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A BS TRACT: Background: In movement disorders such as Parkinson's disease (PD), cholinergic signaling is disrupted by the loss of basal forebrain cholinergic neurons, as well as aberrant activity in striatal cholinergic interneurons (ChIs). Several lines of evidence suggest that gait imbalance, a key disabling symptom of PD, may be driven by alterations in high-level frontal cortical and cortico-striatal processing more typically associated with cognitive dysfunction. Methods: Here we describe the corticostriatal circuitry that mediates the cognitive-motor interactions underlying such complex movement control. The ability to navigate dynamic, obstacle-rich environments requires the continuous integration of information about the environment with movement selection and sequencing. The corticalattentional processing of extero-and interoceptive cues requires modulation by cholinergic activity to guide striatal movement control. Cue-derived information is "transferred" to striatal circuitry primarily via frontostriatal glutamatergic projections. Result: Evidence from parkinsonian fallers and from a rodent model reproducing the dual cholinergicdopaminergic losses observed in these patients supports the main hypotheses derived from this neuronal circuitryguided conceptualization of parkinsonian falls. Furthermore, in the striatum, ChIs constitute a particularly critical node for the integration of cortical with midbrain dopaminergic afferents and thus for cues to control movements. Conclusion: Procholinergic treatments that enhance or rescue cortical and striatal mechanisms may improve complex movement control in parkinsonian fallers and perhaps also in older persons suffering from gait disorders and a propensity for falls.

Sign tracking versus goal tracking in rats indicate vulnerability and resistance, respectively, to Pavlovian cue-evoked addictive drug taking and relapse. Here, we tested hypotheses predicting that the opponent cognitive-behavioral styles indexed by sign tracking versus goal tracking include variations in attentional performance which differentially depend on basal forebrain projection systems. Pavlovian Conditioned Approach (PCA) testing was used to identify male and female sign-trackers (STs) and goal-trackers (GTs), as well as rats with an intermediate phenotype (INTs). Upon reaching asymptotic performance in an operant task requiring the detection of visual signals (hits) as well as the reporting of signal absence for 40 min per session, GTs scored more hits than STs, and hit rates across all phenotypes correlated with PCA scores. STs missed relatively more signals than GTs specifically during the last 15 min of a session. Chemogenetic inhibition of the basal forebrain decreased hit rates in GTs but was without effect in STs. Moreover, the decrease in hits in GTs manifested solely during the last 15 min of a session. Transfection efficacy in the horizontal limb of the diagonal band (HDB), but not substantia innominate (SI) or nucleus basalis of Meynert (nbM), predicted the behavioral efficacy of chemogenetic inhibition in GTs. Furthermore, the total subregional transfection space, not transfection of just cholinergic neurons, correlated with performance effects. These results indicate that the cognitive-behavioral phenotype indexed by goal tracking, but not sign tracking, depends on activation of the basal forebrain-frontal cortical projection system and associated biases toward top-down or model-based performance.

Transport of choline via the neuronal high-affinity choline transporter (CHT;SLC5A7) is essential for cholinergic terminals to synthesize and release acetylcholine (ACh). In humans, we previously demonstrated an association between a common CHT coding substitution (rs1013940; Ile89Val) and reduced attentional control as well as attenuated frontal cortex activation. Here, we used a CRISPR/Cas9 approach to generate mice expressing the I89V substitution and assessed,in vivo, CHT-mediated choline transport, and ACh release. Relative to wild-type (WT) mice, CHT-mediated clearance of choline in male and female mice expressing one or two Val89 alleles was reduced by over 80% in cortex and over 50% in striatum. Choline clearance in CHT Val89 mice was further reduced by neuronal inactivation. Deficits in ACh release, 5 and 10 min after repeated depolarization at a low, behaviorally relevant frequency, support an attenuated reloading capacity of cholinergic neurons in mutant mice. The density of CHTs in total synaptosomal lysates and neuronal plasma-membrane-enriched fractions was not impacted by the Val89 variant, indicating a selective impact on CHT function. When challenged with a visual disruptor to reveal attentional control mechanisms, Val89 mice failed to adopt a more conservative response bias. Structural modeling revealed that Val89 may attenuate choline transport by altering conformational changes of CHT that support normal transport rates. Our findings support the view that diminished sustained cholinergic signaling capacity underlies perturbed attentional performance in individuals expressing CHT Val89. The CHT Val89 mouse serves as a valuable model to study heritable risk for cognitive disorders arising from cholinergic dysfunction.SIGNIFICANCE STATEMENTAcetylcholine (ACh) signaling depends on the functional capacity of the neuronal choline transporter (CHT). Previous research demonstrated that humans expressing the common CHT coding variant Val89 exhibit attentional vulnerabilities and attenuated fronto-cortical activation during attention. Here, we find that mice engineered to express the Val89 variant exhibit reduced CHT-mediated choline clearance and a diminished capacity to sustain ACh release. Additionally, Val89 mice lack cognitive flexibility in response to an attentional challenge. These findings provide a mechanistic and cognitive framework for interpreting the attentional phenotype associated with the human Val89 variant and establish a model that permits a more invasive interrogation of CNS effects as well as the development of therapeutic strategies for those, including Val89 carriers, with presynaptic cholinergic perturbations.

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