Dopamine replacement improves motor learning of an upper extremity task in people with Parkinson disease.

BACKGROUND: Dopamine replacement medication has positive effects on existing motor skills for people with Parkinson disease (PD), but may have detrimental effects on the learning of motor skills necessary for effective rehabilitation according to the dopamine overdose hypothesis. OBJECTIVES: This study aimed to determine whether dopamine replacement medication (i.e. levodopa) affects: learning of a novel upper extremity task, decrements in skill following withdrawal of practice, the rate of learning, and the transfer of movement skill to untrained upper extremity tasks compared to training "off" medication, in people with PD. METHODS: Participants with mild-moderate PD (Hoehn and Yahr stage 2) were randomized to train "on" (n = 12) or "off" (n = 11) levodopa medication. Participants practiced 10 blocks of five trials of a functional motor task with their non-dominant upper extremity over three consecutive days (acquisition period), followed by a single block of five trials two and nine days later. Participants were also assessed "on" levodopa with two transfer tasks (the nine-hole peg test and a functional dexterity task) prior to any practice and nine days after the end of the acquisition period. RESULTS: Participants who practiced "on" levodopa medication learned the upper extremity task to a greater extent that those who practiced "off" medication, as determined by retained performance two days after practice. Skill decrement and skill transfer were not significantly different between groups. Rate of learning was unable to be modelled in this sample. CONCLUSIONS: Levodopa medication improved the learning of an upper extremity task in people with mild-moderate PD.

Blocking tactile input to one finger using anaesthetic enhances touch perception and learning in other fingers.

Brain plasticity is a key mechanism for learning and recovery. A striking example of plasticity in the adult brain occurs following input loss, for example, following amputation, whereby the deprived zone is "invaded" by new representations. Although it has long been assumed that such reorganization leads to functional benefits for the invading representation, the behavioral evidence is controversial. Here, we investigate whether a temporary period of somatosensory input loss to one finger, induced by anesthetic block, is sufficient to cause improvements in touch perception ("direct" effects of deafferentation). Further, we determine whether this deprivation can improve touch perception by enhancing sensory learning processes, for example, by training ("interactive" effects). Importantly, we explore whether direct and interactive effects of deprivation are dissociable by directly comparing their effects on touch perception. Using psychophysical thresholds, we found brief deprivation alone caused improvements in tactile perception of a finger adjacent to the blocked finger but not to non-neighboring fingers. Two additional groups underwent minimal tactile training to one finger either during anesthetic block of the neighboring finger or a sham block with saline. Deprivation significantly enhanced the effects of tactile perceptual training, causing greater learning transfer compared with sham block. That is, following deafferentation and training, learning gains were seen in fingers normally outside the boundaries of topographic transfer of tactile perceptual learning. Our results demonstrate that sensory deprivation can improve perceptual abilities, both directly and interactively, when combined with sensory learning. This dissociation provides novel opportunities for future clinical interventions to improve sensation. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

L-DOPA reduces model-free control of behavior by attenuating the transfer of value to action.

Dopamine is a key neurotransmitter in action control. However, influential theories of dopamine function make conflicting predictions about the effect of boosting dopamine neurotransmission. Here, we tested if increases in dopamine tone by administration of L-DOPA upregulate reward learning as predicted by reinforcement learning theories, and if increases are specific for deliberative "model-based" control or reflexive "model-free" control. Alternatively, L-DOPA may impair learning as suggested by "value" or "thrift" theories of dopamine. To this end, we employed a two-stage Markov decision-task to investigate the effect of L-DOPA (randomized cross-over) on behavioral control while brain activation was measured using fMRI. L-DOPA led to attenuated model-free control of behavior as indicated by the reduced impact of reward on choice. Increased model-based control was only observed in participants with high working memory capacity. Furthermore, L-DOPA facilitated exploratory behavior, particularly after a stream of wins in the task. Correspondingly, in the brain, L-DOPA decreased the effect of reward at the outcome stage and when the next decision had to be made. Critically, reward-learning rates and prediction error signals were unaffected by L-DOPA, indicating that differences in behavior and brain response to reward were not driven by differences in learning. Taken together, our results suggest that L-DOPA reduces model-free control of behavior by attenuating the transfer of value to action. These findings provide support for the value and thrift accounts of dopamine and call for a refined integration of valuation and action signals in reinforcement learning models.

Outcome-specific Pavlovian-to-instrumental transfer (PIT) with alcohol cues and its extinction.

The acquired motivational impact of conditioned stimuli has been studied using the Pavlovian-to-instrumental transfer (PIT) task, where a cue paired with a reward is consistently shown to energize responses separately trained with that same reward ("specific" PIT). However, most alcohol studies have shown that alcohol-related cues elevate responses trained with either the same alcohol reward or with other non-alcoholic rewards ("general" PIT). The effects of extinction on this alcohol PIT effect have not been fully explored. We tested the hypothesis that cues signaling different-tasting alcohols might acquire specific craving reactions for those alcohols leading to specific PIT, but that these effects might be sensitive to extinction. Three experiments examined the specificity of PIT using alcohol and non-alcohol outcomes. Rats first consumed different-flavored alcohol solutions in their home cages. Then they were trained to perform two responses, each reinforced with distinctly flavored solutions, using a Polycose fading procedure. The outcomes were sweet (4% sucrose) or salty (0.9% NaCl) ethanol (10% v/v) solutions (Experiments 1 and 2) or one plain or salty alcohol vs. a non-alcoholic sweet solution (Experiment 3). Then, two cues were each differentially paired with these outcomes. In PIT tests, animals performed both responses in the presence and absence of these cues without any rewards. Experiments 1, 2, and 3 showed that a cue paired with a flavored alcohol produced a small but consistent bias toward the response trained with the same alcohol solution (specific PIT). Experiment 2 showed that extinction eliminated this effect. Experiment 3 demonstrated that specific PIT occurred when contrasting salty, or plain, alcohol to a non-alcoholic solution. These results provide evidence that alcohol-related stimuli can elicit craving for specific types of alcohol (as revealed by specific PIT), but that this effect is sensitive to extinction. This paradigm of contrasting two distinctly flavored alcohols may be an especially useful animal model of alcohol addiction.

Repeated cocaine exposure dysregulates cognitive control over cue-evoked reward-seeking behavior during Pavlovian-to-instrumental transfer.

Drug-paired cues acquire powerful motivational properties, but only lead to active drug-seeking behavior if they are potent enough to overwhelm the cognitive control processes that serve to suppress such urges. Studies using the Pavlovian-to-instrumental transfer (PIT) task have shown that rats pretreated with cocaine or amphetamine exhibit heightened levels of cue-motivated food-seeking behavior, suggesting that exposure to these drugs sensitizes the incentive motivational system. However, the PIT testing protocol can also create conflict between two competing behavioral responses to the reward-paired cue: active reward seeking (e.g., lever pressing) and passive conditioned food-cup approach behavior. We therefore investigated whether repeated cocaine exposure alters the way in which rats use cue-based reward expectations to resolve such conflict. In-depth analysis of previously published and new research confirmed that when drug-naïve rats are given a cue that signals the timing of a delayed noncontingent reward, they adaptively transition from reward seeking to conditioned approach behavior, facilitating efficient collection of the predicted reward. In contrast, cocaine-exposed rats exhibit pronounced behavioral dysregulation, increasing, rather than suppressing, their reward-seeking behavior over time, disrupting their ability to passively collect reward. Such findings speak to the important and sometimes overlooked role that cognitive control plays in determining the motivational impact of cues associated with drug and nondrug rewards.

Enhanced incentive motivation in obesity-prone rats is mediated by NAc core CP-AMPARs.

Studies in humans suggest that stronger incentive motivational responses to Pavlovian food cues may drive over-consumption leading to and maintaining obesity, particularly in susceptible individuals. However, whether this enhanced incentive motivation emerges as a consequence of obesity or rather precedes obesity is unknown. Moreover, while human imaging studies have provided important information about differences in striatal responsiveness between susceptible and non-susceptible individuals, the neural mechanisms mediating these behavioral differences are unknown. The Nucleus Accumbens (NAc) mediates cue-triggered reward seeking and activity in the NAc is enhanced in obesity-susceptible populations. Therefore here, we used selectively-bred obesity-prone and obesity-resistant rats to examine intrinsic differences in incentive motivation, and the role of NAc AMPARs in the expression of these behaviors prior to obesity. We found that obesity-prone rats exhibit robust cue-triggered food-seeking (Pavlovian-to-instrumental transfer, PIT). Using intra-NAc infusion of AMPAR antagonists, we show that this behavior is selectively mediated by CP-AMPARs in the NAc core. Additionally, biochemical data suggest that this is due in part to experience-induced increases in CP-AMPAR surface expression in the NAc of obesity-prone rats. In contrast, in obesity-resistant rats PIT was weak and unreliable and training did not increase NAc AMPAR surface expression. Collectively, these data show that food cues acquire greater incentive motivational control in obesity-susceptible populations prior to the development of obesity. This provides support to the idea that enhanced intrinsic incentive motivation may be a contributing factor, rather than a consequence of obesity. In addition, these data demonstrate a novel role for experience-induced up-regulation of NAc CP-AMPARs in PIT, pointing to potential mechanistic parallels between the processes leading to addiction and to obesity.

Noradrenergic Regulation of Central Amygdala in Aversive Pavlovian-to-Instrumental Transfer.

The neural mechanisms through which a Pavlovian conditioned stimulus (CS) elicits innate defense responses are well understood. But a Pavlovian CS can also invigorate ongoing instrumental responding, as shown by studies of aversive Pavlovian-to-instrumental transfer (PIT). While the neural circuitry of appetitive PIT has been studied extensively, little is known about the brain mechanisms of aversive PIT. We recently showed the central amygdala (CeA) is essential for aversive PIT. In the current studies, using pharmacology and designer receptors in rodents, we demonstrate that noradrenergic (NE) activity negatively regulates PIT via brainstem locus coeruleus (LC) activity and LC projections to CeA. Our results provide evidence for a novel pathway through which response modulation occurs between brainstem neuromodulatory systems and CeA to invigorate adaptive behavior in the face of threat.

Sequential learning during contextual fear conditioning guides the rate of systems consolidation: Implications for consolidation of multiple memory traces.

Systems consolidation has been described as a time-dependent reorganization process involving the neocortical and hippocampal networks underlying memory storage and retrieval. Previous studies of our lab were able to demonstrate that systems consolidation is a dynamic process, rather than a merely passive, time-dependent phenomenon. Here, we studied the influence of sequential learning in contextual fear conditioning (CFC) with different training intensities in the time-course of hippocampal dependency and contextual specificity. We found that sequential learning with high-intensity shocks during CFC induces generalization of the first learning (context A) and maintains contextual specificity of the second learning (context B) 15 days after acquisition. Moreover, subsequent experiences reorganize brain structures involved in retrieval, accelerating the involvement of cortical structures and diminishing the hippocampal participation. Exposure to original context before novelty seems to only induce context specificity in hippocampal-dependent memories. We propose that systems consolidation could be considered a potential biological mechanism for reducing possible interferences between similar memory traces. © 2017 Wiley Periodicals, Inc.

Ghrelin receptor activation in the ventral tegmental area amplified instrumental responding but not the excitatory influence of Pavlovian stimuli on instrumental responding.

Pavlovian stimuli predictive of food are able to amplify instrumental responding for food. This phenomenon termed Pavlovian-instrumental transfer (PIT) critically depends on intact VTA function and mesoaccumbens dopamine transmission. Considerable evidence suggests that food-predictive stimuli can enhance the release of ghrelin, an orexigen hormone that promotes food-directed responding. The ventral tegmental area (VTA) appears to be a key region through which stimulation of ghrelin receptors (GHS-R1A) invigorates food-directed responding, in part by activating the mesoaccumbens dopamine system. Thus, it is conceivable that stimulation of GHS-R1A in the VTA can amplify PIT, i.e. stimulus-elicited increase in lever pressing for food. Here we examined in rats the effects of VTA ghrelin microinfusion on PIT. Our results demonstrate that ghrelin microinfusion into the VTA failed to enhance PIT suggesting that VTA GHS-R1A stimulation was unable to enhance the motivational significance of food-predictive stimuli. Consistent with previous studies, our results further indicate that intra-VTA ghrelin microinfusion invigorated instrumental responding under a progressive ratio schedule. These data provide support to the notion that VTA GHS-R1A stimulation increases the tendency to work for food.

Adolescent exposure to methylphenidate impairs serial pattern learning in the serial multiple choice (SMC) task in adult rats.

The long-term effects of adolescent exposure to methylphenidate (MPD) on adult cognitive capacity are largely unknown. We utilized a serial multiple choice (SMC) task, which is a sequential learning paradigm for studying complex learning, to observe the effects of methylphenidate exposure during adolescence on later serial pattern acquisition during adulthood. Following 20.0mg/kg/day MPD or saline exposure for 5 days/week for 5 weeks during adolescence, male rats were trained to produce a highly structured serial response pattern in an octagonal operant chamber for water reinforcement as adults. During a transfer phase, a violation to the previously-learned pattern structure was introduced as the last element of the sequential pattern. Results indicated that while rats in both groups were able to learn the training and transfer patterns, adolescent exposure to MPD impaired learning for some aspects of pattern learning in the training phase which are learned using discrimination learning or serial position learning. In contrast adolescent exposure to MPD had no effect on other aspects of pattern learning which have been shown to tap into rule learning mechanisms. Additionally, adolescent MPD exposure impaired learning for the violation element in the transfer phase. This indicates a deficit in multi-item learning previously shown to be responsible for violation element learning. Thus, these results clearly show that adolescent MPD produced multiple cognitive impairments in male rats that persisted into adulthood long after MPD exposure ended.

Oral supplementation of Ocimum basilicum has the potential to improves the locomotory, exploratory, anxiolytic behavior and learning in adult male albino mice.

The aim of this project was to determine the effect of 100 mg/ml solvent/kg body weight of Ocimum basilicum leaf extract on neuromuscular co-ordination, exploratory, locomotory and short-term memory formation in male albino mice. Five weeks old, male albino mice were used as the experimental animals in order to demonstrate the effect of O. basilicum's extract on learning and memory. Each male albino mouse was weighted and orally treated either with 100 mg/ml solvent/kg body weight of O. basilicum leaf extract or with commercially available saline solution (Otsuka, Pakistan) for 7 days. Behavioral observations were made by applying a series of neurological tests (Elevated plus maze, Light and dark box, Open field and Rota rod). Dose supplementation continued during neurological testing. It was observed that 100 mg/ml solvent/kg body weight of leaf extract improves neuromuscular co-ordination and male albino mouse performance in open field, light dark box and during novel object test when compared with control group. We concluded that 100 mg/ml solvent/kg body weight of leaf extract has the potential to improve neuromuscular co-ordination, exploratory behavior, object recognition ability and transfer latency in male albino mice and can be safely administrated orally.

Chronic alcohol alters rewarded behaviors and striatal plasticity.

Chronic intermittent ethanol (CIE) alters neural functions and behaviors mediated by the dorsolateral striatum (DLS) and prefrontal cortex. Here, we examined the effects of prolonged (16-bout) CIE on DLS plasticity and DLS-mediated behaviors. Ex vivo electrophysiological recordings revealed loss in efficacy of DLS synaptically induced activation and absent long-term depression after CIE. CIE increased two-bottle choice drinking and impaired Pavlovian-to-instrumental transfer but not discriminated approach. These data suggest prolonged CIE impaired DLS plasticity, to produce associated changes in drinking and cue-controlled reward-seeking. Given recent evidence that less-prolonged CIE can promote certain dorsal striatal-mediated behaviors, CIE may drive chronicity-dependent adaptations in corticostriatal systems regulating behavior.

Interoceptive conditioning with nicotine using extinction and re-extinction to assess stimulus similarity with bupropion.

Bupropion is an atypical antidepressant that increases long-term quit rates of tobacco smokers. A better understanding of the relation between nicotine and this first-line medication may provide insight into improving treatment. For all experiments, rats first had nicotine (0.4 mg base/kg) and saline session intermixed; intermittent access to sucrose only occurred on nicotine session. Nicotine in this protocol comes to differentially control "anticipatory" dipper entries. To more closely examine the overlap in the interoceptive stimulus effects of nicotine and bupropion, we assessed whether subsequent prolonged and repeated non-reinforced (extinction) sessions with the bupropion stimulus could weaken responding to nicotine (i.e., transfer of extinction). We also examined whether retraining the discrimination after initial extinction and then conducting extinction again (i.e., re-extinction) with bupropion would affect responding. We found that bupropion (20 and 30 mg/kg) fully substituted for the nicotine stimulus in repeated 20-min extinction sessions. The extent of substitution in extinction did not necessarily predict performance in the transfer test (e.g., nicotine responding unchanged after extinction with 20 mg/kg bupropion). Generalization of extinction back to nicotine was not seen with 20 mg/kg bupropion even after increasing the number of extinction session from 6 to 24. Finally, there was evidence that learning in the initial extinction phase was retained in the re-extinction phase for nicotine and bupropion. These findings indicate that learning involving the nicotine stimuli are complex and that assessment approach for stimulus similarity changes conclusions regarding substitution by bupropion. Further research will be needed to identify whether such differences may be related to different facets of nicotine dependence and/or its treatment.

Phasic mesolimbic dopamine signaling encodes the facilitation of incentive motivation produced by repeated cocaine exposure.

Drug addiction is marked by pathological drug seeking and intense drug craving, particularly in response to drug-related stimuli. Repeated psychostimulant administration is known to induce long-term alterations in mesolimbic dopamine (DA) signaling that are hypothesized to mediate this heightened sensitivity to environmental stimuli. However, there is little direct evidence that drug-induced alteration in mesolimbic DA function underlies this hypersensitivity to motivational cues. In the current study, we tested this hypothesis using fast-scan cyclic voltammetry to monitor phasic DA signaling in the nucleus accumbens core of cocaine-pretreated (6 once-daily injections of 15 mg/kg, i.p.) and drug-naive rats during a test of cue-evoked incentive motivation for food-the Pavlovian-to-instrumental transfer task. We found that prior cocaine exposure augmented both reward seeking and DA release triggered by the presentation of a reward-paired cue. Furthermore, cue-evoked DA signaling positively correlated with cue-evoked food seeking and was found to be a statistical mediator of this behavioral effect of cocaine. Taken together, these findings provide support for the hypothesis that repeated cocaine exposure enhances cue-evoked incentive motivation through augmented phasic mesolimbic DA signaling. This work sheds new light on a fundamental neurobiological mechanism underlying motivated behavior and its role in the expression of compulsive reward seeking.

The motivational drive to natural rewards is modulated by prenatal glucocorticoid exposure.

Exposure to elevated levels of glucocorticoids (GCs) during neurodevelopment has been identified as a triggering factor for the development of reward-associated disorders in adulthood. Disturbances in the neural networks responsible for the complex processes that assign value to rewards and associated stimuli are critical for disorders such as depression, obsessive­compulsive disorders, obesity and addiction. Essential in the understanding on how cues influence behavior is the Pavlovian­instrumental transfer (PIT), a phenomenon that refers to the capacity of a Pavlovian stimulus that predicts a reward to elicit instrumental responses for that same reward. Here, we demonstrate that in utero exposure to GCs (iuGC) impairs both general and selective versions of the PIT paradigm, suggestive of deficits in motivational drive. The iuGC animals presented impaired neuronal activation pattern upon PIT performance in cortical and limbic regions, as well as morphometric changes and reduced levels of dopamine in prefrontal and orbitofrontal cortices, key regions involved in the integration of Pavlovian and instrumental stimuli. Normalization of dopamine levels rescued this behavior, a process that relied on D2/D3, but not D1, dopamine receptor activation. In summary, iuGC exposure programs the mesocorticolimbic dopaminergic circuitry, leading to a reduction in the attribution of the incentive salience to cues, in a dopamine-D2/D3-dependent manner. Ultimately, these results are important to understand how GCs bias incentive processes, a fact that is particularly relevant for disorders where differential attribution of incentive salience is critical.

Differential effects of systemic cholinergic receptor blockade on Pavlovian incentive motivation and goal-directed action selection.

Reward-seeking actions can be guided by external cues that signal reward availability. For instance, when confronted with a stimulus that signals sugar, rats will prefer an action that produces sugar over a second action that produces grain pellets. Action selection is also sensitive to changes in the incentive value of potential rewards. Thus, rats that have been prefed a large meal of sucrose will prefer a grain-seeking action to a sucrose-seeking action. The current study investigated the dependence of these different aspects of action selection on cholinergic transmission. Hungry rats were given differential training with two unique stimulus-outcome (S1-O1 and S2-O2) and action-outcome (A1-O1 and A2-O2) contingencies during separate training phases. Rats were then given a series of Pavlovian-to-instrumental transfer tests, an assay of cue-triggered responding. Before each test, rats were injected with scopolamine (0, 0.03, or 0.1 mg/kg, intraperitoneally), a muscarinic receptor antagonist, or mecamylamine (0, 0.75, or 2.25 mg/kg, intraperitoneally), a nicotinic receptor antagonist. Although the reward-paired cues were capable of biasing action selection when rats were tested off-drug, both anticholinergic treatments were effective in disrupting this effect. During a subsequent round of outcome devaluation testing-used to assess the sensitivity of action selection to a change in reward value--we found no effect of either scopolamine or mecamylamine. These results reveal that cholinergic signaling at both muscarinic and nicotinic receptors mediates action selection based on Pavlovian reward expectations, but is not critical for flexibly selecting actions using current reward values.

The effects of amphetamine sensitization on conditioned inhibition during a Pavlovian-instrumental transfer task in rats.

RATIONALE: Psychostimulant sensitization heightens behavioral and motivational responses to reward-associated stimuli; however, its effects on stimuli associated with reward absence are less understood. OBJECTIVES: We examined whether amphetamine sensitization alters performance during Pavlovian-instrumental transfer (PIT) to conditioned excitors and inhibitors. We further sought to characterize the effects of amphetamine sensitization on learning versus performance by exposing rats to amphetamine prior to Pavlovian training or between training and test. METHODS: Adult male Long-Evans rats were given conditioned inhibition (A+/AX-) and Pavlovian (B+) training, followed by variable-interval instrumental conditioning. Rats were sensitized to D-amphetamine (2 mg/kg daily injections for 7 days) or served as non-exposed controls. Rats were given a PIT test, in which they were presented with stimulus B alone or in compound with the conditioned inhibitor (BX). RESULTS: During the PIT test, control rats significantly reduced instrumental responding on BX trials (to approximately 50 % of responding to B). Amphetamine sensitization prior to Pavlovian conditioning increased lever pressing on BX trials and reduced lever pressing on B trials compared to controls. Amphetamine sensitization between training and test increased lever pressing on B and BX trials compared to controls. No effects of sensitization were observed on conditioned food cup approach. CONCLUSIONS: Amphetamine sensitization increases instrumental responding during PIT to a conditioned inhibitor by enhancing the excitation of conditioned stimuli and reducing the inhibition of conditioned inhibitors.

Post-training glucocorticoid receptor activation during Pavlovian conditioning reduces Pavlovian-instrumental transfer in rats.

Considerable evidence suggests that glucocorticoid receptor activation can enhance memory consolidation in Pavlovian learning tasks. For instance, post-training injections of the synthetic glucocorticoid receptor agonist dexamethasone increased conditioned responding to reward-predictive Pavlovian stimuli. Here we explored whether post-training dexamethasone injections can enhance appetitive Pavlovian learning and amplify the ability of Pavlovian stimuli to invigorate instrumental behaviour, a phenomenon termed Pavlovian-instrumental transfer (PIT). Animals were given 8 training days with two sessions per day, an instrumental training session in the morning and a Pavlovian training session in the afternoon. Dexamethasone or vehicle injections were administered daily immediately after Pavlovian training sessions. In a subsequent transfer test, we measured the general PIT effect, i.e. the enhancement of lever pressing for expected reward during presentation of an appetitive Pavlovian stimulus predictive for the same reward. Repeated high-dose (1.2 mg/kg, i.p.) dexamethasone injections elicited pronounced body weight loss, markedly reduced instrumental performance and left Pavlovian learning unaltered, whereas repeated low-dose (3 µg/kg, i.p.) dexamethasone injections inhibited body weight gain, slightly reduced instrumental performance and left Pavlovian learning unaltered during training. Importantly, in rats subjected to high- and low-dose dexamethasone injections, the overall response rates and the PIT effect were reduced in the transfer test. Thus, dexamethasone given after Pavlovian training was not able to amplify the invigorating effects of Pavlovian stimuli on instrumental action. Considerable evidence suggests that body weight changes after repeated low- and high-dose dexamethasone treatment as observed here are associated with muscle atrophy that could impair response capabilities. However, our data suggest that impaired response capabilities are not a major factor accounting for reduced PIT in dexamethasone-treated animals.

The effects of acute stress on Pavlovian-instrumental transfer in rats.

Pavlovian stimuli invigorate ongoing instrumental action, a phenomenon termed the Pavlovian-instrumental transfer (PIT) effect. Acute stressors can markedly enhance the release of corticotropin-releasing factor (CRF), and CRF injection into the nucleus accumbens increases the PIT effect. However, it is unknown whether acute stressors by themselves would amplify the PIT effect. Here, we examined the effects of acute stressors on PIT. Rats first received Pavlovian and instrumental training, and then the impact of the Pavlovian stimuli on instrumental responding was analyzed in the subsequent PIT test. Acute stressors were applied prior to the PIT test. Because the effects of acute stressors critically depend on stressor type and time of day, we used two acute stressors that involved one or several distinct stressors (denoted here as "single" vs. "multiple" stressors) applied either in the light or the dark period of the light:dark cycle. The results revealed that single and multiple stressors applied in the light period did not alter the PIT effect--that is, the ability of an appetitive Pavlovian stimulus to enhance leverpressing--or the basal leverpress rate. When applied in the dark period, single and multiple stressors also did not alter the PIT effect, but they did markedly reduce the basal leverpress rate. Diazepam pretreatment did not counteract the declines in basal instrumental responding in the PIT test that were induced by either a single or multiple stressors. Our findings suggest that acute stressors were unable to amplify the incentive salience of reward-predictive Pavlovian stimuli to activate instrumental responding, but, depending on the time of day of stressor exposure, they did reduce basal instrumental responding.

Effects of statins and cholesterol on memory functions in mice.

Studies on influence of lipid lowering therapies have generated wide controversial results on the role of cholesterol on memory function. However recent studies revealed that cholesterol lowering treatment substantially reduce the risk of dementia. The objectives of this study were to analyze the effect of statins on memory function and to establish the relationship between increase/decrease in cholesterol synthesis, total cholesterol level and memory function in animals. We examined the relationship between biosynthesis of cholesterol and memory function using two statins (lipophilic simvastatin and hydrophilic pravastatin) and high cholesterol diet in mice for 15 days and 4 months. Memory performance was evaluated with two different behavioral tests and various biochemical parameters such as serum cholesterol, whole brain cholesterol, brain 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) activity and brain acetylcholine esterase (AChE) activity. We found that statin treatment for 4 months, but not for 15 days, showed significant improvement in memory function whereas high cholesterol diet showed significant impairment of memory. However long-term statin treatment showed significant decrease in serum cholesterol level as well as brain AChE level. Moreover high cholesterol diet showed significant decrease in memory function with an increase in serum cholesterol level as well as brain AChE level. There is no direct correlation between brain cholesterol level, as well as HMG-CoA activity with memory function regulation. However there is definite link between plasma cholesterol level and AChE level. A long-standing plasma cholesterol alteration may be essential to regulate memory function which in turn might be mediated through AChE modulated pathway.