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1.  Oxytocin reduces amygdala activity, increases social interactions and reduces anxiety-like behavior irrespective of NMDAR antagonism 
Behavioral neuroscience  2015;129(4):389-398.
Standard dopamine therapies for schizophrenia are not efficacious for negative symptoms of the disease, including asociality. This reduced social behavior may be due to glutamatergic dysfunction within the amygdala leading to increased fear and social anxiety. Several studies have demonstrated the pro-social effects of oxytocin in schizophrenia patients. Therefore, this study evaluates the effect of sub-chronic oxytocin on electroencephalographic (EEG) activity in amygdala of mice during performance of the three chamber social choice and open field tests following acute ketamine as a model of glutamatergic dysfunction. Oxytocin did not restore social deficits introduced by ketamine, but did significantly increase sociality in comparison to the control group. Ketamine had no effect on time spent in the center during the open field trials, while oxytocin increased overall center time across all groups, suggesting a reduction in anxiety. Amygdala activity was consistent across all drug groups during social and nonsocial behavioral trials. However, oxytocin reduced overall amygdala EEG power during the two behavioral tasks. Alternatively, ketamine did not significantly affect EEG power throughout the tasks. Decreased EEG power in the amygdala, as caused by oxytocin, may be related to both reduced anxiety and increased social behaviors. Data suggest that separate pro-social and social anxiety pathways may mediate social preference.
PMCID: PMC4518468  PMID: 26214213
Oxytocin; Electroencephalography; Amygdala; N-Methyl D-Aspartate Receptor; Social
2.  Stability and flexibility of the message carried by semiochemical stimuli, as revealed by devaluation of carbon disulfide followed by social transmission of food preference 
Behavioral neuroscience  2014;128(4):413-418.
Semiochemicals are volatile compounds that communicate specific meaning between individuals, and elicit specific behavioral and/or physiological responses mediated by highly sensitive and highly specific olfactory pathways. Recent work suggests that semiochemicals can activate multiple olfactory pathways at once, but the degree to which parallel pathways activated by the same semiochemical interact, and what the behavioral consequences of such interactions are, remains a topic of debate. Here we approached this question behaviorally, investigating whether rats could be trained to avoid carbon disulfide (CS2) via taste-potentiated odor aversion, and asking whether any such learning would have an impact on the rats’ subsequent use of CS2 as a semiochemical cue (i.e., in a socially transmitted food preference paradigm). The results show that CS2-mediated food preference learning is unimpaired by aversions conditioned to CS2, a result indicating that canonical and semiochemical pathways for the processing of CS2 function in a largely independent manner.
PMCID: PMC4107047  PMID: 24841743
carbon disulfide; pheromones; semiochemicals; olfaction
3.  Intake-dependent effects of cocaine self-administration on impulsive choice in a delay discounting task 
Behavioral neuroscience  2014;128(4):419-429.
Cocaine use is associated with high levels of impulsive choice (greater discounting of delayed rewards) in humans, but the cause/effect relationships between cocaine use and impulsive choice are not fully understood. In previous work, we found that both experimenter- and self-administration of fixed quantities of cocaine caused lasting increases in impulsive choice in rats. The present study extended these findings by taking into account baseline impulsive choice prior to self-administration, and by allowing rats free access to cocaine. Male Long-Evans rats were trained in a delay discounting task in which they made discrete-trial choices between small immediate and large delayed food rewards. Half of the rats were then implanted with intravenous catheters and, following recovery, allowed to self-administer cocaine HCl (1.0 mg/kg/infusion) in 6 hour sessions over 14 days. Control rats orally self-administered a sucrose solution under similar conditions. Upon completion of self-administration training, rats remained abstinent for 3 weeks before retesting in the delay discounting task. Cocaine and control groups did not differ prior to self-administration, but afterward, the cocaine group showed greater impulsive choice (fewer choices of large, delayed rewards) than controls. Additional analyses revealed that the effects of cocaine on impulsive choice were intake-dependent; rats classified as “low intake” did not differ from controls, whereas rats classified as “high intake” were significantly more impulsive than both controls and their pre-cocaine baseline. These findings are consistent with the idea that cocaine-induced, pharmacologically based neural adaptations promote the development of impulsive decision making.
PMCID: PMC4107092  PMID: 24841739
Decision-making; impulsivity; cocaine; delay discounting; intertemporal choice; rat
4.  Genetic Relationship Between Ethanol-Induced Conditioned Place Preference and Other Ethanol Phenotypes in 15 Inbred Mouse Strains 
Behavioral neuroscience  2014;128(4):430-445.
The genetic relationships between different behaviors used to index the rewarding or reinforcing effects of alcohol are poorly understood. To address this issue, ethanol-induced conditioned place preference (CPP) was tested in a genetically diverse panel of inbred mouse strains and strain means from this study and other inbred strain studies were used to examine the genetic correlation between CPP and several ethanol-related phenotypes, including activity measures recorded during CPP training and testing. Mice from each strain were exposed to a well-characterized unbiased place conditioning procedure using ethanol doses of 2 or 4 g/kg; an additional group from each strain was exposed to saline alone on all trials. Genotype had a significant effect on CPP, basal locomotor activity, ethanol-stimulated activity and the effect of repeated ethanol exposure on activity. Correlational analyses showed significant negative genetic correlations between CPP and sweetened ethanol intake and between CPP and test session activity, as well as a significant positive genetic correlation between CPP and chronic ethanol withdrawal severity. Moreover, there was a trend toward a positive genetic correlation between CPP and ethanol-induced conditioned taste aversion. These genetic correlations suggest overlap in the genetic mechanisms underlying CPP and each of these traits. The patterns of genetic relationships suggest a greater impact of ethanol’s aversive effects on drinking and a greater impact of ethanol’s rewarding effects on CPP. Overall, these data support the idea that genotype influences ethanol’s rewarding effect, a factor that may contribute importantly to addictive vulnerability.
PMCID: PMC4107118  PMID: 24841742
alcohol; reward; activity; learning; inbred strains
5.  Altered exploration and sensorimotor gating of the chakragati mouse model of schizophrenia 
Behavioral neuroscience  2014;128(4):460-467.
Schizophrenia is a prevalent neurodevelopmental psychiatric disorder with poor prognosis and limited understanding of its etiology. This limited etiological understanding renders developing animal models of schizophrenia difficult. While attempts are made to recreate putative etiologies in models, these models may only enable the generation of treatments targeted at the mechanisms manipulated. Although the chakragati mouse was not created as a result of a specific gene target, reports to date suggest these mice exhibit behavioral abnormalities that are consistent with some observed in patients with schizophrenia.
As an initial screen on the relevance of these mice to schizophrenia, we tested the exploration and sensorimotor gating of male and female chakragati mice in the cross-species tests Behavioral Pattern Monitor (BPM) and prepulse inhibition (PPI), respectively. The chakragati mice exhibited hyperactive yet more meandering/circling movements of exploration compared with wildtype (WT) littermates. Moreover, chakragati mice exhibited impaired PPI compared with WT mice, primarily at high prepulse intensity levels. Thus, Chakragati mice share some of the abnormal exploratory and PPI behaviors that are observed in patients with schizophrenia. These behaviors can be used to screen for novel antipsychotics which may be based on novel mechanisms of action. The multivariate abnormal exploration of these mice may also yield further information for treatment effects. Further characterization of these mice in tasks with putative links to negative or cognitive symptoms may further advance the utility of these mice as a screen for novel treatments for schizophrenia.
PMCID: PMC4107138  PMID: 24708299
animal model; behavioral pattern monitor; prepulse inhibition
6.  Post-learning stress differentially affects memory for emotional gist and detail in naturally cycling women and women on hormonal contraceptives 
Behavioral neuroscience  2014;128(4):482-493.
Sex differences in emotional memory have received increasing interest over the past decade. However, to date, no work has explored how a post-learning stressor might modulate the influence of sex hormone status on memory for gist and peripheral detail in an emotional versus neutral context. Here, we tested three predictions. First, compared to naturally cycling women (NC women) in the luteal phase, women on hormonal contraception (HC women) would have significantly blunted HPA reactivity to physical stress. Second, post-learning stress would enhance detail and gist memory from an emotional story in NC women, and finally, post-learning stress would not affect emotional memory for details or gist in HC women. Healthy NC and HC women viewed a brief, narrated story containing neutral or emotionally arousing elements. Immediately after, Cold Pressor Stress (CPS) or a control procedure was administered. One week later, participants received a surprise free recall test for story elements. NC women exhibited significantly greater cortisol increases to CPS compared to HC women. NC women who viewed the emotional story and were administered CPS recalled the most peripheral details overall and more gist from the emotional compared to the neutral story. In HC women, however, the post-learning cortisol release did not affect memory for gist or peripheral details from the emotional or neutral story in any way. Additionally, NC and HC women performed similarly on measures of attention and arousal. These findings suggest that in women, post-learning stress differentially affects memory for emotional information depending on their hormonal contraceptive status.
PMCID: PMC4107172  PMID: 24841741
hormonal contraception; emotional memory; stress; cortisol; pupil dilation
7.  Auditory Gap-in-Noise Detection Behavior in Ferrets and Humans 
Behavioral Neuroscience  2015;129(4):473-490.
The precise encoding of temporal features of auditory stimuli by the mammalian auditory system is critical to the perception of biologically important sounds, including vocalizations, speech, and music. In this study, auditory gap-detection behavior was evaluated in adult pigmented ferrets (Mustelid putorius furo) using bandpassed stimuli designed to widely sample the ferret’s behavioral and physiological audiogram. Animals were tested under positive operant conditioning, with psychometric functions constructed in response to gap-in-noise lengths ranging from 3 to 270 ms. Using a modified version of this gap-detection task, with the same stimulus frequency parameters, we also tested a cohort of normal-hearing human subjects. Gap-detection thresholds were computed from psychometric curves transformed according to signal detection theory, revealing that for both ferrets and humans, detection sensitivity was worse for silent gaps embedded within low-frequency noise compared with high-frequency or broadband stimuli. Additional psychometric function analysis of ferret behavior indicated effects of stimulus spectral content on aspects of behavioral performance related to decision-making processes, with animals displaying improved sensitivity for broadband gap-in-noise detection. Reaction times derived from unconditioned head-orienting data and the time from stimulus onset to reward spout activation varied with the stimulus frequency content and gap length, as well as the approach-to-target choice and reward location. The present study represents a comprehensive evaluation of gap-detection behavior in ferrets, while similarities in performance with our human subjects confirm the use of the ferret as an appropriate model of temporal processing.
PMCID: PMC4516322  PMID: 26052794
ferret; human; behavior; temporal processing; auditory gap detection
8.  Hippocampal Acetylcholine Depletion Has No Effect on Anxiety, Spatial Novelty Preference, or Differential Reward for Low Rates of Responding (DRL) Performance in Rats 
Behavioral Neuroscience  2015;129(4):491-501.
We investigated the role of the septo-hippocampal cholinergic projection in anxiety, spatial novelty preference, and differential reward for low rates of responding (DRL) performance. Cholinergic neurons of the rat medial septum (MS) and the vertical limb of the diagonal band of Broca (VDB) were lesioned using the selective immunotoxin, 192 IgG-saporin. Rats were then tested on several behavioral tests previously shown to be sensitive to either (a) hippocampal lesions or (b) nonselective MS/VDB lesions which target both cholinergic and γ-aminobutyric acid (GABA)-ergic projections, or both. Saporin lesions substantially reduced hippocampal cholinergic innervation, resulting in an absence of acetyl cholinesterase staining and markedly reduced choline acetyltransferase activity (mean reduction: 80 ± 5%; range: 50–97%). However, the saporin-lesioned rats did not differ from control rats in any of the behavioral tests. Thus we found no evidence from these lesion studies that the septo-hippocampal cholinergic projection plays an essential role in anxiety, spatial novelty preference, or DRL.
PMCID: PMC4516321  PMID: 26214215
acetylcholine; hippocampus; medial septum; anxiety; spatial memory; behavioral inhibition
9.  Interaction of Metabolic Stress with Chronic Mild Stress in Altering Brain Cytokines and Sucrose Preference 
Behavioral neuroscience  2015;129(3):321-330.
There is growing evidence that metabolic stressors increase an organism’s risk of depression. Chronic mild stress is a popular animal model of depression and several serendipitous findings have suggested that food deprivation prior to sucrose testing in this model is necessary to observe anhedonic behaviors. Here, we directly tested this hypothesis by exposing animals to chronic mild stress and used an overnight two bottle sucrose test (food ad libitum) on day 5 and 10, then food and water deprive animals overnight and tested their sucrose consumption and preference in a 1h sucrose test the following morning. Approximately 65% of stressed animals consumed sucrose and showed a sucrose preference similar to non-stressed controls in an overnight sucrose test, while 35% showed a decrease in sucrose intake and preference. Following overnight food and water deprivation the previously ‘resilient’ animals showed a significant decrease in sucrose preference and greatly reduced sucrose intake. In addition, we evaluated whether the onset of anhedonia following food and water deprivation corresponds to alterations in corticosterone, epinephrine, circulating glucose, or interleukin-1 beta expression in limbic brain areas. While all stressed animals showed adrenal hypertrophy and elevated circulating epinephrine, only stressed animals that were food deprived were hypoglycemic compared to food deprived controls. Additionally, food and water deprivation significantly increased hippocampus IL-1β while food and water deprivation only increased hypothalamus IL-1β in stress susceptible animals. These data demonstrate that metabolic stress of food and water deprivation interacts with chronic stressor exposure to induce physiological and anhedonic responses.
PMCID: PMC4501026  PMID: 25914924
Chronic Mild Stress; Depression; Anhedonia; Interleukin-1β
10.  Interpreting the Effects of Exercise on Fear Conditioning: The Influence of Time of Day 
Behavioral neuroscience  2010;124(6):868-872.
Previous studies indicate that physical exercise improves contextual fear memory as evidenced by increased freezing behavior when rats are returned to a training environment that was initially paired with foot shock. However, freezing behavior could also be affected by fatigue, especially since rats were tested shortly after the end of the dark cycle, which is when most wheel running was likely to occur. In addition, exercise has been shown to have anxiolytic effects, further confounding interpretation of the effects of exercise on cognition when using aversive conditioning tasks. These factors were examined in the present study by comparing freezing behavior in exercising and non-exercising rats that were tested at different times in the light cycle. In addition, all rats were tested on an elevated plus maze to assess anxiety-like behavior and in an open field apparatus to measure locomotor activity in order to directly examine interactions between freezing, anxiety-like behavior, and locomotion. Consistent with prior studies, exercising rats exhibited more context freezing than sedentary rats when tested early in the light cycle. However, the opposite pattern of results was obtained when testing occurred late in the light cycle, an effect driven by a difference in the amount of freezing exhibited by the sedentary control groups. Indeed, the levels of context freezing exhibited by exercising rats were comparable regardless of when the rats were tested during the light cycle. These data have implications for interpreting the effects of exercise on aversive conditioning.
PMCID: PMC4476371  PMID: 21038936
context; rat; hippocampus; running
11.  Seeking behavior, place conditioning and resistance to conditioned suppression of feeding in rats intermittently exposed to palatable food 
Behavioral neuroscience  2015;129(2):219-224.
Binge eating disorder is characterized by excessive consumption of highly palatable food within short periods of time accompanied by loss of control over eating. Extensive evidence provides support for the consideration of binge eating disorder as an addiction-like disorder. In this study, we wanted to determine whether rats undergoing an operant binge-like eating procedure could develop maladaptive forms of conditioned feeding behaviors. For this purpose, we trained male rats to self-administer either a sugary, highly palatable diet (Palatable rats) or a chow diet (Chow rats) for 1 hour a day. Following escalation and stabilization of palatable food intake, we tested Chow and Palatable rats in i) a conditioned place preference test, ii) a second-order schedule of reinforcement, and iii) a cue-induced suppression of feeding test. In the conditioned place preference task, Palatable rats spent significantly more time in the compartment that was previously paired with the palatable food, compared to Chow controls. Furthermore, in the second order schedule of reinforcement task, Palatable rats exhibited active lever responding 4- to 6-fold higher than Chow control rats. Finally, in the cue-induced suppression of feeding test, while Chow control subjects reduced responding by 32% in the presence of the conditioned punishment, Palatable rats persevered in responding despite the aversive cue. These results further characterize this animal model of binge-like eating and provide additional evidence for the addictive properties of highly palatable food.
PMCID: PMC4456453  PMID: 25798634
binge eating disorder; conditioned place preference; food seeking; conditioned punishment; compulsive eating; loss of control
12.  A critical role of nucleus accumbens dopamine D1-family receptors in renewal of alcohol seeking after punishment-imposed abstinence 
Behavioral neuroscience  2015;129(3):281-291.
In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, where alcohol seeking that is suppressed with extinction training in a context (B) renews when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence due to the negative consequences of excessive use. We recently developed a procedure to study renewal in laboratory rats after abstinence is imposed by negative consequences (footshock punishment). The mechanisms of renewal of punished alcohol seeking are largely unknown. Here we used the D1-family receptor antagonist SCH 23390 to examine the role of nucleus accumbens (NAc) shell and core dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We trained alcohol preferring ‘P rats’ to self-administer 20% alcohol in context A and subsequently suppressed alcohol taking via response-contingent footshock punishment in context B. We tested the effects of systemic, NAc shell, or NAc core injections of SCH 23390 on renewal of alcohol seeking after punishment-imposed abstinence. We found that both systemic and NAc shell and core injections of SCH 23390 decreased renewal of punished alcohol seeking. Our results demonstrate a critical role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We discuss these results in reference to the brain mechanisms of renewal of alcohol seeking after extinction versus punishment.
PMCID: PMC4451375  PMID: 25914922
alcohol; relapse; renewal; context; punishment; nucleus accumbens; dopamine D1 receptor
Behavioral neuroscience  2015;129(3):257-268.
Several studies in our lab and others have demonstrated age-related declines in mnemonic discrimination during a recognition memory paradigm using repeated items, similar lures, and novel foils. In particular, older adults exhibit a shift in lure discriminability, identifying similar lures as old items at a greater rate than young adults. This shift likely reflects deficits in pattern separation processing as a result of underlying changes in the dentate gyrus of the hippocampus. Here, we explored whether alterations in the task design could rescue the age-related impairment or whether it was ubiquitous as one might expect if the neurobiological mechanisms were truly disturbed by typical aging. Despite overt instructions to study item details during encoding, we replicated the age-related deficit in mnemonic discrimination. We established reliable effects with short lists of stimuli and with repeated testing. Altering the task design from a study/test to a continuous recognition paradigm replicated the age-related shift in lure discrimination as well. Modifying the task to an old/new response (rather than old/similar/new) showed the same effect and a d′ analysis showed that lure items were more akin to target items in older adults. Finally, we varied the test instructions in order to promote gist or veridical responses in the old/new task. Even these overt, veridical test instructions did not ameliorate older adults’ lure discrimination problems. Together, these findings demonstrate the robust nature of this age-related deficit and support the hypothesis that typical aging results in neurobiological changes that underlie this impairment.
PMCID: PMC4451612  PMID: 26030427
Pattern separation; lure discrimination; aging; hippocampus
14.  Circadian rhythms and addiction: Mechanistic insights and future directions 
Behavioral neuroscience  2014;128(3):387-412.
Circadian rhythms are prominent in many physiological and behavioral functions. Circadian disruptions either by environmental or molecular perturbation can have profound health consequences, including the development and progression of addiction. Both animal and humans studies indicate extensive bidirectional relationships between the circadian system and drugs of abuse. Addicted individuals display disrupted rhythms, and chronic disruption or particular chronotypes, may increase the risk for substance abuse and relapse. Moreover, polymorphisms in circadian genes and an evening chronotype have been linked to mood and addiction disorders, and recent efforts suggest an association with the function of reward neurocircuitry. Animal studies are beginning to determine how altered circadian gene function results in drug induced neuroplasticity and behaviors. Many studies suggest a critical role for circadian rhythms in reward-related pathways in the brain and indicate that drugs of abuse directly affect the central circadian pacemaker. In this review, we highlight key findings demonstrating the importance of circadian rhythms in addiction, and how future studies will reveal important mechanistic insights into the involvement of circadian rhythms in drug addiction.
PMCID: PMC4041815  PMID: 24731209
Circadian rhythms; addiction; reward; dopamine; alcohol
15.  Basic Sleep and Circadian Science as Building Blocks for Behavioral Interventions: A Translational Approach for Mood Disorders 
Behavioral neuroscience  2014;128(3):360-370.
Sleep and circadian functioning has been of particular interest to researchers focused on improving treatments for psychiatric illness. The goal of the present paper is to highlight the exciting research that utilizes basic sleep and circadian science as building blocks for intervention in the mood disorders. The reviewed evidence suggests that the sleep and circadian systems are 1) disrupted in the mood disorders and linked to symptoms, 2) open systems that can be modified, 3) the focus of interventions which have been developed to effectively treat sleep disturbance within mood disorders, and 4) intimately linked with mood, such that improvements in sleep are associated with improvements in mood. Although, significant positive treatment effects are evident, more research is needed to fill the gap in our basic understanding of the relationship between sleep and mood.
PMCID: PMC4164530  PMID: 24773429
sleep; circadian; mood disorders; cognitive-behavior therapy for insomnia; interpersonal social rhythms therapy; light therapy; sleep deprivation
Behavioral neuroscience  2014;128(3):250-263.
Despite the predominance of sleep in early infancy, developmental science has yet to play a major role in shaping concepts and theories about sleep and its associated ultradian and circadian rhythms. Here we argue that developmental analyses help us to elucidate the relative contributions of the brainstem and forebrain to sleep-wake control and to dissect the neural components of sleep-wake rhythms. Developmental analysis also makes it clear that sleep-wake processes in infants are the foundation for those of adults. For example, the infant brainstem alone contains a fundamental sleep-wake circuit that is sufficient to produce transitions among wakefulness, quiet sleep, and active sleep. Also, consistent with the requirements of a “flip-flop” model of sleep-wake processes, this brainstem circuit supports rapid transitions between states. Later in development, strengthening bidirectional interactions between the brainstem and forebrain contribute to the consolidation of sleep and wake bouts, the elaboration of sleep homeostatic processes, and the emergence of diurnal or nocturnal circadian rhythms. The developmental perspective promoted here critically constrains theories of sleep-wake control and provides a needed framework for the creation of fully realized computational models. Finally, with a better understanding of how this system is constructed developmentally, we will gain insight into the processes that govern its disintegration due to aging and disease.
PMCID: PMC4062979  PMID: 24708298
circadian rhythm; ultradian rhythm; nocturnal; diurnal; sleep homeostasis; fragmentation; consolidation; suprachiasmatic nucleus; brainstem; hypothalamus; development; flip-flop; sleep switch; sleep disorders; Norway rat; Nile grass rat
17.  Adaptive and Pathological Inhibition of Neuroplasticity Associated with Circadian Rhythms and Sleep 
Behavioral neuroscience  2014;128(3):273-282.
The circadian system organizes sleep and wake through imposing a daily cycle of sleep propensity on the organism. Sleep has been shown to play an important role in learning and memory. Apart from the daily cycle of sleep propensity, however, direct effects of the circadian system on learning and memory also have been well documented. Many mechanistic components of the memory consolidation process ranging from the molecular to the systems level have been identified and studied. The question that remains is how do these various processes and components work together to produce cycles of increased and decreased learning abilities, and why should there be times of day when neural plasticity appears to be restricted? Insights into this complex problem can be gained through investigations of the learning disabilities caused by circadian disruption in Siberian hamsters and by aneuploidy in Down syndrome mice. A simple working hypothesis that has been explored in this work is that the observed learning disabilities are due to an altered excitation/inhibition balance in the CNS. Excessive inhibition is the suspected cause of deficits in memory consolidation. In this paper we present the evidence that excessive inhibition in these cases of learning disability involves GABAergic neurotransmission, that treatment with GABA receptor inhibitors can reverse the learning disability, and that the efficacy of the treatment is time sensitive coincident with the major daily sleep phase, and that it depends on sleep. The evidence we present leads us to hypothesize that a function of the circadian system is to reduce neuroplasticity during the daily sleep phase when processes of memory consolidation are taking place.
PMCID: PMC4060045  PMID: 24886189
Down syndrome; GABA; Siberian hamster; mouse; learning; memory; pentylenetetrazole; novel object recognition
18.  Early Life Stress Produces Compulsive-Like, but Not Impulsive, Behavior in Females 
Behavioral Neuroscience  2015;129(3):300-308.
Adverse experiences during childhood are associated with the development of psychiatric disorders later in life. In particular, childhood abuse and neglect are risk factors for addictive disorders, such as substance misuse and pathological gambling. Impulsivity and compulsivity are key features of these disorders. Therefore, we investigated whether childhood adversity might increase vulnerability for addictive disorders through promotion of compulsive and impulsive behaviors. Rats were exposed to a brief, variable childhood or prepubertal stress protocol (Postnatal Days 25–27), and their behavior in a delay discounting task was compared with that of control animals in adulthood. Prepubertal stress produced compulsive-type behavior in females. Specifically, stressed females displayed inappropriate responses during a choice phase of the task, perseverating with nosepoke responding instead of choosing between 2 levers. Stressed females also showed learning impairments during task training. However, prepubertal stress was not associated with the development of impulsive behavior, as rates of delay discounting were not affected in either sex. Childhood adversity may contribute to the establishment and maintenance of addictive disorders by increasing perseveration in females. Perseverative behavior may therefore provide a viable therapeutic target for preventing the development of addictive disorders in individuals exposed to childhood adversity. These effects were not seen in males, highlighting sex differences in response to early life stress.
PMCID: PMC4450884  PMID: 26030429
compulsivity; impulsivity; perseveration; childhood stress; sex differences
19.  Perirhinal Cortex Lesions in Rats: Novelty Detection and Sensitivity to Interference 
Behavioral Neuroscience  2015;129(3):227-243.
Rats with perirhinal cortex lesions received multiple object recognition trials within a continuous session to examine whether they show false memories. Experiment 1 focused on exploration patterns during the first object recognition test postsurgery, in which each trial contained 1 novel and 1 familiar object. The perirhinal cortex lesions reduced time spent exploring novel objects, but did not affect overall time spent exploring the test objects (novel plus familiar). Replications with subsequent cohorts of rats (Experiments 2, 3, 4.1) repeated this pattern of results. When all recognition memory data were combined (Experiments 1–4), giving totals of 44 perirhinal lesion rats and 40 surgical sham controls, the perirhinal cortex lesions caused a marginal reduction in total exploration time. That decrease in time with novel objects was often compensated by increased exploration of familiar objects. Experiment 4 also assessed the impact of proactive interference on recognition memory. Evidence emerged that prior object experience could additionally impair recognition performance in rats with perirhinal cortex lesions. Experiment 5 examined exploration levels when rats were just given pairs of novel objects to explore. Despite their perirhinal cortex lesions, exploration levels were comparable with those of control rats. While the results of Experiment 4 support the notion that perirhinal lesions can increase sensitivity to proactive interference, the overall findings question whether rats lacking a perirhinal cortex typically behave as if novel objects are familiar, that is, show false recognition. Rather, the rats retain a signal of novelty but struggle to discriminate the identity of that signal.
PMCID: PMC4450885  PMID: 26030425
habituation; hippocampus; learning; perirhinal cortex; recognition memory
20.  Behavioral Characterization of Amygdala Involvement in Mediating Intra-Accumbens Opioid-Driven Feeding Behavior 
Behavioral neuroscience  2009;123(4):781-793.
The present experiments were conducted to provide a more detailed behavioral analysis of the dissociable roles of the basolateral (BLA) and central nucleus (CeA) of the amygdala in mediating intra-accumbens (Acb) opioid-induced feeding of a high-fat diet. Confirming previous findings, temporary inactivation of the CeA with the GABAA agonist muscimol reduced DAMGO (D-Ala2-NMe-Phe4-Glyol5-enkephalin)-induced and baseline food intake, whereas intra-BLA muscimol selectively blocked only DAMGO-induced food intake, leaving baseline feeding intact. However, although inactivation of the BLA reduced DAMGO-induced food intake to control levels, this treatment led to exaggerated number and duration of food hopper entries after food intake had ended. A subsequent experiment under conditions of limited access to the diet found the identical pattern of behavior following intra-Acb administration of DAMGO, regardless of whether the BLA was inactivated. Last, BLA inactivation was shown to have no influence on feeding driven by a state of negative-energy balance (24-hr food deprivation), demonstrating a specific influence of the BLA on opioid-driven feeding. These findings suggest that BLA mediates palatability-driven feeding and that this influence is particular to the consummatory act of ingestion.
PMCID: PMC4445738  PMID: 19634936
palatability; food reward; muscimol; feeding; food deprivation; high-fat diet
21.  Voluntary Running-Wheel Exercise Decreases the Threshold for Rewarding Intracranial Self-Stimulation 
Behavioral neuroscience  2012;126(4):582-587.
Physical exercise has mood-enhancing and antidepressant properties although the mechanisms underlying these effects are not known. The present experiment investigated the effects of prolonged access to a running wheel on electrical self-stimulation of the lateral hypothalamus (LHSS), a measure of hedonic state, in rats. Rats with continuous voluntary access to a running wheel for either 2 or 5 weeks exhibited dramatic leftward shifts in the effective current 50 (ECu50; current value that supports half of maximum responding) of their LHSS current-response functions compared to their baselines, indicating a decrease in reward threshold, whereas control rats current-response functions after 2 or 5 weeks were not significantly different from baseline. An inverse correlation existed between the change in ECu50 from baseline and the amount an animal had run in the day prior to LHSS testing, indicating that animals that exhibited higher levels of running showed a more robust decrease in LHSS threshold. We conclude that long-term voluntary exercise increases sensitivity to rewarding stimuli, which may contribute to its antidepressant properties.
PMCID: PMC4433312  PMID: 22845707
exercise; reward; intracranial self-stimulation; anhedonia; depression
22.  Dissociation of thirst and sodium appetite in the furo/cap model of extracellular dehydration and a role for N-methyl-D-aspartate receptors in the sensitization of sodium appetite 
Behavioral neuroscience  2013;127(6):890-898.
Depletion of extracellular fluids motivates many animals to seek out and ingest water and sodium. Animals with a history of extracellular dehydration display enhanced sodium appetite and in some cases thirst. The progressive increase in sodium intake induced by repeated sodium depletions is known as sensitization of sodium appetite. Administration of the diuretic and natriuretic drug, furosemide, along with a low dose of captopril (furo/cap), elicits thirst and a rapid onset of sodium appetite. In the present studies the furo/cap model was used to explore the physiological mechanisms of sensitization of sodium appetite. However, when thirst and sodium appetite were measured concurrently in the furo/cap model, individual rats exhibited sensitization of either thirst or sodium appetite. In subsequent studies, thirst and sodium appetite were dissociated by offering either water prior to sodium or sodium before water. When water and sodium intake were dissociated in time, the furo/cap model reliably produced sensitization of sodium appetite. It is likely that neuroplasticity mediates this sensitization. Glutamatergic N-methyl-d-aspartate receptor (NMDA-R) activation is critical for the development of most forms of neuroplasticity. Therefore, we hypothesized that integrity of NMDA-R function is necessary for the sensitization of sodium appetite. Pharmacological blockade of NMDA-Rs with systemic administration of MK-801 (0.15mg/kg) prevented the sensitization of fluid intake in general when water and sodium were offered concurrently, and prevented sensitization of sodium intake specifically when water and sodium intake were dissociated. The involvement of NMDA-Rs provides support for the possibility that sensitization of sodium appetite is mediated by neuroplasticity.
PMCID: PMC4433317  PMID: 24341713
Sodium appetite; Thirst; Sensitization; Neuroplasticity
23.  Frontostriatal and Mediotemporal Lobe Contributions to Implicit Higher-Order Spatial Sequence Learning Declines in Aging and Parkinson’s Disease 
Behavioral neuroscience  2013;127(2):204-221.
Sequence learning depends on the striatal system, but recent findings also implicate the mediotemporal lobe (MTL) system. Schendan, Searl, Melrose, & Stern (2003) found higher-order associative, learning-related activation in the striatum, dorsolateral prefrontal cortex, and the MTL during the early acquisition phase of both implicit and explicit variants of a serial response time task. This functional magnetic resonance imaging (fMRI) study capitalized on this task to determine how changes in MTL function observed in aging and compromised frontostriatal function characteristic of Parkinson’s disease (PD) patients impacts sequence learning and memory under implicit instructions. Brain activity was compared between “Sequence” and “Random” conditions in 12 non-demented PD patients and education and gender matched healthy control participants of whom 12 were age matched (MC) and 14 were younger (YC). Behaviorally, sequence-specific learning of higher-order associations was reduced with aging and changed further with PD and resulted primarily in implicit knowledge in the older participants. FMRI revealed reduced intensity and extent of sequence learning-related activation in older relative to younger people in frontostriatal circuits and the MTL. This was because signal was greater for the Sequence than Random condition in younger people, whereas older people, especially those with PD, showed the opposite pattern. Both older groups also showed increased activation to the task itself relative to baseline fixation. In addition, right MTL showed hypoactivation and left MTL hyperactivation in PD relative to the MC group. The results suggest changes in frontostriatal and MTL activity occur during aging that affect task-related activity and the initial acquisition phase of implicit higher-order sequence learning. In addition, the results suggest that Parkinson’s disease adversely affects processes in the MTL including sequence learning and memory.
PMCID: PMC4425128  PMID: 23565935
Parkinson’s disease; aging; implicit learning; medial temporal lobe; striatum; prefrontal cortex
24.  Modeling Parkinson’s Disease Falls Associated With Brainstem Cholinergic Systems Decline 
Behavioral neuroscience  2015;129(2):96-104.
In addition to the primary disease-defining symptoms, approximately half of patients with Parkinson’s disease (PD) suffer from postural instability, impairments in gait control and a propensity for falls. Consistent with evidence from patients, we previously demonstrated that combined striatal dopamine (DA) and basal forebrain (BF) cholinergic cell loss causes falls in rats traversing dynamic surfaces. Because evidence suggests that degeneration of brainstem cholinergic neurons arising from the pedunculopontine nucleus (PPN) also contributes to impaired gait and falls, here we assessed the effects of selective cholinergic PPN lesions in combination with striatal DA loss or BF cholinergic cells loss as well as losses in all 3 regions. Results indicate that all combination losses that included the BF cholinergic system slowed traversal and increased slips and falls. However, the performance of rats with losses in all 3 regions (PPN, BF, and DA) was not more severely impaired than following combined BF cholinergic and striatal DA lesions. These results confirm the hypothesis that BF cholinergic-striatal disruption of attentional-motor interactions is a primary source of falls. Additional losses of PPN cholinergic neurons may worsen posture and gait control in situations not captured by the current testing conditions.
PMCID: PMC4392884  PMID: 25798629
Parkinson’s disease; falls; basal forebrain; striatum; pedunculopontine nucleus; rat
25.  A Time to Remember: The Role of Circadian Clocks in Learning and Memory 
Behavioral neuroscience  2014;128(3):283-303.
The circadian system has pronounced influence on learning and memory, manifesting as marked changes in memory acquisition and recall across the day. From a mechanistic level, the majority of studies have investigated mammalian hippocampal dependent learning and memory, as this system is highly tractable. The hippocampus plays a major role in learning and memory and has the potential to integrate circadian information in many ways, including information from local, independent oscillators, and through circadian modulation of neurogenesis, synaptic remodeling, intracellular cascades, and epigenetic regulation of gene expression. These local processes are combined with input from other oscillatory systems to synergistically augment hippocampal rhythmic function. This overview presents an account of the current state of knowledge on circadian interactions with learning and memory circuitry and provides a framework for those interested in further exploring these interactions.
PMCID: PMC4385793  PMID: 24708297

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