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

AbstractThe human dopamine transporter(hDAT) plays a major role in dopamine homeostasis and regulation of neurotransmission by clearing dopamine from the extracellular space using secondary active transport. Dopamine is an essential monoamine chemical messenger that regulates reward seeking behavior, motor control, hormonal release, and emotional response in humans. Psychostimulants such as cocaine primarily target the central binding site of hDAT and lock the transporter in an outward-facing conformation, thereby inhibiting dopamine reuptake. The inhibition of dopamine reuptake leads to accumulation of dopamine in the synapse causing heightened signaling. In addition, hDAT is implicated in various neurological disorders and disease-associated neurodegeneration. Despite its significance, the molecular architecture of hDAT and its various conformational states are poorly understood. Instability of hDAT in detergent micelles has been a limiting factor in its successful biochemical, biophysical, and structural characterization. To overcome this hurdle, first we identified ligands that stabilize hDAT in detergent micelles. Then, we screened ∼200 single residue mutants of hDAT using high-throughput scintillation proximity assay, and identified a thermostable variant(I248Y). Here we report a robust strategy to overexpress and successfully purify a thermostable variant of hDAT in an inhibitor and allosteric ligand bound conformation.

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Systematic Exploration and Uncertainty Dominate Young Children’s Choices

10.31234/osf.io/72sfx ◽

2019 ◽

Author(s):

Nathaniel J. Blanco ◽

Vladimir Sloutsky

Keyword(s):

Decision Making ◽

Young Children ◽

Cognitive Control ◽

Exploration And Exploitation ◽

Top Down ◽

Reward Seeking ◽

Systematic Fashion ◽

Systematic Exploration ◽

Competing Demands ◽

Exploration Exploitation

Organisms need to constantly balance the competing demands of gathering information and using previously acquired information to obtain rewarding outcomes (i.e., the “exploration- exploitation” dilemma). Exploration is critical to obtain information to discover how the world works, which should be particularly important for young children. While studies have shown that young children explore in response to surprising events, little is known about how they balance exploration and exploitation across multiple decisions or about how this process changes with development. In this study we compare decision-making patterns of children and adults and evaluate the relative influences of reward-seeking, random exploration, and systematic switching (which approximates uncertainty-directed exploration). In a second experiment we directly test the effect of uncertainty on children’s choices. Influential models of decision-making generally describe systematic exploration as a computationally refined capacity that relies on top-down cognitive control. We demonstrate that (1) systematic patterns dominate young children’s behavior (facilitating exploration), despite protracted development of cognitive control, and (2) that uncertainty plays a major, but complicated, role in determining children’s choices. We conclude that while young children’s immature top-down control should hinder adult-like systematic exploration, other mechanisms may pick up the slack, facilitating broad information gathering in a systematic fashion to build a foundation of knowledge for use later in life.

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P.0234 Optogenetic shift of mesolimbic dopamine to tonic pattern reduces reward-seeking behavior

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2021.10.224 ◽

2021 ◽

Vol 53 ◽

pp. S169-S170

Author(s):

E. Budygin ◽

V. Grinevich

Keyword(s):

Mesolimbic Dopamine ◽

Reward Seeking ◽

Seeking Behavior ◽

Tonic Pattern

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