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

Turning on cue or stopping at a red light requires attending to such cues to select action sequences, or suppress action, in accordance with learned 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 STs, turn cue-locked glutamate concentrations frequently peaked twice or three times, contrasting with predominately single peaks in GTs. In GTs, but not STs, inhibition of prelimbic-DMS projections attenuated turn rates and turn cue-evoked glutamate concentrations and increased the number of turn cue-locked glutamate peaks. These findings indicate 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. As cortico-striatal dysfunction has been hypothesized to contribute to a wide range of disorders, including complex movement control deficits in Parkinson’s disease and compulsive drug taking, the demonstration of phenotypic contrasts in cortico-striatal control implies the presence of individual vulnerabilities for such disorders.

Methods
Subjects and Behavioral Training: Male and female rats were trained on the Cue-Triggered Turning Task (CTTT) to assess cued turn and stop performance. Rats were classified as goal trackers (GTs) or sign trackers (STs) via Pavlovian Conditioned Approach (PCA) screening.The number of cued turns, missed turns, cued stops, and false turns were extracted from offline scoring of CTTT session videos. For the analysis of baseline CTTT performance, and because rats generated a variable number of cued turns during the 4 sessions used for this analysis, individual turn onset and completion times were averaged across the test sessions. 

Chemogenetic Manipulation: Rats underwent intracranial infusions of Cre-dependent Designer Receptor Exclusively Activated by Designer Drug (DREADD) and retrogradely transported Cre-expressing plasmids to inhibit fronto-cortical projections to the dorsomedial striatum (DMS) before CTTT acquisition. A second surgery was performed for the implantation of microelectrode arrays (MEAs) into the dorsomedial striatum following CTTT acquisition.

CNO Administration: Clozapine N-oxide (CNO, 5.0 mg/kg) or vehicle was administered intraperitoneally 50 minutes prior to CTTT testing on alternate days. CNO effects were assessed in rats with either the DREADD or control vector, and for electrochemical data, CNO was given just before baseline recordings. Statistical analyses were performed to examine the effects of CNO or vehicle treatment on behavior, using repeated measures ANOVA and Tukey’s post hoc tests.

Electrochemical Data Collection: Glutamate concentrations in the dorsomedial striatum were recorded using glutamate-sensitive microelectrode arrays (MEAs). Data were collected at a fixed potential of 0.7 V using a FAST-16 potentiostat at 5 Hz and processed offline with MATLAB scripts. Calibration curves were used to quantify glutamate concentrations, and data were analyzed during baseline, cue, and reward periods of the CTTT. Statistical analyses included linear mixed-effects models and repeated measures ANOVA, with Bonferroni corrections for post hoc comparisons.

Histology and Verification: Following the study, rats were euthanized, and brains were processed for histological verification of viral infusion and electrode placement. Fluorescent microscopy and confocal imaging were used to assess the distribution of transfected neurons. Transfection efficacy was semi-quantified based on GFP and mCherry labeling, and cell counts were performed to determine the proportion of double-labeled neurons.