Prior Cocaine Experience Impairs Normal Phasic Dopamine Signals of Reward Value in Accumbens Shell

Dopamine signals have repeatedly been linked to associative learning and motivational processes. However, there is considerably less agreement on a role for dopamine in reward processing, and therefore whether neuroplastic changes in dopamine function following chronic exposure to drugs of abuse such as cocaine may impair appropriate valuation of rewarding stimuli. To quantify this, we voltammetrically measured real-time dopamine release in the nucleus accumbens (NAc) core or shell while rats received unsignaled deliveries of either a small (1 pellet) or large (2 pellets) reward. In drug-naive controls, core dopamine signals did not discriminate between reward size at any point, while in the shell dopamine encoded magnitude differences only in a slower postpeak period. Despite this lack of discrimination between rewards by the peak DA response, controls easily discriminated between reward options in a subsequent choice task. In contrast, phasic dopamine reward signals were strongly altered by cocaine experience; core dopamine decreased peak response but increased discrimination between reward magnitudes while shell lost phasic responses to reward receipt altogether. Notably, animals with cocaine-associated alterations in dopamine signals for reward magnitude failed to subsequently discriminate between reward options. These findings suggest that cocaine self-administration alters the ability for dopamine signals to appropriately assign value to rewards and thus may in part contribute to later deficits in behaviors that depend on appropriate outcome valuation

Dopamine, reward learning, and active inference

Temporal difference learning models propose phasic dopamine signaling encodes reward prediction errors that drive learning. This is supported by studies where optogenetic stimulation of dopamine neurons can stand in lieu of actual reward. Nevertheless, a large body of data also shows that dopamine is not necessary for learning, and that dopamine depletion primarily affects task performance. We offer a resolution to this paradox based on an hypothesis that dopamine encodes the precision of beliefs about alternative actions, and thus controls the outcome-sensitivity of behavior. We extend an active inference scheme for solving Markov decision processes to include learning, and show that simulated dopamine dynamics strongly resemble those actually observed during instrumental conditioning. Furthermore, simulated dopamine depletion impairs performance but spares learning, while simulated excitation of dopamine neurons drives reward learning, through aberrant inference about outcome states. Our formal approach provides a novel and parsimonious reconciliation of apparently divergent experimental findings

Temperament, Distraction, and Learning in Toddlerhood

The word- and nonword-learning abilities of toddlers were tested under various conditions of environmental distraction, and evaluated with respect to children\u27s temperamental attentional focus. Thirty-nine children and their mothers visited the lab at child age 21-months, where children were exposed to fast-mapping word-learning trials and nonlinguistic sequential learning trials. It was found that both word- and nonword-learning were adversely affected by the presentation of environmental distractions. But it was also found that the effect of the distractions sometimes depended on children\u27s level of attentional focus. Specifically, children high in attentional focus were less affected by environmental distractions than children low in attentional focus when attempting to learn from a model, whereas children low in attentional focus demonstrated little learning from the model. Translationally, these results may be of use to child health-care providers investigating possible sources of cognitive and language delay

Design, Assembly and Triggering of Interlocked DNA Nanoarchitectures

Interlocked molecular systems are well known in supramolecular chemistry and are widely used for various applications like sensors, molecular machines and logic gates. However, these systems present some drawbacks, as the synthesis is demanding and their handling in aqueous media and biocompatibility is rather problematic. Due to Watson Crick base pairing rules, DNA is an optimal material for the self-assembly of highly ordered and complex nanoarchitectures. Furthermore, it is synthetically accessible, relatively stable, water-soluble and shows good biocompatibility. Therefore, the study of novel DNA based interlocked systems is of interest for nanotechnology. Indeed, a DNA rotaxane reported by Famulok et al. gained great attention and the threading principle described in that work was used for the assembly of various interlocked DNA architectures. In the present study, DNA rotaxanes were modified in order to precisely control and switch on and off the molecular motion of its mechanically trapped components. Such switching was utilized to create a molecular shuttle in which a macrocycle is translocated along an axle from one station towards another in a controlled fashion. Another aim of this research was to design and assemble entirely new DNA based interlocked systems suitable for the introduction of diverse functions. In this context, a [3]pseudorotaxane was assembled and fully characterized by means of gel electrophoresis and Atomic Force Microscopy. Indeed, by introducing different triggers into this system, a logic AND gate could be created. Apart from the rotaxane structures, also novel catenane structures could be assembled and properly characterized, which were then used for several applications, such as the construction of complex logic gates or catalytic activity control in a DNAzyme based system. The presented DNA based systems proved to be optimal frameworks for the introduction of highly controllable functionality and pave the way in order to build dynamic nanostructures and complex nanomachinery