Cortico-striatal action control inherent of opponent cognitive-motivational styles.

Turning on cue or stopping at a red light requires the detection of such cues to select action sequences, or suppress action, in accordance with cue-associated action rules. Cortico-striatal projections are an essential part of the brain's attention-motor interface. Glutamate-sensing microelectrode arrays were used to measure glutamate transients in the dorsomedial striatum (DMS) of male and female rats walking a treadmill and executing cued turns and stops. Prelimbic-DMS projections were chemogenetically inhibited to determine their behavioral necessity and the cortico-striatal origin of cue-evoked glutamate transients. Furthermore, we investigated rats exhibiting preferably goal-directed (goal trackers, GTs) versus cue-driven attention (sign trackers, STs), to determine the impact of such cognitive-motivational biases on cortico-striatal control. GTs executed more cued turns and initiated such turns more slowly than STs. During turns, but not missed turns or cued stops, cue-evoked glutamate concentrations were higher in GTs than in STs. In conjunction with turn cue-evoked glutamate spike levels, the presence of a single spike rendered GTs to be almost twice as likely to turn than STs. In contrast, multiple glutamate spikes predicted GTs to be less likely to turn than STs. In GTs, but not STs, inhibition of prelimbic-DMS projections attenuated turn rates, turn cue-evoked glutamate peaks, and increased the number of spikes. These findings suggest that turn cue-evoked glutamate release in GTs is tightly controlled by cortico-striatal neuronal activity. In contrast, in STs, glutamate release from DMS glutamatergic terminals may be regulated by other striatal circuitry, preferably mediating cued suppression of action and reward tracking. Significance Statement: Adaptive behavior involves the selection of behaviorally significant cues and the capacity of selected cues to control behavioral action. Neuronal projections from cortex to striatum are essential for such an integration of attentional with motor functions. Here we demonstrated that glutamate release from cortico-striatal projections primarily influences cued turns but not cued suppression of actions (cued stops). Cortico-striatal control of cued turning was especially powerful in rats which, as a psychological trait, preferably deploy goal-directed attention. Together, our findings demonstrate the role of cortico-striatal input in cued action selection, and they emphasize the experimental and biopsychological significance of investigating the brain's attentional-motor interface in the context of broader cognitive-motivational styles.

Disrupted Choline Clearance and Sustained Acetylcholine Release In Vivo by a Common Choline Transporter Coding Variant Associated with Poor Attentional Control in Humans.

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 STATEMENT Acetylcholine (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.

Basal Forebrain Chemogenetic Inhibition Converts the Attentional Control Mode of Goal-Trackers to That of Sign-Trackers.

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.

Make a Left Turn: Cortico-Striatal Circuitry Mediating the Attentional Control of Complex Movements.

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 cortical-attentional 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 fronto-striatal glutamatergic projections. RESULT: Evidence from parkinsonian fallers and from a rodent model reproducing the dual cholinergic-dopaminergic losses observed in these patients supports the main hypotheses derived from this neuronal circuitry-guided 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. © 2021 International Parkinson and Movement Disorder Society.

Complex Movement Control in a Rat Model of Parkinsonian Falls: Bidirectional Control by Striatal Cholinergic Interneurons.

Older persons and, more severely, persons with Parkinson's disease (PD) exhibit gait dysfunction, postural instability and a propensity for falls. These dopamine (DA) replacement-resistant symptoms are associated with losses of basal forebrain and striatal cholinergic neurons, suggesting that falls reflect disruption of the corticostriatal transfer of movement-related cues and their striatal integration with movement sequencing. To advance a rodent model of the complex movement deficits of Parkinsonian fallers, here we first demonstrated that male and female rats with dual cortical cholinergic and striatal DA losses (DL rats) exhibit cued turning deficits, modeling the turning deficits seen in these patients. As striatal cholinergic interneurons (ChIs) are positioned to integrate movement cues with gait, and as ChI loss has been associated with falls in PD, we next used this task, as well as a previously established task used to reveal heightened fall rates in DL rats, to broadly test the role of ChIs. Chemogenetic inhibition of ChIs in otherwise intact male and female rats caused cued turning deficits and elevated fall rates. Spontaneous turning was unaffected. Furthermore, chemogenetic stimulation of ChIs in DL rats reduced fall rates and restored cued turning performance. Stimulation of ChIs was relatively more effective in rats with viral transfection spaces situated lateral to the DA depletion areas in the dorsomedial striatum. These results indicate that striatal ChIs are essential for the control of complex movements, and they suggest a therapeutic potential of stimulation of ChIs to restore gait and balance, and to prevent falls in PD.SIGNIFICANCE STATEMENT In persons with Parkinson's disease, gait dysfunction and the associated risk for falls do not benefit from dopamine replacement therapy and often result in long-term hospitalization and nursing home placement. Here, we first validated a new task to demonstrate impairments in cued turning behavior in rodents modeling the cholinergic-dopaminergic losses observed in Parkinsonian fallers. We then demonstrated the essential role of striatal cholinergic interneurons for turning behavior as well as for traversing dynamic surfaces and avoiding falls. Stimulation of these interneurons in the rat model rescued turning performance and reduced fall rates. Our findings indicate the feasibility of investigating the neuronal circuitry underling complex movement control in rodents, and that striatal cholinergic interneurons are an essential node of such circuitry.