Matching Items (29)

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Does chronic unpredictable restraint produce dendritic retraction in long-shaft CA3 hippocampal neurons?

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Major Depressive Disorder (MDD) is a widespread mood disorder that affects more than 300 million people worldwide and yet, high relapse rates persist. This current study aimed to use an

Major Depressive Disorder (MDD) is a widespread mood disorder that affects more than 300 million people worldwide and yet, high relapse rates persist. This current study aimed to use an animal model for depression, unpredictable intermittent restraint (UIR), to investigate changes in a subset of neurons within the hippocampus, a region of high susceptibility in MDD. Adult male and female Sprague-Dawley rats were randomly assigned to four treatment groups based on sex (n = 48, n = 12/group). Half of the rats underwent UIR that involved restraint with orbital shaking (30 min or 1 h) for 2-6 consecutive days, followed by one or two days of no stressors; the other half of the rats were undisturbed (CON). UIR rats were stressed for 28 days (21 days of actual stressors) before behavioral testing began with UIR continuing between testing days for nearly 70 days. Rats were then euthanized between 9 and 11 days after the last UIR session. Brains were processed for Golgi stain and long-shaft (LS) neurons within the hippocampal CA3a and CA3b regions were quantified for dendritic complexity using a Camera Lucida attachment. Our findings failed to support our hypothesis that UIR would produce apical dendritic retraction in CA3 hippocampal LS neurons in both males and females. Given that UIR failed to produce CA3 apical dendritic retraction in males, which is commonly observed in the literature, we discuss several reasons for these findings including, time from the end of UIR to when brains were sampled, and the effects of repeated cognitive testing. Given our published findings that UIR impaired spatial ability in males, but not females, we believe that UIR holds validity as a chronic stress paradigm, as UIR attenuated body weight gain in both males and females and produced reductions in thymus gland weight in UIR males. These findings corroborate UIR as an effective stressor in males and warrant further research into the timing of UIR-induced changes in hippocampal CA3 apical dendritic morphology.

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Date Created
  • 2020-12

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Relationships Between the Inflammatory Responses of the Immune System and Periods of Critical Hormonal Shifts in Females Across the Lifespan: A Pregnancy Review

Description

In females, critical hormonal shifts occur during puberty, menstruation, pregnancy, and <br/>menopause. The fluctuating ovarian hormone levels across a woman’s lifespan likely contribute <br/>to inflammatory responses driven by the immune

In females, critical hormonal shifts occur during puberty, menstruation, pregnancy, and <br/>menopause. The fluctuating ovarian hormone levels across a woman’s lifespan likely contribute <br/>to inflammatory responses driven by the immune system, which is regulated by a variety of <br/>physiological pathways and microbiological cues. Pregnancy in particular results in drastic <br/>changes in circulating hormone profiles, and involves a variety of physiological changes, <br/>including inflammatory responses of the immune system. There is evidence that these effects are <br/>mediated, in part, by the significant hormone fluctuations that characterize pregnancy and <br/>postpartum periods. This thesis highlights and synthesizes important physiological changes <br/>associated with pregnancy, and their potential implications on cognitive and brain aging in <br/>women. A tertiary model of cognition is presented depicting interactions between hormonal <br/>history, reproductive history, and immune functions. This research is important to create a better <br/>understanding of women’s health and enhance medical care for women throughout pregnancy <br/>and across reproductive hormone shifts across the lifespan.

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Date Created
  • 2021-05

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Modeling acquisition of nicotine self-administration in rats

Description

Nicotine is thought to underlie the reinforcing and dependence-producing effects of tobacco-containing products. Nicotine supports self-administration in rodents, although measures of its reinforcing effects are often confounded by procedures that

Nicotine is thought to underlie the reinforcing and dependence-producing effects of tobacco-containing products. Nicotine supports self-administration in rodents, although measures of its reinforcing effects are often confounded by procedures that are used to facilitate acquisition, such as food restriction, prior reinforcement training, or response-contingent co-delivery of a naturally reinforcing light. This study examined whether rats acquire nicotine self-administration in the absence of these facilitators. A new mathematical modeling procedure was used to define the criterion for acquisition and to determine dose-dependent differences in rate and asymptote levels of intake. Rats were trained across 20 daily 2-h sessions occurring 6 days/week in chambers equipped with active and inactive levers. Each active lever press resulted in nicotine reinforcement (0, 0.015, 0.03, 0.06 mg/kg, IV) and retraction of both levers for a 20-s time out, whereas inactive lever presses had no consequences. Acquisition was defined by the best fit of a logistic function (i.e., S-shaped) versus a constant function (i.e., flat line) for reinforcers obtained across sessions using a corrected Akaike information criterion (AICc) as a model selection tool. The results showed an inverted-U shaped function for dose in relation to the percentage of animals that acquired nicotine self-administration, with 46% acquiring at 0.015 mg/kg, 73% at 0.03 mg/kg, and 58% at 0.06 mg/kg. All saline rats failed to acquire as expected. For rats that acquired nicotine self-administration, multiple model comparisons demonstrated that the asymptote (highest number of reinforcers/session) and half learning point (h; session during which half the assymptote had been achieved) were justified as free parameters of the reinforcers/session function, indicating that these parameters vary with nicotine dose. Asymptote exhibited an inverted U-shaped function across doses and half learning point exhibited a negative relationship to dose (i.e., the higher the dose the fewer sessions to reach h). These findings suggest that some rats acquire nicotine self-administration without using procedures that confound measures of acquisition rate. Furthermore, the modeling approach provides a new way of defining acquisition of drug self-administration that takes advantage of using all data generated from individual subjects and is less arbitrary than some criteria that are currently used.

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Date Created
  • 2011

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Cellular mechanisms underlying the effects of repeated D₂-like agonist treatment on prepulse Inhibition

Description

Patients with schizophrenia have deficits in sensorimotor gating, the ability to gate out irrelevant stimuli in order to attend to relevant stimuli. Prepulse inhibition (PPI) of the startle response is

Patients with schizophrenia have deficits in sensorimotor gating, the ability to gate out irrelevant stimuli in order to attend to relevant stimuli. Prepulse inhibition (PPI) of the startle response is a reliable and valid model of sensorimotor gating across species. Repeated D2-like agonist treatment alleviates prior PPI deficits in rats, termed a PPI recovery, and is observable 28 days after treatment. The aim of the current project is to illuminate the underlying mechanism for this persistent change of behavior and determine the clinical relevance of repeated D2-like agonist treatment. Our results revealed a significant increase in Delta FosB, a transcription factor, in the nucleus accumbens (NAc) 10 days after repeated D2-like agonist treatment. Additionally, we investigated if Delta FosB was necessary for long-lasting PPI recovery and discovered a bilateral infusion of dominant-negative Delta JunD prevented PPI recovery after repeated D2-like agonist treatment. To further develop the underlying mechanism of PPI recovery, we observed that dominant negative mutant cyclic adenosine monophosphate (cAMP) response biding element protein (CREB) prevented repeated D2-like agonist-induced Delta FosB expression in the NAc. We then compared our previous behavioral and intracellular findings to the results of repeated aripiprazole, a novel D2-like partial agonist antipsychotic, to determine if repeated D2-like receptor agonist action is a clinically relevant pharmacological approach. As compared to previous PPI recovery and Delta FosB expression after repeated D2-like agonist treatment, we found similar PPI recovery and Delta FosB expression after repeated aripiprazole treatment in rats. We can conclude that repeated D2-like agonist treatment produces persistent PPI recovery through CREB phosphorylation and Delta FosB, which is necessary for PPI recovery. Furthermore, this pharmacological approach produces behavioral and intracellular changes similar to an effective novel antipsychotic. These findings suggest the underlying intracellular mechanism for sustained PPI recovery is clinically relevant and may be a potential target of therapeutic intervention to alleviate sensorimotor gating deficits, which are associated with cognitive symptoms of schizophrenia.

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Date Created
  • 2013

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Chronic stress and plasticity in the limbic system: implications for post traumatic stress disorder

Description

The brain is a fundamental target of the stress response that promotes adaptation and survival but the repeated activation of the stress response has the potential alter cognition, emotion, and

The brain is a fundamental target of the stress response that promotes adaptation and survival but the repeated activation of the stress response has the potential alter cognition, emotion, and motivation, key functions of the limbic system. Three structures of the limbic system in particular, the hippocampus, medial prefrontal cortex (mPFC), and amygdala, are of special interest due to documented structural changes and their implication in post-traumatic stress disorder (PTSD). One of many notable chronic stress-induced changes include dendritic arbor restructuring, which reflect plasticity patterns in parallel with the direction of alterations observed in functional imaging studies in PTSD patients. For instance, chronic stress produces dendritic retraction in the hippocampus and mPFC, but dendritic hypertrophy in the amygdala, consistent with functional imaging in patients with PTSD. Some have hypothesized that these limbic region's modifications contribute to one's susceptibility to develop PTSD following a traumatic event. Consequently, we used a familiar chronic stress procedure in a rat model to create a vulnerable brain that might develop traits consistent with PTSD when presented with a challenge. In adult male rats, chronic stress by wire mesh restraint (6h/d/21d) was followed by a variety of behavioral tasks including radial arm water maze (RAWM), fear conditioning and extinction, and fear memory reconsolidation to determine chronic stress effects on behaviors mediated by these limbic structures. In chapter 2, we corroborated past findings that chronic stress caused hippocampal CA3 dendritic retraction. Importantly, we present new findings that CA3 dendritic retraction corresponded with poor spatial memory in the RAWM and that these outcomes reversed after a recovery period. In chapter 3, we also showed that chronic stress impaired mPFC-mediated extinction memory, findings that others have reported. Using carefully assessed behavior, we present new findings that chronic stress impacted nonassociative fear by enhancing contextual fear during extinction that generalized to a new context. Moreover, the generalization behavior corresponded with enhanced functional activation in the hippocampus and amygdala during fear extinction memory retrieval. In chapter 5, we showed for the first time that chronic stress enhanced amygdala functional activation during fear memory retrieval, i.e., reactivation. Moreover, these enhanced fear memories were resistant to protein synthesis interference to disrupt a previously formed memory, called reconsolidation in a novel attempt to weaken chronic stress enhanced traumatic memory. Collectively, these studies demonstrated the plastic and dynamic effects of chronic stress on limbic neurocircuitry implicated in PTSD. We showed that chronic stress created a structural and functional imbalance across the hippocampus, mPFC, and amygdala, which lead to a PTSD-like phenotype with persistent and exaggerated fear following fear conditioning. These behavioral disruptions in conjunction with morphological and functional imaging data reflect a chronic stress-induced imbalance between hippocampal and mPFC regulation in favor of amygdala function overdrive, and supports a novel approach for traumatic memory processing in PTSD.

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Date Created
  • 2013

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Dose and delivery method impact cognitive outcome of Ethinyl Estradiol administration in the surgically menopausal rat

Description

Ethinyl estradiol, (EE) a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives (Shively, C., 1998), and is found in at least 30 different

Ethinyl estradiol, (EE) a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives (Shively, C., 1998), and is found in at least 30 different contraceptive formulations currently prescribed to women (Curtis et al., 2005). EE is also used in hormone therapies prescribed to menopausal women, such as FemhrtTM (Simon et al., 2003). Thus, EE is prescribed clinically to women at ages ranging from puberty through reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young, female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection. For these studies, the low and medium doses correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to the range of doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. For each study, cognition was evaluated with a battery of maze tasks tapping several domains of spatial learning and memory. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; this was seen for both cyclic and tonic regimens. Cyclic and tonic delivery of low EE, a dose that corresponds to doses used in the clinic today, resulted in transient and null impairments, respectively, on cognition.

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Date Created
  • 2012

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Hippocampal BDNF mediates recovery from chronic stress-induced spatial reference memory deficits

Description

Chronic restraint stress impairs hippocampal-mediated spatial learning and memory, which improves following a post-stress recovery period. Here, we investigated whether brain derived neurotrophic factor (BDNF), a protein important for hippocampal

Chronic restraint stress impairs hippocampal-mediated spatial learning and memory, which improves following a post-stress recovery period. Here, we investigated whether brain derived neurotrophic factor (BDNF), a protein important for hippocampal function, would alter the recovery from chronic stress-induced spatial memory deficits. Adult male Sprague-Dawley rats were infused into the hippocampus with adeno- associated viral vectors containing the coding sequence for short interfering (si)RNA directed against BDNF or a scrambled sequence (Scr), with both containing the coding information for green fluorescent protein to aid in anatomical localization. Rats were then chronically restrained (wire mesh, 6h/d/21d) and assessed for spatial learning and memory using a radial arm water maze (RAWM) either immediately after stressor cessation (Str-Imm) or following a 21-day post-stress recovery period (Str-Rec). All groups learned the RAWM task similarly, but differed on the memory retention trial. Rats in the Str-Imm group, regardless of viral vector contents, committed more errors in the spatial reference memory domain than did non-stressed controls. Importantly, the typical improvement in spatial memory following recovery from chronic stress was blocked with the siRNA against BDNF, as Str-Rec-siRNA performed worse on the RAWM compared to the non-stressed controls or Str-Rec-Scr. These effects were specific for the reference memory domain as repeated entry errors that reflect spatial working memory were unaffected by stress condition or viral vector contents. These results demonstrate that hippocampal BDNF is necessary for the recovery from stress-induced hippocampal dependent spatial memory deficits in the reference memory domain.

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Date Created
  • 2013

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Diffuse Brain Injury Incites Sexual Differences and Hypothalamic-Pituitary-Adrenal Axis Disruptions

Description

Of the 2.87 million traumatic brain injuries (TBI) sustained yearly in the United States, 75% are diffuse injuries. A single TBI can have acute and chronic influences on the neuroendocrine

Of the 2.87 million traumatic brain injuries (TBI) sustained yearly in the United States, 75% are diffuse injuries. A single TBI can have acute and chronic influences on the neuroendocrine system leading to hypothalamic-pituitary-adrenal axis (HPA) dysregulation and increased affective disorders. Preliminary data indicate TBI causes neuroinflammation in the hippocampus, likely due to axonal damage, and in the paraventricular nucleus of the hypothalamus (PVN), where no axonal damage is apparent. Mechanisms regulating neuroinflammation in the PVN are unknown. Furthermore, chronic stress causes HPA dysregulation and glucocorticoid receptor (GR)-mediated neuroinflammation in the PVN. The goal of this project was to evaluate neuroinflammation in the HPA axis and determine if GR levels change at 7 days post-injury (DPI).

Adult male and female Sprague Dawley rats were subjected to midline fluid percussion injury. At 7 DPI, half of each brain was post-fixed for immunohistochemistry (IBA-1) and half biopsied for gene/protein analysis. IBA-1 staining was analyzed for microglia activation via skeleton analysis in the hypothalamus and hippocampus. Extracted RNA and protein were used to quantify mRNA expression and protein levels for GRs. Data indicate increased microglia cell number and decreased endpoints/cell and process length in the PVN of males, but not females. In the dentate gyrus, both males and females have an increased microglia cell number after TBI, but there is also an interaction between sex and injury in microglia presentation, where males exhibit a more robust effect than females. Both sexes have significant decreases of endpoints/cell and process length. In both regions, GR protein levels decreased for injured males, but in the hippocampus, GR levels increased for injured females. Data indicate that diffuse TBI causes alterations in microglia morphology and GR levels in the hypothalamus and hippocampus at 7 DPI, providing a potential mechanism for HPA axis dysregulation at a sub-acute time point.

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Date Created
  • 2019

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Epigenetic Dysregulation in the Basocortical Cholinergic Projection System During the Progression of Alzheimer's Disease

Description

Alzheimer’s disease (AD) is characterized by the degeneration of cholinergic basal forebrain (CBF) neurons in the nucleus basalis of Meynert (nbM), which provides the majority of cholinergic input to the

Alzheimer’s disease (AD) is characterized by the degeneration of cholinergic basal forebrain (CBF) neurons in the nucleus basalis of Meynert (nbM), which provides the majority of cholinergic input to the cortical mantle and together form the basocortical cholinergic system. Histone deacetylase (HDAC) dysregulation in the temporal lobe has been associated with neuronal degeneration during AD progression. However, whether HDAC alterations play a role in cortical and cortically-projecting cholinergic nbM neuronal degeneration during AD onset is unknown. In an effort to characterize alterations in the basocortical epigenome semi-quantitative western blotting and immunohistochemistry were utilized to evaluate HDAC and sirtuin (SIRT) levels in individuals that died with a premortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD (mAD), or severe AD (sAD). In the frontal cortex, immunoblots revealed significant increases in HDAC1 and HDAC3 in MCI and mAD, followed by a decrease in sAD. Cortical HDAC2 levels remained stable across clinical groups. HDAC4 was significantly increased in prodromal and mild AD compared to aged cognitively normal controls. HDAC6 significantly increased during disease progression, while SIRT1 decreased in MCI, mAD, and sAD compared to controls. Basal forebrain levels of HDAC1, 3, 4, 6 and SIRT1 were stable across disease progression, while HDAC2 levels were significantly decreased in sAD. Quantitative immunohistochemistry was used to identify HDAC2 protein levels in individual cholinergic nbM nuclei immunoreactive for the early phosphorylated tau marker AT8, the late-stage apoptotic tau marker TauC3, and Thioflavin-S, a marker of mature neurofibrillary tangles (NFTs). HDAC2 nuclear immunoreactivity was reduced in individual cholinergic nbM neurons across disease stages, and was exacerbated in tangle-bearing cholinergic nbM neurons. HDAC2 nuclear reactivity correlated with multiple cognitive domains and with NFT formation. These findings identify global HDAC and SIRT alterations in the cortex while HDAC2 dysregulation contributes to cholinergic nbM neuronal dysfunction and NFT pathology during the progression of AD.

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Date Created
  • 2018

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Glutamatergic and neuroimmune mechanisms of N-acetylcysteine-mediated inhibition of cue-induced nicotine seeking

Description

Nicotine self-administration is associated with decreased expression of the glial glutamate transporter 1 (GLT-1) and the cystine-glutamate exchange protein xCT in the nucleus accumbens core (NAcore). N-acetylcysteine (NAC), which is

Nicotine self-administration is associated with decreased expression of the glial glutamate transporter 1 (GLT-1) and the cystine-glutamate exchange protein xCT in the nucleus accumbens core (NAcore). N-acetylcysteine (NAC), which is an antioxidant, anti-inflammatory, and glutamatergic agent, restores these proteins associated with increased relapse vulnerability. However, the specific molecular mechanisms driving NAC inhibitory effects on cue-induced nicotine reinstatement are unknown. Thus, the present study assessed NAC’s effects on cue-induced nicotine reinstatement are dependent on NAcore GLT-1 expression. Here, rats were treated with NAC in combination with intra-NAcore vivo-morpholinos to examine the role of GLT-1 in NAC-mediated inhibition of cue-induced nicotine seeking. Subchronic NAC treatment attenuated cue-induced nicotine seeking in male rats and an antisense vivo-morpholino (AS) designed to selectively suppress GLT-1 expression in the NAcore blocked this effect. NAC treatment was also associated with an inhibition of pro-inflammatory tumor necrosis factor alpha (TNFα) expression in the NAcore. As well, GLT-1 AS markedly increased expression of CD40, a known marker of pro-inflammatory M1 activation of microglia and macrophages. To further examine whether NAC-induced decreases in nicotine seeking involve suppression of TNFα, we manipulated a downstream mediator of this pathway, nuclear factor kappa B (NF-kB). Considering the putative role of NF-κB in learning, memory, and synaptic plasticity, separate experiments were performed where rats were treated with herpes simplex virus (HSV) vectors designed to increase (HSV-IKKca) or decrease (HSV-IKKdn) NF-κB signaling through interactions with IκB Kinase (IKK). The goal was to examine the role of NF-κB signaling in mediating nicotine seeking behavior and if NF-κB signaling regulates GLT-1 expression. HSV-IKKdn alone and in combination with NAC inhibited cue-induced nicotine reinstatement, while HSV-IKKca blocked the attenuating effect of NAC on reinstatement. Interestingly, both HSV-IKKdn and HSV-IKKca, regardless of NAC treatment, inhibited GLT-1 expression. Taken together, these results suggest that while GLT-1 may be a conserved neurobiological substrate underlying relapse vulnerability across drugs of abuse, immunomodulatory mechanisms may regulate drug-induced alterations in glutamatergic plasticity that mediate cue-induced drug-seeking behavior through GLT-1-independent mechanisms.

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Date Created
  • 2019