Neuroprotective efficacy of the glucocorticoid receptor modulator PT150 in the rotenone mouse model of Parkinson's disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder worldwide. Current treatments for PD largely center around dopamine replacement therapies and fail to prevent the progression of pathology, underscoring the need for neuroprotective interventions. Approaches that target neuroinflammation, which occurs prior to dopaminergic neuron (DAn) loss in the substantia nigra (SN), represent a promising therapeutic strategy. The glucocorticoid receptor (GR) has been implicated in the neuropathology of PD and modulates numerous neuroinflammatory signaling pathways in the brain. Therefore, we investigated the neuroprotective effects of the novel GR modulator, PT150, in the rotenone mouse model of PD, postulating that inhibition of glial inflammation would protect DAn and reduce accumulation of neurotoxic misfolded ⍺-synuclein protein. C57Bl/6 mice were exposed to 2.5 mg/kg/day rotenone by intraperitoneal injection for 14 days. Upon completion of rotenone dosing, mice were orally treated at day 15 with 30 mg/kg/day or 100 mg/kg/day PT150 in the 14-day post-lesioning incubation period, during which the majority of DAn loss and α-synuclein (α-syn) accumulation occurs. Our results indicate that treatment with PT150 reduced both loss of DAn and microgliosis in the nigrostriatal pathway. Although morphologic features of astrogliosis were not attenuated, PT150 treatment promoted potentially neuroprotective activity in these cells, including increased phagocytosis of hyperphosphorylated α-syn. Ultimately, PT150 treatment reduced the loss of DAn cell bodies in the SN, but not the striatum, and prohibited intra-neuronal accumulation of α-syn. Together, these data indicate that PT150 effectively reduced SN pathology in the rotenone mouse model of PD.

Temperature and Neurologic Outcomes in Neonates Undergoing Cardiac Surgery: A Society of Thoracic Surgeons Study.

BACKGROUND: There is significant variability in postoperative neurological injury rates in patients with congenital heart disease, with early injuries impacting long-term neurodevelopmental outcomes; therefore, there is an urgent need for identifying effective strategies to mitigate such injuries. OBJECTIVES: This study aims to assess the association between nadir intraoperative temperature (NIT) and early neurological outcomes in neonates undergoing congenital heart surgery. METHODS: Analyzing data from 24,345 neonatal cardiac operations from the Society for Thoracic Surgeons Congenital Heart Surgery Database between 2010 and 2019, NIT was assessed using a mixed-effect logistic regression model, targeting major neurological injury (stroke, seizure, or deficit at discharge) as a primary endpoint. RESULTS: The study observed a shift from hypothermic circulatory arrest to cerebral perfusion with an increase in mean nadir temperature from 23.9 °C to 25.6 °C (P < 0.0001). Major neurological injury was noted in 4.9% of the cohort, with variations based on surgical procedure. After adjusting for risk, NIT was not significantly associated with major neurological injuries overall, but a lower NIT showed protective effects in the Norwood subgroup. Factors increasing the risk of major neurological injury included younger age at surgery, the Norwood procedure, longer cardiopulmonary bypass times, younger gestational age, presence of noncardiac abnormalities, and chromosomal anomalies. CONCLUSIONS: Whereas neurological injuries are prevalent after neonatal cardiac surgery, current practices lean towards higher core temperatures. This trend is supported by the nonsignificant impact of NIT on neurological outcomes. However, lower NIT in the Norwood subgroup indicates that reduced temperatures may be beneficial amidst specific risk factors.

Bioaccessibility of bioactive compounds from Pereskia aculeata and their cellular antioxidant effect.

Ora-pro-nobis (Pereskia aculeata) is a Cactaceae plant with edible leaves and fruits whose extracts are consumed to promote health, albeit bioactive compounds' bioaccessibility was still not assessed. To address this, ora-pro-nobis fruits (FE) and leaf extracts (LE) were subjected to in vitro digestion to better understand how this process impacts the bioactivities of the extracts. The study investigated the composition of the extracts, their cytotoxicity, and their chemical, plasmatic, and cellular antioxidant capacity. The results revealed that total polyphenolics were about 70% bioaccessible in LE and FE, with phenylalanine being the most bioaccessible essential amino acid in leaves (42.7%) and fruits (83.6%). The samples' antioxidant activity (CUPRAC) was reduced by 25%. LE demonstrated antioxidant activity against human plasma oxidation and haemolysis (21.8%), but digestion mitigated these activities. FE diminished haemolysis (47.0%) and presented cytotoxicity (IC50 = 1086 µg/mL) to HUVEC cells, but these properties were lost following digestion. Ultimately, digestion partially degraded the samples' bioactive compounds, diminishing their cellular protection against oxidative stress.

Early Methylglyoxal Exposure Leads to Worsened Cardiovascular Function in Young Rats.

BACKGROUND: Though maternal diabetes effects are well described in the literature, the effects of maternal diabetes in postnatal phases are often overlooked. Diabetic individuals have higher levels of circulating glycotoxins, and there is a positive correlation between maternal-derived glycotoxins and circulating glycotoxins in their progeny. Previous studies evaluated the metabolic effects of high glycotoxin exposure during lactation in adult animals. However, here we focus on the cardiovascular system of juvenile rats. METHODS: For this, we used two experimental models: 1. High Methylglyoxal (MG) environment: pregnant Wistar rats were injected with PBS (VEH group) or Methylglyoxal (MG group; 60 mg/kg/day; orally, postnatal day (PND) 3 to PND14). 2. GLO-1 inhibition: pregnant Wistar rats were injected with dimethyl sulfoxide (VEH group) or a GLO-1 inhibitor (BBGC group; 5 mg/kg/day; subcutaneously, PND1-PND5). The offspring were evaluated at PND45. RESULTS: MG offspring presented cardiac dysfunction and subtly worsened vasomotor responses in the presence of perivascular adipose tissue, without morphological alterations. In addition, an endogenous increase in maternal glycotoxins impacts offspring vasomotricity due to impaired redox status. CONCLUSIONS: Our data suggest that early glycotoxin exposure led to cardiac and vascular impairments, which may increase the risk for developing cardiovascular diseases later in life.

Early Life Adversity Predicts Reduced Hippocampal Volume in the Adolescent Brain Cognitive Development Study.

PURPOSE: Cross-sectional studies in adults have demonstrated associations between early life adversity (ELA) and reduced hippocampal volume, but the timing of these effects is not clear. The present study sought to examine whether ELA predicts changes in hippocampal volume over time in a large sample of early adolescents. METHODS: The Adolescent Brain Cognitive Development Study provides a large dataset of tabulated neuroimaging, youth-reported adverse experiences, and parent-reported financial adversity from a sample of children around the United States. Linear mixed effects modeling was used to determine the relationship between ELA and hippocampal volume change within youth (n = 7036) from ages 9-10 to 11-12 years. RESULTS: Results of the models indicated that the number of early adverse events predicted bilateral hippocampal volume change (ß = -0.02, t = -2.02, p < .05). Higher adversity was associated with lower hippocampal volume at Baseline (t = 5.55, p < .01) and at Year 2 (t = 6.14, p < .001). DISCUSSION: These findings suggest that ELA may affect hippocampal development during early adolescence. Prevention and early intervention are needed to alter the course of this trajectory. Future work should examine associations between ELA, hippocampal development, and educational and socioemotional outcomes.

Long-Term Statistical Process Monitoring of an Ultrafiltration Water Treatment Process.

As water treatment technology has improved, the amount of available process data has substantially increased, making real-time, data-driven fault detection a reality. One shortcoming of the fault detection literature is that methods are usually evaluated by comparing their performance on hand-picked, short-term case studies, which yields no insight into long-term performance. In this work, we first evaluate multiple statistical and machine learning approaches for detrending process data. Then, we evaluate the performance of a PCA-based fault detection approach, applied to the detrended data, to monitor influent water quality, filtrate quality, and membrane fouling of an ultrafiltration membrane system for indirect potable reuse. Based on two short case studies, the adaptive lasso detrending method is selected, and the performance of the multivariate approach is evaluated over more than a year. The method is tested for different sets of three critical tuning parameters, and we find that for long-term, autonomous monitoring to be successful, these parameters should be carefully evaluated. However, in comparison with industry standards of simpler, univariate monitoring or daily pressure decay tests, multivariate monitoring produces substantial benefits in long-term testing.

Impacts of early deprivation on behavioral and neural measures of executive function in early adolescence.

Children reared in institutional settings experience early deprivation that has lasting implications for multiple aspects of neurocognitive functioning, including executive function (EF). Changes in brain development are thought to contribute to these persistent EF challenges, but little research has used fMRI to investigate EF-related brain activity in children with a history of early deprivation. This study examined behavioral and neural data from a response conflict task in 12-14-year-olds who spent varying lengths of time in institutional care prior to adoption (N = 84; age at adoption - mean: 15.85 months, median: 12 months, range: 4-60 months). In initial analyses, earlier- and later-adopted (EA, LA) youth were compared to a group of children raised in their biological families (non-adopted, NA). NA youth performed significantly more accurately than LA youth, with EA youth falling in between. Imaging data suggested that previously institutionalized (PI) youth activated additional frontoparietal regions, including dorsolateral prefrontal cortex, as compared to NA youth. In addition, EA youth uniquely activated medial prefrontal regions, and LA uniquely activated parietal regions during this task. A separate analysis in a larger group of PI youth examined whether behavioral or brain measures of EF varied with the duration of deprivation experienced. Duration of deprivation was negatively associated with activation of default mode network (DMN) regions. Overall, results suggest that there are lasting effects of deprivation on EF, but that those who are removed from institutional care earlier may be able to recruit additional neural resources as a compensatory mechanism.

An unusual case of acquired generalized lipodystrophy (panniculitis variety).

Acquired generalized lipodystrophy (AGL) is a rare disease characterized by variable loss of adipose tissue and concurrent metabolic derangements, typically with childhood or adolescent onset. AGL has three subclassifications: panniculitis (type 1), autoimmune disease (type 2), and idiopathic (type 3). This report highlights a rare case of AGL type 1 in a previously healthy 3-year-old female who presented with diffuse erythematous subcutaneous nodules, progressive lipoatrophy, and histopathological findings of a lobular panniculitis.

ACR Appropriateness Criteria® Cerebrovascular Diseases-Stroke and Stroke-Related Conditions.

Cerebrovascular disease encompasses a vast array of conditions. The imaging recommendations for stroke-related conditions involving noninflammatory steno-occlusive arterial and venous cerebrovascular disease including carotid stenosis, carotid dissection, intracranial large vessel occlusion, and cerebral venous sinus thrombosis are encompassed by this document. Additional imaging recommendations regarding complications of these conditions including intraparenchymal hemorrhage and completed ischemic strokes are also discussed. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Co-designing discharge communication interventions for mental health visits to the pediatric emergency department: a mixed-methods study.

BACKGROUND: Discharge communication is essential to convey information regarding the care provided and follow-up plans after a visit to a hospital emergency department (ED), but it can be lacking for visits for pediatric mental health crises. Our objective was to co-design and conduct usability testing of new discharge communication interventions to improve pediatric mental health discharge communication. METHODS: The study was conducted in two phases using experience-based co-design (EBCD). In phase 1 (Sep 2021 to Jan 2022), five meetings were conducted with a team of six parents and two clinicians to co-design new ED discharge communication interventions for pediatric mental health care. Thematic analysis was used to identify patterns in team discussions and participant feedback related to discharge communication improvement and the Capability, Opportunity, Motivation, Behavior (COM-B) model was used to identify strategies to support the delivery of the new interventions. After meeting five, team members completed the Public and Patient Engagement Evaluation Tool (PPEET) to evaluate the co-design experience. In phase 2 (Apr to Jul 2022), intervention usability and satisfaction were evaluated by a new group of parents, youth aged 16-24 years, ED physicians, and nurses (n = 2 of each). Thematic analysis was used to identify usability issues and a validated 5-point Likert survey was used to evaluate user satisfaction. Evaluation results were used by the co-design team to finalize the interventions and delivery strategies. RESULTS: Two discharge communication interventions were created: a brochure for families and clinicians to use during the ED visit, and a text-messaging system for families after the visit. There was high satisfaction with engagement in phase 1 (overall mean PPEET score, 4.5/5). In phase 2, user satisfaction was high (mean clinician score, 4.4/5; mean caregiver/youth score, 4.1/5) with both interventions. Usability feedback included in the final intervention versions included instructions on intervention use and ensuring the text-messaging system activates within 12-24 h of discharge. CONCLUSIONS: The interventions produced by this co-design initiative have the potential to address gaps in current discharge practices. Future testing is required to evaluate the impact on patients, caregivers, and health care system use after the ED visit.

Discharge communication is an important component of an emergency department (ED) visit for a mental health crisis as most children who visit the ED for mental health care are discharged home. To date, patients and their caregivers have not been involved in developing discharge communication interventions for this type of care. Our aim was to involve patients and caregivers to improve the communication provided to children and their caregivers during ED visits for mental health crises. We established a design team made up of six parents and two clinicians to design two new discharge communication interventions: a brochure for families and clinicians to use together during the ED visit, and a text-messaging system to support families after the visit. We tested how useable these interventions were with four other ED health care providers, two parents, and two youth. These participants reported high user satisfaction with the brochure, and usability feedback was used by the design team to improve the final versions of the two interventions. At the end of the project, the design team reported high satisfaction with their engagement experiences with the project. The interventions created by the team have the potential to address knowns gaps in current discharge practices, but future testing is required to evaluate the impact of these interventions on patients, caregivers, and health care system use after the ED visit.

Electron-Activated Dissociation and Collision-Induced Dissociation Glycopeptide Fragmentation for Improved Glycoproteomics.

Tandem mass spectrometry coupled with liquid chromatography (LC-MS/MS) has proven a versatile tool for the identification and quantification of proteins and their post-translational modifications (PTMs). Protein glycosylation is a critical PTM for the stability and biological function of many proteins, but full characterization of site-specific glycosylation of proteins remains analytically challenging. Collision-induced dissociation (CID) is the most common fragmentation method used in LC-MS/MS workflows, but the loss of labile modifications renders CID inappropriate for detailed characterization of site-specific glycosylation. Electron-based dissociation methods provide alternatives that retain intact glycopeptide fragments for unambiguous site localization, but these methods often underperform CID due to increased reaction times and reduced efficiency. Electron-activated dissociation (EAD) is another strategy for glycopeptide fragmentation. Here, we use a ZenoTOF 7600 SCIEX instrument to compare the performance of various fragmentation techniques for the analysis of a complex mixture of mammalian O- and N-glycopeptides. We found CID fragmentation identified the most glycopeptides and generally produced higher quality spectra, but EAD provided improved confidence in glycosylation site localization. Supplementing EAD with CID fragmentation (EAciD) further increased the number and quality of glycopeptide identifications, while retaining localization confidence. These methods will be useful for glycoproteomics workflows for either optimal glycopeptide identification or characterization.

Non-transgenic guinea pig strains exhibit divergent age-related changes in hippocampal mitochondrial respiration.

AIM: Alzheimer's disease (AD) is the most common form of dementia. However, while 150+ animal models of AD exist, drug translation from preclinical models to humans for treatment usually fails. One factor contributing to low translation is likely the absence of neurodegenerative models that also encompass the multi-morbidities of human aging. We previously demonstrated that, in comparison to the PigmEnTed (PET) guinea pig strain which models "typical" brain aging, the Hartley strain develops hallmarks of AD like aging humans. Hartleys also exhibit age-related impairments in cartilage and skeletal muscle. Impaired mitochondrial respiration is one driver of both cellular aging and AD. In humans with cognitive decline, diminished skeletal muscle and brain respiratory control occurs in parallel. We previously reported age-related declines in skeletal muscle mitochondrial respiration in Hartleys. It is unknown if there is concomitant mitochondrial dysfunction in the brain. METHODS: Therefore, we assessed hippocampal mitochondrial respiration in 5- and 12-month Hartley and PET guinea pigs using high-resolution respirometry. RESULTS: At 12 months, PETs had higher complex I supported mitochondrial respiration paralleling their increase in body mass compared to 5 months PETs. Hartleys were also heavier at 12 months compared to 5 months but did not have higher complex I respiration. Compared to 5 months Hartleys, 12 months Hartleys had lower complex I mitochondrial efficiency and compensatory increases in mitochondrial proteins collectively suggesting mitochondrial dysfunction with age. CONCLUSIONS: Therefore, Hartleys might be a relevant model to test promising therapies targeting mitochondria to slow brain aging and AD progression.

Electroencephalographic Patterns on Follow-Up Visits in Extremely Premature Infants With Periventricular Leukomalacia: An Observational Study.

BACKGROUND: Periventricular leukomalacia (PVL) is a common brain injury in premature infants, and epilepsy remains a significant complication. One concerning electroencephalographic (EEG) pattern found is developmental and/or epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS). This pattern is associated with persistent neuropsychological and motor deficits, even without a diagnosis of epilepsy. The purpose of this study is to identify the relationships between various PVL grades and EEG patterns in this population on follow-up visits, especially the occurrence of DEE-SWAS pattern on EEG. METHODS: This is a retrospective study of <36 weeks gestational age newborns who were followed in the neurodevelopmental clinic at Corewell Health East/Corewell Health Children's Hospital in Royal Oak, Michigan, between 2020 and 2022. Patients' demographics along with prematurity complications, diagnostic head ultrasound (HUS), and EEG studies were reviewed and graded. EEG studies are usually ordered when seizures were suspected. RESULTS: A total of 155 newborns met the inclusion criteria. Twenty-six patients had PVL. Nine patients had grade 2 to 3 PVL based on HUS review. EEG was performed on 15 patients with PVL at a mean age of 22 months. More severe PVL grades were significantly associated with worse EEG patterns (P = 0.005). Five patients had DEE-SWAS pattern on EEG, all of whom had grade 2 or 3 PVL. Epilepsy was eventually diagnosed in three infants with PVL. CONCLUSIONS: EEG can help identify important abnormal electrographic patterns in premature infants with PVL early in life; this might give a window of opportunity to intervene early and improve long-term developmental outcomes in this population.

Tirzepatide modulates the regulation of adipocyte nutrient metabolism through long-acting activation of the GIP receptor.

Tirzepatide, a glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 receptor (GIPR/GLP-1R) agonist, has, in clinical trials, demonstrated greater reductions in glucose, body weight, and triglyceride levels compared with selective GLP-1R agonists in people with type 2 diabetes (T2D). However, cellular mechanisms by which GIPR agonism may contribute to these improved efficacy outcomes have not been fully defined. Using human adipocyte and mouse models, we investigated how long-acting GIPR agonists regulate fasted and fed adipocyte functions. In functional assays, GIPR agonism enhanced insulin signaling, augmented glucose uptake, and increased the conversion of glucose to glycerol in a cooperative manner with insulin; however, in the absence of insulin, GIPR agonists increased lipolysis. In diet-induced obese mice treated with a long-acting GIPR agonist, circulating triglyceride levels were reduced during oral lipid challenge, and lipoprotein-derived fatty acid uptake into adipose tissue was increased. Our findings support a model for long-acting GIPR agonists to modulate both fasted and fed adipose tissue function differentially by cooperating with insulin to augment glucose and lipid clearance in the fed state while enhancing lipid release when insulin levels are reduced in the fasted state.

A real-time prognostic model for venous thromboembolic events among hospitalized adults.

Background: Hospital-acquired venous thromboembolism (HA-VTE) is a leading cause of morbidity and mortality among hospitalized adults. Guidelines recommend use of a risk-prediction model to estimate HA-VTE risk for individual patients. Extant models do not perform well for broad patient populations and are not conducive to automation in clinical practice. Objectives: To develop an automated, real-time prognostic model for venous thromboembolism during hospitalization among all adult inpatients using readily available data from the electronic health record. Methods: The derivation cohort included inpatient hospitalizations ("encounters") for patients ≥16 years old at Vanderbilt University Medical Center between 2018 and 2020 (n = 132,330). HA-VTE events were identified using International Classification of Diseases, 10th Revision, codes. The prognostic model was developed using least absolute shrinkage and selection operator regression. Temporal external validation was performed in a validation cohort of encounters between 2021 and 2022 (n = 62,546). Prediction performance was assessed by discrimination accuracy (C statistic) and calibration (integrated calibration index). Results: There were 1187 HA-VTEs in the derivation cohort (9.0 per 1000 encounters) and 864 in the validation cohort (13.8 per 1000 encounters). The prognostic model included 25 variables, with placement of a central line among the most important predictors. Prediction performance of the model was excellent (C statistic, 0.891; 95% CI, 0.882-0.900; integrated calibration index, 0.001). The model performed similarly well across subgroups of patients defined by age, sex, race, and type of admission. Conclusion: This fully automated prognostic model uses readily available data from the electronic health record, exhibits superior prediction performance compared with existing models, and generates granular risk stratification in the form of a predicted probability of HA-VTE for each patient.

Contribution of emissions from the oil sands activities in Alberta, Canada to atmospheric concentration and deposition of nitrogen and sulfur species at a downwind site.

Oil sands activities in the Athabasca Oil Sands Region in Alberta, Canada, are large sources of atmospheric NOx and SO2. This study investigated the impact of oil sands emissions on the atmospheric deposition of nitrogen and sulfur species at a downwind site, about 350 km from the oil sands facilities. Measurement data are from the Canadian Air and Precipitation Monitoring Network (CAPMoN) from 2015 to 2019, including ambient concentrations of HNO3, pNO3-, NO2, pNH4+, NH3, SO2, pSO42- and base cations, as well as concentrations of NO3-, SO42-, NH4+, and base cations in precipitation. Sector analysis of air mass back trajectories was conducted to distinguish measurements with different air mass origins. Median atmospheric concentrations and dry deposition fluxes of HNO3, pNO3-, NO2, pNH4+, pSO42-, and SO2 on days when the air masses came from the oil sands sector were significantly greater than those with the "Clean" sector by 34-67%, whereas the difference in NH3 concentration was not significant. Contributions of the oil sands emissions to dry deposition fluxes of these species ranged from 3.8 to 13.1%. The precipitation-weighted mean concentrations of NO3-, SO42-, and NH4+ in samples with the oil sands sector were 76 %, 65 % and 81 % greater than those with the "Clean" sector, respectively. Contributions of the oil sands emissions to wet deposition of NO3-, SO42-, and NH4+ were 12.5 ± 8.9 %, 8.7 ± 4.4 %, and 6.0 ± 3.3 %, respectively. The annual total deposition of nitrogen and sulfur were 1.9 kg-N ha-1 and 0.74 kg-S ha-1, respectively, of which 8.0 ± 3.5 % and 8.7 ± 3.6 % were from oil sands emissions. The total deposition of sulfur and nitrogen did not exceed the critical loads (CL) of acidity, but nitrogen deposition exceeded the CLs of nutrient nitrogen in the region.

Molecular and circuit determinants in the globus pallidus mediating control of cocaine-induced behavioral plasticity.

The globus pallidus externus (GPe) is a central component of the basal ganglia circuit, receiving strong input from the indirect pathway and regulating a variety of functions, including locomotor output and habit formation. We recently showed that it also acts as a gatekeeper of cocaine-induced behavioral plasticity, as inhibition of parvalbumin-positive cells in the GPe (GPe PV ) prevents the development of cocaine-induced reward and sensitization. However, the molecular and circuit mechanisms underlying this function are unknown. Here we show that GPe PV cells control cocaine reward and sensitization by inhibiting GABAergic neurons in the substantia nigra pars reticulata (SNr GABA ), and ultimately, selectively modulating the activity of ventral tegmental area dopamine (VTA DA ) cells projecting to the lateral shell of the nucleus accumbens (NAcLat). A major input to GPe PV cells is the indirect pathway of the dorsomedial striatum (DMS D 2 ), which receives DAergic innervation from collaterals of VTA DA →NAcLat cells, making this a closed-loop circuit. Cocaine likely facilitates reward and sensitization not directly through actions in the GPe, but rather in the upstream DMS, where the cocaine-induced elevation of DA triggers a depression in DMS D 2 cell activity. This cocaine-induced elevation in DA levels can be blocked by inhibition of GPe PV cells, closing the loop. Interestingly, the level of GPe PV cell activity prior to cocaine administration is correlated with the extent of reward and sensitization that animals experience in response to future administration of cocaine, indicating that GPe PV cell activity is a key predictor of future behavioral responses to cocaine. Single nucleus RNA-sequencing of GPe cells indicated that genes encoding voltage-gated potassium channels KCNQ3 and KCNQ5 that control intrinsic cellular excitability are downregulated in GPe PV cells following a single cocaine exposure, contributing to the elevation in GPe PV cell excitability. Acutely activating channels containing KCNQ3 and/or KCNQ5 using the small molecule carnosic acid, a key psychoactive component of Salvia rosmarinus (rosemary) extract, reduced GPe PV cell excitability and also impaired cocaine reward, sensitization, and volitional cocaine intake, indicating its potential as a therapeutic to counteract psychostimulant use disorder. Our findings illuminate the molecular and circuit mechanisms by which the GPe orchestrates brain-wide changes in response to cocaine that are required for reward, sensitization, and self-administration behaviors.