Papers by Ruth Barrientos
Brain Behavior and Immunity
In normal aging, a peripheral immune challenge induces a sensitized and protracted neuroinflammat... more In normal aging, a peripheral immune challenge induces a sensitized and protracted neuroinflammatory response in parallel with long-term memory (LTM) impairments. Pro-inflammatory mediators of neuroinflammation impair LTM, synaptic plasticity and LTP. The immediate early gene Arc is considered a critical protein regulating LTM and synaptic plasticity. The present investigation examined whether (1) a peripheral Escherichia coli infection suppresses hippocampal Arc expression, and (2) central pro-inflammatory cytokines (IL-1β and IL-6) mediate the effects of peripheral E. coli infection on Arc and LTM. In 24 months F344 × BN F1 rats, E. coli infection suppressed basal Arc gene expression as well as contextual fear conditioning-induced Arc expression. E. coli treatment failed to alter either basal or conditioning-induced c-Fos expression. At 24 h post-infection, intra-cisterna magna (ICM) treatment with the anti-inflammatory cytokine IL-1RA blocked the E. coli-induced suppression of hi...
Journal of neuroimmunology
The present study tested whether aging sensitizes hippocampal microglia to a pro-inflammatory cha... more The present study tested whether aging sensitizes hippocampal microglia to a pro-inflammatory challenge ex vivo. Hippocampal microglia from 3 and 24 mo old male F344 x BN F1 rats were exposed to LPS (0, 0.1, 1, 10 and 100 ng/ml) ex vivo. 2 h post-LPS challenge, gene expression of microglial activation markers and cytokines were assessed. 24 mo old animals exhibited a potentiated pro-inflammatory cytokine (IL-1β and IL-6) response to LPS and increased levels of CD11b, Iba-1 and MHCII irrespective of LPS treatment. The present results demonstrate that aging sensitizes hippocampal microglia to pro-inflammatory challenges.
Brain Behavior and Immunity
We previously reported that aging F344XBN rats are more vulnerable to disruptions of memory conso... more We previously reported that aging F344XBN rats are more vulnerable to disruptions of memory consolidation processes following an injection of Escherichia coli than are young rats. Furthermore, this disruption was specific to hippocampal-dependent memory. In the present study we examined the time course of the proinflammatory cytokine IL-1 beta in young and old rats following a peripheral injection of E. coli. Compared to young rats, aging rats treated with E. coli showed an exaggerated and prolonged up-regulation of IL-1 beta protein in the hippocampus, but not in hypothalamus, parietal cortex, prefrontal cortex, serum or spleen. Aging rats showed greater hippocampal IL-1 beta protein levels than their young counterparts 4h after E. coli, and these levels remained significantly elevated for 8 but not 14 days after E. coli. In a second experiment, aging rats exhibited anterograde memory consolidation impairments 4 and 8 days after an E. coli injection, but not after 14 days. A third ...
Healthy aged individuals are more likely to suffer profound memory impairments following a challe... more Healthy aged individuals are more likely to suffer profound memory impairments following a challenging life event such as a severe bacterial infection, surgery, or an intense psychological stressor, than are younger adults. These peripheral challenges are capable of producing a neuroinflammatory response, (e.g., increased pro-inflammatory cytokines), and in the healthy aged brain this response is exaggerated and prolonged. Normal aging primes or sensitizes microglia and this appears to be the source of this amplified response. Among the outcomes of this exaggerated neuroinflammatory response is an impairment in synaptic plasticity, and a reduction in key downstream mediators such as Arc and BDNF. Each of these mechanisms is important for long-term memory formation, and is compromised by elevated pro-inflammatory cytokines. Pharmacological, dietary and physical interventions are discussed as potential therapies to abrogate the challenge-induced neuroinflammatory response, thereby pre...
Aging and disease, 2010
Healthy aged individuals are more likely to suffer profound memory impairments following a challe... more Healthy aged individuals are more likely to suffer profound memory impairments following a challenging life event such as a severe bacterial infection, surgery, or an intense psychological stressor, than are younger adults. These peripheral challenges are capable of producing a neuroinflammatory response, (e.g., increased pro-inflammatory cytokines), and in the healthy aged brain this response is exaggerated and prolonged. Normal aging primes or sensitizes microglia and this appears to be the source of this amplified response. Among the outcomes of this exaggerated neuroinflammatory response is an impairment in synaptic plasticity, and a reduction in key downstream mediators such as Arc and BDNF. Each of these mechanisms is important for long-term memory formation, and is compromised by elevated pro-inflammatory cytokines. Pharmacological, dietary and physical interventions are discussed as potential therapies to abrogate the challenge-induced neuroinflammatory response, thereby pre...
Brain, Behavior, and Immunity, 2014
High-fat diet (HFD)-induced obesity is reaching worldwide proportions. In addition to causing obe... more High-fat diet (HFD)-induced obesity is reaching worldwide proportions. In addition to causing obesity, HFDs also induce a variety of health disorders, which includes cognitive decline. Hippocampal function may be particularly vulnerable to the negative consequences of HFD, and it is suspected that 'primed' neuroinflammatory processes may mediate this response. To examine the link between diet, hippocampal function and neuroinflammation, male Wistar rats were fed a medium or HFD. Hippocampal memory function was measured using contextual pre-exposure fear conditioning (CPE-FC). Rats fed a HFD demonstrated impaired memory, an effect that was augmented with longer duration of HFD consumption. HFD-induced memory impairments were linked to potentiated levels of interleukin-1 beta (IL-1b) protein in the hippocampus 2 h after the foot-shock that occurs during CPE-FC. Central IL-1 receptor antagonism, with intracisterna magna (ICM) administration of hIL-1RA prior to the foot-shock prevented the dietinduced memory disruption, suggesting a critical role for IL-1b in this phenomenon. Additionally, obese animals whose diet regimen was reversed from HFD back to standard chow recovered memory function and did not demonstrate a foot-shock-induced hippocampal IL-1b increase. Interestingly, dietary reversal neutralized the negative impact of HFD on memory and IL-1b, yet animals maintained physiological evidence of obesity (increased body mass and serum leptin), indicating that dietary components, not body mass, may mediate the negative effects on memory. j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / y b r b i Please cite this article in press as: Sobesky, J.L., et al. High-fat diet consumption disrupts memory and primes elevations in hippocampal IL-1b, an effect that can be prevented with dietary reversal or IL-1 receptor antagonism. Brain Behav. Immun. (2014), http://dx.
Brain, Behavior, and Immunity, 2014
The circadian system regulates many physiological functions including inflammatory responses. For... more The circadian system regulates many physiological functions including inflammatory responses. For example, mortality caused by lipopolysaccharide (LPS) injection varies depending on the time of immunostimulation in mammals. The effects of more subtle challenges on the immune system and cellular mechanisms underlying circadian differences in neuroinflammatory responses are not well understood.
Manipulations that increase the expression of the pro-inflammatory cytokine interleukin-1 (IL-1... more Manipulations that increase the expression of the pro-inflammatory cytokine interleukin-1 (IL-1) in the hippocampus (e.g. peripheral administration of lipopolysaccharide, i.c.v. glycoprotein 120, social isolation) as well as the intrahippocampal injection of IL-1 following a learning experience, dramatically impair the memory of that experience if the formation of the memory requires the hippocampus. Here we employed social isolation to further study this phenomenon, as well as its relation to brain-derived neurotrophic factor (BDNF). BDNF was studied because of its well-documented role in the formation of hippocampally based memory. A 6 h period of social isolation immediately after contextual fear conditioning impaired memory for context fear measured 48 h later, and decreased BDNF mRNA in the dentate gyrus and the CA3 region of the hippocampus assessed immediately after the isolation. Moreover, an intrahippocampal injection of the IL-1 receptor antagonist prior to the isolation period prevented both the BDNF downregulation and the memory impairments produced by the isolation. These data suggest that hippocampal-dependent memory impairments induced by elevated levels of brain IL-1 may occur via an IL-1-induced downregulation in hippocampal BDNF.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, Jan 17, 2014
Alterations in reward valuation are thought to have a central role at all stages of the addiction... more Alterations in reward valuation are thought to have a central role at all stages of the addiction process. We previously reported work aversion in an effortful T-maze task following a binge exposure to methamphetamine, and no such changes in effort following escalating doses. Limitations of the T-maze task include its two available options, with an effort requirement, in the form of increasing barrier height, varying incrementally as a function of time, and reward magnitudes held constant. Reward preferences and choices, however, are likely affected by the number of options available and the manner in which alternatives are presented. In the present experiment, we investigated the long-lasting, off-drug effects of methamphetamine on reward choices in a novel effortful maze task with three possible courses of action, each associated with different effort requirements and reward magnitudes. Neuroinflammatory responses associated with drug exposure, proposed as one of the mechanisms co...
Neurobiology of Aging, 2014
Healthy aging individuals are more likely to suffer profound memory impairments following an immu... more Healthy aging individuals are more likely to suffer profound memory impairments following an immune challenge than are younger adults. These challenges produce a brain inflammatory response that is exaggerated with age. Sensitized microglia found in the normal aging brain are responsible for this amplified response, which in turn interferes with processes involved in memory formation. Here, we examine factors that may lead aging to sensitize microglia. Aged rats exhibited higher corticosterone levels in the hippocampus, but not in plasma, throughout the daytime (diurnal inactive phase). These elevated hippocampal corticosterone levels were associated with increased hippocampal 11b-hydroxysteroid dehydrogenase type 1 protein expression, the enzyme that catalyzes glucocorticoid formation and greater hippocampal glucocorticoid receptor (GR) activation. Intracisternal administration of mifepristone, a GR antagonist, effectively reduced immune-activated proinflammatory responses, specifically from hippocampal microglia and prevented Escherichia colieinduced memory impairments in aged rats. Voluntary exercise as a therapeutic intervention significantly reduced total hippocampal GR expression. These data strongly suggest that increased GR activation in the aged hippocampus plays a critical role in sensitizing microglia.
Brain, Behavior, and Immunity, 2015
Bi-directional communication between the peripheral and central nervous systems has been extensiv... more Bi-directional communication between the peripheral and central nervous systems has been extensively demonstrated. Aged rats exhibit a prolonged proinflammatory response in the hippocampus region of the brain following a peripheral bacterial infection, and this response in turn causes robust memory declines.
Journal of Neuroscience, 2011
For reasons that are not well understood, aging significantly increases brain vulnerability to ch... more For reasons that are not well understood, aging significantly increases brain vulnerability to challenging life events. High functioning older individuals often experience significant cognitive decline after an inflammatory event such as surgery, infection or injury. We have modeled this phenomenon in rodents, and have previously reported that a peripheral immune challenge (intraperitoneal injection of live E. coli) selectively disrupts consolidation of hippocampusdependent memory in aged (24-month-old), but not young (3-month-old) F344xBN rats. More recently, we have demonstrated that this infection-evoked memory deficit is mirrored by a selective deficit in long-lasting synaptic plasticity in the hippocampus. Interestingly, these deficits occur in forms of long-term memory and synaptic plasticity known to be strongly dependent on BDNF.
Journal of Neuroscience, 2012
To investigate the role of the pro-inflammatory cytokine interleukin-1beta (IL-1β) in postoperati... more To investigate the role of the pro-inflammatory cytokine interleukin-1beta (IL-1β) in postoperative cognitive dysfunction (POCD) in aged rats, we employed laparotomy to mimic human abdominal surgery in adult (3 mo) and aged (24 mo) F344/BN rats. We demonstrated that memory consolidation of the hippocampal-dependent contextual fear conditioning task is significantly impaired in aged, but not young rats 4 days following surgery. Hippocampal-independent auditory-cued fear memory was not disrupted by laparotomy in either age group. The hippocampal-dependent memory impairment was paralleled by elevations of IL-1β in the hippocampus of aged animals 1 and 4 days following surgery. These findings support our substantial line of previous research showing that aged animals are more vulnerable to cognitive decline following a peripheral immune challenge. In addition, we demonstrated that a single intracisternal administration of interleukin-1 receptor antagonist (IL-1RA; 112ug) at the time of surgery was sufficient to block both the behavioral deficit and the neuroinflammatory response. Injecting the same dose of IL-1RA peripherally failed to have a protective effect. These data provide strong support for the specific role of central, not peripheral IL-1β in POCD. Furthermore, the long-lasting presence of IL-1RA in the brain (4 days) compared to in the blood (<24 hr) underscores the value of intracisternal administration of IL-1RA for therapeutic purposes.
Journal of Neuroscience, 2011
We have previously found that healthy aged rats are more likely to suffer profound memory impairm... more We have previously found that healthy aged rats are more likely to suffer profound memory impairments following a severe bacterial infection than are younger adult rats. Such a peripheral challenge is capable of producing a neuroinflammatory response, and in the aged brain this response is exaggerated and prolonged. Normal aging primes, or sensitizes microglia and this appears to be the source of this amplified inflammatory response. Among the outcomes of this exaggerated neuroinflammatory response are impairments in synaptic plasticity, and reductions of brain derived neurotrophic factor (BDNF), both of which have been associated with cognitive impairments. Since it has been shown that physical exercise increases BDNF mRNA in the hippocampus, the present study examined voluntary exercise in 24 mos old F344xBN rats as a neuroprotective therapeutic in our bacterial infection model. Although aged rats ran only an average of 0.7 km per week, this small amount of exercise was sufficient to completely reverse infection-induced impairments in hippocampus-dependent long-term memory compared to sedentary animals. Strikingly, exercise prevented the infection-induced exaggerated neuroinflammatory response and the blunted BDNF mRNA induction seen in the hippocampus of sedentary rats. Moreover, voluntary exercise abrogated age-related microglial sensitization, suggesting a possible mechanism for exercise-induced neuroprotection in aging.
Journal of Neuroscience, 2010
Variability in cognitive functioning increases markedly with age, as does cognitive vulnerability... more Variability in cognitive functioning increases markedly with age, as does cognitive vulnerability to physiological and psychological challenges. Exploring the basis of this vulnerability may provide important insights into the mechanisms underlying aging-associated cognitive decline. As we have previously reported, the cognitive abilities of aging (24-month-old) F344xBN rats are generally good, but are more vulnerable to the consequences of a peripheral immune challenge (an i.p. injection of live E. coli) than those of their younger (3-month-old) counterparts. Four days after the injection, the aging, but not the young rats show profound memory deficits, specific to the consolidation of hippocampus-dependent memory processes.
Psychoneuroendocrinology, 2010
Pain, 2004
Snakebites constitute a serious public health problem in Central and South America, where species... more Snakebites constitute a serious public health problem in Central and South America, where species of the lancehead pit vipers (genus Bothrops) cause the majority of accidents. Bothrops envenomations are very painful, and this effect is not neutralized by antivenom treatment. Two variants of secretory phospholipases A2 (sPLA2), corresponding to Asp49 and Lys49 PLA2s, have been isolated from Bothrops asper venom. These sPLA2s induce hyperalgesia in rats following subcutaneous injection. However, venom in natural Bothrops bites is frequently delivered intramuscularly, thereby potentially reaching peripheral nerve bundles. Thus, the present series of experiments tested whether these sPLA2s could exert pain-enhancing effects following administration around healthy sciatic nerve. Both were found to produce mechanical allodynia ipsilateral to the injection site; no thermal hyperalgesia was observed. As no prior study has examined potential spinal mechanisms underlying sPLA2 actions, a series of anatomical and pharmacological studies were performed. These demonstrated that both sPLA2s produce activation of dorsal horn astrocytes and microglia that is more prominent ipsilateral to the site of injection. As proinflammatory cytokines and nitric oxide have each been previously implicated in spinally mediated pain facilitation, the effect of pharmacological blockade of these substances was tested. The results demonstrate that mechanical allodynia induced by both sPLA2s is blocked by interleukin-1 receptor antagonist, anti-rat interleukin-6 neutralizing antibody, the anti-inflammatory cytokine interleukin-10, and a nitric oxide synthesis inhibitor (L-NAME). As a variety of immune cells also produce and release sPLA2s during inflammatory states, the data may have general implications for the understanding of inflammatory pain. q
Neurobiology of Aging, 2006
In normal brain aging, CNS resident macrophages exhibit increased expression of major histocompat... more In normal brain aging, CNS resident macrophages exhibit increased expression of major histocompatibility complex (MHC) II expression. However, the transcriptional basis for this observation has not been clarified nor have age-related alterations in pivotal pro-inflammatory genes been characterized. Age-related mRNA alterations in MHC II, MHC II accessory molecules and several pro-inflammatory mediators were measured in older (24 months) and younger (3 months) male F344xBN F1 rats. Real time RT-PCR was utilized to measure steady state mRNA levels in hippocampus. Older as compared to younger animals exhibited increased mRNA levels of MHC II, CD86, CIITA and IFN-␥. Furthermore, IL-10 and CD200 mRNA, molecules that down-regulate macrophage activation, was decreased in older animals. The present results indicate that normal brain aging is characterized by a shift towards a pro-inflammatory microenvironment in the CNS.
Neurobiology of Aging, 2012
Aging increases the likelihood of cognitive decline after negative life events such as infection ... more Aging increases the likelihood of cognitive decline after negative life events such as infection or injury. We have modeled this increased vulnerability in aged (24-month-old), but otherwise unimpaired F344xBN rats. In these animals, but not in younger (3-month-old) counterparts, a single intraperitoneal injection of E. coli leads to specific deficits in long-term memory and longlasting synaptic plasticity in hippocampal area CA1 -processes strongly dependent on BDNF.
Neurobiology of Aging, 2006
We report that a peripheral injection of Escherichia coli produces both anterograde and retrograd... more We report that a peripheral injection of Escherichia coli produces both anterograde and retrograde amnesia in 24 month old, but not 3 month old rats for memories that depend on the hippocampus, that is, memory of context, contextual fear, and place learning. The anterograde effect was restricted to measures of long-term memory. Short-term memory was not affected, nor did E. coli produce amnesia for auditory-cue fear conditioning. There were no age related effects on memory in vehicle-treated rats. In addition to these age-related cognitive effects of E.coli, we report that it produced a marked increased in IL-1 levels in the hippocampus, but not in parietal cortex or serum. These findings support the hypothesis that age is a vulnerability factor that increases the likelihood that an immune challenge will produce a cognitive impairment. It is possible that this cognitive vulnerability is mediated by age-related changes in the glial environment that results in an exaggerated brain pro-inflammatory response to infection.
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Papers by Ruth Barrientos