title: Unresponsive Choline Transporter as a Trait Neuromarker and a Causal Mediator of Bottom-Up Attentional Biases.
abstract: Some rats [sign-trackers (STs)] are prone to attribute incentive salience to reward cues, which can manifest as a propensity to approach and contact pavlovian cues, and for addiction-like behavior. STs also exhibit poor attentional performance, relative to goal-trackers (GTs), which is associated with attenuated acetylcholine (ACh) levels in prefrontal cortex (Paolone et al., 2013). Here, we demonstrate a cellular mechanism, linked to ACh synthesis, that accounts for attenuated cholinergic capacity in STs. First, we found that electrical stimulation of the basal forebrain increased cortical choline transporter (CHT)-mediated choline transport in GTs, paralleled by a redistribution of CHTs to the synaptic plasma membrane. Neither increases in choline uptake nor translocation of CHTs occurred in STs. Second, and consistent with uptake/translocation alterations, STs demonstrated a reduced ability to support cortical ACh releasein vivocompared with GTs after reverse-dialysis to elevate extracellular potassium levels. Third, rats were significantly more likely to develop sign-tracking behavior if treated systemically before pavlovian conditioned approach training with the CHT inhibitor VU6001221. Consistent with its proposed mechanisms, administration of VU6001221 attenuated potassium-evoked ACh levels in prefrontal cortex measured within vivomicrodialysis. We propose that loss of CHT-dependent activation of cortical cholinergic activity in STs degrades top-down executive control over behavior, producing a bias for bottom-up or stimulus-driven attention. Such an attentional bias contributes to nonadaptive reward processing and thus identifies a novel mechanism that can support psychopathology, including addiction.SIGNIFICANCE STATEMENTThe vulnerability for addiction-like behavior has been associated with psychological traits, such as the propensity to attribute incentive salience to reward cues that is modeled in rats by sign-tracking behavior. Sign-trackers tend to approach and contact cues associated with reward, whereas their counterparts, the goal-trackers, have a preference for approaching the location of the reward. Here, we show that the capacity of presynaptic cholinergic synapses to respond to stimulation by elevating presynaptic choline uptake and releasing acetylcholine is attenuated in sign-trackers. Furthermore, pharmacological inhibition of choline transport induced sign-tracking behavior. Our findings suggest that reduced levels of cholinergic neuromodulation can mediate an attentional bias toward reward-related cues, thereby allowing such cues to exert relatively greater control over behavior.
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Ajeesh
authors.identifier: 0000-0001-7571-5279
authors.initials: A
authors.lastname: Koshy Cherian
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Aaron
authors.identifier: 0000-0003-2573-3422
authors.initials: A
authors.lastname: Kucinski
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Kyle
authors.identifier: 0000-0002-9609-3445
authors.initials: K
authors.lastname: Pitchers
authors.affiliation: Department of Psychology and Neuroscience Program, Temple University, Philadelphia, Pennsylvania 19122.
authors.forename: Brittney
authors.initials: B
authors.lastname: Yegla
authors.affiliation: Department of Psychology and Neuroscience Program, Temple University, Philadelphia, Pennsylvania 19122.
authors.forename: Vinay
authors.identifier: 0000-0003-1939-5703
authors.initials: V
authors.lastname: Parikh
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Youngsoo
authors.identifier: 0000-0001-8289-0331
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109.|Institute of Physiology, First Faculty of Medicine, Charles University, Prague 12800, Czech Republic.
authors.forename: Paulina
authors.initials: P
authors.lastname: Valuskova
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109.
authors.forename: Sarika
authors.initials: S
authors.lastname: Gurnani
authors.affiliation: Vanderbilt Center for Neuroscience Drug Discovery, Departments of Pharmacology and Chemistry, Vanderbilt University Medical Center, Nashville, Tennessee 37232, and.
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
authors.affiliation: Brain Institute and Department of Biomedical Science, Charles E. Schmidt College of Medicine, Florida Atlantic University, Jupiter, Florida 33458.
authors.forename: Randy D
authors.identifier: 0000-0002-2182-6966
authors.initials: RD
authors.lastname: Blakely
authors.affiliation: Department of Psychology and Neuroscience Program, University of Michigan, Ann Arbor, Michigan 48109, msarter@umich.edu.
authors.forename: Martin
authors.identifier: 0000-0003-0441-9936
authors.initials: M
authors.lastname: Sarter
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000818:Animals; D000070379:Attentional Bias / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D015984:Causality; D002794:Choline / Q000378:metabolism; D059329:Cholinergic Neurons / Q000502:physiology*; D003463:Cues; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D018377:Neurotransmitter Agents / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012201:Reward
chemical_list: D015415:Biomarkers; D026901:Membrane Transport Proteins; D018377:Neurotransmitter Agents; C065637:choline transporter; D002794:Choline; D000109:Acetylcholine
keywords: acetylcholine; addiction; attention; choline transporter; motivation; sign-tracking