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Jacqueline Blundell - One of the best experts on this subject based on the ideXlab platform.

  • Stress Across Generations: DNA Methylation as a Potential Mechanism Underlying Intergenerational Effects of Stress in Both Post-traumatic Stress Disorder and Pre-clinical Predator Stress Rodent Models.
    Frontiers in behavioral neuroscience, 2019
    Co-Authors: Sriya Bhattacharya, Audrey Fontaine, Phillip E. Maccallum, James R. Drover, Jacqueline Blundell
    Abstract:

    Although most humans will experience some type of traumatic event in their lifetime only a small set of individuals will go on to develop post-traumatic Stress disorder (PTSD). Differences in sex, age, trauma type, and comorbidity, along with many other elements, contribute to the heterogenous manifestation of this disorder. Nonetheless, aberrant hypothalamus-pituitary-adrenal (HPA) axis activity, especially in terms of cortisol and glucocorticoid receptor (GR) alterations, has been postulated as a tenable factor in the etiology and pathophysiology of PTSD. Moreover, emerging data suggests that the harmful effects of traumatic Stress to the HPA axis in PTSD can also propagate into future generations, making offspring more prone to psychopathologies. Predator Stress models provide an ethical and ethologically relevant way to investigate tentative mechanisms that are thought to underlie this phenomenon. In this review article, we discuss findings from human and laboratory Predator Stress studies that suggest changes to DNA methylation germane to GRs may underlie the generational effects of trauma transmission. Understanding mechanisms that promote Stress-induced psychopathology will represent a major advance in the field and may lead to novel treatments for such devastating, and often treatment-resistant trauma and Stress-disorders.

  • Absence of neurogenic response following robust Predator-induced Stress response.
    Neuroscience, 2016
    Co-Authors: Catherine Lau, Mark Hebert, Marc A. Vani, Sue G. Walling, Shawn Hayley, Diane C. Lagace, Jacqueline Blundell
    Abstract:

    Traumatic events contribute to a variety of neuropsychiatric disorders including post-traumatic Stress disorder (PTSD). Identifying the neural mechanisms that affect the Stress response may improve treatment for Stress-related disorders. Neurogenesis, the production of neurons, occurs within the adult brain and disturbances in neurogenesis in the subgranular zone (SGZ) of the hippocampus have been linked to mood and anxiety disorders. Chronic Stress models have mainly suggested correlations with Stress reducing adult SGZ neurogenesis, whereas acute Stress models and those with a naturalistic component that are also associated with long-lasting behavioral changes have produced inconsistent results. Therefore, the goal of the current study was to examine the effects of acute Predator Stress on adult neurogenesis. Predator Stress involved a single 10-min unprotected rat to cat exposure that has previously been shown to produce contextual fear, hyperarousal, and anxiety-like behavior lasting at least 3weeks. As expected, Predator Stress produced a Stress response as detected by elevated corticosterone (CORT) levels immediately after Stress. Despite this robust Stress response, there was no significant difference between Stressed and handled control rats in the number of proliferating or surviving cells as assessed by a 5-bromo-2'-deoxyuridine-immunoreactive (BrdU-IR) labeling 2h or 4weeks post-Stress throughout the rostro-caudal axis of the SGZ, respectively. Additionally, 90% of 4-week-old BrdU-IR cells in both conditions expressed NeuN, suggesting no change in cell fate with Stress exposure. Overall, these data give caution to the notion that acute Predator Stress can alter the production or survival of adult-generated cells.

  • Time-dependent effects of rapamycin on consolidation of Predator Stress-induced hyperarousal.
    Behavioural brain research, 2015
    Co-Authors: Kathleen Fifield, Mark Hebert, Kimberly Williams, Victoria Linehan, Jesse D. Whiteman, Phillip E. Mac Callum, Jacqueline Blundell
    Abstract:

    Previous studies have indicated that rapamycin, a potent inhibitor of the mammalian target of rapamycin (mTOR) pathway, blocks consolidation of shock-induced associative fear memories. Moreover, rapamycin's block of associative fear memories is time-dependent. It is unknown, however, if rapamycin blocks consolidation of Predator Stress-induced non-associative fear memories. Furthermore, the temporal pattern of mTOR activation following Predator Stress is unknown. Thus, the goal of the current studies was to determine if rapamycin blocks consolidation of Predator Stress-induced fear memories and if so, whether rapamycin's effect is time-dependent. Male rats were injected systemically with rapamycin at various time points following Predator Stress. Predator Stress involves an acute, unprotected exposure of a rat to a cat, which causes long-lasting non-associative fear memories manifested as generalized hyperarousal and increased anxiety-like behaviour. We show that rapamycin injected immediately after Predator Stress blocked consolidation of Stress-induced startle. However, rapamycin injected 9, 24 or 48h post Predator Stress potentiated Stress-induced startle. Consistent with shock-induced associative fear memories, we show that mTOR signalling is essential for consolidation of Predator Stress-induced hyperarousal. However, unlike shock-induced fear memories, a second, persistent, late phase mTOR-dependent process following Predator Stress actually dampens startle. Consistent with previous findings, our data support the potential role for rapamycin in treatment of Stress related disorders such as posttraumatic Stress disorder. However, our data suggest timing of rapamycin administration is critical.

  • Inhibition of mTOR kinase via rapamycin blocks persistent Predator Stress-induced hyperarousal.
    Behavioural brain research, 2013
    Co-Authors: Kathleen Fifield, Mark Hebert, Robert E. Adamec, Rebecca Angel, Jacqueline Blundell
    Abstract:

    Traumatic, Stressful life events are thought to trigger acquired anxiety disorders such as post-traumatic Stress disorder (PTSD). Recent data suggests that the mammalian target of rapamycin (mTOR) plays a key role in the formation of traumatic memories. The Predator Stress paradigm allows us to determine whether mTOR mediates the formation of both context-dependent (associative) and context-independent (non-associative) fear memories. Predator Stress involves an acute, unprotected exposure of a rat to a cat which causes long-lasting non-associative fear memories manifested as generalized hyperarousal and increased anxiety-like behavior. Here, we show that rapamycin, an mTOR inhibitor, attenuates Predator Stress-induced hyperarousal, lasting at least three weeks. In addition, rapamycin blocks a subset of anxiety-like behaviors as measured in the elevated plus maze and hole board. Furthermore, when re-exposed to the Predator Stress context, rapamycin-treated Stressed rats showed increased activity compared to vehicle controls suggesting that rapamycin blocks Predator Stress-induced associative fear memory. Taken together with past research, our results indicate that mTOR regulation of protein translation is required for the formation of both associative and non-associative fear memories. Overall, these data suggest that mTOR activation may contribute to the development of acquired anxiety disorders such as PTSD.

  • a comparison of activation patterns of cells in selected prefrontal cortical and amygdala areas of rats which are more or less anxious in response to Predator exposure or submersion Stress
    Physiology & Behavior, 2012
    Co-Authors: Robert E. Adamec, Mate Toth, J Haller, Jozsef Halasz, Jacqueline Blundell
    Abstract:

    This study had two purposes. First: to compare Predator and water submersion Stress cFos activation in medial prefrontal cortices (mPFC) and the medial amygdala (MeA). Second: to identify markers of vulnerability to Stressors within these areas. Rats were either Predator or submersion Stressed and tested 1.75 h later for anxiety. Immediately thereafter, rats were sacrificed and cFos expression was examined. Predator and submersion Stress equally increased anxiety-like behavior in the elevated plus maze (EPM) and hole board. To examine vulnerability, rats which were less anxious (LA) and more (highly) anxious (MA) in the EPM were selected from among handled control and Stressed animals. LA Stressed rats were considered Stress non-responsive while MA Stressed rats were considered Stress responsive. Predator Stress, but not submersion Stress, activated MeA cFos. CFos expression of mPFC cells was elevated in LA rats and reduced in MA rats in Predator Stressed animals only, correlating negatively with anxiety. These findings are consistent with data implicating greater mPFC excitability in protection against the effects on affect of traumatic Stress. The findings also suggest that this conclusion is Stressor specific, applying to Predator Stress but not submersion Stress. Both Stressors have been suggested to model hyperarousal and comorbid anxiety aspects of PTSD in humans. Hence the use of these paradigms to identify brain bases of vulnerability and resilience to traumatic Stress in PTSD has translation potential. On the other hand, our evidence of Stressor specificity of vulnerability/resilience markers raises a caution. The data suggest that preclinical markers of vulnerability/resilience in a given Stress paradigm are at best suggestive, and translational value must ultimately be confirmed in humans.

Robert E. Adamec - One of the best experts on this subject based on the ideXlab platform.

  • Inhibition of mTOR kinase via rapamycin blocks persistent Predator Stress-induced hyperarousal.
    Behavioural brain research, 2013
    Co-Authors: Kathleen Fifield, Mark Hebert, Robert E. Adamec, Rebecca Angel, Jacqueline Blundell
    Abstract:

    Traumatic, Stressful life events are thought to trigger acquired anxiety disorders such as post-traumatic Stress disorder (PTSD). Recent data suggests that the mammalian target of rapamycin (mTOR) plays a key role in the formation of traumatic memories. The Predator Stress paradigm allows us to determine whether mTOR mediates the formation of both context-dependent (associative) and context-independent (non-associative) fear memories. Predator Stress involves an acute, unprotected exposure of a rat to a cat which causes long-lasting non-associative fear memories manifested as generalized hyperarousal and increased anxiety-like behavior. Here, we show that rapamycin, an mTOR inhibitor, attenuates Predator Stress-induced hyperarousal, lasting at least three weeks. In addition, rapamycin blocks a subset of anxiety-like behaviors as measured in the elevated plus maze and hole board. Furthermore, when re-exposed to the Predator Stress context, rapamycin-treated Stressed rats showed increased activity compared to vehicle controls suggesting that rapamycin blocks Predator Stress-induced associative fear memory. Taken together with past research, our results indicate that mTOR regulation of protein translation is required for the formation of both associative and non-associative fear memories. Overall, these data suggest that mTOR activation may contribute to the development of acquired anxiety disorders such as PTSD.

  • a comparison of activation patterns of cells in selected prefrontal cortical and amygdala areas of rats which are more or less anxious in response to Predator exposure or submersion Stress
    Physiology & Behavior, 2012
    Co-Authors: Robert E. Adamec, Mate Toth, J Haller, Jozsef Halasz, Jacqueline Blundell
    Abstract:

    This study had two purposes. First: to compare Predator and water submersion Stress cFos activation in medial prefrontal cortices (mPFC) and the medial amygdala (MeA). Second: to identify markers of vulnerability to Stressors within these areas. Rats were either Predator or submersion Stressed and tested 1.75 h later for anxiety. Immediately thereafter, rats were sacrificed and cFos expression was examined. Predator and submersion Stress equally increased anxiety-like behavior in the elevated plus maze (EPM) and hole board. To examine vulnerability, rats which were less anxious (LA) and more (highly) anxious (MA) in the EPM were selected from among handled control and Stressed animals. LA Stressed rats were considered Stress non-responsive while MA Stressed rats were considered Stress responsive. Predator Stress, but not submersion Stress, activated MeA cFos. CFos expression of mPFC cells was elevated in LA rats and reduced in MA rats in Predator Stressed animals only, correlating negatively with anxiety. These findings are consistent with data implicating greater mPFC excitability in protection against the effects on affect of traumatic Stress. The findings also suggest that this conclusion is Stressor specific, applying to Predator Stress but not submersion Stress. Both Stressors have been suggested to model hyperarousal and comorbid anxiety aspects of PTSD in humans. Hence the use of these paradigms to identify brain bases of vulnerability and resilience to traumatic Stress in PTSD has translation potential. On the other hand, our evidence of Stressor specificity of vulnerability/resilience markers raises a caution. The data suggest that preclinical markers of vulnerability/resilience in a given Stress paradigm are at best suggestive, and translational value must ultimately be confirmed in humans.

  • Dendritic morphology of amygdala and hippocampal neurons in more and less Predator Stress responsive rats and more and less spontaneously anxious handled controls.
    Behavioural brain research, 2011
    Co-Authors: Robert E. Adamec, Mark Hebert, Jacqueline Blundell, Ronald F Mervis
    Abstract:

    We investigated the neurobiological bases of variation in response to Predator Stress (PS). Sixteen days after treatment (PS or handling), rats were grouped according to anxiety in the elevated plus maze (EPM). Acoustic startle was also measured. We examined the structure of dendritic trees of basolateral amygdala (BLA) output neurons (stellate and pyramidal cells) and of dorsal hippocampal (DHC) dentate granule cells of less anxious (LA) and more (extremely) anxious (MA) Stressed animals (PSLA and PSMA). Handled controls (HC) which were less anxious (HCLA) and spontaneously more anxious (HCMA) equivalently to Predator Stressed subgroups were also studied. Golgi analysis revealed BLA output neurons of HCMA rats exhibited longer, more branched dendrites with higher spine density than the other groups of rats, which did not differ. Finally, spine density of DHC granule cells was equally depressed in HCMA and PSMA rats relative to HCLA and PSLA rats. Total dendritic length of BLA pyramidal and stellate cells (positive predictor) and DHC spine density (negative predictor) together accounted for 96% of the variance of anxiety of handled rats. DHC spine density was a negative predictor of PSMA and PSLA anxiety, accounting for 70% of the variance. Data are discussed in the context of morphological differences as phenotypic markers of a genetic predisposition to anxiety in handled controls, and a possible genetic vulnerability to Predator Stress expressed as reduced spine density in the DHC. Significance of findings for animal models of anxiety and hyperarousal comorbidities of PTSD are discussed.

  • Glucocorticoids are required for extinction of Predator Stress-induced hyperarousal.
    Neurobiology of learning and memory, 2011
    Co-Authors: Rachel Clay, Mark Hebert, Greg Gill, Lesley Ann Stapleton, Allison Pridham, Meaghan Coady, Jillian Bishop, Robert E. Adamec, Jacqueline Blundell
    Abstract:

    Abstract Background The role of glucocorticoids in extinction of traumatic memories has not been fully characterized despite its potential as a therapeutic target for acquired posttraumatic Stress disorder (PTSD). The Predator Stress paradigm allows us to determine whether glucocorticoids mediate the extinction of both context-dependent and context-independent fear memories. Methods Male C57BL/6J mice were exposed to a Predator (cat) then repeatedly exposed to the Predator Stress context in the absence of the cat. Context-dependent (associative) fear memory was assessed as suppression of activity during re-exposure to the Predator Stress context without the cat (extinction trials). Context-independent fear (non-associative) was assessed seven days after extinction trials using measures of hyperarousal and anxiety-like behaviours in environments unlike the Predator Stress context. To assess the role of glucocorticoids, mice were injected with metyrapone (50 mg/kg) 90 min prior to extinction trials in Predator Stressed mice and context-dependent and context-independent fear memories were assessed. Finally, metyrapone-treated Predator Stressed mice were injected with corticosterone (5 or 10 mg/kg) immediately following extinction trials and context-dependent and context-independent fear memories were assessed. Results Repeated re-exposure to the Predator Stress context without the cat present extinguished context-dependent fear memory, and also reduced hyperarousal, a generalized, chronic PTSD-like symptom. We show that extinction of context-independent Predator Stress-induced hyperarousal is dependent on endogenous glucocorticoids during the extinction trials. Furthermore, the inhibition of extinction by metyrapone on startle amplitude was reduced by exogenous administration of corticosterone following extinction trials. Overall, these data implicate glucocorticoids in the extinction of hyperarousal, a core symptom of PTSD.

  • Long lasting effects of Predator Stress on pCREB expression in brain regions involved in fearful and anxious behavior.
    Behavioural brain research, 2011
    Co-Authors: Robert E. Adamec, Mark Hebert, Jacqueline Blundell
    Abstract:

    Abstract Predator Stress is one animal model of posttraumatic Stress disorder (PTSD). Neural plasticity in amygdala afferent and efferent pathways underlies anxiogenic effects of Predator Stress. Predator Stress increases pCREB expression in these pathways 20 min after Stress, implicating pCREB in Stress-induced neural plasticity. Here we examined impact of Predator Stress on pCREB expression 6–24 h and 7 days after Stress in amygdala pathways and in the supramammillary nucleus (SuM). Patterns of change in pCREB expression were complex, time dependent, column dependent in the periaqueductal gray (PAG), and AP plane dependent in the amygdala. In contrast to past work at 20 min after Stress, there were no Stress-induced increases in pCREB in the amygdala in the anterior AP plane or in the lateral PAG at 6 h onward after Stress. However, dorsal PAG pCREB was increased bilaterally at 24 h and 7 days after Stress. In the mid AP plane of all amygdala nuclei there were bilateral Stress-induced increases in pCREB at 6 h followed by decreases at 24 h post Stress. A similar pattern was observed in the posterior AP plane. In addition, we found a persistent increase (6 h to 7 days after Stress) in pCREB expression in the SuM. Further study of this nucleus as a contributor to fear sensitization following Predator Stress is warranted. Overall, these data highlight persistent neuroplastic changes in key brain areas following traumatic Stress. Identification of these changes may aid in understanding the neural mechanisms underlying acquired anxiety disorders such as PTSD.

Paul Burton - One of the best experts on this subject based on the ideXlab platform.

  • lasting anxiogenic effects of feline Predator Stress in mice sex differences in vulnerability to Stress and predicting severity of anxiogenic response from the Stress experience
    Physiology & Behavior, 2006
    Co-Authors: Robert E. Adamec, Paul Burton, Jacqueline Blundell, David Head, Olivier Berton
    Abstract:

    Previous work in male Swiss Webster (CFW) mice demonstrated a long lasting effect of Predator Stress on risk assessment in the elevated plus maze (EPM). Most severe effects (increases in risk assessment) were seen following a brief unprotected exposure to a cat. Lesser effects were produced by a brief exposure of mice to the cat exposure room without a cat in the room (room Stress). This graded response is analogous to the covariation of symptom severity and severity of the precipitating Stressor in posttraumatic Stress disorder (PTSD). The present study extended these findings to another strain of mice, C57/BL6, and a broader range of tests of anxiety-like behavior, including EPM, acoustic startle response and light/dark box test. Sex was introduced as a variable to investigate if females might be more susceptible to the effects of Stressors than males, as has been suggested in human PTSD. Graded and lasting (7 days) effects of a 10 min exposure to a cat (Predator Stress) or to the cat exposure room only (room Stress) were observed on lighted chamber avoidance in the light/dark box. Room Stress was without effect on startle responses, but Predator Stress enhanced peak startle amplitudes measured in the light or in the dark. There was no evidence of light-enhancement of startle in C57 mice. Female mice were more susceptible to the effects of Predator and room Stress, depending on the measure. Females only responded to cat exposure with a lasting increase in average startle amplitude. This was due to an increased and more prolonged multipeak response to startle after the first and maximal peak startle response. In addition, in females, room and Predator Stress were equally anxiogenic in measures of open arm avoidance in the EPM. In contrast, room Stress was without effect on open arm avoidance in males, but cat exposure was as anxiogenic in males as it was in females. These findings suggest EPM anxiety in females is affected more by the milder Stress of room exposure. Severity of effects of Predator Stress on anxiety-like behaviors in EPM and startle were well predicted (60% of the variance) by measures of cat behavior and probability of mouse defensive response to particular cat behaviors during the cat exposure. Finally, factor analysis indicated that different tests of anxiety-like behavior may be measuring different and independent aspects of mouse affect. Moreover, Stressors had no lasting effects on sugar solution consumption. Implications of these findings for modeling PTSD and using transgenic strains of mice to study lasting effects of Stress on affect are discussed.

  • Vulnerability to mild Predator Stress in serotonin transporter knockout mice.
    Behavioural brain research, 2006
    Co-Authors: Robert E. Adamec, Paul Burton, Jacqueline Blundell, Dennis L. Murphy, Andrew Holmes
    Abstract:

    Abstract Effect of Predator Stress on rat and mouse anxiety-like behavior may model aspects of post traumatic Stress disorder (PTSD). A single cat exposure of wild type (C57, CFW) mice can produce lasting anxiety-like effects in the elevated plus maze, light/dark box tests and startle. In addition, female but not male C57 mice are made more anxious in the plus maze by exposure to Predator odors alone, suggesting differential vulnerability to Predator Stressors of differing intensity. There is a link between genetic variation in the serotonin (5-HT) transporter (SERT) and anxiety in humans. This prompted the generation of SERT knockout mice [see Holmes A, Murphy DL, Crawley JN. Biol Psychiatry 2003;54(10):953–9]. Present work used these mice to determine if there was a link between vulnerability to the anxiogenic effects of Predator odors and abnormalities of 5-HT transmission induced by a life long reduction in 5-HT reuptake. Wild type (WT, C57 background), heterozygous (SERT +/−, HET) mice and homozygous knockout (SERT −/−, KO) were assigned to handled control groups or groups exposed for 10 min to a large testing room rich in cat odor. One week after handling or room exposure, anxiety testing took place in the dark phase of the light/dark cycle, in red light. Predator odor exposure was selectively anxiogenic in the plus maze and light/dark box tests in SERT −/− mice. Exposure to Predator odor did not potentiate startle. Findings suggest a role for abnormalities in 5-HT transmission in vulnerability to some of the lasting anxiogenic effects of species relevant Stressors and possibly in vulnerability to PTSD.

  • Protein synthesis and the mechanisms of lasting change in anxiety induced by severe Stress
    Behavioural brain research, 2005
    Co-Authors: Robert E. Adamec, Paul Burton, Jacqueline Blundell, Kirby Strasser, Donald W. Mckay
    Abstract:

    Brief, unprotected exposure of rats to cats (Predator Stress) may be lastingly anxiogenic in a variety of tests of rodent anxiety. Recent findings suggest that Predator Stress induced plasticity in neural circuitry implicated in fear learning underlies some of these anxiogenic effects. In addition, recent work implicates a consolidation-like process in the impact of Predator Stress on anxiety in that effects of Predator Stress may be interrupted by immediate post Stressor pharmacological interventions. The present study tested whether "consolidation" of the anxiogenic effects of Predator Stress were dependent on protein synthesis. In addition, the study examined whether a protein synthesis dependent reconsolidation-like process was at work when rats were exposed to a cat twice. Anisomycin (210 mg/kg) or vehicle (Tween 80 in saline) was injected subcutaneously 1 min after a single cat exposure (consolidation test paradigm) or a 1 min after a second cat exposure (reconsolidation test paradigm) and behavior tested 7-8 days after Predator Stress. In the consolidation test paradigm, anisomycin blocked the anxiogenic effects of Predator Stress in the elevated plus maze (EPM) measured with open arm exploration. Moreover, anisomycin blocked the potentiation of startle by Predator Stress when rats were startled in the light, but not when startled in the dark. In contrast, the delay of habituation of startle produced by Predator Stress was unaffected by anisomycin. Suppression of risk assessment in the EPM by Predator Stress was not affected by anisomycin either. In startle testing, vehicle injection 1 min after Predator Stress led to a lasting suppression, rather than enhancement of startle response. Vehicle plus Predator Stress enhanced and prolonged corticosterone level changes sampled over 30-180 min after treatment when compared to handled or Predator Stressed only rats. In addition, Predator Stress plus vehicle suppression of startle was blocked by a benzodiazepine anxiolytic (chloradiazepoxide) or the glucorticoid receptor (GR) blocker RU486. Both drugs returned startle to the Predator Stressed only heightened levels. It is argued that an added anxiogenic effect of vehicle injection plus Predator Stress leads to a suppression, rather than enhancement of startle. Startle suppression appears to be mediated, in part, by activation of GR by corticosterone which engages a protein synthesis dependent process, since anisomycin blocked the startle suppressive effects of vehicle. Startle suppression also appeared to be independent of the startle enhancing effect of Predator Stress and in competition with it. Since Predator Stress may model aspects of hyperarousal associated with post traumatic Stress disorder (PTSD), implications of these findings for understanding of mechanisms of initiation of the disorder and for treatment are discussed.

  • Role of NMDA receptors in the lateralized potentiation of amygdala afferent and efferent neural transmission produced by Predator Stress.
    Physiology & Behavior, 2005
    Co-Authors: Robert E. Adamec, Jacqueline Blundell, Paul Burton
    Abstract:

    The present study investigated the role of NMDA receptors in behavioral and neuroplastic changes in amygdala efferent (central amygdala to periaqueductal gray-ACE-PAG) and amygdala afferent (ventral angular bundle to basolateral amygdala-VAB-BLA) pathways in response to Predator Stress. Effects on brain and behavioral response to Predator Stress of competitive block of NMDA receptors with a dose of 10 mg/kg of CPP (3-(2-carboxypiperazin4-yl)propyl-l-phosphonic acid) were studied. Behavioral response to Stress was tested with hole board, elevated plus maze, light/dark box, social interaction and acoustic startle tests. CPP was administered i.p. 30 min prior to Predator Stress and blocked the effects of Predator on some but not all behaviors measured 8-9 days later. Effects of Predator Stress and CPP on potentials evoked in the PAG by single pulse stimulation of the ACE and in the BLA by single pulse stimulation of VAB were assessed 10-11 days after Predator Stress. Predator Stress potentiated ACE-PAG evoked potentials in the right but not the left hemisphere, replicating previous work. Predator Stress potentiated VAB-BLA transmission in both hemispheres 10-11 days after Predator Stress. Right hemisphere VAB-BLA potentiation replicated and extended past studies showing right hemisphere potentiation at 1 and 9 days after Stress. Left VAB-BLA potentiation effects differed from the long term depression seen in VAB-BLA at 1 and 9 days after Stress in previous studies. CPP blocked Predator Stress-induced potentiation of ACE-PAG and VAB-BLA evoked potentials in the right hemisphere. CPP did not block left VAB-BLA potentiation, rather CPP amplified it. Left hemisphere effects of CPP were interpreted as reflecting block of NMDA dependent long term depression, which unmasked a non-NMDA dependent potentiation. Taken together, the findings add to a body of evidence suggesting that a syndrome of behavioral changes follows Predator Stress. Components of this syndrome likely depend on changes in separable neural substrates. Potentiation of ACE-PAG and VAB-BLA evoked potentials in the right hemisphere likely mediates a subset of changes in behavior. Moreover, a medial ACE-PAG pathway is implicated in mediating Stress-induced changes in startle amplitude. In contrast, a lateral ACE-PAG pathway is implicated in mediating changes in startle habituation. Finally, consistent with cat and human studies, the right hemisphere appears particularly important in long term response to Stress.

  • Role of NMDA receptors in the syndrome of behavioral changes produced by Predator Stress.
    Physiology & Behavior, 2005
    Co-Authors: Jacqueline Blundell, Robert E. Adamec, Paul Burton
    Abstract:

    Abstract Effects on behavioral response to Predator Stress of competitive block of NMDA receptors with doses of .1, 1.0 and 10 mg/kg of CPP (3-(2-carboxypiperazin4-yl)propyl-l-phosphonic acid) were studied. An affect test battery assessed behavioral response to Stress and employed hole board, elevated plus maze, light/dark box, social interaction, social avoidance and response to acoustic startle tests. Doses of 1–10 mg/kg of CPP administered ip 30 min prior to Predator Stress blocked the effects of Predator Stress on some but not all behaviors measured 8–9 days later. Predator Stress normally reduces open arm exploration and risk assessment in the plus maze, decreases entries into the lighted arm of the light dark box and delays habituation of the acoustic startle response. CPP blocked all of these effects of Predator Stress. A dose of 10 mg/kg of CPP was required for all behaviors except habituation to startle. Block of effects on habituation to startle occurred at 1 and 10 mg/kg. Behaviors in which effects of Predator Stress were not blocked by CPP included reduction in unprotected head dips in the elevated plus maze and reduced social interaction. In addition, Predator Stress was without effect on social avoidance measured with the Haller test. These findings extend previous work showing NMDA receptor dependence of effects of Predator Stress on behavior in the elevated plus maze and on amplitude of acoustic startle response. Novel findings include NMDA receptor dependence of Predator Stress effects on light dark box behavior and startle habituation. Taken together, the findings add to a body of evidence showing that a syndrome of behavioral changes follows Predator Stress. Components of this syndrome of behavioral changes likely depend on changes in separable neural substrates initiated in part by NMDA receptors as well as by other neurochemical means.

David M. Diamond - One of the best experts on this subject based on the ideXlab platform.

  • Influence of Pre-Training Predator Stress on the Expression of c-fos mRNA in the Hippocampus, Amygdala, and Striatum Following Long-Term Spatial Memory Retrieval.
    Frontiers in behavioral neuroscience, 2011
    Co-Authors: Michael B. Vanelzakker, Collin R. Park, Phillip R. Zoladz, Vanessa M. Thompson, Joshua D. Halonen, Robert L. Spencer, David M. Diamond
    Abstract:

    We have studied the influence of pre-training psychological Stress on the expression of c-fos mRNA following long-term spatial memory retrieval. Rats were trained to learn the location of a hidden escape platform in the radial-arm water maze, and then their memory for the platform location was assessed 24 hr later. Rat brains were extracted 30 min after the 24 hr memory test trial for analysis of c-fos mRNA. Four groups were tested: 1) Rats given standard training (Standard); 2) Rats given cat exposure (Predator Stress) 30 min prior to training (Pre-Training Stress); 3) Rats given water exposure only (Water Yoked); and 4) Rats given no water exposure (Home Cage). The Standard trained group exhibited excellent 24 hr memory which was accompanied by increased c-fos mRNA in the dorsal hippocampus and basolateral amygdala (BLA). The Water Yoked group exhibited no increase in c-fos mRNA in any brain region. Rats in the Pre-Training Stress group were classified into two subgroups: good and bad memory performers. Neither of the two Pre-Training Stress subgroups exhibited a significant change in c-fos mRNA expression in the dorsal hippocampus or BLA. Instead, Stressed rats with good memory exhibited significantly greater c-fos mRNA expression in the dorsolateral striatum (DLS) compared to Stressed rats with bad memory. This finding suggests that Stressed rats with good memory used their DLS to generate a non-spatial (cue-based) strategy to learn and subsequently retrieve the memory of the platform location. Collectively, these findings provide evidence at a molecular level for the involvement of the hippocampus and BLA in the retrieval of spatial memory and contribute novel observations on the influence of pre-training Stress in activating the DLS in response to long-term memory retrieval.

  • The antidepressant agomelatine blocks the adverse effects of Stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the hippocampus of rats
    The international journal of neuropsychopharmacology, 2008
    Co-Authors: Lisa Conboy, Collin R. Park, Phillip R. Zoladz, Adam M Campbell, Cihan Tanrikut, Cecilia Gabriel, Elisabeth Mocaer, Carmen Sandi, David M. Diamond
    Abstract:

    Agomelatine, a novel antidepressant with established clinical efficacy, acts as a melatonin receptor agonist and 5-HT(2C) receptor antagonist. As Stress is a significant risk factor in the development of depression, we sought to determine if chronic agomelatine treatment would block the Stress-induced impairment of memory in rats trained in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. Moreover, since neural cell adhesion molecule (NCAM) is known to be critically involved in memory consolidation and synaptic plasticity, we evaluated the effects of agomelatine on NCAM, and polysialylated NCAM (PSA-NCAM) expression in rats given spatial memory training with or without Predator Stress. Adult male rats were pre-treated with agomelatine (10 mg/kg i.p., daily for 22 d), followed by a single day of RAWM training and memory testing. Rats were given 12 training trials and then they were placed either in their home cages (no Stress) or near a cat (Predator Stress). Thirty minutes later the rats were given a memory test trial followed immediately by brain extraction. We found that: (1) agomelatine blocked the Predator Stress-induced impairment of spatial memory; (2) agomelatine-treated Stressed, as well as non-Stressed, rats exhibited a rapid training-induced increase in the expression of synaptic NCAM in the ventral hippocampus; and (3) agomelatine treatment blocked the water-maze training-induced decrease in PSA-NCAM levels in both Stressed and non-Stressed animals. This work provides novel observations which indicate that agomelatine blocks the adverse effects of Stress on hippocampus-dependent memory and activates molecular mechanisms of memory storage in response to a learning experience.

  • Acute Predator Stress impairs the consolidation and retrieval of hippocampus-dependent memory in male and female rats
    Learning & memory (Cold Spring Harbor N.Y.), 2008
    Co-Authors: Collin R. Park, Phillip R. Zoladz, Cheryl D. Conrad, Monika Fleshner, David M. Diamond
    Abstract:

    We have studied the effects of an acute Predator Stress experience on spatial learning and memory in adult male and female Sprague-Dawley rats. All rats were trained to learn the location of a hidden escape platform in the radial-arm water maze (RAWM), a hippocampus-dependent spatial memory task. In the control (non-Stress) condition, female rats were superior to the males in the accuracy and consistency of their spatial memory performance tested over multiple days of training. In the Stress condition, rats were exposed to the cat for 30 min immediately before or after learning, or before the 24-h memory test. Predator Stress dramatically increased corticosterone levels in males and females, with females exhibiting greater baseline and Stress-evoked responses than males. Despite these sex differences in the overall magnitudes of corticosterone levels, there were significant sex-independent correlations involving basal and Stress-evoked corticosterone levels, and memory performance. Most importantly, Predator Stress impaired short-term memory, as well as processes involved in memory consolidation and retrieval, in male and female rats. Overall, we have found that an intense, ethologically relevant Stressor produced a largely equivalent impairment of memory in male and female rats, and sex-independent corticosterone-memory correlations. These findings may provide insight into commonalities in how traumatic Stress affects the brain and memory in men and women.

  • Pre-training administration of tianeptine, but not propranolol, protects hippocampus-dependent memory from being impaired by Predator Stress
    European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2007
    Co-Authors: Adam M Campbell, Collin R. Park, Phillip R. Zoladz, Monika Fleshner, Carmen Muñoz, David M. Diamond
    Abstract:

    Abstract Extensive research has shown that the antidepressant tianeptine blocks the adverse effects of chronic Stress on hippocampal functioning. The current series of experiments extended this area of investigation by examining the influence of tianeptine on acute Stress-induced impairments of spatial (hippocampus-dependent) memory. Tianeptine (10 mg/kg, ip) administered to adult male rats before, but not after, water maze training blocked the amnestic effects of Predator Stress (occurring between training and retrieval) on memory. The protective effects of tianeptine on memory occurred in rats which had extensive pre-Stress training, as well as in rats which had only a single day of training. Tianeptine blocked Stress effects on memory without altering the Stress-induced increase in corticosterone levels. Propranolol, a β-adrenergic receptor antagonist (5 and 10 mg/kg, ip), in contrast, did not block Stress-induced amnesia. These findings indicate that treatment with tianeptine, unlike propanolol, provides an effective means with which to block the adverse effects of Stress on cognitive functions of the hippocampus.

  • influence of Predator Stress on the consolidation versus retrieval of long term spatial memory and hippocampal spinogenesis
    Hippocampus, 2006
    Co-Authors: David M. Diamond, Collin R. Park, Cheryl D. Conrad, Adam M Campbell, James C Woodson, Adam D Bachstetter, Ronald F Mervis
    Abstract:

    We have studied the influence of Predator Stress (30 min of cat exposure) on long-term (24 h) spatial memory and the density of spines in basilar dendrites of CA1 neurons. Predator Stress occurred either immediately before water maze training (Stress Pre-Training) or before the 24 h memory test (Stress Pre-Retrieval). The Control (nonStress) group exhibited excellent long-term spatial memory and a robust increase in the density of stubby, but not mushroom, shaped spines. The Stress Pre-Training group had impaired long-term memory and did not exhibit any changes in spine density. The Stress Pre-Retrieval group was also impaired in long-term memory performance, but this group exhibited an increase in the density of stubby, but not mushroom, shaped spines, which was indistinguishable from the control group. These findings indicate that: (1) A single day of water maze training under control conditions produced intact long-term memory and an increase in the density of stubby spines in CA1; (2) Stress before training interfered with the consolidation of information into long-term memory and suppressed the training-induced increase in spine density; and (3) Stress immediately before the 24 h memory test trial impaired the retrieval of the stored memory, but did not reverse the training-induced increase in CA1 spine density. Overall, this work provides evidence of structural plasticity in dendrites of CA1 neurons which may be involved in the consolidation process, and how spinogenesis and memory are modulated by Stress.

Ronald F Mervis - One of the best experts on this subject based on the ideXlab platform.

  • Dendritic morphology of amygdala and hippocampal neurons in more and less Predator Stress responsive rats and more and less spontaneously anxious handled controls.
    Behavioural brain research, 2011
    Co-Authors: Robert E. Adamec, Mark Hebert, Jacqueline Blundell, Ronald F Mervis
    Abstract:

    We investigated the neurobiological bases of variation in response to Predator Stress (PS). Sixteen days after treatment (PS or handling), rats were grouped according to anxiety in the elevated plus maze (EPM). Acoustic startle was also measured. We examined the structure of dendritic trees of basolateral amygdala (BLA) output neurons (stellate and pyramidal cells) and of dorsal hippocampal (DHC) dentate granule cells of less anxious (LA) and more (extremely) anxious (MA) Stressed animals (PSLA and PSMA). Handled controls (HC) which were less anxious (HCLA) and spontaneously more anxious (HCMA) equivalently to Predator Stressed subgroups were also studied. Golgi analysis revealed BLA output neurons of HCMA rats exhibited longer, more branched dendrites with higher spine density than the other groups of rats, which did not differ. Finally, spine density of DHC granule cells was equally depressed in HCMA and PSMA rats relative to HCLA and PSLA rats. Total dendritic length of BLA pyramidal and stellate cells (positive predictor) and DHC spine density (negative predictor) together accounted for 96% of the variance of anxiety of handled rats. DHC spine density was a negative predictor of PSMA and PSLA anxiety, accounting for 70% of the variance. Data are discussed in the context of morphological differences as phenotypic markers of a genetic predisposition to anxiety in handled controls, and a possible genetic vulnerability to Predator Stress expressed as reduced spine density in the DHC. Significance of findings for animal models of anxiety and hyperarousal comorbidities of PTSD are discussed.

  • influence of Predator Stress on the consolidation versus retrieval of long term spatial memory and hippocampal spinogenesis
    Hippocampus, 2006
    Co-Authors: David M. Diamond, Collin R. Park, Cheryl D. Conrad, Adam M Campbell, James C Woodson, Adam D Bachstetter, Ronald F Mervis
    Abstract:

    We have studied the influence of Predator Stress (30 min of cat exposure) on long-term (24 h) spatial memory and the density of spines in basilar dendrites of CA1 neurons. Predator Stress occurred either immediately before water maze training (Stress Pre-Training) or before the 24 h memory test (Stress Pre-Retrieval). The Control (nonStress) group exhibited excellent long-term spatial memory and a robust increase in the density of stubby, but not mushroom, shaped spines. The Stress Pre-Training group had impaired long-term memory and did not exhibit any changes in spine density. The Stress Pre-Retrieval group was also impaired in long-term memory performance, but this group exhibited an increase in the density of stubby, but not mushroom, shaped spines, which was indistinguishable from the control group. These findings indicate that: (1) A single day of water maze training under control conditions produced intact long-term memory and an increase in the density of stubby spines in CA1; (2) Stress before training interfered with the consolidation of information into long-term memory and suppressed the training-induced increase in spine density; and (3) Stress immediately before the 24 h memory test trial impaired the retrieval of the stored memory, but did not reverse the training-induced increase in CA1 spine density. Overall, this work provides evidence of structural plasticity in dendrites of CA1 neurons which may be involved in the consolidation process, and how spinogenesis and memory are modulated by Stress.

  • Influence of Predator Stress on the consolidation versus retrieval of long-term spatial memory and hippocampal spinogenesis.
    Hippocampus, 2006
    Co-Authors: David M. Diamond, Collin R. Park, Cheryl D. Conrad, Adam M Campbell, James C Woodson, Adam D Bachstetter, Ronald F Mervis
    Abstract:

    We have studied the influence of Predator Stress (30 min of cat exposure) on long-term (24 h) spatial memory and the density of spines in basilar dendrites of CA1 neurons. Predator Stress occurred either immediately before water maze training (Stress Pre-Training) or before the 24 h memory test (Stress Pre-Retrieval). The Control (nonStress) group exhibited excellent long-term spatial memory and a robust increase in the density of stubby, but not mushroom, shaped spines. The Stress Pre-Training group had impaired long-term memory and did not exhibit any changes in spine density. The Stress Pre-Retrieval group was also impaired in long-term memory performance, but this group exhibited an increase in the density of stubby, but not mushroom, shaped spines, which was indistinguishable from the control group. These findings indicate that: (1) A single day of water maze training under control conditions produced intact long-term memory and an increase in the density of stubby spines in CA1; (2) Stress before training interfered with the consolidation of information into long-term memory and suppressed the training-induced increase in spine density; and (3) Stress immediately before the 24 h memory test trial impaired the retrieval of the stored memory, but did not reverse the training-induced increase in CA1 spine density. Overall, this work provides evidence of structural plasticity in dendrites of CA1 neurons which may be involved in the consolidation process, and how spinogenesis and memory are modulated by Stress. © 2006 Wiley-Liss, Inc.