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1.  Nicotinic agonist-induced improvement of vigilance in mice in the 5-choice continuous performance test 
Behavioural brain research  2012;240:119-133.
Impaired attentional processing is prevalent in numerous neuropsychiatric disorders and may negatively impact other cognitive and functional domains. Nicotine – a nonspecific nicotinic acetylcholine receptor (nAChR) agonist – improves vigilance in healthy subjects and schizophrenia patients as measured by continuous performance tests (CPTs), but the nAChR mediating this effect remains unclear. Here we examine the effects of: a) nicotine; b) the selective α7 nAChR agonist PNU 282987; and c) the selective α4β2 nAChR agonist ABT-418 alone and in combination with scopolamine-induced disruption of mouse 5-choice (5C-)CPT performance. This task requires the inhibition of responses to non-target stimuli as well as active responses to target stimuli, consistent with human CPTs.
C57BL/6N mice were trained to perform the 5C-CPT. Drug effects were examined in extended session and variable stimulus-duration challenges of performance. Acute drug effects on scopolamine-induced disruption in performance were also investigated.
Nicotine and ABT-418 subtly but significantly improved performance of normal mice and attenuated scopolamine-induced disruptions in the 5C-CPT. PNU 282–987 had no effects on performance.
The similarity of nicotine and ABT-418 effects provides support for an α4β2 nAChR mechanism of action for nicotine-induced improvement in attention/vigilance. Moreover, the data provide pharmacological predictive validation for the 5C-CPT because nicotine improved and scopolamine disrupted normal performance of the task, consistent with healthy humans in the CPT. Future studies using more selective agonists may result in more robust improvements in performance.
doi:10.1016/j.bbr.2012.11.028
PMCID: PMC3538919  PMID: 23201359
nicotine; continuous performance test; attention; impulsivity; nicotinic acetylcholine receptors; scopolamine
2.  Differential effects of dopamine transporter inhibitors in the rodent Iowa Gambling Task: Relevance to mania 
Psychopharmacology  2012;225(3):661-674.
Rationale
The Iowa Gambling Task (IGT) can be used to quantify impulsive and risky choice behaviors in psychiatric patients, e.g. Bipolar Disorder (BD) sufferers. Although developing treatments for these behaviors is important, few predictive animal models exist. Inhibition of the dopamine transporter (DAT) can model profiles of altered motor activity and exploration seen in patients with BD. The effect of DAT inhibition on impulsive choices related to BD has received limited study however. We used a rodent IGT to elucidate the effects of similarly acting drugs on risky choice behavior.
Objectives
We hypothesized that 1) C57BL/6 mice could adopt the ‘safe’ choice options in the IGT and 2) DAT inhibition would alter risk preference.
Methods
Mice were trained in the IGT to a stable risk-preference and then administered the norepinephrine/DAT inhibitor amphetamine, or the more selective DAT inhibitors modafinil or GBR12909.
Results
Mice developed a preference for the ‘safe’ option, which was potentiated by amphetamine administration. GBR12909 or modafinil administration increased motor impulsivity, motivation significantly, and risk preference subtly.
Conclusions
The rodent IGT can measure different impulse-related behaviors and differentiate similarly acting BD-related drugs. The contrasting effects of amphetamine and modafinil in mice are similar to effects in rats and humans in corresponding IGT tasks, supporting the translational validity of the task. GBR12909 and modafinil elicited similar behaviors in the IGT, likely through a shared mechanism. Future studies using a within-session IGT are warranted to confirm the suitability of DAT inhibitors to model risk-preference in BD.
doi:10.1007/s00213-012-2854-2
PMCID: PMC3537839  PMID: 22945515
Iowa Gambling Task; dopamine transporter; bipolar disorder; risk-taking; mice; modafinil; GBR12909; amphetamine; mania; impulsivity
3.  Examining the genetic and neural components of cognitive flexibility using mice 
Physiology & behavior  2012;107(5):666-669.
This commentary summarizes the research presented during the symposium “Examining the genetic and neural components of cognitive flexibility using mice” at the annual meeting of the International Behavioral Neuroscience Society 2011. Research presented includes examining: 1) Corticostriatal networks underlying reversal learning using GluN2B knockout mice, cFos expression, and in vivo electrophysiological recording; 2) Cerebellar contribution to reversal learning using mutants with Purkinje cell loss and in vivo electrochemical recording; 3) Parvalbumin contribution to reversal learning and set-shifting using PLAUR mutants and in vitro recording to examine fast-spiking interneurones; and 4) Alpha 7 nAChR contribution to reversal learning, set-shifting, motivation, and the ‘eureka moment’ of rule acquisition. It is proposed that these studies revealed more about the neurobiology underlying these behaviors than could be discovered using pharmacological techniques alone. Together, the research presented stressed the importance of exploring the genetic contribution to neuropsychiatric disease and the important role that the mouse, coupled with robust behavioral measures, can play in understanding neurobiology underlying cognitive flexibility.
doi:10.1016/j.physbeh.2011.12.024
PMCID: PMC3337351  PMID: 22234243
executive functioning; reversal learning; mouse; in vivo electrophysiology; learning
4.  Mouse pharmacological models of cognitive disruption relevant to schizophrenia 
Neuropharmacology  2011;62(3):1381-1390.
Schizophrenia is a debilitating cognitive disorder. The link between cognitive debilitation and functional outcome in patients with schizophrenia has prompted research to develop procognitive therapies. It is hoped that by improving cognition in these patients, their functional outcome will also improve. Although no established treatments exist as yet, progress has been made toward understanding how to evaluate putative compounds in the clinic. Genetic mouse models and pharmacological rat models of cognitive disruption are being developed that may help to evaluate these putative compounds preclinically. Considering the increased number of genetic mouse models relevant to schizophrenia, there is a need to evaluate pharmacological manipulations on cognition in mice. Here we review the current literature on mouse pharmacological models relevant to schizophrenia. In this review, we discuss where different pharmacological effects between rats and mice on cognitive tasks are observed and assess the validity offered by these models. We conclude that the predictive validity of these models is currently difficult to assess and that much more needs to be done to develop useful mouse pharmacological models of cognitive disruption in schizophrenia.
doi:10.1016/j.neuropharm.2011.06.013
PMCID: PMC3217063  PMID: 21726569
Mice; pharmacological; animal models; schizophrenia; learning; memory; attention; phencyclidine, amphetamine, scopolamine
5.  Increased risk-taking behavior in dopamine transporter knockdown mice: further support for a mouse model of mania 
Reduced functioning of the dopamine transporter (DAT) has been linked to bipolar disorder (BD). Mice with reduced DAT functioning (knockdown, KD) exhibit a behavioral profile in the mouse Behavioral Pattern Monitor (BPM) consistent with patients with BD mania in the human BPM. Patients with BD also exhibit increased risk taking, which can be quantified using the Iowa Gambling Task (IGT). We hypothesized that DAT KD mice would exhibit increased risk-taking behavior in a novel mouse version of the IGT. DAT KD and wildtype (WT) littermates were trained in the mouse IGT. In session 1, KD mice initially made riskier choices, but later performed comparably to WT mice. Once trained to stable choice performance, DAT KD mice continued to exhibit a trend to choose the riskier options more than WT mice. Finally, we confirmed that these DAT KD mice also exhibited an exploratory profile in the BPM consistent with patients with BD mania, where risky choice behavior modestly correlated with specific exploration. These data demonstrate that DAT KD mice chose the riskier options more than WT mice, providing further support for the use of DAT KD mice as a model of BD mania.
doi:10.1177/0269881111400646
PMCID: PMC3568506  PMID: 21421642
Dopamine transport; Iowa Gambling Task; mania; mice; model
6.  Working memory span capacity improved by a D2 but not D1 receptor family agonist 
Behavioural brain research  2011;219(2):181-188.
Patients with schizophrenia exhibit poor working memory (WM). Although several subcomponents of WM can be measured, evidence suggests the primary subcomponent affected in schizophrenia is span capacity (WMC). Indeed, the NIMH-funded MATRICS initiative recommended assaying the WMC when assessing the efficacy of a putative therapeutic for FDA approval. Although dopamine D1 receptor agonists improve delay-dependent memory in animals, evidence for improvements in WMC due to dopamine D1 receptor activation is limited. In contrast, the dopamine D2-family agonist bromocriptine improves WMC in humans. The radial arm maze (RAM) can be used to assess WMC, although complications due to ceiling effects or strategy confounds have limited its use. We describe a 12-arm RAM protocol designed to assess whether the dopamine D1-family agonist SKF 38393 (0, 1, 3, and 10 mg/kg) or bromocriptine (0, 1, 3, and 10 mg/kg) could improve WMC in C57BL/6N mice (n=12) in cross-over designs. WMC increased and strategy usage decreased with training. The dopamine D1 agonist SKF 38393 had no effect on WMC or long-term memory. Bromocriptine decreased WMC errors, without affecting long-term memory, consistent with human studies. These data confirm that WMC can be measured in mice and reveal drug effects that are consistent with reported effects in humans. Future research is warranted to identify the subtype of the D2-family of receptors responsible for the observed improvement in WMC. Finally, this RAM procedure may prove useful in developing animal models of deficient WMC to further assess putative treatments for the cognitive deficits in schizophrenia.
doi:10.1016/j.bbr.2010.12.037
PMCID: PMC3073724  PMID: 21232557
Working memory; span capacity; dopamine D1 receptor; dopamine D2 receptor; bromocriptine; mice
7.  Prepulse inhibition in HIV-1 gp120 transgenic mice after withdrawal from chronic methamphetamine 
Behavioural pharmacology  2014;25(1):12-22.
HIV infection is frequently comorbid with methamphetamine (METH) dependence. Both factors are associated with impairment in inhibitory function that continues even after abstinence from the drug. Deficits in prepulse inhibition (PPI), a measure of sensorimotor gating, are induced by acute stimulant administration, but the combined effect of HIV and chronic METH exposure on PPI is not well characterized. We quantified baseline acoustic startle and PPI in mice expressing the HIV-1 gp120 envelope protein (gp120tg) and in wild-type (WT) littermates; thereafter, we administered a chronic regimen of METH or vehicle and tested startle and PPI after 7 days of drug withdrawal. We hypothesized that METH-treated gp120tg mice would exhibit PPI deficits compared with vehicle-treated WT or gp120tg animals. Before METH administration, drug-naive female gp120tg mice exhibited decreased PPI compared with female WT mice, whereas male gp120tg mice exhibited increased startle compared with other groups. After drug withdrawal, no consistent genotype effect was observed, but METH-treated mice exhibited increased PPI compared with vehicle, in contrast to previous reports of acute METH-induced PPI deficits. In summary, PPI impairment in HIV could depend on factors such as sex, whereas changes in PPI following METH withdrawal may depend on the quantity and duration of drug exposure.
doi:10.1097/FBP.0000000000000012
PMCID: PMC3926694  PMID: 24281153
gp120; HIV; methamphetamine; mouse; prepulse inhibition; sensorimotor gating
8.  Chronic valproate attenuates some, but not all, facets of mania-like behavior in mice 
Bipolar Disorder (BD) mania is a psychiatric disorder with multifaceted symptoms. Development of targeted treatments for BD mania may benefit from animal models that mimic multiple symptoms, as opposed to hyperactivity alone. Using the reverse-translated multivariate exploratory paradigm, the Behavioral Pattern Monitor (BPM), we reported that patients with BD mania exhibit hyperactivity as well as increased specific exploration and more linear movements through space. This abnormal profile is also observed in mice with reduced function of the dopamine transporter (DAT) through either constitutive genetic (knockdown (KD)) or acute pharmacological (GBR12909) means. Here, we assessed the pharmacological predictive validity of these models by administering the BD-treatment valproic acid (VPA) for 28 days. After 28 days of 1.5% VPA- or regular-chow treatment, C57BL/6J mice received GBR12909 (9 mg/kg) or saline and were tested in the BPM. Similarly, DAT KD and WT littermates were treated with VPA-chow and tested in the BPM. GBR12909-treated and DAT KD mice on regular chow were hyperactive, exhibited increased specific exploration, and moved in straighter patterns compared to saline-treated and WT mice respectively. Chronic 1.5% VPA-chow treatment resulted in therapeutic concentrations of VPA and ameliorated hyperactivity in both models, while specific exploration and behavioral organization remained unaffected. Hence, the mania-like profile of mice with reduced functional DAT was partially attenuated by chronic VPA treatment, consistent with the incomplete symptomatic effect of VPA treatment in BD patients. Both DAT models may help to identify therapeutics that impact the full spectrum of BD mania.
doi:10.1017/S1461145712001198
PMCID: PMC3920978  PMID: 23164454
bipolar mania; dopamine transporter; chronic treatment; valproate; mice
9.  EVALUATION OF THE CLINICAL EFFICACY OF ASENAPINE IN SCHIZOPHRENIA 
Expert opinion on pharmacotherapy  2010;11(12):2107-2115.
Importance of the field
Asenapine is a new atypical antipsychotic medication with high affinity for D2 and 5HT2A receptors that has been approved by the FDA in adults for the acute treatment of schizophrenia in the United States. The purpose of this review is to describe the compound and examine whether it addresses some of the unmet clinical needs in treating schizophrenia.
Areas covered in this review
The development of asenapine is described with attention to its chemistry, pharmacodynamic and pharmacokinetic profile. Pre-clinical and clinical trials of safety and efficacy are reviewed. The advantages and disadvantages of asenapine relative to other antipsychotic medications are discussed.
What the reader will gain
Asenapine will be evaluated for whether it: a) causes a reduction in symptoms of schizophrenia; b) has a side-effect profile minimizing extrapyramidal symptoms, weight gain, and cardiac effects; and c) affects negative and/or cognitive symptoms.
Take home message
Asenapine is a recently approved agent with an acceptable cardiometabolic profile that exhibits similar efficacy as other antipsychotic medications, primarily on positive symptoms of schizophrenia. Relatively less weight gain compared to other agents may confer a notable advantage. Sublingual administration may have positive and negative effects on patient compliance. Potential “pro-cognitive” effects of asenapine are preliminary and require further investigation.
doi:10.1517/14656566.2010.506188
PMCID: PMC2924192  PMID: 20642375
antipsychotic; asenapine; bipolar disorder; dopamine; SAPHRIS; schizophrenia; serotonin
10.  Action of modafinil – increased motivation via the dopamine transporter inhibition and D1 receptors? 
Biological psychiatry  2010;67(8):784-787.
Background
Modafinil is prescribed for the treatment of narcolepsy. It has been postulated that modafinil may treat cognitive disruption in neuropsychiatric disorders. The mechanisms underlying such modafinil-induced improvements in performance have yet to be delineated however. Recent evidence suggests that modafinil may block the dopamine transporter (DAT) and that the dopamine D1 receptor (D1R) may contribute to modafinil effects.
Methods
Dopamine D1R wildtype (WT), heterozygous (HT), and knockout (KO) mice received vehicle, modafinil, or the selective DAT blocker GBR12909 in a progressive ratio breakpoint study.
Results
Both modafinil and GBR12909 increased motivation in the task as measured by an increase in breakpoint in WT and HT mice. These drug-induced increases in motivation were reduced in dopamine D1R HT mice relative to their WT littermates. D1R KO mice did not respond in the task.
Conclusions
These data support the hypothesis that modafinil increases motivation. Moreover, given the similarity of effects with GBR12909, the data corroborate evidence that the behavioral effects of modafinil may be due to DAT inhibition. Furthermore, the dopamine D1R may play a downstream role in mediating modafinil-induced increases in motivation. Thus studies reporting cognition-enhancing effects of modafinil may have been influenced by its ability to increase motivation.
doi:10.1016/j.biopsych.2009.12.015
PMCID: PMC2849918  PMID: 20132929
Modafinil; dopamine transporter; D1 receptor; motivation; knockout; mice
11.  Behavioral Effects of Chronic Methamphetamine Treatment in HIV-1 gp120 Transgenic Mice 
Behavioural brain research  2012;236C:210-220.
Methamphetamine (METH) dependence is frequently comorbid with HIV infection. Both factors are independently characterized by inhibitory deficits, which may manifest as increased motor activity, inappropriate perseverative behavior, and elevated exploratory responses to novel stimuli, but the effect of combined METH exposure and HIV is not well understood. In this study, we administered a chronic escalation/binge regimen of METH or vehicle treatment to wildtype (WT) or transgenic (tg) mice expressing the HIV-1 gp120 envelope protein and quantified disinhibition during the 7 days following drug withdrawal. We hypothesized that gp120tg mice administered chronic METH would exhibit more pronounced inhibitory deficits compared to vehicle-treated WT or gp120tg animals. Our results showed that METH treatment alone increased novel object interaction while female METH-treated gp120tg mice exhibited the highest level of exploration (holepoking) compared to other female mice. Transgenic mice exhibited fewer rears relative to WT, slightly less locomotion, and also demonstrated a trend towards more perseverative motor patterns. In summary, both METH treatment and gp120 expression may modify inhibition, but such effects are selective and dependent upon variations in age and sex that could impact dopamine and frontostriatal function. These findings illustrate the need to improve our knowledge about the combined effects of HIV and substance use and facilitate improved treatment methods for comorbid disease and drug dependence.
doi:10.1016/j.bbr.2012.08.037
PMCID: PMC3482284  PMID: 22960458
HIV; methamphetamine; gp120; inhibition; behavioral pattern monitor
12.  Four factors underlying mouse behavior in an open field 
Behavioural brain research  2012;233(1):10.1016/j.bbr.2012.04.045.
The observation of the locomotor and exploratory behaviors of rodents in an open field is one of the most fundamental methods used in the field of behavioral pharmacology. A variety of behaviors can be recorded automatically and can readily generate a multivariate pattern of pharmacological effects. Nevertheless, the optimal ways to characterize observed behaviors and concomitant drug effects are still under development. The aim of this study was to extract meaningful behavioral factors that could explain variations in the observed variables from mouse exploration. Behavioral data were recorded from male C57BL/6J mice (n = 268) using the Behavioral Pattern Monitor (BPM). The BPM data were subjected to the exploratory factor analysis. The factor analysis extracted four factors: activity, sequential organization, diversive exploration, and inspective exploration. The activity factor and the two types of exploration factors correlated positively with one another, while the sequential organization factor negatively correlated with the remaining factors. The extracted factor structure constitutes a behavioral model of mouse exploration. This model will provide a platform on which one can assess the effects of psychoactive drugs and genetic manipulations on mouse exploratory behavior. Further studies are currently underway to examine the factor structure of similar multivariate data sets from humans tested in a human BPM.
doi:10.1016/j.bbr.2012.04.045
PMCID: PMC3866095  PMID: 22569582
Dimension; Exploration; Factor analysis; Locomotion; Open field
13.  Dopamine D1 and D2 receptor family contributions to modafinil-induced wakefulness 
doi:10.1523/JNEUROSCI.5843-08.2009
PMCID: PMC2697968  PMID: 19261860
Modafinil; wakefulness; sleep; D1; D2; dopamine transporter; knockout; mice
14.  Reward learning as a potential target for pharmacological augmentation of cognitive remediation for schizophrenia: a roadmap for preclinical development 
Rationale: Impaired cognitive abilities are a key characteristic of schizophrenia. Although currently approved pharmacological treatments have demonstrated efficacy for positive symptoms, to date no pharmacological treatments successfully reverse cognitive dysfunction in these patients. Cognitively-based interventions such as cognitive remediation (CR) and other psychosocial interventions however, may improve some of the cognitive and functional deficits of schizophrenia. Given that these treatments are time-consuming and labor-intensive, maximizing their effectiveness is a priority. Augmenting psychosocial interventions with pharmacological treatments may be a viable strategy for reducing the impact of cognitive deficits in patients with schizophrenia.
Objective: We propose a strategy to develop pharmacological treatments that can enhance the reward-related learning processes underlying successful skill-learning in psychosocial interventions. Specifically, we review clinical and preclinical evidence and paradigms that can be utilized to develop these pharmacological augmentation strategies. Prototypes for this approach include dopamine D1 receptor and α7 nicotinic acetylcholine receptor agonists as attractive targets to specifically enhance reward-related learning during CR.
Conclusion: The approach outlined here could be used broadly to develop pharmacological augmentation strategies across a number of cognitive domains underlying successful psychosocial treatment.
doi:10.3389/fnins.2013.00103
PMCID: PMC3684768  PMID: 23785309
schizophrenia; cognitive remediation; augmentation; DRD1; nAChR
15.  The effect of reduced dopamine D4 receptor expression in the 5-choice continuous performance task: Separating response inhibition from premature responding 
Behavioural brain research  2011;222(1):183-192.
Impairments in attention/vigilance and response disinhibition are commonly observed in several neuropsychiatric disorders. Validating animal models could help in developing therapeutics for cognitive deficits and improving functional outcomes in such disorders. The 5-choice continuous performance test (5C-CPT) in mice offers the opportunity to assess vigilance and two forms of impulsivity. Since reduced dopamine D4 receptor (DRD4) function is implicated in several disorders, DRD4 is a potential therapeutic target for cognition enhancement.
We trained wildtype (WT), heterozygous (HT), and knockout (KO) mice of the murine Drd4 to perform the 5C-CPT under baseline and variable stimulus duration conditions. To dissect motor impulsivity (premature responding) from behavioral disinhibition (false alarms), we administered the 5-HT2C antagonist SB242084 during an extended inter-trial-interval session. We also examined the preattentive and exploratory profile of these mice in prepulse inhibition (PPI) and the Behavioral Pattern Monitor (BPM).
Reduced Drd4 expression in HT mice, as confirmed by quantitative RT-PCR, resulted in response dis-inhibition and impaired 5C-CPT performance, while premature responding was unaffected. Conversely, SB242084 increased premature responding without affecting response inhibition or attentional measures. No genotypic differences were observed in PPI or BPM behavior.
Thus, reduced Drd4 expression impairs attentional performance, but not other behaviors associated with neuropsychiatric disorders. Moreover, the use of signal and non-signal stimuli in the 5C-CPT enabled the differentiation of response disinhibition from motor impulsivity in a vigilance task.
doi:10.1016/j.bbr.2011.03.054
PMCID: PMC3531561  PMID: 21458500
Attention; Dopamine D4 receptor; Impulsivity; Vigilance; 5-HT2C receptor
16.  Dopamine Receptor Mediation of the Exploratory/Hyperactivity Effects of Modafinil 
Neuropsychopharmacology  2011;36(7):1385-1396.
Modafinil (2-((diphenylmethyl)sulfinyl)acetamide) is described as an atypical stimulant and is a putative cognition enhancer for schizophrenia, but the precise mechanisms of action remain unclear. Receptor knockout (KO) mice offer an opportunity to identify receptors that contribute to a drug-induced effect. Here we examined the effects of modafinil on exploration in C57BL/6J mice, in dopamine drd1, drd2, drd3, and drd4 wild-type (WT), heterozygous (HT), and KO mice, and in 129/SJ mice pretreated with the drd1 antagonist SCH23390 using a cross-species test paradigm based on the behavioral pattern monitor. Modafinil increased activity, specific exploration (rearing), and the smoothness of locomotor paths (reduced spatial d) in C57BL/6J and 129/SJ mice (increased holepoking was also observed in these mice). These behavioral profiles are similar to that produced by the dopamine transporter inhibitor GBR12909. Modafinil was ineffective at increasing activity in male drd1 KOs, rearing in female drd1 KOs, or reducing spatial d in all drd1 KOs, but produced similar effects in drd1 WT and HT mice as in C57BL/6J mice. Neither dopamine drd2 nor drd3 mutants attenuated modafinil-induced effects. Drd4 mutants exhibited a genotype dose-dependent attenuation of modafinil-induced increases in specific exploration. Furthermore, the drd1 KO effects were largely supported by the SCH23390 study. Thus, the dopamine drd1 receptor appears to exert a primary role in modafinil-induced effects on spontaneous exploration, whereas the dopamine drd4 receptor appears to be important for specific exploration. The modafinil-induced alterations in exploratory behavior may reflect increased synaptic dopamine and secondary actions mediated by dopamine drd1 and drd4 receptors.
doi:10.1038/npp.2011.23
PMCID: PMC3096808  PMID: 21412225
modafinil; dopamine receptors; D1; D4; exploration; dopamine transporter; D1; D2; D3; D4; dopamine; exploration; knockout; mice; modafinil; neurotransmitters; psychostimulants; receptor pharmacology
17.  Attentional Processing in C57BL/6J Mice Exposed to Developmental Vitamin D Deficiency 
PLoS ONE  2012;7(4):e35896.
Epidemiological evidence suggests that Developmental Vitamin D (DVD) deficiency is associated with an increased risk of schizophrenia. DVD deficiency in mice is associated with altered behaviour, however there has been no detailed investigation of cognitive behaviours in DVD-deficient mice. The aim of this study was to determine the effect of DVD deficiency on a range of cognitive tasks assessing attentional processing in C57BL/6J mice. DVD deficiency was established by feeding female C57BL/6J mice a vitamin D-deficient diet from four weeks of age. After six weeks on the diet, vitamin D-deficient and control females were mated with vitamin D-normal males and upon birth of the pups, all dams were returned to a diet containing vitamin D. The adult offspring were tested on a range of cognitive behavioural tests, including the five-choice serial reaction task (5C-SRT) and five-choice continuous performance test (5C-CPT), as well as latent inhibition using a fear conditioning paradigm. DVD deficiency was not associated with altered attentional performance on the 5C-SRT. In the 5C-CPT DVD-deficient male mice exhibited an impairment in inhibiting repetitive responses by making more perseverative responses, with no changes in premature or false alarm responding. DVD deficiency did not affect the acquisition or retention of cued fear conditioning, nor did it affect the expression of latent inhibition using a fear conditioning paradigm. DVD-deficient mice exhibited no major impairments in any of the cognitive domains tested. However, impairments in perseverative responding in DVD-deficient mice may indicate that these animals have specific alterations in systems governing compulsive or reward-seeking behaviour.
doi:10.1371/journal.pone.0035896
PMCID: PMC3338544  PMID: 22563415
18.  Initial evidence linking synaptic superoxide production with poor short-term memory in aged mice 
Brain research  2010;1368:65-70.
Unregulated production of reactive oxygen species (ROS) is a marker of cellular and organismal aging linked to cognitive decline in humans and rodents. The sources of elevated ROS contributing to cognitive decline are unknown. Because NADPH oxidase (Nox) inhibition may prevent memory decline with age, we hypothesized that Nox and not mitochondrial sources of synaptic ROS production are linked to individual variance in cognitive performance in aged mice. Young (8 mo) and aged (26 mo) mice were tested in the novel object recognition task (NORT). Mitochondrial and Nox ROS production was assayed in isolated synaptosomes using spin-trapping electron paramagnetic resonance (EPR) spectroscopy. Aged mice exhibited variance in NORT performance, with some performing similar to young mice while others exhibited poorer short-term memory. EPR studies indicated that Nox rather than mitochondria was the major ROS source at the synapse, and Nox- but not mitochondrial-induced ROS levels correlated with NORT performance in aged mice. Our findings support the hypothesis that variance in Nox-specific synaptic ROS production may predict short-term memory deficits with age.
doi:10.1016/j.brainres.2010.11.009
PMCID: PMC3018762  PMID: 21075081
aging; short-term memory; superoxide; NADPH oxidase; mitochondria; synaptosomes
19.  Repeated Assessment of Exploration and Novelty Seeking in the Human Behavioral Pattern Monitor in Bipolar Disorder Patients and Healthy Individuals 
PLoS ONE  2011;6(8):e24185.
Background
Exploration and novelty seeking are cross-species adaptive behaviors that are dysregulated in bipolar disorder (BD) and are critical features of the illness. While these behaviors have been extensively quantified in animals, multivariate human paradigms of exploration are lacking. The human Behavioral Pattern Monitor (hBPM), a human version of the animal open field, identified a signature pattern of hyper-exploration in manic BD patients, but whether exploratory behavior changes with treatment is unknown. The objective of this study was to assess the sensitivity of the hBPM to changes in manic symptoms, a necessary step towards elucidating the neurobiology underlying BD.
Methodology and Principal Findings
Twelve acutely hospitalized manic BD subjects and 21 healthy volunteers were tested in the hBPM over three sessions; all subjects were retested one week after their first session and two weeks after their second session. Motor activity, spatial and entropic (degree of unpredictability) patterns of exploration, and interactions with novel objects were quantified. Manic BD patients demonstrated greater motor activity, extensive and more unpredictable patterns of exploration, and more object interactions than healthy volunteers during all three sessions. Exploration and novelty-seeking slightly decreased in manic BD subjects over the three sessions as their symptoms responded to treatment, but never to the level of healthy volunteers. Among healthy volunteers, exploration did not significantly decrease over time, and hBPM measures were highly correlated between sessions.
Conclusions/Significance
Manic BD patients showed a modest reduction in symptoms yet still demonstrated hyper-exploration and novelty seeking in the hBPM, suggesting that these illness features may be enduring characteristics of BD. Furthermore, behavior in the hBPM is not subject to marked habituation effects. The hBPM can be reliably used in a repeated-measures design to characterize exploration and novelty seeking and, in parallel with animal studies, can contribute to developing treatments that target neuropsychiatric disease.
doi:10.1371/journal.pone.0024185
PMCID: PMC3166173  PMID: 21912623
20.  Factor analysis of attentional set-shifting performance in young and aged mice 
Background
Executive dysfunction may play a major role in cognitive decline with aging because frontal lobe structures are particularly vulnerable to advancing age. Lesion studies in rats and mice have suggested that intradimensional shifts (IDSs), extradimensional shifts (EDSs), and reversal learning are mediated by the anterior cingulate cortex, the medial prefrontal cortex, and the orbitofrontal cortex, respectively. We hypothesized that the latent structure of cognitive performance would reflect functional localization in the brain and would be altered by aging.
Methods
Young (4 months, n = 16) and aged (23 months, n = 18) C57BL/6N mice performed an attentional set-shifting task (ASST) that evaluates simple discrimination (SD), compound discrimination (CD), IDS, EDS, and reversal learning. The performance data were subjected to an exploratory factor analysis to extract the latent structures of ASST performance in young and aged mice.
Results
The factor analysis extracted two- and three-factor models. In the two-factor model, the factor associated with SD and CD was clearly separated from the factor associated with the rest of the ASST stages in the young mice only. In the three-factor model, the SD and CD loaded on distinct factors. The three-factor model also showed a separation of factors associated with IDS, EDS, and CD reversal. However, the other reversal learning variables, ID reversal and ED reversal, had somewhat inconsistent factor loadings.
Conclusions
The separation of performance factors in aged mice was less clear than in young mice, which suggests that aged mice utilize neuronal networks more broadly for specific cognitive functions. The result that the factors associated with SD and CD were separated in the three-factor model may suggest that the introduction of an irrelevant or distracting dimension results in the use of a new/orthogonal strategy for better discrimination.
doi:10.1186/1744-9081-7-33
PMCID: PMC3174878  PMID: 21838910
21.  The mania-like exploratory profile in genetic dopamine transporter mouse models is diminished in a familiar environment and reinstated by subthreshold psychostimulant administration 
Bipolar Disorder (BD) is a neuropsychiatric disorder characterized by symptoms ranging from a hyperactive manic state to depression, with periods of relative stability, known as euthymia, in between. Although prognosis for BD sufferers remains poor, treatment development has been restricted due to a paucity of validated animal models. Moreover, most models focus on the manic state of BD with little done to characterize the longitudinal behavior of these models. We recently presented two dopamine transporter (DAT) mouse models of BD mania: genetic (DAT knockdown; KD, mice) and pharmacological (the selective DAT inhibitor GBR 12909). These models exhibit an exploratory profile consistent with the quantified exploratory profile of manic BD patients observed in the cross-species translational test, the Behavioral Pattern Monitor (BPM).
To further explore the suitability of these models, we examined the effects of reduced DAT function on the behavior of mice testing after familiarization to the BPM environment. Testing with 16 mg/kg GBR 12909 in familiarized mice resulted in a consistent mania-like profile. In contrast, the mania-like profile of DAT KD mice disappears in a familiar environment, with partial reinstatement elicited by the introduction of novelty. In addition, we found that a sub-threshold dose of GBR 12909 (9 mg/kg) reinstated the mania-like profile in DAT KD mice without affecting wildtype behavior.
Thus, the mania-like exploratory profile of DAT KD mice is reduced in a familiar environment, partially reinstated with novelty, but is fully restored when administered a stimulant that is ineffective in wildtype mice. These mice may provide a model of BD from mania to euthymia and back again with stimulant treatment. Acute blockade of the DAT by GBR 12909 however, may provide a consistent model for BD mania.
doi:10.1016/j.pbb.2010.03.014
PMCID: PMC2878916  PMID: 20363246
22.  Cross-species assessments of Motor and Exploratory Behavior related to Bipolar Disorder 
Alterations in exploratory behavior are a fundamental feature of bipolar mania, typically characterized as motor hyperactivity and increased goal-directed behavior in response to environmental cues. In contrast, abnormal exploration associated with schizophrenia and depression can manifest as prominent withdrawal, limited motor activity, and inattention to the environment. While motor abnormalities are cited frequently as clinical manifestations of these disorders, relatively few empirical studies have quantified human exploratory behavior. This article reviews the literature characterizing motor and exploratory behavior associated with bipolar disorder and genetic and pharmacological animal models of the illness. Despite sophisticated assessment of exploratory behavior in rodents, objective quantification of human motor activity has been limited primarily to actigraphy studies with poor cross-species translational value. Furthermore, symptoms that reflect the cardinal features of bipolar disorder have proven difficult to establish in putative animal models of this illness. Recently, however, novel tools such as the Human Behavioral Pattern Monitor provide multivariate translational measures of motor and exploratory activity, enabling improved understanding of the neurobiology underlying psychiatric disorders.
doi:10.1016/j.neubiorev.2010.04.002
PMCID: PMC2900445  PMID: 20398694
bipolar disorder; animal models; rodent; open field test; exploration; hyperactivity; behavior pattern monitor; dopamine
23.  Quantifying over-activity in bipolar and schizophrenia patients in a human open field Paradigm 
Psychiatry research  2010;178(1):84-91.
It has been suggested that a cardinal symptom of mania is over-activity and exaggerated goal-directed behavior. Nevertheless, few attempts have been made to quantify this behavior objectively in a laboratory environment. Having a methodology to assess over-activity reliably might be useful in distinguishing manic bipolar disorder (BD) from schizophrenia (SCZ) during highly activated states. In the current study, quantifiable measures of object-interaction were assessed using a multivariate approach. Additionally, symptom correlates of over-activity were assessed. Patients admitted to an acute care psychiatric hospital for either BD with mania or SCZ (paranoid and non-paranoid subtypes) as well as non-patient comparison (NC) participants were assessed in an open field setting referred to as the human Behavioral Pattern Monitor (hBPM). Activity and interactions with novel and engaging objects were recorded for 15 minutes via a concealed video camera and rated for exploratory behavior. Both BD and SCZ patients spent more time near the objects and exhibited more overall walking compared to NC. In contrast, BD patients exhibited greater physical contact with objects (number of object interactions and time spent with objects) relative to SCZ patients or NC participants, as well as more perseverative and socially disinhibited behaviors, indicating a unique pattern of over-activity and goal-directed behavior. Further analyses revealed a distinction between SCZ patients according to their subtype. The current study extends our methodology for quantifying exploration and over-activity in a controlled laboratory setting and aids in assessing the overlap and distinguishing characteristics of BD and SCZ.
doi:10.1016/j.psychres.2010.04.032
PMCID: PMC2914139  PMID: 20471103
24.  Age-associated improvements in cross-modal prepulse inhibition in mice 
Behavioral neuroscience  2010;124(1):133-140.
Prepulse inhibition (PPI) is an operational measure of sensorimotor gating that is thought to probe pre-attentional filtering mechanisms. PPI is deficient in several neuropsychiatric disorders, possibly reflecting abnormalities in frontal-cortical-striatal circuitry. Several studies support the predictive validity of animal PPI to model human sensorimotor gating phenomena but only limited studies have addressed the effects of aging. Studies in humans suggest that PPI is improved or unaffected as humans age (>60 years) and does not correlate with cognitive decline in aged populations. Rodent studies to date, however, suggest that PPI declines with age. Here we tested the hypothesis that PPI measures in rodents are sensitive to stimulus modality, with the prediction that intact sensory modalities in aged animals would be predictive of aging-induced increases in PPI. To test our hypothesis, we assessed PPI using acoustic, tactile, and visual prepulses in young (4 month) and old (23 month) C57BL/6N mice. Consistent with data across species, we observed reduced startle reactivity in older mice. Aging effects on PPI interacted significantly with prepulse modality, with deficient acoustic PPI but increased visual and tactile PPI in aged animals. These data are therefore consistent with PPI studies in older humans when controlling for hearing impairments. The results are discussed in terms of 1) cross-species translational validity for mouse PPI testing, 2) the need for startle reactivity differences to be accounted for in PPI analyses, and 3) the utility of cross-modal PPI testing in subjects where hearing loss has been documented.
doi:10.1037/a0018462
PMCID: PMC3088993  PMID: 20141288
Prepulse Inhibition; aging; cross-modal; translational validity
25.  Increased hippocampal accumulation of autophagosomes predicts short-term recognition memory impairment in aged mice 
Age  2011;34(2):305-316.
Constitutive macroautophagy involved in the turnover of defective long-lived proteins and organelles is crucial for neuronal homeostasis. We hypothesized that macroautophagic dysregulation in selective brain regions was associated with memory impairment in aged mice. We used the single-trial object recognition test to measure short-term memory in 18 aged mice compared to 22 young mice and employed immunohistochemistry to assess cellular distribution of proteins involved in the selective degradation of ubiquitinated proteins via macroautophagy. Values of the discrimination ratio (DR, a measure of short-term recognition memory performance) in aged mice were significantly lower than those in young mice (median, 0.54 vs. 0.67; p = 0.005, U test). Almost exclusively in aged mice, there were clusters of puncta immunoreactive for microtubule-associated protein 1 light chain 3 (LC3), ubiquitin- and LC3-binding protein p62, and ubiquitin in neuronal processes predominantly in the hippocampal formation, olfactory bulb/tubercle, and cerebellar cortex. The hippocampal burden of clustered puncta immunoreactive for LC3 and p62 exhibited inverse linear correlations with DR in aged mice (ρ = −0.48 and −0.55, p = 0.044 and 0.018, respectively, Spearman’s rank correlation). These findings suggest that increased accumulation of autophagosomes within neuronal processes in selective brain regions is characteristic of aging. The dysregulation of macroautophagy can adversely affect the turnover of aggregate-prone proteins and defective organelles, which may contribute to memory impairment in aged mice.
doi:10.1007/s11357-011-9234-4
PMCID: PMC3312638  PMID: 21431350
Autophagy; Brain aging; MAP1LC3; Object recognition test; p62; Ubiquitin

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