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1.  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
2.  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
3.  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
4.  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
5.  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
6.  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
7.  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
8.  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
9.  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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  Measures of Anxiety, Amygdala Volumes, and Hippocampal Scopolamine phMRI Response in Elderly Female Rhesus Macaques 
Neuropharmacology  2011;62(1):385-390.
In nonhuman primates, anxiety levels are typically assessed by observing social hierarchies or behavior in an intruder task. As measures of anxiety might influence performance on a particular cognitive task, it is important to analyze these measures in the same room as used for the cognitive task. As we use a playroom for the spatial maze test, we classified elderly female rhesus macaques (Macaca mulatta) monkeys, as bold or reserved monkeys based on the time spent in specific areas of this room. Based on their exploratory behavior in the playroom, bold monkeys were defined as animals that spent 20% more time in the unprotected areas of the room than in the protected areas, whereas reserved monkeys spent a comparable amount of time in both areas. MRI analyses showed that reserved monkeys had a smaller amygdala compared to bold monkeys but there were no group differences in hippocampal volumes. In addition, the amount of time spent in the corners of the room was negatively correlated with the right and total amygdala size. Finally, reserved monkeys showed a lower phMRI response to the muscarinic receptor antagonist scopolamine compared to the bold monkeys. Thus, in elderly female nonhuman primates measures of anxiety are associated with structural amygdala differences and hippocampal muscarinic receptor function.
doi:10.1016/j.neuropharm.2011.08.014
PMCID: PMC3195963  PMID: 21867720
anxiety; nonhuman primate; amygdala; hippocampus; scopolamine; phMRI
18.  Hippocampal M1 receptor function associated with spatial learning and memory in aged female rhesus macaques 
Age  2010;33(3):309-320.
Of the acetylcholine muscarinic receptors, the type 1 (M1) and type 2 (M2) receptors are expressed at the highest levels in the prefrontal cortex (PFC) and hippocampus, brain regions important for cognition. As equivocal findings of age-related changes of M1 and M2 in the nonhuman primate brain have been reported, we first assessed age-related changes in M1 and M2 in the PFC and hippocampus using saturation binding assays. Maximum M1 receptor binding, but not affinity of M1 receptor binding, decreased with age. In contrast, the affinity of M2 receptor binding, but not maximum M2 receptor binding, increased with age. To determine if in the elderly cognitive performance is associated with M1 or M2 function, we assessed muscarinic function in elderly female rhesus macaques in vivo using a scopolamine challenge pharmacological magnetic resonance imaging and in vitro using saturation binding assays. Based on their performance in a spatial maze, the animals were classified as good spatial performers (GSP) or poor spatial performers (PSP). In the hippocampus, but not PFC, the GSP group showed a greater change in T2*-weighted signal intensity after scopolamine challenge than the PSP group. The maximum M1 receptor binding and receptor binding affinity was greater in the GSP than the PSP group, but no group difference was found in M2 receptor binding. Parameters of circadian activity positively correlated with the difference in T2*-weighted signal intensity before and after the challenge, the maximum M1 receptor binding, and the M1 receptor binding affinity. Thus, while in rhesus macaques, there are age-related decreases in M1 and M2 receptor binding, in aged females, hippocampal M1, but not M2, receptor function is associated with spatial learning and memory and circadian activity.
doi:10.1007/s11357-010-9184-2
PMCID: PMC3168603  PMID: 20890730
M1 receptor; Scopolamine phMRI; Spatial maze
19.  Opposing Roles of mGluR8 in Measures of Anxiety involving Non-Social and Social Challenges 
Behavioural brain research  2011;221(1):50-54.
Metabotropic glutamate receptors (mGluRs) modulate glutamatergic and GABAergic neurotransmission. mGluR8, a member of group III receptors, is generally located presynaptically where it regulates neurotransmitter release. Previously we reported higher measures of anxiety in 6- and 12-month-old mGluR8−/− male mice than age- and sex-matched wild-type mice and that acute pharmacological stimulation with the mGluR8 agonist (S)-3,4,-dicarboxyphenylglycine (DCPG) or the Positive Allosteric Modulator (PAM) AZ12216052 reduced measures of anxiety in wild-type mice. As in humans and animals, ageing is associated with enhanced measures of anxiety following non-social and social challenges, increased understanding of these measures and how to potentially modulate them is particularly important in the elderly. Here we determined whether the effects of AZ12216052 on measures of anxiety are mediated by mGluR8 using 24-month-old mGluR8−/− and wild-type male mice. AZ12216052 also reduced measures of anxiety in the elevated zero maze and the acoustic startle response in mGluR8−/− mice. The remaining anxiolytic effects of AZ12216052 in mGluR8−/− mice might involve mGluR4, as the mGluR4 PAM VU 0155041 also reduced measures of anxiety in wild-type mice. In contrast, mGluR8−/− mice show enhanced social interaction but AZ12216052 does not affect social interaction in wild-type mice. Thus, while mGluR8 is an attractive target to modulate measures of anxiety and social interaction, the effects of AZ12216052 on measures of anxiety likely also involve receptors other than mGluR8.
doi:10.1016/j.bbr.2011.02.049
PMCID: PMC3079808  PMID: 21382421
metabotropic; group-III mGluR; allosteric modulator; zero maze; acoustic startle; social interaction
20.  Statistical analysis of latency outcomes in behavioral experiments 
Behavioural brain research  2011;221(1):271-275.
In experimental designs of animal models, memory is often assessed by the time for a performance measure to occur (latency). Depending on the cognitive test, this may be the time it takes an animal to escape to a hidden platform (water maze), an escape tunnel (Barnes maze) or to enter a dark component (passive avoidance test). Latency outcomes are usually statistically analyzed using ANOVAs. Besides strong distributional assumptions, ANOVA cannot properly deal with animals not showing the performance measure within the trial time, potentially causing biased and misleading results. We propose an alternative approach for statistical analyses of latency outcomes. These analyses have less distributional assumptions and adequately handle results of trials in which the performance measure did not occur within the trial time. The proposed method is well known from survival analyses, provides comprehensible statistical results and allows the generation of meaningful graphs. Experiments of behavioral neuroscience and anesthesiology are used to illustrate this method.
doi:10.1016/j.bbr.2011.03.007
PMCID: PMC3103828  PMID: 21397635
Statistical analysis; Latency; Barnes maze; Morris water maze; Passive avoidance
21.  Age, Sex, and Handedness Differentially Contribute to Neurospatial Function on the Memory Island and Novel-Image Novel-Location Tests 
Physiology & behavior  2011;103(5):513-522.
Memory Island and the Novel-Image Novel-Location are recently developed measures of spatial learning and recognition-memory modeled after the Morris water maze and the novel object-recognition tests. The goal of this study was to characterize how sex, age, and handedness contribute to Memory Island and Novel-Image Novel-Location performance. Volunteers (N=287, ages 6 to 67) from a local science museum completed four Memory Island trials containing a visible target and four trials containing a hidden target. A pronounced sex difference favoring males was noted in all measures of hidden trial performance. The total latency during the hidden trials among older-adults was longer than younger-adults or adolescents. Faster and more efficient performance by males was also identified during the visible trials, particularly among children. Adolescents and younger-adults outperformed children and older ages. Sinistrals had a lower cumulative distance to the target. Novel-Image Novel-Location behavior was examined in a separate sample (N=128, ages 6 to 86). Females had higher Novel-Image and Novel-Location scores than males. Novel-Image performance was independent of age while sinistrals had elevated Novel-Image scores relative to dextrals. Together, these findings identify how sex, age, and handedness uniquely contribute to performance on these tasks.
doi:10.1016/j.physbeh.2011.03.024
PMCID: PMC3108852  PMID: 21463643
aging; female; learning; left-handedness; memory; sinistrality
22.  mGluR8 Modulates Excitatory Transmission in the Bed Nucleus of the Stria Terminalis in a Stress-Dependent Manner 
Neuropsychopharmacology  2011;36(8):1599-1607.
Metabotropic glutamate receptors (mGluRs) are important modulators of excitatory transmission, and have been implicated in anxiety and stress-related behaviors. Previously, we showed that group III mGluR agonists could depress excitatory synaptic transmission in the bed nucleus of the stria terminalis (BNST), an integral component of the anxiety circuitry. Here, we provide converging evidence indicating that this effect is mediated primarily by mGluR8, is exerted presynaptically, and is modulated by noradrenergic signaling and stress. The effects of the group III mGluR agonist L-AP4 on excitatory transmission are not potentiated by the mGluR4-selective allosteric potentiator PHCCC, but are mimicked by the mGluR8-selective agonist DCPG. Consistent with these results, mGluR8-like immunoreactivity is seen in the BNST, and the actions of L-AP4 on excitatory transmission are absent in slices from mGluR8 knockout (KO) mice. Application of DCPG is associated with an increase in paired-pulse evoked glutamate synaptic currents, and a decrease in spontaneous glutamate synaptic current frequency, consistent with a primarily presynaptic action. mGluR8-mediated suppression of excitatory transmission is disrupted ex vivo by activation of α1 adrenergic receptors (α1 ARs). BNST mGluR8 function is also disrupted by both acute and chronic in vivo exposure to restraint stress, and in brain slices from α2A AR KO mice. These studies show that mGluR8 is an important regulator of excitatory transmission in the BNST, and suggest that this receptor is selectively disrupted by noradrenergic signaling and by both acute and chronic stress.
doi:10.1038/npp.2011.40
PMCID: PMC3138653  PMID: 21451497
mGluR8; stress; glutamate; norepinephrine; α1 ARs; BNST; glutamate; mood/anxiety/stress disorders; catecholamines; neurophysiology; mGluR8; alpha1 adrenergic receptors; BNST; norepinephrine
23.  Histamine-dependent behavioral response to methamphetamine in 12-month-old male mice 
Brain research  2011;1393:23-30.
Methamphetamine (MA) use is a growing problem across the United States. Effects of MA include hyperactivity and increased anxiety. Using a mouse model system, we examined behavioral performance in the open field and elevated zero maze and shock-startle response of 12-month-old wild-type mice injected with MA once (1mg/kg) 30 min prior to behavioral testing. MA treatment resulted in behavioral sensitization in the open field, consistent with studies in younger mice. There was an increased activity in the elevated zero maze and an increased shock-startle response 30 and 60 min post-injection. Since histamine mediates some effects of MA in the brain, we assessed whether 12-month-old mice lacking histidine decarboxylase (Hdc−/−), the enzyme required to synthesize histamine, respond differently to MA than wild-type (Hdc+/+) mice. Compared to saline treatment, acute and repeated MA administration increased activity in the open field and measures of anxiety, though more so in Hdc−/− than Hdc+/+ mice. In the elevated zero maze, opposite effects of MA on activity and measures of anxiety were seen in Hdc+/+ mice. In contrast, MA similarly increased the shock-startle response in Hdc−/− and Hdc+/+ mice, compared to saline-treated genotype-matched mice. These results are similar to those in younger mice suggesting that the effects are not age-dependent. Overall, single or repeated MA treatment causes histamine-dependent changes in 12-month-old mice in the open field and elevated zero-maze, but not in the shock-startle response.
doi:10.1016/j.brainres.2011.03.070
PMCID: PMC3091991  PMID: 21466792
HDC; mouse; open field; elevated zero-maze; shock startle
24.  Long-Term Effects of Neonatal Methamphetamine Exposure on Cognitive Function in Adolescent Mice 
Behavioural brain research  2011;219(1):159-164.
Exposure to methamphetamine during brain development impairs cognition in children and adult rodents. In mice, these impairments are greater in females than males. Adult female, but not male, mice show impairments in novel location recognition following methamphetamine exposure during brain development. In contrast to adulthood, little is known about the potential effects of methamphetamine exposure on cognition in adolescent mice. As adolescence is an important time of development and is relatively understudied, the aim of the current study was to examine potential long-term effects of neonatal methamphetamine exposure on behavior and cognition during adolescence. Male and female mice were exposed to methamphetamine (5 mg/kg) or saline once a day from postnatal day 11-20, the period of rodent hippocampal development. Behavioral and cognitive function was assessed during adolescence beginning on postnatal day 30. During the injection period, methamphetamine-exposed mice gained less weight on average compared to saline-exposed mice. In both male and female mice, methamphetamine exposure significantly impaired novel object recognition and there was a trend towards impaired novel location recognition. Anxiety-like behavior, sensorimotor gating, and contextual and cued fear conditioning were not affected by methamphetamine exposure. Thus, neonatal methamphetamine exposure affects cognition in adolescence and unlike in adulthood equally affects male and female mice.
doi:10.1016/j.bbr.2011.01.015
PMCID: PMC3062671  PMID: 21238498
Methamphetamine; cognition; adolescence; hippocampus; postnatal
25.  Abnormalities in Parentally Rated Executive Function in Methamphetamine/Polysubstance Exposed Children 
Methamphetamine/polysubstance abuse in women of childbearing age is a major concern because of the potential long-term detrimental effects on the brain function of the fetus following in utero exposure. A battery of established tests, including the Wechsler Abbreviated Scale of Intelligence, Conners’ Continuous Performance Test II, Behavioral Rating Inventory of Executive Function, the CMS Family Pictures and Dot Location tests, the Spatial Span test from the WISC-IV-Integrated, and a recently developed spatial learning and memory measure (Memory Island), was used to assess the effects of prenatal drug exposure on neurobehavioral performance. Participants were 7 to 9 year old children from similar socioeconomic backgrounds who either had (N = 31) or had not (N = 35) been exposed to methamphetamine/polysubstance during pregnancy. Compared to unexposed children, exposed children showed pronounced elevations (i.e. more problems) in parental ratings of executive function, including behavioral regulation and metacognition. Exposed children also exhibited subtle reductions in spatial performance in the Memory Island test. In contrast, IQ, Spatial Span, Family Pictures, Dot Location, and vigilance performance was unaffected by prenatal drug exposure history. Thus, children of women who reported using methamphetamine and other recreational drugs during pregnancy showed a selective profile of abnormalities in parentally rated executive function.
doi:10.1016/j.pbb.2011.02.013
PMCID: PMC3069661  PMID: 21334365
alcohol; learning; neuropsychology; nicotine

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