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1.  Intermittent access to sweet high-fat liquid induces increased palatability and motivation to consume in a rat model of binge consumption 
Physiology & behavior  2013;0:21-31.
Binge eating disorders are characterized by discrete episodes of rapid and excessive food consumption. In rats, giving intermittent access to sweet fat food mimics this aspect of binge eating. These models typically employ solid food; however, the total amount consumed depends on motivation, palatability and satiety, which are difficult to dissociate with solid food. In contrast, lick microstructure analysis can be used to dissociate these parameters when the ingestant is a liquid. Therefore, we developed a binge model using a liquid emulsion composed of corn oil, heavy cream and sugar. We show that rats given intermittent access to this high-fat emulsion develop binge-like behavior comparable to that previously observed with solid high-fat food. One feature of this behavior was a gradual escalation in consumption across 2.5 weeks of intermittent access, which was not apparent in rats given lower-fat liquid on the same access schedule. Lick microstructure analysis suggests that this escalation was due at least in part to increases in both motivation to consume and palatability-driven consumption.
doi:10.1016/j.physbeh.2013.03.005
PMCID: PMC3648600  PMID: 23499930
2.  Prenatal exposure to stressful life events is associated with masculinized anogenital distance (AGD) in female infants 
Physiology & behavior  2013;0:14-20.
In animal models, prenatal stress programs reproductive development in the resulting offspring, however little is known about effects in humans. Anogenital distance (AGD) is a commonly used, sexually dimorphic biomarker of prenatal androgen exposure in many species. In rodents, prenatally stressed males have shorter AGD than controls (suggesting lower prenatal androgen exposure), whereas prenatally stressed females have longer AGD than controls (suggesting greater prenatal androgen exposure). Our objective was to investigate the relationship between stressful life events in pregnancy and infant AGD. In a prospective cohort study, pregnant women and their partners reported exposure to stressful life events during pregnancy. Pregnancies in which the couple reported 4+ life events were considered highly stressed. After birth (average 16.5 months), trained examiners measured AGD in the infants (137 males, 136 females). After adjusting for age, body size and other covariates, females born to couples reporting high stress had significantly longer (i.e. more masculine) AGD than females born to couples reporting low stress (p=0.015). Among males, high stress was weakly, but not significantly, associated with shorter AGD. Our results suggest prenatal stress may masculinize some aspects of female reproductive development in humans. More sensitive measures of prenatal stress and additional measures of reproductive development are needed to better understand these relationships and clarify mechanisms.
doi:10.1016/j.physbeh.2013.03.004
PMCID: PMC3650607  PMID: 23499769
3.  Low Home Cage Social Behaviors in BTBR T+tf/J Mice during Juvenile Development 
Physiology & behavior  2013;0:49-54.
BTBR T+ tf/J (BTBR) is a genetically homogenous inbred strain of mice that displays abnormal social behaviors, deficits in vocalizations, and high levels of repetitive behaviors, relevant to the three diagnostic symptoms of autism spectrum disorder, leading to the use of this strain as a mouse model of autism. Comprehensive observations of BTBR social behaviors within the home cage during early stages of development have not been conducted. Here we evaluate the home cage behaviors of BTBR in two laboratory environments (NIMH, Bethesda, Maryland versus UC Davis, Davis, California), starting from the day of weaning and continuing into adulthood. Extensive ethogram parameters were scored for BTBR in home cages that contained four BTBR conspecifics, versus home cages that contained four C57BL/6J (B6) conspecifics. BTBR were considerably less interactive than B6 in the home cage at both sites, as measured during the early dark stage of their circadian cycle. A novel home cage behavioral measure, frequency of long interactions, was found to be more frequent and of longer duration in B6 versus BTBR home cages across experimental sites. Significant strain differences in the occurrence of investigative and affiliative behaviors were also seen, however these findings were not fully consistent across the two testing sites. At the end of the 30-day home cage observation period, each seven-week old subject mouse was tested in the three-chambered social approach task. BTBR displayed lack of sociability and B6 displayed significant sociability, consistent with previous reports. Our findings reveal that BTBR engaged in lower levels of some components of spontaneous conspecific social interactions in the home cage environment throughout juvenile development, consistent with their deficits in juvenile and adult sociability as measured in specialized social tasks.
doi:10.1016/j.physbeh.2013.03.006
PMCID: PMC3652551  PMID: 23510981
inbred strain; home cage observation; social interaction
4.  Limited physical contact through a mesh barrier is sufficient for social reward-conditioned place preference in adolescent male rats 
Physiology & behavior  2011;105(3):749-756.
Adolescence is a period of enhanced sensitivity to social influences and vulnerability to drug abuse. Social reward in adolescent rats has been demonstrated with the conditioned place preference (CPP) model, but it is not clear whether limited contact with another rat without play is sufficient to produce reward. We investigated this issue using an apparatus containing two main compartments each with a wire mesh barrier that allowed rats placed on either side of the barrier to have limited physical contact. Adolescent male rats were given two conditioning sessions/day for 2 or 8 days following baseline preference tests. Rats were placed into their preferred side alone for one daily 10-min session and into their initially non-preferred side (i.e., CS) for the other session during which they either had restricted or unrestricted physical access to another rat (Rat/Mesh or Rat/Phys, respectively) or to a tennis ball (Ball/Mesh or Ball/Phys, respectively) unconditioned stimulus (US). Only the Rat/Phys group exhibited CPP after 2 CS-US pairings; however, after 8 CS-US pairings, the Rat/Mesh and Ball/Phys groups also exhibited CPP. During conditioning, the rat US elicited more robust approach and contact behavior compared to the ball, regardless of physical or restricted access. The incidence of contact and/or approach increased as the number of exposures increased. The results suggest that the rank order of US reward efficacy was physical contact with a rat > limited contact with a rat > physical contact with a ball, and that rough-and-tumble play is not necessary to establish social reward-CPP. The findings have important implications for emerging drug self-administration models in which two rats self-administering drug intravenously have limited physical contact via a mesh barrier shared between their respective operant conditioning chambers.
doi:10.1016/j.physbeh.2011.10.001
PMCID: PMC3975131  PMID: 22008744
rough-and-tumble play behavior; place conditioning; adolescence; drug self-administration
5.  A test of maternal programming of offspring stress response to predation risk in threespine sticklebacks 
Physiology & behavior  2013;122:222-227.
Non-genetic maternal effects are widespread across taxa and challenge our traditional understanding of inheritance. Maternal experience with predators, for example, can have lifelong consequences for offspring traits, including fitness. Previous work in threespine sticklebacks showed that females exposed to simulated predation risk produced eggs with higher cortisol content and offspring with altered anti-predator behavior. However, it is unknown whether this maternal effect is mediated via the offspring glucocorticoid stress response and if it is retained over the entire lifetime of offspring. Therefore, we tested the hypothesis that maternal exposure to simulated predation risk has long-lasting effects on the cortisol response to simulated predation risk in stickleback offspring. We measured circulating concentrations of cortisol before (baseline), 15 min after, and 60 min after exposure to a simulated predation risk. We compared adult offspring of predator-exposed mothers and control mothers in two different social environments (alone or in a group). Relative to baseline, offspring plasma cortisol was highest 15 min after exposure to simulated predation risk and decreased after 60 min. Offspring of predator-exposed mothers differed in the cortisol response to simulated predation risk compared to offspring of control mothers. In general, females had higher cortisol than males, and fish in a group had lower cortisol than fish that were by themselves. The buffering effect of the social environment did not differ between maternal treatments or between males and females. Altogether the results show that while a mother’s experience with simulated predation risk might affect the physiological response of her adult offspring to a predator, sex and social isolation have much larger effects on the stress response to predation risk in sticklebacks.
doi:10.1016/j.physbeh.2013.04.004
PMCID: PMC3965370  PMID: 23628383
Parental effect; Glucocorticoid; HPA axis; Predators; Maternal programming
6.  Measuring salivary analytes from free-ranging monkeys 
Physiology & behavior  2010;101(5):601-607.
Studies of large free-ranging mammals have been revolutionized by non-invasive methods for assessing physiology, which usually involve the measurement of fecal or urinary biomarkers. However, such techniques are limited by numerous factors. To expand the range of physiological variables measurable non-invasively from free-ranging primates, we developed techniques for sampling monkey saliva by offering monkeys ropes with oral swabs sewn on the ends. We evaluated different attractants for encouraging individuals to offer samples, and proportions of individuals in different age/sex categories willing to give samples. We tested the saliva samples we obtained in three commercially available assays: cortisol, Salivary Alpha Amylase, and Secretory Immunoglobulin A. We show that habituated free-ranging rhesus macaques will give saliva samples voluntarily without training, with 100% of infants, and over 50% of adults willing to chew on collection devices. Our field methods are robust even for analytes that show poor recovery from cotton, and/or that have concentrations dependent on salivary flow rate. We validated the cortisol and SAA assays for use in rhesus macaques by showing aspects of analytical validation, such as that samples dilute linearly and in parallel to assay standards. We also found that values measured correlated with biologically meaningful characteristics of sampled individuals (age and dominance rank). The SIgA assay tested did not react to samples. Given the wide range of analytes measurable in saliva but not in feces or urine, our methods considerably improve our ability to study physiological aspects of the behavior and ecology of free-ranging primates, and are also potentially adaptable to other mammalian taxa.
doi:10.1016/j.physbeh.2010.09.003
PMCID: PMC3959823  PMID: 20837036
field methods; laboratory methods; enzyme-immuno-assay; immune function; cortisol; alpha amylase; secretory immunoglobulin A; saliva; mammalian
7.  Effect of reproductive status on hypothalamic-pituitary-adrenal (HPA) activity and reactivity in male California mice (Peromyscus californicus) 
Physiology & behavior  2013;0:70-76.
Previous studies indicate that reproductive condition can alter the stress response and glucocorticoid release. Although the functional significance of hypothalamic-pituitary-adrenal (HPA) axis modulation by breeding condition is not fully understood, one possible explanation is the behavior hypothesis, which states that an animal’s need to express parental behavior may be driving modulation of the HPA axis. This possibility is consistent with findings of blunted activity and reactivity of the HPA axis in lactating female mammals; however, effects of reproductive status on HPA function have not been well characterized in male mammals that express parental behavior. Therefore, we tested this hypothesis in the monogamous and biparental California mouse. Several aspects of HPA activity were compared in males from three reproductive conditions: virgin males (housed with another male), non-breeding males (housed with a tubally ligated female), and first-time fathers (housed with a female and their first litter of pups). In light of the behavior hypothesis we predicted that new fathers would differ from virgin and non-breeding males in several aspects of HPA function and corticosterone (CORT) output: decreased amplitude of the diurnal rhythm in CORT, a blunted CORT increase following predator-odor stress, increased sensitivity to glucocorticoid negative feedback, and/or a blunted CORT response to pharmacological stimulation. In addition, we predicted that first-time fathers would be more resistant to CORT-induced suppression of testosterone secretion, as testosterone is important for paternal behavior in this species. We found that virgin males, non-breeding males and first-time fathers did not display any CORT differences in diurnal rhythm, response to a predator-odor stressor, or response to pharmacological suppression or stimulation. Additionally, there were no differences in circulating testosterone concentrations. Adrenal mass was, however, significantly lower in new fathers than in virgin or non-breeding males. These results suggest that the behavior hypothesis does not explain HPA function across reproductive conditions in male California mice.
doi:10.1016/j.physbeh.2013.02.016
PMCID: PMC3622192  PMID: 23474132
HPA axis; Corticosterone; glucocorticoid; stress; paternal behavior; California mouse; Peromyscus californicus; behavior hypothesis
8.  Influence of estrous and circadian cycles on calcium intake of the rat 
Physiology & behavior  2013;0:56-60.
The food, water and sodium intake of laboratory rats fluctuates over the circadian and estrous cycles. Blood calcium and calcium-regulating hormones also wax and wane in response to these cycles, raising the possibility that the same might be true of calcium intake. To investigate this, we monitored the fluid intakes of female Long-Evans rats given a choice between water and 10 mM CaCl2 solution for two consecutive estrous cycles. We found that calcium solution intake changed over the circadian cycle in a similar manner to water intake; the preference scores for CaCl2 solution remained stable. We did not detect any changes in calcium solution intake or preference scores during the estrous cycle despite a decrease in fluid intake at estrus. Thus, fluctuations in intake of calcium solution during the circadian cycle appear to be nonspecific and probably the result of changes in fluid balance. Estrous changes either do not influence calcium intake or their effects are masked by other factors, resulting in stable levels of calcium intake.
doi:10.1016/j.physbeh.2013.02.011
PMCID: PMC3633607  PMID: 23458631
drinking patterns; diurnal; estrogen; progesterone; TSE Phenomaster
9.  Effects of Stressor Controllability on Diurnal Physiological Rhythms 
Physiology & behavior  2013;0:32-39.
Disruptions in circadian and diurnal rhythms are associated with stress-related psychiatric disorders and stressor exposure can disrupt these rhythms. The controllability of the stressor can modulate various behavioral and neurochemical responses to stress. Uncontrollable, but not controllable, stress produces behaviors in rats that resemble symptoms of anxiety and depression. Whether acute stress-induced disruptions in physiological rhythms are sensitive to controllability of the stressor, however, remains unknown. To examine the role of controllability in diurnal rhythm disruption, adult male Sprague Dawley rats were implanted with Data Sciences International (DSI) biotelemetry devices. Real-time measurements were obtained before, during and after exposure to a controllable or yoked uncontrollable stressor. Controllable and uncontrollable stress equally disrupted diurnal rhythms of locomotor activity and body temperature but not heart rate. The diurnal heart rate the day following stressor exposure was flattened to a greater extent and was significantly higher in rats with control over stress suggesting a relationship between stressor controllability and the heart rate response. Our results are consistent with the conclusion that acute stress-induced disruptions in diurnal physiological rhythms likely contribute little to the behavioral and affective consequences of stress that are sensitive to stressor controllability.
doi:10.1016/j.physbeh.2013.02.009
PMCID: PMC3637963  PMID: 23454291
Controllability; Stress; Diurnal Rhythm; Heart Rate; Body Temperature; Locomotor Activity
10.  Pubertal testosterone programs context-appropriate agonistic behavior and associated neural activation patterns in male Syrian hamsters 
Physiology & behavior  2013;0:1-7.
Pubertal testosterone programs the level of aggressive behavior displayed by male Syrian hamsters during resident-intruder interactions. To further explore the pubertal programming of adult male agonistic behaviors, the current study investigated the formation, stability, and maintenance of dominant-subordinate relationships in males that either did (T@P) or did not (NoT@P) experience testicular hormones during adolescent development. NoT@P males were gonadectomized prepubertally and T@P males were gonadectomized in adulthood. Four weeks after gonadectomy, all males received testosterone-replacement. Two weeks later, two males of the same hormonal history were given a 60 min introductory trial in a neutral arena, followed immediately and again 24 h later by three 5-min trials. During the introductory trial, each male was deemed dominant, subordinate, or no-status. Brains were collected 1 h after the last trial and sections were stained for Fos-immunoreactivity. Dominant T@P males flank marked more frequently than subordinate and no-status T@P males; this difference was not found in NoT@P males. NoT@P males showed an increase in the number of offensive postures the day after the first series of tests, whereas T@P males did not. Dominant T@P males had significantly more Fos expression than no-status T@P males in anterior cingulate cortex; this relationship was not observed in NoT@P males. Additionally, dominant T@P males had higher Fos expression than dominant NoT@P males in lateral septum. Thus, pubertal testosterone does not organize the formation or stability of male-male relationships, but does program the behavioral strategies used to maintain these relationships over time and the neural correlates of status.
doi:10.1016/j.physbeh.2013.02.003
PMCID: PMC3654525  PMID: 23419537
puberty; testosterone; fos; agonistic behavior; cingulate cortex; lateral septum
11.  Prior access to a sweet is more protective against cocaine self-administration in female rats than male rats 
Physiology & behavior  2013;0:96-103.
It is well established that female rats are more sensitive than male rats to the reinforcing effects of cocaine (Lynch, 2008 for review). We hypothesized that greater preference for cocaine would support greater avoidance of a cocaine-paired taste cue in female vs. male rats. Moreover, at least in male rats, greater avoidance of the taste cue is associated with greater cocaine self-administration (Grigson & Twining, 2002). Thus, we anticipated that female rats would not only demonstrate greater avoidance of the drug-paired taste cue, but greater drug-taking as well. We tested these hypotheses by examining avoidance of a saccharin cue in male and female rats following several pairings with self-administered saline or cocaine (0.16, 0.33, or 0.66 mg/infusion). Contrary to expectations, the results showed that female rats exhibited less avoidance of the cocaine-associated saccharin cue than male rats and self-administered less, rather than more, cocaine, Thus, while female rats reportedly take more drug than male rats when the drug is presented in the absence of an alternative reward, they take less drug than male rats when the opportunity to self-administer cocaine is preceded by access to a palatable sweet. Females, then, may not simply be more sensitive to the rewarding properties of drug, but also to the reinforcing properties of natural rewards and this increase in sensitivity to sweets may serve to protect against drug-taking behavior.
doi:10.1016/j.physbeh.2013.02.017
PMCID: PMC3665359  PMID: 23474135
reward; sex differences; drug abuse; conditioning; cocaine; self-administration
12.  Mother–infant interactions in free-ranging rhesus macaques: Relationships between physiological and behavioral variables 
Physiology & behavior  2008;96(0):613-619.
Studies of mother–infant relationships in nonhuman primates have increasingly attempted to understand the neuroendocrine bases of interindividual variation in mothering styles and the mechanisms through which early exposure to variable mothering styles affects infant behavioral development. In this study of free-ranging rhesus macaques on Cayo Santiago, Puerto Rico, we aimed to: 1) compare lactating and nonlactating females to investigate whether lactation is associated with changes in plasma cortisol, prolactin and oxytocin, as well as changes in CSF levels of serotonin and dopamine metabolites (5-HIAA and HVA); 2) examine the extent to which interindividual variation in maternal physiology is associated with variation in maternal behavior; 3) examine the extent to which interindividual variation in infant physiology and behavior is accounted for by variation in maternal physiology and behavior. Lactating females had higher plasma concentrations of cortisol, prolactin, and oxytocin but lower CSF concentrations of HVA than nonlactating females. Variation in maternal rejection behavior was positively correlated with variation in maternal plasma cortisol levels and in CSF 5-HIAA levels while variation in the time spent nursing and grooming was associated with maternal plasma oxytocin levels. Infants who were protected more by their mothers had higher cortisol levels than those who were protected less, while infants who were rejected more had lower CSF 5-HIAA than infants who were rejected less. Since exposure to high levels of maternal protectiveness and rejection is known to affect the offspring’s behavior and responsiveness to the environment later in life, our results are consistent with the hypothesis that these effects are mediated by long-term changes in the activity of the offspring’s HPA axis and brain serotonergic system.
doi:10.1016/j.physbeh.2008.12.016
PMCID: PMC3955190  PMID: 19150451
Maternal behavior; Infant behavior; Cortisol; Monoamine neurotransmitters; Oxytocin; Prolactin; Rhesus monkeys
13.  ‘Roid rage in rats? Testosterone effects on aggressive motivation, impulsivity and tyrosine hydroxylase 
Physiology & behavior  2012;0:6-12.
In humans and animals, anabolic-androgenic steroids (AAS) increase aggression, but the underlying behavioral mechanisms are unclear. AAS may increase the motivation to fight. Alternatively, AAS may increase impulsive behavior, consistent with the popular image of ‘roid rage. To test this, adolescent male rats were treated chronically with testosterone (7.5 mg/kg) or vehicle and tested for aggressive motivation and impulsivity. Rats were trained to respond on a nose-poke on a 10 min fixed-interval schedule for the opportunity to fight in their home cage with an unfamiliar rat. Although testosterone increased aggression (6.3±1.3 fights/5 min vs 2.4±0.8 for controls, p<0.05), there was no difference in operant responding (28.4±1.6 nose-pokes/ 10 min for testosterone, 32.4±7.0 for vehicle). This suggests that testosterone does not enhance motivation for aggression. To test for impulsivity, rats were trained to respond for food in a delay-discounting procedure. In an operant chamber, one lever delivered one food pellet immediately, the other lever gave 4 pellets after a delay (0, 15, 30 or 45 s). In testosterone- and vehicle-treated rats, body weights and food intake did not differ. However, testosterone-treated rats chose the larger, delayed reward more often (4.5±0.7 times in 10 trials with 45 s delay) than vehicle controls (2.5±0.5 times, p<0.05), consistent with a reduction in impulsive choice. Thus, although chronic high-dose testosterone enhances aggression, this does not include an increase in impulsive behavior or motivation to fight. This is further supported by measurement of tyrosine hydroxylase (TH) by Western immunoblot analysis in brain regions important for motivation (nucleus accumbens, Acb) and executive function (medial prefrontal cortex, PFC). There were no differences in TH between testosterone- and vehicle-treated rats in Acb or PFC. However, testosterone significantly reduced TH (to 76.9±3.1% of controls, p<0.05) in the caudate-putamen, a brain area important for behavioral inhibition, motor control and habit learning.
doi:10.1016/j.physbeh.2012.12.005
PMCID: PMC3615053  PMID: 23266798
Anabolic agents; Agonistic behavior; Androgen; Fighting; Dopamine
14.  Overexpression of neuropeptide Y in the dorsomedial hypothalamus increases trial initiation but does not significantly alter concentration-dependent licking to sucrose in a brief-access taste test 
Physiology & behavior  2013;0:109-114.
Evidence in the literature raises the possibility that alterations in neuropeptide Y (NPY) in the dorsomedial hypothalamus (DMH) may contribute to hyperphagia leading to body weight gain. Previously, we have shown that compared to AAVGFP controls, adeno-associated virus (AAV)-mediated overexpression of NPY in the DMH of lean rats resulted in significantly higher body weight gain that was attributed to increased food intake, and this was further exacerbated by a high-fat diet. Here, we tested AAVNPY and AAVGFP control rats in a brief-access taste procedure (10-s trials, 30-min sessions) to an array of sucrose concentrations under ad libitum and partial food and water access conditions. The test allows for some segregation of the behavioral components by providing a measure of trial initiation (appetitive) and unconditioned licks at each concentration (consummatory). Consistent with previous findings suggesting that NPY has a primary effect on appetitive function, overexpression of DMH NPY did not significantly alter concentration-dependent licking response to sucrose but when tested in a non-restricted food and water schedule, AAVNPY rats initiated significantly more sucrose trials compared to AAVGFP controls in a brief-access taste test.
doi:10.1016/j.physbeh.2013.01.003
PMCID: PMC3615091  PMID: 23313404
NPY; hypothalamus; adeno-associated virus; sucrose; appetitive; taste
15.  Differences in the Neuronal Response to Food in Obesity-Resistant as Compared to Obesity-Prone Individuals 
Physiology & behavior  2013;0:122-128.
Despite living in an obesogenic environment, some individuals maintain a thin phenotype compared to the majority who are at risk for weight gain and obesity. Understanding how these different phenotypes regulate energy intake is critical. The objective of this study was to examine the differences in neuronal response to visual food cues in adults recruited as either obesity-resistant (OR) or obesity-prone (OP) based on self-identification, BMI, and personal/family weight history. 25 OR and 28 OP individuals were studied after 4 days of eucaloric energy intake. Functional magnetic resonance imaging (fMRI) was performed in the fasted and acute fed states (30 minutes after a test meal) while subjects viewed images of foods of high hedonic value and neutral non-food objects. Measures of appetite using visual analog scales were performed before and every 30 minutes after the test meal for 3 hours. In the fasted state, food as compared to nonfood images elicited significant response in the insula, somatosensory cortex, parietal cortex, and visual cortex in both OR and OP. The acute fed state resulted in significant attenuation of these and other brain areas in the OR but not OP individuals. Furthermore, OP as compared to OR individuals showed greater activation of medial and anterior prefrontal cortex (PFC) in response to the test meal. Adjusting for fat mass did not impact these results. Attenuation of insula/PFC response to food images in the fed state was associated with greater reductions in hunger. These findings suggest that individuals prone to weight gain and obesity have altered neuronal responses to food cues in brain regions known to be important in energy intake regulation. These altered responses may represent an important mechanism contributing to excess energy intake and risk for obesity.
doi:10.1016/j.physbeh.2013.01.002
PMCID: PMC3615115  PMID: 23313402
fMRI; neuroimaging; pre-obesity; overweight; insula; prefrontal cortex
16.  Chronobiology of alcohol: Studies in C57BL/6J and DBA/2J inbred mice 
Physiology & behavior  2013;0:140-147.
Human alcoholics display dramatic disruptions of circadian rhythms that may contribute to the maintenance of excessive drinking, thus creating a vicious cycle. While clinical studies cannot establish direct causal mechanisms, recent animal experiments have revealed bidirectional interactions between circadian rhythms and ethanol intake, suggesting that the chronobiological disruptions seen in human alcoholics are mediated in part by alterations in circadian pacemaker function. The present study was designed to further explore these interactions using C57BL/6J (B6) and DBA/2J (D2) inbred mice, two widely employed strains differing in both circadian and alcohol-related phenotypes. Mice were maintained in running-wheel cages with or without free-choice access to ethanol and exposed to a variety of lighting regimens, including standard light–dark cycles, constant darkness, constant light, and a “shift-lag” schedule consisting of repeated light–dark phase shifts. Relative to the standard light–dark cycle, B6 mice showed reduced ethanol intake in both constant darkness and constant light, while D2 mice showed reduced ethanol intake only in constant darkness. In contrast, shift-lag lighting failed to affect ethanol intake in either strain. Access to ethanol altered daily activity patterns in both B6 and D2 mice, and increased activity levels in D2 mice, but had no effects on other circadian parameters. Thus, the overall pattern of results was broadly similar in both strains, and consistent with previous observations that chronic ethanol intake alters circadian activity patterns while environmental perturbation of circadian rhythms modulates voluntary ethanol intake. These results suggest that circadian-based interventions may prove useful in the management of alcohol use disorders.
doi:10.1016/j.physbeh.2013.01.001
PMCID: PMC3760341  PMID: 23313401
Circadian rhythm; Ethanol intake; Inbred mice; Environmental lighting
17.  Novelty-Seeking Behavior Predicts Vulnerability in a Rodent Model of Depression 
Physiology & behavior  2011;103(2):210-216.
Background
The onset of major depressive disorder is likely precipitated by a combination of heredity and life stress. The present study tested the hypothesis that rats selectivity bred on a trait related to emotional reactivity would show differential susceptibility or resilience to the development of depression-like signs in response to chronic mild variable intermittent stress (CMS).
Methods
Male Sprague-Dawley rats that were bred based on the trait of either high or low locomotor activity in response to a novel environment were exposed to four weeks of CMS or control conditions. Changes in hedonic behavior were assessed using weekly sucrose preference tests and anxiety-like behavior was evaluated using the novelty-suppressed feeding test.
Results
During four weeks of CMS, bred low responder (bLR) rats became anhedonic at a faster rate and to a larger degree than bred high responder (bHR) rats, based on weekly sucrose preference tests. Measures of anxiety-like behavior in the novelty-suppressed feeding test were also significantly increased in the CMS-exposed bLR rats, though no differences were observed between CMS-exposed bHR rats and their unstressed controls.
Conclusions
These findings present further evidence that increased emotional reactivity is an important factor in stress susceptibility and the etiology of mood disorders, and that bHR and bLR rats provide a model of resistance or vulnerability to stress-induced depression. Furthermore, exposing bHR and bLR rats to CMS provides an excellent way to study the interaction of genetic and environmental factors in the development of depression-like behavior.
doi:10.1016/j.physbeh.2011.02.001
PMCID: PMC3925672  PMID: 21303678
depression; chronic mild stress; high responder; low responder; selectively bred rat; vulnerability
18.  Pregnancy decreases GABAergic inhibition of the hypothalamic paraventricular nucleus 
Physiology & behavior  2009;97(2):171-179.
Depressor responses to peripheral or central infusion of Angiotensin II type 1 (AT1) receptor antagonists (AT1X) are greater in pregnant (P) compared to nonpregnant (NP) animals. AT1 and ionotropic excitatory amino acid (EAA) receptors contribute to pressor responses to GABAA receptor blockade with bicuculline (Bic) in the paraventricular nucleus (PVN) of male rats. Therefore, we hypothesized that GABAergic inhibition is decreased and AT1 receptors play a greater excitatory role in the PVN of P versus NP rats. Unilateral microinjection of Bic was performed before (Bic1), after AT1X (Bic2), and after AT1X + EAA blockade (kynurenate, Kyn) (Bic3) in the PVN. Increases in mean arterial pressure (MAP: NP= 20 ± 2; P= 12 ± 2 mmHg), heart rate (HR: NP= 57 ± 6; P= 19 ± 6 beats/min) and renal sympathetic nerve activity (RSNA: NP= 70 ± 9; P= 33 ± 7 %) due to Bic (Bic1) were attenuated in P rats. Responses to AT1X and Kyn alone were insignificant in both groups. In NP rats, AT1X attenuated (+12 ± 4 mmHg), and AT1X + Kyn further decreased the pressor response to Bic in the PVN (+6 ± 2 mmHg). In P rats AT1X reduced the pressor response to Bic (+5 ± 1 mm Hg), and Kyn had no additional effect (+3 ± 1 mmHg). Effects of PVN Bic to alter the autospectra of RSNA were suppressed by prior AT1X and Kyn in both groups. Thus, tonic GABAergic inhibition is decreased and the contribution of AT1 receptors in the PVN may be greater in P rats.
doi:10.1016/j.physbeh.2009.02.018
PMCID: PMC3906727  PMID: 19254733
rats; excitatory amino acid receptors; angiotensin AT1 receptors; renal sympathetic nerve activity; kynurenate; L158,809; bicuculline; PVN
19.  Postoral glucose stimulation of intake and conditioned flavor preference in C57BL/6J mice: A concentration-response study 
Physiology & behavior  2012;109:33-41.
In a recent study, intragastric (IG) self-infusion of 16% glucose stimulated 1-h intake and conditioned a preference for a flavored saccharin solution in C57BL/6J mice (Zukerman et al., 2011). Experiment 1 of the present study presents a concentration-response analysis of IG glucose-induced intake stimulation monitored by recording licking response every min of the 1 h/day sessions. Separate groups of food-restricted mice consumed a flavored saccharin solution (the CS−) paired with IG self-infusions of water (Test 0) followed by a different flavored solution (the CS+) paired with IG self-infusions of 2, 4, 8, 16, or 32% glucose (Tests 1–3). Following additional CS− and CS+ training sessions, a two-bottle CS+ vs. CS− choice test was conducted without infusions. Self-infusions of 8%, 16% or 32% glucose stimulated CS+ licking within 12 min of the first test session and even earlier in subsequent test sessions, and also conditioned significant CS+ preferences in the two-bottle test. The stimulation of early licking and CS+ preference increased as a function of glucose concentration. The amount of glucose solute self-infused increased with sugar concentration as did post-infusion blood glucose levels. The 2% glucose infusion did not stimulate CS+ intake and the 2% and 4% infusions failed to produce a CS+ preference in the 1-h test. Experiment 2 revealed that intraperitoneal self-infusions of 8% glucose, unlike IG glucose self-infusions, failed to stimulate CS+ licking or preference despite producing maximal increases in blood glucose levels. Taken together, these and other findings suggest that glucose rapidly produces concentration-dependent intestinal signals that stimulate intake and condition flavor preferences while postoral satiation signals limit total amounts consumed.
doi:10.1016/j.physbeh.2012.11.004
PMCID: PMC3557835  PMID: 23200639
Postoral sugar conditioning; intragastric; intraperitoneal; appetition
20.  Caffeine prevents weight gain and cognitive impairment caused by a high-fat diet while elevating hippocampal BDNF 
Physiology & behavior  2012;109:69-74.
Obesity, high-fat diets, and subsequent type 2 diabetes (T2DM) are associated with cognitive impairment. Moreover, T2DM increases the risk of Alzheimer’s disease (AD) and leads to abnormal elevation of brain beta-amyloid levels, one of the hallmarks of AD. The psychoactive alkaloid caffeine has been shown to have therapeutic potential in AD but the central impact of caffeine has not been well-studied in the context of a high-fat diet. Here we investigated the impact of caffeine administration on metabolism and cognitive performance, both in control rats and in rats placed on a high-fat diet. The effects of caffeine were significant: caffeine both (i) prevented the weight-gain associated with the high-fat diet and (ii) prevented cognitive impairment. Caffeine did not alter hippocampal metabolism or insulin signaling, likely because the high-fat-fed animals did not develop full-blown diabetes; however, caffeine did prevent or reverse a decrease in hippocampal brain-derived neurotrophic factor (BDNF) seen in high-fat-fed animals. These data confirm that caffeine may serve as a neuroprotective agent against cognitive impairment caused by obesity and/or a high-fat diet. Increased hippocampal BDNF following caffeine administration could explain, at least in part, the effects of caffeine on cognition and metabolism.
doi:10.1016/j.physbeh.2012.11.008
PMCID: PMC3586379  PMID: 23220362
21.  Behavioural and physiological expression of arousal during decision-making in laying hens☆ 
Physiology & Behavior  2014;123(100):93-99.
Human studies suggest that prior emotional responses are stored within the brain as associations called somatic markers and are recalled to inform rapid decision-making. Consequently, behavioural and physiological indicators of arousal are detectable in humans when making decisions, and influence decision outcomes. Here we provide the first evidence of anticipatory arousal around the time of decision-making in non-human animals. Chickens were subjected to five experimental conditions, which varied in the number (one versus two), type (mealworms or empty bowl) and choice (same or different) of T-maze goals. As indicators of arousal, heart-rate and head movements were measured when goals were visible but not accessible; latency to reach the goal indicated motivation. We found a greater increase in heart-rate from baseline to the goal-viewing period, more head movements and shorter latencies in all conditions including mealworms compared to those with empty bowls. More head movements when two mealworm bowls were available compared to just one, and prior to occasions when hens accessed an empty bowl rather than declining to move, showed that arousal preceded and influenced decision-making. Our results provide an important foundation for investigating arousal during animal decision-making and suggest that the somatic-marker hypothesis might not only apply to humans.
Highlights
•Anticipatory arousal was detectable around the time of decision-making in chickens.•Increased heart-rate and head movements were measured prior to preferred goal access.•More head movements were measured when two preferred goals were available.•Fewer head movements were measured preceding decisions not to access a goal.•Provides an important foundation for exploring arousal during animal decision-making.
doi:10.1016/j.physbeh.2013.10.008
PMCID: PMC3866659  PMID: 24432355
Chicken; Choice; Heart-rate; Head movements; Anticipation; Motivation
22.  EXPOSURE TO DEXAMETHASONE DURING LATE GESTATION CAUSES FEMALE-SPECIFIC DECREASES IN CORE BODY TEMPERATURE AND PREPRO-THYROTROPIN-RELEASING HORMONE EXPRESSION IN THE PARAVENTRICULAR NUCLEUS OF THE HYPOTHALAMUS IN RATS 
Physiology & behavior  2012;108:6-12.
Synthetic glucocorticoids (GC) have been used to promote lung development in preterm infants, thereby decreasing respiratory distress syndrome and mortality, yet, concern has arisen from reports that such treatment predisposes individuals to disease in adulthood. Given the variety of preclinical studies that show metabolic and behavioral abnormalities in adulthood following fetal exposure to synthetic GC, we examined the effect of in utero exposure to the synthetic GC, dexamethasone (DEX), on hypothalamic expression of thyrotropin-releasing hormone (TRH) a central neuropeptide involved in mediating behavior and metabolic balance. Pregnant Sprague-Dawley rats were administered 0.4 mg/kg DEX on gestational days 18–21. As adults (postnatal day (PD) 60), the offspring were fitted with temperature sensing transmitters allowing real-time monitoring of core body temperature (CBT) across the 24 hr light dark period. This revealed a significant decrease in CBT throughout the day in prenatal DEX-treated females on estrus and diestrus, but not in male offspring. The reduction in CBT by prenatal DEX exposure was accompanied by a significant decrease in the expression of Trh transcript in the paraventricular nucleus of the hypothalamus (PVN) of female rats at PD 60 and this effect was also present on PD7. There was also a female-specific reduction in the number of preproTRH -immunoreactive (ir) neurons in the PVN, with ppTRH-ir nerve fibers decreases that were present in both male and female offspring. No changes in thyroid hormone (triiodothyronine, T3; thyroxine, T4) were observed in adult offspring, but during development, both males and females (PD14) had lower T3 and T4 levels. These data indicate abnormal expression of TRH results from fetal DEX exposure during late gestation, possibly explaining the decreased CBT observed in the female offspring.
doi:10.1016/j.physbeh.2012.07.010
PMCID: PMC3513498  PMID: 22884559
Thyrotropin Releasing Hormone; Thyroid Hormone; Dexamethasone; Glucocorticoid; Core Body Temperature
23.  Obese and Lean Zucker Rats Demonstrate Differential Sensitivity to Rates of Food Reinforcement in a Choice Procedure 
Physiology & behavior  2012;108:19-27.
The obese Zucker rat carries two recessive fa alleles that result in the expression of an obese phenotype. Obese Zuckers have higher food intake than lean controls in free-feed studies in which rats have ready access to a large amount of one type of food. The present study examined differences in obese and lean Zucker rats using concurrent schedules of reinforcement, which more ecologically models food selection using two food choices that have limited, but generally predictable, availability. Lever-pressing of ten lean (Fa/Fa or Fa/fa) and ten obese (fa/fa) Zucker rats was placed under three concurrent variable interval variable interval (conc VI VI) schedules of sucrose and carrot reinforcement, in which the reinforcer ratios for 45-mg food pellets were 5:1, 1:1, and 1:5. Allocation of responses to the two food alternatives was characterized using the generalized matching equation, which allows sensitivity to reinforcer rates (a) and bias toward one alternative (log k) to be quantified. All rats showed a bias to sucrose, though there were no differences between lean and obese Zucker rats. In addition, obese Zucker rats exhibited higher sensitivity to reinforcement rates than lean rats. This efficient pattern of responding was related to overall higher deliveries of food pellets. Effective matching for food, then, may be another behavioral pattern that contributes to an obese phenotype.
doi:10.1016/j.physbeh.2012.10.001
PMCID: PMC3513500  PMID: 23046726
concurrent schedules of reinforcement; generalized matching; obesity; palatability; sensitivity; Zucker rats (fa/fa)
24.  Disruption of Cue-Potentiated Feeding in Mice with Blocked Ghrelin Signaling 
Physiology & behavior  2012;108:34-43.
The peptide hormone ghrelin regulates a variety of eating behaviors. Not only does it potently increase intake of freely-available food, but it also shifts food preference towards diets rich in fat, enhances operant responding for food rewards, and induces conditioned place preference for food rewards. Here, we postulated that ghrelin also enables cue-potentiated feeding, in which eating is enhanced upon presentation of a food-conditioned stimulus. To test this hypothesis, a novel cue-potentiated feeding protocol adapted for use in mice was designed and validated, and then the effects of pharmacologic ghrelin receptor (GHSR) antagonism and GHSR transcriptional blockade (as occurs in GHSR-null mice) were assessed. Sated C57BL/6J mice indeed demonstrated cue-potentiated intake of grain-based pellets specifically upon presentation of a positive conditioned stimulus (CS+) but not a negative conditioned stimulus (CS-). Treatment with a GHSR antagonist blocked potentiated feeding in sated C57BL/6J mice in response to the CS+. In contrast, while GHSR-null mice also lacked a potentiation of feeding specifically in response to the CS+, they displayed an enhanced intake of pellets in response to both the positive and negative conditioned stimuli. The pattern of immediate early gene expression within the basolateral amygdala -- a brain region previously linked to cue-potentiated feeding -- paralleled the observed behavior of these mice, suggesting uncharacteristic activation of the amygdala in response to negative conditioned stimuli in GHSR-null mice as compared to wild-type littermates. Thus, although the observed disruptions in cue-potentiated feeding are different depending upon whether GHSR activity or GHSR expression is blocked, a key role for GHSRs in establishing a specific positive cue-food association has now been established.
doi:10.1016/j.physbeh.2012.10.003
PMCID: PMC3513523  PMID: 23063723
ghrelin; GHSR; amygdala; feeding; cue
25.  Low Sociability in BTBR T+tf/J Mice is Independent of Partner Strain 
Physiology & behavior  2012;107(5):649-662.
Inbred mouse strains differ greatly in social behaviors, making them a valuable resource to study genetic and non-genetic mechanisms underlying social deficits relevant to autism spectrum disorders. A hallmark symptom of autism is a lack of ability to understand other people’s thoughts and intentions, which leads to impairments in adjusting behaviors in response to ever-changing social situations in daily life. We compared the ability of BTBR T+ tf/J (BTBR), a strain with low sociability, and C57BL/6J (B6), a strain with high sociability, for their abilities to modulate responses to social cues from different partners in the reciprocal social interaction test. Results indicate that BTBR exhibited low sociability toward different partners and displayed minimal ability to modify behaviors toward different partners. In contract, B6 showed high sociability toward different partners and was able to modify social behaviors toward different partners. Consistent results were found in two independent cohorts of different ages, and in both sexes. In the three-chambered test, high sociability in B6 and low sociability in BTBR were independent of strain of the novel mouse. Since social deficits in BTBR could potentially be caused by physical disabilities in detecting social olfactory cues, or in cognitive abilities, we tested BTBR and B6 mice on measures of olfaction and cognition. BTBR mice displayed more sniffing of social odors emitted by soiled bedding than of an odorless novel object, but failed to show a preference for a live novel mouse over a novel object. On olfactory habituation/dishabituation to a sequence of odors, BTBR displayed discrimination abilities across three non-social and two social odors. However, as compared to B6, BTBR displayed less sniff time for both non-social and social odors, and no significant dishabituation between cage odors from two different novel mouse strains, findings that will be important to investigate further. BTBR was generally normal in spatial acquisition on the Morris water maze test, but showed deficits in reversal learning. Time spent freezing on contextual and cued fear conditioning was lower in BTBR than in B6. Our findings suggest that BTBR has poor abilities to modulate its responses to different social partners, which may be analogous to social cognition deficits in autism, adding to the value of this strain as a mouse model of autism.
doi:10.1016/j.physbeh.2011.12.025
PMCID: PMC3330157  PMID: 22245067
Autism; mouse models mouse social behaviors; inbred strains; three-chambered social approach task; reciprocal social interaction; BTBR T+tf/J; social partner; olfactory habituation/dishabituation; repetitive behaviors

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