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Open Access Publications from the University of California

Scholarly Works (9 results)

  • Article
  • Peer Reviewed
UC Irvine Previously Published Works (2015)
No studies to date have examined whether immediate-early gene (IEG) activation is driven by context memory recall. To address this question, we utilized the context preexposure facilitation effect (CPFE) paradigm. In CPFE, animals acquire contextual fear conditioning through hippocampus-dependent rapid retrieval of a previously formed contextual representation. Despite differences in behavior, we did not find any difference in CA1 or CA3 IEG activity associated with this rapid recall phase when comparing context preexposed and non-pre-exposed groups. These findings indicate that IEG activation in CA1 and CA3 is not an accurate readout of the neural activity associated with hippocampus-dependent rapid memory retrieval.
    Cover page: Immediate-early gene transcriptional activation in hippocampus CA1 and CA3 does not accurately reflect rapid, pattern completion-based retrieval of context memoryCreative Commons 'BY-NC' version 4.0 license
    • Article
    • Peer Reviewed
    UC Irvine Previously Published Works (2014)
    Although it is known that immune system activation can impair cognition, no study to date has linked cognitive deficits during acute neuroinflammation to dysregulation of task-relevant neuronal ensemble activity. Here, we assessed both neural circuit activity and context discrimination memory retrieval, in a within-subjects design, of male rats given systemic administration of saline or lipopolysaccharide (LPS). Rats were exposed over several days to two similar contexts: one of which was paired with weak foot shock and the other was not. After reaching criteria for discriminative freezing, rats were given systemic LPS or saline injection and tested for retrieval of context discrimination 6 h later. Importantly, LPS administration produced an acute neuroinflammatory response in dorsal hippocampus at this time (as assessed by elevation of proinflammatory cytokine mRNA levels) and abolished retrieval of the previously acquired discrimination. The impact of neuroinflammation on hippocampal CA3 and CA1 neural circuit activity was assessed using the Arc/Homer1a cellular analysis of temporal activity by fluorescence in situ hybridization imaging method. Whereas the saline-treated subjects discriminated and had low overlap of hippocampal ensembles activated in the two contexts, LPS-treated subjects did not discriminate and had greater ensemble overlap (i.e., reduced orthogonalization). Additionally, retrieval of standard contextual fear conditioning, which does not require context discrimination, was not affected by pretesting LPS administration. Together, the behavioral and circuit analyses data provide compelling evidence that LPS administration impairs context discrimination memory by disrupting cellular pattern separation processes within the hippocampus, thus linking acute neuroinflammation to disruption of specific neural circuit functions and cognitive impairment.
      Cover page: Acute Neuroinflammation Impairs Context Discrimination Memory and Disrupts Pattern Separation Processes in HippocampusCreative Commons 'BY-NC-SA' version 4.0 license
      • Thesis
      • Peer Reviewed
      UC Irvine Electronic Theses and Dissertations (2018)

      It is increasingly recognized that the immune system can exert profound effects on the central nervous system. Past research has shown that peripheral immune activation has the capability of affecting cognition, including memory function. While there has been much research on how immune stimulation can affect neuronal function or behavioral performance in memory tasks, there is a lack of research linking molecular alterations to behavioral impairment. This dissertation examines effects of acute immune challenge on hippocampus-dependent memory with a systematic approach that links molecular mechanisms, neural circuit activity, and behavior within a consistent experimental model. For all experiments, subjects received a systemic injection of lipopolysaccharide (LPS) that served as a mild immune challenge that reliably induced a proinflammatory tone within the brain. Afterward, subjects were tested for context discrimination memory followed by analysis of circuit activity patterns and/or neural gene expression in dorsal hippocampus. Chapter 2 asks whether pharmacological attenuation of neuroimmune activation prevents impairments of contextual memory and circuit activity that had been previously observed during acute neuroinflammation. Blocking neuroimmune activation successfully prevented LPS-induced impairments in memory and circuit activity, and the extent of circuit activity disruption was associated with behavior of a given subject. In Chapter 3, gene expression was analyzed for the same subjects employed in Chapter 2. Using statistical modeling, differential gene expression was linked to circuit activity patterns and memory performance in order to build an overarching experimental model of neuroimmune modulation of memory function. Furthermore, specific genes with potential roles in neuroimmune-mediated impairment were identified. The study detailed in Chapter 4 asked whether environmental enrichment, a behavioral intervention providing enhanced physical, cognitive, and social stimulation, is able to protect memory impairment during neuroinflammation. Unlike the pharmacological intervention used in Chapter 2, this study did not find robust protective effects associated with environmental enrichment, but ways in which the experiment could be improved are discussed. Collectively, the experiments contained within Chapters 2-4 contribute knowledge on fundamental interactions between an activated immune system and memory processes. Future study is needed for translation of findings into therapeutic advances for people suffering from cognitive symptoms during proinflammatory disease.

        Cover page: Neuroimmune Modulation of Memory: From Genes and Neural Circuit Activity to Behavior
        • Article
        • Peer Reviewed
        UC Irvine Previously Published Works (2015)
        Neuroinflammation is implicated in impairments in neuronal function and cognition that arise with aging, trauma, and/or disease. Therefore, understanding the underlying basis of the effect of immune system activation on neural function could lead to therapies for treating cognitive decline. Although neuroinflammation is widely thought to preferentially impair hippocampus-dependent memory, data on the effects of cytokines on cognition are mixed. One possible explanation for these inconsistent results is that cytokines may disrupt specific neural processes underlying some forms of memory but not others. In an earlier study, we tested the effect of systemic administration of bacterial lipopolysaccharide (LPS) on retrieval of hippocampus-dependent context memory and neural circuit function in CA3 and CA1 (Czerniawski and Guzowski, 2014). Paralleling impairment in context discrimination memory, we observed changes in neural circuit function consistent with disrupted pattern separation function. In the current study we tested the hypothesis that acute neuroinflammation selectively disrupts memory retrieval in tasks requiring hippocampal pattern separation processes. Male Sprague-Dawley rats given LPS systemically prior to testing exhibited intact performance in tasks that do not require hippocampal pattern separation processes: novel object recognition and spatial memory in the water maze. By contrast, memory retrieval in a task thought to require hippocampal pattern separation, context-object discrimination, was strongly impaired in LPS-treated rats in the absence of any gross effects on exploratory activity or motivation. These data show that LPS administration does not impair memory retrieval in all hippocampus-dependent tasks, and support the hypothesis that acute neuroinflammation impairs context discrimination memory via disruption of pattern separation processes in hippocampus.
          Cover page: Systemic lipopolysaccharide administration impairs retrieval of context–object discrimination, but not spatial, memory: Evidence for selective disruption of specific hippocampus-dependent memory functions during acute neuroinflammation
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2017)
            Cover page: NTOX-04. INVESTIGATION OF N-ACETYLCYSTEINE FOR THE PREVENTION OF CISPLATIN CHEMOTHERAPY-RELATED COGNITIVE IMPAIRMENTS
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2014)
            The association of environmental cues with drugs of abuse results in persistent drug-cue memories. These memories contribute significantly to relapse among addicts. While conditioned place preference (CPP) is a well-established paradigm frequently used to examine the modulation of drug-cue memories, very few studies have used the non-preference-based model conditioned activity (CA) for this purpose. Here, we used both experimental approaches to investigate the neural substrates of cocaine-cue memories. First, we directly compared, in a consistent setting, the involvement of cortical and subcortical brain regions in cocaine-cue memory retrieval by quantifying activity-regulated cytoskeletal-associated (Arc) protein expression in both the CPP and CA models. Second, because NMDA receptor activation is required for Arc expression, we investigated the NMDA receptor dependency of memory persistence using the CA model. In both the CPP and CA models, drug-paired animals showed significant increases in Arc immunoreactivity in regions of the frontal cortex and amygdala compared to unpaired controls. Additionally, administration of a NMDA receptor antagonist (MK-801 or memantine) immediately after cocaine-CA memory reactivation impaired the subsequent conditioned locomotion associated with the cocaine-paired environment. The enhanced Arc expression evident in a subset of corticolimbic regions after retrieval of a cocaine-context memory, observed in both the CPP and CA paradigms, likely signifies that these regions: (i) are activated during retrieval of these memories irrespective of preference-based decisions, and (ii) undergo neuroplasticity in order to update information about cues previously associated with cocaine. This study also establishes the involvement of NMDA receptors in maintaining memories established using the CA model, a characteristic previously demonstrated using CPP. Overall, these results demonstrate the utility of the CA model for studies of cocaine-context memory and suggest the involvement of an NMDA receptor-dependent Arc induction pathway in drug-cue memory interference.
              Cover page: Retrieval-induced NMDA receptor-dependent Arc expression in two models of cocaine-cue memory
              • Article
              • Peer Reviewed
              UC Irvine Previously Published Works (2017)
              Abstract

              OBJECTIVES

              Chemotherapy-related cognitive impairment (CRCI) is a major clinical problem, which diminishes the quality of life of cancer survivors. We focus on the neurocognitive impairments provoked by cisplatin, a chemotherapy agent widely used as treatment for various malignancies including ovarian, testicular, head and neck cancers, and pediatric brain tumors. More than 30% of advanced ovarian cancer patients develop CRCI during and after cisplatin-based chemotherapy. We examined mitochondrial dysfunction as a mechanism underlying cisplatin CRCI, and the ability of the antioxidant N-acetylcysteine to mitigate these toxicities in a rat model, and in-vitro in cultured rat hippocampal neurons and neural stem/progenitor cells (NSC).

              METHODS

              We examined the effects of cisplatin on neuronal morphology, apoptosis, and cognition in rats. We assessed the effects of cisplatin on mitochondrial respiratory function, reactive-oxygen species (ROS) production, caspase-9 activation, and glutathione levels in-vitro.

              RESULTS

              Cisplatin reduced neuronal dendritic branching and spine density and induced apoptotic cell death in the rat hippocampus. Chronic cisplatin treatment impaired cognitive function; this impairment was mitigated by N-acetylcysteine administration. In-vitro, cisplatin damaged mitochondrial DNA, impaired respiratory activity, elevated ROS levels, and depleted glutathione. N-acetylcysteine mitigated cisplatin-induced neural ROS levels and glutathione depletion, apoptotic cell death, and neuronal post-synaptic density-95 puncta loss, while not interfering with cisplatin’s anti-cancer effect in two ovarian cancer cell lines when administered 10 h following cisplatin.

              DISCUSSION

              The cognitive deficits caused by cisplatin in rats result from the loss of excitatory synapses and dendritic spines that anchor them, as well as from injury to mature and developing neurons. This neuronal toxicity derives from mitochondrial damage. Importantly, treatment with N-acetylcysteine mitigates cisplatin-induced neurotoxicity and cognitive deficits. We are planning a Phase I study to examine if NAC administration to ovarian cancer patients receiving cisplatin is safe, and if it ameliorates the cognitive deficits previously described in this patient population.
                Cover page: NTOX-04. INVESTIGATION OF N-ACETYLCYSTEINE FOR THE PREVENTION OF CISPLATIN CHEMOTHERAPY-RELATED COGNITIVE IMPAIRMENTS
                • Article
                • Peer Reviewed
                UC Irvine Previously Published Works (2017)
                  Cover page: INVESTIGATION OF N-ACETYLCYSTEINE FOR THE PREVENTION OF CISPLATIN CHEMOTHERAPY-RELATED COGNITIVE IMPAIRMENTSCreative Commons 'BY' version 4.0 license
                  • Article
                  • Peer Reviewed
                  UC Irvine Previously Published Works (2017)

                  Purpose

                  Chemotherapy-related cognitive impairment (CRCI) is commonly reported following the administration of chemotherapeutic agents and comprises a wide variety of neurological problems. No effective treatments for CRCI are currently available. Here we examined the mechanisms involving cisplatin-induced hippocampal damage following cisplatin administration in a rat model and in cultured rat hippocampal neurons and neural stem/progenitor cells (NSCs). We also assessed the protective effects of the antioxidant, N-acetylcysteine in mitigating these damages.

                  Experimental design

                  Adult male rats received 6mg/kg cisplatin in the acute studies. In chronic studies, rats received 5mg/kg cisplatin or saline injections once per week for 4 weeks. N-acetylcysteine (250mg/kg/day) or saline was administered for five consecutive days during cisplatin treatment. Cognitive testing was performed 5 weeks after treatment cessation. Cisplatin-treated cultured hippocampal neurons and NSCs were examined for changes in mitochondrial function, oxidative stress production, caspase-9 activation, and neuronal dendritic spine density.

                  Results

                  Acute cisplatin treatment reduced dendritic branching and spine density, and induced mitochondrial degradation. Rats receiving the chronic cisplatin regimen showed impaired performance in contextual fear conditioning, context object discrimination, and novel object recognition tasks compared to controls. Cisplatin induced mitochondrial DNA damage, impaired respiratory activity, increased oxidative stress, and activated caspase-9 in cultured hippocampal neurons and NSCs. N-acetylcysteine treatment prevented free radical production, ameliorated apoptotic cellular death and dendritic spine loss, and partially reversed the cisplatin-induced cognitive impairments.

                  Conclusions

                  Our results suggest that mitochondrial dysfunction and increased oxidative stress are involved in cisplatin-induced cognitive impairments. Therapeutic agents, such as N-acetylcysteine, may be effective in mitigating the deleterious effects of cisplatin.
                    Cover page: Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in ratsCreative Commons 'BY' version 4.0 license
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