recent years, DNA methylation has been the special issue to reveal the pattern of a lot of human diseases. Huge amount of data would be the inescapable phenomenon in this case. In addition, some researchers interesting to take some predictions based on these huge data, especially using regression analysis. The classical approach would be failed to take the task. Model averaging by Ando and Li [1] could be an alternative approach to face this problem. This research applied the model averaging to get the best prediction in high dimension of data. In the practice, the case study by Vargas et al [3], data of exposure to aflatoxin B1 (AFB1) and DNA methylation in white blood cells of infants in The Gambia, take the implementation of model averaging. The best ensemble model selected based on the minimum of MAPE, MAE, and MSE of predictions. The result is ensemble model by model averaging with number of predictors in model candidate is 15.

Temporal factors in the extinction of fear in inbred mouse strains differing in extinction efficacy.

PubMed

MacPherson, Kathryn; Whittle, Nigel; Camp, Marguerite; Gunduz-Cinar, Ozge; Singewald, Nicolas; Holmes, Andrew

2013-07-05

Various neuropsychiatric conditions, including posttraumatic stress disorder (PTSD), are characterized by deficient fear extinction, but individuals differ greatly in risk for these. While there is growing evidence that fear extinction is influenced by certain procedural variables, it is unclear how these influences might vary across individuals and subpopulations. To model individual differences in fear extinction, prior studies identified a strain of inbred mouse, 129S1/SvImJ (S1), which exhibits a profound deficit in fear extinction, as compared to other inbred strains, such as C57BL/6J (B6). Here, we assessed the effects of procedural variables on the impaired extinction phenotype of the S1 strain and, by comparison, the extinction-intact B6 strain. The variables studied were 1) the interval between conditioning and extinction, 2) the interval between cues during extinction training, 3) single-cue exposure before extinction training, and 4) extinction of a second-order conditioned cue. Conducting extinction training soon after ('immediately') conditioning attenuated fear retrieval in S1 mice and impaired extinction in B6 mice. Spacing cue presentations with long inter-trial intervals during extinction training augmented fear in S1 and B6 mice. The effect of spacing was lost with one-trial fear conditioning in B6, but not S1 mice. A single exposure to a conditioned cue before extinction training did not alter extinction retrieval, either in B6 or S1 mice. Both the S1 and B6 strains exhibited robust second-order fear conditioning, in which a cue associated with footshock was sufficient to serve as a conditioned exciter to condition a fear association to a second cue. B6 mice extinguished the fear response to the second-order conditioned cue, but S1 mice failed to do so. These data provide further evidence that fear extinction is strongly influenced by multiple procedural variables and is so in a highly strain-dependent manner. This suggests that the efficacy of extinction-based behavioral interventions, such as exposure therapy, for trauma-related anxiety disorders will be determined by the procedural parameters employed and the degree to which the patient can extinguish.

Cannabidiolic acid methyl ester, a stable synthetic analogue of cannabidiolic acid, can produce 5-HT1A receptor-mediated suppression of nausea and anxiety in rats.

PubMed

Pertwee, Roger G; Rock, Erin M; Guenther, Kelsey; Limebeer, Cheryl L; Stevenson, Lesley A; Haj, Christeene; Smoum, Reem; Parker, Linda A; Mechoulam, Raphael

2018-01-01

The aim of this study was to compare the abilities of cannabidiolic acid methyl ester (HU-580) and cannabidiolic acid (CBDA) to enhance 5-HT 1A receptor activation in vitro and produce 5-HT 1A -mediated reductions in nausea and anxiety in vivo. We investigated the effects of HU-580 and CBDA on (i) activation by 8-hydroxy-2-(di-n-propylamino)tetralin of human 5-HT 1A receptors in CHO cell membranes, using [ 35 S]-GTPγS binding assays, (ii) gaping by rats in acute and anticipatory nausea models, and (iii) stress-induced anxiety-like behaviour, as indicated by exit time from the light compartment of a light-dark box of rats subjected 24 h earlier to six tone-paired foot shocks. HU-580 and CBDA increased the E max of 8-hydroxy-2-(di-n-propylamino) tetralin in vitro at 0.01-10 and 0.1-10 nM, respectively, and reduced signs of (i) acute nausea at 0.1 and 1 μg·kg -1 i.p. and at 1 μg·kg -1 i.p., respectively, and (ii) anticipatory nausea at 0.01 and 0.1 μg·kg -1 , and at 0.1 μg·kg -1 i.p. respectively. At 0.01 μg·kg -1 , HU-580, but not CBDA, increased the time foot-shocked rats spent in the light compartment of a light-dark box. The anti-nausea and anti-anxiety effects of 0.01 or 0.1 μg·kg -1 HU-580 were opposed by the 5-HT 1A antagonist, WAY100635 (0.1 mg·kg -1 i.p.). HU-580 is more potent than CBDA at enhancing 5-HT 1A receptor activation, and inhibiting signs of acute and anticipatory nausea, and anxiety. Consequently, HU-580 is a potential medicine for treating some nausea and anxiety disorders and possibly other disorders ameliorated by enhancement of 5-HT 1A receptor activation. © 2017 The British Pharmacological Society.

Intracellular signalling and plasma hormone profiles associated with the expression of unconditioned and conditioned fear and anxiety in female rats.

PubMed

Simone, Jonathan J; McCormick, Cheryl M

2017-02-01

There is considerable overlap in the neural regions and intracellular signalling pathways implicated in anxiety and fear, although less is known in females. Here, we investigated whether unconditioned and conditioned fear are associated with distinct patterns of expression of extracellular signal-regulated kinase-1 and -2 (ERK1/2), protein kinase B (Akt), and calcineurin (CaN) (proteins that are key regulators of the expression of and/or memory processes of fear and anxiety) in the dorsal and ventral hippocampus, medial prefrontal cortex, and amygdala (important regions in neural fear circuitry) of adult female rats, and used a multivariate approach to find patterns of signalling that might discriminate between the different states of fear. To isolate fear to the conditioned cue from generalized fear to the test context, rats were conditioned to an auditory tone (i.e. tone paired with footshock) and twenty-four hours later exposed to a novel context in the presence or absence of the conditioned cue. A third group that was exposed to the conditioning context without undergoing fear conditioning was included to control for unconditioned responses to the testing procedures, which are anxiogenic. A discriminate function analysis and MANOVA determined that hippocampal signalling best discriminated the three groups from each other. The addition of values for plasma concentrations of corticosterone and progesterone (as indices of activation of the hypothalamic-pituitary-adrenal stress axis) to statistical analyses increased the separation of the three groups. There was high degree of association among the three signalling molecules in the four brain regions within each group. There was an absence of the associations between the medial prefrontal cortex and the amygdala in the cued fear recall group that were strong for the non-conditioned group. These results demonstrated unique neuronal and hormonal signalling profiles associated with unconditioned, generalized, and conditioned fear expression in females and highlight the importance of including appropriate comparisons to best discriminate between these different emotional states. Copyright © 2016 Elsevier Inc. All rights reserved.

The D1CT-7 mouse model of Tourette syndrome displays sensorimotor gating deficits in response to spatial confinement.

PubMed

Godar, Sean C; Mosher, Laura J; Strathman, Hunter J; Gochi, Andrea M; Jones, Cori M; Fowler, Stephen C; Bortolato, Marco

2016-07-01

The D1CT-7 mouse is one of the best known animal models of Tourette syndrome (TS), featuring spontaneous tic-like behaviours sensitive to standard TS therapies; these characteristics ensure a high face and predictive validity of this model, yet its construct validity remains elusive. To address this issue, we studied the responses of D1CT-7 mice to two critical components of TS pathophysiology: the exacerbation of tic-like behaviours in response to stress and the presence of sensorimotor gating deficits, which are thought to reflect the perceptual alterations causing the tics. D1CT-7 and wild-type (WT) littermates were subjected to a 20 min session of spatial confinement (SC) within an inescapable, 10 cm wide cylindrical enclosure. Changes in plasma corticosterone levels, tic-like behaviours and other spontaneous responses were measured. SC-exposed mice were also tested for the prepulse inhibition (PPI) of the startle response (a sensorimotor gating index) and other TS-related behaviours, including open-field locomotion, novel object exploration and social interaction and compared with non-confined counterparts. SC produced a marked increase in corticosterone concentrations in both D1CT-7 and WT mice. In D1CT-7, but not WT mice, SC exacerbated tic-like and digging behaviours, and triggered PPI deficits and aggressive responses. Conversely, SC did not modify locomotor activity or novel object exploration in D1CT-7 mice. Both tic-like behaviours and PPI impairments in SC-exposed D1CT-7 mice were inhibited by standard TS therapies and D1 dopamine receptor antagonism. These findings collectively support the translational and construct validity of D1CT-7 mice with respect to TS. This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc. © 2015 The British Pharmacological Society.

Contextual fear conditioning differs for infant, adolescent, and adult rats

PubMed Central

Esmorís-Arranz, Francisco J.; Méndez, Cástor; Spear, Norman E.

2009-01-01

Contextual fear conditioning was tested in infant, adolescent, and adult rats in terms of Pavlovian conditioned suppression. When a discrete auditory conditioned stimulus (CS) was paired with footshock (unconditioned stimulus, US) within the largely olfactory context, infants and adolescents conditioned to the context with substantial effectiveness but adult rats did not. When unpaired presentations of the CS and US occurred within the context, contextual fear conditioning was strong for adults, weak for infants, but about as strong for adolescents as when pairings of CS and US occurred in the context. Nonreinforced presentations of either the CS or context markedly reduced contextual fear conditioning in infants, but, in adolescents, CS extinction had no effect on contextual fear conditioning, although context extinction significantly reduced it. Neither CS extinction nor context extinction affected responding to the CS-context compound in infants, suggesting striking discrimination between the compound and its components. Female adolescents showed the same lack of effect of component extinction on response to the compound as infants, but CS extinction reduced responding to the compound in adolescent males, a sex difference seen also in adults. Theoretical implications are discussed for the development of perceptual-cognitive processing and hippocampus role. PMID:18343048

Similar effects of substance P on learning and memory function between hippocampus and striatal marginal division

PubMed Central

Yu, Yan; Zeng, Changchun; Shu, Siyun; Liu, Xuemei; Li, Chuhua

2014-01-01

Substance P is an endogenous neurokinin that is present in the central and peripheral nervous systems. The neuropeptide substance P and its high-affinity receptor neurokinin 1 receptor are known to play an important role in the central nervous system in inflammation, blood pressure, motor behavior and anxiety. The effects of substance P in the hippocampus and the marginal division of the striatum on memory remain poorly understood. Compared with the hippocampus as a control, immunofluorescence showed high expression of the substance P receptor, neurokinin 1, in the marginal division of the striatum of normal rats. Unilateral or bilateral injection of an antisense oligonucleotide against neurokinin 1 receptor mRNA in the rat hippocampus or marginal division of the striatum effectively reduced neurokinin 1 receptor expression. Independent of injection site, rats that received this antisense oligonucleotide showed obviously increased footshock times in a Y-maze test. These results indicate that the marginal division of the striatum plays a similar function in learning and memory to the hippocampus, which is a valuable addition to our mechanistic understanding of the learning and memory functions of the marginal division of the striatum. PMID:25206901

Analysis and Purification of Bioactive Natural Products: The AnaPurNa Study

PubMed Central

2012-01-01

Based on a meta-analysis of data mined from almost 2000 publications on bioactive natural products (NPs) from >80 000 pages of 13 different journals published in 1998–1999, 2004–2005, and 2009–2010, the aim of this systematic review is to provide both a survey of the status quo and a perspective for analytical methodology used for isolation and purity assessment of bioactive NPs. The study provides numerical measures of the common means of sourcing NPs, the chromatographic methodology employed for NP purification, and the role of spectroscopy and purity assessment in NP characterization. A link is proposed between the observed use of various analytical methodologies, the challenges posed by the complexity of metabolomes, and the inescapable residual complexity of purified NPs and their biological assessment. The data provide inspiration for the development of innovative methods for NP analysis as a means of advancing the role of naturally occurring compounds as a viable source of biologically active agents with relevance for human health and global benefit. PMID:22620854

Ten metre global sea-level change associated with South Atlantic Aptian salt deposition

NASA Technical Reports Server (NTRS)

Burke, Kevin; Sengor, A. M. Celal

1988-01-01

Catastrophic filling of the kind of subsea-level depression commonly formed during ocean opening and ocean closing is the only mechanism, other than glacial eustacy, capable of rapidly lowering sea level. Aptian evaporites overlying oceanic crust on both sides of the South Atlantic between the Walvis Ridge and the Niger Delta were deposited in such a basin by repeated spilling of ocean water. The final flooding of the South Atlantic north of the Walvis Ridge extracted about 14 x 10 to the 8th cu km of sea water from the world ocean and effected about 10 m of sea-level lowering. It is speculated that the middle Aptian unconformity, which is one of the more prominent world-wide unconformities, is associated with this sea-level drop of about 10 m. A corollary of this interpretation is that if the catastrophic sea-level lowerings during the Mesozoic era had amplitudes substantially greater than 10 m, then a glacial mechanism to explain them would seem inescapable although the stratigraphic record has not yet yielded any evidence of such glaciation.

Volunteering leads to rock-paper-scissors dynamics in a public goods game

NASA Astrophysics Data System (ADS)

Semmann, Dirk; Krambeck, Hans-Jürgen; Milinski, Manfred

2003-09-01

Collective efforts are a trademark of both insect and human societies. They are achieved through relatedness in the former and unknown mechanisms in the latter. The problem of achieving cooperation among non-kin has been described as the `tragedy of the commons', prophesying the inescapable collapse of many human enterprises. In public goods experiments, initial cooperation usually drops quickly to almost zero. It can be maintained by the opportunity to punish defectors or the need to maintain good reputation. Both schemes require that defectors are identified. Theorists propose that a simple but effective mechanism operates under full anonymity. With optional participation in the public goods game, `loners' (players who do not join the group), defectors and cooperators will coexist through rock-paper-scissors dynamics. Here we show experimentally that volunteering generates these dynamics in public goods games and that manipulating initial conditions can produce each predicted direction. If, by manipulating displayed decisions, it is pretended that defectors have the highest frequency, loners soon become most frequent, as do cooperators after loners and defectors after cooperators. On average, cooperation is perpetuated at a substantial level.

Transient Dissipation and Structural Costs of Physical Information Transduction

NASA Astrophysics Data System (ADS)

Boyd, Alexander B.; Mandal, Dibyendu; Riechers, Paul M.; Crutchfield, James P.

2017-06-01

A central result that arose in applying information theory to the stochastic thermodynamics of nonlinear dynamical systems is the information-processing second law (IPSL): the physical entropy of the Universe can decrease if compensated by the Shannon-Kolmogorov-Sinai entropy change of appropriate information-carrying degrees of freedom. In particular, the asymptotic-rate IPSL precisely delineates the thermodynamic functioning of autonomous Maxwellian demons and information engines. How do these systems begin to function as engines, Landauer erasers, and error correctors? We identify a minimal, and thus inescapable, transient dissipation of physical information processing, which is not captured by asymptotic rates, but is critical to adaptive thermodynamic processes such as those found in biological systems. A component of transient dissipation, we also identify an implementation-dependent cost that varies from one physical substrate to another for the same information processing task. Applying these results to producing structured patterns from a structureless information reservoir, we show that "retrodictive" generators achieve the minimal costs. The results establish the thermodynamic toll imposed by a physical system's structure as it comes to optimally transduce information.

Environmental health implications of global climate change.

PubMed

Watson, Robert T; Patz, Jonathan; Gubler, Duane J; Parson, Edward A; Vincent, James H

2005-09-01

This paper reviews the background that has led to the now almost-universally held opinion in the scientific community that global climate change is occurring and is inescapably linked with anthropogenic activity. The potential implications to human health are considerable and very diverse. These include, for example, the increased direct impacts of heat and of rises in sea level, exacerbated air and water-borne harmful agents, and--associated with all the preceding--the emergence of environmental refugees. Vector-borne diseases, in particular those associated with blood-sucking arthropods such as mosquitoes, may be significantly impacted, including redistribution of some of those diseases to areas not previously affected. Responses to possible impending environmental and public health crises must involve political and socio-economic considerations, adding even greater complexity to what is already a difficult challenge. In some areas, adjustments to national and international public health practices and policies may be effective, at least in the short and medium terms. But in others, more drastic measures will be required. Environmental monitoring, in its widest sense, will play a significant role in the future management of the problem.

Casual Set Approach to a Minimal Invariant Length

NASA Astrophysics Data System (ADS)

Raut, Usha

2007-04-01

Any attempt to quantize gravity would necessarily introduce a minimal observable length scale of the order of the Planck length. This conclusion is based on several different studies and thought experiments and appears to be an inescapable feature of all quantum gravity theories, irrespective of the method used to quantize gravity. Over the last few years there has been growing concern that such a minimal length might lead to a contradiction with the basic postulates of special relativity, in particular the Lorentz-Fitzgerald contraction. A few years ago, Rovelli et.al, attempted to reconcile an invariant minimal length with Special Relativity, using the framework of loop quantum gravity. However, the inherently canonical formalism of the loop quantum approach is plagued by a variety of problems, many brought on by separation of space and time co-ordinates. In this paper we use a completely different approach. Using the framework of the causal set paradigm, along with a statistical measure of closeness between Lorentzian manifolds, we re-examine the issue of introducing a minimal observable length that is not at odds with Special Relativity postulates.

Care of the dying: how do we replace the Liverpool Care Pathway?

PubMed

Davis, Charles; Tomas, Jon

2014-12-01

Death is an inescapable certainty of life. Variability in care for dying persons, however, is present. The Liverpool Care Pathway (LCP) sought to guide care for the last days of life but was phased out after intense scrutiny. A governmental report and rapid review of evidence were considered alongside mass and social media reporting. An evidence review of end-of-life care was undertaken. Any person's death is inherently challenging. Much consideration must be given to holistic needs when approaching death. Communication skills may be lacking for professional and patient alike. The LCP became flawed in use rather than intention or principle. Seeming financial gains from death were concerning to all. We have responsibility for making choices prospectively in order for them to influence our care when we are dying. Normalization of death is key on both micro- and macro communication levels. Perceptions of relevant terminology; review of the definition of dying; improved recognition of the dying process and measuring the impact of communication skills training. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Mining in New Caledonia: environmental stakes and restoration opportunities.

PubMed

Losfeld, Guillaume; L'Huillier, Laurent; Fogliani, Bruno; Jaffré, Tanguy; Grison, Claude

2015-04-01

New Caledonia is a widely recognised marine and terrestrial biodiversity hot spot. However, this unique environment is under increasing anthropogenic pressure. Major threats are related to land cover change and include fire, urban sprawling and mining. Resulting habitat loss and fragmentation end up in serious erosion of the local biodiversity. Mining is of particular concern due to its economic significance for the island. Open cast mines were exploited there since 1873, and scraping out soil to access ores wipes out flora. Resulting perturbations on water flows and dramatic soil erosion lead to metal-rich sediment transport downstream into rivers and the lagoon. Conflicting environmental and economic aspects of mining are discussed in this paper. However, mining practices are also improving, and where impacts are inescapable ecological restoration is now considered. Past and ongoing experiences in the restoration of New Caledonian terrestrial ecosystems are presented and discussed here. Economic use of the local floristic diversity could also promote conservation and restoration, while providing alternative incomes. In this regard, Ecocatalysis, an innovative approach to make use of metal hyperaccumulating plants, is of particular interest.

Restricted emigration, system inescapability, and defense of the status quo: system-justifying consequences of restricted exit opportunities.

PubMed

Laurin, Kristin; Shepherd, Steven; Kay, Aaron C

2010-08-01

The freedom to emigrate at will from a geographic location is an internationally recognized human right. However, this right is systematically violated by restrictive migration policies. In three experiments, we explored the psychological consequences of violating the right to mobility. Our results suggest that, ironically, restricted freedom of movement can lead to increased system justification (i.e., increased support of the status quo). In Study 1, we found that participants who read that their country was difficult to leave became stronger defenders of their system's legitimacy than before, even in domains unrelated to emigration policy (e.g., gender relations). In Study 2, we demonstrated that this increased system defense was the result of a motivated process. In Study 3, we broadened the scope of this psychological phenomenon by conceptually replicating it using a different system (participants' university) and measure of system defense. The importance of these two findings-the first experimental demonstration of the psychological consequences of restrictive emigration policies and the introduction of a novel psychological phenomenon-is discussed.

Non-musicians also have a piano in the head: evidence for spatial-musical associations from line bisection tracking.

PubMed

Hartmann, Matthias

2017-02-01

The spatial representation of ordinal sequences (numbers, time, tones) seems to be a fundamental cognitive property. While an automatic association between horizontal space and pitch height (left-low pitch, right-high pitch) is constantly reported in musicians, the evidence for such an association in non-musicians is mixed. In this study, 20 non-musicians performed a line bisection task while listening to irrelevant high- and low-pitched tones and white noise (control condition). While pitch height had no influence on the final bisection point, participants' movement trajectories showed systematic biases: When approaching the line and touching the line for the first time (initial bisection point), the mouse cursor was directed more rightward for high-pitched tones compared to low-pitched tones and noise. These results show that non-musicians also have a subtle but nevertheless automatic association between pitch height and the horizontal space. This suggests that spatial-musical associations do not necessarily depend on constant sensorimotor experiences (as it is the case for musicians) but rather reflect the seemingly inescapable tendency to represent ordinal information on a horizontal line.

Translating dynamic defense patterns from rodents to people.

PubMed

Blanchard, D Caroline

2017-05-01

Specific defensive behaviors of rodents are shaped by features of the eliciting threat stimuli and situation. Threat scenarios confirmed these relationships in people, with results substantially replicated in 4 additional scenario studies. Subsequent human studies involve computer games measuring fear as flight from threat stimuli and anxiety as alternation between two threats. Stabilometric studies have shown reduction in sway (freezing) to inescapable (e.g. with gun pointed at subject) threatening photographs; but enhanced lateral sway (flight attempts) to escapable threats; (gun pointed away from subject). Relationships between threat ambiguity, risk assessment, and anxiety have been validated by identification of videos of facial expressions to ambiguous threats, as anxiety; and systematic biases toward threat stimuli by anxious individuals. Enhanced rumination, interpretable as unsuccessful risk assessment, is a dynamic component of both anxiety and depression, particularly in women. While there is less experimental work on defensive threat/attack, a transdiagnostic "Fear of Harm" phenotype of aggression associated with fear suggests that this is a component of pathological as well as normal human defensive behavior. Copyright © 2016. Published by Elsevier Ltd.

Opposite monosynaptic scaling of BLP–vCA1 inputs governs hopefulness- and helplessness-modulated spatial learning and memory

PubMed Central

Yang, Ying; Wang, Zhi-Hao; Jin, Sen; Gao, Di; Liu, Nan; Chen, Shan-Ping; Zhang, Sinan; Liu, Qing; Liu, Enjie; Wang, Xin; Liang, Xiao; Wei, Pengfei; Li, Xiaoguang; Li, Yin; Yue, Chenyu; Li, Hong-lian; Wang, Ya-Li; Wang, Qun; Ke, Dan; Xie, Qingguo; Xu, Fuqiang; Wang, Liping; Wang, Jian-Zhi

2016-01-01

Different emotional states lead to distinct behavioural consequences even when faced with the same challenging events. Emotions affect learning and memory capacities, but the underlying neurobiological mechanisms remain elusive. Here we establish models of learned helplessness (LHL) and learned hopefulness (LHF) by exposing animals to inescapable foot shocks or with anticipated avoidance trainings. The LHF animals show spatial memory potentiation with excitatory monosynaptic upscaling between posterior basolateral amygdale (BLP) and ventral hippocampal CA1 (vCA1), whereas the LHL show memory deficits with an attenuated BLP–vCA1 connection. Optogenetic disruption of BLP–vCA1 inputs abolishes the effects of LHF and impairs synaptic plasticity. By contrast, targeted BLP–vCA1 stimulation rescues the LHL-induced memory deficits and mimics the effects of LHF. BLP–vCA1 stimulation increases synaptic transmission and dendritic plasticity with the upregulation of CREB and intrasynaptic AMPA receptors in CA1. These findings indicate that opposite excitatory monosynaptic scaling of BLP–vCA1 controls LHF- and LHL-modulated spatial memory, revealing circuit-specific mechanisms linking emotions to memory. PMID:27411738

Opposite monosynaptic scaling of BLP-vCA1 inputs governs hopefulness- and helplessness-modulated spatial learning and memory.

PubMed

Yang, Ying; Wang, Zhi-Hao; Jin, Sen; Gao, Di; Liu, Nan; Chen, Shan-Ping; Zhang, Sinan; Liu, Qing; Liu, Enjie; Wang, Xin; Liang, Xiao; Wei, Pengfei; Li, Xiaoguang; Li, Yin; Yue, Chenyu; Li, Hong-Lian; Wang, Ya-Li; Wang, Qun; Ke, Dan; Xie, Qingguo; Xu, Fuqiang; Wang, Liping; Wang, Jian-Zhi

2016-07-14

Different emotional states lead to distinct behavioural consequences even when faced with the same challenging events. Emotions affect learning and memory capacities, but the underlying neurobiological mechanisms remain elusive. Here we establish models of learned helplessness (LHL) and learned hopefulness (LHF) by exposing animals to inescapable foot shocks or with anticipated avoidance trainings. The LHF animals show spatial memory potentiation with excitatory monosynaptic upscaling between posterior basolateral amygdale (BLP) and ventral hippocampal CA1 (vCA1), whereas the LHL show memory deficits with an attenuated BLP-vCA1 connection. Optogenetic disruption of BLP-vCA1 inputs abolishes the effects of LHF and impairs synaptic plasticity. By contrast, targeted BLP-vCA1 stimulation rescues the LHL-induced memory deficits and mimics the effects of LHF. BLP-vCA1 stimulation increases synaptic transmission and dendritic plasticity with the upregulation of CREB and intrasynaptic AMPA receptors in CA1. These findings indicate that opposite excitatory monosynaptic scaling of BLP-vCA1 controls LHF- and LHL-modulated spatial memory, revealing circuit-specific mechanisms linking emotions to memory.

Rodent models of depression: forced swim and tail suspension behavioral despair tests in rats and mice.

PubMed

Castagné, Vincent; Moser, Paul; Roux, Sylvain; Porsolt, Roger D

2011-04-01

The development of antidepressants requires simple rodent behavioral tests for initial screening before undertaking more complex preclinical tests and clinical evaluation. Presented in the unit are two widely used screening tests used for antidepressants, the forced swim (also termed behavioral despair) test in the rat and mouse, and the tail suspension test in the mouse. These tests have good predictive validity and allow rapid and economical detection of substances with potential antidepressant-like activity. The behavioral despair and the tail suspension tests are based on the same principle: measurement of the duration of immobility when rodents are exposed to an inescapable situation. The majority of clinically used antidepressants decrease the duration of immobility. Antidepressants also increase the latency to immobility, and this additional measure can increase the sensitivity of the behavioral despair test in the mouse for certain classes of antidepressant. Testing of new substances in the behavioral despair and tail suspension tests allows a simple assessment of their potential antidepressant activity by the measurement of their effect on immobility. © 2011 by John Wiley & Sons, Inc.

Highly improved photo-induced bias stability of sandwiched triple layer structure in sol-gel processed fluorine-doped indium zinc oxide thin film transistor

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, Dongha; Park, Hyungjin; Bae, Byeong-Soo, E-mail: bsbae@kaist.ac.kr

In order to improve the reliability of TFT, an Al{sub 2}O{sub 3} insulating layer is inserted between active fluorine doped indium zinc oxide (IZO:F) thin films to form a sandwiched triple layer. All the thin films were fabricated via low-cost sol-gel process. Due to its large energy bandgap and high bonding energy with oxygen atoms, the Al{sub 2}O{sub 3} layer acts as a photo-induced positive charge blocking layer that effectively blocks the migration of both holes and V {sub o}{sup 2+} toward the interface between the gate insulator and the semiconductor. The inserted Al{sub 2}O{sub 3} triple layer exhibits amore » noticeably low turn on voltage shift of −0.7 V under NBIS as well as the good TFT performance with a mobility of 10.9 cm{sup 2}/V ⋅ s. We anticipate that this approach can be used to solve the stability issues such as NBIS, which is caused by inescapable oxygen vacancies.« less

Morality Principles for Risk Modelling: Needs and Links with the Origins of Plausible Inference

NASA Astrophysics Data System (ADS)

Solana-Ortega, Alberto; Solana, Vicente

2009-12-01

In comparison with the foundations of probability calculus, the inescapable and controversial issue of how to assign probabilities has only recently become a matter of formal study. The introduction of information as a technical concept was a milestone, but the most promising entropic assignment methods still face unsolved difficulties, manifesting the incompleteness of plausible inference theory. In this paper we examine the situation faced by risk analysts in the critical field of extreme events modelling, where the former difficulties are especially visible, due to scarcity of observational data, the large impact of these phenomena and the obligation to assume professional responsibilities. To respond to the claim for a sound framework to deal with extremes, we propose a metafoundational approach to inference, based on a canon of extramathematical requirements. We highlight their strong moral content, and show how this emphasis in morality, far from being new, is connected with the historic origins of plausible inference. Special attention is paid to the contributions of Caramuel, a contemporary of Pascal, unfortunately ignored in the usual mathematical accounts of probability.

Establishing a learned-helplessness effect paradigm in C57BL/6 mice: behavioural evidence for emotional, motivational and cognitive effects of aversive uncontrollability per se.

PubMed

Pryce, Christopher R; Azzinnari, Damiano; Sigrist, Hannes; Gschwind, Tilo; Lesch, Klaus-Peter; Seifritz, Erich

2012-01-01

Uncontrollability of major life events has been proposed to be central to depression onset and maintenance. The learned helplessness (LH) effect describes a deficit in terminating controllable aversive stimuli in individuals that experienced aversive stimuli as uncontrollable relative to individuals that experienced the same stimuli as controllable. The LH effect translates across species and therefore can provide an objective-valid readout in animal models of depression. Paradigms for a robust LH effect are established and currently applied in rat but there are few reports of prior and current study of the LH effect in mouse. This includes the C57BL/6 mouse, typically the strain of choice for application of molecular-genetic tools in pre-clinical depression research. The aims of this study were to develop a robust paradigm for the LH effect in BL/6 mice, provide evidence for underlying psychological processes, and study the effect of a depression-relevant genotype on the LH effect. The apparatus used for in/escapable electro-shock exposure and escape test was a two-way shuttle arena with continuous automated measurement of locomotion, compartment transfers, e-shock escapes, vertical activity and freezing. Brother-pairs of BL/6 mice were allocated to either escapable e-shocks (ES) or inescapable e-shocks (IS), with escape latencies of the ES brother used as e-shock durations for the IS brother. The standard two-way shuttle paradigm was modified: the central gate was replaced by a raised divider and e-shock escape required transfer to the distal part of the safe compartment. These refinements yielded reduced superstitious, pre-adaptive e-shock transfers in IS mice and thereby increased the LH effect. To obtain a robust LH effect in all brother pairs, pre-screening for minor between-brother ES differences was necessary and did not confound the LH effect. IS mice developed reduced motor responses to e-shock, consistent with a motivational deficit, and absence of a learning curve for escapes at escape test, consistent with a cognitive deficit. When a tone CS was used to predict e-shock, IS mice exhibited increased reactivity to the CS, consistent with hyper-emotionality. There was no ES-IS difference in pain sensitivity. Mice heterozygous knockout for the 5-HTT gene exhibited an increased LH effect relative to wildtype mice. This mouse model will allow for the detailed molecular study of the aetiology, psychology, neurobiology and neuropharmacology of uncontrollability of aversive stimuli, a potential major aetiological factor and state marker in depression. This article is part of a Special Issue entitled 'Anxiety and Depression'. Copyright © 2011 Elsevier Ltd. All rights reserved.

Temporal factors in the extinction of fear in inbred mouse strains differing in extinction efficacy

PubMed Central

2013-01-01

Background Various neuropsychiatric conditions, including posttraumatic stress disorder (PTSD), are characterized by deficient fear extinction, but individuals differ greatly in risk for these. While there is growing evidence that fear extinction is influenced by certain procedural variables, it is unclear how these influences might vary across individuals and subpopulations. To model individual differences in fear extinction, prior studies identified a strain of inbred mouse, 129S1/SvImJ (S1), which exhibits a profound deficit in fear extinction, as compared to other inbred strains, such as C57BL/6J (B6). Methods Here, we assessed the effects of procedural variables on the impaired extinction phenotype of the S1 strain and, by comparison, the extinction-intact B6 strain. The variables studied were 1) the interval between conditioning and extinction, 2) the interval between cues during extinction training, 3) single-cue exposure before extinction training, and 4) extinction of a second-order conditioned cue. Results Conducting extinction training soon after (‘immediately’) conditioning attenuated fear retrieval in S1 mice and impaired extinction in B6 mice. Spacing cue presentations with long inter-trial intervals during extinction training augmented fear in S1 and B6 mice. The effect of spacing was lost with one-trial fear conditioning in B6, but not S1 mice. A single exposure to a conditioned cue before extinction training did not alter extinction retrieval, either in B6 or S1 mice. Both the S1 and B6 strains exhibited robust second-order fear conditioning, in which a cue associated with footshock was sufficient to serve as a conditioned exciter to condition a fear association to a second cue. B6 mice extinguished the fear response to the second-order conditioned cue, but S1 mice failed to do so. Conclusions These data provide further evidence that fear extinction is strongly influenced by multiple procedural variables and is so in a highly strain-dependent manner. This suggests that the efficacy of extinction-based behavioral interventions, such as exposure therapy, for trauma-related anxiety disorders will be determined by the procedural parameters employed and the degree to which the patient can extinguish. PMID:23830244

Propranolol–induced Impairment of Contextual Fear Memory Reconsolidation in Rats: A similar Effect on Weak and Strong Recent and Remote Memories

PubMed Central

Taherian, Fatemeh; Vafaei, Abbas Ali; Vaezi, Gholam Hassan; Eskandarian, Sharaf; Kashef, Adel; Rashidy-Pour, Ali

2014-01-01

Introduction Previous studies have demonstrated that the β-adrenergic receptor antagonist propranolol impairs fear memory reconsolidation in experimental animals. There are experimental parameters such as the age and the strength of memory that can interact with pharmacological manipulations of memory reconsolidation. In this study, we investigated the ability of the age and the strength of memory to influence the disrupting effects of propranolol on fear memory reconsolidation in rats. Methods The rats were trained in a contextual fear conditioning using two (weak training) or five (strong training) footshocks (1mA). Propranolol (10mg/kg) injection was immediately followed retrieval of either a one-day recent (weak or strong) or 36-day remote (weak or strong) contextual fear memories. Results We found that propranolol induced a long-lasting impairment of subsequent expression of recent and remote memories with either weak or strong strength. We also found no memory recovery after a weak reminder shock. Furthermore, no significant differences were found on the amount of memory deficit induced by propranolol among memories with different age and strength. Discussion Our data suggest that the efficacy of propranolol in impairing fear memory reconsolidation is not limited to the age or strength of the memory. PMID:25337385

Modulation of Gene Expression in Contextual Fear Conditioning in the Rat

PubMed Central

Macchi, Monica; Ciampini, Cristina; Bernardi, Rodolfo; Baldi, Elisabetta; Bucherelli, Corrado; Brunelli, Marcello; Scuri, Rossana

2013-01-01

In contextual fear conditioning (CFC) a single training leads to long-term memory of context-aversive electrical foot-shocks association. Mid-temporal regions of the brain of trained and naive rats were obtained 2 days after conditioning and screened by two-directional suppression subtractive hybridization. A pool of differentially expressed genes was identified and some of them were randomly selected and confirmed with qRT-PCR assay. These transcripts showed high homology for rat gene sequences coding for proteins involved in different cellular processes. The expression of the selected transcripts was also tested in rats which had freely explored the experimental apparatus (exploration) and in rats to which the same number of aversive shocks had been administered in the same apparatus, but temporally compressed so as to make the association between painful stimuli and the apparatus difficult (shock-only). Some genes resulted differentially expressed only in the rats subjected to CFC, others only in exploration or shock-only rats, whereas the gene coding for translocase of outer mitochondrial membrane 20 protein and nardilysin were differentially expressed in both CFC and exploration rats. For example, the expression of stathmin 1 whose transcripts resulted up regulated was also tested to evaluate the transduction and protein localization after conditioning. PMID:24278235

Decreased pain sensitivity due to trimethylbenzene exposure ...

EPA Pesticide Factsheets

Traditionally, human health risk assessments have relied on qualitative approaches for hazard identification, often using the Hill criteria and weight of evidence determinations to integrate data from multiple studies. Recently, the National Research Council has recommended the development of quantitative approaches for evidence integration, including the application of meta-analyses. The following hazard identification case study applies qualitative as well as meta-analytic approaches to trimethylbenzene (TMB) isomers exposure and the potential neurotoxic effects on pain sensitivity. In the meta-analytic approach, a pooled effect size is calculated, after consideration of multiple confounding factors, in order to determine whether the entire database under consideration indicates that TMBs are likely to be a neurotoxic hazard. The pain sensitivity studies included in the present analyses initially seem discordant in their results: effects on pain sensitivity are seen immediately after termination of exposure, appear to resolve 24 hours after exposure, and then reappear 50 days later following foot-shock. Qualitative consideration of toxicological and toxicokinetic characteristics of the TMB isomers suggests that the observed differences between studies are due to testing time and can be explained through a complete consideration of the underlying biology of the effect and the nervous system as a whole. Meta-analyses and –regressions support this conclus

Neural correlates of appetitive-aversive interactions in Pavlovian fear conditioning.

PubMed

Nasser, Helen M; McNally, Gavan P

2013-03-19

We used Pavlovian counterconditioning in rats to identify the neural mechanisms for appetitive-aversive motivational interactions. In Stage I, rats were trained on conditioned stimulus (CS)-food (unconditioned stimulus [US]) pairings. In Stage II, this appetitive CS was transformed into a fear CS via pairings with footshock. The development of fear responses was retarded in rats that had received Stage I appetitive training. This counterconditioning was associated with increased levels of phosphorylated mitogen activated protein kinase immunoreactivity (pMAPK-IR) in several brain regions, including midline thalamus, rostral agranular insular cortex (RAIC), lateral amygdala, and nucleus accumbens core and shell, but decreased expression in the ventrolateral quadrant of the midbrain periaqueductal gray. These brain regions showing differential pMAPK-IR have previously been identified as part of the fear prediction error circuit. We then examined the causal role of RAIC MAPK in fear learning and showed that Stage II fear learning was prevented by RAIC infusions of the MEK inhibitor PD098059 (0.5 µg/hemisphere). Taken together, these results show that there are opponent interactions between the appetitive and aversive motivational systems during fear learning and that the transformation of a reward CS into a fear CS is linked to heightened activity in the fear prediction error circuit.

Early adolescent adversity inflates threat estimation in females and promotes alcohol use initiation in both sexes.

PubMed

Walker, Rachel A; Andreansky, Christopher; Ray, Madelyn H; McDannald, Michael A

2018-06-01

Childhood adversity is associated with exaggerated threat processing and earlier alcohol use initiation. Conclusive links remain elusive, as childhood adversity typically co-occurs with detrimental socioeconomic factors, and its impact is likely moderated by biological sex. To unravel the complex relationships among childhood adversity, sex, threat estimation, and alcohol use initiation, we exposed female and male Long-Evans rats to early adolescent adversity (EAA). In adulthood, >50 days following the last adverse experience, threat estimation was assessed using a novel fear discrimination procedure in which cues predict a unique probability of footshock: danger (p = 1.00), uncertainty (p = .25), and safety (p = .00). Alcohol use initiation was assessed using voluntary access to 20% ethanol, >90 days following the last adverse experience. During development, EAA slowed body weight gain in both females and males. In adulthood, EAA selectively inflated female threat estimation, exaggerating fear to uncertainty and safety, but promoted alcohol use initiation across sexes. Meaningful relationships between threat estimation and alcohol use initiation were not observed, underscoring the independent effects of EAA. Results isolate the contribution of EAA to adult threat estimation, alcohol use initiation, and reveal moderation by biological sex. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Combined treatment with subchronic lithium and acute intracerebral mirtazapine microinjection into the median raphe nucleus exerted an anxiolytic-like effect synergistically.

PubMed

An, Yan; Inoue, Takeshi; Kitaichi, Yuji; Chen, Chong; Nakagawa, Shin; Wang, Ce; Kusumi, Ichiro

2016-07-15

Although preclinical and clinical studies have established the efficacy of lithium augmentation of antidepressant drugs, the mechanism of action of lithium augmentation is not fully understood. Our previous study reported that subchronic lithium treatment enhanced the anxiolytic-like effect of systemic mirtazapine. In the present study, we examined the effect of subchronic lithium in combination with acute local intracerebral injection of mirtazapine on fear-related behaviors in a contextual fear conditioning test in rats to clarify the target brain region of lithium augmentation of mirtazapine. After conditioning by footshock, diet (food pellets) containing Li2CO3 at a concentration of 0.2% was administered for 7 days. Ten min before testing and 7 days after conditioning, mirtazapine (3μg/site) in a volume of 0.5µl was acutely injected into the median raphe nucleus (MRN), hippocampus or amygdala. The combination of subchronic lithium and acute mirtazapine microinjection into the MRN but not the hippocampus or the amygdala reduced fear expression synergistically. These results suggest that intra-MRN mirtazapine treatment with subchronic lithium exerts the anxiolytic-like effect through the facilitation of the MRN-5HT pathway. Copyright © 2016 Elsevier B.V. All rights reserved.

Balancing Risk and Reward: A Rat Model of Risky Decision-Making

PubMed Central

Simon, Nicholas W.; Gilbert, Ryan J.; Mayse, Jeffrey D.; Bizon, Jennifer L.; Setlow, Barry

2009-01-01

We developed a behavioral task in rats to assess the influence of risk of punishment on decision-making. Male Long-Evans rats were given choices between pressing a lever to obtain a small, “safe” food reward and a large food reward associated with risk of punishment (footshock). Each test session consisted of 5 blocks of 10 choice trials, with punishment risk increasing with each consecutive block (0, 25, 50, 75, 100%). Preference for the large, “risky” reward declined with both increased probability and increased magnitude of punishment, and reward choice was not affected by the level of satiation or the order of risk presentation. Performance in this risky decision-making task was correlated with the degree to which the rats discounted the value of probabilistic rewards, but not delayed rewards. Finally, the acute effects of different doses of amphetamine and cocaine on risky decision-making were assessed. Systemic amphetamine administration caused a dose-dependent decrease in choice of the large risky reward (i.e. – it made rats more risk-averse). Cocaine did not cause a shift in reward choice, but instead impaired rats’ sensitivity to changes in punishment risk. These results should prove useful for investigating neuropsychiatric disorders in which risk taking is a prominent feature, such as attention deficit/hyperactivity disorder and addiction. PMID:19440192

Neural population-level memory traces in the mouse hippocampus.

PubMed

Chen, Guifen; Wang, L Phillip; Tsien, Joe Z

2009-12-16

One of the fundamental goals in neurosciences is to elucidate the formation and retrieval of brain's associative memory traces in real-time. Here, we describe real-time neural ensemble transient dynamics in the mouse hippocampal CA1 region and demonstrate their relationships with behavioral performances during both learning and recall. We employed the classic trace fear conditioning paradigm involving a neutral tone followed by a mild foot-shock 20 seconds later. Our large-scale recording and decoding methods revealed that conditioned tone responses and tone-shock association patterns were not present in CA1 during the first pairing, but emerged quickly after multiple pairings. These encoding patterns showed increased immediate-replay, correlating tightly with increased immediate-freezing during learning. Moreover, during contextual recall, these patterns reappeared in tandem six-to-fourteen times per minute, again correlating tightly with behavioral recall. Upon traced tone recall, while various fear memories were retrieved, the shock traces exhibited a unique recall-peak around the 20-second trace interval, further signifying the memory of time for the expected shock. Therefore, our study has revealed various real-time associative memory traces during learning and recall in CA1, and demonstrates that real-time memory traces can be decoded on a moment-to-moment basis over any single trial.

Tetrodotoxin-dependent glutamate release in the rat nucleus accumbens during concurrent presentation of appetitive and conditioned aversive stimuli.

PubMed

Saulskaya, Natalia B; Soloviova, Nina A

2004-12-30

In vivo microdialysis combined with a high-performance liquid chromatography was used to monitor extracellular glutamate (GLU) levels in the nucleus accumbens (N.Acc) of Sprague-Dawley rats during their behavioral responses to the concurrent presentation of appetitive and conditioned aversive stimuli. The presentation of a highly palatable diet followed by a tone previously paired with footshock to rats trained to take a pellet of the diet under these experimental conditions resulted in a marked and short lasting increase in extracellular glutamate, whereas the tone alone had no effect. A similar increase of the glutamate release was observed during the presentation of a piece of rubber instead of the diet. In both cases, the increase in extracellular glutamate was completely prevented by intra-accumbal infusions through the dialysis probe of 1 microM tetrodotoxin (a voltage-dependent Na(+) channel blocker), whereas (S)-4-carboxyphenylglycine (a cystine/glutamate exchange blocker, 5 microM) had no effect. The data obtained suggest that behavioral responses to unpredicted change in motivational value of expected reward appear to be associated with an increase of the extracellular glutamate level in the nucleus accumbens, and impulse-dependent synaptic release, rather than non-vesicular glutamate release via cystine/glutamate exchange, is responsible for this phenomenon.

Contextual Fear Conditioning in Humans: Cortical-Hippocampal and Amygdala Contributions

PubMed Central

Alvarez, Ruben P.; Biggs, Arter; Chen, Gang; Pine, Daniel S.; Grillon, Christian

2008-01-01

Functional imaging studies of cued fear conditioning in humans have largely confirmed findings in animals, but it is unclear whether the brain mechanisms that underlie contextual fear conditioning in animals are also preserved in humans. We investigated this issue using fMRI and virtual reality contexts. Subjects underwent differential context conditioning in which they were repeatedly exposed to two contexts (CXT+ and CXT-) in semi-random order, with contexts counterbalanced across participants. An un-signaled footshock was consistently paired with the CXT+, and no shock was ever delivered in the CXT-. Evidence for context conditioning was established using skin conductance and anxiety ratings. Consistent with animal models centrally implicating the hippocampus and amygdala in a network supporting context conditioning, CXT+ compared to CXT- significantly activated right anterior hippocampus and bilateral amygdala. In addition, context conditioning was associated with activation in posterior orbitofrontal cortex, medial dorsal thalamus, anterior insula, subgenual anterior cingulate, and parahippocampal, inferior frontal and parietal cortices. Structural equation modeling was used to assess interactions among the core brain regions mediating context conditioning. The derived model indicated that medial amygdala was the source of key efferent and afferent connections including input from orbitofrontal cortex. These results provide evidence that similar brain mechanisms may underlie contextual fear conditioning across species. PMID:18550763

Balancing risk and reward: a rat model of risky decision making.

PubMed

Simon, Nicholas W; Gilbert, Ryan J; Mayse, Jeffrey D; Bizon, Jennifer L; Setlow, Barry

2009-09-01

We developed a behavioral task in rats to assess the influence of risk of punishment on decision making. Male Long-Evans rats were given choices between pressing a lever to obtain a small, 'safe' food reward and a large food reward associated with risk of punishment (footshock). Each test session consisted of 5 blocks of 10 choice trials, with punishment risk increasing with each consecutive block (0, 25, 50, 75, 100%). Preference for the large, 'risky' reward declined with both increased probability and increased magnitude of punishment, and reward choice was not affected by the level of satiation or the order of risk presentation. Performance in this risky decision-making task was correlated with the degree to which the rats discounted the value of probabilistic rewards, but not delayed rewards. Finally, the acute effects of different doses of amphetamine and cocaine on risky decision making were assessed. Systemic amphetamine administration caused a dose-dependent decrease in choice of the large risky reward (ie, it made rats more risk averse). Cocaine did not cause a shift in reward choice, but instead impaired the rats' sensitivity to changes in punishment risk. These results should prove useful for investigating neuropsychiatric disorders in which risk taking is a prominent feature, such as attention deficit/hyperactivity disorder and addiction.

The effect of the steroid sulfatase inhibitor (p-O-sulfamoyl)-tetradecanoyl tyramine (DU-14) on learning and memory in rats with selective lesion of septal-hippocampal cholinergic tract.

PubMed

Babalola, P A; Fitz, N F; Gibbs, R B; Flaherty, P T; Li, P-K; Johnson, D A

2012-10-01

Dehydroepiandrosterone sulfate (DHEAS), is an excitatory neurosteroid synthesized within the CNS that modulates brain function. Effects associated with augmented DHEAS include learning and memory enhancement. Inhibitors of the steroid sulfatase enzyme increase brain DHEAS levels and can also facilitate learning and memory. This study investigated the effect of steroid sulfatase inhibition on learning and memory in rats with selective cholinergic lesion of the septo-hippocampal tract using passive avoidance and delayed matching to position T-maze (DMP) paradigms. The selective cholinergic immunotoxin 192 IgG-saporin (SAP) was infused into the medial septum of animals and then tested using a step-through passive avoidance paradigm or DMP paradigm. Peripheral administration of the steroid sulfatase inhibitor, DU-14, increased step-through latency following footshock in rats with SAP lesion compared to both vehicle treated control and lesioned animals (p<0.05). However, in the DMP task, steroid sulfatase inhibition impaired acquisition in lesioned rats while having no effect on intact animals. These results suggest that steroid sulfatase inhibition facilitates memory associated with contextual fear, but impairs acquisition of spatial memory tasks in rats with selective lesion of the septo-hippocampal tract. Copyright © 2012 Elsevier Inc. All rights reserved.

Assessment of Attentional Workload while Driving by Eye-fixation-related Potentials

NASA Astrophysics Data System (ADS)

Takeda, Yuji; Yoshitsugu, Noritoshi; Itoh, Kazuya; Kanamori, Nobuhiro

How do drivers cope with the attentional workload of in-vehicle information technology? In the present study, we propose a new psychophysiological measure for assessing drivers' attention: eye-fixation-related potential (EFRP). EFRP is a kind of event-related brain potential measurable at the eye-movement situation that reflects how closely observers examine visual information at the eye-fixated position. In the experiment, the effects of verbal working memory load and spatial working memory load during simulated driving were examined by measuring the number of saccadic eye-movements and EFRP as the indices of drivers' attention. The results showed that the spatial working memory load affected both the number of saccadic eye-movements and the amplitude of the P100 component of EFRP, whereas the verbal working memory load affected only the number of saccadic eye-movements. This implies that drivers can perform time-sharing processing between driving and the verbal working memory task, but the decline of accuracy of visual processing during driving is inescapable when the spatial working memory load is given. The present study suggests that EFRP can provide a new index of drivers' attention, other than saccadic eye-movements.

Novelty seeking, incentive salience and acquisition of cocaine self-administration in the rat

PubMed Central

Beckmann, Joshua S.; Marusich, Julie A.; Gipson, Cassandra D.; Bardo, Michael T.

2010-01-01

It has been suggested that incentive salience plays a major role in drug abuse and the development of addiction. Additionally, novelty seeking has been identified as a significant risk factor for drug abuse. However, how differences in the readiness to attribute incentive salience relate to novelty seeking and drug abuse vulnerability has not been explored. The present experiments examined how individual differences in incentive salience attribution relate to novelty seeking and acquisition of cocaine self-administration in a preclinical model. Rats were first assessed in an inescapable novelty task and a novelty place preference task (measures of novelty seeking), followed by a Pavlovian conditioned approach task for food (a measure of incentive salience attribution). Rats then were trained to self-administer cocaine (0.3 or 1.0 mg/kg/infusion) using an autoshaping procedure. The results demonstrate that animals that attributed incentive salience to a food-associated cue were higher novelty seekers and acquired cocaine self-administration more quickly at the lower dose. The results suggest that novelty-seeking behavior may be a mediator of incentive salience attribution and that incentive salience magnitude may be an indicator of drug reward. PMID:20655954

High internal noise and poor external noise filtering characterize perception in autism spectrum disorder.

PubMed

Park, Woon Ju; Schauder, Kimberly B; Zhang, Ruyuan; Bennetto, Loisa; Tadin, Duje

2017-12-14

An emerging hypothesis postulates that internal noise is a key factor influencing perceptual abilities in autism spectrum disorder (ASD). Given fundamental and inescapable effects of noise on nearly all aspects of neural processing, this could be a critical abnormality with broad implications for perception, behavior, and cognition. However, this proposal has been challenged by both theoretical and empirical studies. A crucial question is whether and how internal noise limits perception in ASD, independently from other sources of perceptual inefficiency, such as the ability to filter out external noise. Here, we separately estimated internal noise and external noise filtering in ASD. In children and adolescents with and without ASD, we computationally modeled individuals' visual orientation discrimination in the presence of varying levels of external noise. The results revealed increased internal noise and worse external noise filtering in individuals with ASD. For both factors, we also observed high inter-individual variability in ASD, with only the internal noise estimates significantly correlating with severity of ASD symptoms. We provide evidence for reduced perceptual efficiency in ASD that is due to both increased internal noise and worse external noise filtering, while highlighting internal noise as a possible contributing factor to variability in ASD symptoms.

Upstream healthy public policy: lessons from the battle of tobacco.

PubMed

McKinlay, J B; Marceau, L D

2000-01-01

Many consider public health and politics to be entirely separate worlds. Public health activities are generally well-motivated by public interest, perceived as value-free, scientific, and devoid of partisan preference. Politics, in contrast, can be viewed as a distasteful activity involving self-interested pressure groups, misuse of state power, and influence of money on national decisions. Public health and politics are inappropriate bedfellows if politics is reduced to party politics. Politics, of course, involves more than just party activities; it concerns the structure, distribution, and effects of power in society. Which groups pattern the social order? What are their sources of influence? How do they retain privileged status? What social effects result from the policies these groups shape? Viewed in this broader sense, politics is essential for effective public health and thus is the inescapable context of public health interventions. To disregard sociopolitical determinants of health is to relegate public health to prevention and promotion of individual risk behaviors. If public health is to be more successful in the 21st century, it must comprehend the magnitude of the forces against it and the strategies used to engineer its defeat. Public health interventions in the new millennium must be appropriate to their sociocultural context.

Water and Western Energy: Impacts, Issues, and Choices

NASA Astrophysics Data System (ADS)

Haimes, Yacov Y.

Since the 1973 oil embargo numerous studies have been commissioned on the subject of water and energy, and thus the proliferation of books and reports on associated problems is not surprising. The importance of the issues at stake and the realization that we were relatively unprepared to deal with the anticipated high level of future coal and shale development in the West altered our perceptions of many water-energy issues; the issues were elevated, at least in some quarters, from the level of a common planning problem to the level of a crisis. For those of us who were captured in this syndrome and were a part of these “crisis studies,” this document inescapably brings a sense of déja vu.The review of books serves multiple goals and purposes for readers as well as authors. For example, when I read book reviews in Eos, I am most interested in one that briefly introduces the book's topics, indicates the depth and breadth of the discussion, constructively highlights the major attributes and limitations of the book, critically evaluates the book as a whole, and, if possible, suggests other documents that either supplement or complement the book's writings. I will attempt to do just this.

Civil engineering at the crossroads in the twenty-first century.

PubMed

Ramírez, Francisco; Seco, Andres

2012-12-01

The twenty-first century presents a major challenge for civil engineering. The magnitude and future importance of some of the problems perceived by society are directly related to the field of the civil engineer, implying an inescapable burden of responsibility for a group whose technical soundness, rational approach and efficiency is highly valued and respected by the citizen. However, the substantial changes in society and in the way it perceives the problems that it considers important call for a thorough review of our structures, both professional and educational; so that our profession, with its undeniable historical prestige, may modernize certain approaches and attitudes in order to continue to be a reliable instrument in the service of society, giving priority from an ethical standpoint to its actions in pursuit of "the public good". It possesses important tools to facilitate this work (new technologies, the development of communications, the transmission of scientific thought.···); but there is nevertheless a need for deep reflection on the very essence of civil engineering: what we want it to be in the future, and the ability and willingness to take the lead at a time when society needs disinterested messages, technically supported, reasonably presented and dispassionately transmitted.

Acquisition of natural humoral immunity to P. falciparum in early life in Benin: impact of clinical, environmental and host factors.

PubMed

Dechavanne, Célia; Sadissou, Ibrahim; Bouraima, Aziz; Ahouangninou, Claude; Amoussa, Roukiyath; Milet, Jacqueline; Moutairou, Kabirou; Massougbodji, Achille; Theisen, Michael; Remarque, Edmond J; Courtin, David; Nuel, Gregory; Migot-Nabias, Florence; Garcia, André

2016-09-27

To our knowledge, effects of age, placental malaria infection, infections during follow-up, nutritional habits, sickle-cell trait and individual exposure to Anopheles bites were never explored together in a study focusing on the acquisition of malaria antibody responses among infants living in endemic areas.Five hundred and sixty-seven Beninese infants were weekly followed-up from birth to 18 months of age. Immunoglobulin G (IgG), IgG1 and IgG3 specific for 5 malaria antigens were measured every 3 months. A linear mixed model was used to analyze the effect of each variable on the acquisition of antimalarial antibodies in 6-to18-month old infants in univariate and multivariate analyses. Placental malaria, nutrition intakes and sickle-cell trait did not influence the infant antibody levels to P. falciparum antigens. In contrary, age, malaria antibody levels at birth, previous and present malaria infections as well as exposure to Anopheles bites were significantly associated with the natural acquisition of malaria antibodies in 6-to18-month old Beninese infants. This study highlighted inescapable factors to consider simultaneously in an immuno-epidemiological study or a vaccine trial in early life.

What kind of time for a Time Machine?

NASA Astrophysics Data System (ADS)

Alfano, Marina; Buccheri, Rosolino

2013-09-01

The linear, unstructured, parameter t used in the equations of mechanics, in spite of its great aptness in describing the nature's laws, does not fit with the unidirectional flow of time tssubjectively experienced by humans, just the investigators of nature. Being ts the main foundation upon which we build our knowledge of nature through our continuous and inescapable reciprocal interaction - the possible key factor of our cerebral modulation, mediator between us and the world -, its objective essence appears to be inevitably destined to remain unveiled. We derive that any imagined and theoretically possible Time Machine, aimed to get us in our past or in our future allowing us to act there, does not have any practical grounds if it is built by using the illusory, impersonal, time, modeled by the parameter t, at the place of our interpersonal lived time ts. A real, humanly-tuned, Time Machine could perhaps arise by integrating tsin the body of a new kind of rationality - a `complex thought' - where empiricism and logic-mathematic are harmonized with participation and interaction. Ongoing joint research in neurophysiology and physics (without neglecting any important contribution coming from anthropology) will surely help achieving such a goal.

Religious leaders' opinions and guidance towards oral health maintenance and promotion: a qualitative study.

PubMed

Zini, Avraham; Sgan-Cohen, Harold D; Feder-Bubis, Paula

2015-04-01

Religions emphasize the supreme value of life. However, potential or concrete conflicts of perception between dictates of faith and science often present an inescapable dilemma. The aim of this qualitative research was to examine the views of spiritual and religious leaders towards general and oral health issues. A total of 11 eminent Jewish spiritual and religious community leaders were purposively chosen. They were interviewed using a semi-structured questionnaire. The verbatim transcriptions of the interviews were analysed in the spirit of grounded theory, using qualitative data analysis software. Open, axial, and thematic coding served to build categories and themes. Analysis of participants' perspectives reflected that they, based upon Jewish theology, attributed high importance to primary prevention at both personal and community levels. Religious and orthodox people were depicted as being motivated towards maintaining oral health behaviours due to a sense of obligation to follow religious edicts, strong social support, and elevated perceived spiritual levels. We offer a theoretical model that can explain the potential high motivation among these communities towards implementing positive general and oral health behaviours. Religiosity may be regarded as an example of a psycho-social health determinant, encompassing spiritual belief ("psycho") and social support ("social") components.

Ab-Initio Description and Prediction of Properties of Carbon-Based and Other Non-Metallic Materials

NASA Technical Reports Server (NTRS)

Bagayoko, D.; Zhao, G. L.; Hasan, S.

2001-01-01

We have resolved the long-standing problem consisting of 30%-50% theoretical underestimates of the band gaps of non-metallic materials. We describe the Bagayoko, Zhao, and Williams (BZW) method that rigorously circumvents the basis-set and variational effect presumed to be a cause of these underestimates. We present ab-initio, computational results that are in agreement with experiment for diamond (C), silicon (Si), silicon carbides (3C-SiC and 4H-SiC), and other semiconductors (GaN, BaTiO3, AlN, ZnSe, ZnO). We illustrate the predictive capability of the BZW method in the case of the newly discovered cubic phase of silicon nitride (c-Si3N4) and of selected carbon nanotabes [(10,0), and (8,4)]. Our conclusion underscores the inescapable need for the BZW method in ab-initio calculations that employ a basis set in a variational approach. Current nanoscale trends amplify this need. We estimate that the potential impact of applications of the BZW method in advancing our understanding of nonmetallic materials, in informing experiment, and particularly in guiding device design and fabrication is simply priceless.

Magnetic Field-Vector Measurements in Quiescent Prominences via the Hanle Effect: Analysis of Prominences Observed at Pic-Du-Midi and at Sacramento Peak

NASA Technical Reports Server (NTRS)

Bommier, V.; Leroy, J. L.; Sahal-Brechot, S.

1985-01-01

The Hanle effect method for magnetic field vector diagnostics has now provided results on the magnetic field strength and direction in quiescent prominences, from linear polarization measurements in the He I E sub 3 line, performed at the Pic-du-Midi and at Sacramento Peak. However, there is an inescapable ambiguity in the field vector determination: each polarization measurement provides two field vector solutions symmetrical with respect to the line-of-sight. A statistical analysis capable of solving this ambiguity was applied to the large sample of prominences observed at the Pic-du-Midi (Leroy, et al., 1984); the same method of analysis applied to the prominences observed at Sacramento Peak (Athay, et al., 1983) provides results in agreement on the most probable magnetic structure of prominences; these results are detailed. The statistical results were confirmed on favorable individual cases: for 15 prominences observed at Pic-du-Midi, the two-field vectors are pointing on the same side of the prominence, and the alpha angles are large enough with respect to the measurements and interpretation inaccuracies, so that the field polarity is derived without any ambiguity.

Straightening the Hierarchical Staircase for Basis Set Extrapolations: A Low-Cost Approach to High-Accuracy Computational Chemistry

NASA Astrophysics Data System (ADS)

Varandas, António J. C.

2018-04-01

Because the one-electron basis set limit is difficult to reach in correlated post-Hartree-Fock ab initio calculations, the low-cost route of using methods that extrapolate to the estimated basis set limit attracts immediate interest. The situation is somewhat more satisfactory at the Hartree-Fock level because numerical calculation of the energy is often affordable at nearly converged basis set levels. Still, extrapolation schemes for the Hartree-Fock energy are addressed here, although the focus is on the more slowly convergent and computationally demanding correlation energy. Because they are frequently based on the gold-standard coupled-cluster theory with single, double, and perturbative triple excitations [CCSD(T)], correlated calculations are often affordable only with the smallest basis sets, and hence single-level extrapolations from one raw energy could attain maximum usefulness. This possibility is examined. Whenever possible, this review uses raw data from second-order Møller-Plesset perturbation theory, as well as CCSD, CCSD(T), and multireference configuration interaction methods. Inescapably, the emphasis is on work done by the author's research group. Certain issues in need of further research or review are pinpointed.

Goldilocks and the three inorganic equilibria: how Earth's chemistry and life coevolve to be nearly in tune.

PubMed

Rickaby, R E M

2015-03-13

Life and the chemical environment are united in an inescapable feedback cycle. The periodic table of the elements essential for life has transformed over Earth's history, but, as today, evolved in tune with the elements available in abundance in the environment. The most revolutionary time in life's history was the advent and proliferation of oxygenic photosynthesis which forced the environment towards a greater degree of oxidation. Consideration of three inorganic chemical equilibria throughout this gradual oxygenation prescribes a phased release of trace metals to the environment, which appear to have coevolved with employment of these new chemicals by life. Evolution towards complexity was chemically constrained, and changes in availability of notably Fe, Zn and Cu paced the systematic development of complex organisms. Evolving life repeatedly catalysed its own chemical challenges via the unwitting release of new and initially toxic chemicals. Ultimately, the harnessing of these allowed life to advance to greater complexity, though the mechanism responsible for translating novel chemistry to heritable use remains elusive. Whether a chemical acts as a poison or a nutrient lies both in the dose and in its environmental history. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

Electron scattering data as the basis for kinetic models -- what can we realistically provide, and how?

NASA Astrophysics Data System (ADS)

Buckman, Stephen

2009-10-01

It is unlikely that anyone would dispute the important role that the availability of accurate data can play in the modeling and simulation of low temperature plasmas. Fundamental measurements of collision processes, from the relatively simple (eg. elastic scattering) to the complex (eg. molecular dissociation) are critical to developing an understanding of discharge and plasma behaviour. While there has been a healthy relationship between the data users and data gatherers at meetings such as GEC for many years, there are often misunderstandings about the capabilities that reside in each of these areas, and how best to maintain and strengthen the communication between them. This paper will attempt to summarise those electron-driven processes that are accessible, in a quantitative sense, in modern scattering experiments. Advances in treating reactive and excited species will also be discussed, as will the potential to push our measurement technologies further. An inescapable conclusion is that the collision community can best contribute through a strategic alliance between experiment and theory. Theory should be benchmarked against experiment for those processes and targets that are accessible, and used wisely for those processes where experiment cannot contribute.

An examination of the roles of glutamate and sex in latent inhibition: Relevance to the glutamate hypothesis of schizophrenia?

PubMed

Huang, Andrew Chih Wei; Bo-Han He, Alan; Chen, Chih-Chung

2017-10-01

The present study examined the effects of the glutamate receptor antagonist MK-801, the glutamate receptor agonist N-methyl-D-aspartate (NMDA), and sexual dimorphism on latent inhibition to elucidate the glutamate hypothesis of schizophrenia. During the pre-exposure phase, 56 male and 65 female Wistar rats were intracerebroventricularly administered normal saline, MK-801 or NMDA, in the left ventricle and then exposed to a passive avoidance box (or a different context) in three trials over 3 days. Then, all of the rats were placed in the light compartment of the passive avoidance box and were allowed to enter the dark compartment, where they each received a footshock (1mA, 2s) in five trials over 5 days. Injections of the glutamate drugs NMDA and MK-801 did not affect latent inhibition. Sexual dimorphism did not occur in latent inhibition. The present data on the male rats indicated that the glutamate system did not affect latent inhibition, indicating that the glutamate system was not like the dopamine system in terms of mediating the positive symptoms of schizophrenia. The glutamate system might be involved in the negative and cognitive symptoms of schizophrenia. The results may provide information for novel treatments of the negative and cognitive symptoms of schizophrenia. Copyright © 2017 Elsevier B.V. All rights reserved.

Passive avoidance and complex maze learning in the senescence accelerated mouse (SAM): age and strain comparisons of SAM P8 and R1.

PubMed

Spangler, Edward L; Patel, Namisha; Speer, Dorey; Hyman, Michael; Hengemihle, John; Markowska, Alicja; Ingram, Donald K

2002-02-01

Two strains of the senescence accelerated mouse, P8 and R1,were tested in footshock-motivated passive avoidance (PA; P8, 3-21 months; R1, 3-24 months) and 14-unit T-maze (P8 and R1, 9, and 15 months) tasks. For PA, entry to a dark chamber from a lighted chamber was followed by a brief shock. Latency to enter the dark chamber 24 hours later served as a measure of retention. Two days of active avoidance training in a straight runway preceded 2 days (8 trials/day) of testing in the 14-unit T-maze. For PA retention, older P8 mice entered the dark chamber more quickly than older R1 mice, whereas no differences were observed between young P8 or R1 mice. In the 14-unit T-maze, age-related learning performance deficits were reflected in higher error scores for older mice. P8 mice were actually superior learners; that is, they had lower error scores compared with those of age-matched R1 counterparts. Although PA learning results were in agreement with other reports, results obtained in the 14-unit T-maze were not consistent with previous reports of learning impairments in the P8 senescence accelerated mouse.

Opioid receptors mediate direct predictive fear learning: evidence from one-trial blocking.

PubMed

Cole, Sindy; McNally, Gavan P

2007-04-01

Pavlovian fear learning depends on predictive error, so that fear learning occurs when the actual outcome of a conditioning trial exceeds the expected outcome. Previous research has shown that opioid receptors, including mu-opioid receptors in the ventrolateral quadrant of the midbrain periaqueductal gray (vlPAG), mediate such predictive fear learning. Four experiments reported here used a within-subject one-trial blocking design to study whether opioid receptors mediate a direct or indirect action of predictive error on Pavlovian association formation. In Stage I, rats were trained to fear conditioned stimulus (CS) A by pairing it with shock. In Stage II, CSA and CSB were co-presented once and co-terminated with shock. Two novel stimuli, CSC and CSD, were also co-presented once and co-terminated with shock in Stage II. The results showed one-trial blocking of fear learning (Experiment 1) as well as one-trial unblocking of fear learning when Stage II training employed a higher intensity footshock than was used in Stage I (Experiment 2). Systemic administrations of the opioid receptor antagonist naloxone (Experiment 3) or intra-vlPAG administrations of the selective mu-opioid receptor antagonist CTAP (Experiment 4) prior to Stage II training prevented one-trial blocking. These results show that opioid receptors mediate the direct actions of predictive error on Pavlovian association formation.

Time Determines the Neural Circuit Underlying Associative Fear Learning

PubMed Central

Guimarãis, Marta; Gregório, Ana; Cruz, Andreia; Guyon, Nicolas; Moita, Marta A.

2011-01-01

Ultimately associative learning is a function of the temporal features and relationships between experienced stimuli. Nevertheless how time affects the neural circuit underlying this form of learning remains largely unknown. To address this issue, we used single-trial auditory trace fear conditioning and varied the length of the interval between tone and foot-shock. Through temporary inactivation of the amygdala, medial prefrontal-cortex (mPFC), and dorsal-hippocampus in rats, we tested the hypothesis that different temporal intervals between the tone and the shock influence the neuronal structures necessary for learning. With this study we provide the first experimental evidence showing that temporarily inactivating the amygdala before training impairs auditory fear learning when there is a temporal gap between the tone and the shock. Moreover, imposing a short interval (5 s) between the two stimuli also relies on the mPFC, while learning the association across a longer interval (40 s) becomes additionally dependent on a third structure, the dorsal-hippocampus. Thus, our results suggest that increasing the interval length between tone and shock leads to the involvement of an increasing number of brain areas in order for the association between the two stimuli to be acquired normally. These findings demonstrate that the temporal relationship between events is a key factor in determining the neuronal mechanisms underlying associative fear learning. PMID:22207842

Getting to compliance in forced exercise in rodents: a critical standard to evaluate exercise impact in aging-related disorders and disease.

PubMed

Arnold, Jennifer C; Salvatore, Michael F

2014-08-22

There is a major increase in the awareness of the positive impact of exercise on improving several disease states with neurobiological basis; these include improving cognitive function and physical performance. As a result, there is an increase in the number of animal studies employing exercise. It is argued that one intrinsic value of forced exercise is that the investigator has control over the factors that can influence the impact of exercise on behavioral outcomes, notably exercise frequency, duration, and intensity of the exercise regimen. However, compliance in forced exercise regimens may be an issue, particularly if potential confounds of employing foot-shock are to be avoided. It is also important to consider that since most cognitive and locomotor impairments strike in the aged individual, determining impact of exercise on these impairments should consider using aged rodents with a highest possible level of compliance to ensure minimal need for test subjects. Here, the pertinent steps and considerations necessary to achieve nearly 100% compliance to treadmill exercise in an aged rodent model will be presented and discussed. Notwithstanding the particular exercise regimen being employed by the investigator, our protocol should be of use to investigators that are particularly interested in the potential impact of forced exercise on aging-related impairments, including aging-related Parkinsonism and Parkinson's disease.

Unconditioned- and Conditioned- Stimuli Induce Differential Memory Reconsolidation and β-AR-Dependent CREB Activation

PubMed Central

Huang, Bing; Zhu, Huiwen; Zhou, Yiming; Liu, Xing; Ma, Lan

2017-01-01

Consolidated long-term fear memories become labile and reconsolidated upon retrieval by the presentation of conditioned stimulus (CS) or unconditioned stimulus (US). Whether CS-retrieval or US-retrieval will trigger different memory reconsolidation processes is unknown. In this study, we introduced a sequential fear conditioning paradigm in which footshock (FS) was paired with two distinct sounds (CS-A and CS-B). The treatment with propranolol, a β-adrenergic receptor (β-AR) antagonist, after US (FS)-retrieval impaired freezing behavior evoked by either CS-A or CS-B. Betaxolol, a selective β1-AR antagonist, showed similar effects. However, propranolol treatment after retrieval by one CS (e.g., CS-A) only inhibited freezing behavior evoked by the same CS (i.e., CS-A), not the other CS (CS-B). These data suggest that β-AR is critically involved in reconsolidation of fear memory triggered by US- and CS-retrieval, whereas β-AR blockade after US-retrieval disrupts more CS-US associations than CS-retrieval does. Furthermore, significant CREB activation in almost the whole amygdala and hippocampus was observed after US-retrieval, but CS-retrieval only stimulated CREB activation in the lateral amygdala and the CA3 of hippocampus. In addition, propranolol treatment suppressed memory retrieval-induced CREB activation. These data indicate that US-retrieval activates more memory traces than CS-retrieval does, leading to memory reconsolidation of more CS-US associations. PMID:28848401

Lesions of the entorhinal cortex or fornix disrupt the context-dependence of fear extinction in rats.

PubMed

Ji, Jinzhao; Maren, Stephen

2008-12-12

Recent studies have shown that the hippocampus is critical for the context-dependent expression of extinguished fear memories. Here we used Pavlovian fear conditioning in rats to explore whether the entorhinal cortex and fornix, which are the major cortical and subcortical interfaces of the hippocampus, are also involved in the context-dependence of extinction. After pairing an auditory conditional stimulus (CS) with an aversive footshock (unconditional stimulus or US) in one context, rats received an extinction session in which the CS was presented without the US in another context. Conditional fear to the CS was then tested in either the extinction context or a third familiar context; freezing behavior served as the index of fear. Sham-operated rats exhibited little conditional freezing to the CS in the extinction context, but showed a robust renewal of fear when tested outside of the extinction context. In contrast, rats with neurotoxic lesions in the entorhinal cortex or electrolytic lesions in the fornix did not exhibit a renewal of fear when tested outside the extinction context. Impairments in freezing behavior to the auditory CS were not able to account for the observed results, insofar as rats with either entorhinal cortex or fornix lesions exhibited normal freezing behavior during the conditioning session. Thus, contextual memory retrieval requires not only the hippocampus proper, but also its cortical and subcortical interfaces.

Electrical Stimulation of Lateral Habenula during Learning: Frequency-Dependent Effects on Acquisition but Not Retrieval of a Two-Way Active Avoidance Response

PubMed Central

Wetzel, Wolfram; Scheich, Henning; Ohl, Frank W.

2013-01-01

The lateral habenula (LHb) is an epithalamic structure involved in signaling reward omission and aversive stimuli, and it inhibits dopaminergic neurons during motivated behavior. Less is known about LHb involvement in the acquisition and retrieval of avoidance learning. Our previous studies indicated that brief electrical stimulation of the LHb, time-locked to the avoidance of aversive footshock (presumably during the positive affective “relief” state that occurs when an aversive outcome is averted), inhibited the acquisition of avoidance learning. In the present study, we used the same paradigm to investigate different frequencies of LHb stimulation. The effect of 20 Hz vs. 50 Hz vs. 100 Hz stimulation was investigated during two phases, either during acquisition or retrieval in Mongolian gerbils. The results indicated that 50 Hz, but not 20 Hz, was sufficient to produce a long-term impairment in avoidance learning, and was somewhat more effective than 100 Hz in this regard. None of the stimulation parameters led to any effects on retrieval of avoidance learning, nor did they affect general motor activity. This suggests that, at frequencies in excess of the observed tonic firing rates of LHb neurons (>1–20 Hz), LHb stimulation may serve to interrupt the consolidation of new avoidance memories. However, these stimulation parameters are not capable of modifying avoidance memories that have already undergone extensive consolidation. PMID:23840355

Effects of acute administration of nicotine, amphetamine, diazepam, morphine, and ethanol on risky decision-making in rats

PubMed Central

Mitchell, Marci R.; Vokes, Colin M.; Blankenship, Amy L.; Simon, Nicholas W.

2011-01-01

Rationale Most individuals can accurately assess the risks and rewards associated with choice alternatives and decide accordingly; however, drug users often display maladaptive decision-making, such that choices are biased toward excessively risky options. Objective The purpose of this study was to investigate the effects of a range of drugs of abuse on risky decision-making. Methods Male Long–Evans rats were trained in the Risky Decision-Making Task, in which they chose between two levers, one which produced a small, “safe” food reward and the other which produced a large, “risky” food reward. The large reward was accompanied by the risk of a mild footshock, the probability of which increased over the course of each test session (0%, 25%, 50%, 75%, and 100%). Results Nicotine (0.6 mg/kg) and amphetamine (1.5 mg/kg) caused a significant decrease in choice of the large risky reward (decreased risk taking). Diazepam (1.0 mg/kg) caused a significant increase in choice of the large risky reward (increased risk taking), whereas morphine (3.0 mg/kg) caused only a trend toward increased choice of the large risky reward. Ethanol had no effect on choice behavior. Conclusions These results show that acute administration of drugs of abuse can modulate risk taking in a drug-specific manner, either increasing or decreasing preference for highly rewarding, but risky, options. PMID:21638222

PREFACE TO: "PHARMACEUTICALS AND PERSONAL ...

EPA Pesticide Factsheets

Often overlooked in our daily lives are the inescapable, intimate, and immediate connections between our personal activities and the environment in which we live. This is especially true with regard to the use and disposal of consumer chemicals. A significant aspect of our global society that illustrates the potential impact of our lives on the environment is the widespread and escalating use of pharmaceuticals and personal care products - simply referred to as PPCPS. Many of these chemicals are specifically designed to elicit potent pharmacological or toxicological effects. In distinct contrast to nearly all agro/industrial chemicals, which are often used on large, relatively confined scales, the end use for PPCPs is highly dispersed and centered around the activities and actions of the individual. PPCPs enjoy worldwide usage and attendant discharge or inadvertent release to the environment. Their introduction to the environment has no geographic boundaries or climatic-use limitations as do many other synthetic chemicals - they are discharged to the environment wherever people live or visit, regardless of the time of year. It is difficult for the individual to perceive their small-scale activities as having any measurable impact on the larger environment - personal actions are often deemed minuscule or inconsequential in the larger scheme. Yet it is the combined actions and activities of individuals that indeed can significantly impact the environment in a myri

Overcoming O: Dewey and the Problem of Bion's Metaphysics.

PubMed

Soffer-Dudek, Nir

2015-10-01

Bion guides us to eschew memory, desire, and understanding in order to become one with O-the ultimate reality of the analytic moment. However, his directions are valid only to the extent that such a meta-reality actually exists. Otherwise there is nothing to unite with and no reason to shun memory or desire. The present work inquires whether we may provide Bion's technique with a less speculative philosophy, specifically Dewey's pragmatist theory of aesthetics. It begins with reviewing the similarities between the two writers' methods, highlighting their shared emphasis on openness to the unknown. Yet listening to their intonations reveals that they actually convey opposite ideas as to what this "unknown" may be. Whereas Dewey sanguinely portrays the possibilities of the "yet-unknown," Bion emphasizes the dread of our inescapable encounter with the unknowable. This dread is embodied in his concept of O. Thus, rather than being merely a metaphysical speculation, O communicates Bion's conviction that fear forms the core of our existence. Banishing O from the counseling room may indeed aid his method in becoming accessible to a wider audience; at the same time, however, doing so might also deprive it of the very context that gives it meaning. © 2015 by the American Psychoanalytic Association.

Extinction after fear memory reactivation fails to eliminate renewal in rats.

PubMed

Goode, Travis D; Holloway-Erickson, Crystal M; Maren, Stephen

2017-07-01

Retrieving fear memories just prior to extinction has been reported to effectively erase fear memories and prevent fear relapse. The current study examined whether the type of retrieval procedure influences the ability of extinction to impair fear renewal, a form of relapse in which responding to a conditional stimulus (CS) returns outside of the extinction context. Rats first underwent Pavlovian fear conditioning with an auditory CS and footshock unconditional stimulus (US); freezing behavior served as the index of conditioned fear. Twenty-four hours later, the rats underwent a retrieval-extinction procedure. Specifically, 1h prior to extinction (45 CS-alone trials; 44 for rats receiving a CS reminder), fear memory was retrieved by either a single exposure to the CS alone, the US alone, a CS paired with the US, or exposure to the conditioning context itself. Over the next few days, conditional freezing to the extinguished CS was tested in the extinction and conditioning context in that order (i.e., an ABBA design). In the extinction context, rats that received a CS+US trial before extinction exhibited higher levels of conditional freezing than animals in all other groups, which did not differ from one another. In the renewal context, all groups showed renewal, and none of the reactivation procedures reduced renewal relative to a control group that did not receive a reactivation procedure prior to extinction. These data suggest retrieval-extinction procedures may have limited efficacy in preventing fear renewal. Copyright © 2017 Elsevier Inc. All rights reserved.

Evidence of Pavlovian conditioned fear following electrical stimulation of the periaqueductal grey in the rat.

PubMed

Di Scala, G; Mana, M J; Jacobs, W J; Phillips, A G

1987-01-01

Stimulation of the periaqueductal grey (PAG) has been used to support aversive conditioning in a variety of species with several experimental paradigms. However, it has not been clearly demonstrated whether the behavioral changes produced by PAG stimulation in these paradigms are mediated by associative or nonassociative mechanisms. The present studies demonstrate that electrical stimulation of the PAG in the rat may be used to support associative learning in a Pavlovian paradigm. In each experiment, a fully controlled conditional emotional response (CER) procedure was used to examine the unconditional aversive properties of PAG stimulation. In Experiment 1a, weak associative conditioning was observed when a light CS was paired with PAG stimulation over 6 conditioning trials. In Experiment 1b, robust associative conditioning was obtained with a light CS when 18 conditioning trials were used. In Experiment 2, robust associative conditioning was demonstrated with a tone CS when 6 conditioning trials were used. The results parallel those found when other aversive stimuli are used as a UCS (e.g., footshock or intraorbital air puff), and because the present experiments included the proper control procedures the results clearly indicate that the behavioral changes produced by PAG stimulation are mediated by associative Pavlovian learning mechanisms rather than nonassociative mechanisms such as sensitization or pseudoconditioning. The present technique may be useful for assessing the neuroanatomical and neurochemical substrates underlying the aversive effects of brain-stimulation, and for screening the effects of drugs on the conditional and unconditional responses produced by such stimulation.

Origins and Evolution of Social Medicine and Contemporary Social Medicine in Korea.

PubMed

Han, Dal Sun; Bae, Sang-Soo; Kim, Dong-Hyun; Choi, Yong-Jun

2017-01-01

Social medicine is recognized as one of medical specialties in many countries. However, social medicine has never been formally introduced to Korea, presumably because the term and its principles were not accepted for some years in the past in American medicine, which has strongly influenced Korean medicine. This paper describes the origins and evolution of social medicine and briefly discusses contemporary social medicine in Korea. Social medicine was initiated in France and Germany in 1848. Since then, it has expanded globally and developed in diverse ways. Included in core principles of social medicine is that social and economic conditions have important effects on health and disease, and that these relationships must be subjected to scientific investigation. The term 'social medicine' is rarely used in Korea, but many of its subject matters are incorporated into preventive medicine which, besides prevention, deals with population health that is inescapably social. However, the Korean preventive medicine directs little attention to the basic concepts and principles of social medicine, upon which systematic development of social medicine can be based. Thus, it is necessary to supplement the social medicine contents of preventive medicine through formalizing the linkages between the two fields. One way of doing so would be to change the title of 'preventive medicine' course in medical colleges to 'preventive and social medicine,' as in many other countries, and to adjust the course contents accordingly.

When, not if: the inescapability of an uncertain climate future.

PubMed

Ballard, Timothy; Lewandowsky, Stephan

2015-11-28

Climate change projections necessarily involve uncertainty. Analysis of the physics and mathematics of the climate system reveals that greater uncertainty about future temperature increases is nearly always associated with greater expected damages from climate change. In contrast to those normative constraints, uncertainty is frequently cited in public discourse as a reason to delay mitigative action. This failure to understand the actual implications of uncertainty may incur notable future costs. It is therefore important to communicate uncertainty in a way that improves people's understanding of climate change risks. We examined whether responses to projections were influenced by whether the projection emphasized uncertainty in the outcome or in its time of arrival. We presented participants with statements and graphs indicating projected increases in temperature, sea levels, ocean acidification and a decrease in arctic sea ice. In the uncertain-outcome condition, statements reported the upper and lower confidence bounds of the projected outcome at a fixed time point. In the uncertain time-of-arrival condition, statements reported the upper and lower confidence bounds of the projected time of arrival for a fixed outcome. Results suggested that people perceived the threat as more serious and were more likely to encourage mitigative action in the time-uncertain condition than in the outcome-uncertain condition. This finding has implications for effectively communicating the climate change risks to policy-makers and the general public. © 2015 The Author(s).

Enhanced P, N and C removal from domestic wastewater using constructed wetland employing construction solid waste (CSW) as main substrate.

PubMed

Yang, Y; Wang, Z M; Liu, C; Guo, X C

2012-01-01

Construction solid waste (CSW), an inescapable by-product of the construction and demolition process, was used as main substrate in a four-stage vertical subsurface flow constructed wetland system to improve phosphorus P removal from domestic wastewater. A 'tidal flow' operation was also employed in the treatment system. Under a hydraulic loading rate (HLR) of 0.76 m3/m2 d for 1st and 3rd stage and HLR of 0.04 m3/m2 d for 2nd and 4th stage of the constructed wetland system respectively and tidal flow operation strategy, average removal efficiencies of 99.4% for P, 95.4% for ammoniacal-nitrogen, 56.5% for total nitrogen and 84.5% for total chemical oxygen demand were achieved during the operation period. The CSW-based constructed wetland system presents excellent P removal performance. The adoption of tidal flow strategy creates the aerobic/anoxic condition intermittently in the treatment system. This can achieve better oxygen transfer and hence lead to more complete nitrification and organic matter removal and enhanced denitrification. Overall, the CSW-based tidal flow constructed wetland system holds great promise for enabling high rate removal of P, ammoniacal-nitrogen and organic matter from domestic wastewater, and transforms CSW from a waste into a useful material.

Ascertainment-adjusted parameter estimation approach to improve robustness against misspecification of health monitoring methods

NASA Astrophysics Data System (ADS)

Juesas, P.; Ramasso, E.

2016-12-01

Condition monitoring aims at ensuring system safety which is a fundamental requirement for industrial applications and that has become an inescapable social demand. This objective is attained by instrumenting the system and developing data analytics methods such as statistical models able to turn data into relevant knowledge. One difficulty is to be able to correctly estimate the parameters of those methods based on time-series data. This paper suggests the use of the Weighted Distribution Theory together with the Expectation-Maximization algorithm to improve parameter estimation in statistical models with latent variables with an application to health monotonic under uncertainty. The improvement of estimates is made possible by incorporating uncertain and possibly noisy prior knowledge on latent variables in a sound manner. The latent variables are exploited to build a degradation model of dynamical system represented as a sequence of discrete states. Examples on Gaussian Mixture Models, Hidden Markov Models (HMM) with discrete and continuous outputs are presented on both simulated data and benchmarks using the turbofan engine datasets. A focus on the application of a discrete HMM to health monitoring under uncertainty allows to emphasize the interest of the proposed approach in presence of different operating conditions and fault modes. It is shown that the proposed model depicts high robustness in presence of noisy and uncertain prior.

"You are free to set your own hours": governing worker productivity and health through flexibility and resilience.

PubMed

MacEachen, Ellen; Polzer, Jessica; Clarke, Judy

2008-03-01

Flexible work is now endemic in modern economies. A growing literature both praises work flexibility for accommodating employees' needs and criticizes it for fueling contingency and job insecurity. Although studies have identified varied effects of flexible work, questions remain about the workplace dimensions of flexibility and how occupational workplace health is managed in these workplaces. This paper presents findings from a qualitative study of how managers in the computer software industry situate workplace flexibility and approach worker health. In-depth interviews were conducted with managers (and some workers) at 30 firms in Ontario, Canada. Using a critical discourse analysis approach, we examine managers' optimistic descriptions of flexibility which emphasize how flexible work contributes to workers' life balance. We then contrast this with managers' depictions of flexibility work practices as intense and inescapable. We suggest that the discourse of flexibility, and the work practices they foster, make possible and reinforce an increased intensity of work that is driven by the demands of technological pace and change that characterize the global information technology and computer software industries. Finally, we propose that flexible knowledge work has led to a re-framing of occupational health management involving a focus on what we call "strategies of resilience" that aim to buttress workers' capacities to withstand intensive and uncertain working conditions.

Copability, coping, and learning as focal concepts in the evaluation of computerised diabetes disease management.

PubMed

Boisen, Egil; Bygholm, Ann; Cavan, David; Hejlesen, Ole K

2003-07-01

Within diabetes care, the majority of health decisions are in the hands of the patient. Therefore, the concepts of disease management and self-care represent inescapable challenges for both patient and healthcare professionals, entailing a considerable amount of learning. Thus, a computerised diabetes disease management systems (CDDM) is to be seen not merely as tools for the medical treatment, but also as pedagogical tools to enhance patient competence. The unfortunate lack of success for most knowledge-based systems might be related to the problem of finding an adequate way of evaluating the systems from their development through the implementation phase to the daily clinical practice. The following presents the initial methodological considerations for evaluating the usefulness of a CDDM system called DiasNet, which is being implemented as a learning tool for patients. The evaluation of usefulness of a CDDM, we claim, entails clinical assessment taking into account the challenges and pitfalls in diabetes disease management. Drawing on activity theory, we suggest the concept of copability as a supplement to 'usability' and 'utility' when determining 'usefulness'. We maintain that it is necessary to ask how well the user copes with the new situation using the system. As ways to measure copability of DiasNet the concepts of coping and learning are discussed, as well as ways this methodology might inform systems development, implementation, and daily clinical practice.

Cluster based architecture and network maintenance protocol for medical priority aware cognitive radio based hospital.

PubMed

Al Mamoon, Ishtiak; Muzahidul Islam, A K M; Baharun, Sabariah; Ahmed, Ashir; Komaki, Shozo

2016-08-01

Due to the rapid growth of wireless medical devices in near future, wireless healthcare services may face some inescapable issue such as medical spectrum scarcity, electromagnetic interference (EMI), bandwidth constraint, security and finally medical data communication model. To mitigate these issues, cognitive radio (CR) or opportunistic radio network enabled wireless technology is suitable for the upcoming wireless healthcare system. The up-to-date research on CR based healthcare has exposed some developments on EMI and spectrum problems. However, the investigation recommendation on system design and network model for CR enabled hospital is rare. Thus, this research designs a hierarchy based hybrid network architecture and network maintenance protocols for previously proposed CR hospital system, known as CogMed. In the previous study, the detail architecture of CogMed and its maintenance protocols were not present. The proposed architecture includes clustering concepts for cognitive base stations and non-medical devices. Two cluster head (CH selector equations are formulated based on priority of location, device, mobility rate of devices and number of accessible channels. In order to maintain the integrity of the proposed network model, node joining and node leaving protocols are also proposed. Finally, the simulation results show that the proposed network maintenance time is very low for emergency medical devices (average maintenance period 9.5 ms) and the re-clustering effects for different mobility enabled non-medical devices are also balanced.