How Emotion Strengthens the Recollective Experience: A Time-Dependent Hippocampal Process

Emotion significantly strengthens the subjective recollective experience even when objective accuracy of the memory is not improved. Here, we examine if this modulation is related to the effect of emotion on hippocampal-dependent memory consolidation. Two critical predictions follow from this hypothesis. First, since consolidation is assumed to take time, the enhancement in the recollective experience for emotional compared to neutral memories should become more apparent following a delay. Second, if the emotion advantage is critically dependent on the hippocampus, then the effects should be reduced in amnesic patients with hippocampal damage. To test these predictions we examined the recollective experience for emotional and neutral photos at two retention intervals (Experiment 1), and in amnesics and controls (Experiment 2). Emotional memories were associated with an enhancement in the recollective experience that was greatest after a delay, whereas familiarity was not influenced by emotion. In amnesics with hippocampal damage the emotion effect on recollective experience was reduced. Surprisingly, however, these patients still showed a general memory advantage for emotional compared to neutral items, but this effect was manifest primarily as a facilitation of familiarity. The results support the consolidation hypothesis of recollective experience, but suggest that the effects of emotion on episodic memory are not exclusively hippocampally mediated. Rather, emotion may enhance recognition by facilitating familiarity when recollection is impaired due to hippocampal damage

TorsinA and the TorsinA-Interacting Protein Printor Have No Impact on Endoplasmic Reticulum Stress or Protein Trafficking in Yeast

Early-onset torsion dystonia is a severe, life-long disease that leads to loss of motor control and involuntary muscle contractions. While the molecular etiology of the disease is not fully understood, a mutation in an AAA+ ATPase, torsinA, has been linked to disease onset. Previous work on torsinA has shown that it localizes to the endoplasmic reticulum, where there is evidence that it plays roles in protein trafficking, and potentially also protein folding. Given the high level of evolutionary conservation among proteins involved in these processes, the ability of human such proteins to function effectively in yeast, as well as the previous successes achieved in examining other proteins involved in complex human diseases in yeast, we hypothesized that Saccharomyces cerevisiae might represent a useful model system for studying torsinA function and the effects of its mutants. Since torsinA is proposed to function in protein homeostasis, we tested cells for their ability to respond to various stressors, using a fluorescent reporter to measure the unfolded protein response, as well as their rate of protein secretion. TorsinA did not impact these processes, even after co-expression of its recently identified interacting partner, printor. In light of these findings, we propose that yeast may lack an additional cofactor necessary for torsinA function or proteins required for essential post-translational modifications of torsinA. Alternatively, torsinA may not function in endoplasmic reticulum protein homeostasis. The strains and assays we describe may provide useful tools for identifying and investigating these possibilities and are freely available.Howard Hughes Medical InstituteBachmann-Strauss Dystonia and Parkinson Foundatio

Operant Sensation Seeking Requires Metabotropic Glutamate Receptor 5 (mGluR5)

Pharmacological and genetic studies have suggested that the metabotropic glutamate receptor 5 (mGluR5) is critically involved in mediating the reinforcing effects of drugs of abuse, but not food. The purpose of this study was to use mGluR5 knockout (KO), heterozygous (Het), and wildtype (WT) mice to determine if mGluR5 modulates operant sensation seeking (OSS), an operant task that uses varied sensory stimuli as a reinforcer. We found that mGluR5 KO mice had significantly reduced OSS responding relative to WT mice, while Het mice displayed a paradoxical increase in OSS responding. Neither KO nor Het mice exhibited altered operant responding for food as a reinforcer. Further, we assessed mGluR5 KO, Het and WT mice across a battery of cocaine locomotor, place preference and anxiety related tests. Although KO mice showed expected differences in some locomotor and anxiety measures, Het mice either exhibited no phenotype or an intermediate one. In total, these data demonstrate a key role for mGluR5 in OSS, indicating an important role for this receptor in reinforcement-based behavior

The 5-Choice Continuous Performance Test: Evidence for a Translational Test of Vigilance for Mice

Attentional dysfunction is related to functional disability in patients with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and Alzheimer's disease. Indeed, sustained attention/vigilance is among the leading targets for new medications designed to improve cognition in schizophrenia. Although vigilance is assessed frequently using the continuous performance test (CPT) in humans, few tests specifically assess vigilance in rodents.We describe the 5-choice CPT (5C-CPT), an elaboration of the 5-choice serial reaction (5CSR) task that includes non-signal trials, thus mimicking task parameters of human CPTs that use signal and non-signal events to assess vigilance. The performances of C57BL/6J and DBA/2J mice were assessed in the 5C-CPT to determine whether this task could differentiate between strains. C57BL/6J mice were also trained in the 5CSR task and a simple reaction-time (RT) task involving only one choice (1CRT task). We hypothesized that: 1) C57BL/6J performance would be superior to DBA/2J mice in the 5C-CPT as measured by the sensitivity index measure from signal detection theory; 2) a vigilance decrement would be observed in both strains; and 3) RTs would increase across tasks with increased attentional load (1CRT task<5CSR task<5C-CPT).C57BL/6J mice exhibited superior SI levels compared to DBA/2J mice, but with no difference in accuracy. A vigilance decrement was observed in both strains, which was more pronounced in DBA/2J mice and unaffected by response bias. Finally, we observed increased RTs with increased attentional load, such that 1CRT task<5CSR task<5C-CPT, consistent with human performance in simple RT, choice RT, and CPT tasks. Thus we have demonstrated construct validity for the 5C-CPT as a measure of vigilance that is analogous to human CPT studies

Interactions of Cathinone NPS with Human Transporters and Receptors in Transfected Cells

Pharmacological assays carried out in transfected cells have been very useful for describing the mechanism of action of cathinone new psychoactive substances (NPS). These in vitro characterizations provide fast and reliable information on psychoactive substances soon after they emerge for recreational use. Well-investigated comparator compounds, such as methamphetamine, 3,4-methylenedioxymethamphetamine, cocaine, and lysergic acid diethylamide, should always be included in the characterization to enhance the translation of the in vitro data into clinically useful information. We classified cathinone NPS according to their pharmacology at monoamine transporters and receptors. Cathinone NPS are monoamine uptake inhibitors and most induce transporter-mediated monoamine efflux with weak to no activity at pre- or postsynaptic receptors. Cathinones with a nitrogen-containing pyrrolidine ring emerged as NPS that are extremely potent transporter inhibitors but not monoamine releasers. Cathinones exhibit clinically relevant differences in relative potencies at serotonin vs. dopamine transporters. Additionally, cathinone NPS have more dopaminergic vs. serotonergic properties compared with their non-β-keto amphetamine analogs, suggesting more stimulant and reinforcing properties. In conclusion, in vitro pharmacological assays in heterologous expression systems help to predict the psychoactive and toxicological effects of NPS

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits

Background Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. Objective The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. Results The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Conclusions Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression