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remote memory [keywords]
- Early Exposure to Volatile Anesthetics Impairs Long-Term Associative Learning and Recognition Memory. [JOURNAL ARTICLE]
- PLoS One 2014; 9(8):e105340.
Anesthetic exposure early in life affects neural development and long-term cognitive function, but our understanding of the types of memory that are altered is incomplete. Specific cognitive tests in rodents that isolate different memory processes provide a useful approach for gaining insight into this issue.Postnatal day 7 (P7) rats were exposed to either desflurane or isoflurane at 1 Minimum Alveolar Concentration for 4 h. Acute neuronal death was assessed 12 h later in the thalamus, CA1-3 regions of hippocampus, and dentate gyrus. In separate behavioral experiments, beginning at P48, subjects were evaluated in a series of object recognition tests relying on associative learning, as well as social recognition.Exposure to either anesthetic led to a significant increase in neuroapoptosis in each brain region. The extent of neuronal death did not differ between groups. Subjects were unaffected in simple tasks of novel object and object-location recognition. However, anesthetized animals from both groups were impaired in allocentric object-location memory and a more complex task requiring subjects to associate an object with its location and contextual setting. Isoflurane exposure led to additional impairment in object-context association and social memory.Isoflurane and desflurane exposure during development result in deficits in tasks relying on associative learning and recognition memory. Isoflurane may potentially cause worse impairment than desflurane.
- Immune checkpoint blockade for glioblastoma: preclinical activity of single agent and combinatorial therapy. [Journal Article]
- Neuro Oncol 2014 Jul.:iii11-iii12.
Outcome for glioblastoma (GBM) remains dismal and innovative treatment strategies are desperately needed. Growing data support the contribution of local and systemic immune checkpoint molecules to regulating immunosuppression by GBM tumors.Luciferized GL261 cells (GL261-Luc) were stereotactically implanted intracranially in albino C57BL/6 mice. Cohorts of mice with growing tumors (increasing bioluminescence) were treated with murine monoclonal antibodies (MAb) against PD-L1, PD-L2, CTLA-4 and combinations thereof every 3 days X 8 doses beginning 6 days following tumor implantation. Treated mice and appropriate controls were followed for overall survival and subsets of mice underwent magnetic resonance imaging (MRI) as well as analysis of tumor infiltrating immune cells, and evaluation of systemic immune cells and immunocytokines. Tumor re-challenge experiments were performed among long-term surviving treated mice.Improved survival was noted among mice treated with immune checkpoint blockade compared to appropriate controls. The most robust survival benefit was noted among mice treated with combinatorial therapy. MRI imaging among long-term surviving animals demonstrated clear evidence of initial tumor growth followed by regression and eradication of tumors. Long-term surviving mice appeared fully intact neurologically and exhibited no evidence of tumor growth following re-challenge of GL261-Luc cells injected subcutaneously. Characterization of tumor infiltrating immune cells as well as systemic immune cells and immunocytokines is ongoing.Immune checkpoint blockade provides significant survival benefit and appears safe in this immunocompetent, orthotopic GBM model. Re-challenge experiments demonstrate evidence of long-term immunologic memory and further elucidation of underlying mechanisms of immune-mediated anti-tumor activity is ongoing. These data strongly support the evaluation of immune checkpoint inhibitors among patients with GBM.Preclinical Experimental Therapeutics.
- CX3CL1 is up-regulated in the rat hippocampus during memory-associated synaptic plasticity. [JOURNAL ARTICLE]
- Front Cell Neurosci 2014.:233.
Several cytokines and chemokines are now known to play normal physiological roles in the brain where they act as key regulators of communication between neurons, glia, and microglia. In particular, cytokines and chemokines can affect cardinal cellular and molecular processes of hippocampal-dependent long-term memory consolidation including synaptic plasticity, synaptic scaling and neurogenesis. The chemokine, CX3CL1 (fractalkine), has been shown to modulate synaptic transmission and long-term potentiation (LTP) in the CA1 pyramidal cell layer of the hippocampus. Here, we confirm widespread expression of CX3CL1 on mature neurons in the adult rat hippocampus. We report an up-regulation in CX3CL1 protein expression in the CA1, CA3 and dentate gyrus (DG) of the rat hippocampus 2 h after spatial learning in the water maze task. Moreover, the same temporal increase in CX3CL1 was evident following LTP-inducing theta-burst stimulation in the DG. At physiologically relevant concentrations, CX3CL1 inhibited LTP maintenance in the DG. This attenuation in dentate LTP was lost in the presence of GABAA receptor/chloride channel antagonism. CX3CL1 also had opposing actions on glutamate-mediated rise in intracellular calcium in hippocampal organotypic slice cultures in the presence and absence of GABAA receptor/chloride channel blockade. Using primary dissociated hippocampal cultures, we established that CX3CL1 reduces glutamate-mediated intracellular calcium rises in both neurons and glia in a dose dependent manner. In conclusion, CX3CL1 is up-regulated in the hippocampus during a brief temporal window following spatial learning the purpose of which may be to regulate glutamate-mediated neurotransmission tone. Our data supports a possible role for this chemokine in the protective plasticity process of synaptic scaling.
- Short- and long-term treatment with modafinil differentially affects adult hippocampal neurogenesis. [JOURNAL ARTICLE]
- Neuroscience 2014 Aug 23.
The generation of new neurons in the dentate gyrus of the adult brain has been demonstrated in many species including humans and is suggested to have functional relevance for learning and memory. The wake promoting drug modafinil has popularly been categorized as a so-called neuroenhancer due to its positive effects on cognition. We here show that short- and long-term treatment with modafinil differentially effects hippocampal neurogenesis. We used different thymidin analogues (BdU, CldU, IdU) and labeling protocols to investigate distinct regulative events during hippocampal neurogenesis, namely cell proliferation and survival. Eight weeks old mice that were treated with modafinil (64mg/kg, i.p.) every 24 hours for four days show increased proliferation in the dentate gyrus indicated by BrdU-labeling and more newborn granule cells three weeks after treatment. Short-term treatment for four days also enhanced the number of postmitotic calretinin-expressing progenitor cells that were labeled with BrdU one week prior to treatment indicating an increased survival of new born immature granule cells. Interestingly, long-term treatment for 14 days resulted in an increased number of newborn Prox1(+) granule cells, but we could not detect an additive effect of the prolonged treatment on proliferation and survival of newborn cells. Moreover, daily administration for 14 days did not influence the number of proliferating cells in the dentate gyrus. Together, modafinil has an acute impact on precursor cell proliferation as well as survival but looses this ability during longer treatment durations.
- Early deprivation reduced anxiety and enhanced memory in adult male rats. [JOURNAL ARTICLE]
- Brain Res Bull 2014 Aug 22.
The effects of early deprivation (ED, which involves both dam and littermate deprivation) on anxiety and memory are less investigated in comparison with maternal separation (MS), and it is not yet clear how ED affects long-term potentiation (LTP) in the hippocampal Schaffer collateral pathway. By using a series of behavioral tests, enzyme-linked immunosorbent assay and field potential recording, we explored the effect of pre-weaning daily 3-h ED on anxiety, memory and potential mechanisms in adult male rats. Compared with control, ED rats spent longer time in open arms of elevated plus maze and in light compartment of light-dark transition box. Consistently, stress-induced blood plasma corticosterone level was also lower in ED rats. Moreover, ED rats showed better performance in social recognition and Morris water maze test. In accordance with results in memory tests, the threshold of LTP induction in hippocampal CA3-CA1 pathway of ED rats was also reduced. Our results indicate ED reduced anxiety, but enhanced social recognition and spatial reference memory. We suggest the diminished hypothalamic-pituitary-adrenal axis response and facilitated hippocampal LTP may contribute to the anxiety-reducing and memory-enhancing effects of ED, respectively.
- Correlation between Orphan Nuclear Receptor Nurr1 expression and Amyloid deposition in 5XFAD mice, an animal model of Alzheimer's disease. [JOURNAL ARTICLE]
- J Neurochem 2014 Aug 25.
The functional roles of the orphan nuclear receptor, Nurr1, have been extensively studied and well established in the development and survival of midbrain dopamine neurons. Since Nurr1 and other NR4A members are widely expressed in the brain in overlapping and distinct manners, it has been an open question whether Nurr1 has important function(s) in other brain areas. Recent studies suggest that up-regulation of Nurr1 expression is critical for cognitive functions and/or long-term memory in forebrain areas including hippocampal formation. Questions remain about the association between Nurr1 expression and Alzheimer's disease (AD) brain pathology. Here, using our newly developed Nurr1-selective antibody, we report that Nurr1 protein is prominently expressed in brain areas with Aβ accumulation, i.e., the subiculum and the frontal cortex, in the 5XFAD mouse and that Nurr1 is highly co-expressed with Aβ at early stages. Furthermore, the number of Nurr1-expressing cells significantly declines in the 5XFAD mouse in an age-dependent manner, accompanied by increased plaque deposition. Thus, our findings suggest that altered expression of Nurr1 is associated with AD progression. This article is protected by copyright. All rights reserved.
- Long-Term Blood Pressure Variability Throughout Young Adulthood and Cognitive Function in Midlife: The Coronary Artery Risk Development in Young Adults (CARDIA) Study. [JOURNAL ARTICLE]
- Hypertension 2014 Aug 25.
Whether long-term blood pressure (BP) variability throughout young adulthood is associated with cognitive function in midlife remains uncertain. Using data from the Coronary Artery Risk Development in Young Adults (CARDIA), which recruited healthy young adults aged 18 to 30 years (mean age, 25 years) at baseline (Y0), we assessed BP variability by SD and average real variability (ARV) for 25 years (8 visits). Cognitive function was assessed with the Digit Symbol Substitution Test (psychomotor speed test), the Rey Auditory Verbal Learning Test (verbal memory test), and the modified Stroop test (executive function test) at follow-up (Y25). At the Y25 examination, participants (n=2326) had a mean age of 50.4 years, 43% were men, and 40% were black. In multivariable-adjusted linear regression models, higher ARVSBP, ARVDBP, and SDDBP were significantly associated with lower scores of Digit Symbol Substitution Test (β [SE]: -0.025 [0.006], -0.029 [0.007], and -0.029 [0.007], respectively; all P<0.001) and Rey Auditory Verbal Learning Test (β [SE]: -0.016 [0.006], -0.021 [0.007], and -0.019 [0.007], respectively; all P<0.05) after adjustment for demographic and clinical characteristics and with cumulative exposure to BP through Y0 to Y25. Neither SDBP nor ARVBP was associated with the Stroop score. The associations between ARVBP or SDBP and each cognitive function test were similar between blacks and whites except for 1 significant interaction between race and SDSBP on the Digit Symbol Substitution Test (P<0.05). Long-term BP variability for 25 years beginning in young adulthood was associated with worse psychomotor speed and verbal memory tests in midlife, independent of cumulative exposure to BP during follow-up.
- Ethanol inhibits LTP in hippocampal CA1 neurons, irrespective of lamina and stimulus strength, through neurosteroidogenesis. [JOURNAL ARTICLE]
- Hippocampus 2014 Aug 25.
Ethanol inhibits memory encoding and the induction of long-term potentiation (LTP) in CA1 neurons of the hippocampus. Hippocampal LTP at Schaffer collateral synapses onto CA1 pyramidal neurons has been widely studied as a cellular model of learning and memory, but there is striking heterogeneity in the underlying molecular mechanisms in distinct regions and in response to distinct stimuli. Basal and apical dendrites differ in terms of innervation, input specificity, and molecular mechanisms of LTP induction and maintenance, and different stimuli determine distinct molecular pathways of potentiation. However, lamina or stimulus dependent effects of ethanol on LTP have not been investigated. Here, we tested the effect of acute application of 60 mM ethanol on LTP induction in distinct dendritic compartments (apical versus basal) of CA1 neurons, and in response to distinct stimulation paradigms (single versus repeated, spaced high frequency stimulation). We found that ethanol completely blocks LTP in apical dendrites, whereas it reduces the magnitude of LTP in basal dendrites. Acute ethanol treatment for just 15 minutes altered pre- and post-synaptic protein expression. Interestingly, ethanol increases the neurosteroid allopregnanolone, which causes ethanol-dependent inhibition of LTP, more prominently in apical dendrites, where ethanol has greater effects on LTP. This suggests that ethanol has general effects on fundamental properties of synaptic plasticity, but the magnitude of its effect on LTP differs depending on hippocampal sub-region and stimulus strength. © 2014 Wiley Periodicals, Inc.
- [The effect of fluoxetine and tianeptine on emotional and eating disorders in postmenopausal women]. [English Abstract, Journal Article]
- Pol Merkur Lekarski 2014 Jul; 37(217):35-8.
In postmenopausal period, there occur a variety of psychosomatic symptoms in a female organism, which include deterioration of mood, anxiety, fear, sleep disorders, excessive irritability, impaired concentration and memory, overt depression with psychomotor retardation, decreased interest and life activity, decreased or increased appetite. Fluoxetine -selective serotonin reuptake inhibitor (SSRI) is used in the treatment of obesity and depression. Tianeptine--selective serotonin reuptake enhancer (SSRE) is used in the treatment of depressive episodes. Metabolic effects of prolonged tianeptine use are not well known. The aim of the study was the evaluation of the effect of long-term use of fluoxetine and tianeptine on emotional state and eating disorders in postmenopausal women.The study was conducted in two groups of 30 postmenopausal women each, aged 52-66 years. The patients took fluoxetine for 6 months at a dose of 1 x 20 mg in the morning (group I) or tianeptine at a dose of 3 x 12.5 mg/daily (group II). Follow-up visits were conducted at 2, 4, 8, 12, 16 and 20 weeks. At week 24, extended tests were performed, including the assessment of the level of anxiety (Hamilton Anxiety Rating Scale-HARS) and depression (Beck Depression Inventory-BDI), the body mass index (BMI) and the waist/ hip ratio (WHR), which were compared with the corresponding results prior to the treatment with fluoxetine and tianeptine.After 6 months, in the group receiving fluoxetine, the reduction of the level of anxiety was obtained from 22.92 +/- 4.08 points to 12.36 +/- 2.43 points (p < 0.001) and a decrease in depression symptoms from 19.28 +/- 2.53 points to 10, 44 +/- 2.02 points (p < 0.001), but no reduction in body mass index was obtained -respectively 29.4 +/- 3.54 and 29.7 +/- 3.26 (p > 0.05) nor in the waist/ hip ratio--respectively 0.886 +/- 0.03 and 0.879 +/- 0.03 (p > 0.05). After 6 months, in the group receiving tianeptine, the reduction of the level of anxiety was achieved from 22.00 +/- 3.35 points to 15.20 +/- 3.42 points (p < 0.001) and a decrease in depression symptoms from 18.80 +/- 2.45 points to 14,16 +/- 4.06 points (p < 0.001), whereas no reduction in body mass index was obtained- respectively 27.7 +/- 2.81 and 27.4 +/- 2.65 (p > 0.05), even though slightly reduced waist/ hip ratio--from 0.877 +/- 0.03 to 0.863 +/- 0.03 (p < 0.05) was observed. Fluoxetine was more effective than tianeptine in the reduction of the level of anxiety (chi2 = 17.459, p < 0.01) as well as the reduction in the symptoms of depression (chi2 = 17.469, p < 0.01).Both tianeptine and fluoxetine are effective in the treatment of emotional disturbances in postmenopausal women. Both drugs may decrease appetite but long-term treatment does not alter body weight to the desired extent and they do not match the standards as monotherapy for obesity.
- Long-term memory, forgetting, and deferred imitation in 12-month-old infants. [JOURNAL ARTICLE]
- Dev Sci 1999 Mar; 2(1):102-113.
Long-term recall memory, as indexed by deferred imitation, was assessed in 12-month-old infants. Independent groups of infants were tested after retention intervals of 3 min, 1 week and 4 weeks. Deferred imitation was assessed using the 'observation-only' procedure in which infants were not allowed motor practice on the tasks before the delay was imposed. Thus, the memory could not have been based on re-accessing a motor habit, because none was formed in the first place. After the delay, memory was assessed either in the same or a different environmental context from the one in which the adult had originally demonstrated the acts. In Experiments 1 and 3, infants observed the target acts while in an unusual environment (an orange and white polka-dot tent), and recall memory was tested in an ordinary room. In Experiment 2, infants observed the target acts in their homes and were tested for memory in a university room. The results showed recall memory after all retention intervals, including the 4 week delay, with no effect of context change. Interestingly, the forgetting function showed that the bulk of the forgetting occurred during the first week. The findings of recall memory without motor practice support the view that infants as young as 12 months old use a declarative (nonprocedural) memory system to span delay intervals as long as 4 weeks.