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1.  Male rats that differ in novelty exploration demonstrate distinct patterns of sexual behavior 
Behavioral neuroscience  2013;127(1):47-58.
High versus low novelty exploration predicts a variety of behavioral differences. For example, rats selectively-bred for high novelty exploration (bred High Responders, bHR) exhibit exaggerated aggression, impulsivity, and proclivity to addictive behaviors compared to low novelty-reactive rats (bred Low Responders, bLRs), which are characterized by a high anxiety/depressive-like phenotype. Since bHR/bLR rats exhibit differences in dopaminergic circuitry and differential response to rewarding stimuli (i.e., psychostimulants, food), the present study examined whether they also differ in another key hedonic behavior – sex. Thus, adult bHR/bLR males were given five 30-min opportunities to engage in sexual activity with a receptive female. Sexual behavior and motivation were examined and compared between the groups. The bHR/bLR phenotype affected both sexual motivation and behavior, with bLR males demonstrating reduced motivation for sex compared with bHR males (i.e., fewer animals copulated, longer latency to engage in sex). The bHR males required more intromissions at a faster pace per ejaculation than did bLR males. Thus, neurobiological differences that affect motivation for drugs of abuse, aggression, and impulsivity in rats also affect sexual motivation and performance.
PMCID: PMC3982402  PMID: 23398441
bred High Responder (bHR); bred Low Responder (bLR); sexual performance; reward; dopamine
2.  Cerebellar Structure and Function in Male Wistar-Kyoto Hyperactive Rats 
Behavioral neuroscience  2013;127(2):311-324.
Previous research has suggested that the Wistar-Kyoto Hyperactive (WKHA) rat strain may model some of the behavioral features associated with attention-deficit/hyperactivity disorder (ADHD). We have shown that, in cerebellar-dependent eyeblink conditioning, WKHA emit eyeblink CRs with shortened onset latencies. To further characterize the shortened CR onset latencies seen in WKHA rats, we examined 750-ms delay conditioning with either a tone CS or a light CS, we extended acquisition training, and we included Wistar rats as an additional, outbred control strain. Our results indicated that WKHAs learned more quickly and showed a shortened CR onset latency to a tone CS compared to both Wistar-Kyoto Hypertensive (WKHT) and Wistars. WKHAs and Wistars show a lengthening of CR onset latency over conditioning with a tone CS and an increasing confinement of CRs to the later part of the tone CS (inhibition of delay). WKHAs learned more quickly to a light CS only in comparison to WKHTs and showed a shortened CR onset latency only in comparison to Wistars. Wistars showed an increasing confinement of CRs to the late part of the light CS over conditioning. We used unbiased stereology to estimate the number of Purkinje and granule cells in the cerebellar cortex of the three strains. Our results indicated that WKHAs have more granule cells than Wistars and WKHTs and more Purkinje cells than Wistars. Results are discussed in terms of CS processing and cerebellar cortical contributions to EBC.
PMCID: PMC3975598  PMID: 23398437
WKHA; eyeblink classical conditioning; Purkinje cells; granule cells; timing; inhibition of delay; stereology
3.  Emergence of Nonmotor Symptoms as the Focus of Research and Treatment of Parkinson's Disease: Introduction to the Special Section on Nonmotor Dysfunctions in Parkinson's Disease 
Behavioral neuroscience  2013;127(2):135-138.
Parkinson's disease (PD) is traditionally characterized by the cardinal motor symptoms of tremor, rigidity, slowness of movement, and impairments of posture, gait, and balance. A relatively new focus of research and treatment is the nonmotor symptoms of the disease, following from recent understanding of the neuropathological stages. Disruptions of arousal, mood, sleep, and autonomic function before the first motor signs of PD implicate the lower brainstem, which is affected before the substantia nigra and dopaminergic system. In later stages of the disease, the pathology extends to the cortex, accompanied by impairments in cognition and perception. The articles in this special section advance our knowledge of the brain bases of the nonmotor symptoms of PD, including disrupted visual perception, impaired cognition across a range of domains, and psychiatric and artistic manifestations. Subtypes under investigation include those described by side of disease onset (left or right body side), predominant cognitive profile, and gender. Taken together, the articles in this special section reflect the field's growing focus on the nonmotor symptoms of PD, their brain bases, and the corresponding potential for their treatment.
PMCID: PMC3758873  PMID: 23565933
Parkinson's disease; nonmotor; brainstem; cognition; subtypes
4.  Line Bisection in Parkinson’s Disease: Investigation of Contributions of Visual Field, Retinal Vision, and Scanning Patterns to Visuospatial Function 
Behavioral neuroscience  2013;127(2):151-163.
Parkinson’s disease (PD) is characterized by disorders of visuospatial function that can impact everyday functioning. Visuospatial difficulties are more prominent in those whose motor symptoms begin on the left body side (LPD) than the right body side (RPD) and have mainly been attributed to parietal dysfunction. The source of visuospatial dysfunction is unclear, as in addition to subcortical–cortical changes, there are irregularities of visual scanning and potentially of retinal-level vision in PD. To assess these potential contributors, performance on a visuospatial task—line bisection—was examined together with retinal structure (nerve fiber layer thickness, measured by optical coherence tomography [OCT]), retinal function (contrast sensitivity, measured by frequency-doubling technology [FDT]), and visual scanning patterns. Participants included 20 nondemented patients (10 LPD, 10 RPD) and 11 normal control (NC) adults. Relative to the other groups, LPD were expected to show rightward bias on horizontal line bisection, especially within the left visual hemispace, and downward bias on vertical bisection. LPD relative rightward bias was confirmed, though not mainly within the left hemispace and not correlated with retinal structure or function. Retinal thinning was seen in LPD relative to RPD. Qualitative visualization of eye movements suggested greater LPD exploration of the right than left side of the line during horizontal bisection, and some overall compression of scanning range in RPD (both orientations) and LPD (primarily vertical). Results indicated that rightward visuospatial bias in our LPD sample arose not from abnormalities at the retinal level but potentially from attentional biases, reflected in eye movement patterns.
PMCID: PMC3762594  PMID: 23356329
visuospatial; retina; Parkinson’s disease; optical coherence tomography; frequency doubling technology
5.  Frontal and Posterior Subtypes of Neuropsychological Deficit in Parkinson's Disease 
Behavioral neuroscience  2013;127(2):175-183.
Mild cognitive impairment in Parkinson's disease (PD) is heterogeneous in regard to affected domains. Although patterns of cognitive performance that may predict later dementia are as yet undetermined, posterior-versus frontal-type assessments show promise for differential predictive value. The present study included 70 individuals: 42 with idiopathic PD without dementia and 28 age- and education-matched healthy control adults (HC). Participants completed assessments of cognition with emphasis on tests that are sensitive to frontal and posterior deficits. PD patients were classified into cognitive subgroups and the subgroups were compared on demographic and disease variables. Individual performance across neuropsychological tests was evaluated for the PD group. Patients with PD performed more poorly than HC on several measures of cognition, and they were classified into frontal (12), posterior (3), both (10) and neither subgroups (17), the latter two in reference to frontal- and posterior-type deficits. The neither subgroup was distinguished by less motor impairment than the both subgroup, but the four subgroups did not otherwise differ on demographic or disease variables. Across patients, the tests most sensitive to cognitive impairment included measures of attention and executive functioning (frontal-type tests). Examination of individual test performance for PD revealed substantial heterogeneity across tests with respect to number and severity of deficits. The current study provides insight into which commonly used neuropsychological tests are most sensitive to cognitive deficits (strictly defined) in a nondemented, well characterized PD sample, and into the relation of cognitive subgroups to demographic and disease-specific variables.
PMCID: PMC3819031  PMID: 23398433
Parkinson's; cognition; subtypes; frontal; parietal; posterior
6.  The medial preoptic area modulates cocaine-induced activity in female rats 
Behavioral neuroscience  2013;127(2):293-302.
Drugs of abuse exert their effects by exploiting natural neurobiological reward mechanisms, especially the mesolimbic dopamine (DA) system. However, the mesolimbic system does not operate in isolation, and input from other reward-relevant structures may play a role in cocaine’s rewarding effects. The medial preoptic area (mPOA) of the hypothalamus is involved in the regulation of two essential and naturally rewarding behaviors, sexual and maternal behaviors. It also makes strong neuroanatomical connections with areas of the mesolimbic system, particularly the ventral tegmental area (VTA). As such, the mPOA is a logical candidate for a neuroanatomical locus modulating activity in the mesolimbic system and emergent behavioral expressions of drug reward, yet the role of this structure is largely unexplored. Here, using a female rat model, we show that the mPOA innervates the VTA in a region-specific manner, lesions of the mPOA augment cocaine-induced Fos expression in the nucleus accumbens and cocaine-induced conditioned place preference. We also show that approximately 68% of mPOA-VTA efferents release γ-aminobutyric acid (GABA), over 75% are sensitive to DA as evidenced by co-localization with DA receptors, and nearly 60% of these contain both DA receptors and GABA, which suggests a novel key role for the mPOA in the inhibition of the mesolimbic DA circuit. Combined, these results reveal the mPOA as a critical modulating structure in cocaine-induced mesolimbic activity and behavioral manifestation of reward, at least in part via GABAergic output that is sensitive to DA input.
PMCID: PMC3951916  PMID: 23565937
medial preoptic area; reward; cocaine; addiction; dopamine
7.  Implications of temporal variation in maternal care for the prediction of neurobiological and behavioral outcomes in offspring 
Behavioral neuroscience  2013;127(1):33-46.
Previous studies in Long-Evans rats demonstrated a significant relationship between variation in pup licking/grooming and arched-back nursing (LG-ABN) and offspring development. However, maternal care is dynamic and exhibits significant temporal variation. In the current study, we assessed temporal variation in LG and ABN in lactating rats across the circadian cycle and determined the impact of these behaviors for the prediction of offspring hypothalamic gene expression, anxiety-like behavior, and responsiveness to high fat diet (HFD). We find that distinguishing between dams that engage in stable individual differences in maternal behavior (Low, Mid, High) requires assessment across the light-dark phases of the light cycle and across multiple postpartum days. Amongst juvenile female offspring, we find a positive correlation between maternal LG and mRNA levels of estrogen receptor alpha and beta and the oxytocin receptor (when LG is assessed across the light-dark cycle or in the dark phase). In young adults, we find sex-specific effects, with female High LG offspring exhibiting increased exploration of a novel environment and increased latency to approach HFD and male High LG offspring displaying increased activity in a novel environment and reduced HFD consumption. Importantly, these effects on behavior were primarily evident when LG was assessed across the light-dark cycle and ABN was not associated with these measures. Overall, our findings illustrate the dissociation between the effects of LG and ABN on offspring development and provide critical insights into the temporal characteristics of maternal behavior that have methodological implications for the study of maternal effects.
PMCID: PMC3947603  PMID: 23398440
medial preoptic area; open-field test; high fat diet; circadian; Long Evans rats
8.  Performance Asymmetries in Tool Use are Associated with Corpus Callosum Integrity in Chimpanzees (Pan troglodytes): A Diffusion Tensor Imaging Study 
Behavioral neuroscience  2013;127(1):106-113.
We examined the relationship of corpus callosum morphology and organization to hand preference and performance on a motor skill task in chimpanzees. Handedness was assessed using a complex tool use task that simulated termite fishing. Chimpanzees were initially allowed to perform the task wherein they could choose which hand to use (preference measure); then they were required to complete trials using each hand (performance measure). Two measures were used to assess the corpus callosum: midsagittal area obtained from in vivo magnetic resonance images and density of transcallosal connections as determined by fractional anisotropy values obtained from diffusion tensor imaging. We hypothesized that chimpanzees would perform better on their preferred hand compared to the non-preferred hand, and that strength of behavioral lateralization (rather the direction) on this task would be negatively correlated to regions of the corpus callosum involved in motor processing. Our results indicate that the preferred hand was the most adept hand. Performance asymmetries correlated with FA measures but not area measures of the CC.
PMCID: PMC3939601  PMID: 23398443
Corpus callosum; DTI; chimpanzee; handedness; tool use
9.  Ontogeny of trace eyeblink conditioning to shock-shock pairings in the rat pup 
Behavioral neuroscience  2012;127(1):114-120.
Rats are responsive to shock from an early age but eyeblink conditioning to a tone conditioned stimulus (CS) paired with a shock unconditioned stimulus (US) does not emerge until postnatal day 20 (P20). More generalized postural responses such as conditioned freezing can occur at P16. Using the same periorbital shock as both the CS and US in a US-US conditioning paradigm previously shown to be effective in adult animals, we found that shock-shock pairings with a 200-ms trace interval resulted in eyeblink conditioning in younger animals than previously thought. Some rat pups showed conditioned eyeblink responses as early as P12, and by P18, conditioned responses were fully developed in all animals. Unpaired control subjects confirmed that responding in paired subjects was associative. Although many stimuli can act as a CS in adults, the advantage of using US-US pairings is that responses to first US ensure young rat pups are capable of detecting the stimulus – something that may not be true when auditory or visual stimuli are used early in the development of altricial animals. The US-US pairing paradigm could be used to study the ontogeny and neural substrates of learning and memory before other sensory systems mature and evaluate learning and memory in animal models of early developmental disorders.
PMCID: PMC3939836  PMID: 23244289
development; eyeblink conditioning; ontogeny; rat pup; trace conditioning
10.  Uncertainty about mapping future actions into rewards may underlie performance on multiple measures of impulsivity in behavioral addiction: Evidence from Parkinson’s disease 
Behavioral neuroscience  2013;127(2):245-255.
A subset of patients with Parkinson disease (PD) develops behavioral addictions, which may be due to their dopamine replacement therapy. Recently, several groups have been comparing PD patients with and without behavioral addictions on tasks that are thought to measure aspects of impulsivity. Several of these experiments, including information sampling, a bias towards novel stimuli and temporal discounting, have shown differences between PD patients with and without behavioral addictions. We have developed a unifying theoretical framework which allows us to model behavior in all three of these tasks. By exploring the performance of the patient groups on the three tasks with a single framework we can ask questions about common mechanisms that underlie all three. Our results suggest that the effects seen in all three tasks can be accounted for by uncertainty about the ability to map future actions into rewards. More specifically, the modeling is consistent with the hypothesis that the group with behavioral addictions behaves as if they cannot use information provided within the experimental context to improve future reward guided actions. Future studies will be necessary to more firmly establish (or refute) this hypothesis. We discuss this result in light of what is known about the pathology that underlies the behavioral addictions in the Parkinson patients.
PMCID: PMC3935250  PMID: 23565936
11.  Effects of Aromatase Inhibition and Androgen Activity on Serotonin and Behavior in Male Macaques 
Behavioral neuroscience  2013;127(3):400-414.
Aggression in humans and animals has been linked to androgens and serotonin function. To further our understanding of the effect of androgens on serotonin and aggression in male macaques, we sought to manipulate circulating androgens and the activity of aromatase; and to then determine behavior and the endogenous availability of serotonin. Male Japanese macaques (Macaca fuscata) were castrated for 5-7 months and then treated for 3 months with [1] placebo, [2] testosterone (T), [3] T+Dutasteride (5a reductase inhibitor; AvodartTM), [4] T+Letrozole (non-steroidal aromatase inhibitor; FemeraTM), [5] Flutamide+ATD (androgen antagonist plus steroidal aromatase inhibitor) or [6] dihydrotestosterone (DHT)+ATD (n=5/group). Behavioral observations were made during treatments. At the end of the treatment period, each animal was sedated with propofol and administered a bolus of fenfluramine (5 mg/kg). Fenfluramine causes the release of serotonin proportional to endogenous availability and in turn, serotonin stimulates the secretion of prolactin. Therefore, serum prolactin concentrations reflect endogenous serotonin. Fenfluramine significantly increased serotonin/prolactin in all groups (p <0.0001). Fenfluramine-induced serotonin/prolactin in the T-treated group was significantly higher than the other groups (p<0.0001). Castration partially reduced the serotonin/prolactin response; and Letrozole partially blocked the effect of T. Complete inhibition of aromatase with ATD, a non-competitve inhibitor, significantly and similarly reduced the fenfluramine-induced serotonin/prolactin response in the presence or absence of DHT. Neither aggressive behavior nor yawning (indicators of androgen activity) correlated with serotonin/prolactin, but posited aromatase activity correlated significantly with prolactin (p<0.0008; r2 =0.95). In summary, androgens induced aggressive behavior but they did not regulate serotonin. Altogether, the data suggest that aromatase activity supports serotonin production and that androgens increase aggression by another mechanism.
PMCID: PMC3910396  PMID: 23506438
Aggression; androgen; serotonin; fenfluramine; aromatase; letrozole; dutasteride
12.  The Role of the Nucleus Accumbens Core in Impulsive Choice, Timing, and Reward Processing 
Behavioral neuroscience  2010;124(1):26-43.
The present series of experiments aimed to pinpoint the source of nucleus accumbens core (AcbC) effects on delay discounting. Rats were trained with an impulsive choice procedure between an adjusting smaller sooner reward and a fixed larger later reward. The AcbC-lesioned rats produced appropriate choice behavior when the reward magnitude was equal. An increase in reward magnitude resulted in a failure to increase preference for the larger later reward in the AcbC-lesioned rats, whereas a decrease in the larger later reward duration resulted in normal alterations in choice behavior in AcbC-lesioned rats. Subsequent experiments with a peak timing (Experiments 2 and 3) and a behavioral contrast (Experiment 4) indicated that the AcbC-lesioned rats suffered from decreased incentive motivation during changes in reward magnitude (Experiments 2 and 4) and when expected rewards were omitted (Experiments 2 and 3), but displayed intact anticipatory timing of reward delays (Experiments 2 and 3). The results indicate that the nucleus accumbens core is critical for determining the incentive value of rewards, but does not participate in the timing of reward delays.
PMCID: PMC3909469  PMID: 20141278
nucleus accumbens; impulsivity; delay discounting; timing; rats
13.  Environmental Rearing Effects on Impulsivity and Reward Sensitivity 
Behavioral neuroscience  2013;127(5):712-724.
Previous research has indicated that rearing in an enriched environment may promote self-control in an impulsive choice task. To further assess the effects of rearing environment on impulsivity, 2 experiments examined locomotor activity, impulsive action, impulsive choice, and different aspects of reward sensitivity and discrimination. In Experiment 1, rats reared in isolated or enriched conditions were tested on an impulsive choice procedure with a smaller-sooner versus a larger-later reward, revealing that the isolated rats valued the smaller-sooner reward more than the enriched rats. A subsequent reward challenge was presented in which the delay to the 2 rewards was the same but the magnitude difference remained. The enriched rats did not choose the larger reward as often as the isolated rats, reflecting poorer reward discrimination. Impulsive action was assessed using a differential-reinforcement-of-low-rate task, which revealed deficits in the enriched rats. In Experiment 2, rats reared in isolated, standard, or enriched conditions were tested on reward contrast and reward magnitude sensitivity procedures. The rats were presented with 2 levers that delivered different magnitudes of food on variable interval 30-s schedules. Across all tests, the enriched and social rats displayed more generalized responding to the small-reward lever, but a similar response to the large-reward lever, compared with the isolated rats. This confirmed the results of Experiment 1, indicating poorer reward discrimination in the enriched condition compared with the isolated condition. The results suggest that enrichment may moderate reward generalization/discrimination processes through alterations in incentive motivational processes.
PMCID: PMC3906647  PMID: 24128360
environmental enrichment; isolation rearing; impulsive choice; impulsive action; reward processing
14.  Yoked delivery of cocaine is aversive and protects against the motivation for drug in rats 
Behavioral neuroscience  2009;123(4):10.1037/a0016498.
In Experiment 1, water deprived rats were given 5 min access to saccharin followed by either the active or the yoked delivery of saline or cocaine (0.33 mg/infusion) via an intravenous catheter. Both cocaine groups avoided intake of the saccharin cue following saccharin-cocaine pairings, however, the rats in the yoked condition exhibited greater avoidance of the taste cue than did those that actively self-administered the same dose of the drug. Experiment 2 evaluated subsequent self-administration behavior on fixed and progressive ratio schedules of reinforcement. The results showed that prior yoked exposure to cocaine reduced subsequent drug taking behavior on a progressive ratio but not on a fixed ratio schedule. Finally, Experiment 3 used a choice test to determine the impact of yoked drug delivery on the relative preference for cocaine vs. water. The results showed that rats with a history of self-administering cocaine preferred to perform operant behaviors on the side of the chamber previously paired with cocaine, whereas the rats with a history of yoked delivery of cocaine avoided this side and, instead, preferred to perform operant behaviors on the opposite side of the chamber. These data show that, in most rats, the unpredictable, uncontrollable delivery of cocaine protects against the subsequent motivation for cocaine through an aversive mechanism.
PMCID: PMC3861880  PMID: 19634952
addiction; abuse; craving; stimulant; tolerance; taste aversion; devaluation; motivation; reward; compensatory
15.  Effects of age on cerebrospinal fluid oxytocin levels in free-ranging adult female and infant rhesus macaques 
Behavioral neuroscience  2010;124(3):10.1037/a0019576.
There is growing interest in studying oxytocin biology in the context of social functioning in human and non-human primates. Studies of human subjects are typically restricted to peripheral oxytocin assessments because opportunities to collect cerebrospinal fluid (CSF) are rare. A few studies have examined CSF oxytocin levels in captive adult primates, but none to our knowledge have been conducted under free-ranging conditions and inclusive of young infants. The main goal of the present study was to establish feasibility of quantifying CSF oxytocin levels in free-ranging adult female and infant rhesus monkeys living on the island of Cayo Santiago, Puerto Rico. CSF oxytocin levels were examined in relation to individuals’ demographic and reproductive characteristics, as well as in relation to plasma cortisol levels. CSF oxytocin concentrations ranged from 36.02 to 134.41 pg/ml in adult females (ages 7–26 years; N = 31) and 35.94 to 77.3 pg/ml in infants (ages 38–134 days; N = 17). CSF oxytocin levels were positively correlated with adult female age and negatively correlated with infant age. The former correlation was driven by reproductive status. CSF oxytocin levels were unrelated to dominance rank or plasma cortisol levels. In contrast to a previous study of plasma oxytocin concentrations in this population, CSF oxytocin levels did not differ significantly between lactating and non-lactating females. In summary, these findings: 1) provide feasibility data for examining CSF oxytocin biology in free-ranging nonhuman primates and 2) indicate that CSF oxytocin levels may be a biomarker of age-related central nervous system changes across lifespan development. Although our study did not report significant associations between CSF oxytocin levels and socially-relevant demographic variables, the relationships between CSF oxytocin levels and assessments of social functioning warrant future investigation.
PMCID: PMC3859199  PMID: 20528088
Age; CSF; infant; cortisol; free-ranging; oxytocin; rhesus monkey
16.  Predictors of Susceptibility and Resilience in an Animal Model of Post Traumatic Stress Disorder 
Behavioral neuroscience  2012;126(6):749-761.
Animal models of post traumatic stress disorder (PTSD) are based on fear conditioning where innocuous cues elicit reactions that originally occur to traumatic events – a core feature of PTSD. Another core feature is hyperarousal – exaggerated reactions to stressful events. One limitation of animal models of PTSD is that group effects do not model the sporadic incidence of PTSD. We developed an animal model of PTSD in which rabbit nictitating membrane responses become exaggerated as a function of classical conditioning to a tone conditioned stimulus (CS) paired with a shock unconditioned stimulus (US). Exaggerated responses to the US are a form of hyperarousal termed conditioning-specific reflex modification (CRM) and occur in the absence of the CS. Inspecting data across several experiments, we determined 25% of our rabbits exhibit strong CRM despite all subjects having high levels of conditioning. To determine how prone rabbits were to CRM (susceptibility) or how resistant (resilience), we examined data from 135 rabbits analyzing for factors during CS-US pairings and during US prescreening that would predict CRM. We found the magnitude of CRM was correlated with the onset latency and area of conditioned responding during CS-US pairings and with the peak latency of a response during US pretesting. In an animal model of PTSD that more accurately reflects clinical prevalence, we can begin to predict susceptibility not only during responding to a stressful conditioning situation but also during a screening process before the stressful situation takes place. The results suggest relatively innocuous testing may help detect PTSD after trauma and screen for it before trauma occurs.
PMCID: PMC3513376  PMID: 23181382
fear conditioning; nictitating membrane response; post traumatic stress disorder; rabbit; resilience; susceptibility
17.  Impairment in Delayed Non-Matching to Sample Following Lesions of Dorsal Prefrontal Cortex 
Behavioral neuroscience  2012;126(6):772-780.
The prefrontal cortex has been identified as essential for executive function, as well as for aspects of rule learning and recognition memory. As part of our studies to assess prefrontal cortical function in the monkey, we evaluated the effects of damage to the dorsal prefrontal cortex (DPFC) on the Category Set Shifting Task (CSST), a test of abstraction and set-shifting, and on the Delayed Non Matching-to-Sample (DNMS) task, a benchmark test of rule learning and recognition memory. The DPFC lesions in this study included dorsolateral and dorsomedial aspects of the PFC. In a previous report, we published evidence of an impairment on the CSST as a consequence of DPFC lesions (Moore et al, 2009). Here we report that monkeys with lesions of the DPFC were also markedly impaired relative to controls on both the acquisition (rule learning) and performance (recognition memory) conditions of trial-unique DNMS. The presence and extent of the deficits that we observed were of some surprise and support the possibility that the dorsal prefrontal cortex plays a more direct role in learning and recognition memory than had been previously thought.
PMCID: PMC3518867  PMID: 23088539
Dorsal prefrontal cortex; Delayed Non-matching to Sample; Recognition memory; Rule learning; Rhesus monkey
18.  Physical Exercise and Catecholamine Re-uptake Inhibitors Affect Orienting Behavior and Social Interaction in a Rat Model of ADHD 
Behavioral neuroscience  2012;126(6):762-771.
The effects of methylphenidate (MPH), atomoxetine (ATMX), and/or physical exercise (EX) on orienting behavior and social interaction were examined in Spontaneously Hypertensive Rats (SHR), a commonly used animal model of (ADHD). During the orienting procedure, rats received repeated presentations of a non-reinforced visual stimulus. As observed previously, orienting behavior (rearing up on the hind legs) habituated across trials in normo-active control rats (Wistars) but not in SHRs, suggesting that SHRs have difficulty ignoring irrelevant behavioral stimuli. Treatment with MPH (0.125 mg/kg), ATMX (0.125 mg/kg), or EX (3 weeks of access to a running wheel), alone or in combination, reduced rearing behavior in SHRs to the level observed in the Wistar control group. Similarly, drug treatment and/or EX reduced the number of social interactions exhibited by SHRs, while having no effects on locomotor activity. Importantly, EX was just as effective as MPH or ATMX in reducing orienting behavior and social interaction. In contrast to the SHRs, neither MPH nor ATMX affected orienting or social behavior in Wistar rats. Together, these findings support the growing literature that EX may be useful as an adjunctive or replacement therapy in ADHD.
PMCID: PMC3786448  PMID: 23067385
Attention; Attention-Deficit/Hyperactivity Disorder; rat; methylphenidate; atomoxetine; locomotor activity
19.  Blockade of the serotonin 5-HT2A receptor suppresses cue-evoked reinstatement of cocaine-seeking behavior in a rat self-administration model 
Behavioral neuroscience  2009;123(2):10.1037/a0014592.
The serotonin 5-HT2A receptor (5-HT2AR) may play a role in reinstatement of drug-seeking. This study investigated the ability of a selective 5-HT2A receptor (5-HT2AR) antagonist to suppress reinstatement evoked by exposure to cues conditioned to cocaine self-administration. Cocaine self-administration (0.75 mg/kg/0.1 mL/6 s infusion; FR 4) was trained in naïve, free-fed rats to allow interpretation of results independent from changes related to food deprivation stress. Pretreatment with the selective 5-HT2AR antagonist M100907 (volinanserin) failed to reduce rates of operant responding for cocaine infusions. On the other hand, M100907 (0.001 – 0.8 mg/kg, i.p.) significantly suppressed the cue-induced reinstatement of cocaine-seeking behavior following extinction; effective M100907 doses did not alter operant responding for cues previously associated with sucrose self-administration. Importantly, a greater magnitude of active lever presses on the initial extinction session (“high extinction” responders) predicted the maximal susceptibility to M100907-induced suppression of cue-evoked reinstatement. The findings indicate that blockade of the 5-HT2AR attenuates the incentive-motivational effects of cocaine-paired cues, particularly in “high extinction” responders, and suggests that M100907 may afford a therapeutic advance in suppression of cue-evoked craving and/or relapse.
PMCID: PMC3830454  PMID: 19331461
Cocaine self-administration; Cue-induced reinstatement; Extinction; M100907; 5-HT2AR antagonist
20.  Chronic Stress Impairs Prefrontal Cortex-Dependent Response Inhibition and Spatial Working Memory 
Behavioral neuroscience  2012;126(5):605-619.
Chronic stress leads to neurochemical and structural alterations in the prefrontal cortex (PFC) that correspond to deficits in PFC-mediated behaviors. The present study examined the effects of chronic restraint stress on response inhibition (using a response-withholding task, fixed-minimum interval schedule of reinforcement, or FMI), and working memory (using a radial arm water maze, RAWM). Adult male Sprague Dawley rats were first trained on the RAWM and subsequently trained on FMI. Following acquisition of FMI, rats were assigned to a restraint stress (6h/d/28d in wire mesh restrainers) or control condition. Immediately after chronic stress, rats were tested on FMI and subsequently on RAWM. FMI results suggest that chronic stress reduces response inhibition capacity and motivation to initiate the task on selective conditions when food reward was not obtained on the preceding trial. RAWM results suggest that chronic stress produces transient deficits in working memory without altering previously consolidated reference memory. Behavioral measures from FMI failed to correlate with metrics from RAWM except for one in which changes in FMI timing precision negatively correlated with changes in RAWM working memory errors for the controls, a finding that was not observed following chronic stress. Fisher’s r to z transformation revealed no significant differences between control and stress with correlation coefficients. These findings are the first to show that chronic stress impairs both response inhibition and working memory, two behaviors that have never been direct compared within the same animals following chronic stress, using FMI, an appetitive task, and RAWM, a non-appetitive task.
PMCID: PMC3463780  PMID: 22905921
Impulsivity; Reference Memory; Radial arm water maze; fixed minimum interval; rat
21.  The Anterior Thalamus is Critical for Overcoming Interference in a Context-Dependent Odor Discrimination Task 
Behavioral neuroscience  2012;126(5):710-719.
The anterior thalamus (AT) is anatomically interconnected with the hippocampus and other structures known to be involved in memory, and the AT is involved in many of the same learning and memory functions as the hippocampus. For example, like the hippocampus, the AT is involved in spatial cognition and episodic memory. The hippocampus also has a well-documented role in contextual memory processes, but it is not known whether the AT is similarly involved in contextual memory. In the present study, we assessed the role of the AT in contextual memory processes by temporarily inactivating the AT and training rats on a recently developed context-based olfactory list learning task, which was designed to assess the use of contextual information to resolve interference. Rats were trained on one list of odor discrimination problems, followed by training on a second list in either the same context or a different context. In order to induce interference, some of the odors appeared on both lists with their predictive value reversed. Control rats that learned the two lists in different contexts performed significantly better than rats that learned the two lists in the same context. However, AT lesions completely abolished this contextual learning advantage, a result that is very similar to the effects of hippocampal inactivation. These findings demonstrate that the AT, like the hippocampus, is involved in contextual memory and suggest that the hippocampus and AT are part of a functional circuit involved in contextual memory.
PMCID: PMC3464499  PMID: 23025833
anterior thalamus; learning; memory; interference; context
22.  Role of amygdala central nucleus in feature negative discriminations 
Behavioral neuroscience  2012;126(5):670-680.
Consistent with a popular theory of associative learning, the Pearce-Hall (1980) model, the surprising omission of expected events enhances cue associability (the ease with which a cue may enter into new associations), across a wide variety of behavioral training procedures. Furthermore, previous experiments from this laboratory showed that these enhancements are absent in rats with impaired function of the amygdala central nucleus (CeA). A notable exception to these assertions is found in feature negative (FN) discrimination learning, in which a “target” stimulus is reinforced when it is presented alone but nonreinforced when it is presented in compound with another, “feature” stimulus. According to the Pearce-Hall model, reinforcer omission on compound trials should enhance the associability of the feature relative to control training conditions. However, prior experiments have shown no evidence that CeA lesions affect FN discrimination learning. Here we explored this apparent contradiction by evaluating the hypothesis that the surprising omission of an event confers enhanced associability on a cue only if that cue itself generates the disconfirmed prediction. Thus, in a FN discrimination, the surprising omission of the reinforcer on compound trials would enhance the associability of the target stimulus but not that of the feature. Our data confirmed this hypothesis, and showed this enhancement to depend on intact CeA function, as in other procedures. The results are consistent with modern reformulations of both cue and reward processing theories that assign roles for both individual and aggregate error terms in associative learning.
PMCID: PMC3468906  PMID: 22889308
attention; associability; associative learning; feature negative discrimination; amygdala
23.  Pavlovian-to-Instrumental Transfer in Cocaine Seeking Rats 
Behavioral neuroscience  2012;126(5):681-689.
Drug-associated cues are believed to be important mediators of addiction and drug relapse. Although such cues may influence drug-seeking behavior through multiple routes, it is their putative incentive motivational properties – their ability to elicit “craving” – that interests many addiction researchers. The Pavlovian-to-instrumental transfer paradigm is commonly used to assay cue-evoked incentive motivation in situations involving natural rewards, but has not been widely applied to the study of drug self-administration. We used this paradigm to determine if cues paired with intravenous cocaine could promote performance of an independently trained task in which rats self-administered cocaine by completing a chain of two different lever press actions, a procedure used to parse behavior into cocaine-seeking (first action) and cocaine-taking (second action). Rats showed significant transfer, increasing task performance during cocaine-paired cues. This effect was observed for both seeking and taking actions, although a trend towards greater cocaine taking was observed, a result that is consistent with studies using natural rewards. Our results demonstrate that cocaine-paired cues can provoke the pursuit of cocaine through a Pavlovian motivational process. This phenomenon may provide a useful new tool for modeling drug relapse, particularly as a method for targeting the response-invigorating effects of stimulus-drug learning.
PMCID: PMC3496413  PMID: 22866668
Pavlovian instrumental transfer; cocaine; self-administration; seeking taking chain; addiction
24.  Effects of Muscimol in the Nucleus Accumbens Shell on Salt Appetite and Sucrose Intake: A Microstructural Study With a Comment on the Sensitization of Salt Intake 
Behavioral neuroscience  2012;126(5):699-709.
Previous work has demonstrated that injections of the γ-aminobutyric acidA (GABAA) agonist muscimol into the nucleus accumbens shell (AcbSh) induce pronounced increases in the intake of solid foods and sucrose solutions, but do not potentiate water intake. In order to clarify the range of situations in which inactivation of the AcbSh potentiates ingestive behavior, we examined the effects of muscimol injections on the intake of a 3% NaCl solution in sodium-depleted animals. Although sodium-depleted subjects avidly consumed this solution, muscimol injections had no effect either on the volume consumed or on a variety of microstructural licking parameters. In contrast, in these same animals, muscimol injections significantly increased licking of a 10% sucrose solution. These results suggest that inactivation of the AcbSh may selectively increase the intake of foods, but not that of other homeostatically relevant ingestates. Examination of microstructural parameters suggested that the effect of muscimol on sucrose intake was not mediated by alterations in the “palatability” of the sucrose solution. We also observed that sodium-depleted subjects displayed significantly larger salt intakes after their second experience with sodium depletion than their first, and microstructural analysis in this case indicated that this sensitization effect was produced in a manner consistent with the animals showing increased “hedonic responsiveness” to the salt solution.
PMCID: PMC3507417  PMID: 22889311
ventral striatum; ingestive behavior; sodium hunger; sodium appetite; blood chemistry
25.  Noradrenergic, but not cholinergic modulation of olfactory bulb during processing of near threshold concentration stimuli 
Behavioral neuroscience  2012;126(5):720-728.
Neuromodulatory systems such as noradrenaline (NE), acetylcholine (ACh) and serotonin (5HT) serve important functions in sensory perception. We use the olfactory bulb (OB) as a model system to study the roles of individual neuromodulators in sensory perception. Using a spontaneous, non-reward motivated detection task, as well as a reward-motivated task, we show that rats can easily respond to odorants at very low concentrations when motivated to do so in a food rewarded task, despite not showing spontaneous responses to these low concentration odorants. Using the same tasks paired with local bulbar infusions of noradrenergic and cholinergic drugs, we then show that rats engage their noradrenergic, but not their cholinergic system to better respond to near threshold odorants. These results suggest that while cholinergic modulation of OB function is mostly important for odor decorrelation and discrimination, noradrenergic modulation is important for signal-to-noise modulation.
PMCID: PMC3563246  PMID: 23025834
Olfaction; neuromodulation; olfactory bulb; noradrenaline; acetylcholine

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