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1.  Dorsal hippocampus inactivation impairs spontaneous recovery of Pavlovian magazine approach responding in rats 
Behavioural brain research  2014;269:37-43.
Destruction or inactivation of the dorsal hippocampus (DH) has been shown to eliminate the renewal of extinguished fear [1–4]. However, it has recently been reported that the contextual control of responding to extinguished appetitive stimuli is not disrupted when the DH is destroyed or inactivated prior to tests for renewal of Pavlovian conditioned magazine approach [5]. In the present study we extend the analysis of DH control of appetitive extinction learning to the spontaneous recovery of Pavlovian conditioned magazine approach responding. Subjects were trained to associate two separate stimuli with the delivery of food and had muscimol or vehicle infused into the DH prior to a single test-session for spontaneous recovery occurring immediately following extinction of one of these stimuli, but one week following extinction of the other. While vehicle treated subjects showed more recovery to the distally extinguished stimulus than the proximal one, muscimol treated subjects failed to show spontaneous recovery to either stimulus. This result suggests that, while the DH is not involved in the control of extinction by physical contexts [5], it may be involved when time is the gating factor controlling recovery of extinguished responding.
PMCID: PMC4094020  PMID: 24742862
Extinction; Spontaneous recovery; Magazine approach; Hippocampus
2.  Pair Housing Reverses Post-Stroke Depressive Behaviour in Mice 
Behavioural brain research  2014;269:155-163.
Social isolation (SI) has been linked epidemiologically to high rates of morbidity and mortality following stroke. In contrast, strong social support enhances recovery and lowers stroke recurrence. However, the mechanism by which social support influences stroke recovery has not been adequately explored. The goal of this study was to examine the effect of post-stroke pair housing and SI on behavioural phenotypes and chronic functional recovery in mice. Young male mice were paired for 14 days before a 60 minute transient middle cerebral artery occlusion (MCAO) or sham surgery and assigned to various housing environments immediately after stroke. Post-stroke mice paired with either a sham or stroke partner showed significantly higher (p<0.05) sociability after MCAO than isolated littermates. Sociability deficits worsened over time in isolated animals. Pair-housed mice showed restored sucrose consumption (p<0.05) and reduced immobility in the tail suspension test compared to isolated cohorts. Pair-housed stroked mice demonstrated significantly reduced cerebral atrophy after 6 weeks (17.5 ± 1.5% in PH vs. 40.8 ± 1.3% in SI; p<0.001). Surprisingly, total brain arginase-1, a marker of a M2 “alternatively activated” myeloid cells was higher in isolated mice. However, a more detailed assessment of cellular expression showed a significant increase in the number of microglia that co-labeled with arginase-1 in the peri-infarct region in PH stroke mice compared to SI mice. Pair housing enhances sociability and reduces avolitional and anhedonic behaviour. Pair housing reduced serum IL-6 and enhanced peri-infarct microglia arginase-1 expression. Social interaction reduces post-stroke depression and improves functional recovery.
PMCID: PMC4114771  PMID: 24793492
Sociability; Ischemic Stroke; Social Isolation; Post stroke depression; Arginase-1; IL-6
3.  Spatial learning by mice in three dimensions 
Behavioural Brain Research  2015;289:125-132.
•Mouse spatial memory was tested on a novel 3D radial arm maze.•Mice exhibited learning on working and reference memory tasks on the 3D maze.•Working memory was not impaired on the 3D maze when compared with a 2D analogue.•Reference memory was impaired on the 3D maze when compared with the 2D maze.•This may be explained by a differential encoding of vertical and horizontal space.
We tested whether mice can represent locations distributed throughout three-dimensional space, by developing a novel three-dimensional radial arm maze. The three-dimensional radial maze, or “radiolarian” maze, consists of a central spherical core from which arms project in all directions. Mice learn to retrieve food from the ends of the arms without omitting any arms or re-visiting depleted ones. We show here that mice can learn both a standard working memory task, in which all arms are initially baited, and also a reference memory version in which only a subset are ever baited. Comparison with a two-dimensional analogue of the radiolarian maze, the hexagon maze, revealed equally good working-memory performance in both mazes if all the arms were initially baited, but reduced working and reference memory in the partially baited radiolarian maze. This suggests intact three-dimensional spatial representation in mice over short timescales but impairment of the formation and/or use of long-term spatial memory of the maze. We discuss potential mechanisms for how mice solve the three-dimensional task, and reasons for the impairment relative to its two-dimensional counterpart, concluding with some speculations about how mammals may represent three-dimensional space.
PMCID: PMC4451476  PMID: 25930216
Navigation; 3D; Mice; Memory
4.  Autism-related behavioral phenotypes in an Inbred Rat Substrain 
Behavioural brain research  2014;0:103-114.
Behavioral and genetic differences among Wistar-Kyoto (WKY) rats from different vendors and different breeders have long been observed, but generally overlooked. In our prior work, we found that two closely related WKY substrains, the WKY/NCrl and WKY/NHsd rats, differ in a small percentage of their genome which appeared to be highly enriched for autism risk genes. Although both substrains have been used widely in studies of hypertension, attention deficit/hyperactivity disorder (ADHD) and depression, they have not been tested for any autism-related behavioral phenotypes. Furthermore, these two substrains have often been used interchangeably in previous studies; no study has systematically examined the phenotypic differences that could be attributed by their small yet potentially meaningful genetic differences. In this paper we compared these two substrains on a battery of neurobehavioral tests. Although two substrains were similar in locomotor activity, WKY/NCrl rats were significantly different from WKY/NHsd rats in the elevated plus maze test, as well as measures of social interaction and ultrasonic vocalization. These strains were also compared with Sprague Dawley (SD) rats, a common outbred strain, and spontaneous hypertensive rats (SHR), an inbred rat model for ADHD and hypertension, which were derived from the same ancestor strain as the WKY strains. Our behavioral findings suggest that WKY/NCrl rats may be useful as a model autism spectrum disorders due to their lower social interest, lower ultrasonic vocalization and higher anxiety levels when WKY/NHsd rats are used as the control strain. Given the small genetic difference between the two inbred substrains, future studies to identify the exact gene and sequence variants that differ between the two may be useful for identifying the genetic mechanisms underlying these behaviors.
PMCID: PMC4040443  PMID: 24780868
WKY; substrain; social interaction; ultrasonic vocalization; inbred rat
5.  Individual differences in impulsive and risky choice: Effects of environmental rearing conditions 
Behavioural brain research  2014;269:115-127.
The present experiment investigated early-rearing environment modulation of individual differences in impulsive and risky choice. Rats were reared in an isolated condition (IC; n = 12), in which they lived alone without novel stimuli, or an enriched condition (EC; n = 12), in which they lived among conspecifics with novel stimuli. The impulsive choice task involved choices between smaller-sooner (SS) versus larger-later (LL) rewards. The risky choice task involved choices between certain-smaller (C-S) versus uncertain-larger (U-L) rewards. Following choice testing, incentive motivation to work for food was measured using a progressive ratio task and correlated with choice behavior. HPLC analyses were conducted to determine how monoamine concentrations within the prefrontal cortex (PFC) and nucleus accumbens (NAC) related to behavior in different tasks. IC rats were more impulsive than EC rats, but they did not differ in risky choice behavior. However, choice behavior across tasks was significantly correlated (i.e., the more impulsive rats were also riskier). There were no group differences in monoamine levels, but noradrenergic and serotonergic concentrations were significantly correlated with impulsive and risky choice. Furthermore, serotonin and norepinephrine concentrations in the NAC significantly correlated with incentive motivation and the timing of the reward delays within the choice tasks. These results suggest a role for domain general processes in impulsive and risky choice and indicate the importance of the NAC and/or PFC in timing, reward processing, and choice behavior.
PMCID: PMC4069030  PMID: 24769268
impulsive choice; risky choice; differential rearing; individual difference; monoamine concentration; rat
6.  Dyspraxia, Motor Function and Visual-Motor Integration in Autism 
Behavioural brain research  2014;269:95-102.
This project assessed dyspraxia in high-functioning school aged children with autism with a focus on Ideational Praxis. We examined the association of specific underlying motor function including eye movement with ideational dyspraxia (sequences of skilled movements) as well as the possible role of visual-motor integration in dyspraxia. We found that compared to IQ-, sex- and age-matched typically developing children, the children with autism performed significantly worse on: Ideational and Buccofacial praxis; a broad range of motor tests, including measures of simple motor skill, timing and accuracy of saccadic eye movements and motor coordination; and tests of visual-motor integration. Impairments in individual children with autism were heterogeneous in nature, although when we examined the praxis data as a function of a qualitative measure representing motor timing, we found that children with poor motor timing performed worse on all praxis categories and had slower and less accurate eye movements while those with regular timing performed as well as typical children on those same tasks. Our data provide evidence that both motor function and visual-motor integration contribute to dyspraxia. We suggest that dyspraxia in autism involves cerebellar mechanisms of movement control and the integration of these mechanisms with cortical networks implicated in praxis.
PMCID: PMC4072207  PMID: 24742861
Autism; Dyspraxia; Motor; Visual-Motor Integration; Eye Movement; Cerebellum
7.  Adenylyl cylases 1 and 8 mediate select striatal-dependent behaviors and sensitivity to ethanol stimulation in the adolescent period following acute neonatal ethanol exposure 
Behavioural brain research  2014;269:66-74.
Neonatal alcohol exposure in rodents causes dramatic neurodegenerative effects throughout the developing nervous system, particularly in the striatum, acutely after exposure. These acute neurodegenerative effects are augmented in mice lacking adenylyl cyclases 1 and 8 (AC1/8) as neonatal mice with a genetic deletion of both AC isoforms (DKO) have increased vulnerability to ethanol-induced striatal neurotoxicity compared to wild type (WT) controls. While neonatal ethanol exposure is known to negatively impact cognitive behaviors, such as executive functioning and working memory in adolescent and adult animals, the threshold of ethanol exposure required to impinge upon developmental behaviors in mice has not been extensively examined. Therefore, the purpose of this study was to determine the behavioral effects of neonatal ethanol exposure using various striatal-dependent developmental benchmarks and to assess the impact of AC1/8 deletion on this developmental progression. WT and DKO mice were treated with 2.5 g/kg ethanol or saline on postnatal day (P)6 and later subjected to the wire suspension, negative geotaxis, postural reflex, grid hang, tail suspension and accelerating rotarod tests at various time points. At P30, mice were evaluated for their hypnotic responses to 4.0 g/kg ethanol by using the loss of righting reflex assay and ethanol-induced stimulation of locomotor activity after 2.0 g/kg ethanol.
Ethanol exposure significantly impaired DKO performance in the negative geotaxis test while genetic deletion of AC1/8 alone increased grid hang time and decreased immobility time in the tail suspension test with a concomitant increase in hindlimb clasping behavior. Locomotor stimulation was significantly increased in animals that received ethanol as neonates, peaking significantly in ethanol-treated DKO mice compared to ethanol-treated WT controls, while sedation duration following high-dose ethanol challenge was unaffected.
These data indicate that the maturational parameters examined in the current study may not be sensitive enough to detect effects of a single ethanol exposure during the brain growth spurt period. Genetic deletion of AC1/8 reveals a role for these cylases in attenuating ethanol-induced behavioral effects in the neonatally-exposed adolescent.
PMCID: PMC4074522  PMID: 24769171
Fetal Alcohol Spectrum Disorders (FASD); Adenylyl Cyclase; Ethanol; Behavior; Striatum
8.  Effects of moderate prenatal ethanol exposure and age on social behavior, spatial response perseveration errors and motor behavior 
Behavioural brain research  2014;269:44-54.
Persistent deficits in social behavior are among the major negative consequences associated with exposure to ethanol during prenatal development. Prior work from our laboratory has linked deficits in social behavior following moderate prenatal alcohol exposure (PAE) in the rat to functional alterations in the ventrolateral frontal cortex [21]. In addition to social behaviors, the regions comprising the ventrolateral frontal cortex are critical for diverse processes ranging from orofacial motor movements to flexible alteration of behavior in the face of changing consequences. The broader behavioral implications of altered ventrolateral frontal cortex function following moderate PAE have, however, not been examined. In the present study we evaluated the consequences of moderate PAE on social behavior, tongue protrusion, and flexibility in a variant of the Morris water task that required modification of a well-established spatial response. PAE rats displayed deficits in tongue protrusion, reduced flexibility in the spatial domain, increased wrestling, and decreased investigation, indicating that several behaviors associated with ventrolateral frontal cortex function are impaired following moderate PAE. A linear discriminant analysis revealed that measures of wrestling and tongue protrusion provided the best discrimination of PAE rats from saccharin-exposed control rats. We also evaluated all behaviors in young adult (4-5 mos.) or older (10-11 mos.) rats to address the persistence of behavioral deficits in adulthood and possible interactions between early ethanol exposure and advancing age. Behavioral deficits in each domain persisted well into adulthood (10-11 mos.), however, there was no evidence that age enhances the effects of moderate PAE within the age ranges that were studied.
PMCID: PMC4134935  PMID: 24769174
Fetal Alcohol Spectrum Disorders; Fetal Alcohol Syndrome; Prefrontal Cortex; Morris water task; Spatial Navigation; Aggression; Aging
9.  Identification of Hyperactive Intrinsic Amygdala Network Connectivity Associated with Impulsivity in Abstinent Heroin Addicts 
Behavioural brain research  2010;216(2):639-646.
Impulsivity is a pathological hallmark of drug addiction. However, little is known about the neuropsychological underpinnings of this impaired impulsive control network on drug addiction. Twenty two abstinent heroin dependent (HD) subjects and fifteen cognitively normal (CN) subjects participated in this study. Resting-state functional connectivity MRI was employed to measure abnormalities in the intrinsic amygdala functional connectivity (iAFC) network activity and the Barratt Impulsive Scale, 11th version was used to measure impulsivity. Linear regression analysis was applied to detect the neural constructs underlying impulsivity by correlating iAFC network activity with impulsive scores. In the HD group, higher impulsivity scores and significantly enhanced iAFC network activity were found, especially in bilateral thalamus, right insula, and inferior frontal gyrus. Markedly decreased anticorrelated iAFC network activity was seen in the left precuneus, and even switched to positive correlation pattern in right precuneus, relative to the CN group. The iAFC network strengths in the HD group were positively correlated with impulsivity in the right subcallosal gyrus, insula, thalamus and posterior cingulate cortex, and negatively correlated in left fusiform area. In the CN group, the left pre-somamotor area-amygdala connectivity was positively correlated, and right orbital frontal cortex-amygdala and precuneus-amygdala connectivity were negatively correlated with impulsivity scores. Our study demonstrates different constructs of the impulsive network in HD and CN subjects. Altered iAFC network connectivity in HD subjects may contribute to the loss of impulsive control. This further facilitates our understanding of the neural underpinnings of behavior dysfunction in addiction.
PMCID: PMC4518715  PMID: 20851718
Heroin dependent; impulsivity; functional connectivity MRI; amygdala network
10.  Antidepressant Effects of Resveratrol in an Animal Model of Depression 
Resveratrol (3,4’,5-trihydroxy-trans-stilbene) is a natural non-flavonoid polyphenol antioxidant extracted from red grapes in the processing of wine. Initially it was studied for its potential as anticancer drug, and later was found to reduce cardiovascular disease. More recently resveratrol was shown to alleviate depressive-like symptoms induced by stress or other means in mice and rats. The major purpose of this study was to investigate whether resveratrol would manifest an antidepressant effect in Wistar-Kyoto (WKY) rats, a putative and non-induced animal model of depression, and whether this effect might be associated with an increase in hippocampal and frontal cortical brain-derived neurotrophic factor (BDNF), a protein implicated in chronic effects of many antidepressants. Adult male WKY rats were injected with two doses of resveratrol (10 and 40 mg/kg, i.p.) and their behavior in the open field locomotor activity (LMA), forced swim test (FST: a measure of helplessness), and sucrose preference test (SPT: a measure of anhedonia) was evaluated after a single acute injection or following 7 days of daily treatment. Both acute and chronic administration of resveratrol resulted in a dose-dependent decrease in FST. However, only chronic resveratrol resulted in dose-dependent increase in sucrose consumption. LMA was not affected by any treatment. Parallel to the observed behavioral effects the level of hippocampal, but not frontal cortical, BDNF was also dose-dependently elevated after chronic resveratrol administration. These findings indicate an antidepressant-like effect of resveratrol in an animal model of depression possibly via activation of hippocampal BDNF, and suggest therapeutic potential of resveratrol in at least a subpopulation of depressed patients.
PMCID: PMC4033784  PMID: 24717328
Resveratrol; Depression; Animal Model; BDNF; Hippocampus
11.  Effects of dopaminergic therapy on locomotor adaptation and adaptive learning in persons with Parkinson's disease 
Behavioural brain research  2014;268:31-39.
Persons with Parkinson’s disease (PD) are characterized by multifactorial gait deficits, though the factors which influence the abilities of persons with PD to adapt and store new gait patterns are unclear. The purpose of this study was to investigate the effects of dopaminergic therapy on the abilities of persons with PD to adapt and store gait parameters during split-belt treadmill (SBT) walking.
Ten participants with idiopathic PD who were being treated with stable doses of orally-administered dopaminergic therapy participated. All participants performed two randomized testing sessions on separate days: once while optimally-medicated (ON meds) and once after 12-hour withdrawal from dopaminergic medication (OFF meds). During each session, locomotor adaptation was investigated as the participants walked on a SBT for ten minutes while the belts moved at a 2:1 speed ratio. We assessed locomotor adaptive learning by quantifying: 1) aftereffects during de-adaptation (once the belts returned to tied speeds immediately following SBT walking) and 2) savings during re-adaptation (as the participants repeated the same SBT walking task after washout of aftereffects following the initial SBT task).
The withholding of dopaminergic medication diminished step length aftereffects significantly during de-adaptation. However, both locomotor adaptation and savings were unaffected by levodopa. These findings suggest that dopaminergic pathways influence aftereffect storage but do not influence locomotor adaptation or savings within a single session of SBT walking. It appears important that persons with PD should be optimally-medicated if walking on the SBT as gait rehabilitation.
PMCID: PMC4034129  PMID: 24698798
Parkinson’s disease; adaptation; split-belt treadmill; dopamine; motor learning
12.  Protective effects of phosphodiesterase 2 inhibitor on depression- and anxiety-like behaviors: involvement of antioxidant and anti-apoptotic mechanisms 
Behavioural brain research  2014;268:150-158.
Stress occurs in everyday life, but the relationship between stress and the onset or development of depression/anxiety remains unknown. Increasing evidence suggests that the impairment of antioxidant defense and the neuronal cell death are important in the process of emotional disorders. Chronic stress impairs the homeostasis of antioxidants/oxidation, which results in the aberrant stimulation of the cell cycle proteins where cGMP-PKG signaling is thought to have an inhibitory role. Phosphodiesterase 2 (PDE2) is linked to cGMP-PKG signaling and highly expressed in the limbic brain regions including hippocampus and amygdala, which may play important roles in the treatment of depression and anxiety. To address the possible effects of PDE2 inhibitors on depression-/anxiety-like behaviors and the underlying mechanisms, Bay 60-7550 (0.75, 1.5 and 3 mg/kg, i.p.) was administered 30 min before chronic stress. The results suggested that Bay 60-7550 not only restored the behavioral changes but also regulated Cu/Zn superoxide dismutase (SOD) levels differentially in hippocampus and amygdala, which were increased in the hippocampus while decreased in the amygdala. It was also significant that Bay 60-7550 regulated the abnormalities of pro- and anti-apoptotic components, such as Bax, Caspase 3 and Bcl-2, and the indicator of PKG signaling characterized by pVASPser239, in these two brain regions. The results suggested that Bay 60-7550 is able to alleviate oxidative stress and mediate part of the apoptotic machinery in neuronal cells possibly through SOD-cGMP/PKG-anti-apoptosis signaling and that inhibition of PDE2 may represent a novel therapeutic target for psychiatric disorders, such as depression and anxiety.
PMCID: PMC4075066  PMID: 24694839
Phosphodiesterase 2; Oxidative damage; Neuronal apoptosis; Cyclic GMP
13.  Effects of dopamine D1 receptor blockade in the prelimbic prefrontal cortex or lateral dorsal striatum on frontostriatal function in Wistar and Spontaneously Hypertensive Rats 
Behavioural brain research  2014;268:229-238.
Attention Deficit Hyperactivity Disorder (ADHD) is associated with dysfunctional prefrontal and striatal circuitry and dysregulated dopamine neurotransmission. Spontaneously Hypertensive Rats (SHR), a heuristically useful animal model of ADHD, were evaluated against normotensive Wistar (WIS) controls to determine whether dopamine D1 receptor blockade of either prelimbic prefrontal cortex (plPFC) or lateral dorsal striatum (lDST) altered learning functions of both interconnected sites. A strategy set shifting task measured plPFC function (behavioral flexibility/executive function) and a reward devaluation task measured lDST function (habitual responding). Prior to tests, rats received bilateral infusions of SCH 23390 (1.0 μg/side) or vehicle into plPFC or lDST. Following vehicle, SHR exhibited longer lever press reaction times, more trial omissions, and fewer completed trials during the set shift test compared to WIS, indicating slower decision-making and attentional/motivational impairment in SHR. After reward devaluation, vehicle-treated SHR responded less than WIS, indicating relatively less habitual responding in SHR. After SCH 23390 infusions into plPFC, WIS expressed the same behavioral phenotype as vehicle-treated SHR during set shift and reward devaluation tests. In SHR, SCH 23390 infusions into plPFC exacerbated behavioral deficits in the set shift test and maintained the lower rate of responding in the reward devaluation test. SCH 23390 infusions into lDST did not modify set shifting in either strain, but produced lower rates of responding than vehicle infusions after reward devaluation in WIS. This research provides pharmacological evidence for unidirectional interactions between prefrontal and striatal brain regions, which has implications for the neurological basis of ADHD and its treatment.
PMCID: PMC4078764  PMID: 24755309
Attention Deficit Hyperactivity Disorder; Behavioral Flexibility; Dorsal Striatum; Dopamine D1 Receptors; Executive Function; Prefrontal Cortex; Reward Devaluation
14.  Partial inactivation of nucleus accumbens core decreases delay discounting in rats without affecting sensitivity to delay or magnitude 
Behavioural brain research  2014;268:159-168.
Increased preference for smaller, sooner rewards (delay discounting) is associated with several behavioral disorders, including ADHD and substance use disorders. However, delay discounting is a complex cognitive process and the relationship is unclear between the pathophysiology of the disorders and the component processes underlying delay discounting, including sensitivity to reinforcer delay and sensitivity to reinforcer magnitude. To investigate these processes, male Long Evans rats were trained in one of three tasks measuring sensitivity to delay, sensitivity to magnitude, or both (typical delay discounting task). After learning the task, animals were implanted with bilateral cannulae into either the nucleus accumbens core (AcbC) or the lateral orbitofrontal cortex (lOFC), both of which have been implicated in delay discounting. Upon recovering from the surgery, a baclofen/muscimol cocktail was infused to temporarily inactivate each of these two regions and task performance was assessed. Unlike previous studies showing that lesions of the AcbC increased delay discounting, partial inactivation of the AcbC decreased delay discounting, although it had no effects on the tasks independently assessing either sensitivity to delay or magnitude. The effects of AcbC inactivation were larger in animals that had low levels of delay discounting at baseline. Inactivation of the lOFC had no effects on behavior in any task. These findings suggest that the AcbC may act to promote impulsive choice in individuals with low impulsivity. Furthermore, the data suggest that the AcbC is able to modulate delay and magnitude sensitivity together, but not either of the two in isolation.
PMCID: PMC4084517  PMID: 24704637
Delay discounting; Impulsive choice; intertemporal choice; Nucleus Accumbens; Orbitofrontal cortex; Rats
15.  A Large Scale (N = 102) Functional Neuroimaging Study of Error processing in a Go/NoGo Task 
Behavioural brain research  2014;268:127-138.
We report a functional magnetic resonance imaging (fMRI) study of 102 healthy participants who completed a demanding Go/NoGo task. The primary purpose of this study was to delineate the neural systems underlying responses to errors in a large sample. We identified a number of regions engaged during error processing including the anterior cingulate, left lateral prefrontal areas and bilateral inferior frontal gyrus, and the subthalamic nucleus. The power afforded by the large cohort enabled identification of regions not consistently measured during Go/NoGo tasks thus helping to incrementally refine our understanding of the neural correlates of error processing. With the present fMRI results, in combination with our previous exploration of response inhibition (Steele et al. [1]), we outline a comprehensive set of regions associated with both response inhibition and error processing.
PMCID: PMC4095785  PMID: 24726752
error processing; fMRI; Go/NoGo; response inhibition
Behavioural brain research  2014;268:66-71.
Early life stress leads to several effects on neurological development, affecting health and well-being later in life. Instances of child abuse and neglect are associated with higher rates of depression, risk taking behavior, and an increased risk of drug abuse later in life. This study used repeated neonatal separation of rat pups as a model of early life stress. Rat pups were either handled and weighed as controls or separated for 180 minutes per day during postnatal days 2-8. In adulthood, male and female rats were tested for methamphetamine conditioned place preference reward and methamphetamine induced locomotor activity. Tissue samples were collected and mRNA was quantified for the norepinephrine transporter in the prefrontal cortex and the dopamine transporter in the nucleus accumbens. Results indicated rats given methamphetamine formed a conditioned place preference, but there was no effect of early separation or sex. Separated males showed heightened methamphetamine-induced locomotor activity, but there was no effect of early separation for females. Overall females were more active than males in response to both saline and methamphetamine. No differences in mRNA levels were observed across any conditions. These results suggest early neonatal separation affects methamphetamine-induced locomotor activity in a sex-dependent manner but has no effects on methamphetamine conditioned place preference.
PMCID: PMC4109814  PMID: 24713150
maternal separation; methamphetamine; conditioned place preference; locomotor activity
17.  Dietary choline supplementation to dams during pregnancy and lactation mitigates the effects of in utero stress exposure on adult anxiety-related behaviors 
Behavioural brain research  2014;268:104-110.
Brain cholinergic dysfunction is associated with neuropsychiatric illnesses such as depression, anxiety, and schizophrenia. Maternal stress exposure is associated with these same illnesses in adult offspring, yet the relationship between prenatal stress and brain cholinergic function is largely unexplored. Thus, using a rodent model, the current study implemented an intervention aimed at buffering the potential effects of prenatal stress on the developing brain cholinergic system. Specifically, control and stressed dams were fed choline-supplemented or control chow during pregnancy and lactation, and the anxiety-related behaviors of adult offspring were assessed in the open field, elevated zero maze and social interaction tests. In the open field test, choline supplementation significantly increased center investigation in both stressed and nonstressed female offspring, suggesting that choline-supplementation decreases female anxiety-related behavior irrespective of prenatal stress exposure. In the elevated zero maze, prenatal stress increased anxiety-related behaviors of female offspring fed a control diet (normal choline levels). However, prenatal stress failed to increase anxiety-related behaviors in female offspring receiving supplemental choline during gestation and lactation, suggesting that dietary choline supplementation ameliorated the effects of prenatal stress on anxiety-related behaviors. For male rats, neither prenatal stress nor diet impacted anxiety-related behaviors in the open field or elevated zero maze. In contrast, perinatal choline supplementation mitigated prenatal stress-induced social behavioral deficits in males, whereas neither prenatal stress nor choline supplementation influenced female social behaviors. Taken together, these data suggest that perinatal choline supplementation ameliorates the sex-specific effects of prenatal stress.
PMCID: PMC4144861  PMID: 24675162
18.  Striatal dopamine receptor plasticity in neurotensin deficient mice 
Behavioural brain research  2014;280:160-171.
Schizophrenia is thought to be caused, at least in part, by dysfunction in striatal dopamine neurotransmission. Both clinical studies and animal research have implicated the dopamine neuromodulator neurotensin (NT) in the pathophysiology of schizophrenia. Utilizing male mice lacking the NT gene (NT−/−), these studies examined the consequences of NT deficiency on dopaminergic tone and function, investigating (1) dopamine concentrations and dopamine receptor and transporter expression and binding in dopaminergic terminal regions, and (2) the behavioral effects of selective dopamine receptor agonists on locomotion and sensorimotor gating in adult NT−/− mice compared to wildtype (NT+/+) mice. NT−/− mice did not differ from NT+/+ mice in concentrations of dopamine or its metabolite DOPAC in any brain region examined. However, NT−/− mice showed significantly increased D1 receptor, D2 receptor, and dopamine transporter (DAT) mRNA in the caudate putamen compared to NT+/+ controls. NT−/− mice also showed elevated D2 receptor binding densities in both the caudate putamen and nucleus accumbens shell compared to NT+/+ mice. In addition, some of the behavioral effects of the D1-type receptor agonist SKF-82958 and the D2-type receptor agonist quinpirole on locomotion, startle amplitude, and prepulse inhibition were dose-dependently altered in NT−/− mice, showing altered D1-type and D2-type receptor sensitivity to stimulation by agonists in the absence of NT. The results indicate that NT deficiency alters striatal dopamine receptor expression, binding, and function. This suggests a critical role for the NT system in the maintenance of striatal DA system homeostasis and implicates NT deficiency in the etiology of dopamine-associated disorders such as schizophrenia.
PMCID: PMC4496790  PMID: 25449842
Neurotensin; Dopamine; Dopamine receptor; Striatum; Schizophrenia
19.  Long-term atorvastatin treatment leads to alterations in behavior, cognition, and hippocampal biochemistry 
Behavioural brain research  2014;267:6-11.
Membrane/lipid rafts (MLR) are plasmalemmal microdomains that are essential for neuronal signaling and synaptic development/stabilization. Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in the biosynthesis of mevalonic, a precursor to cholesterol via the mevalonate pathway. Because there has been controversy over the effects of statins on neuronal and cognitive function, we investigated the impact of long-term atorvastatin treatment (5mg/kg/d for 7 months by oral gavage) on behavior, cognition, and brain biochemistry in mice. We hypothesized that long-term statin treatment would alter lipid rafts and cognitive function. Atorvastatin treatment resulted in behavioral deficits as measured in paradigms for basic exploration (open field activity) and cognitive function (Barnes maze, startle response) without impairment in global motor function (Rotor Rod). Furthermore, significant changes in MLR-associated proteins (syntaxin-1α and synaptophysin) and a global change of post-synaptic density protein-95 (PSD95) were observed. The observed decreases in the MLR-localized pre-synaptic vesicle proteins syntaxin-1α and synaptophysin suggest a molecular mechanism for the statin-associated impairment of cognitive function that was observed and that has been suggested by the clinical literature.
PMCID: PMC4059187  PMID: 24657594
brain; cholesterol; atorvastatin; lipid; hypercholesterolemia; pharmacology
20.  Impaired sensorimotor gating in Fmr1 knock out and Fragile X premutation model mice 
Behavioural brain research  2014;267:42-45.
Fragile X Syndrome (FXS) is a common inherited cause of intellectual disability that results from a CGG repeat expansion in the FMR1 gene. Large repeat expansions trigger both transcriptional and translational suppression of Fragile X protein (FMRP) production. Fragile X-associated Tremor/Ataxia Syndrome (FXTAS) is an allelic neurodegenerative disease caused by smaller “pre-mutation” CGG repeat expansions that enhance FMR1 transcription but lead to translational inefficiency and reduced FMRP expression in animal models. Sensorimotor gating as measured by pre-pulse inhibition (PPI) is altered in both FXS patients and Fmr1 knock out (KO) mice. Similarly, FXTAS patients have demonstrated PPI deficits. Recent work suggests there may be overlapping synaptic defects between Fmr1 KO and CGG knock-in premutation mouse models (CGG KI). We therefore sought to interrogate PPI in CGG KI mice. Using a quiet PPI protocol more akin to human testing conditions, we find that Fmr1 KO animals have significantly impaired PPI. Using tis same protocol, we find CGG KI mice demonstrate an age-dependent impairment in PPI compared to wild type (WT) controls. This study describes a novel phenotype in CGG KI mice that can be used in future therapeutic development targeting premutation associated symptoms.
PMCID: PMC4070219  PMID: 24657592
Fragile X; premutation carriers; prepulse inhibition; sensorimotor gating
21.  Diet-induced obesity attenuates cytokine production following an immune challenge 
Behavioural brain research  2014;267:33-41.
Obesity increases susceptibility for numerous diseases and neurological disorders including cardiovascular disease, metabolic syndrome, and dementia. One factor that may contribute to the increased risk for these conditions is the development of chronic inflammation. The current study evaluated whether diet-induced obesity (DIO) affects cognitive performance by increasing neuroinflammation and prolonging the behavioral and inflammatory response to an immune challenge. Adult male C57BL/6J mice were fed a high-fat (60% fat) or control diet (10% fat) for 2 or 5 months. After consuming their respective diets for two months, sickness associated behaviors were assessed 4 and 24 hours after a lipopolysaccharide (LPS) or saline injection. In a separate experiment, DIO and control mice were tested for spatial learning in the water maze and challenged with LPS one month later. Peripheral cytokine production was assessed in adipose and spleen samples and the neuroinflammatory response was assessed in hippocampal, cortical, and brain samples. DIO impaired acquisition of a spatial learning task relative to control mice. However, these deficits are unlikely to be related to inflammation as DIO showed no changes in basal cytokine levels within the periphery or brain. Further, in response to LPS DIO mice showed comparable or attenuated levels of the proinflammatory cytokines interleukin-1β and interleukin-6 relative to control mice. DIO also reduced hippocampal expression of brain-derived neurotrophic factor and the pre-synaptic marker synaptophysin. Presently, the data indicate that DIO suppresses aspects of the immune response and that cognitive deficits associated with DIO may be related to reduced neurotrophic support rather than inflammation.
PMCID: PMC4475353  PMID: 24657736
High-fat diet; LPS; CD74; spatial learning; BDNF; synaptophysin
22.  Buildup of spatial information over time and across eye-movements 
Behavioural brain research  2014;275:281-287.
To interact rapidly and effectively with our environment, our brain needs access to a neural representation of the spatial layout of the external world. However, the construction of such a map poses major challenges, as the images on our retinae depend on where the eyes are looking, and shift each time we move our eyes, head and body to explore the world. Research from many laboratories including our own suggests that the visual system does compute spatial maps that are anchored to real-world coordinates. However, the construction of these maps takes time (up to 500 ms) and also attentional resources. We discuss research investigating how retinotopic reference frames are transformed into spatiotopic reference-frames, and how this transformation takes time to complete. These results have implications for theories about visual space coordinates and particularly for the current debate about the existence of spatiotopic representations.
PMCID: PMC4378607  PMID: 25224817
Spatiotopic representation; Saccade; Spatial stability
23.  The role of the medial prefrontal cortex in the acquisition, retention, and reversal of a tactile visuospatial conditional discrimination task 
Behavioural brain research  2012;236(1):94-101.
The medial prefrontal cortex (mPFC) is responsible for executive functions such as abstract rule coding. strategy switching, and behavioral flexibility; however, there is some debate regarding the extent to which mPFC is involved in reversal learning, especially in complex multisensory tasks such as conditional discrimination. Therefore, we investigated the effects of mPFC inactivation on the acquisition, retention. and reversal of a visuospatial conditional discrimination (CD) task. In experiment 1. muscimol was infused through bilateral cannulae on days 1,2, and 3 to rest the effects of mPFC inactivation on task acquisition and days 19,. 20, and 21 to test the effects on retention of the task. For experiment 2, rats were trained on the CD task for 21 days with no infusions given, after which the reward contingency was reversed, with infusions given during the first six days of reversal. The results of experiment 1 showed that the muscimol and saline groups did not differ on acquisition or retention. However, experiment 2 showed that the muscimol group displayed significantly more performance errors than the control group during reversal. Compared to the control group, the muscimol group also showed a decreased tendency to use a side-bias strategy during the intermediate stages of reversal. The failure of the muscimol group to exhibit a side bias suggests that the mPFC is necessary for sampling strategies necessary for the reversal of a visuospatial CD task.
PMCID: PMC4467825  PMID: 22940456
Medial prefrontal cortex; Behavioral flexibility; Reversal; Conditional discrimination; T-maze; Muscimol; Configural learning
24.  Structural pathology underlying neuroendocrine dysfunction in schizophrenia 
Behavioural brain research  2010;218(1):106-113.
Polydipsic hyponatremic schizophrenic (PHS) patients exhibit altered neuroendocrine activity that has been linked to their life-threatening water imbalance, as well as to impaired function and reduced volume of the anterior hippocampus. Polydipsic patients without hyponatremia (polydipsic normonatremic schizophrenics: PNS) exhibit similar, albeit less marked, changes in neuroendocrine activity and anterior hippocampal function, but not reduced anterior hippocampal volume. Indeed, reduced anterior hippocampal volume is seen in patients with normal water balance (nonpolydipsic normonatremic schizophrenics: NNS) whose neuroendocrine activity and anterior hippocampal function differ markedly from those with polydipsia. In an effort to reconcile these findings we measured hippocampal, amygdala and 3rd ventricle shapes in 26 schizophrenic patients (10 PNS, 7 PHS, 9 NNS) and 12 healthy controls matched for age and gender. Bilateral inward deformations were localized to the anterior lateral hippocampal surface (part of a neurocircuit which modulates neuroendocrine responses to psychological stimuli) in PHS and to a lesser extent in PNS, while deformations in NNS were restricted to the medial surface. Proportional deformations of the right medial amygdala, a key segment of this neurocircuit, were seen in both polydipsic groups, and correlated with the volume of the 3rd ventricle, which lies adjacent to the neuroendocrine nuclei. Finally, these structural findings were most marked in those with impaired hippocampal-mediated stress responses. These results reconcile previously conflicting data, and support the view that anterior lateral hippocampal pathology disrupts neuroendocrine function in polydipsic patients with and without hyponatremia. The relationship of these findings to the underlying mental illness remains to be established.
PMCID: PMC4465073  PMID: 21093493
hyponatremia; polydipsia; morphometry; 3rd ventricle; amygdala; stress diathesis; shape analysis; LDDMM
25.  Ethanol Conditioned Place Preference and Alterations in ΔFosB Following Adolescent Nicotine Administration Differ in Rats Exhibiting High or Low Behavioral Reactivity to a Novel Environment 
Behavioural brain research  2014;262:101-108.
This study determined the effects of adolescent nicotine administration on adult alcohol preference in rats exhibiting high or low behavioral reactivity to a novel environment, and ascertained whether nicotine altered ΔFosB in the ventral striatum (vStr) and prefrontal cortex (PFC) immediately after drug administration or after rats matured to adulthood. Animals were characterized as exhibiting high (HLA) or low (LLA) locomotor activity in the novel open field on postnatal day (PND) 31 and received injections of saline (0.9%) or nicotine (0.56 mg free base/kg) from PND 35–42. Ethanol-induced conditioned place preference (CPP) was assessed on PND 68 following 8 days conditioning in a biased paradigm; ΔFosB was measured on PND 43 or PND 68. Following adolescent nicotine exposure, HLA animals demonstrated a CPP when conditioned with ethanol; LLA animals were unaffected. Further, adolescent nicotine exposure for 8 days increased levels of ΔFosB in limbic regions in both HLA and LLA rats, but this increase persisted into adulthood only in LLA animals. Results indicate that adolescent nicotine exposure facilitates the establishment of an ethanol CPP in HLA rats, and that sustained elevations in ΔFosB are not necessary or sufficient for the establishment of an ethanol CPP in adulthood. These studies underscore the importance of assessing behavioral phenotype when determining the behavioral and cellular effects of adolescent nicotine exposure.
PMCID: PMC4457313  PMID: 24412683
Addiction; Adolescent; ΔFosB; Ethanol; Nicotine; Reward

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