Rewards that are near increase impulsive action.

In modern society, the natural drive to behave impulsively in order to obtain rewards must often be curbed. A continued failure to do so is associated with a range of outcomes including drug abuse, pathological gambling, and obesity. Here, we used virtual reality technology to investigate whether spatial proximity to rewards has the power to exacerbate the drive to behave impulsively toward them. We embedded two behavioral tasks measuring distinct forms of impulsive behavior, impulsive action, and impulsive choice, within an environment rendered in virtual reality. Participants responded to three-dimensional cues representing food rewards located in either near or far space. Bayesian analyses revealed that participants were significantly less able to stop motor actions when rewarding cues were near compared with when they were far. Since factors normally associated with proximity were controlled for, these results suggest that proximity plays a distinctive role in driving impulsive actions for rewards.

Nicotine modulates contextual fear extinction through changes in ventral hippocampal GABAergic function.

Numerous studies have attributed the psychopathology of anxiety and stress disorders to maladaptive behavioral responses such as an inability to extinguish fear. Therefore, understanding neural substrates of fear extinction is imperative for developing more effective therapies for anxiety and stress disorders. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs in the fear extinction process. In the present study, we first examined the involvement of several brain regions essential for fear extinction (i.e., dorsal and ventral hippocampus, dHPC and vHPC; infralimbic, IL, and prelimbic, PL of the medial prefrontal cortex, mPFC; basolateral nucleus of the amygdala, BLA) in the impairing effects of a nAChR agonist, nicotine, on contextual fear extinction in mice. Our results showed that systemic administration of nicotine during contextual fear extinction increased c-fos expression in the vHPC and BLA while not affecting dHPC, IL or PL. In line with these results, local nicotine infusions into the vHPC, but not dHPC, resulted in impaired contextual fear extinction. Interestingly, we found that local nicotine infusions into the PL also resulted in impairment of contextual fear extinction. Second, we measured the protein levels of the GABA synthesizing enzymes GAD65 and GAD67 in the dHPC and vHPC during contextual fear extinction. Our results showed that in the group that received acute nicotine, both GAD65 and GAD67 protein levels were downregulated in the vHPC, but not in dHPC. This effect was negatively correlated with the level of freezing response during fear extinction suggesting that the downregulated GAD65/67 levels were associated with disrupted fear extinction. Finally, using c-fos/GAD65/67 double immunofluorescence, we showed that nicotine mainly increased c-fos expression in non-GABAergic ventral hippocampal cells, indicating that acute nicotine increases vHPC excitability. Overall, our results suggest that acute nicotine's impairing effects on fear extinction are associated with ventral hippocampal disinhibition. Therefore, these results further our understanding of the interaction between nicotine addiction and anxiety and stress disorders by describing novel neural mechanisms mediating fear extinction.

Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction.

Anxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown. Therefore, based on the previous studies showing that brain-derived neurotrophic factor is central for fear extinction learning and acute nicotine dysregulates brain-derived neurotrophic factor signaling, we hypothesized that the nicotine-induced impairment of contextual fear extinction may involve changes in tyrosine receptor kinase B signaling. To test this hypothesis, we systemically, intraperitoneally, injected C57BL/6J mice sub-threshold doses (2.5 and 4.0 mg/kg) of 7,8-dihydroxyflavone, a small-molecule tyrosine receptor kinase B agonist that fully mimics the effects of brain-derived neurotrophic factor, or vehicle an hour before each contextual fear extinction session. Mice also received injections, intraperitoneally, of acute nicotine (0.18 mg/kg) or saline 2-4 min before extinction sessions. While the animals that received only 7,8-dihydroxyflavone did not show any changes in contextual fear extinction, 4.0 mg/kg of 7,8-dihydroxyflavone ameliorated the extinction deficits in mice administered acute nicotine. Overall, these results suggest that acute nicotine-induced impairment of context extinction may be related to a disrupted brain-derived neurotrophic factor signaling.

Chronic fluoxetine ameliorates adolescent chronic nicotine exposure-induced long-term adult deficits in trace conditioning.

Development of the brain, including the prefrontal cortex and hippocampus, continues through adolescence. Chronic nicotine exposure during adolescence may contribute to long-term deficits in forebrain-dependent learning. It is unclear if these deficits emerge immediately after exposure and if they can be ameliorated. In this study, C57BL/6J mice were treated with chronic nicotine (6.3 or 12.6 mg/kg/day) over 12 days beginning at adolescence, postnatal day (PND) 38, or adulthood, PND 56-63 ± 3. We investigated the effects of short-term (24 h) abstinence on trace fear conditioning and found that adult treatment resulted in deficits (6.3 and 12.6 mg/kg/day), but adolescent chronic nicotine treatment had no effect. In contrast, adolescent treatment with chronic nicotine (12.6 mg/kg/day) elicited a long-term (30 days) learning deficit, but adult chronic nicotine treatment did not. Using the elevated plus maze (EPM) we found no long-term changes in anxiety-related behavior after chronic nicotine exposure at either time-point. We investigated if chronic fluoxetine (FLX) could ameliorate adolescent chronic nicotine-associated long-term deficits in trace conditioning. We found that chronic FLX (160 mg/L) in drinking water ameliorated the long-term deficit in trace fear conditioning associated with nicotine exposure during adolescence. Additionally, in the same animals, we examined changes in total BDNF protein in the dorsal hippocampus (DH), ventral hippocampus (VH), and prefrontal cortex (PFC). Chronic FLX increased DH BDNF. Our data indicate nicotine administration during adolescence leads to late onset, long-lasting deficits in hippocampus-dependent learning that chronic FLX treatment ameliorate.

Nicotine disrupts safety learning by enhancing fear associated with a safety cue via the dorsal hippocampus.

Learned safety, a learning process in which a cue becomes associated with the absence of threat, is disrupted in individuals with post-traumatic stress disorder (PTSD). A bi-directional relationship exists between smoking and PTSD and one potential explanation is that nicotine-associated changes in cognition facilitate PTSD emotional dysregulation by disrupting safety associations. Therefore, we investigated whether nicotine would disrupt learned safety by enhancing fear associated with a safety cue. In the present study, C57BL/6 mice were administered acute or chronic nicotine and trained over three days in a differential backward trace conditioning paradigm consisting of five trials of a forward conditioned stimulus (CS)+ (Light) co-terminating with a footshock unconditioned stimulus followed by a backward CS- (Tone) presented 20 s after cessation of the unconditioned stimulus. Summation testing found that acute nicotine disrupted learned safety, but chronic nicotine had no effect. Another group of animals administered acute nicotine showed fear when presented with the backward CS (Light) alone, indicating the formation of a maladaptive fear association with the backward CS. Finally, we investigated the brain regions involved by administering nicotine directly into the dorsal hippocampus, ventral hippocampus, and prelimbic cortex. Infusion of nicotine into the dorsal hippocampus disrupted safety learning.

Integration of individual and social information for decision-making in groups of different sizes.

When making judgments in a group, individuals often revise their initial beliefs about the best judgment to make given what others believe. Despite the ubiquity of this phenomenon, we know little about how the brain updates beliefs when integrating personal judgments (individual information) with those of others (social information). Here, we investigated the neurocomputational mechanisms of how we adapt our judgments to those made by groups of different sizes, in the context of jury decisions for a criminal. By testing different theoretical models, we showed that a social Bayesian inference model captured changes in judgments better than 2 other models. Our results showed that participants updated their beliefs by appropriately weighting individual and social sources of information according to their respective credibility. When investigating 2 fundamental computations of Bayesian inference, belief updates and credibility estimates of social information, we found that the dorsal anterior cingulate cortex (dACC) computed the level of belief updates, while the bilateral frontopolar cortex (FPC) was more engaged in individuals who assigned a greater credibility to the judgments of a larger group. Moreover, increased functional connectivity between these 2 brain regions reflected a greater influence of group size on the relative credibility of social information. These results provide a mechanistic understanding of the computational roles of the FPC-dACC network in steering judgment adaptation to a group's opinion. Taken together, these findings provide a computational account of how the human brain integrates individual and social information for decision-making in groups.

Attention Diversion Improves Response Inhibition of Immediate Reward, But Only When it Is Beneficial: An fMRI Study.

Deficits of self-control are associated with a number of mental state disorders. The ability to direct attention away from an alluring stimulus appears to aid inhibition of an impulsive response. However, further functional imaging research is required to assess the impact of shifts in attention on self-regulating processes. We varied the level of attentional disengagement in an functional magnetic resonance imaging (fMRI)-based Go/No-go task to probe whether diversion of attention away from alluring stimuli facilitates response inhibition. We used the attention-grabbing characteristic of faces to exogenously direct attention away from stimuli and investigated the relative importance of attention and response inhibition mechanisms under different delayed reward scenarios [i.e., where forgoing an immediate reward ($1) led to a higher ($10) or no payoff in the future]. We found that diverting attention improved response inhibition performance, but only when resistance to an alluring stimulus led to delayed reward. Region of interest analyses indicated significant increased activity in posterior right inferior frontal gyrus during successful No-go trials for delayed reward trials compared to no delayed reward trials, and significant reduction in activity in the superior temporal gyri and left caudate in contexts of high attentional diversion. Our findings imply that strategies that increase the perceived benefits of response inhibition might assist individuals in abstaining from problematic impulsive behaviors.

The role of working memory and declarative memory in trace conditioning.

Translational assays of cognition that are similarly implemented in both lower and higher-order species, such as rodents and primates, provide a means to reconcile preclinical modeling of psychiatric neuropathology and clinical research. To this end, Pavlovian conditioning has provided a useful tool for investigating cognitive processes in both lab animal models and humans. This review focuses on trace conditioning, a form of Pavlovian conditioning typified by the insertion of a temporal gap (i.e., trace interval) between presentations of a conditioned stimulus (CS) and an unconditioned stimulus (US). This review aims to discuss pre-clinical and clinical work investigating the mnemonic processes recruited for trace conditioning. Much work suggests that trace conditioning involves unique neurocognitive mechanisms to facilitate formation of trace memories in contrast to standard Pavlovian conditioning. For example, the hippocampus and prefrontal cortex (PFC) appear to play critical roles in trace conditioning. Moreover, cognitive mechanistic accounts in human studies suggest that working memory and declarative memory processes are engaged to facilitate formation of trace memories. The aim of this review is to integrate cognitive and neurobiological accounts of trace conditioning from preclinical and clinical studies to examine involvement of working and declarative memory.

Thyroid receptor ß involvement in the effects of acute nicotine on hippocampus-dependent memory.

Cigarette smoking is common despite adverse health effects. Nicotine's effects on learning may contribute to addiction by enhancing drug-context associations. Effects of nicotine on learning could be direct or could occur by altering systems that modulate cognition. Because thyroid signaling can alter cognition and nicotine/smoking may change thyroid function, nicotine could affect learning through changes in thyroid signaling. These studies investigate the functional contributions of thyroid receptor (TR) subtypes ß and α1 to nicotine-enhanced learning and characterize the effects of acute nicotine and learning on thyroid hormone levels. We conducted a high throughput screen of transcription factor activity to identify novel targets that may contribute to the effects of nicotine on learning. Based on these results, which showed that combined nicotine and learning uniquely acted to increase TR activation, we identified TRs as potential targets of nicotine. Further analyses were conducted to determine the individual and combined effects of nicotine and learning on thyroid hormone levels, but no changes were seen. Next, to determine the role of TRß and TRα1 in the effects of nicotine on learning, mice lacking the TRß or TRα1 gene and wildtype littermates were administered acute nicotine prior to fear conditioning. Nicotine enhanced contextual fear conditioning in TRα1 knockout mice and wildtypes from both lines but TRß knockout mice did not show nicotine-enhanced learning. This finding supports involvement of TRß signaling in the effect of acute nicotine on hippocampus-dependent memory. Acute nicotine enhances learning and these effects may involve processes regulated by the transcription factor TRß.

ABT-089, but not ABT-107, ameliorates nicotine withdrawal-induced cognitive deficits in C57BL6/J mice.

Nicotine withdrawal produces cognitive deficits that can predict relapse. Amelioration of these cognitive deficits emerges as a target in current smoking cessation therapies. In rodents, withdrawal from chronic nicotine disrupts contextual fear conditioning (CFC), whereas acute nicotine enhances this hippocampus-specific learning and memory. These modifications are mediated by ß2-subunit-containing (ß2*) nicotinic acetylcholine receptors in the hippocampus. We aimed to test ABT-089, a partial agonist of α4ß2*, and ABT-107, an α7 nicotinic acetylcholine receptor agonist, for amelioration of cognitive deficits induced by withdrawal from chronic nicotine in mice. Mice underwent chronic nicotine administration (12.6 mg/kg/day or saline for 12 days), followed by 24 h of withdrawal. At the end of withdrawal, mice received 0.3 or 0.6 mg/kg ABT-089 or 0.3 mg/kg ABT-107 (doses were determined through initial dose-response experiments and prior studies) and were trained and tested for CFC. Nicotine withdrawal produced deficits in CFC that were reversed by acute ABT-089, but not ABT-107. Cued conditioning was not affected. Taken together, our results suggest that modulation of hippocampal learning and memory using ABT-089 may be an effective component of novel therapeutic strategies for nicotine addiction.

Motivationally significant self-control: enhanced action withholding involves the right inferior frontal junction.

In everyday life, people use self-control to withhold actions. This ability is particularly important when the consequences of action withholding have an impact on the individual's well-being. Despite its importance, it is unclear as to how the neural nodes implicated in action withholding contribute to this real-world type of self-control. By modifying an action withholding paradigm, the go/no-go task, we examined how the brain exerts self-control during a scenario in which the implications of withholding an action are meaningful and motivationally significant. A successfully withheld response contributed to long-term monetary rewards, whereas failure to withhold a response incurred an immediate monetary punishment. Compared with neutral action withholding, participants significantly improved their performance when these contingencies were applied. Crucially, although the right IFG and pre-SMA were found to promote overall action withholding, the enhancement in behavioral performance relative to a neutral condition was only reflected by a physiological change in a region encompassing the right inferior frontal junction and precentral gyrus. We speculate that the ability to flexibly modulate attention to goal-relevant stimuli is crucial to enhanced, motivationally driven action withholding and that this ability is subserved by the right inferior frontal junction. These findings suggest that control-modulating factors, rather than action withholding processes per se, can be critical to improving motivationally significant action withholding outcomes.

The influence of commercial energy shots on response time and power output in recreational cyclists.

BACKGROUND: Caffeine based energy shot products accounted for $1.3 billion in sales in 2011. Caffeine has been shown to confer numerous benefits during exercise and is oftentimes combined with ingredients such as carbohydrates and taurine in the hope of further performance improvement. The purpose of this project was to compare auditory response time, power output, and physiological responses between the ingestion of a CHO, PRO, caffeine supplement (CPC), a caffeine-taurine-niacin based supplement (CTN), and a placebo (PL) in commercially formulated products that make claims as to improving performance. METHODS: Fourteen subjects cycled an interval exercise of 70% VO2max for 13 minutes and 90% of VO2max for two minutes for a total of 120 minutes which was then followed by a six-minute power output (PO) task. Subjects ingested a total of 45 g CHO, 7.5 g PRO, and 375 mg caffeine for CPC while 512 mg caffeine and 1200 mg taurine were ingested for CTN throughout the exercise. The treatments were administered in a double blind, randomly assigned protocol. Response time was assessed by auditory response. Significance was set at p < 0.05. RESULTS: Average PO was significantly greater for CPC: 309 ± 60 W than CTN: 290 ± 57 W and PL: 282 ± 63 W. Response time was significantly faster for the CPC: 0.219 ± .049 s than CTN: 0.232 ± .060 s and PL: 0.228 ± .047 s. HR was significantly greater for CTN: 143 ± 16 bpm than CPC: 139 ± 16 bpm. RPE was significantly lower for CPC: 13.0 ± 1.7 than CTN: 13.5 ± 1.2 and PL: 13.8 ± 1.9. Blood glucose was greater for CPC: 5.5 ± 0.8 mM/L than CTN: 4.9 ± 0.7 mM/L and PL: 4.6 ± 1.1 mM/L. No significant differences were observed for RER. CONCLUSIONS: The co-ingestion of CPC improved both cycling power output and auditory response time following 2 hours of moderate and high intensity interval cycling compared to CTN and PL. It is possible that the CPC treatment conferred not only a positive peripheral effect, but also a central effect. Even with a large caffeine dose, the combination of caffeine, taurine, niacin led to an inhibitory pattern which did not improve power output or response time performances over a PL.

Donepezil reverses nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6J mice.

Withdrawal from chronic nicotine is associated with cognitive deficits. Therapies that ameliorate cognitive deficits during withdrawal aid in preventing relapse during quit attempts. Withdrawal-induced deficits in contextual learning are associated with nicotinic acetylcholine receptor upregulation. The aim of the present study was to determine if the acetylcholinesterase inhibitor donepezil has the ability to reverse nicotine withdrawal-induced deficits in contextual learning. Results demonstrated that low doses of donepezil, which do not enhance contextual learning or alter locomotor activity/anxiety-related behavior, can reverse nicotine withdrawal-induced deficits in contextual learning. Thus, donepezil may have therapeutic value for ameliorating cognitive deficits associated with nicotine withdrawal and for preventing relapse.

Behavioral sensitivity to reward is reduced for far objects.

Many studies have demonstrated that people will adjust their behavioral response to a reward on the basis of the time taken to receive the reward. Yet despite growing evidence that time and space are not mentally independent, there has been no examination of whether spatial distance may also affect the way people respond to rewarding objects. We examined speeded binary decisions about objects associated with high, low, or no reward for correct responses. Using a 3-D display, we varied perceived spatial distance so that objects appeared at distances near to or far from participants. Both the speed and the accuracy of responses were better for high-reward objects compared with low- and no-reward objects, but this difference occurred only when the objects appeared at near distance to participants. These results demonstrate that when people respond to rewarding objects, they show sensitivity to spatial-distance information even if the information is irrelevant to the task.

An investigation of gender differences in semantic processing in individuals with high schizotypy.

Semantic processing deficits may underlie thought disorder in schizophrenia. Cognitive Disorganisation (CD) in schizotypy is a thought disorder analogue. This study established CD was related to abnormal strategic semantic processing on an indirect semantic priming task. There were no gender differences. It also confirms the importance of replicating underpowered studies.

Effects of reward and punishment on brain activations associated with inhibitory control in cigarette smokers.

BACKGROUND AND AIMS: Susceptibility to use of addictive substances may result, in part, from a greater preference for an immediate small reward relative to a larger delayed reward or relative insensitivity to punishment. This functional magnetic resonance imaging (fMRI) study examined the neural basis of inhibiting an immediately rewarding stimulus to obtain a larger delayed reward in smokers. We also investigated whether punishment could modulate inhibitory control. DESIGN: The Monetary Incentive Go/NoGo (MI-Go/NoGo) task was administered that provided three types of reward outcomes contingent upon inhibitory control performance over rewarding stimuli: inhibition failure was either followed by no monetary reward (neutral condition), a small monetary reward with immediate feedback (reward condition) or immediate monetary punishment (punishment condition). In the reward and punishment conditions, successful inhibitory control resulted in larger delayed rewards. SETTING: Community sample of smokers in the Melbourne (Australia) area. PARTICIPANTS: Nineteen smokers were compared with 17 demographically matched non-smoking controls. MEASUREMENTS: Accuracy, reaction times and brain activation associated with the MI-Go/NoGo task. FINDINGS: Smokers showed hyperactivation in the right insula (P < 0.01), inferior and middle frontal gyrus (P < 0.01), dorsolateral prefrontal cortex (P = 0.001) and inferior parietal lobe (P < 0.01) both during inhibition of an immediately rewarding stimulus to obtain a larger delayed reward, and during inhibition of neutral stimuli. Group differences in brain activity were not significant in the punishment condition in the right insula and dorsolateral prefrontal cortex, most probably as a result of increased activation in non-smoking controls. CONCLUSIONS: Compared with non-smokers, smokers showed increased neural activation when resisting immediately rewarding stimuli and may be less sensitive to punishment as a strategy to increase control over rewarding stimuli.

Successful inhibitory control over an immediate reward is associated with attentional disengagement in visual processing areas.

We examined the neural basis of the capacity to resist an immediately rewarding stimulus in order to obtain a larger delayed reward. This was investigated with a Go/No-go task employing No-go targets that provided two types of reward outcomes. These were contingent on inhibitory control performance: failure to inhibit Reward No-go targets provided a small monetary reward with immediate feedback; while successful inhibitory control resulted in larger rewards with delayed feedback based on the highest number of consecutive inhibitions. We observed faster Go trial responses with maintained levels of inhibition accuracy during the Reward No-go condition compared to a neutral No-go condition. Comparisons between conditions of BOLD activity showed successful inhibitory control over rewarding No-Go targets was associated with hypoactivity in regions previously associated with regulating emotion and inhibitory control, including insula and right inferior frontal gyrus. In addition, regions previously associated with visual processing centers that are modulated as a function of visual attention, namely the left fusiform and right superior temporal gyri, were hypoactive. These findings suggest a role for attentional disengagement as an aid to withholding response over a rewarding stimulus and are consistent with the notion that gratification can be delayed by directing attention away from immediate rewards.