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Publications in this journal

• Sensorimotor Gating and Memory Deficits in an APP/PS1 Double Transgenic Mouse Model of Alzheimer's Disease.

  Authors: Hongxing Wang, Jue He, Ruiguo Zhang, Shenghua Zhu, Junhui Wang, Jiming Kong, Xin-Min Li

  Behavioural brain research.

  Alzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive deterioration and neuropsychiatric symptoms. Sensorimotor gating deficit has been identified in neuropsychiatricAlzheimer's disease (AD) is a neurodegenerative disorder associated with cognitive deterioration and neuropsychiatric symptoms. Sensorimotor gating deficit has been identified in neuropsychiatric diseases. The aim of the present study was to evaluate the possible sensorimotor gating deficit and its correlation to memory impairment and cerebral β-amyloid (Aβ) plaque deposits in an amyloid precursor protein (APP)/presenilin-1 (PS1) double transgenic mouse model of AD. The sensorimotor gating in 3-, 7- and 22-month old non-transgenic and transgenic mice was evaluated in a prepulse inhibition (PPI) task. Results revealed that the PPI was lower in the 7- and 22-month old transgenic mice compared with the age-matched control, while the response to startle pulse-alone in the transgenic and non-transgenic mice was comparable. Congo red staining showed that Aβ neuropathology of transgenic mice aggravated with age, and the 3-month old transgenic mice started to have minimum brain Aβ plaques, corresponding to the early stage of AD phenotype. Furthermore, memory impairment in the 7-month old transgenic mice was detected in a water maze test. These results suggest that the sensorimotor gating is impaired with the progressing of AD phenotype, and its deficit may be correlated to cerebral Aβ neuropathology and memory impairment in the APP/PS1 transgenic mouse model of AD.

• Behavioral Effects of Environmental Enrichment during Gestation in WKY and Wistar rats.

  Authors: Ateret Rosenfeld, Aron Weller

  Behavioural brain research.

  Effects of prenatal environmental enrichment (EE) were examined in Wistar Kyoto (WKY) "depressive- and anxious-like" rats and Wistar rats. During gestation, dams lived in standard cages or in EEEffects of prenatal environmental enrichment (EE) were examined in Wistar Kyoto (WKY) "depressive- and anxious-like" rats and Wistar rats. During gestation, dams lived in standard cages or in EE cages. Their behavior during gestation and lactation was observed. On weaning day they were tested in the forced swimming test, and corticosterone concentration was measured from their plasma. The offspring, reared in standard environment, were tested as juveniles or young adults in the Elevated plus maze, Open field and Forced swimming tests. Corticosterone concentration in feces was analyzed. EE offspring showed more anxiety-like behaviors and less activity, compared to controls. Effects were more prominent at youth than at adulthood and in Wistar rats more than in WKY. EE lowered corticosterone concentration in young WKY rats' feces. EE induced changes in the dams' behavior during gestation and lactation. These changes in dams' behavior could be mediators of the effects on the offspring.

• Disruption of overshadowing and latent inhibition in high schizotypy individuals.

  Authors: K T Granger, J Prados, A M J Young

  Behavioural brain research.

  Deficits in selective attention are seen in positively symptomatic schizophrenia sufferers, and in normal people displaying schizotypal traits. We investigated the relationship between selectiveDeficits in selective attention are seen in positively symptomatic schizophrenia sufferers, and in normal people displaying schizotypal traits. We investigated the relationship between selective attention and schizotypy in undergraduate students, by comparing participants' performance in two models of selective attention, overshadowing and latent inhibition, with psychoticism scores derived from the Oxford-Liverpool Inventory of Feelings and Experiences (O-LIFE). Using a novel within-subject overshadowing task, we showed that the unusual experiences dimension of schizotypy, but not the other three O-LIFE dimensions, was negatively related to overshadowing score. We also replicated findings that the unusual experiences dimension of schizotypy was negatively related to latent inhibition score. These experiments provide evidence that selective attention is disrupted in normal individuals showing traits relating to positive-like schizophrenic symptoms, and has implications for interpreting selective attention deficits measured in schizophrenia patients.

• Dopamine signaling in the medial prefrontal cortex and amygdala is required for the acquisition of fructose-conditioned flavor preferences in rats.

  Authors: Danielle Malkusz, Theodore Banakos, Andrew Mohamed, Tracy Vongwattanakit, Gina Malkusz, Shermeen Saeed, Tara Bohn, Stewart Martinez, Fizza Mahmud, Cammi Liss, Abraham Rozi, Khalid Touzani, Anthony Sclafani, Richard J Bodnar

  Behavioural brain research.

  Systemic administration of dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC) antagonists blocked both acquisition and expression of fructose-conditioned flavor preferences (CFP). It isSystemic administration of dopamine (DA) D1 (SCH23390: SCH) and D2 (raclopride: RAC) antagonists blocked both acquisition and expression of fructose-conditioned flavor preferences (CFP). It is unclear what brain circuits are involved in mediating these effects. The present study investigated DA signaling within the nucleus accumbens shell (NAcS), amygdala (AMY) and medial prefrontal cortex (mPFC) in the acquisition and expression of fructose-CFP. In Experiment 1, separate groups of rats were injected daily in the NAcS or AMY with saline, SCH (24 nmol) or RAC (24 nmol) prior to training sessions with a flavor (CS+) mixed with 8% fructose and 0.2% saccharin (CS+/F) and a different flavor (CS-) mixed with only 0.2% saccharin. In the two-bottle choice tests with 0.2% saccharin, only rats injected with RAC in the AMY failed to acquire a CS+ preference (45-54%). In Experiment 2, new rats were identically trained, but saline, SCH and RAC were injected in the mPFC. In subsequent two-bottle choice tests, SCH-and RAC-treated rats failed to exhibit a CS+ preference (50-56%). In Experiment 3, new rats were trained with CS+/F and CS- without injections. Subsequent two-bottle choice tests were then conducted following bilateral injections of SCH or RAC in the mPFC at total doses of 0, 12, 24 and 48 nmol. Expression of the CS+ preference failed to be affected by either antagonist, indicating that the mPFC is not involved in the maintenance of this preference. These data indicate that the acquisition of fructose-CFP is dependent on DA signaling in the mPFC and AMY.

• Activation of GABAergic pathway by hypocretin in the median raphe nucleus (MRN) mediates stress-induced theta rhythm in rats.

  Authors: Yi-Tse Hsiao, Shou-Bin Jou, Pei-Lu Yi, Fang-Chia Chang

  Behavioural brain research.

  The frequency of electroencephalograms (EEGs) is predominant in theta rhythm during stress (e.g. footshock) in rats. Median raphe nucleus (MRN) desynchronizes hippocampal theta waves via activationThe frequency of electroencephalograms (EEGs) is predominant in theta rhythm during stress (e.g. footshock) in rats. Median raphe nucleus (MRN) desynchronizes hippocampal theta waves via activation of GABAergic neurons in the medial septum-diagonal band of Broca (MS-DBB), a theta rhythm pacemaker. Increased hypocretin mediates stress responses in addition to the maintenance of wakefulness. Hypocretin receptors are abundant in the MRN, suggesting a possible role of hypocretin in modulating stress-induced theta rhythm. Our results indicated that the intensity of theta waves was enhanced by footshock and that a hypocretin receptor antagonist (TCS1102) suppressed the footshock-induced theta waves. Administration of hypocretin-1 (1 and 10μg) and hypocretin-2 (10μg) directly into the MRN simulated the effect of footshock and significantly increased theta waves. Co-administration of GABA(A) receptor antagonist, bicuculline, into the MRN blocked the increase of theta waves induced by hypocretins or footshock. These results suggested that stress enhances the release of hypocretins, activates GABAergic neurons in the MRN, blocks the ability of MRN to desynchronize theta waves, and subsequently increases the intensity of theta rhythm.

• Evidence of a progressive motor dysfunction in Mucopolysaccharidosis type I mice.

  Authors: Guilherme Baldo, Fabiana Quoos Mayer, Barbara Martinelli, Anna Dilda, Fabiola Meyer, Katherine P Ponder, Roberto Giugliani, Ursula Matte

  Behavioural brain research.

  Mucopolysaccharidosis (MPS) type I (Hurler syndrome) is a lysosomal storage disorder characterized by deficiency of alpha-L-iduronidase (IDUA), intracellular storage of glycosaminoglycans (GAGs) andMucopolysaccharidosis (MPS) type I (Hurler syndrome) is a lysosomal storage disorder characterized by deficiency of alpha-L-iduronidase (IDUA), intracellular storage of glycosaminoglycans (GAGs) and progressive neurological pathology. The MPS I mouse model provides an opportunity to study the pathophysiology of this disorder and to determine the efficacy of novel therapies. Previous work has demonstrated a series of abnormalities in MPS I mice behavior, but so far some important brain functions have not been addressed. Therefore, in the present study we aimed to determine if MPS I mice have motor abnormalities, and at what age they become detectable. MPS I and normal male mice from 2 to 8 months of age were tested in open-field for locomotor activity, hindlimb gait analysis and hang wire performance. We were able to detect a progressive reduction in the crossings and rearings in the open field test and in the hang wire test in MPS I mice from 4 months, as well as a reduction in the gait length at 8 months. Histological examination of 8-month old mice cortex and cerebellum revealed storage of GAGs in Purkinje cells and neuroinflammation, evidenced by GFAP immunostaining. However TUNEL staining was negative, suggesting that death does not occur. Our findings suggest that MPS I mice have a progressive motor dysfunction, which is not caused by loss of neuron cells but might be related to a neuroinflammatory process.

• Voluntary exercise offers anxiolytic potential and amplifies galanin gene expression in the locus coeruleus of the rat.

  Authors: Natale R Sciolino, Rodney K Dishman, Philip V Holmes

  Behavioural brain research.

  Although exercise improves anxiety in humans, it is controversial whether exercise is anxiolytic in rodents. We tested the hypothesis that stress influences the effect of exercise on anxiety-like andAlthough exercise improves anxiety in humans, it is controversial whether exercise is anxiolytic in rodents. We tested the hypothesis that stress influences the effect of exercise on anxiety-like and defensive behaviors. To explore the neurobiological mechanisms of exercise, we also examined whether exercise alters gene expression for the stress-related peptide galanin. Rats were housed in the presence or absence of a running wheel for 21 d. A subset of these rats were (1) not injected or received a single high, dose of the β-carboline FG7142 (inverse agonist at the benzodiazepine receptor site) immediately prior to testing or (2) were injected repeatedly with vehicle or FG7142 during the last 10 d of exercise. On day 22, anxiety-like and defensive behaviors were measured in the elevated plus maze, shock probe defensive burying, and defensive withdrawal tests. Locus coeruleus prepro-galanin mRNA was measured by in situ hybridization. Exercise and sedentary rats that were not injected exhibited similar behavior in all tests, whereas FG7142 injected immediately prior to the test battery produced intense avoidance and immobility consistent with an anxiety-like response. However, exercise produced anxiolytic-like and active defensive behaviors in the test battery relative to the sedentary condition in rats injected repeatedly with vehicle or FG7142. Exercise also increased prepro-galanin mRNA in the locus coeruleus relative to sedentary controls. These data suggest that the emergence of enhanced adaptive behavior after chronic voluntary exercise is influenced by stress. Our data support a role for galanin in the beneficial consequences of wheel running.

• Sex differences in object recognition are modulated by object similarity.

  Authors: Tania Bettis, Lucia F Jacobs

  Behavioural brain research.

  How females and males differ in performance in object recognition tasks appears to vary among mammalian species, with female superiority found in the laboratory rat and humans but not in theHow females and males differ in performance in object recognition tasks appears to vary among mammalian species, with female superiority found in the laboratory rat and humans but not in the laboratory mouse. Here we assessed sex differences in object recognition in C57BL/J6 mice by varying the similarity between objects to be learned. Females outperformed males in object recognition when the novel object was similar to a previously learned object.

• Involvement of the basolateral complex and central nucleus of amygdala in the omission effects of different magnitudes of reinforcement.

  Authors: Danielle M Judice-Daher, Tatiane F Tavares, José Lino O Bueno

  Behavioural brain research.

  Evidence from appetitive Pavlovian and instrumental conditioning studies suggest that the amygdala is involved in modulation of responses correlated with motivational states, and therefore, to theEvidence from appetitive Pavlovian and instrumental conditioning studies suggest that the amygdala is involved in modulation of responses correlated with motivational states, and therefore, to the modulation of processes probably underlying reinforcement omission effects. The present study aimed to clarify whether or not the mechanisms related to reinforcement omission effects of different magnitudes depend on basolateral complex and central nucleus of amygdala. Rats were trained on a fixed-interval 12s with limited hold 6s signaled schedule in which correct responses were always followed by one of two reinforcement magnitudes. Bilateral lesions of the basolateral complex and central nucleus were made after acquisition of stable performance. After postoperative recovery, the training was changed from 100% to 50% reinforcement schedules. The results showed that lesions of the basolateral complex and central nucleus did not eliminate or reduce, but interfere with reinforcement omission effects. The response from rats of both the basolateral complex and central nucleus lesioned group was higher relative to that of the rats of their respective sham-lesioned groups after reinforcement omission. Thus, the lesioned rats were more sensitive to the omission effect. Moreover, the basolateral complex lesions prevented the magnitude effect on reinforcement omission effects. Basolateral complex lesioned rats showed no differential performance following omission of larger and smaller reinforcement magnitude. Thus, the basolateral complex is involved in incentive processes relative to omission of different reinforcement magnitudes. Therefore, it is possible that reinforcement omission effects are modulated by brain circuitry which involves amygdala.

• The effects of lesion of the olfactory epithelium on morphine-induced sensitization and conditioned place preference in mice.

  Authors: Haichen Niu, Yingwei Zheng, Joshua D Rizak, Yaodong Fan, Wei Huang, Yuanye Ma, Hao Lei

  Behavioural brain research.

  Animals attain information about their environment through different sense organs. For example, the dominant external resource about the environment for rodents is obtained through olfaction.Animals attain information about their environment through different sense organs. For example, the dominant external resource about the environment for rodents is obtained through olfaction. However, many environmental conditions (stress or enriched environment) are known to affect an animal's susceptibility to drug addiction. However, it is not known how external information is integrated and paired with drug stimuli to develop into addictive behavior. Here, we investigated the effects of olfactory epithelium lesions induced with ZnSO4 effusion (ZnE) on morphine-induced sensitization and conditioned place preference in mice. We found that the lesion of the olfactory epithelium attenuated the repeated morphine (40mg/kg)-induced behavioral sensitization and morphine-induced conditioned place preference (CPP) behaviors, such as hyper-locomotion during morphine (40mg/kg) conditioned training. Additionally, the expression of FosB-like proteins, transcription factors associated with behavioral alterations, in the nucleus accumbens of the brain was attenuated in morphine administered mice treated by ZnE. Taken together, these results indicated that lesion of the olfactory epithelium lead to a decrease in morphine sensitization and CPP behavior in mice as well as modulate specific molecular markers of neuroadaption to drugs of abuse. These findings also suggest that olfaction plays an important role in the development of addictive behaviors that can be modulated by external actions.

• Neurotransmitter-mediated action of an antagonist of growth hormone-releasing hormone on anxiolysis in mice.

  Authors: Gyula Telegdy, Andrew V Schally

  Behavioural brain research.

  Antagonists of growth hormone-releasing hormone (GH-RH), such as MZ-4-71 suppress the secretion of GH. These fiindings suggest that GH-RH antagonists could be used for the therapy of disordersAntagonists of growth hormone-releasing hormone (GH-RH), such as MZ-4-71 suppress the secretion of GH. These fiindings suggest that GH-RH antagonists could be used for the therapy of disorders characterized by excessive GH secretion. It has been also demonstrated that MZ-4-71 displays antidepressant effects in a modified forced swimming test in mice, exerts anxiolytic effects in an elevated plus maze test, improves memory consolidation in passive avoidance learning, and corrects the impairment of memory consolidation caused by β-amyloid (25-35) in mice. However, little is known about the mechanisms of action of MZ-4-71 on brain functions. In the present work, the involvement of the adrenergic, serotonergic and GABA-ergic receptors in the anxiolytic action of MZ-4-71 was studied in an elevated plus maze. Mice were pretreated with a nonselective α-adrenergic receptor antagonist, phenoxybenzamine, an α1/α2β-adrenergic receptor antagonist, prazosin, an α2-adrenergic receptor antagonist, yohimbine, a mixed 5-HT1/5-HT2 serotonergic receptor antagonist, methysergide, a non-selective 5-HT2 serotonergic receptor antagonist, cyproheptadine, and a γ-aminobutyric acid subunit (GABA-A) receptor antagonist, bicuculline. Phenoxybenzamine, prazosin, yohimbine, methysergide, cyproheptadine and bicuculline prevented the effects of MZ-4-71 on the elevated plus maze revealing that the anxiolytic actions of MZ-4-71 in this test are mediated, at least in part, by the an interaction of the α1/α2-adrenergic, 5-HT1/5-HT2 serotonergic and GABA-A-ergic receptors.

• Deficits in Emotional Learning and Memory in an Animal Model of Schizophrenia.

  Authors: Monica M Bolton, Chelcie F Heaney, Jonathan J Sabbagh, Andrew S Murtishaw, Christy M Magcalas, Jefferson W Kinney

  Behavioural brain research.

  Alterations in N-methyl-D-aspartate (NMDA) receptor function have been linked to numerous behavioral deficits and neurochemical alterations. Recent investigations have begun to explore the role ofAlterations in N-methyl-D-aspartate (NMDA) receptor function have been linked to numerous behavioral deficits and neurochemical alterations. Recent investigations have begun to explore the role of NMDA receptor function on principally inhibitory neurons and their role in network function. One of the prevailing models of schizophrenia proposes a reduction in NMDA receptor function on inhibitory interneurons and the resulting disinhibition may give rise to aspects of the disorder. Studies using NMDA receptor antagonists such as PCP and ketamine have induced schizophrenia-like behavioral deficits in animal model systems as well as changes in inhibitory circuits. The current study, investigated whether the administration of a subanesthetic dose of ketamine (8mg/kg subcutaneously), that disrupts sensorimotor gating, also produces impairments in a Pavlovian emotional learning and memory task. We utilized both standard delay and a trace cued and contextual fear conditioning (CCF) paradigms to examine if ketamine produces differential effects when the task is more difficult and relies on connectivity between specific brain regions. Rats administered ketamine displayed no significant deficits in cued or contextual fear following the delay conditioning protocol. However, ketamine did produce a significant impairment in the more difficult trace conditioning protocol. Analyses of tissue from the hippocampus and amygdala indicated that the administration of ketamine produced an alteration in GABA receptor protein levels differentially depending on the task. These data indicate that 8mg/kg of ketamine impairs learning in the more difficult emotional classical conditioning task and may be related to altered signaling in GABAergic systems.

• Dendritic morphology in the striatum and hypothalamus differentially exhibits experience-dependent changes in response to maternal care and early social isolation.

  Authors: Soaleha Shams, Jodi L Pawluski, Munmun Chatterjee-Chakraborty, Hannah Oatley, Angela Mastroianni, Alison S Fleming

  Behavioural brain research.

  Changes in neuron morphology, stemming from experiences in early life or adulthood, may be the basis for changes in behavior and their underlying functional mechanisms. For example, reproductiveChanges in neuron morphology, stemming from experiences in early life or adulthood, may be the basis for changes in behavior and their underlying functional mechanisms. For example, reproductive experience has been shown to significantly alter neuron morphology in the hippocampus and prefrontal cortex. In contrast to the effects of reproductive experience, a form of enrichment, on neuron morphology, our understanding of the effects of early social isolation on adult neuron morphology is limited. Therefore, the present study examined changes in neuron morphology in the dorsal (caudate nucleus) and ventral (nucleus accumbens, shell region) striatum and the medial preoptic area of adult virgin and postpartum females exposed to either artificial or maternal rearing during development. Primary results show that regardless of early social isolation, neurons in the caudate nucleus of postpartum females have decreased dendritic complexity compared to virgin females. Maternal experience also increased dendritic complexity in neurons of the nucleus accumbens shell. However, both early social isolation and maternal experience in adulthood influenced dendritic complexity in the medial preoptic area. Together these findings suggest that hypothalamic and striatal neurons show experience-dependent dendritic plasticity and the type and timing of these experiences differentially affect the location and degree of these morphological changes.

• Frontal and parietal activity after sleep deprivation is dependent on task difficulty and can be predicted by the fMRI response after normal sleep.

  Authors: Karen E Lythe, Steven C R Williams, Clare Anderson, Vincenzo Libri, Mitul A Mehta

  Behavioural brain research.

  Sleep disturbance in neurological and psychiatric disorders is common and associated with diminished cognitive functioning. Whilst these deficits can be localised predominantly to frontal andSleep disturbance in neurological and psychiatric disorders is common and associated with diminished cognitive functioning. Whilst these deficits can be localised predominantly to frontal and parietal regions, there have been reported inconsistencies which may be due to differences in the difficulty and type of task. In the present study we examined the effects of sleep deprivation whilst parametrically varying working memory load using an n-back task. 20 right-handed males performed the n-back task after a night of normal sleep (RW: rested wakefulness) and after approximately 31hours of SD. Comparison of load responsive cerebral activation identified two clusters where the parametric response was altered after SD. In the right ventrolateral prefrontal cortex activity was reduced at the most difficult working memory load, whereas in the right inferior parietal lobe activity was increased at the simplest working memory load. The strength of activation in both of these regions during RW predicted the response of those same regions to SD. While the ability to predict signal change has previously been demonstrated using behavioural measures, to our knowledge this is the first study to show that the neuronal effects of SD can be predicted based upon activation during a normal rested condition.

• Practice on conflict tasks promotes executive function of working memory in the elderly.

  Authors: Mariko Osaka, Ken Yaoi, Yuki Otsuka, Maya Katsuhara, Naoyuki Osaka

  Behavioural brain research.

  Effects of practice on a conflict task in elderly individuals are examined with a focus on its impact on executive function in working memory. During a short-term practice period, healthy elderlyEffects of practice on a conflict task in elderly individuals are examined with a focus on its impact on executive function in working memory. During a short-term practice period, healthy elderly participants practiced switching attention using a Stroop task that involved a conflict between a task relevant stimulus and an irrelevant stimulus. To explore neural substrates underlying practice effects, two working memory tasks were used: a focus reading span test (F-RST) and a non-focus reading span test (NF-RST); the NF-RST test demanded greater switching attention due to a conflict between the relevant task stimulus and an irrelevant task stimulus, thus requiring an attention switch from the latter to the former. Following the Stroop task practice, fMRI data showed that participants who had engaged in practice had significant increases in activation in the anterior cingulate cortex (ACC), the left inferior parietal lobule (IPL), the left dorsolateral prefrontal cortex (DLPFC) and the precuneus regions during the NF-RST. By contrast, a control group, which did not practice, showed no significant increases in these regions. Results suggest that practice on conflict tasks in elderly individuals activated regions related to conflict perceiving and attention switching regions as well as attention-maintenance regions thereby improving performance on tasks requiring a high degree of attention control of working memory.

• Isolation rearing as a preclinical model of attention/deficit-hyperactivity disorder.

  Authors: Justin R Yates, Mahesh Darna, Cassandra D Gipson, Linda P Dwoskin, Michael T Bardo

  Behavioural brain research.

  Rats raised in an isolated condition (IC) are impulsive and hyperactive compared to rats raised in an enriched condition (EC), suggesting that isolation rearing may be a preclinical model ofRats raised in an isolated condition (IC) are impulsive and hyperactive compared to rats raised in an enriched condition (EC), suggesting that isolation rearing may be a preclinical model of attention-deficit/hyperactivity disorder (ADHD). The current study determined if administration of methylphenidate (MPH), a dopamine transporter (DAT) blocker used in the treatment of ADHD, reduces the hyperactivity observed in IC rats toward levels observed in EC rats. Another goal was to determine if chronic MPH treatment differentially alters DAT function in EC and IC rats in medial prefrontal cortex (mPFC) or orbital frontal cortex (OFC). IC and EC rats were treated with either MPH (1.5mg/kg, p.o.) or vehicle from postnatal days (PND) 28-51. On PND 28 and 51, rats were evaluated for MPH-induced locomotor activity. On PND 55-63, in vitro [(3)H]DA uptake assays were performed in mPFC and OFC. At both PND 28 and 51, IC rats were hyperactive compared to EC rats. At PND 28, MPH increased activity in EC rats only. At PND 51, MPH did not alter locomotor activity in IC or EC rats. Beginning at PND 55, basal uptake of [(3)H]dopamine in IC rats was higher in mPFC and lower in OFC compared to EC rats. The basal differences in DAT function were normalized by MPH treatment in mPFC, but not in OFC. These findings suggest that isolation rearing may not represent a valid predictive model for screening effective medications in the treatment of hyperactivity associated with ADHD.

• Four factors underlying mouse behavior in an open field.

  Authors: Shoji Tanaka, Jared W Young, Adam L Halberstadt, Virginia L Masten, Mark A Geyer

  Behavioural brain research.

  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 canThe 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.

• Downregulation of cAMP response element-binding protein by lentiviral vector-mediated RNAi attenuates morphine withdrawal syndromes in rats.

  Authors: Qiang Wu, Minghui Cao, Tinghuai Wang, Ping Jiang, Kewen Zhou

  Behavioural brain research.

  cAMP response element-binding protein(CREB) and the cAMP cascade play a pivotal role in the opiate-dependence. The blockade of this cascade is believed to attenuate signs of physical opiatecAMP response element-binding protein(CREB) and the cAMP cascade play a pivotal role in the opiate-dependence. The blockade of this cascade is believed to attenuate signs of physical opiate withdrawal. A lentiviral vector (LV) expressing a small hairpin RNA (shRNA) to silence CREB in vitro and in vivo was used in this study. The effect of the shRNA on the regulation of the relevant protein expression and the signs of opiate withdrawal were subsequently evaluated in rats undergoing chronic morphine treatment. In cultured primary locus coeruleus (LC) neurons, the designed lentiviral vectors were successfully infected into the cells and led to 70% knockdown in CREB expression. In cells treated with chronic morphine, the expression of CREB, adenylyl cyclase (AC) and protein kinase A (PKA) were increased, while in cells infected with LV-CREB3, treated with chronic morphine treatment failed to increase the expressions of CREB and AC. Consistently, in the rat model for chronic morphine treatment, morphine increased the expression of CREB, AC and PKA in LC neurons. However, in rats received bilateral microinjections of LV-CREB3 into the LC, morphine did not alter the levels of these proteins. Moreover, microinjection of LV-CREB3 significantly attenuated the appearance of certain withdrawal behaviors. In conclusion, the lentiviral vectors expressing CREB shRNA inhibited the increase of CREB and AC expression induced by chronic morphine treatment both in vivo and in vitro. This inhibition was associated with the alleviation of some withdrawal behaviors. These findings suggested that lentivirus-mediated RNA interference could be a useful for opiate-dependence therapy.

• Association between locomotor response to novelty and light reinforcement: sensory reinforcement as a rodent model of sensation seeking.

  Authors: Amy M Gancarz, Mykel A Robble, Michael A Kausch, David R Lloyd, Jerry B Richards

  Behavioural brain research. 230(2):380-8.

  The human personality trait of sensation seeking (SS) indicates an attraction to novel sensations and experiences, and is associated with greater likelihood of drug abuse. In rodents, locomotorThe human personality trait of sensation seeking (SS) indicates an attraction to novel sensations and experiences, and is associated with greater likelihood of drug abuse. In rodents, locomotor activity in a novel environment (Loco) has been found to predict drug self-administration (SA), and has been hypothesized to be a translational model of human SS. Previously, we reported (Gancarz et al., 2011) that high responder (HR) animals responded more than low responder (LR) animals to produce a response contingent light onset. The primary goal of this paper was a detailed analysis of the association between Loco and light contingent responding in a large sample of rats (n = 93). Male rats were pre-exposed to dark operant test chambers for ten 30 min sessions and baseline levels of responding (snout poking) were determined. The pre-exposure phase was followed by 6 sessions during which active responding produced a visual sensory reinforcer (VSR; 5 s light onset) according to a variable interval 1 min schedule of reinforcement. After completion of the VSR phase, Loco was tested. The activating effects (total responding) of light were associated with Loco, but the response guiding effects (proportion of active responding) of the light were not. In addition, HR rats habituated more slowly in both the VSR and Loco tests than LR rats. These data indicate that VSR measures aspects of the rodent’s response to novel sensations and experiences that are not detected by Loco. These data provide some evidence for the use of light reinforcement as an animal model of SS.

• The metabotropic glutamate 2/3 receptor antagonist LY341495 differentially affects recognition memory in rats.

  Authors: Nikolaos Pitsikas, Eleanna Kaffe, Athina Markou

  Behavioural brain research. 230(2):374-9.

  Experimental evidence suggests that metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists affect cognitive function, although contradictory findings have been reported. To clarify the role ofExperimental evidence suggests that metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists affect cognitive function, although contradictory findings have been reported. To clarify the role of mGlu2/3 receptor antagonists in one aspect of cognition, the present study investigated the effects of a broad range of doses of the mGlu2/3 receptor antagonist LY341495 on post-training recognition memory components (storage and/or retrieval) in rats. The efficacy of LY341495 in antagonizing the extinction of recognition memory was also investigated. The novel object recognition test was used as the memory test. The highest LY341495 doses administered (0.3, 1, and 3 mg/kg) disrupted performance in this recognition memory procedure in rats at all delay conditions tested, whereas administration of lower doses (0.05 and 0.1 mg/kg) did not impair recognition memory. Moreover, administration of the low LY341495 doses (0.05 and 0.1 mg/kg) counteracted the extinction of recognition memory. The present results indicate that administration of the mGlu2/3 receptor antagonist LY341495 can either impair or enhance recognition memory in rats, depending on the dose of the compound and delay period used. Thus, together with previously reported findings, the present data suggest complex effects of this compound on cognitive function, particularly recognition memory.

• Sensitivity of modified Biel-maze task, compared with Y-maze task, to measure spatial learning and memory deficits of ethanol teratogenicity in the guinea pig.

  Authors: Christine C Dobson, Daniel L Mongillo, Margo Poklewska-Koziell, Andrew Winterborn, James F Brien, James N Reynolds

  Behavioural brain research.

  Ethanol consumption during pregnancy can produce a variety of teratogenic effects in offspring, termed Fetal Alcohol Spectrum Disorder (FASD). The most debilitating and permanent consequence ofEthanol consumption during pregnancy can produce a variety of teratogenic effects in offspring, termed Fetal Alcohol Spectrum Disorder (FASD). The most debilitating and permanent consequence of chronic prenatal ethanol exposure (CPEE) is neurobehavioral teratogenicity, which often manifests as cognitive and behavioral impairments, including deficits in spatial learning and memory. This study tested the hypothesis that a modified dry-land version of the multi-choice Biel-maze task is more sensitive than the rewarded-alternation Y-maze task for the determination of spatial learning and memory deficits of ethanol teratogenicity. Pregnant guinea pigs received ethanol (4g/kg maternal body weight/day) or isocaloric-sucrose/pair-feeding (control) for 5days/week throughout gestation. CPEE resulted in ethanol neurobehavioral teratogenicity in offspring, as demonstrated by increased spontaneous locomotor activity at postnatal day (PD) 10 and decreased brain weight at euthanasia (PD 150-200). On PD 21, offspring were randomly assigned to one of two tasks to assess spatial learning and memory performance: a dry-land version of the Biel maze or a rewarded-alternation Y-maze. Animals were habituated to the environment of their assigned task and performance of each CPEE or control offspring was measured. In the modified Biel maze, CPEE and control offspring were not different for percent completed trials or time to complete a trial. However, CPEE offspring made more errors (reversals and entering dead ends) in the Biel maze, demonstrating impaired spatial learning and memory. In contrast, CPEE offspring did not have impaired performance of the rewarded-alternation Y-maze task. Therefore, the modified dry-land version of the Biel-maze task, which measures cognitive performance using a complex multi-choice design, is more sensitive in demonstrating CPEE-induced spatial learning and memory deficits compared with a simple, rewarded-alternation Y-maze task.

• Absence of social conditioned place preference in BTBR T+tf/J mice: Relevance for social motivation testing in rodent models of autism.

  Authors: Brandon L Pearson, Jaclyn K Bettis, Ksenia Z Meyza, Lace Y Yamamoto, D Caroline Blanchard, Robert J Blanchard

  Behavioural brain research.

  A major goal of translation research in autism is to characterize the physiological and psychological processes underlying behavioral abnormalities. Since autism reflects impairments in socialA major goal of translation research in autism is to characterize the physiological and psychological processes underlying behavioral abnormalities. Since autism reflects impairments in social motivation, we modified the mouse three-chamber social approach apparatus for use as a social conditioned place preference arena. We paired one of two unique contexts with social interactions in juvenile mice for five or ten conditioning sessions in BTBR T+tf/J mice and a control strain with normal approach behaviors (C57BL/6J) since the BTBR T+tf/J inbred mouse strain displays a variety of behavioral alterations analogous to symptoms of autism spectrum disorders. While C57BL/6J mice formed a conditioned place preference to the context associated with social interactions, particularly those receiving ten days of conditioning, BTBR T+tf/J mice did not. Neither absence of social proximity nor avoidance due to high rates of autogrooming appeared to underlie the impaired positive incentive value of the unconditioned social stimulus in the BTBR T+tf/J strain. These data contribute to a growing body of evidence suggesting that the BTBR T+tf/J strain shows impairments in all diagnostic domains of autism including social motivation. Additionally, social conditioning testing might provide an important social motivation measure in other rodent models of neuropsychiatric disorders characterized by social abnormalities.

• Re-examining the ontogeny of the context preexposure facilitation effect in the rat through multiple dependent variables.

  Authors: M V Pisano, S Ferreras, F A Krapacher, G Paglini, C Arias

  Behavioural brain research.

  The capability to acquire context conditioning does not emerge until weaning, at least when the defining features of the context lack explicit and salient olfactory cues. Contextual learning deficitsThe capability to acquire context conditioning does not emerge until weaning, at least when the defining features of the context lack explicit and salient olfactory cues. Contextual learning deficits in preweanling rats have been associated with functional immaturity of the dorsal hippocampus. According to recent studies, the so-called context preexposure facilitation effect (CPFE) - a hippocampus-dependent effect - is not observed until postnatal day 23 (PD23). In these studies the footshock intensity employed was higher (1.5mA) than in adult studies, and context conditioning was inferred from a single behavioral measure (percentage of freezing). The present study examined the CPFE on PD17 and PD23 by analyzing multiple dependent variables, including fecal boli and an ethogram covering the complete behavioral repertoire of the rat. A non-shocked control group was included in the design and two footshock intensities were employed (0.5 and 1.5mA). Results showed clear evidence of contextual fear conditioning in preweanling and weanling rats, as well as evidence of conditioned fear in non-preexposed rats from both age groups. In some cases, some dependent variables, such as grooming or vertical exploration, were more sensitive than freezing for detecting evidence of memory. Strong fear responses were detected in weanling (but not preweanling) rats, when rats were evaluated in a different context from the one employed at conditioning. These results indicate that preweanling rats are capable of acquiring contextual conditioning, even in a context lacking explicit odor cues, and highlight the importance of multiple dependent variables for analyzing the ontogeny of memory.

• The effect of neonatal N-methyl-d-aspartate receptor blockade on exploratory and anxiety-like behaviors in adult BALB/c and C57BL/6 mice.

  Authors: Kubra Akillioglu, Secil Binokay, Sayad Kocahan

  Behavioural brain research.

  N-methyl-d-aspartate (NMDA) receptors play an important role in brain maturation and developmental processes. In our study, we evaluated the effects of neonatal NMDA receptor blockade on exploratoryN-methyl-d-aspartate (NMDA) receptors play an important role in brain maturation and developmental processes. In our study, we evaluated the effects of neonatal NMDA receptor blockade on exploratory locomotion and anxiety-like behaviors of adult BALB/c and C57BL/6 mice. In this study, NMDA receptor hypofunction was induced 7-10 days after birth using MK-801 in BALB/c and C57BL/6 mice (0.25mg/kg twice a day for 4 days via intraperitoneal injection). The open-field (OF) and elevated plus maze (EPM) tests were used to evaluate exploratory locomotion and anxiety-like behaviors. In the OF, BALB/c mice spent less time in the center of the field (p<0.05) and had less vertical locomotor activity (p<0.01) compared to C57BL/6 mice. In BALB/c mice, MK-801 caused a decrease in vertical and horizontal locomotor activity in the OF test, compared to the control group (p<0.05). In C57BL/6 mice, MK-801 treatment increased horizontal locomotor activity and decreased time spent in the center in the OF test (p<0.05). In the EPM, the number of open-arm entries, the percentage of open-arm time (p<0.01) and total arm entries (p<0.05) were lower in BALB/c mice compared to C57BL/6 mice. In BALB/c mice, MK-801 caused an increase in the percentage of open-arm time compared to the control group (p<0.05). In C57BL/6 mice, MK-801 caused a decrease in the percentage of open-arm time compared to the control group (p<0.05). MK-801 decreased exploratory and anxiety-like behaviors in BALB/c mice. In contrast, MK-801 increased exploratory and anxiety-like behaviors in C57BL/6 mice. In conclusion, hereditary factors may play an important role in neonatal NMDA receptor blockade-induced responses.

• Discrimination reversal and attentional sets in zebrafish (Danio rerio).

  Authors: Matthew O Parker, Jessica Gaviria, Alastair Haigh, Mollie E Millington, Verity J Brown, Fraser J Combe, Caroline H Brennan

  Behavioural brain research.

  The potential of zebrafish as a comparative model in behavioural neuroscience is currently hampered only by the lack of reliable and validated behavioural assays available to researchers. In theThe potential of zebrafish as a comparative model in behavioural neuroscience is currently hampered only by the lack of reliable and validated behavioural assays available to researchers. In the present experiment, we describe the performance of zebrafish in a test of attentional set formations. The fish were initially trained on a two-choice colour discrimination. Upon reaching acquisition criterion, the reinforced alternative was switched to the previously unreinforced alternative. Again, upon reaching criterion, the cues were replaced with a novel pair of colours (intra-dimensional shift) and reversed again on reaching criteria. We found that zebrafish show a steady decrease in trials-to-criteria over the four phases of the experiment, suggesting that they are forming and maintaining an attentional set, as has previously been demonstrated with mammals. Reversal learning deficits have been implicated in a variety of human psychological disorders (e.g., disorders of impulse control) and as such, we propose that performance of zebrafish in this procedure may represent a useful comparative model to complement existing rodent models.

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