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1.  Locomotor Activity Predicts Acquisition of Self-Administration Behavior but Not Cocaine Intake 
Behavioral neuroscience  2005;119(2):464-472.
The current study investigates locomotor activity in a novel environment and correlates these activity levels with cocaine self-administration in rats that were either trained or untrained on a lever-pressing task prior to cocaine self-administration. The authors report that it is the rate of learning the lever-pressing task, not cocaine self-administration, that correlates with locomotor activity. The results suggest that a correlation between locomotor activity and cocaine self-administration is secondary to a link between locomotor activity and rate of learning to lever press for a reward. The authors conclude that locomotor activity is not necessarily an indicator of propensity to self-administer cocaine and demonstrate that environmental novelty and rate of learning an operant task are important considerations when designing experiments on drug-seeking behaviors.
PMCID: PMC4327862  PMID: 15839792
addiction; learning; self-administration; cocaine; locomotion
2.  Alterations of attention and emotional processing following childhood-onset damage to the prefrontal cortex 
Behavioral neuroscience  2013;128(1):1-11.
The prefrontal cortex (PFC), especially the medial sector, plays a crucial role in emotional processing. Damage to this region results in impaired processing of emotional information, perhaps due to an inability to initiate and maintain attention toward emotional materials, a process that is normally automatic. Childhood onset damage to the PFC impairs emotional processing more than adult-onset PFC damage. The aim of this work was to study the involvement of the PFC in attention to emotional stimuli, and to explore how age at lesion onset affects this involvement. To address these issues, we studied both the emotional and attentional modulation of the startle reflex. Our sample was composed of 4 patients with childhood-onset PFC damage, 6 patients with adult-onset PFC damage, and 10 healthy comparison participants. Subjects viewed 54 affective pictures; acoustic startle probes were presented at 300 ms after picture onset in 18 pictures (as an index of attentional modulation) and at 3,800 ms after picture onset in 18 pictures (as an index of emotional modulation). Childhood-onset PFC patients did not show attentional or emotional modulation of the response, in contrast to adult-onset PFC damage and comparison participants. Early-onset damage to the PFC results, therefore, in more severe dysfunction in the processing of affective stimuli than adult-onset PFC damage, perhaps reflecting limited plasticity in the neural systems that support these processes.
PMCID: PMC4324722  PMID: 24377423
Emotion; Attention; Prefrontal cortex; Childhood-onset brain damage; Startle reflex; Prepulse inhibition
3.  The Plasticity of Human Maternal Brain: Longitudinal Changes in Brain Anatomy During the Early Postpartum Period 
Behavioral neuroscience  2010;124(5):695-700.
Animal studies suggest that structural changes occur in the maternal brain during the early postpartum period in regions such as the hypothalamus, amygdala, parietal lobe, and prefrontal cortex and such changes are related to the expression of maternal behaviors. In an attempt to explore this in humans, we conducted a prospective longitudinal study to examine gray matter changes using voxel-based morphometry on high resolution magnetic resonance images of mothers’ brains at two time points: 2–4 weeks postpartum and 3–4 months postpartum. Comparing gray matter volumes across these two time points, we found increases in gray matter volume of the prefrontal cortex, parietal lobes, and midbrain areas. Increased gray matter volume in the midbrain including the hypothalamus, substantia nigra, and amygdala was associated with maternal positive perception of her baby. These results suggest that the first months of motherhood in humans are accompanied by structural changes in brain regions implicated in maternal motivation and behaviors.
PMCID: PMC4318549  PMID: 20939669
maternal brain; maternal behavior; postpartum; brain structure; neuroimaging
4.  [No title available] 
PMCID: PMC3947509  PMID: 24512067
5.  [No title available] 
PMCID: PMC3963440  PMID: 24512065
6.  [No title available] 
PMCID: PMC4049454  PMID: 24512061
7.  Transient inactivation of the thalamic nucleus reuniens and rhomboid nucleus produces deficits of a working-memory dependent tactile-visual conditional discrimination task 
Behavioral neuroscience  2013;127(6):860-866.
Working memory depends on communication between the hippocampus and the prefrontal cortex (PFC); however, the neural circuitry that mediates interactions between these brain areas has not been well characterized. Two candidate structures are the thalamic reuniens (RE) and rhomboid (Rh) nuclei, which are reciprocally connected with both the hippocampus and PFC. These known anatomical connections suggest that RE/Rh may be involved in mediating hippocampal-prefrontal communication, and therefore may be critical for working memory processing. To test the hypothesis that RE/Rh are necessary for working memory, we trained separate groups of rats to perform one of two tasks in a T-maze. The first task was a working memory-dependent conditional discrimination (CDWM) task, and the second task was a non-working memory-dependent conditional discrimination (CD) task. These tasks took place in the same maze, featured the same number of trials, and utilized the same cue (a tactile-visual maze insert). After rats had learned either task, RE/Rh were transiently inactivated with the GABAA receptor agonist muscimol, and performance was assessed. RE/Rh inactivation caused performance deficits on the CDWM task, but not the CD task. This result suggests that RE/Rh are a necessary component of working memory task performance, which is also thought to depend on the hippocampal-prefrontal circuit. RE/Rh inactivation did not cause a performance deficit on the CD task, suggesting that RE/Rh have dissociable contributions to working memory-dependent and non-working memory-dependent tasks, independently of the known contributions of these two thalamic nuclei to the sensorimotor and attention-related aspects of other memory tasks.
PMCID: PMC4009727  PMID: 24341710
Nucleus reuniens; rhomboid nucleus; working memory; conditional discrimination; hippocampal-prefrontal circuit
8.  17β-estradiol enhances memory duration in the main olfactory bulb in CD-1 mice 
Behavioral neuroscience  2013;127(6):923-931.
Rodents rely heavily on odor detection, discrimination, and memory to locate food, find mates, care for pups, and avoid predators. Estrogens have been shown to increase memory retention in rodents performing spatial memory and object placement tasks. Here we evaluate the extent to which 17β-estradiol modulates memory formation and duration in the olfactory system. Adult CD-1 mice were gonadectomized (GDx) and given either systemic 17β-estradiol replacement, local 17β-estradiol in the main olfactory bulb, or no replacement. Before performing the behavioral task the mice were given saline or PHTPP (an estrogen receptor β (ER-β) antagonist) via bilateral infusion into the main olfactory bulb. As the beta-type estrogen receptor (ER-β) is more abundant than the alpha-type estrogen receptor in the murine main olfactory bulb, the current study focuses on 17β-estradiol and its interactions with ERβ. Habituation, a simple non-associative learning task in which an animal is exposed to the same odor over successive presentations, was used to evaluate the animals' ability to detect odors and form an olfactory memory. To evaluate memory duration, we added a final trial of inter-trial interval time (30 or 60 minutes) in which we presented the habituated odor. Neither surgical nor drug manipulation affected the ability of mice to detect or habituate to an odor. After habituation, GDx 17β-estradiol treated mice retained memory of an odor for 30 minutes while non-estradiol treated, 17β-estradiol + ERβ antagonist (PHTPP), and untreated male mice did not remember an odor 30 minutes post habituation. The results show that both systemic and local bulbar infusions of 17β-estradiol enhance odor memory duration in mice.
PMCID: PMC4112518  PMID: 24341716
Olfactory bulb; estrogen; olfactory memory; habituation; neuromodulation
9.  Lesions of the perirhinal cortex do not impair integration of visual and geometric information in rats 
Behavioral neuroscience  2010;124(3):311-320.
Rats with lesions of the perirhinal cortex, and a control group, were required to find a platform in one corner of a white rectangle, and in the reflection of this corner in a black rectangle. Test trials revealed that these groups were able to integrate information regarding the shape of the pool and the color of its walls (black or white) in order to identify the correct location of the platform. A clear effect of the perirhinal cortex lesions was, however, revealed using an object recognition task that involved the spontaneous exploration of novel objects. The results challenge the view that the perirhinal cortex enables rats to solve discriminations involving feature ambiguity.
PMCID: PMC4233324  PMID: 20528074
Perirhinal cortex; spatial discrimination; object recognition memory; geometry
10.  Suppression to visual, auditory and gustatory stimuli habituates normally in rats with excitotoxic lesions of the perirhinal cortex 
Behavioral neuroscience  2009;123(6):1238-1250.
In 3 habituation experiments, rats with excitotoxic lesions of the perirhinal cortex were found to be indistinguishable from control rats. Two of the habituation experiments examined the habituation of suppression of responding on an appetitive, instrumental baseline. One of those experiments used stimuli selected from the visual modality (lights), the other used auditory stimuli. The third experiment examined habituation of suppression of novel-flavored water consumption. In contrast to the null results on the habituation experiments, the perirhinal lesions disrupted transfer performance on a configural, visual discrimination, indicating the behavioral effectiveness of the lesions. Implications for comparator theories of habituation are considered and we conclude that others’ demonstrations of the sensitivity of object recognition to perirhinal cortex damage is not the result of standard habituation.
PMCID: PMC4231296  PMID: 20001107
perirhinal cortex; familiarity; novelty; habituation; recognition memory
11.  Temporally dimorphic recruitment of dopamine neurons into stress response circuitry in Drosophila 
Behavioral neuroscience  2013;127(5):725-733.
Many studies have pointed to vulnerability to stress and stress-related pathologies at different timepoints during an individual’s lifespan. These sensitive windows are usually during periods of neural development, such as embryogenesis, infancy, and adolescence. It is critical to understand how neural circuitry may change as an individual ages in ways that could affect susceptibility to stress. Here we compare two stages in Drosophila melanogaster: sexual immaturity and sexual maturity. We used the genetic resources available in Drosophila to manipulate pre- and post-synaptic dopamine signaling in sexually immature and mature animals that were then assayed for heart rate and locomotor behavior in response to starvation and oxidative stress. Our results show significant differences in the stress response for sexually immature and mature animals for heart rate, periods of high mobility, mean velocity, and several other parameters of locomotor behavior. Our data show that dopamine neurons are differentially recruited into the stress response circuitry for sexually immature and mature individuals. By observing behaviors that have been previously shown in mammalian models to be affected by stress and altered in models of affective disorders, we provide a genetically tractable model for development and maintenance of the stress response circuitry during sexual maturation.
PMCID: PMC4212825  PMID: 23895060
age; behavior; starvation; paraquat; locomotion; heart rate; oxidative stress
12.  Sexually Dimorphic Recruitment of Dopamine Neurons into the Stress Response Circuitry 
Behavioral neuroscience  2013;127(5):734-743.
Several previous studies in mammalian systems have shown sexually dimorphic behaviors, neuroendocrine changes, and alterations in neurotransmitter release in response to stress. Additionally, men and women are differentially vulnerable to stress-related pathologies, which have led to the hypothesis that the stress response circuitry differs depending on sex. We used the genetic tractability of Drosophila to manipulate pre- or post-synaptic dopamine signaling in transgenic animals, which were assayed for several parameters of locomotion and heart rate following exposure to two environmental stressors, starvation and oxidative stress. Our results show significant differences in the stress response for males and females by analyzing heart rate, centering time, and high mobility in addition to other locomotor parameters with translational relevance. These data demonstrate that both pre- and post-synaptic neurons are differentially recruited into the dopaminergic stress response circuitry for males and females. Our results also show that the response circuits differ depending on the stressor and behavioral output. Furthermore, our studies provide a translatable Drosophila model for further elucidation of factors involved in the sexually dimorphic recruitment of neurons into the stress response circuitry.
PMCID: PMC4191714  PMID: 24128361
behavior; starvation; paraquat; locomotion; heart rate; oxidative stress
13.  Videos of conspecifics elicit interactive looking patterns and facial expressions in monkeys 
Behavioral neuroscience  2011;125(4):639-652.
A broader understanding of the neural basis of social behavior in primates requires the use of species-specific stimuli that elicit spontaneous, but reproducible and tractable behaviors. In this context of natural behaviors, individual variation can further inform about the factors that influence social interactions. To approximate natural social interactions similar to those documented by field studies, we used unedited video footage to induce in viewer monkeys spontaneous facial expressions and looking patterns in the laboratory setting. Three adult male monkeys, previously behaviorally and genetically (5-HTTLPR) characterized (Gibboni et al., 2009), were monitored while they watched 10 s video segments depicting unfamiliar monkeys (movie monkeys) displaying affiliative, neutral, and aggressive behaviors. The gaze and head orientation of the movie monkeys alternated between ‘averted’ and ‘directed’ at the viewer. The viewers were not reinforced for watching the movies, thus their looking patterns indicated their interest and social engagement with the stimuli. The behavior of the movie monkey accounted for differences in the looking patterns and facial expressions displayed by the viewers. We also found multiple significant differences in the behavior of the viewers that correlated with their interest in these stimuli. These socially relevant dynamic stimuli elicited spontaneous social behaviors, such as eye-contact induced reciprocation of facial expression, gaze aversion, and gaze following, that were previously not observed in response to static images. This approach opens a unique opportunity to understanding the mechanisms that trigger spontaneous social behaviors in humans and non-human primates.
PMCID: PMC4184141  PMID: 21688888
emotion; gaze following; eye contact; arousal; individual differences
14.  Differential Effects of the Cannabinoid Agonist WIN55,212-2 on Delay and Trace Eyeblink Conditioning 
Behavioral neuroscience  2013;127(5):694-702.
Central cannabinoid-1 receptors (CB1R) play a role in the acquisition of delay eyeblink conditioning but not trace eyeblink conditioning in humans and animals. However, it is not clear why trace conditioning is immune to the effects of cannabinoid receptor compounds. The current study examined the effects of variants of delay and trace conditioning procedures to elucidate the factors that determine the effects of CB1R agonists on eyeblink conditioning. In Experiment 1 rats were administered the cannabinoid agonist WIN55,212-2 during delay, long delay, or trace conditioning. Rats were impaired during delay and long delay but not trace conditioning; the impairment was greater for long delay than delay conditioning. Trace conditioning was further examined in Experiment 2 by manipulating the trace interval and keeping constant the conditioned stimulus (CS) duration. It was found that when the trace interval was 300 ms or less WIN55,212-2 administration impaired the rate of learning. Experiment 3 tested whether the trace interval duration or the relative durations of the CS and trace interval were critical parameters influencing the effects of WIN55,212-2 on eyeblink conditioning. Rats were not impaired with a 100 ms CS, 200 ms trace paradigm but were impaired with a 1000 ms CS, 500 ms trace paradigm, indicating that the duration of the trace interval does not matter but the proportion of the interstimulus interval occupied by the CS relative to the trace period is critical. Taken together the results indicate that cannabinoid agonists affect cerebellar learning the CS is longer than the trace interval.
PMCID: PMC3963426  PMID: 24128358
cannabinoid receptor; cannabis; cerebellum; cerebellar cortex; eyeblink conditioning; THC
15.  Inactivation of the ventral lateral geniculate and nucleus of the optic tract impairs retention of visual eyeblink conditioning 
Behavioral neuroscience  2013;127(5):690-693.
Reversible inactivation was used to examine the conditioned stimulus (CS) pathway for visual eyeblink conditioning (EBC). Previous research has shown that the ventral lateral geniculate (LGNv) and nucleus of the optic tract (NOT) could play a role in visual EBC through ipsilateral projections to the medial pontine nuclei. Rats were given visual EBC followed by inactivation of the ventral lateral geniculate (LGNv), nucleus of the optic tract (NOT), or both nuclei contralateral to the conditioned eye. Muscimol infusions into the NOT or LGNv impaired retention. Combined inactivation of LGNv/NOT produced the most severe impairment. Rats given inactivation of these visual nuclei after training with a vibration CS showed no impairment. The findings indicate that a parallel pathway of visual CS information projects from the LGNv and NOT to the medial pontine nuclei.
PMCID: PMC3967585  PMID: 23978151
ventral lateral geniculate; nucleus of the optic tract; eyeblink conditioning; visual CS; CS pathway
16.  Gonadal Hormones and Voluntary Exercise Interact to Improve Discrimination Ability in a Set-Shift Task 
Behavioral neuroscience  2013;127(5):744-754.
Exercise has been demonstrated to improve multiple facets of health, including cognitive function. Rodent studies have suggested that exercise has robust effects on the hippocampus, and on tasks that require the hippocampus. However, studies of the effects of exercise in humans often focus on the benefits to cognitive processes that engage areas outside of the hippocampus, such as executive function. Additionally, when exercise’s cognitive benefits are examined, consideration of both males and females, and gonadal hormones, is rarely made. Here we looked at the interaction of gonadal hormones and exercise in terms of the ability of male and female rats to learn to discriminate rewarded from unrewarded arms in a T-maze based on either brightness (white vs. black) or texture (rough vs. smooth), and then to set-shift (a measure of executive function), where this required discrimination based on the opposite dimension. Gonadectomized or intact males and females had access to running wheels for two weeks before being tested. Intact males and females given access to unlocked running wheels performed better at the initial discrimination (Set 1) compared to intact males and females with locked running wheels, but not at the set-shift (Set 2). No advantage of exercise was observed in gonadectomized rats.
PMCID: PMC3970407  PMID: 23978149
Set-shifting; voluntary exercis; wheel running; estrogen; testosterone
17.  Either Main or Accessory Olfactory System Signaling Can Mediate the Rewarding Effects of Estrous Female Chemosignals in Sexually Naïve Male Mice 
Behavioral neuroscience  2013;127(5):755-762.
A long-held view has been that interest of male mice in female body odors reflects an activation of reward circuits in the male brain following their detection by the vomeronasal organ (VNO) and processing via the accessory olfactory system. We found that adult, sexually naïve male mice acquired a conditioned place preference (CPP) after repeatedly receiving estrous female urine on the nose and being placed in an initially non-preferred chamber with soiled estrous bedding on the floor. CPP was not acquired in control mice that received saline on the nose before being placed in a non-preferred chamber with clean bedding. Robust acquisition of a CPP using estrous female odors as the reward persisted in separate groups of mice in which VNO-accessory olfactory function was disrupted by bilateral lesioning of the accessory olfactory bulb (AOB) or in which main olfactory function was disrupted by zinc sulfate lesions of the main olfactory epithelium (MOE). By contrast, no CPP was acquired for estrous odors in males that received combined AOB and MOE lesions. Either the main or the accessory olfactory system suffices to mediate the rewarding effects of estrous female odors in the male mouse, even in the absence of prior mating experience. The main olfactory system is part of the circuitry that responds to chemosignals involved in motivated behavior, a role that may be particularly important for humans which lack a functional accessory olfactory system.
PMCID: PMC3983571  PMID: 23978150
vomeronasal organ; conditioned place preference; reward circuits
18.  Fischer rats are more sensitive than Lewis rats to the suppressive effects of morphine and the aversive κ-opioid agonist spiradoline 
Behavioral neuroscience  2013;127(5):763-770.
Data suggest that rats avoid intake of an otherwise palatable saccharin cue when paired with a drug of abuse, at least in part, because the value of the taste cue pales in anticipation of the availability of the highly rewarding drug. Earlier support for this hypothesis was provided by the finding that relative to the less sensitive Fischer rats, Lewis rats exhibit greater avoidance of a saccharin cue when paired with a rewarding sucrose or cocaine unconditioned stimulus (US), but not when paired with the aversive agent, lithium chloride (LiCl). More recent data, however, have shown that Fischer rats actually exhibit greater, not less, avoidance of the same saccharin cue when morphine serves as the US. Therefore, Experiment 1 evaluated morphine-induced suppression of intake of the taste cue in Lewis and Fischer rats when the morphine US was administered subcutaneously, rather than ip. Experiment 2 examined the effect of strain on the suppression of intake of the saccharin cue when paired with spiradoline, a selective κ-opioid receptor agonist. The results confirm that Fischer rats are more responsive to the suppressive effects of morphine than Lewis rats and that Fischer rats also exhibit greater avoidance of the saccharin cue when paired with spiradoline, despite the fact that spiradoline is devoid of reinforcing properties. Taken together, the data suggest that the facilitated morphine-induced suppression observed in Fischer rats, compared with Lewis rats, may reflect an increased sensitivity to the aversive, κ-mediated properties of opiates.
PMCID: PMC3973147  PMID: 24128363
addiction; drug abuse; natural rewards; reward comparison; withdrawal
19.  Variable effects of parabrachial nucleus lesions on salt appetite in rats depending upon experimental paradigm and saline concentration 
Behavioral neuroscience  2013;127(2):275-284.
Previous studies have demonstrated that bilateral lesions of the gustatory (medial) zone of the parabrachial nucleus (PBN) in the pons eliminate the salt appetite induced in rats by treatment with the diuretic drug, furosemide. The present studies re-examined NaCl intake of rats with PBN lesions induced by ibotenic acid, using multiple models of salt appetite. The impairment of a conditioned taste aversion, an established consequence of PBN damage, was used as an initial screen with which to assess the effectiveness of the lesions. Rats with PBN lesions did not drink either 0.3 M NaCl or 0.5 M NaCl in response to daily treatment with desoxycorticosterone acetate. These findings suggest that the excitatory stimulus of salt appetite mediated by mineralocorticoids is abolished by PBN lesions. In contrast, rats with PBN lesions drank some 0.5 M NaCl, and more 0.3 M NaCl, in addition to water in response to hypovolemia induced by subcutaneous injection of 30% polyethylene glycol solution. Those findings suggest that an excitatory stimulus of salt appetite, presumably mediated by angiotensin II, is not abolished by PBN lesions. These and other observations indicate that lesions of the gustatory PBN in rats may or may not eliminate salt appetite, depending on which model is used and which concentration of NaCl solution is available.
PMCID: PMC4174430  PMID: 23398436
conditioned taste aversion; DOCA; hypovolemia; NaCl; thirst
20.  Lesions of the dorsal tegmental nuclei disrupt control of navigation by distal landmarks in cued, directional, and place variants of the Morris water task 
Behavioral neuroscience  2013;127(4):566-581.
Navigation depends on a network of neural systems that accurately monitor an animal’s directional heading and location in an environment. Within this navigation system are head direction (HD) cells, which discharge as a function of an animal’s directional heading, providing an animal with a neural compass to guide ongoing spatial behavior. Experiments were designed to test this hypothesis by damaging the dorsal tegmental nucleus (DTN), a mid-brain structure that plays a critical role in the generation of the rodent HD cell signal, and evaluating landmark based navigation using variants of the Morris water task. In Experiments 1 and 2, shams and DTN lesioned rats were trained to navigate toward a cued platform in the presence of a constellation of distal landmarks located outside the pool. After reaching a training criteria, rats were tested in three probe trials in which 1) the cued platform was completely removed from the pool, 2) the pool was repositioned and the cued platform remained in the same absolute location with respect to distal landmarks, or 3) the pool was repositioned and the cued platform remained in the same relative location in the pool. In general, DTN-lesioned rats required more training trials to reach performance criterion, were less accurate to navigate to the platform position when it was removed, and navigated directly to the cued platform regardless of its position in the pool, indicating a general absence of control over navigation by distal landmarks. In Experiment 3, DTN and control rats were trained in directional and place navigation variants of the water task where the pool was repositioned for each training trial and a hidden platform was placed either in the same relative location (direction) in the pool or in the same absolute location (place) in the distal room reference frame. DTN-lesioned rats were initially impaired in the direction task, but ultimately performed as well as controls. In the place task, DTN-lesioned rats were severely impaired and displayed little evidence of improvement over the course of training. Together, these results support the conclusion that the DTN is required for accurate landmark navigation.
PMCID: PMC3997071  PMID: 23731069
21.  Rapid effects of 17β-estradiol on male copulatory behaviors are not elicited by the novel membrane active estrogenic compound STX 
Behavioral neuroscience  2013;127(4):598-605.
Estrogens have been shown to rapidly promote male copulatory behaviors with a time-course that suggests rapid signaling events are involved. The present study tested the hypothesis that estrogen acts through a novel Gq protein-coupled membrane estrogen receptor (ER). Thus, either estradiol (E2), STX (a diphenylacrylamide compound that selectively activates a membrane ER pathway), or vehicle were administered acutely to castrated male rats that bore sc dihydrotestosterone implants to maintain genital sensitivity. Appetitive (level changes, genital investigation) and consummatory (mounts, intromissions, ejaculations) components of male sexual behavior were measured in a bilevel testing apparatus. Testing showed that E2 treatment promoted olfactory and mounting behaviors, but had no effect on motivation as measured by anticipatory level changes. STX treatment showed no effect on either component of male sexual behavior. These results support previous results that showed that E2 can rapidly affect male sexual behaviors, but fail to support a role for the specific membrane-initiated pathway activated by STX.
PMCID: PMC3953449  PMID: 23731070
estradiol; STX; copulatory behavior; mounting behavior; olfactory behavior; bilevel test; sexual motivation
22.  Noradrenergic alpha-2 receptor modulators in the ventral bed nucleus of the stria terminalis – effects on anxiety behavior in postpartum and virgin female rats 
Behavioral neuroscience  2013;127(4):582-597.
Emotional hyper-reactivity can inhibit maternal responsiveness in female rats and other animals. Maternal behavior in postpartum rats is disrupted by increasing norepinephrine release in the ventral bed nucleus of the stria terminalis (BSTv) with the α2-autoreceptor antagonist, yohimbine, or the more selective α2-autoreceptor antagonist, idazoxan (Smith et al., 2012). Because high noradrenergic activity in the BSTv can also increase anxiety-related behaviors, increased anxiety may underlie the disrupted mothering of dams given yohimbine or idazoxan. To assess this possibility, anxiety-related behaviors in an elevated plus maze were assessed in postpartum rats after administration of yohimbine or idazoxan. It was further assessed if the α2-autoreceptor agonist clonidine (which decreases norepinephrine release) would, conversely, reduce dams’ anxiety. Groups of diestrous virgins were also examined. It was found that peripheral or intra-BSTv yohimbine did increase anxiety-related behavior in postpartum females. However, BSTv infusion of idazoxan did not reproduce yohimbine’s anxiogenic effects and anxiety was not reduced by peripheral or intra-BSTv clonidine. Because yohimbine is a weak 5HT1A receptor agonist, other groups of females received BSTv infusion of the 5HT1A receptor agonist 8OH-DPAT, but it did not alter their anxiety-related behavior. Lastly, levels of norepinephrine and serotonin in tissue punches from the BSTv did not differ between postpartum and diestrous rats, but serotonin turnover was lower in mothers. These results suggest that the impaired maternal behavior after BSTv infusion of yohimbine or idazoxan cannot both be readily explained by an increase in dams’ anxiety, and that BSTv α2-autoreceptor modulation alone has little influence anxiety-related behaviors in postpartum or diestrous rats.
PMCID: PMC3947518  PMID: 23796237
anxiety; bed nucleus of the stria terminalis; lactation; maternal behavior; norepinephrine; serotonin
23.  Contrasting Networks for Recognition Memory and Recency Memory Revealed by Immediate-Early Gene Imaging in the Rat 
Behavioral Neuroscience  2014;128(4):504-522.
The expression of the immediate-early gene c-fos was used to compare networks of activity associated with recency memory (temporal order memory) and recognition memory. In Experiment 1, rats were first familiarized with sets of objects and then given pairs of different, familiar objects to explore. For the recency test group, each object in a pair was separated by 110 min in the time between their previous presentations. For the recency control test, each object in a pair was separated by less than a 1 min between their prior presentations. Temporal discrimination of the objects correlated with c-fos activity in the recency test group in several sites, including area Te2, the perirhinal cortex, lateral entorhinal cortex, as well as the dentate gyrus, hippocampal fields CA3 and CA1. For both the test and control conditions, network models were derived using structural equation modeling. The recency test model emphasized serial connections from the perirhinal cortex to lateral entorhinal cortex and then to the CA1 subfield. The recency control condition involved more parallel pathways, but again highlighted CA1 within the hippocampus. Both models contrasted with those derived from tests of object recognition (Experiment 2), because stimulus novelty was associated with pathways from the perirhinal cortex to lateral entorhinal cortex that then involved both the dentate gyrus (and CA3) and CA1 in parallel. The present findings implicate CA1 for the processing of familiar stimuli, including recency discriminations, while the dentate gyrus and CA3 pathways are recruited when the perirhinal cortex signals novel stimuli.
PMCID: PMC4105319  PMID: 24933661
recency memory; recognition memory; rat; immediate-early genes; network models
24.  NMDA Receptor Antagonism Impairs Reversal Learning in Developing Rats 
Behavioral neuroscience  2006;120(5):1071-1083.
Four experiments examined the effect of dizocilpine maleate (MK-801), a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, on reversal learning during development. On postnatal days (PND) 21, 26, or 30, rats were trained on spatial discrimination and reversal in a T-maze. When MK-801 was administered (intraperitoneally) before both acquisition and reversal, 0.18 mg/kg generally impaired performance, whereas doses of 0.06 mg/kg and 0.10 mg/kg, but not 0.03 mg/kg, selectively impaired reversal learning (Experiments 1 and 3). The selective effect on reversal was not a result of sensitization to the second dose of MK-801 (Experiment 2) and was observed when the drug was administered only during reversal in an experiment addressing state-dependent learning (Experiment 4). Spatial reversal learning is more sensitive to NMDA-receptor antagonism than is acquisition. No age differences in sensitivity to MK-801 were found between PND 21 and 30.
PMCID: PMC4089549  PMID: 17014258
spatial discrimination; reversal; MK-801; development
25.  Differences in Response Initiation and Behavioral Flexibility Between Adolescent and Adult Rats 
Behavioral neuroscience  2013;127(1):23-32.
Adolescence is a period of increased vulnerability to psychiatric illnesses such as addiction, mood disorders, and schizophrenia. Rats provide a useful animal model for investigating the differences in behavior and biology between adults and adolescents that stem from ongoing brain development. We developed the Cued Response Inhibition Task, or CRIT, to assess response inhibition and initiation processes by measuring the ability of rodents to withhold a response during an inhibitory cue and then to respond promptly after cue termination. We found no difference between adult and adolescent rats in the ability to appropriately inhibit a response during cue presentation. Adolescents, however, were unable to initiate a response as quickly as adults after cue termination. Further, we observed that this difference in responding was abolished after adolescent rats aged to adulthood with no additional training. In a separate experiment, adult and adolescent rats were trained in CRIT and then trained in another protocol in which the response inhibitory cue from CRIT was used as a Pavlovian cue predictive of reward. Adolescents demonstrated more reward-seeking behavior during the previously inhibitory Pavlovian cue than adults, indicative of greater behavioral flexibility. Taken together, these data suggest that, compared with adults, adolescent rats (a) are less able to initiate a response after response inhibition, (b) equally inhibit behavioral responses, and (c) are more adept at flexibly switching behavioral patterns. Furthermore, this study characterizes a task that is well suited for future pharmacological and electrophysiological investigations for assessing neuronal processing differences between adolescents and adults.
PMCID: PMC4075123  PMID: 23398439
adolescent; cognition; impulsivity; flexibility

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