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1.  Effects of Radiation Combined Injury on Hippocampal Function are Modulated in Mice Deficient in Chemokine Receptor 2 (CCR2) 
Radiation research  2013;180(1):78-88.
Chemokines and their receptors play a crucial role in normal brain function as well as in pathological conditions such as injury and disease-associated neuroinflammation. Chemokine receptor-2 (CCR2), which mediates the recruitment of infiltrating and resident microglia to sites of central nervous system (CNS) inflammation, is upregulated by ionizing irradiation and traumatic brain injury. Our objective was to determine if a deficiency in CCR2 and subsequent effects on brain microglia affect neurogenesis and cognitive function after radiation combined injury (RCI). CCR2 knock-out (−/−) and wild-type (WT) mice received 4 Gy of whole body 137Cs irradiation. Immediately after irradiation, unilateral traumatic brain injury was induced using a controlled cortical impact system. Forty-four days postirradiation, animals were tested for hippocampus-dependent cognitive performance in the Morris water-maze. After cognitive testing, animals were euthanized and their brains snap frozen for immunohistochemical assessment of neuroinflammation (activated microglia) and neurogenesis in the hippocampal dentate gyrus. All animals were able to locate the visible and hidden platform locations in the water maze; however, treatment effects were seen when spatial memory retention was assessed in the probe trials (no platform). In WT animals that received combined injury, a significant impairment in spatial memory retention was observed in the probe trial after the first day of hidden platform training (first probe trial). This impairment was associated with increased neurogenesis in the ipsilateral hemisphere of the dentate gyrus. In contrast, CCR2−/− mice, independent of insult showed significant memory retention in the first probe trial and there were no differences in the numbers of newly born neurons in the animals receiving irradiation, trauma or combined injury. Although the mechanisms involved are not clear, our data suggests that CCR2 deficiency can exert a protective effect preventing the impairment of cognitive function after combined injury.
doi:10.1667/RR3344.1
PMCID: PMC4282166  PMID: 23772926
2.  Spatial navigation, episodic memory, episodic future thinking, and theory of mind in children with autism spectrum disorder: evidence for impairments in mental simulation? 
Frontiers in Psychology  2014;5:1411.
This study explored spatial navigation alongside several other cognitive abilities that are thought to share common underlying neurocognitive mechanisms (e.g., the capacity for self-projection, scene construction, or mental simulation), and which we hypothesized may be impaired in autism spectrum disorder (ASD). Twenty intellectually high-functioning children with ASD (with a mean age of ~8 years) were compared to 20 sex, age, IQ, and language ability matched typically developing children on a series of tasks to assess spatial navigation, episodic memory, episodic future thinking (also known as episodic foresight or prospection), theory of mind (ToM), relational memory, and central coherence. This is the first study to explore these abilities concurrently within the same sample. Spatial navigation was assessed using the “memory island” task, which involves finding objects within a realistic, computer simulated, three-dimensional environment. Episodic memory and episodic future thinking were assessed using a past and future event description task. ToM was assessed using the “animations” task, in which children were asked to describe the interactions between two animated triangles. Relational memory was assessed using a recognition task involving memory for items (line drawings), patterned backgrounds, or combinations of items and backgrounds. Central coherence was assessed by exploring differences in performance across segmented and unsegmented versions of block design. Children with ASD were found to show impairments in spatial navigation, episodic memory, episodic future thinking, and central coherence, but not ToM or relational memory. Among children with ASD, spatial navigation was found to be significantly negatively related to the number of repetitive behaviors. In other words, children who showed more repetitive behaviors showed poorer spatial navigation. The theoretical and practical implications of the results are discussed.
doi:10.3389/fpsyg.2014.01411
PMCID: PMC4256988  PMID: 25538661
autism spectrum disorder; episodic future thinking; episodic memory; mental simulation; scene construction; self-projection; spatial navigation; theory of mind
3.  Impaired memory and reduced sensitivity to the circadian period lengthening effects of methamphetamine in mice selected for high methamphetamine consumption 
Behavioural brain research  2013;256:10.1016/j.bbr.2013.08.015.
Drug abuse runs in families suggesting the involvement of genetic risk factors. Differences in addiction-related neurobiological systems, including learning and memory and circadian rhythms, may exist prior to developing addiction. We characterized the cognitive phenotypes and the free-running circadian period of mouse lines selectively bred for high methamphetamine (MA) drinking (MA high drinking or MAHDR) and low MA drinking (MA low drinking or MALDR). MA-naïve MALDR mice showed spatial memory retention while MAHDR mice did not. MA-naïve MAHDR mice had elevated hippocampal levels of the AMPA receptor subunits GluA2 (old terminology: GluR2), but not GluA1 (old terminology: GluR1). There were no line differences in the free running period (τ) when only water was available. During a 25 mg/L MA solution access period (vs water), there was an increase in τ in MALDR but not MAHDR mice, although MAHDR mice consumed significantly more MA. During a 50 mg/L MA solution access period (vs water), both lines showed an increased τ. There was a positive correlation between MA consumption and τ from baseline in MALDR, but not MAHDR, mice. Thus, a heritable proclivity for elevated MA self-administration may be associated with impairments in hippocampus-dependent memory and reduced sensitivity to effects of MA on lengthening of the circadian period.
doi:10.1016/j.bbr.2013.08.015
PMCID: PMC3815974  PMID: 23954232
circadian; water maze; methamphetamine; glutamate receptors; GluA1/2; spatial memory
4.  Executive Function and Mental Health in Adopted Children with a History of Recreational Drug Exposures 
PLoS ONE  2014;9(10):e110459.
Adoptive children are at increased risk for problematic behaviors but the origin of these individual differences in neurobehavioral function is unclear. This investigation examined whether adopted children with prenatal exposure to a wide variety of recreational drugs exhibited higher scores (i.e. more problems) with executive function and psychiatric symptomology. Caregivers of children ages 5 to 18 completed an online survey with items about use of alcohol, nicotine, or methamphetamine during pregnancy followed by the Behavior Rating Inventory of Executive Function (BRIEF, N = 437 including 59 adoptive parents) or the Child Behavior Checklist (CBCL, N = 549 including 54 adoptive parents). Relative to a comparison group of children raised by their biological parents, adoptive children that were polysubstance exposed during prenatal development exhibited higher rates of academic difficulties and were behind their classmates in math and reading. Adoptive children had statistically and clinically significant higher BRIEF ratings and this pattern was similar for boys and girls. CBCL ratings were significantly increased in adoptive children, particularly for Externalizing and Attention problems. Adoptive children with a history of polysubstance exposures including alcohol, nicotine, and methamphetamine are at heightened risk for difficulties with executive function as well as various psychopathologies. These findings suggest that increased monitoring to identify and implement remediation strategies may be warranted for adopted children with a history of in utero drug exposures.
doi:10.1371/journal.pone.0110459
PMCID: PMC4206404  PMID: 25337917
5.  Related functions of mGlu4 and mGlu8 
Metabotropic glutamate receptors modulate glutamatergic and GABAergic neurotransmission. Our previous pharmacological data indicate that metabotropic receptor 4 (mGlu4) and metabotropic receptor 8 (mGlu8) might have related and overlapping functions. We explored this by analyzing the behavioral phenotypes of mice deficient in either (mGlu4−/− or mGlu8−/−) or both receptors (mGlu4/8−/−). Our analysis focused on measures of anxiety in the open field and elevated zero maze, sensorimotor function on the rotorod, and fear conditioning, as mGlu4 and/or mGlu8 were shown to affect performance in these tests. mGlu8−/− mice weighed more than mGlu4/8−/− mice. In the open field, mGlu4−/− mice showed lower levels of anxiety than mGlu8−/− and mGlu4/8−/− mice. In the elevated zero maze, mGlu4−/− mice showed lower levels of anxiety than wild-type, mGlu8−/− and mGlu4/8−/− mice. In the open field, but not elevated zero maze, mGlu4−/− mice showed lower activity levels than wild-type, mGlu8−/− and mGlu4/8−/− mice. mGlu4/8−/− female mice showed less contextual freezing than wild-type and mGlu4−/− female mice and there was a trend toward less freezing in male mGlu4/8−/− than wild-type male mice. There were no genotype differences in cued fear conditioning. There were significant negative correlations between body weight and fall latency on the rotorod in wild-type, mGlu8−/− and mGlu4/8−/−, but not mGlu4−/−, mice. These data suggest related functions of mGlu4 and mGlu8 in behavioral performance.
doi:10.1016/j.pbb.2013.07.022
PMCID: PMC3806016  PMID: 23948069
mGlu4; mGlu8; open field; zero maze; fear conditioning; rotorod; body weight
6.  Early Effects of Whole-Body 56Fe Irradiation on Hippocampal Function in C57BL/6J Mice 
Radiation research  2013;179(5):590-596.
Relatively little is known about early irradiation effects on hippocampal function in wild-type mice. In this study, the effects of 56Fe irradiation on hippocampal function were assessed starting 2 weeks after whole-body irradiation. Compared to sham irradiation, radiation impaired novel object recognition in female and male C57BL/6J wild-type mice. There were no effects of irradiation on contextual fear conditioning or spatial memory retention in the water maze. It is possible that oxidative damage might contribute to radiation-induced cognitive changes. Therefore, hippocampal and cortical levels of 3-nitrotyrosine (3NT) and lipid peroxidation, measures of oxidative damage were assessed. There were no effects of irradiation on these measures of oxidative damage. As 56Fe irradiation can increase reactive oxygen species (ROS) levels, which may contribute to the impairments in novel object recognition, the effects of the antioxidant alpha-lipoic acid (ALA) on cognition following sham irradiation and irradiation were also assessed. ALA did not prevent radiation-induced impairments in novel object recognition and impaired spatial memory retention of sham-irradiated and irradiated mice in the probe trial after the first day of hidden platform training in the water maze. Thus, the novel object recognition test is particularly sensitive to detect early cognitive effects of 56Fe irradiation through a mechanism unlikely involving ROS or oxidative damage.
doi:10.1667/RR2946.1
PMCID: PMC4117374  PMID: 23510274
7.  Developmental methamphetamine exposure results in short- and long-term alterations in hypothalamic-pituitary-adrenal axis-associated proteins 
Developmental neuroscience  2013;35(4):10.1159/000351278.
Developmental exposure to methamphetamine (MA) causes long-term behavioral and cognitive deficits. One pathway through which MA might induce these deficits is by elevating glucocorticoid levels. Glucocorticoid overexposure during brain development can lead to long-term disruptions in the hypothalamic-pituitary-adrenal (HPA) axis. These disruptions affect the regulation of stress responses and may contribute to behavioral and cognitive deficits reported following developmental MA exposure. Furthermore, alterations in proteins associated with the HPA axis, including vasopressin, oxytocin, and glucocorticoid receptors (GR), are correlated with disruptions in mood and cognition. We therefore hypothesized that early MA exposure will result in short- and long-term alterations in the expression of HPA axis-associated proteins. Male mice were treated with MA (5 mg/kg daily) or Saline from postnatal day (P) 11–20. At P20 and P90, mice were perfused and their brains processed for vasopressin, oxytocin, and GR-immunoreactivity within HPA axis-associated regions. At P20, there was a significant decrease in the number of vasopressin-immunoreactive cells and area occupied by vasopressin-immunoreactiviy in the paraventricular nucleus (PVN) of MA-treated mice, but no difference in oxytocin-immunoreactivity in the PVN, or GR-immunoreactivity in the hippocampus or PVN. In the central nucleus of the amygdala, area occupied by GR-immunoreactivity was decreased by MA. At P90, the number of vasopressin-immunoreactive cells was still decreased, but the area occupied by vasopressin-immunoreactivity no longer differed from Saline controls. No effects of MA were found on oxytocin or GR-immunoreactivity at P90. Thus developmental MA exposure has short- and long-term effects on vasopressin-immunoreactivity and short-term effects on GR-immunoreactivity.
doi:10.1159/000351278
PMCID: PMC3845800  PMID: 23860125
8.  Role of mGluR4 in acquisition of fear learning and memory 
Neuropharmacology  2012;66:365-372.
Group III metabotropic glutamate receptors (mGluRs), which are generally located presynaptically, modulate synaptic transmission by regulating neurotransmitter release. Previously we showed enhanced amygdala-dependent cued fear conditioning in mGluR4−/− mice 24 hr following training involving two tone-shock pairings. In this study, we assessed the effects of modulating mGluR4 signaling on acquisition and extinction of conditioned fear. mGluR4−/− and wild-type female and male mice received 10 tone-shock pairings during training. Compared to wild-type mice, mGluR4−/− mice showed enhanced acquisition and extinction of cued fear. Next, we assessed whether acute pharmacological stimulation of mGluR4 with the specific orthosteric mGluR4 agonist LSP1-2111 also affects acquisition and extinction of cued fear. Consistent with the enhanced acquisition of cued fear in mGluR4−/−, LSP1-2111, at 2.5 and 5mg/kg, inhibited acquisition of cued fear conditioning in wild-type male mice. The drug’s effect on extinction was less clear and only a subtle effect was seen at 5 mg/kg. Finally, analysis of microarray data of amygdala tissues from mGluR4−/− versus wild-type and from wild-type mice treated with a mGluR4 agonist versus saline revealed a significant overlap in pattern of gene expression. Together, these data support a role for mGluR4 signaling in acquisition of fear learning and memory.
doi:10.1016/j.neuropharm.2012.07.038
PMCID: PMC3508079  PMID: 22884897
mGluR4; fear conditioning; mice; cued
9.  Responses of the central nervous system to high linear energy transfer radiation: NSCOR project highlights 
Journal of Radiation Research  2014;55(Suppl 1):i22-i23.
Overview: The five-university NSCOR project investigates the responses of the central nervous system to space-like charged particle exposure by evaluating: synaptic function, in vitro and in vivo neurogenesis, behavior and behaviorally induced gene expression, and oxidative stress of the mouse hippocampus and cultured neural precursor cells. To test the role of reactive oxygen species in mediating the effects of radiation exposure, we compare responses in a catalase overexpressing transgenic mouse strain to wild type. We also use computational models of the hippocampus in three dimensions, informed by experimental measurements, to provide insight into network behavior.
Radiation exposure protocols include single, acute whole-body exposures to 1H, 28Si and 56Fe ions and mixed field exposures using 1H + 56Fe ions (24 h later). The animal models are 10-week-old C57BL/6J and MCATtg males which are evaluated at 30 and 90 days postirradiation. In vitro models are cultured murine and human neural stem cells irradiated with 1H, 16O, 28Si and 56Fe ions at multiple energies and are evaluated at times from days to weeks.
Highlights: Neural stem cells organized into neurospheres were irradiated with several ions at doses as low as 0.75 cGy. Data show that significant oxidative stress occurs that alters survival, proliferation and differentiation. Overall trends indicate that changes in oxidative stress (persisting for weeks) correlate with particle linear energy transfer (LET). 56Fe ions elicited the largest and most persistent changes in stress markers, including antioxidant enzyme expression levels.
The hippocampus-dependent contextual fear conditioning (CFC) and novel object recognition (NOR) paradigms were used to assess cognition and showed cognitive deficits after irradiation with the NOR paradigm more sensitive than CFC. Analysis of neurogenesis indicates that overall neurogenesis is inhibited at doses ≥1 Gy, but newly born activated microglia are significantly elevated at ≥0.1 Gy. High LET radiation affects all lineages of neural precursor cells and elicits a U-shaped dose–response for cells exhibiting the astrocyte marker GFAP. In a mixed field irradiation regimen (0.1 Gy 1H, then 0.5 Gy 56Fe 24 h later), NOR was impaired with 0.1 Gy 1H or 0.1 Gy 1H + 0.5 Gy 56Fe but not with 0.5 Gy 56Fe alone. A negative correlation between newly born activated microglia and NOR or behaviorally activated Arc gene expression was observed for exposures using protons and iron ions, suggesting that neuroinflammation contributes to the cognitive injury. A set of monocyte chemoattractant chemokines was reduced after the mixed beam exposure but not after the individual exposures suggesting compensatory or adaptive responses are elicited by the proton exposure.
Patch clamp recordings on principal neurons of the CA1 and DG hippocampus fields were conducted on mice irradiated with 1H, 28Si and 56Fe iron ions. Input resistance and resting membrane potential were modified by irradiation in CA1 and protons were found to be the most effective ion species. These parameters suggest that more miniature excitatory post synaptic potentials must be elicited simultaneously to initiate action potentials and therefore the neurons are less responsive post irradiation. Si- and Fe-irradiated animals showed only minor alterations in mEPSCs and mIPSCs. Granule neurons of the DG field showed no differences after 28Si irradiation, but with 56Fe significant increases in AMPA receptor-mediated mEPSC frequency were observed without affecting amplitude. This focuses attention on presynaptic glutamate release mechanisms.
Functional changes in the CA1 network triggered by whole-body irradiation with protons, iron and silicon radiation were assessed with microelectrode array field recordings. Deficits in input–output curves and long-term potentiation (LTP) are observed in proton irradiated mice. In the dentate gyrus field, radiation enhanced input–output curves and LTP which is opposite of the inhibition observed for the CA1 field. This suggests that in the DG the most sensitive targets may be GABA-ergic inhibitory neurons that regulate granular cell excitability. 28Si ion effects appear to be associated with dendro-somatic coupling expected to affect signaling of the hippocampal neurons to other brain structures and vary between rostral and ventral hippocampal regions. Observations on MCATtg mice show attenuation of radiation-elicited responses, which implicates reactive oxygen species as mediators of the biological responses.
Modeling activities using a high-fidelity three-dimensional model of the hippocampus have begun and allow simulation of network activities incorporating neuron structural and functional parameters measured experimentally to probe their individual and combined contributions to network behavior. Changes in firing statistics are observed after incorporating measured electrophysiological parameters into the model.
Clinical trial registration number: not applicable.
doi:10.1093/jrr/rrt214
PMCID: PMC3941509
Brain; High LET radiation; Electrophysiology; Behavior; Neurogenesis
10.  Long-term epigenetic effects of exposure to low doses of 56Fe in the mouse lung 
Journal of Radiation Research  2014;55(4):823-828.
Despite significant progress, the long-term health effects of exposure to high charge (Z) and energy (E) nuclei (HZEs) and the underlying mechanisms remain poorly understood. Mouse studies show that space missions can result in pulmonary pathological states. The goal of this study was to evaluate the pro-fibrotic and pro-carcinogenic effects of exposure to low doses of heavy iron ions (56Fe) in the mouse lung. Exposure to 56Fe (600 MeV; 0.1, 0.2 and 0.4 Gy) resulted in minor pro-fibrotic changes, detected at the beginning of the fibrotic phase (22 weeks post exposure), which were exhibited as increased expression of chemokine Ccl3, and interleukin Il4. Epigenetic alterations were exhibited as global DNA hypermethylation, observed after exposure to 0.4 Gy. Cadm1, Cdh13, Cdkn1c, Mthfr and Sfrp1 were significantly hypermethylated after exposure to 0.1 Gy, while exposure to higher doses resulted in hypermethylation of Cdkn1c only. However, expression of these genes was not affected by any dose. Congruently with the observed patterns of global DNA methylation, DNA repetitive elements were hypermethylated after exposure to 0.4 Gy, with minor changes observed after exposure to lower doses. Importantly, hypermethylation of repetitive elements coincided with their transcriptional repression. The findings of this study will aid in understanding molecular determinants of pathological states associated with exposure to 56Fe, as well as serve as robust biomarkers for the delayed effects of irradiation. Further studies are clearly needed to investigate the persistence and outcomes of molecular alterations long term after exposure.
doi:10.1093/jrr/rru010
PMCID: PMC4100002  PMID: 24585548
heavy iron ions; epigenetics; DNA methylation; repetitive elements; pulmonary fibrosis; lung cancer
11.  Correcting deregulated Fxyd1 expression ameliorates a behavioral impairment in a mouse model of Rett Syndrome 
Brain research  2012;1496:104-114.
Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the MECP2 gene. Several genes have been shown to be MECP2 targets. We previously identified FXYD1 (encoding phospholemman; a protein containing the motif phenylalanine-X-tyrosine-aspartate), a gene encoding a transmembrane modulator of the Na,K-ATPase (NKA) enzyme, as one of them. In the absence of MECP2, FXYD1 expression is increased in the frontal cortex (FC) of both RTT patients and Mecp2Bird null mice. Here, we show that Fxyd1 mRNA levels are also increased in the FC and hippocampus (HC) of male mice carrying a truncating mutation of the Mecp2 gene (Mecp2308). To test the hypothesis that some of the behavioral phenotypes seen in these Mecp2 mutants could be ameliorated by genetically preventing the Fxyd1 response to MECP2 deficiency, we crossed Fxyd1 null male mice with Mecp2308 heterozygous females and behaviorally tested the adult male offspring. Mecp2308 mice had impaired HC-dependent novel location recognition, and this impairment was rescued by deletion of both Fxyd1 alleles. No other behavioral or sensorimotor impairments were rescued. These results indicate that reducing FXYD1 levels improves a specific cognitive impairment in MECP2-deficient mice.
doi:10.1016/j.brainres.2012.12.009
PMCID: PMC3556227  PMID: 23246925
Fxyd1; Mecp2; learning and memory; Rett syndrome; novel object recognition; novel object location; mouse model
12.  Spatial Navigation Impairments Among Intellectually High-Functioning Adults With Autism Spectrum Disorder: Exploring Relations With Theory of Mind, Episodic Memory, and Episodic Future Thinking 
Journal of Abnormal Psychology  2013;122(4):1189-1199.
Research suggests that spatial navigation relies on the same neural network as episodic memory, episodic future thinking, and theory of mind (ToM). Such findings have stimulated theories (e.g., the scene construction and self-projection hypotheses) concerning possible common underlying cognitive capacities. Consistent with such theories, autism spectrum disorder (ASD) is characterized by concurrent impairments in episodic memory, episodic future thinking, and ToM. However, it is currently unclear whether spatial navigation is also impaired. Hence, ASD provides a test case for the scene construction and self-projection theories. The study of spatial navigation in ASD also provides a test of the extreme male brain theory of ASD, which predicts intact or superior navigation (purportedly a systemizing skill) performance among individuals with ASD. Thus, the aim of the current study was to establish whether spatial navigation in ASD is impaired, intact, or superior. Twenty-seven intellectually high-functioning adults with ASD and 28 sex-, age-, and IQ-matched neurotypical comparison adults completed the memory island virtual navigation task. Tests of episodic memory, episodic future thinking, and ToM were also completed. Participants with ASD showed significantly diminished performance on the memory island task, and performance was positively related to ToM and episodic memory, but not episodic future thinking. These results suggest that (contra the extreme male brain theory) individuals with ASD have impaired survey-based navigation skills—that is, difficulties generating cognitive maps of the environment—and adds weight to the idea that scene construction/self-projection are impaired in ASD. The theoretical and clinical implications of these results are discussed.
doi:10.1037/a0034819
PMCID: PMC3906800  PMID: 24364620
autism spectrum disorder; episodic memory; episodic future thinking; spatial navigation; theory of mind
13.  Impairment in Extinction of Contextual and Cued Fear Following Post-Training Whole-Body Irradiation 
Because of the use of radiation in cancer therapy, the risk of nuclear contamination from power plants, military conflicts, and terrorism, there is a compelling scientific and public health interest in the effects of environmental radiation exposure on brain function, in particular hippocampal function and learning and memory. Previous studies have emphasized changes in learning and memory following radiation exposure. These approaches have ignored the question of how radiation exposure might impact recently acquired memories, which might be acquired under traumatic circumstances (cancer treatment, nuclear disaster, etc.). To address the question of how radiation exposure might affect the processing and recall of recently acquired memories, we employed a fear conditioning paradigm wherein animals were trained, and subsequently irradiated (whole-body X-ray irradiation) 24 h later. Animals were given 2 weeks to recover, and were tested for retention and extinction of hippocampus-dependent contextual fear conditioning or hippocampus-independent cued fear conditioning. Exposure to irradiation following training was associated with reduced daily increases in body weights over the 22-days of the study and resulted in greater freezing levels and aberrant extinction 2 weeks later. This was also observed when the intensity of the training protocol was increased. Cued freezing levels and measures of anxiety 2 weeks after training were also higher in irradiated than sham-irradiated mice. In contrast to contextual freezing levels, cued freezing levels were even higher in irradiated mice receiving 5 shocks during training than sham-irradiated mice receiving 10 shocks during training. In addition, the effects of radiation on extinction of contextual fear were more profound than those on the extinction of cued fear. Thus, whole-body irradiation elevates contextual and cued fear memory recall.
doi:10.3389/fnbeh.2014.00231
PMCID: PMC4078460  PMID: 25071488
irradiation; post-training; fear conditioning; wild-type mice; body weight; anxiety
14.  Methamphetamine exposure during brain development alters the brain acetylcholine system in adolescent mice 
Journal of neurochemistry  2011;119(1):10.1111/j.1471-4159.2011.07418.x.
Children exposed to methamphetamine during brain development as a result of maternal drug use have long-term hippocampus-dependent cognitive impairments, but the mechanisms underlying these impairments are not understood. The acetylcholine system plays an important role in cognitive function and potential methamphetamine-induced acetylcholine alterations may be related to methamphetamine-induced cognitive impairments. In this study, we investigated the potential long-term effects of methamphetamine exposure during hippocampal development on the acetylcholine system in adolescence mice on postnatal day 30 and in adult mice on postnatal day 90. Methamphetamine exposure increased the density of acetylcholine neurons in regions of the basal forebrain and the area occupied by acetylcholine axons in the hippocampus in adolescent female mice. In contrast, methamphetamine exposure did not affect the density of GABA cells or total neurons in the basal forebrain. Methamphetamine exposure also increased the number of muscarinic acetylcholine receptors in the hippocampus of adolescent male and female mice. Our results demonstrate for the first time that methamphetamine exposure during hippocampal development affects the acetylcholine system in adolescent mice and that these changes are more profound in females than males.
doi:10.1111/j.1471-4159.2011.07418.x
PMCID: PMC3873861  PMID: 21824143
acetylcholine; adolescence; basal forebrain; development; hippocampus; methamphetamine
15.  Apolipoprotein E Genotype-Dependent Paradoxical Short-Term Effects of 56Fe Irradiation on the Brain 
Purpose
In humans, apolipoprotein E (apoE) is encoded by three major alleles (ε2, ε3, and ε4) and, compared to apoE3, apoE4 increases the risk of developing Alzheimer disease and cognitive impairments following various environmental challenges. Exposure to irradiation, including that of 56Fe, during space missions poses a significant risk to the central nervous system, and apoE isoform might modulate this risk.
Methods and Materials
We investigated whether apoE isoform modulates hippocampus-dependent cognitive performance starting 2 weeks after 56Fe irradiation. Changes in reactive oxygen species (ROS) can affect cognition and are induced by irradiation. Therefore, after cognitive testing, we assessed hippocampal ROS levels in ex vivo brain slices, using the ROS-sensitive fluorescent probe, dihydroethidium (DHE). Brain levels of 3-nitrotyrosine (3-NT), CuZn superoxide dismutase (CuZnSOD), extracellular SOD, and apoE were assessed using Western blotting analysis.
Results
In the water maze, spatial memory retention was impaired by irradiation in apoE2 and apoE4 mice but enhanced by irradiation in apoE3 mice. Irradiation reduced DHE-oxidation levels in the enclosed blade of the dentate gyrus and levels of 3-NT and CuZnSOD in apoE2 but not apoE3 or apoE4 mice. Finally, irradiation increased apoE levels in apoE3 but not apoE2 or apoE4 mice.
Conclusions
The short-term effects of 56Fe irradiation on hippocampal ROS levels and hippocampus-dependent spatial memory retention are apoE isoform-dependent.
doi:10.1016/j.ijrobp.2011.12.049
PMCID: PMC3742074  PMID: 22401921
ApoE; Irradiation; ROS
16.  ApoE Isoform-Dependent Deficits in Extinction of Contextual Fear Conditioning 
Genes, brain, and behavior  2012;11(7):806-812.
The three major human apoE isoforms (apoE2, apoE3, and apoE4) are encoded by distinct alleles (ε2, ε3, and ε4). Compared to ε3, ε4 is associated with increased risk to develop Alzheimer’s disease (AD), cognitive impairments in Parkinson’s disease (PD), and other conditions. In contrast, a recent study indicated an increased susceptibility to the recurring and re-experiencing symptom cluster of Post Traumatic Stress Disorder (PTSD), as well as related memory impairments, in patients carrying at least one ε2 allele. Contextual fear conditioning and extinction are used in human and animal models to study this symptom cluster. In this study, acquisition (day 1, training), consolidation (day 2, first day of re- exposure) and extinction (days 2–5) of conditioned contextual fear in human apo 2, apo 3, and apo 4 targeted replacement (TR) and C57BL/6J wild-type (WT) mice was investigated. Male and female apo 2 mice showed acquisition and retrieval of conditioned fear, but failed to exhibit extinction. In contrast, WT, apoE3 and apoE4 mice showed extinction. While apoE2 mice exhibited lower freezing in response to the context on day 2 than apoE3 and apoE4 mice, this cannot explain their extinction deficit as WT mice exhibited similar freezing levels as apoE2 mice on day 2 but still exhibited extinction. Elevating freezing through extended training preserved extinction in controls, but failed to ameliorate extinction deficits in apoE2 animals. These data along with clinical data showing an association of apoE2 with susceptibility to specific symptom clusters in PTSD supports an important role for apoE isoform in the extinction of conditioned fear.
doi:10.1111/j.1601-183X.2012.00833.x
PMCID: PMC3642038  PMID: 22883220
apoE; PTSD; extinction; acquisition
17.  Nonreplication of an Association of Apolipoprotein E2 With Sinistrality 
Laterality  2012;18(2):251-261.
A recent report found that left-handed adolescents were over three-fold more likely to have an Apolipoprotein (APOE) ε2 allele. This study was unable to replicate this association in young-adults (N=166). A meta-analysis of nine other datasets (N = 360 to 7,559, Power > 0.999) including that of National Alzheimer’s Coordinating Center also failed to find an over-representation of ε2 among left-handers indicating that this earlier outcome was most likely a statistical artifact.
doi:10.1080/1357650X.2012.660164
PMCID: PMC3770935  PMID: 22721421
APOE; handedness; right
18.  A WAVE-1 and WRP Signaling Complex Regulates Spine Density, Synaptic Plasticity, and Memory 
The scaffolding protein WAVE-1 (Wiskott-Aldrich syndrome protein family member 1) directs signals from the GTPase Rac through the Arp2/3 complex to facilitate neuronal actin remodeling. The WAVE-associated GTPase activating protein called WRP is implicated in human mental retardation, and WAVE-1 knock-out mice have altered behavior. Neuronal time-lapse imaging, behavioral analyses, and electrophysiological recordings from genetically modified mice were used to show that WAVE-1 signaling complexes control aspects of neuronal morphogenesis and synaptic plasticity. Gene targeting experiments in mice demonstrate that WRP anchoring to WAVE-1 is a homeostatic mechanism that contributes to neuronal development and the fidelity of synaptic connectivity. This implies that signaling through WAVE-1 complexes is essential for neural plasticity and cognitive behavior.
doi:10.1523/JNEUROSCI.3209-06.2006
PMCID: PMC3740594  PMID: 17215396
WAVE-1; WRP; actin; Arp2/3; dendritic spine; synaptic plasticity
19.  Trauma-Induced Alterations in Cognition and Arc Expression are Reduced by Previous Exposure to 56Fe Irradiation 
Hippocampus  2010;22(3):544-554.
Exposure to ionizing irradiation may affect brain functions directly, but may also change tissue sensitivity to a secondary insult such as trauma, stroke or degenerative disease. To determine if a low dose of particulate irradiation sensitizes the brain to a subsequent injury, C56BL6 mice were exposed to brain only irradiation with 0.5 Gy of 56Fe ions. Two months later, unilateral traumatic brain injury was induced using a controlled cortical impact system. Three weeks after trauma animals received multiple BrdU injections and 30 days later were tested for cognitive performance in the Morris water maze. All animals where able to locate the visible and hidden platform during training; however, treatment effects were seen when spatial memory retention was assessed in the probe trial (no platform). While sham and irradiated animals showed spatial memory retention, mice that received trauma alone did not. When trauma was preceded by irradiation, performance in the water maze was not different from sham-treated animals, suggesting that low dose irradiation had a protective effect in the context of a subsequent traumatic injury. Measures of hippocampal neurogenesis showed that combined injury did not induce any changes greater that those seen after trauma or radiation alone. After trauma there was a significant decrease in the percentage of neurons expressing the behaviorally-induced immediate early gene Arc in both hemispheres, without associated neuronal loss. After combined injury there were no differences relative to sham-treated mice. Our results suggest that combined injury resulted in decreased alterations of our endpoints compared to trauma alone. While the underlying mechanisms are not yet known, these results resemble a preconditioning, adaptive, or inducible-like protective response, where a sublethal or potentially injurious stimulus (i.e. irradiation) induces tolerance to a subsequent and potentially more damaging insult (trauma).
doi:10.1002/hipo.20920
PMCID: PMC3738213  PMID: 21192069
hippocampus; traumatic brain injury; immediate early gene; radiation
20.  Association of microtubule associated protein-2, synaptophysin, and apolipoprotein E mRNA and protein levels with cognition and anxiety levels in aged female Rhesus macaques 
Behavioural Brain Research  2012;232(1):1-6.
The dendritic protein microtubule associated protein 2 (MAP-2), the presynaptic marker synaptophysin (SYN), and apolipoprotein E (apoE), a protein which plays a role in lipid transport and metabolism and affects synaptic activity show changes with age. We analyzed post-mortem tissue from aged female Rhesus macaques cognitively tested in a spatial maze and classified as good spatial performers (GSP) or poor spatial performers (PSP) and behaviorally tested in a playroom and classified as bold or reserved animals. MAP2, SYN, and APOE mRNA and protein levels in the prefrontal cortex (PFC), hippocampus, and amygdala, were assessed using qRT-PCR and western blot. In the amygdala, bold monkeys had higher levels of MAP2 and SYN mRNA than reserved monkeys. MAP2 mRNA correlated positively with amygdala size on the right, left, and combined left and right sides, while SYN mRNA levels correlated positively with the size of the right amygdala. In the hippocampus, SYN and apoE protein levels were higher in GSP than PSP animals. Thus, in aged nonhuman primates, classification of measures of anxiety is associated with differences in selected mRNA, but not protein, levels. In contrast, classification of cognitive performance is associated with differences in selected protein, but not mRNA, levels.
doi:10.1016/j.bbr.2012.03.032
PMCID: PMC3361595  PMID: 22475553
MAP-2; SYN; APOE; cognitive function
21.  Evaluation of a Short-Form of the Berg Card Sorting Test 
PLoS ONE  2013;8(5):e63885.
The Psychology Experimental Building Language http://pebl.sourceforge.net/ Berg Card Sorting Test is an open-source neurobehavioral test. Participants (N = 207, ages 6 to 74) completed the Berg Card Sorting Test. Performance on the first 64 trials were isolated and compared to that on the full-length (128 trials) test. Strong correlations between the short and long forms (total errors: r = .87, perseverative response: r = .83, perseverative errors r = .77, categories completed r = .86) support the Berg Card Sorting Test-64 as an abbreviated alternative for the full-length executive function test.
doi:10.1371/journal.pone.0063885
PMCID: PMC3653789  PMID: 23691107
22.  Effects of Neonatal Methamphetamine and Thioperamide Exposure on Spatial Memory Retention and Circadian Activity Later in Life 
Behavioural Brain Research  2012;230(1):229-236.
Methamphetamine (MA) use increases the likelihood of engaging in risky sexual behavior and most MA-using women are of child-bearing age. Therefore, cognitive effects following MA exposure to the developing brain are concerning. Exposure of mice to MA during hippocampal development causes cognitive impairments in adulthood. These effects are more severe in female than male mice and mimicked by the H3 receptor antagonist thioperamide (THIO). In this study, we assessed whether neonatal exposure to MA or THIO also affects cognition in adolescence. As these effects might be associated with alterations in circadian activity, we also assessed circadian activity in a subgroup of neonatally exposed mice. Sex-dependent treatment effects were seen in the water maze. While THIO-, but not MA-, treated female mice showed hippocampus-dependent spatial memory retention in the first probe trial, MA-, but not THIO-treated female mice showed spatial memory retention in the probe trial following reversal training. In contrast, MA- and THIO-treated male mice showed spatial memory retention in both probe trials. When sensorimotor gating was assessed, MA-treated male mice showed greater pre-pulse inhibition than MA-treated female mice. Regardless of sex, THIO-treated mice gained on average more weight each day and showed an enhanced startle response. In addition, MA increased the length of the circadian period, with an intermediate effect following THIO treatment were observed. No treatment effects in exploratory behavior, measures of anxiety, or contextual or cued fear conditioning. Thus, the water maze is particularly sensitive to detect sex-dependent effects of neonatal MA and THIO exposure on spatial memory retention in adolescence.
doi:10.1016/j.bbr.2012.02.003
PMCID: PMC3310251  PMID: 22330947
Methamphetamine; thioperamide; cognition; circadian; adolescence; hippocampus; postnatal
23.  Assessment of cognition in early dementia 
Better tools for assessing cognitive impairment in the early stages of Alzheimer’s disease (AD) are required to enable diagnosis of the disease before substantial neurodegeneration has taken place and to allow detection of subtle changes in the early stages of progression of the disease. The National Institute on Aging and the Alzheimer’s Association convened a meeting to discuss state of the art methods for cognitive assessment, including computerized batteries, as well as new approaches in the pipeline. Speakers described research using novel tests of object recognition, spatial navigation, attentional control, semantic memory, semantic interference, prospective memory, false memory and executive function as among the tools that could provide earlier identification of individuals with AD. In addition to early detection, there is a need for assessments that reflect real-world situations in order to better assess functional disability. It is especially important to develop assessment tools that are useful in ethnically, culturally and linguistically diverse populations as well as in individuals with neurodegenerative disease other than AD.
doi:10.1016/j.jalz.2011.05.001
PMCID: PMC3613863  PMID: 23559893
24.  Measures of anxiety, sensorimotor function, and memory in male and female mGluR4-/- mice 
Behavioural Brain Research  2012;229(1):21-28.
Metabotropic glutamate receptors (mGluRs) are coupled to second messenger pathways via G proteins and modulate synaptic transmission. Of the eight different types of mGluRs (mGluR1-mGluR8), mGluR4, mGluR6, mGluR7, and mGluR8 are members of group III. Group III receptors are generally located presynaptically, where they regulate neurotransmitter release. Because of their role in modulating neurotransmission, mGluRs are attractive targets for therapies aimed at treating anxiety disorders. Previously we showed that the mGluR4-selective allosteric agonist VU 0155041 reduces anxiety-like behavior in wild-type male mice. Here, we explore the role of mGluR4 in adult (6-month-old) and middle-aged (12-month-old) male and female mice lacking this receptor. Compared to age- and sex-matched wild-type mice, middle-aged mGluR4-/- male mice showed increased measures of anxiety in the open field and elevated zero maze and impaired sensorimotor function on the rotarod. These changes were not seen in adult 6-month old male mice. In contrast to the male mice, mGluR4-/- female mice showed reduced measures of anxiety in the open field and elevated zero maze and enhanced rotarod performance. During the hidden platform training sessions of the water maze, mGluR4-/-mice swam father away from the platform than wild-type mice at 6, but not at 12, months of age. mGluR4-/- mice also showed enhanced amygdala-dependent cued fear conditioning. No genotype differences were seen in hippocampus-dependent contextual fear conditioning. These data indicate that effects of mGluR4 on sensorimotor function and measures of anxiety, but not cued fear conditioning, are critically modulated by sex and age.
doi:10.1016/j.bbr.2011.12.037
PMCID: PMC3294097  PMID: 22227508
mGluR4; anxiety; Group-III mGluR; learning; memory
25.  Apolipoprotein E isoform-dependent effects on anxiety and cognition in female TR mice 
Neurobiology of aging  2010;33(2):345-358.
Compared with apoE3, apoE4 is associated with increased risk to develop age-related cognitive decline, particularly in women. In this study, young, middle-aged, and old female mice expressing human apoE under control of the mouse apoE promoter were behaviorally analyzed. Cognitive performance in the water maze decreased with age in all mice. Compared with apoE2 and apoE3 mice, apoE4 mice showed better cognitive performance and higher measures of anxiety than apoE2 and apoE3 mice. Measures of anxiety correlated with cognitive performance in the water maze and passive avoidance tests and might have contributed to the enhanced cognitive performance of the apoE4 mice. ApoE4 mice showed better water maze learning and higher cortical apoE levels than mice expressing apoE4 in astrocytes under control of the GFAP promoter. This was not seen in apoE3 mice. There were no line differences in either genotype in spatial memory retention in the probe trial following the last day of hidden platform training. Thus, the promoter used to express apoE4 critically modulates its effects on brain function.
doi:10.1016/j.neurobiolaging.2010.03.002
PMCID: PMC2935518  PMID: 20400205
Aging; Anxiety; Apolipoprotein E; Cognition

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