Generalized fear is one purported mechanism of anxiety that is a target of clinical and basic research. Impaired fear discrimination has been primarily examined from the perspective of increased fear learning, rather than how learning about non-threatening stimuli affects fear discrimination. To address this question, we tested how three Safety Conditioning protocols with varied levels of salience allocated to the safety cue compared to classic Fear Conditioning in their impact on subsequent innate anxiety, and differential fear learning of new aversive and neutral cues. Using a high anxiety strain of mice (129SvEv, Taconic), we show that Fear Conditioned animals show little exploration of the anxiogenic center of an open field 24 h later, and poor discrimination during new differential conditioning 7 days later. Three groups of mice underwent Safety Conditioning, (i) the safety tone was unpaired with a shock, (ii) the safety tone was unpaired with the shock and co-terminated with a house light signaling the end of the safety period, and (iii) the safety tone was unpaired with the shock and its beginning co-occurred with a house light, signaling the start of a safety period. Mice from all Safety Conditioning groups showed higher levels of open field exploration than the Fear Conditioned mice 24 h after training. Furthermore, Safety Conditioned animals showed improved discrimination learning of a novel non-threat, with the Salient Beginning safety conditioned group performing best. These findings indicate that high anxiety animals benefit from salient safety training to improve exploration and discrimination of new non-threating stimuli.

Increased generalization between fear-inducing stimuli (e.g., looking over the edge of a tall building) and perceptually-similar neutral stimuli (e.g., an aerial photograph) is observed in all subtypes of anxiety disorders, leading to avoidance behaviors that feed forward from the feared stimulus to other, seemingly unrelated stimuli. However, recent research suggests a much more nuanced relationship between generalization, discrimination, and behavior. This study seeks to extend current understanding by using a mnemonic discrimination task to explore the relationship between risk for anxiety and differences in mnemonic discrimination abilities. Participants self-reported trait anxiety and behavioral inhibition (a temperamental construct linked to risk for anxiety), and also completed a memory task. After incidental encoding of color photographs of neutral everyday objects, participants performed a surprise recognition task, where they categorized each test image as "old" (identical to a previously viewed image), "similar" (new but perceptually-similar to a studied image, with half the images being highly similar and the other half being less similar to the studied images), or "new" (new and perceptually-dissimilar to studied images). We found that those with high behavioral inhibition are more successful at discriminating between previously seen "old" items from highly similar items. In contrast, those with high trait anxiousness are less successful at the same kind of discrimination. Interestingly, these relationships were not apparent in low similarity items. Our data suggest that behavioral inhibition and trait anxiety may be associated with unique aspects of individual differences in mnemonic discrimination abilities.

Emotional and social cognitive deficits were investigated in a group of 24 individuals with mild cognitive impairment (MCI) and 24 healthy controls. Empathic and visual emotional responses were collected, analyzed and correlated to brain structural imaging data by means of: (i) a pictorial matching-to-sample task with facial and non-facial stimuli; (ii) self-reported questionnaires for cognitive and affective emotional components, and alexithymia; (iii) in-depth assessment of cognitive functions. Results indicated that visual processing of faces in MCI individuals did not benefit from fearful emotional content which in healthy controls facilitates stimulus' recognition (emotional enhancement effect). This implicit visuo-emotional disorder was specific for the faces, did not generalize to other categories, and did not correlate to explicit measures of empathy. Thus, our main finding indicates that in MCI individuals, deficits in visual recognition of facial emotions may arise already in the earliest stages of memorization, during the visual encoding of facial emotions. Voxel-based morphometry revealed its association with atrophy in frontal and occipito-temporal regions, mostly involving the anterior medial prefrontal cortex (P<0.05, multiple-comparison correction). Neural evidences were corroborated by clinical scores showing significant correlation between reduction of Emotion Enhancement Effect and deficits in frontal/executive functions. Crucially, the disorder did not appear to be related to the number of impaired cognitive domains (single or multiple-domain MCI) but rather to the involvement of frontal brain networks and frontal/executive functions. This suggests that in prodromal stages of dementia, frontal symptoms may represent a significant signal of emotional recognition disorders.

The medial prefrontal cortex (mPFC) is responsible for executive functions such as abstract rule coding, strategy switching, and behavioral flexibility; however, there is some debate regarding the extent to which mPFC is involved in reversal learning, especially in complex multisensory tasks such as conditional discrimination. Therefore, we investigated the effects of mPFC inactivation on the acquisition, retention, and reversal of a visuospatial conditional discrimination (CD) task. In experiment 1, muscimol was infused through bilateral cannulae on days 1, 2, and 3 to test the effects of mPFC inactivation on task acquisition and days 19, 20, and 21 to test the effects on retention of the task. For experiment 2, rats were trained on the CD task for 21 days with no infusions given, after which the reward contingency was reversed, with infusions given during the first six days of reversal. The results of experiment 1 showed that the muscimol and saline groups did not differ on acquisition or retention. However, experiment 2 showed that the muscimol group displayed significantly more performance errors than the control group during reversal. Compared to the control group, the muscimol group also showed a decreased tendency to use a side-bias strategy during the intermediate stages of reversal. The failure of the muscimol group to exhibit a side bias suggests that the mPFC is necessary for sampling strategies necessary for the reversal of a visuospatial CD task.

Accurate discrimination between safe and dangerous stimuli is essential for survival. Prior research has begun to uncover the neural structures that are necessary for learning this discrimination, but exploration of brain regions involved in this learning process has been mostly limited to males. Recent findings show sex differences in discrimination learning, with reduced fear expression to safe cues in females compared to males. Here, we used male and female Sprague Dawley rats to explore neural activation, as measured by Fos expression, in fear and safety learning related brain regions. Neural activation after fear discrimination (Discrimination) was compared between males and females, as well as with fear conditioned (Fear Only) and stimulus presented (Control) conditions. Correlations of discrimination ability and neural activation were also calculated. We uncovered a correlation between central amygdala (CeA) activation and discrimination abilities in males and females. Anterior medial bed nucleus of the stria terminalis (BNST) was the only region where sex differences in Fos counts were observed in the Discrimination condition, and the only region where neural activation significantly differed between Fear Only and Discrimination conditions. Together, these findings indicate the importance of fear expression circuitry in mediating discrimination responses and generate important questions for future investigation.

Performance on timing tasks changes with age. Whether these changes reflect a real "clock" problem due to aging or a secondary effect of the reduced cognitive resources of older adults is still an unsettled question. Research on processing of time in aged populations marked by severe mnemonic and/or attentional deficits, such as patients with Alzheimer's disease (AD) and Mild Cognitive Impairment (MCI), may help elucidate the role of cognitive resources in age-related temporal distortions. To this end, we conducted a systematic review and meta-analysis of timing studies in AD and MCI patients; both prospective and retrospective timing tasks were considered and analysed separately. As concerns prospective timing, a first random-effect model showed a medium overall effect of neurodegeneration on timing performance. When considering the role of moderator variables(i.e., neurodegenerative condition, type of measure, participants' age and years of education, interval length, and type of timing task), mean score appeared to be a less sensitive measure than accuracy and variability, and the observed temporal impairment was smaller in older samples. In addition, AD patients only exhibited medium-to-high impairment on prospective timing tasks, whereas MCI patients did not significantly differ from controls. However, assuming a mean age of 70 years old and absolute error as dependent variable, a second fitted meta-regression model predicted a significant outcome also for MCI patients. Concerning retrospective timing, a significant but small effect of neurodegeneration was observed for retrospective judgments. None of the moderators, however, explained between-studies variability. Collectively, our findings highlight a clear deficit in prospective timing for AD patients and underscore several issues that future work should carefully consider to better investigate the effect of MCI on prospective temporal judgements. Results from retrospective timing also point to a possible impairment of retrospective judgments in neurodegenerative conditions, albeit more studies are needed to substantiate this finding.

It is well accepted that opioids promote feeding for reward. Some studies suggest a potential involvement in hunger-driven intake, but they suffer from the scarcity of methodologies differentiating between factors that intersect eating for pleasure versus energy. Here, we used a unique food deprivation discrimination paradigm to test a hypothesis that, since opioids appear to control feeding reward, injection of opioid agonists would not produce effects akin to 22 h of food deprivation. We trained rats to discriminate between 22 h and 2 h food deprivation in a two-lever, operant discrimination procedure. We tested whether opioid agonists at orexigenic doses produce discriminative stimulus effects similar to 22 h deprivation. We injected DAMGO, DSLET, or orphanin FQ in the paraventricular hypothalamic nucleus (PVN), a site regulating hunger/satiety, and butorphanol subcutaneously (to produce maximum consumption). We assessed the ability of the opioid antagonist, naltrexone, to reduce the discriminative stimulus effects of 22 h deprivation and of the 22 h deprivation-like discriminative stimulus effects of PVN-injected hunger mediator, neuropeptide Y (NPY). In contrast to PVN NPY, centrally or peripherally injected opioid agonists failed to induce discriminative stimuli similar to those of 22 h deprivation. In line with that, naltrexone did not reduce the hunger discriminative stimuli induced by either 22 h deprivation or NPY administration in 2 h food-restricted subjects, even though doses used therein were sufficient to decrease deprivation-induced feeding in a non-operant setting in animals familiar with consequences of 2 h and 22 h deprivation. We conclude that opioids promote feeding for reward rather than in order to replenish lacking energy.

Fear discrimination is critical for survival, while fear generalization is effective for avoiding dangerous situations. Overgeneralized fear is a typical symptom of anxiety disorders, including generalized anxiety disorder and posttraumatic stress disorder (PTSD). Previous research demonstrated that fear discrimination learning is mediated by prefrontal mechanisms. While the prelimbic (PL) and infralimbic (IL) subdivisions of the medial prefrontal cortex (mPFC) are recognized for their excitatory and inhibitory effects on the fear circuit, respectively, the mechanisms driving fear discrimination are unidentified. To obtain insight into the mechanisms underlying context-specific fear discrimination, we investigated prefrontal neuronal ensembles representing distinct experiences associated with learning to disambiguate between dangerous and similar, but not identical, harmless stimuli. Here, we show distinct quantitative activation differences in response to conditioned and generalized fear experiences, as well as modulation of the neuronal ensembles associated with successful acquisition of context-safety contingencies. These findings suggest that prefrontal neuronal ensembles patterns code functional context-danger and context-safety relationships. The PL subdivision of the mPFC monitors context-danger associations to conditioned fear, whereas differential conditioning sparks additional ensembles associated with the inhibition of generalized fear in both the PL and IL subdivisions of the mPFC. Our data suggest that fear discrimination learning is associated with the modulation of prefrontal subpopulations in a subregion- and experience-specific fashion, and the learning of appropriate responses to conditioned and initially generalized fear experiences is driven by gradual updating and rebalancing of the prefrontal memory representations.

Animals organize reward seeking around aversive events. An abundance of research shows that foot shock, as well as a shock-associated cue, can elicit freezing and suppress reward seeking. Yet, there is evidence that experience can flip the effect of foot shock to facilitate reward seeking. Here we examined cue suppression, foot shock suppression and foot shock facilitation of reward seeking in a single behavioural setting. Male Long Evans rats received fear discrimination consisting of danger, uncertainty, and safety cues. Discrimination took place over a baseline of rewarded nose poking. With limited experience (1-2 sessions), all cues and foot shock suppressed reward seeking. With continued experience (10-16 sessions), suppression became specific to shock-associated cues, foot shock briefly suppressed, then facilitated reward seeking. Our results provide a means of assessing positive properties of foot shock, and may provide insight into maladaptive behaviour around aversive events.

The rodent anterior thalamic nuclei (ATN) are vital for spatial memory. A consideration of their extensive frontal connections suggests that these nuclei may also subserve non-spatial functions. The current experiments explored the importance of the ATN for different aspects of behavioural flexibility, including their contribution to tasks typically associated with frontal cortex. In Experiment 1, rats with ATN lesions were tested on a series of response and visual discriminations in an operant box and, subsequently, in a water tank. The tasks included assessments of reversal learning as well switches between each discrimination dimension. Results revealed a mild and transient deficit on the operant task that was not specific to any stage of the procedure. In the water tank, the lesion animals were impaired on the reversal of a spatial discrimination but did not differ from controls on any other measure. Experiment 2 examined the impact of ATN damage on a rodent analogue of the 'Stroop', which assesses response choice during stimulus conflict. The lesion animals successfully acquired this task and were able to use contextual information to disambiguate conflicting cue information. However, responding during the initial presentation of conflicting cue information was affected by the lesion. Taken together, these results suggest that the ATN are not required for aspects of behavioural flexibility (discrimination learning, reversals or high-order switches) typically associated with the rat medial prefrontal cortex. The results from Experiment 2 suggest that the non-spatial functions of the ATN may be more aligned with those of the anterior cingulate cortex.

Previous research has shown that basal forebrain cholinergic inputs to the cerebral cortex are necessary for attentional processing. However, the key components of attention-demanding tasks for demonstrating deficits following loss of basal forebrain corticopetal cholinergic neurons are unclear. In the present experiment, rats were trained in a visual cued discrimination task with limited explicit attentional demands and then received intrabasalis infusions of the immunotoxin, 192 IgG-saporin, or saline. Postsurgically, attentional demands were increased by decreasing the signal duration or the intertrial interval or by increasing the variability of these parameters. Subsequently, rats were trained in a task that required discrimination of successively presented signals and "blank" trials with no signal presentation. Again, attentional demands were increased by manipulating signal duration or the intertrial interval. Finally, all rats were trained in a task with both the signal duration and the intertrial interval designed to increase attentional demands. Compared to sham-lesioned animals, lesioned animals exhibited deficits in signal detection only during the successive discrimination task with both the signal duration and intertrial interval shorter and variable. The present data suggest that attentional deficits following loss of cortical cholinergic inputs result from overall attentional task demands rather than being dependent on any single task parameter.

Impairments in reversal learning have been attributed to orbitofrontal cortex (OFC) dysfunction in many species. However, the role of subcortical areas interconnected with the OFC such as the striatum remains poorly understood. This study directly evaluated the contribution of core and shell sub-regions of the nucleus accumbens (NAc), dorsomedial (DMS) and dorsolateral (DLS) striatum to reversal learning of an instrumental two-lever spatial discrimination task in rats. Selective NAc core, DMS and DLS lesions were achieved with microinjections of quinolinic acid and NAc shell lesions with ibotenic acid. Damage to NAc core or shell did not affect retention of a previously acquired instrumental spatial discrimination. In contrast, DLS and DMS lesions produced changes in aspects of discrimination performance such as the latency to collect earned food pellets. Neither NAc core or shell lesions nor DLS lesions affected the main indices of reversal performance. Conversely, DMS lesion rats showed a significant impairment in reversal learning. DMS damage increased the number of errors to reach criteria that were perseverative in nature. The deficit in reversal learning in DMS lesion rats was not associated with an impairment to extinguish instrumental responding. There were no effects on spontaneous locomotor activity. Our data are in agreement with recent work showing that lesions of the medial striatum in marmoset monkeys produce perseverative impairments during a serial visual discrimination reversal task and support the hypothesis that dorsomedial striatal dysfunction contributes to pathological perseveration, which is a common feature of many psychiatric disorders.

Species recognition is an essential behavioral outcome of social discrimination, flocking, mobbing, mating, and/or parental care. In songbirds, auditory species recognition cues are processed through specialized forebrain circuits dedicated to acoustic discrimination. Here we addressed the direction of behavioral and neural metrics of zebra finches' (Taeniopygia guttata) responses to acoustic cues of unfamiliar conspecifics vs. heterospecifics. Behaviorally, vocal response rates were greater for conspecific male zebra finch songs over heterospecific Pin-tailed Whydah (Vidua macroura) songs, which paralleled greater multiunit spike rates in the auditory forebrain in response to the same type of conspecific over heterospecific auditory stimuli. In contrast, forebrain activation levels were reversed to species-specific song playbacks during two functional magnetic resonance imaging experiments: we detected consistently greater responses to whydah songs over finch songs and did so independently of whether subjects had been co-housed or not with heterospecifics. These results imply that the directionality of behavioral and neural response selectivity metrics are not always consistent and appear to be experience-independent in this set of stimulus-and-subject experimental paradigms.

Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner.

Drugs used to treat cancer have neurotoxic effects that often produce memory loss and related cognitive deficits. In a test of the hypothesis that chemotherapy-induced cognitive impairment is related to a loss of inhibitory control, rats injected with a combination of methotrexate+5-fluouracil or equal volumes of saline, were administered a retroactive interference task in which memory for a learned discrimination problem was tested under conditions of high- and low-interference. The drugs had no effect on original learning or on re-learning the discrimination response when there was little interference, but the chemotherapy group was severely impaired in the hippocampus-sensitive, high-interference memory test. The impaired performance correlated significantly with reduced neurogenesis in the hippocampus. The failure to suppress interfering influences is consistent with a breakdown in pattern separation, a process that distinguishes and separates overlapping neural representations of experiences that have a high degree of similarity.

Attentional set-shifting deficits are a feature of multiple psychiatric disorders. However, the neurogenetic mechanisms underlying these deficits are largely unknown. In the present study we assessed performance of C57BL/6J and DBA/2J mice on a touchscreen-based attentional set-shifting task similar to those used with humans and non-human primates. In experiment 1, mice discriminated simple white lines followed by compound stimuli composed of white lines superimposed on grey shapes. Although performance of the two strains was largely equivalent during early stages of the task, DBA/2J mice committed significantly more errors compared to C57BL/6J mice on the extra-dimensional shift. Additionally, performance of mice as a group declined across the three compound discrimination reversals. In experiment 2 we assessed salience of the shapes and lines dimensions and determined if dimensional salience, a variable previously shown to affect set-shifting abilities in humans and non-human primates, could be systematically manipulated. Findings from experiment 2 suggested that strain differences during the extra-dimensional shift in experiment 1 were most parsimoniously explained by a consistently impaired ability in DBA/2J mice to discriminate a subset of the compound stimuli. Additionally, unlike maze-based tasks, the relative salience of the two dimensions could be manipulated by systematically altering the width of lines exemplars while retaining other potentially-relevant attributes of the compound stimuli. These findings reveal unique and in some cases strain-dependent phenomena related to discriminations of simple and multidimensional visual stimuli which may facilitate future efforts to identify and fully characterize visual discrimination, reversal learning, and attentional set-shifting deficits in mice.

We hypothesized that bilateral quisqualic acid lesions of the nucleus basalis magnocellularis (NBM) in rats would impair configural but not simple association learning. In experiment 1, rats were tested in a negative patterning operant discrimination where they were food-reinforced for responding to a light or a tone (L+, T+) but not for responding to the configural stimulus consisting of the light and tone presented simultaneously (LT-). Consistent with our hypothesis, NBM-lesioned rats showed a transient but significant impairment, responding normally to L+ and T+ but responding more often to LT-, in addition to responding more often during the inter-trial interval (ITI) than controls. In experiment 2, rats were tested in a simple operant discrimination where rats were food-reinforced for responding to a light (L+) but not for responding to a tone (T-). Although NBM-lesioned rats again responded normally to L+ as predicted, NBM-lesioned rats were transiently impaired, making more T- responses and more ITI responses than controls. Together, these results suggest that the NBM is involved in both configural and simple association learning but that this involvement is limited to learning to withhold responding to non-reinforced contextual or discrete stimuli. Finally, rats from experiment 2 underwent extinction trials, where results showed no difference between NBM-lesioned and control groups, suggesting that the NBM is not involved in the extinction of conditioned responding to previously reinforced stimuli.

Chlorpyrifos (CPF) is an extensively used organophosphate pesticide. Exposure to CPF has been related to neurobehavioral disorders, particularly during neurodevelopment. Apolipoprotein E (apoE) is a lipid and cholesterol carrier and a susceptibility factor for cognitive impairment which can influence the response to toxic exposures. The study was aimed at assessing the effects of postnatal exposure to CPF on object recognition memory and its modulation by sex and APOE genotype. Human apoE3 and apoE4 targeted replacement mice and C57BL/6 mice were postnatally exposed to 0 or 1 mg/kg/day of CPF. Recognition memory was evaluated in an Object Recognition Test (ORT). In order to study the contribution of cholinergic and GABAergic neurotransmitter systems to recognition memory, a pharmacological challenge was included. Sex, genotype and postnatal exposure to CPF were key factors throughout the testing period. Specifically, CPF increased exploratory behavior and impaired discrimination performance. We observed that administering scopolamine, a cholinergic antagonist, was detrimental to recognition memory. However, discrimination in C57BL/6 and apoE4 males improved with the administration of the cholinergic agonist rivastigmine, but the same drug worsened retention in apoE4 females. Finally, the GABAergic agonist alprazolam altered performance in a sex- and genotype-dependent manner. Overall, these results suggest complex interactions between sex, APOE genotype and postnatal CPF exposure and indicate a different functioning of both the cholinergic and GABAergic neurotransmitter system between groups.

The two-note fee bee song of the black-capped chickadee (Poecile atricapillus) is sung at many different absolute frequencies, but the relative frequencies between the start and end of the fee note (the glissando) and between the fee and the bee notes (the inter-note ratio) are preserved regardless of absolute frequency. If these relative frequencies are experimentally manipulated, birds exhibit reduced behavioural responses to playback of altered songs both in field studies and laboratory studies. Interestingly, males appear to be sensitive to alterations in the glissando, while females appear to be sensitive to alterations in both the glissando and the inter-note ratio. In this study, we sought to determine whether the behaviour of male and female chickadees corresponds to differences in zenk protein immunoreactivity (ZENK-ir) in auditory perceptual regions following playback of fee bee songs with typical and altered pitch ratios. Overall, there was a small but significant sex difference in ZENK-ir (females>males), but altering relative frequencies did not reduce ZENK-ir compared to typical song. Birds did vocalize less in response to playback of songs that lacked an inter-note interval, but amount of singing fee bee song, chick-a-dee calls, or gargles was not correlated with ZENK-ir in perceptual regions (caudomedial nidopallium, NCM and caudomedial mesopallium, CMM) or in HVC, which is part of the song system. Our results confirm that ZENK-ir in NCM and CMM is not involved in fine-grain perceptual discrimination, however it did not support the idea that increased vocalizing increases ZENK-ir in HVC.

Though commonly used as a treatment for ADHD, the psychostimulant methylphenidate (MPH) is also misused and abused in adolescence in both clinical and general populations. Although MPH acts via pathways activated by other drugs of abuse, the short- and long-term effects of MPH on reward processing in learning and decision-making are not clearly understood. We examined the effect of adolescent MPH treatment on a battery of reward-directed behaviors both in adolescence during its administration and in adulthood after its discontinuation. We further measured whether MPH had lasting effects on dopamine receptor mRNA expression in orbitofrontal cortex (OFC) that may correspond with behavior. Long-Evans rats were injected with MPH (0, 1, 2.5, or 5mg/kg IP) twice daily from middle to late adolescence (PD38-57). During adolescence, the high dose of MPH reduced preference for large rewards in a Reward Magnitude Discrimination task, but did not affect preference for smaller-sooner rewards in a Delay Discounting task. In adulthood, after discontinuation of MPH, animals previously treated with the moderate dose of MPH showed improved acquisition, but not reversal, in a Reversal Learning task. MPH exposure did not increase preference for large-risky rewards in a Risk task in adulthood. We then quantified mRNA expression of D1, D2, and D3 receptors in the OFC using qPCR. MPH increased mRNA expression of dopamine D3 receptor subtype, but not D1 or D2. Overall, these results indicate that MPH has both immediate and lasting effects on reward-dependent learning and decisions, as well as dopaminergic function in rodents.