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Krishna R.,Rutgers University | Moustafa A.A.,Rutgers University | Moustafa A.A.,University of Western Sydney | Eby L.A.,Bridgewater College | And 3 more authors.
Cognitive and Behavioral Neurology | Year: 2012

Damage to the hippocampal and frontostriatal systems can occur across the adult life span. As these 2 systems are involved in learning processes, mild impairments of learning and generalization might be observed even in healthy aging. In this study, we examined both learning and generalization performance in 3 groups of older adults: young-older (ages 45 to 60 y), middle-older (ages 61 to 75 y), and oldest-older (ages 76 to 90 y). We used a simple computerized concurrent discrimination task in which the learning phase has shown sensitivity to frontostriatal dysfunction, and the generalization phase to hippocampal damage. We found that age significantly affected initial learning performance, but generalization was spared in all but the oldest group, with some individuals still generalizing very well. This finding suggests that (a) learning abilities are affected in healthy aging (consistent with earlier reports of frontostriatal dysfunction in healthy aging) and (b) generalization deficit does not necessarily occur in early older age. We hypothesize that generalization deficits in some in the oldest group may be related to hippocampal pathology. Our data shed light on possible neural system dysfunction in healthy aging and Alzheimer disease. Copyright © 2012 by Lippincott Williams & Wilkins.

PubMed | The College of New Jersey, Neurobehavioral Research Laboratory and Rutgers University
Type: | Journal: PeerJ | Year: 2016

Decisions based on trust are critical for human social interaction. We judge the trustworthiness of partners in social interactions based on a number of partner characteristics as well as experiences with those partners. These decisions are also influenced by personality. The current study examined how the personality trait of behavioral inhibition, which involves the tendency to avoid or withdraw from novelty in both social and non-social situations, is related to explicit ratings of trustworthiness as well as decisions made in the trust game. In the game, healthy young adults interacted with three fictional partners who were portrayed as trustworthy, untrustworthy or neutral through biographical information. Participants could choose to keep $1 or send $3 of virtual money to a partner. The partner could then choose to send $1.5 back to the participant or to keep the entire amount. On any trial in which the participant chose to send, the partner always reciprocated with 50% probability, irrespective of how that partner was portrayed in the biography. Behavioral inhibition was assessed through a self-report questionnaire. Finally, a reinforcement learning computational model was fit to the behavior of each participant. Self-reported ratings of trust confirmed that all participants, irrespective of behavioral inhibition, perceived differences in the moral character of the three partners (trustworthiness of good > neutral > bad partner). Decisions made in the game showed that inhibited participants tended to trust the neutral partner less than uninhibited participants. In contrast, this was not reflected in the ratings of the neutral partner (either pre- or post-game), indicating a dissociation between ratings of trustworthiness and decisions made by inhibited participants. Computational modeling showed that this was due to lower initial trust of the neutral partner rather than a higher learning rate associated with loss, suggesting an implicit bias against the neutral partner. Overall, the results suggest inhibited individuals may be predisposed to interpret neutral or ambiguous information more negatively which could, at least in part, account for the tendency to avoid unfamiliar people characteristic of behaviorally inhibited temperament, as well as its relationship to anxiety disorders.

Moustafa A.A.,University of Western Sydney | Hewedi D.H.,Ain Shams University | Eissa A.M.,Ain Shams University | Myers C.E.,Rutgers University | And 2 more authors.
PLoS ONE | Year: 2012

Previous studies have shown that high total homocysteine levels are associated with Alzheimer's disease (AD) and mild cognitive impairment (MCI). In this study, we test the relationship between cognitive function and total homocysteine levels in healthy subjects (Global Dementia Rating, CDR = 0) and individuals with MCI (CDR = 0.5). We have used a cognitive task that tests learning and generalization of rules, processes that have been previously shown to rely on the integrity of the striatal and hippocampal regions, respectively. We found that total homocysteine levels are higher in MCI individuals than in healthy controls. Unlike what we expected, we found no difference between MCI subjects and healthy controls in learning and generalization. We conducted further analysis after diving MCI subjects in two groups, depending on their Global Deterioration Scale (GDS) scores: individuals with very mild cognitive decline (vMCD, GDS = 2) and mild cognitive decline (MCD, GDS = 3). There was no difference among the two MCI and healthy control groups in learning performance. However, we found that individuals with MCD make more generalization errors than healthy controls and individuals with vMCD. We found no difference in the number of generalization errors between healthy controls and MCI individuals with vMCD. In addition, interestingly, we found that total homocysteine levels correlate positively with generalization errors, but not with learning errors. Our results are in agreement with prior results showing a link between hippocampal function, generalization performance, and total homocysteine levels. Importantly, our study is perhaps among the first to test the relationship between learning (and generalization) of rules and homocysteine levels in healthy controls and individuals with MCI. © 2012 Moustafa et al.

PubMed | Sacred Heart University at Connecticut, U.S. National Institute on Drug Abuse, CUNY - Hunter College and Neurobehavioral Research Laboratory
Type: | Journal: Pharmacology, biochemistry, and behavior | Year: 2016

Chronic stress causes deleterious changes in physiological function in systems ranging from neural cells in culture to laboratory rodents, sub-human primates and humans. It is notable, however, that the vast majority of research in this area has been conducted in males. In this review, we provide information about chronic stress effects on cognition in female rodents and contrast it with responses in male rodents. In general, females show cognitive resilience to chronic stressors which impair male cognitive function using spatial tasks including the radial arm maze, radial arm water maze, Morris water maze, Y-maze and object placement. Moreover, stress often enhances female performance in some of these cognitive tasks. Memory in females is not affected by stress in non-spatial memory tasks like recognition memory and temporal order recognition memory while males show impaired memory following stress. We discuss possible bases for these sex-dependent differences including the use of different strategies by the sexes to solve cognitive tasks. Whether the sex differences result from changes in non-mnemonic factors is also considered. Sex-dependent differences in alcohol and drug influences on stress responses are also described. Finally, the role of neurally derived estradiol in driving sex differences and providing resilience to stress in females is shown. The importance of determining the nature and extent of sex differences in stress responses is that such differences may provide vital information for understanding why some stress related diseases have different incidence rates between the sexes and for developing novel therapeutic treatments.

Somlai Z.,Semmelweis University | Moustafa A.A.,Rutgers University | Keri S.,National Psychiatry Center | Keri S.,University of Szeged | And 3 more authors.
Schizophrenia Research | Year: 2011

Previous studies investigating feedback-driven reinforcement learning in patients with schizophrenia have provided mixed results. In this study, we explored the clinical predictors of reward and punishment learning using a probabilistic classification learning task. Patients with schizophrenia (n = 40) performed similarly to healthy controls (n = 30) on the classification learning task. However, more severe negative and general symptoms were associated with lower reward-learning performance, whereas poorer general psychosocial functioning was correlated with both lower reward- and punishment-learning performances. Multiple linear regression analyses indicated that general psychosocial functioning was the only significant predictor of reinforcement learning performance when education, antipsychotic dose, and positive, negative and general symptoms were included in the analysis. These results suggest a close relationship between reinforcement learning and general psychosocial functioning in schizophrenia. © 2010.

Myers C.E.,NeuroBehavioral Research Laboratory | Myers C.E.,Rutgers University | Bermudez-Hernandez K.,New York University | Bermudez-Hernandez K.,The Nathan Kline Institute for Psychiatric Research | And 2 more authors.
PLoS ONE | Year: 2013

Postnatal neurogenesis of granule cells (GCs) in the dentate gyrus (DG) produces GCs that normally migrate from the subgranular zone to the GC layer. However, GCs can mismigrate into the hilus, the opposite direction. Previous descriptions of these hilar ectopic GCs (hEGCs) suggest that they are rare unless there are severe seizures. However, it is not clear if severe seizures are required, and it also is unclear if severe seizures are responsible for the abnormalities of hEGCs, which include atypical dendrites and electrophysiological properties. Here we show that large numbers of hEGCs develop in a transgenic mouse without severe seizures. The mice have a deletion of BAX, which normally regulates apoptosis. Surprisingly, we show that hEGCs in the BAX-/- mouse have similar abnormalities as hEGCs that arise after severe seizures. We next asked if there are selective effects of hEGCs, i.e., whether a robust population of hEGCs would have any effect on the DG if they were induced without severe seizures. Indeed, this appears to be true, because it has been reported that BAX-/- mice have defects in a behavior that tests pattern separation, which depends on the DG. However, inferring functional effects of hEGCs is difficult in mice with a constitutive BAX deletion because there is decreased apoptosis in and outside the DG. Therefore, a computational model of the normal DG and hippocampal subfield CA3 was used. Adding a small population of hEGCs (5% of all GCs), with characteristics defined empirically, was sufficient to disrupt a simulation of pattern separation and completion. Modeling results also showed that effects of hEGCs were due primarily to "backprojections" of CA3 pyramidal cell axons to the hilus. The results suggest that hEGCs can develop for diverse reasons, do not depend on severe seizures, and a small population of hEGCs may impair DG-dependent function. © 2013 Myers et al.

PubMed | University of Florida, University of Texas Health Science Center at Houston, Rutgers University, Neurobehavioral Research Laboratory and Texas A&M University
Type: Journal Article | Journal: Hippocampus | Year: 2016

Elevated -amyloid and impaired synaptic function in hippocampus are among the earliest manifestations of Alzheimers disease (AD). Most cognitive assessments employed in both humans and animal models, however, are insensitive to this early disease pathology. One critical aspect of hippocampal function is its role in episodic memory, which involves the binding of temporally coincident sensory information (e.g., sights, smells, and sounds) to create a representation of a specific learning epoch. Flexible associations can be formed among these distinct sensory stimuli that enable the transfer of new learning across a wide variety of contexts. The current studies employed a mouse analog of an associative transfer learning task that has previously been used to identify risk for prodromal AD in humans. The rodent version of the task assesses the transfer of learning about stimulus features relevant to a food reward across a series of compound discrimination problems. The relevant feature that predicts the food reward is unchanged across problems, but an irrelevant feature (i.e., the context) is altered. Experiment 1 demonstrated that C57BL6/J mice with bilateral ibotenic acid lesions of hippocampus were able to discriminate between two stimuli on par with control mice; however, lesioned mice were unable to transfer or apply this learning to new problem configurations. Experiment 2 used the APPswe PS1 mouse model of amyloidosis to show that robust impairments in transfer learning are evident in mice with subtle -amyloid-induced synaptic deficits in the hippocampus. Finally, Experiment 3 confirmed that the same transfer learning impairments observed in APPswePS1 mice were also evident in the Tg-SwDI mouse, a second model of amyloidosis. Together, these data show that the ability to generalize learned associations to new contexts is disrupted even in the presence of subtle hippocampal dysfunction and suggest that, across species, this aspect of hippocampal-dependent learning may be useful for early identification of AD-like pathology.

PubMed | Neurobehavioral Research Laboratory and Rutgers University
Type: | Journal: PeerJ | Year: 2015

Avoidance behavior involves learning responses that prevent upcoming aversive events; these responses typically extinguish when the aversive events stop materializing. Stimuli that signal safety from aversive events can paradoxically inhibit extinction of avoidance behavior. In animals, males and females process safety signals differently. These differences help explain why women are more likely to be diagnosed with an anxiety disorder and exhibit differences in symptom presentation and course compared to men. In the current study, we extend an existing model of strain differences in avoidance behavior to simulate sex differences in rats. The model successfully replicates data showing that the omission of a signal associated with a period of safety can facilitate extinction in females, but not males, and makes novel predictions that this effect should depend on the duration of the period, the duration of the signal itself, and its occurrence within that period. Non-reinforced responses during the safe period were also found to be important in the expression of these patterns. The model also allowed us to explore underlying mechanisms for the observed sex effects, such as whether safety signals serve as occasion setters for aversive events, to determine why removing them can facilitate extinction of avoidance. The simulation results argue against this account, and instead suggest the signal may serve as a conditioned reinforcer of avoidance behavior.

PubMed | Veterans Bio Medical Research Institute VBRI East Orange, Syracuse Medical Center and Neurobehavioral Research Laboratory
Type: | Journal: Frontiers in behavioral neuroscience | Year: 2015

Altered medial prefrontal cortex (mPFC) and amygdala function is associated with anxiety-related disorders. While the mPFC-amygdala pathway has a clear role in fear conditioning, these structures are also involved in active avoidance. Given that avoidance perseveration represents a core symptom of anxiety disorders, the neural substrate of avoidance, especially its extinction, requires better understanding. The present study was designed to investigate the activity, particularly, inhibitory neuronal activity in mPFC and amygdala during acquisition and extinction of lever-press avoidance in rats. Neural activity was examined in the mPFC, intercalated cell clusters (ITCs) lateral (LA), basal (BA) and central (CeA) amygdala, at various time points during acquisition and extinction, using induction of the immediate early gene product, c-Fos. Neural activity was greater in the mPFC, LA, BA, and ITC during the extinction phase as compared to the acquisition phase. In contrast, the CeA was the only region that was more activated during acquisition than during extinction. Our results indicate inhibitory neurons are more activated during late phase of acquisition and extinction in the mPFC and LA, suggesting the dynamic involvement of inhibitory circuits in the development and extinction of avoidance response. Together, these data start to identify the key brain regions important in active avoidance behavior, areas that could be associated with avoidance perseveration in anxiety disorders.

Beck K.D.,Neurobehavioral Research Laboratory | Beck K.D.,Stress and Motivated Behavioral Institute | Jiao X.,Stress and Motivated Behavioral Institute | Pang K.C.H.,Neurobehavioral Research Laboratory | And 3 more authors.
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2010

The risk for developing anxiety disorders is greater in females and those individuals exhibiting a behaviorally inhibited temperament. Growth of behavioral avoidance in people is a significant predictor of symptom severity in anxiety disorders, including post-traumatic stress disorder. Using an animal model, our lab is examining how the process of learning avoidant behavior may lead certain individuals to develop anxiety. Here we examined whether the known vulnerabilities of female sex and behaviorally inhibited temperament have individual or additive effects upon the acquisition of an active-avoidance response. A discrete trial lever-press escape-avoidance protocol was used to examine the acquisition of behavioral avoidance in male and female Sprague-Dawley (SD) rats and behaviorally inhibited inbred Wistar-Kyoto (WKY) rats. Overall, WKY rats of both sexes were indistinguishable in their behavior during the acquisition of an active-avoidance response, exhibiting quicker acquisition of reinforced responses both between and within session compared to SD rats. Further WKY rats emitted more non-reinforced responses than SD rats. Sex differences were evident in SD rats in both the acquisition of the reinforced response and the emission of non-reinforced responses, with SD females acquiring the response quicker and emitting more non-reinforced responses following lever presses that led to an escape from shock. As vulnerability factors, behavioral inhibition and female sex were each associated with more prevalent reinforced and non-reinforced avoidant behavior, but an additive effect of these 2 factors was not observed. These data illustrate the importance of genetics (both strain and sex) in the assessment and modeling of anxiety vulnerability through the acquisition of active-avoidance responses and the persistence of emitting those responses in periods of non-reinforcement. © 2010.

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