Working memory and pattern separation in founder strains of the BXD recombinant inbred mouse panel.

Working memory and pattern separation are fundamental cognitive abilities which, when impaired, significantly diminish quality of life. Discovering genetic mechanisms underlying innate and disease-induced variation in these cognitive abilities is a critical step towards treatments for common and devastating neurodegenerative conditions such as Alzheimer's disease. In this regard, the trial-unique nonmatching-to-location assay (TUNL) is a touchscreen operant conditioning procedure allowing simultaneous quantification of working memory and pattern separation in mice and rats. In the present study, we used the TUNL assay to quantify these cognitive abilities in C57BL/6J and DBA/2J mice. These strains are the founders of the BXD recombinant inbred mouse panel which enables discovery of genetic mechanisms underlying phenotypic variation. TUNL testing revealed that pattern separation was significantly influenced by mouse strain, whereas working memory was not. Moreover, horizontal distance and vertical distance between choice-phase stimuli had dissociable effects on TUNL performance. These findings provide novel data on mouse strain differences in pattern separation and support previous findings of equivalent working memory performance in C57BL/6J and DBA/2J mice. Although working memory of the BXD founder strains was equivalent in this study, working memory of BXD strains may be divergent because of transgressive segregation. Collectively, data presented here indicate that pattern separation is heritable in the mouse and that the BXD panel can be used to identify mechanisms underlying variation in pattern separation.

Strain and sex dependent effects of isolation housing relative to environmental enrichment on operant sensation seeking in mice.

Sensation seeking is a multidimensional phenotype that predicts the development of drug addiction in humans and addiction-like drug seeking in rodents. Several lines of evidence suggest that chronic stress increases sensation seeking and addiction-like drug seeking through common genetic mechanisms. Discovery and characterization of these mechanisms would reveal how chronic stress interacts with the genome to influence sensation seeking and how drugs of abuse hijack these fundamental reward mechanisms to drive addiction. To this end, we tested the hypothesis that chronic isolation housing stress (relative to environmental enrichment) influences operant sensation seeking as a function of strain, sex, or their interaction. To determine if the BXD recombinant inbred panel could be used to identify genetic and epigenetic mechanisms underlying any identified gene-by-environment interactions, we used mice from the two BXD founder strains. Following 10 weeks of differential housing, we assessed operant sensation seeking using several reinforcement schedules. The primary finding from this study was that DBA/2J but not C57BL/6J mice were significantly vulnerable to an isolation-induced increase (relative to environmental enrichment) in sensation seeking during extinction when the sensory reward was no longer available; this effect was significantly more robust in females. These data reveal a previously unknown isolation-induced effect on extinction of operant sensation seeking that is sex-dependent, addiction-relevant, and that can be dissected using the BXD recombinant inbred panel.

Reinstating Over-Pouring Behavior: Importance of the Imagined Drinking Context.

BACKGROUND: College students significantly over-pour more than a standard drink in a free-pour simulated alcohol-pouring task. Due to this effect, it is likely that much of the self-report alcohol consumption data incorrectly or underreport actual alcohol consumption. Objective: We sought to determine factors that influence over-pouring. Specifically, in two studies we sought to determine the effect of different factors on the amount of fluid subjects pour in a simulated alcohol-pouring task. Methods: Data were collected from 217 undergraduate students (105 subjects in study 1 and 112 different subjects in study 2). In study one, subjects were asked to pour what they consider to be a standard beer for themselves and an unfamiliar peer. In study two subjects were instructed to pour a beer for themself and the experimenter as if they were at an off-campus party. Results: In study one, we found that size of the cup used to pour into significantly impacted the amount of fluid poured. In addition, subjects poured significantly less for themselves than the unfamiliar peer. In study two, the imagined context in which subjects poured significantly increased the amount of fluid poured demonstrating the importance of imagined contextual cues on alcohol use behavior. Conclusions/Importance: Imagined drinking context, presence of an unfamiliar peer, and cup size affect the amount of fluid poured in a simulated alcohol free pour task. Given the various factors that impact free pouring in college students, self-report alcohol data should be considered with caution.

Environmental enrichment influences novelty reactivity, novelty preference, and anxiety via distinct genetic mechanisms in C57BL/6J and DBA/2J mice.

Environmental factors such as stress drive the development of drug addiction in genetically vulnerable individuals; the genes underlying this vulnerability are unknown. One strategy for uncovering these genes is to study the impact of environmental manipulation on high-throughput phenotypes that predict drug use and addiction-like behaviors. In the present study, we assessed the viability of this approach by evaluating the relative effects of environmental enrichment and isolation housing on three high-throughput phenotypes known to predict variation on distinct aspects of intravenous drug self-administration. Prior to behavioral testing, male and female C57BL/6J and DBA/2J mice (BXD founders) were housed in enrichment or isolation for ten weeks beginning at weaning. Enrichment significantly reduced novelty reactivity; this effect was significantly more robust in C57BL/6J mice relative to DBA/2J mice. Enrichment significantly reduced novelty preference; this effect was significantly dependent on novel environment characteristics and was significantly more robust in DBA/2J mice relative to C57BL/6J mice. Enrichment significantly increased anxiety; this effect was not strain-dependent. Collectively, these data indicate that (1) environmental enrichment influences novelty reactivity, novelty preference, and anxiety via distinct genetic mechanisms in mice, and (2) the BXD panel can be used to discover the genetic and epigenetic mechanisms underlying this phenomenon.

Discovery of a Role for Rab3b in Habituation and Cocaine Induced Locomotor Activation in Mice Using Heterogeneous Functional Genomic Analysis.

Substance use disorders are prevalent and present a tremendous societal cost but the mechanisms underlying addiction behavior are poorly understood and few biological treatments exist. One strategy to identify novel molecular mechanisms of addiction is through functional genomic experimentation. However, results from individual experiments are often noisy. To address this problem, the convergent analysis of multiple genomic experiments can discern signal from these studies. In the present study, we examine genetic loci that modulate the locomotor response to cocaine identified in the recombinant inbred (BXD RI) genetic reference population. We then applied the GeneWeaver software system for heterogeneous functional genomic analysis to integrate and aggregate multiple studies of addiction genomics, resulting in the identification of Rab3b as a functional correlate of the locomotor response to cocaine in rodents. This gene encodes a member of the RAB family of Ras-like GTPases known to be involved in trafficking of secretory and endocytic vesicles in eukaryotic cells. The convergent evidence for a role of Rab3b includes co-occurrence in previously published genetic mapping studies of cocaine related behaviors; methamphetamine response and cocaine- and amphetamine-regulated transcript prepropeptide (Cartpt) transcript abundance; evidence related to other addictive substances; density of polymorphisms; and its expression pattern in reward pathways. To evaluate this finding, we examined the effect of RAB3 complex perturbation in cocaine response. B6;129-Rab3btm1Sud Rab3ctm1sud Rab3dtm1sud triple null mice (Rab3bcd -/-) exhibited significant deficits in habituation, and increased acute and repeated cocaine responses. This previously unidentified mechanism of the behavioral predisposition and response to cocaine is an example of many that can be identified and validated using aggregate genomic studies.

Impact of acute ethanol exposure on body temperatures in aged, adult and adolescent male rats.

The mean population age of the United States continues to increase, and data suggest that by the year 2060 the population of people over the age of 65 will more than double, providing a potentially massive strain on health care systems. Research demonstrates individuals 65 and older continue to consume ethanol, often at high levels. However, preclinical animal models are still being developed to understand how ethanol might interact with the aged population. The current experiments investigated differential body temperature responses in aged rats compared to adult rats and adolescent rats. Aged (19 months of age), adult (70 days of age), or adolescent (30 days of age) male Sprague Dawley rats were administered 1.0 g/kg, 2.0 g/kg, or 3.0 g/kg ethanol, intraperitoneally (i.p.), in a balanced Latin square design. Prior to ethanol administration, a core body temperature via an anal probe was obtained, and then repeatedly determined every 60 min following ethanol exposure for a total of 360 min. In addition, a blood sample was obtained from a tail nick 60, 180, and 300 min following the ethanol injection to investigate the relationship of ethanol levels and body temperature in the same animals. Aged rats had significantly greater reductions in body temperature compared to either adult or adolescent rats following both the 2.0 g/kg and 3.0 g/kg ethanol injection. Additionally, adolescent rats cleared ethanol significantly faster than aged or adult animals. These experiments suggest body temperature regulation in aged rats might be more sensitive to acute ethanol compared to adult rats or adolescent rats. Future studies are needed to identify the neurobiological effects underlying the differential sensitivity in aged rats to ethanol.

Visual Discrimination, Serial Reversal, and Extinction Learning in the mdx Mouse.

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy and the most common neuromuscular disorder. In addition to neuromuscular consequences, some individuals with DMD experience global intellectual dysfunction and executive dysfunction of unknown mechanistic origin. The cognitive profile of the mdx mouse, the most commonly used mouse model of DMD, has been incompletely characterized and has never been assessed using the touchscreen operant conditioning paradigm. The touchscreen paradigm allows the use of protocols that are virtually identical to those used in human cognitive testing and may, therefore, provide the most translational paradigm for quantifying mouse cognitive function. In the present study, we used the touchscreen paradigm to assess the effects of the mdx mutation on visual discrimination learning, serial reversal learning, and extinction learning. To enable measuring task-dependent learning and memory processes while holding demands on sensory-driven information processing constant, we developed equally salient visual stimuli and used them on all experimental stages. Acquisition of the initial pairwise visual discrimination was facilitated in mdx mice relative to wildtype littermates; this effect was not explained by genotypic differences in impulsivity, motivation, or motor deficits. The mdx mutation had no effect on serial reversal or extinction learning. Together, findings from this study and previous studies suggest that mdx effects on cognitive function are task-specific and may be influenced by discrimination type (spatial, visual), reward type (food, escape from a non-preferred environment), sex, and genetic background.

The impact of low to moderate chronic intermittent ethanol exposure on behavioral endpoints in aged, adult, and adolescent rats.

The average age of the population in the United States and other countries is increasing. Understanding the health consequences in the aged population is critical. Elderly individuals consume ethanol, often at elevated rates, and in some cases in a binge episode. The present study sought to investigate whether binge-like ethanol exposure in aged male rats produced differential health and behavioral effects compared to adult male and adolescent male rats. Subjects were exposed to either 1.0 g/kg or 2.0 g/kg ethanol every other day via intraperitoneal injection for 20 days, and tested on a variety of behavioral measures and body weight. Binge-like ethanol exposure produced differential effects on body weight between aged and adolescent and adult rats. In addition, aged rats had a significantly longer loss of righting reflex and demonstrated a trend toward tolerance following the 2.0-g/kg exposure. No significant effects on anxiety-like behavior as measured by open arm entries, depressive-like symptoms as measured by immobility in the forced swim test, or cognitive performance as measured by latency and path length in the Morris water maze were found. These results demonstrate that aged animals are differentially sensitive to the impact of chronic intermittent ethanol exposure in some, but not all behaviors. Future research is needed to understand the mechanisms of these differential effects.

Stimulus Complexity and Mouse Strain Drive Escalation of Operant Sensation Seeking Within and Across Sessions in C57BL/6J and DBA/2J Mice.

Sensation seeking is a heritable trait that is genetically correlated with substance use; the shared genetic mechanisms underlying these traits are largely unknown. The relationship of sensation seeking and substance use has practical importance because discovering genes that drive sensation seeking can reveal genes driving substance use, and quantification of sensation seeking in mice is higher throughput and less technically challenging than quantification of volitional drug use. In order to fully understand the genetic mechanisms driving sensation seeking, it is critical to first understand the nongenetic factors driving sensation seeking. In the present study, we used the operant sensation seeking paradigm to assess the effects of stimulus complexity on sensation seeking in C57BL/6J and DBA/2J mice. These strains are the founders of the BXD recombinant inbred mouse panel which enables the discovery of genes driving phenotypic variation. This study led to four principal conclusions. First, all sensory stimuli used in the study, regardless of complexity or number of stimulus modalities, served as reinforcers for C57BL/6J and DBA/2J mice. Second, for both C57BL/6J and DBA/2J mice, sensation seeking for a high complexity sensory stimulus was significantly greater than sensation seeking for a low complexity sensory stimulus. Third, for both C57BL/6J and DBA/2J mice, sensation seeking escalated significantly within-session when a multimodal sensory stimulus of medium or high complexity was used but not when a unimodal sensory stimulus of low complexity was used. Finally, both the magnitude of sensation seeking and the magnitude of within-session escalation of sensation seeking were significantly greater in mice from the DBA/2J strain relative to mice from the C57BL/6J strain. Collectively, these findings indicate that stimulus complexity and genetic background drive escalation of operant sensation seeking within and across sessions, and that the BXD recombinant inbred mouse panel can be used to discover the genetic mechanisms underlying these phenomena.

Age-dependent effects of chronic intermittent ethanol treatment: Gross motor behavior and body weight in aged, adult and adolescent rats.

The proportion of people in the population who are elderly is rapidly increasing. In addition, dangerous alcohol consumption in this demographic is rising. Approximately 33% of all people with an alcohol use disorder are diagnosed with late onset alcoholism. However, few suitable animal models for late onset alcoholism exist, making it difficult to investigate the impact of alcoholism later in life. The current study investigated if chronic intermittent ethanol exposure via intraperitoneal injections every other day for 20days in aged, adult and adolescent male rats differentially alters body weight and impairs gross motor behavior as measured by the aerial righting reflex. The body weight of aged and adult rats were significantly decreased by chronic intermittent ethanol exposure while the body weight of adolescent rats was not impacted. In addition, the aerial righting reflex of aged rats was significantly more impaired by alcohol exposure than the aerial righting reflex of adult or adolescent animals. Chronic intermittent ethanol exposure did not produce tolerance in the aerial righting reflex for any of the three age groups. The differential age sensitivity in the aerial righting reflex was not due to differential blood ethanol concentrations. The current work demonstrates the risk factors of chronic alcohol use in the elderly and highlights the need for additional study in this vulnerable demographic.

Abnormalities in the Structure and Function of Cerebellar Neurons and Neuroglia in the Lc/+ Chimeric Mouse Model of Variable Developmental Purkinje Cell Loss.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders characterized by impaired and disordered language, decreased social interactions, stereotyped and repetitive behaviors, and impaired fine and gross motor skills. It has been well established that cerebellar abnormalities are one of the most common structural changes seen in the brains of people diagnosed with autism. Common cerebellar pathology observed in autistic individuals includes variable loss of cerebellar Purkinje cells (PCs) and increased numbers of reactive neuroglia in the cerebellum and cortical brain regions. The Lc/+ mutant mouse loses 100 % of cerebellar PCs during the first few weeks of life and provided a valuable model to study the effects of developmental PC loss on underlying structural and functional changes in cerebellar neural circuits. Lurcher (Lc) chimeric mice were also generated to explore the link between variable cerebellar pathology and subsequent changes in the structure and function of cerebellar neurons and neuroglia. Chimeras with the most severe cerebellar pathology (as quantified by cerebellar PC counts) had the largest changes in cFos expression (an indirect reporter of neural activity) in cerebellar granule cells (GCs) and cerebellar nucleus (CN) neurons. In addition, Lc chimeras with the fewest PCs also had numerous reactive microglia and Bergmann glia located in the cerebellar cortex. Structural and functional abnormalities observed in the cerebella of Lc chimeras appeared to be along a continuum, with the degree of pathology related to the number of PCs in individual chimeras.

The Cerebellum and SIDS: Disordered Breathing in a Mouse Model of Developmental Cerebellar Purkinje Cell Loss during Recovery from Hypercarbia.

The cerebellum assists coordination of somatomotor, respiratory, and autonomic actions. Purkinje cell alterations or loss appear in sudden infant death and sudden death in epilepsy victims, possibly contributing to the fatal event. We evaluated breathing patterns in 12 wild-type (WT) and Lurcher mutant mice with 100% developmental cerebellar Purkinje cell loss under baseline (room air), and recovery from hypercapnia, a concern in sudden death events. Six mutant and six WT mice were exposed to 4-min blocks of increasing CO2 (2, 4, 6, and 8%), separated by 4-min recovery intervals in room air. Breath-by-breath patterns, including depth of breathing and end-expiratory pause (EEP) durations during recovery, were recorded. No baseline genotypic differences emerged. However, during recovery, EEP durations significantly lengthened in mutants, compared to WT mice, following the relatively low levels of CO2 exposure. Additionally, mutant mice exhibited signs of post-sigh disordered breathing during recovery following each exposure. Developmental cerebellar Purkinje cell loss significantly affects compensatory breathing patterns following mild CO2 exposure, possibly by inhibiting recovery from elevated CO2. These data implicate cerebellar Purkinje cells in the ability to recover from hypercarbia, suggesting that neuropathologic changes or loss of these cells contribute to inadequate ventilatory recovery to increased environmental CO2. Multiple disorders, including sudden infant death syndrome (SIDS) and sudden unexpected death in epilepsy (SUDEP), appear to involve both cardiorespiratory failure and loss or injury to cerebellar Purkinje cells; the findings support the concept that such neuropathology may precede and exert a prominent role in these fatal events.

Systems genetics of intravenous cocaine self-administration in the BXD recombinant inbred mouse panel.

RATIONALE: Cocaine addiction is a major public health problem with a substantial genetic basis for which the biological mechanisms remain largely unknown. Systems genetics is a powerful method for discovering novel mechanisms underlying complex traits, and intravenous drug self-administration (IVSA) is the gold standard for assessing volitional drug use in preclinical studies. We have integrated these approaches to identify novel genes and networks underlying cocaine use in mice. METHODS: Mice from 39 BXD strains acquired cocaine IVSA (0.56 mg/kg/infusion). Mice from 29 BXD strains completed a full dose-response curve (0.032-1.8 mg/kg/infusion). We identified independent genetic correlations between cocaine IVSA and measures of environmental exploration and cocaine sensitization. We identified genome-wide significant quantitative trait loci (QTL) on chromosomes 7 and 11 associated with shifts in the dose-response curve and on chromosome 16 associated with sessions to acquire cocaine IVSA. Using publicly available gene expression data from the nucleus accumbens, midbrain, and prefrontal cortex of drug-naïve mice, we identified Aplp1 and Cyfip2 as positional candidates underlying the behavioral QTL on chromosomes 7 and 11, respectively. A genome-wide significant trans-eQTL linking Fam53b (a GWAS candidate for human cocaine dependence) on chromosome 7 to the cocaine IVSA behavioral QTL on chromosome 11 was identified in the midbrain; Fam53b and Cyfip2 were co-expressed genome-wide significantly in the midbrain. This finding indicates that cocaine IVSA studies using mice can identify genes involved in human cocaine use. CONCLUSIONS: These data provide novel candidate genes underlying cocaine IVSA in mice and suggest mechanisms driving human cocaine use.

Reduced dopamine release in the nucleus accumbens core of adult rats following adolescent binge alcohol exposure: age and dose-dependent analysis.

RATIONALE: Alcohol use in adolescence is one of the most significant predictors of alcohol dependence in adulthood, yet the neurochemical mechanisms underlying this heightened vulnerability remain unknown. Whereas research has focused on characterizing adaptations in the mesolimbic dopamine (DA) system following ethanol exposure in adolescence, whether these changes persist into adulthood has yet to be determined. OBJECTIVES: The objective of this study is to investigate the effects of binge-intermittent ethanol administration in adolescence (P30-50) or early adulthood (P60-80) on DA in the nucleus accumbens (NAc) core after an ethanol challenge in adulthood following a period of abstinence. METHODS: Male Sprague Dawley rats (n = 160) were administered intermittent ethanol injections, 1 or 3 g/kg, intraperitoneally (i.p.) every other day for 20 days starting on either P30 or 60. Following an ethanol-free period of either 7, 14, or 28 days, we measured DA efflux following an ethanol challenge (3 g/kg, i.p.) using electrochemical recording electrodes bilaterally implanted into the NAc core. RESULTS: Moderate-dose ethanol administration (1 g/kg, i.p.) during adolescence significantly decreased ethanol-evoked DA release in adulthood at 7 and 14 days, but not 28 days, following pretreatment exposure compared to saline controls. Relative to rats pretreated with ethanol in adulthood, moderate-dose ethanol in adolescence significantly reduced DA efflux at all time points measured. Additionally, adult rats pretreated with high dose ethanol administration (3 g/kg, i.p.) displayed significantly decreased DA compared to adolescents after 28 days of withdrawal. CONCLUSIONS: Binge-intermittent ethanol administration during adolescence may induce age-dependent neuroadaptations in the mesolimbic DA system compared to ethanol-treated adults during protracted ethanol withdrawal.

Performance of C57BL/6J and DBA/2J mice on a touchscreen-based attentional set-shifting task.

Attentional set-shifting deficits are a feature of multiple psychiatric disorders. However, the neurogenetic mechanisms underlying these deficits are largely unknown. In the present study we assessed performance of C57BL/6J and DBA/2J mice on a touchscreen-based attentional set-shifting task similar to those used with humans and non-human primates. In experiment 1, mice discriminated simple white lines followed by compound stimuli composed of white lines superimposed on grey shapes. Although performance of the two strains was largely equivalent during early stages of the task, DBA/2J mice committed significantly more errors compared to C57BL/6J mice on the extra-dimensional shift. Additionally, performance of mice as a group declined across the three compound discrimination reversals. In experiment 2 we assessed salience of the shapes and lines dimensions and determined if dimensional salience, a variable previously shown to affect set-shifting abilities in humans and non-human primates, could be systematically manipulated. Findings from experiment 2 suggested that strain differences during the extra-dimensional shift in experiment 1 were most parsimoniously explained by a consistently impaired ability in DBA/2J mice to discriminate a subset of the compound stimuli. Additionally, unlike maze-based tasks, the relative salience of the two dimensions could be manipulated by systematically altering the width of lines exemplars while retaining other potentially-relevant attributes of the compound stimuli. These findings reveal unique and in some cases strain-dependent phenomena related to discriminations of simple and multidimensional visual stimuli which may facilitate future efforts to identify and fully characterize visual discrimination, reversal learning, and attentional set-shifting deficits in mice.

Glutamate dysfunction associated with developmental cerebellar damage: relevance to autism spectrum disorders.

Neural abnormalities commonly associated with autism spectrum disorders include prefrontal cortex (PFC) dysfunction and cerebellar pathology in the form of Purkinje cell loss and cerebellar hypoplasia. It has been reported that loss of cerebellar Purkinje cells results in aberrant dopamine neurotransmission in the PFC which occurs via dysregulation of multisynaptic efferents from the cerebellum to the PFC. Using a mouse model, we investigated the possibility that developmental cerebellar Purkinje cell loss could disrupt glutamatergic cerebellar projections to the PFC that ultimately modulate DA release. We measured glutamate release evoked by local electrical stimulation using fixed-potential amperometry in combination with glutamate selective enzyme-based recording probes in urethane-anesthetized Lurcher mutant and wildtype mice. Target sites included the mediodorsal and ventrolateral thalamic nuclei, reticulotegmental nuclei, pedunculopontine nuclei, and ventral tegmental area. With the exception of the ventral tegmental area, the results indicated that in comparison to wildtype mice, evoked glutamate release was reduced in Lurcher mutants by between 9 and 72% at all stimulated sites. These results are consistent with the notion that developmental loss of cerebellar Purkinje cells drives reductions in evoked glutamate release in cerebellar efferent pathways that ultimately influence PFC dopamine release. Possible mechanisms whereby reductions in glutamate release could occur are discussed.

Effects of adolescent nicotine exposure and withdrawal on intravenous cocaine self-administration during adulthood in male C57BL/6J mice.

Studies of adolescent drug use show (1) a pattern in which the use of tobacco precedes the use of other drugs and (2) a positive relationship between adolescent tobacco use and later drug use. These observations have led to the hypothesis that a causal relationship exists between early exposure to nicotine and the later use of hard drugs such as cocaine. Using male C57BL/6J mice, we tested the hypothesis that nicotine exposure in adolescence leads to increased intravenous self-administration (IVSA) of cocaine in adulthood. Using miniature osmotic pumps, we exposed mice and their littermate controls to nicotine (24 mg/kg/day) or vehicle, respectively, over the entire course of adolescence [postnatal days (P) 28-56]. Nicotine exposure was terminated on P56 and mice were not exposed to nicotine again during the experiment. On P73, mice were allowed to acquire cocaine IVSA (1.0 mg/kg/infusion) and a dose-response curve was generated (0.18, 0.32, 0.56, 1.0, 1.8 mg/kg/infusion). Lever pressing during extinction conditions was also evaluated. All mice rapidly learned to lever press for the combination of cocaine infusions and non-drug stimuli. Analysis of the dose-response curve revealed that adolescent nicotine-exposed mice self-administered significantly more (P < 0.05) cocaine than controls at all but the highest dose. No significant differences were observed between adolescent nicotine-exposed and control mice during the acquisition or extinction stages. These results indicate that adolescent nicotine exposure can increase cocaine IVSA in mice, which suggests the possibility of a causal link between adolescent tobacco use and later cocaine use in humans.

Stimulation-evoked dopamine release in the nucleus accumbens following cocaine administration in rats perinatally exposed to polychlorinated biphenyls.

Exposure to polychlorinated biphenyls (PCBs) alters brain dopamine (DA) concentrations and DA receptor/transporter function, suggesting the reinforcing properties of drugs of abuse acting on the DA system may be affected by PCB exposure. Female Long-Evans rats were orally exposed to 0, 3, or 6 mg/kg/day PCBs from 4 weeks prior to breeding until litters were weaned on postnatal day 21. In vivo fixed potential amperometry (FPA) was used in adult anesthetized offspring to determine whether perinatal PCB exposure altered (1) presynaptic DA autoreceptor (DAR) sensitivity, (2) electrically evoked nucleus accumbens (NAc) DA efflux following administration of cocaine, and (3) the rate of depletion of presynaptic DA stores. One adult male and female littermate were tested using FPA following a single injection of cocaine (20 mg/kg ip), whereas a second adult male and female littermate were tested following the last of seven daily cocaine injections of the same dose. The carbon fiber recording microelectrode was positioned in the NAc core, and DA oxidation currents (i.e., DA release) evoked by brief stimulation of the medial forebrain bundle (MFB) were quantified before and after administration of cocaine. PCB-exposed rats exhibited enhanced stimulation-evoked DA release (relative to baseline) following a single injection of cocaine. Although nonexposed controls exhibited typical DA sensitization following repeated cocaine administration, this effect was attenuated in PCB-exposed rats. In addition, DAR sensitivity was higher (males only), and the rate of depletion of presynaptic DA stores was greater in PCB-exposed animals relative to nonexposed controls. These results indicate that perinatal PCB exposure can modify DA synaptic transmission in the NAc in a manner previously shown to alter the reinforcing properties of cocaine.

Effects of stimulus salience on touchscreen serial reversal learning in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in males and the most common genetic cause of autism. Although executive dysfunction is consistently found in humans with FXS, evidence of executive dysfunction in Fmr1 KO mice, a mouse model of FXS, has been inconsistent. One possible explanation for this is that executive dysfunction in Fmr1 KO mice, similar to humans with FXS, is only evident when cognitive demands are high. Using touchscreen operant conditioning chambers, male Fmr1 KO mice and their male wildtype littermates were tested on the acquisition of a pairwise visual discrimination followed by four serial reversals of the response rule. We assessed reversal learning performance under two different conditions. In the first, the correct stimulus was salient and the incorrect stimulus was non-salient. In the second and more challenging condition, the incorrect stimulus was salient and the correct stimulus was non-salient; this increased cognitive load by introducing conflict between sensory-driven (i.e., bottom-up) and task-dependent (i.e., top-down) signals. Fmr1 KOs displayed two distinct impairments relative to wildtype littermates. First, Fmr1 KOs committed significantly more learning-type errors during the second reversal stage, but only under high cognitive load. Second, during the first reversal stage, Fmr1 KOs committed significantly more attempts to collect a reward during the timeout following an incorrect response. These findings indicate that Fmr1 KO mice display executive dysfunction that, in some cases, is only evident under high cognitive load.

Is autism a disease of the cerebellum? An integration of clinical and pre-clinical research.

Autism spectrum disorders are a group of neurodevelopmental disorders characterized by deficits in social skills and communication, stereotyped and repetitive behavior, and a range of deficits in cognitive function. While the etiology of autism is unknown, current research indicates that abnormalities of the cerebellum, now believed to be involved in cognitive function and the prefrontal cortex (PFC), are associated with autism. The current paper proposes that impaired cerebello-cortical circuitry could, at least in part, underlie autistic symptoms. The use of animal models that allow for manipulation of genetic and environmental influences are an effective means of elucidating both distal and proximal etiological factors in autism and their potential impact on cerebello-cortical circuitry. Some existing rodent models of autism, as well as some models not previously applied to the study of the disorder, display cerebellar and behavioral abnormalities that parallel those commonly seen in autistic patients. The novel findings produced from research utilizing rodent models could provide a better understanding of the neurochemical and behavioral impact of changes in cerebello-cortical circuitry in autism.