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remote memory [keywords]
- Developmental Neurotoxicity of Alcohol and Anesthetic Drugs Is Augmented by Co-Exposure to Caffeine. [JOURNAL ARTICLE]
- Brain Sci 2013 Jul 30; 3(3):1128-1152.
Anesthetic and anti-epileptic drugs used in pediatric and obstetric medicine and several drugs, including alcohol, that are abused by pregnant women, trigger widespread neuroapoptosis in the developing brain of several animal species, including non-human primates. Caffeine (CAF) is often administered to premature infants to stimulate respiration, and these infants are also exposed simultaneously to anesthetic drugs for procedural sedation and/or surgical procedures. Pregnant women who abuse alcohol or other apoptogenic drugs also may heavily consume CAF. We administered CAF to infant mice alone or in combination with alcohol, phencyclidine, diazepam, midazolam, ketamine, or isoflurane, which are drugs of abuse and/or drugs frequently used in pediatric medicine, and found that CAF weakly triggers neuroapoptosis by itself and markedly potentiates the neuroapoptogenic action of each of these other drugs. Exposure of infant mice to CAF + phencyclidine resulted in long-term impairment in behavioral domains relevant to attention deficit/hyperactivity disorder, whereas exposure to CAF + diazepam resulted in long-term learning/memory impairment. At doses used in these experiments, these behavioral impairments either did not occur or were substantially less pronounced in mice exposed to CAF alone or to phencyclidine or diazepam alone. CAF currently enjoys the reputation of being highly beneficial and safe for use in neonatal medicine. Our data suggest the need to consider whether CAF may have harmful as well as beneficial effects on the developing brain, and the need for research aimed at understanding the full advantage of its beneficial effects while avoiding its potentially harmful effects.
- Consequences of early postnatal benzodiazepines exposure in rats. I. Cognitive-like behavior. [Journal Article]
- Front Behav Neurosci 2014.:101.
Clinical and experimental studies suggest possible risks associated with the repeated administration of benzodiazepines (BZDs) during the prenatal or early postnatal period on further development and behavior. In the present study, we assess short- and long-term effects of early exposure to clonazepam (CZP) on cognitive tasks. CZP (0.5 or 1.0 mg/kg/day) was administered from postnatal day (P)7 until P11, and animals were exposed to the following behavioral tests at different developmental stages: (1) a homing response (HR) test, which exploits the motivation of a rat pup to reach its home nest, was administered on P12, P15, P18 and P23 rats; (2) passive avoidance was tested in three trials (at 0, 2 and 24 h intervals) on P12, P15, P18, P25 and P32 rats; (3) within- and between-session habituation was tested in an open field (OF) at P70; and (4) a long-term memory (LTM) version of the Morris water maze (MWM) was tested at P80. A 1.0 mg/kg dose of CZP extended latency in the HR and decreased the number of correct responses when tested at P12 and P23. In the first trial of the passive avoidance test, latency to enter a dark compartment was shorter in the CZP-exposed rats. Both treated and control animals older than P15 learned the passive-avoidance response at the same rate. Irrespective of the treatments, all adult animals showed within-session habituation. Between-session habituation, however, was found only in the controls. With respect to the MWM test, all animals learned to reach the platform, but animals exposed to higher doses of CZP spent more time swimming in the first acquisition test. No difference between groups was found in a repeated acquisition test (10 and 40 days after the first acquisition test). The results of the present study show that even short-term exposure to CZP alters behavioral responsiveness in pre-weaning, juvenile and adult animals. Not only were changes observed on conventional cognitive tests in our study, but the changes also seem to be related to emotional/motivational responsiveness.
- Modulating excitation through plasticity at inhibitory synapses. [REVIEW]
- Front Cell Neurosci 2014.:93.
Learning is believed to depend on lasting changes in synaptic efficacy such as long-term potentiation and long-term depression. As a result, a profusion of studies has tried to elucidate the mechanisms underlying these forms of plasticity. Traditionally, experience-dependent changes at excitatory synapses were assumed to underlie learning and memory formation. However, with the relatively more recent investigation of inhibitory transmission, it had become evident that inhibitory synapses are not only plastic, but also provide an additional way to modulate excitatory transmission and the induction of plasticity at excitatory synapses. Thanks to recent technological advances, progress has been made in understanding synaptic transmission and plasticity from particular interneuron subtypes. In this review article, we will describe various forms of synaptic plasticity that have been ascribed to two fairly well characterized populations of interneurons in the hippocampus, those expressing cholecystokinin (CCK) and parvalbumin (PV). We will discuss the resulting changes in the strength and plasticity of excitatory transmission that occur in the local circuit as a result of the modulation of inhibitory transmission. We will focus on the hippocampus because this region has a relatively well-understood circuitry, numerous forms of activity-dependent plasticity and a multitude of identified interneuron subclasses.
- Intraneuronal accumulation of Aβ42 induces age-dependent slowing of neuronal transmission in Drosophila. [Journal Article]
- Neurosci Bull 2014 Apr; 30(2):185-90.
Beta amyloid (Aβ42)-induced dysfunction and loss of synapses are believed to be major underlying mechanisms for the progressive loss of learning and memory abilities in Alzheimer's disease (AD). The vast majority of investigations on AD-related synaptic impairment focus on synaptic plasticity, especially the decline of long-term potentiation of synaptic transmission caused by extracellular Aβ42. Changes in other aspects of synaptic and neuronal functions are less studied or undiscovered. Here, we report that intraneuronal accumulation of Aβ42 induced an age-dependent slowing of neuronal transmission along pathways involving multiple synapses.
- Trib3 is developmentally and nutritionally regulated in the brain but is dispensable for spatial memory, fear conditioning and sensing of amino Acid-imbalanced diet. [Journal Article]
- PLoS One 2014; 9(4):e94691.
Tribbles homolog 3 (TRIB3) is a mammalian pseudokinase that is induced in neuronal cell cultures in response to cell death-inducing stresses, including neurotrophic factor deprivation. TRIB3 is an inhibitor of activating transcription factor 4 (ATF4), the central transcriptional regulator in the eukaryotic translation initiation factor 2α (eIF2α) phosphorylation pathway that is involved in the cellular stress response and behavioral processes. In this article, we study the expression of Trib3 in the mouse brain, characterize the brain morphology of mice with a genetic ablation of Trib3 and investigate whether Trib3 deficiency alters eIF2α-dependent cognitive abilities. Our data show that the consumption of a leucine-deficient diet induces Trib3 expression in the anterior piriform cortex, the brain region responsible for detecting essential amino acid intake imbalance. However, the aversive response to leucine-devoid diet does not differ in Trib3 knockout and wild type mice. Trib3 deletion also does not affect long-term spatial memory and reversal learning in the Morris water maze and auditory or contextual fear conditioning. During embryonic development, Trib3 expression increases in the brain and persists in the early postnatal stadium. Neuroanatomical characterization of mice lacking Trib3 revealed enlarged lateral ventricles. Thus, although the absence of Trib3 does not alter the eIF2α pathway-dependent cognitive functions of several areas of the brain, including the hippocampus, amygdala and anterior piriform cortex, Trib3 may serve a role in other central nervous system processes and molecular pathways.
- Keeping the eIF2 alpha kinase Gcn2 in check. [REVIEW]
- Biochim Biophys Acta 2014 Apr 11.
The protein kinase Gcn2 is present in virtually all eukaryotes and is of increasing interest due to its involvement in a large array of crucial biological processes. Some of these are universally conserved from yeast to humans, such as coping with nutrient starvation and oxidative stress. In mammals, Gcn2 is important for e.g. long-term memory formation, feeding behaviour and immune system regulation. Gcn2 has been also implicated in diseases such as cancer and Alzheimer's disease. Studies on Gcn2 have been conducted most extensively in Saccharomyces cerevisiae, where the mechanism of its activation by amino acid starvation has been revealed in most detail. Uncharged tRNAs stimulate Gcn2 which subsequently phosphorylates its substrate, eIF2α, leading to reduced global protein synthesis and simultaneously to increased translation of specific mRNAs, e.g. those coding for Gcn4 in yeast and ATF4 in mammals. Both proteins are transcription factors that regulate the expression of a myriad of genes, thereby enabling the cell to initiate a survival response to the initial activating cue. Given that Gcn2 participates in many diverse processes, Gcn2 itself must be tightly controlled. Indeed, Gcn2 is regulated by a vast network of proteins and RNAs, the list of which is still growing. Deciphering molecular mechanisms underlying Gcn2 regulation by effectors and inhibitors is fundamental for understanding how the cell keeps Gcn2 in check ensuring normal organismal function, and how Gcn2-associated diseases may develop or may be treated. This review provides a critical evaluation of the current knowledge on mechanisms controlling Gcn2 activation or activity.
- Long-term consequences of perinatal fatty acid amino hydrolase inhibition. [Journal Article, Research Support, N.I.H., Extramural]
- Br J Pharmacol 2014 Mar; 171(6):1420-34.
Fatty acid amide hydrolase inhibitors show promise as a treatment for anxiety, depression and pain. Here we investigated whether perinatal exposure to URB597, a fatty acid amide hydrolase inhibitor, alters brain development and affects behaviour in adult mice.Mouse dams were treated daily from gestational day 10.5 to 16.5 with 1, 3 or 10 mg kg−1 URB597. MS was used to measure a panel of endocannabinoids and related lipid compounds and brain development was assessed at embryonic day 16.5. Separate cohorts of mouse dams were treated with 10 mg kg−1 URB597, from gestational day 10.5 to postnatal day 7, and the adult offspring were assessed with a battery of behavioural tests.Perinatal URB597 exposure elevated anandamide and related N-acyl amides. URB597 did not induce signs of toxicity or affect dam weight gain, neurogenesis or axonal development at embryonic day 16.5. It did lead to subtle behavioural deficits in adult offspring, manifested by reduced cocaine-conditioned preference, increased depressive behaviours and impaired working memory. Anxiety levels, motor function and sensory-motor gating were not significantly altered.Taken together, the present results highlight how exposure to elevated levels of anandamide and related N-acyl amides during brain development can lead to subtle alterations in behaviour in adulthood.This article is part of a themed section on Cannabinoids 2013. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-6
- Spi6 protects alloreactive CD4(+) but not CD8 (+) memory T cell from granzyme B attack by double-negative T regulatory cell. [Journal Article, Research Support, Non-U.S. Gov't]
- Am J Transplant 2014 Mar; 14(3):580-93.
Memory T (Tm) cells pose a major barrier to long-term transplant survival. Whether regulatory T cells (Tregs)can control them remains poorly defined. Previously,we established that double-negative (DN) Tregs suppress effector T (Teff) cells. Here, we demonstrate that DNTregs effectively suppress CD4+/CD8+Teff and CD8+Tm but not CD4+Tm cells, whereas the suppression on CD8+Tm is abrogated by perforin (PFN) deficiency in DNTregs. Consistently, in a BALB/c to B6-Rag1-/-skin transplantation, transfer of DN Tregs suppressed the rejection mediated by CD4þ/CD8+Teff and CD8+Tmcells (76.0±4.9, 87.5±5.0 and 63.0±4.7 days, respectively)but not CD4þTmcells (25.3±1.4 days). Both CD8þ effector memory T and central memory T compartments significantly reduced after DN Treg transfer. CD4+Tm highly expresses granzyme B (GzmB) inhibitor serine protease inhibitor-6 (Spi6). Spi6 deficiency renders CD4þTm susceptible to DN Treg suppression. In addition,transfer of WT DN Tregs, but not PFN-/-DN Tregs,inhibited the skin allograft rejection mediated by Spi6-/-CD4þTm(75.5±7.9 days). In conclusion, CD4+ and CD8+Tm cells differentially respond toDNTregs’ suppression.The GzmB resistance conferred by Spi6 in CD4þTm cells might hint at the physiological significance of Tmpersistence
- Early memory formation disrupted by atypical PKC inhibitor ZIP in the medial prefrontal cortex but not hippocampus. [JOURNAL ARTICLE]
- Hippocampus 2014 Apr 11.
Atypical isoforms of protein kinase C (aPKCs; particularly protein kinase M zeta: PKMζ) have been hypothesised to be necessary and sufficient for the maintenance of long-term potentiation (LTP) and long term memory by maintaining postsynaptic AMPA receptors via the GluR2 subunit. A myristoylated PKMζ pseudosubstrate peptide (ZIP) blocks PKMζ activity. We examined the actions of ZIP in medial prefrontal cortex (mPFC) and hippocampus in associative recognition memory in rats during early memory formation and memory maintenance. ZIP infusion in either hippocampus or mPFC impaired memory maintenance. However, early memory formation was impaired by ZIP in mPFC but not hippocampus; and blocking GluR2-dependent removal of AMPA receptors did not affect this impairment caused by ZIP in the mPFC. The findings indicate: (i) a difference in the actions of ZIP in hippocampus and medial prefrontal cortex, and (ii) a GluR2-independent target of ZIP (possibly PKCλ) in the mPFC during early memory formation. © 2014 Wiley Periodicals, Inc.
- Epigenetic Signature of Chronic Cerebral Hypoperfusion and Beneficial Effects of S-adenosylmethionine in Rats. [JOURNAL ARTICLE]
- Mol Neurobiol 2014 Apr 12.
Chronic cerebral hypoperfusion is associated with cognitive decline in aging and age-related neurodegenerative disease. Epigenetic mechanisms are involved in the maintenance of long-term hypoxia-adapted cellular phenotypes. In the present study, the epigenetic signatures such as DNA methylation and histone acetylation, as well as S-adenosylmethionine (SAM) cycle using chronic cerebral hypoperfusion rat model were explored. Chronic cerebral hypoxia-induced global DNA hypermethylation associated with the increase of DNA methyltransferase (DNMT) 3A as well as alteration of SAM cycle. Meanwhile, an enhanced level of global histone H4 acetylation accompanied with the upregulation of histone acetyltransferase, p300/CREB-binding protein (CBP), and the downregulation of histone deacetylases (HDACs), was also observed. SAM could improve spatial capacity through the upregulation of acetylcholine and brain-derived neurotrophic factor (BDNF) rather than alteration of DNA methylation levels. In conclusion, we have demonstrated a genome-wide adjustment of DNA methylation and histone acetylation under chronic cerebral hypoxic conditions in a rat's brain. These epigenetic signatures may represent an additional mechanism to promote and maintain a hypoxic-adapted cellular responds with a potential role in memory deficits.