HIV-1 infection of genetically engineered iPSC-derived central nervous system-engrafted microglia in a humanized mouse model.

IMPORTANCE: Our mouse model is a powerful tool for investigating the genetic mechanisms governing central nervous system (CNS) human immunodeficiency virus type-1 (HIV-1) infection and latency in the CNS at a single-cell level. A major advantage of our model is that it uses induced pluripotent stem cell-derived microglia, which enables human genetics, including gene function and therapeutic gene manipulation, to be explored in vivo, which is more challenging to study with current hematopoietic stem cell-based models for neuroHIV. Our transgenic tracing of xenografted human cells will provide a quantitative medium to develop new molecular and epigenetic strategies for reducing the HIV-1 latent reservoir and to test the impact of therapeutic inflammation-targeting drug interventions on CNS HIV-1 latency.

HIV-1 infection of genetically engineered iPSC-derived central nervous system-engrafted microglia in a humanized mouse model.

The central nervous system (CNS) is a major human immunodeficiency virus type 1 reservoir. Microglia are the primary target cell of HIV-1 infection in the CNS. Current models have not allowed the precise molecular pathways of acute and chronic CNS microglial infection to be tested with in vivo genetic methods. Here, we describe a novel humanized mouse model utilizing human-induced pluripotent stem cell-derived microglia to xenograft into murine hosts. These mice are additionally engrafted with human peripheral blood mononuclear cells that served as a medium to establish a peripheral infection that then spread to the CNS microglia xenograft, modeling a trans-blood-brain barrier route of acute CNS HIV-1 infection with human target cells. The approach is compatible with iPSC genetic engineering, including inserting targeted transgenic reporter cassettes to track the xenografted human cells, enabling the testing of novel treatment and viral tracking strategies in a comparatively simple and cost-effective way vivo model for neuroHIV.

The impact of cannabinoids on inflammasome signaling in HIV-1 infection.

Human immunodeficiency virus type 1 (HIV-1) is a chronic disease that afflicts over 38 million people worldwide without a known cure. The advent of effective antiretroviral therapies (ART) has significantly decreased the morbidity and mortality associated with HIV-1 infection in people living with HIV-1 (PWH), thanks to durable virologic suppression. Despite this, people with HIV-1 experience chronic inflammation associated with co-morbidities. While no single known mechanism accounts for chronic inflammation, there is significant evidence to support the role of the NLRP3 inflammasome as a key driver. Numerous studies have demonstrated therapeutic impact of cannabinoids, including exerting modulatory effects on the NLRP3 inflammasome. Given the high rates of cannabinoid use in PWH, it is of great interest to understand the intersecting biology of the role of cannabinoids in HIV-1-associated inflammasome signaling. Here we describe the literature of chronic inflammation in people with HIV, the therapeutic impact of cannabinoids in PWH, endocannabinoids in inflammation, and HIV-1-associated inflammation. We describe a key interaction between cannabinoids, the NLRP3 inflammasome, and HIV-1 viral infection, which supports further investigation of the critical role of cannabinoids in HIV-1 infection and inflammasome signaling.

Inflammasomes as mediators of inflammation in HIV-1 infection.

Human immunodeficiency virus type 1 (HIV-1) infection is a chronic disease without a known cure. The advent of effective antiretroviral therapy (ART) has enabled people with HIV (PWH) to have significantly prolonged life expectancies. As a result, morbidity and mortality associated with HIV-1 infection have declined considerably. However, these individuals experience chronic systemic inflammation whose multifaceted etiology is associated with other numerous comorbidities. Inflammasomes are vital mediators that contribute to inflammatory signaling in HIV-1 infection. Here, we provide an overview of the inflammatory pathway that underlies HIV-1 infection, explicitly highlighting the role of the NLRP3 inflammasome. We also delineate the current literature on inflammasomes and the therapeutic targeting strategies aimed at the NLRP3 inflammasome to moderate HIV-1 infection-associated inflammation. Here we describe the NLRP3 inflammasome as a key pathway in developing novel therapeutic targets to block HIV-1 replication and HIV-1-associated inflammatory signaling. Controlling the inflammatory pathways is critical in alleviating the morbidities and mortality associated with chronic HIV-1 infection in PWH.

Cavitary Legionella Pneumonia in AIDS: When Intracellular Immunity Failure Leads to Rapid Intrapulmonary Cavitation.

Introduction. Legionella is a frequent cause of bacterial pneumonia in patients with AIDS. While multiple organisms have been associated with cavitary pneumonia in this population, Legionella has not. Clinical Case. A middle-aged woman with HIV-AIDS and severely depressed CD-4 count presented with one month of progressively worsening productive cough and dyspnea. Serial imaging showed focal consolidations which multiplied and cavitated over the subsequent days. Legionella urine antigen was positive, and appropriate treatment was continued for 3 weeks total. The patient recovered quickly, and follow-up imaging 8 weeks later showed near-resolution of all lesions. Discussion. Cavitary pneumonia secondary to Legionella has been seldom described, traditionally in the context of immunosuppressive therapy. Patients with AIDS and severely depressed CD4 counts have significantly compromised cell-mediated immunity. This case highlights the importance of consideration for legionellosis in rapidly progressing cavitary pneumonia, especially in patients with severely compromised cell-mediated immunity, including those with HIV-AIDS.

P2RX7 at the Host-Pathogen Interface of Infectious Diseases.

The P2X7 receptor (P2RX7) is an important molecule that functions as a danger sensor, detecting extracellular nucleotides from injured cells and thus signaling an inflammatory program to nearby cells. It is expressed in immune cells and plays important roles in pathogen surveillance and cell-mediated responses to infectious organisms. There is an abundance of literature on the role of P2RX7 in inflammatory diseases and the role of these receptors in host-pathogen interactions. Here, we describe the current knowledge of the role of P2RX7 in the host response to a variety of pathogens, including viruses, bacteria, fungi, protozoa, and helminths. We describe in vitro and in vivo evidence for the critical role these receptors play in mediating and modulating immune responses. Our observations indicate a role for P2X7 signaling in sensing damage-associated molecular patterns released by nearby infected cells to facilitate immunopathology or protection. In this review, we describe how P2RX7 signaling can play critical roles in numerous cells types in response to a diverse array of pathogens in mediating pathogenesis and immunity to infectious agents.

Academic Life in Emergency Medicine Blog and Podcast Watch: Respiratory Emergencies.

The Academic Life in Emergency Medicine (ALiEM) Approved Instructional Resources (AIR) Series and Approved Instruction Resources Professional (AIR-Pro) Series were created in 2014 and 2015, respectively, to address the need for curation of online educational content as well as a nationally available curriculum that meets individualized interactive instruction criteria. These two programs identify high-quality educational blog and podcast content using an expert-based approach. We summarize the accredited posts on respiratory emergencies that met our a priori determined quality criteria per evaluation by eight experienced faculty educators in emergency medicine.

Shadowing emergency medicine residents by medical education specialists to provide feedback on non-medical knowledge-based ACGME sub-competencies.

OBJECTIVE: Non-medical knowledge-based sub-competencies (multitasking, professionalism, accountability, patient-centered communication, and team management) are challenging for a supervising emergency medicine (EM) physician to evaluate in real-time on shift while also managing a busy emergency department (ED). This study examines residents' perceptions of having a medical education specialist shadow and evaluate their nonmedical knowledge skills. METHODS: Medical education specialists shadowed postgraduate year 1 and postgraduate year 2 EM residents during an ED shift once per academic year. In an attempt to increase meaningful feedback to the residents, these specialists evaluated resident performance in selected non-medical knowledge-based Accreditation Council of Graduate Medical Education (ACGME) sub-competencies and provided residents with direct, real-time feedback, followed by a written evaluation sent via email. Evaluations provided specific references to examples of behaviors observed during the shift and connected these back to ACGME competencies and milestones. RESULTS: Twelve residents participated in this shadow experience (six post graduate year 1 and six postgraduate year 2). Two residents emailed the medical education specialists ahead of the scheduled shadow shift requesting specific feedback. When queried, five residents voluntarily requested their feedback to be included in their formal biannual review. Residents received milestone scores and narrative feedback on the non-medical knowledge-based ACGME sub-competencies and indicated the shadow experience and subsequent feedback were valuable. CONCLUSION: Medical education specialists who observe residents over the course of an entire shift and evaluate non-medical knowledge-based skills are perceived by EM residents to provide meaningful feedback and add valuable information for the biannual review process.

Academic Life in Emergency Medicine (ALiEM) Blog and Podcast Watch: Renal and Genitourinary Emergencies.

The Academic Life in Emergency Medicine (ALiEM) Approved Instructional Resources (AIR) series and Approved Instruction Resources Professional (AIR-Pro) series were created in 2014 and 2015, respectively, to address the need for the curation of online educational content as well as a nationally available curriculum that meets individualized interactive instruction criteria. These two programs identify high-quality educational blog and podcast content using an expert-based approach. The AIR series is a continuously building curriculum originally based on the Council of Emergency Medicine Directors (CORD) testing schedule. Using the ALiEM AIR scoring instrument, 49 blog posts and podcasts relevant to renal and genitourinary emergencies published within the previous 12 months were evaluated by eight attending physicians. We summarize the 13 posts that met our a priori determined quality criteria per evaluation by the reviewers. The ALiEM Blog and Podcast Watch series identifies high-quality educational blogs and podcasts for emergency medicine clinicians through its expert panel, using a validated scoring instrument. While this article focuses on renal and genitourinary emergencies, additional AIR modules address other topics in emergency medicine. The AIR and AIR-Pro series provide post-publication accreditation and curation of recent online content to identify and recommend high-quality educational social media content for the EM clinician.

Blog and Podcast Watch: Orthopedic Emergencies.

INTRODUCTION: The WestJEM Blog and Podcast Watch presents high quality open-access educational blogs and podcasts in emergency medicine (EM) based on the ongoing ALiEM Approved Instructional Resources (AIR) and AIR-Professional series. Both series critically appraise resources using an objective scoring rubric. This installment of the Blog and Podcast Watch highlights the topic of orthopedic emergencies from the AIR series. METHODS: The AIR series is a continuously building curriculum that follows the Council of Emergency Medicine Residency Directors (CORD) annual testing schedule. For each module, relevant content is collected from the top 50 Social Media Index sites published within the previous 12 months, and scored by eight AIR board members using five equally weighted measurement outcomes: Best Evidence in Emergency Medicine (BEEM) score, accuracy, educational utility, evidence based, and references. Resources scoring ≥30 out of 35 available points receive an AIR label. Resources scoring 27-29 receive an honorable mention label, if the executive board agrees that the post is accurate and educationally valuable. RESULTS: A total of 87 blog posts and podcasts were evaluated. Key educational pearls from the three AIR posts and the 14 honorable mentions are summarized. CONCLUSION: The WestJEM Blog and Podcast Watch series is based on the AIR and AIR-Pro series, which attempts to identify high quality educational content on open-access blogs and podcasts. This series provides an expert-based, post-publication curation of educational social media content for EM clinicians with this installment focusing on orthopedic emergencies.

Development of a novel sports medicine rotation for emergency medicine residents.

Musculoskeletal complaints are the most common reason for patients to visit a physician, yet competency in musculoskeletal medicine is invariably reported as a deficiency in medical education in the USA. Sports medicine clinical rotations improve both medical students' and residents' musculoskeletal knowledge. Despite the importance of this knowledge, a standardized sports medicine curriculum in emergency medicine (EM) does not exist. Hence, we developed a novel sports medicine rotation for EM residents to improve their musculoskeletal educational experience and to improve their knowledge in musculoskeletal medicine by teaching the evaluation and management of many common musculoskeletal disorders and injuries that are encountered in the emergency department. The University of Arizona has two distinct EM residency programs, South Campus (SC) and University Campus (UC). The UC curriculum includes a traditional 4-week orthopedic rotation, which consistently rated poorly on evaluations by residents. Therefore, with the initiation of a new EM residency at SC, we replaced the standard orthopedic rotation with a novel sports medicine rotation for EM interns. This rotation includes attendance at sports medicine clinics with primary care and orthopedic sports medicine physicians, involvement in sport event coverage, assigned reading materials, didactic experiences, and an on-call schedule to assist with reductions in the emergency department. We analyzed postrotation surveys completed by residents, postrotation evaluations of the residents completed by primary care sports medicine faculty and orthopedic chief residents, as well as the total number of dislocation reductions performed by each graduating resident at both programs over the last 5 years. While all residents in both programs exceeded the ten dislocation reductions required for graduation, residents on the sports medicine rotation had a statistically significant higher rate of satisfaction of their educational experience when compared to the traditional orthopedics rotation. All SC residents successfully completed their sports medicine rotation, had completed postrotation evaluations by attending physicians, and had no duty hour violations while on sports medicine. In our experience, a sports medicine rotation is an effective alternative to the traditional orthopedics rotation for EM residents.

How well will you FIT? Use of a modified MMI to assess applicants' compatibility with an emergency medicine residency program.

PURPOSE: Emergency medicine residency programs have evaluated the use of Multiple Mini Interviews (MMIs) for applicants. The authors developed an MMI-style method called the Fast Interview Track (FIT) to predict an applicant's 'fit' within an individual residency program. METHODS: Applicants meet with up to five residents and are asked one question by each. Residents score the applicant using a Likert scale from 1 to 5 on two questions: 'How well does the applicant think on his/her feet?' and 'How well do you think the applicant will fit in here?'. To assess how well these questions predicted a resident's 'fit', current residents scored fellow residents on these same questions. These scores were compared with the residents' interview FIT scores. A postmatch survey of applicants who did not match at this program solicited applicants' attitudes toward the FIT sessions. RESULTS: Among the junior class, the correlation between interview and current scores was significant for question 1 (rho=0.5192 [p=0.03]) and question 2 (rho=0.5753 [p=0.01]). Among seniors, Spearman's rho was statistically significant for question 2, though not statistically significant for question 1. The chi-square measure of high scores (4-5) versus low scores (1-3) found a statistically significant association between interview and current scores for interns and juniors. Of the 29 responses to the postmatch survey, 16 (55%) felt FIT sessions provided a good sense of the program's personality and only 6 (21%) disagreed. Nine (31%) felt FIT sessions positively impacted our program's ranking and 11 (38%) were 'Neutral'. Only two (7%) reported that FIT sessions negatively impacted their ranking of our program. CONCLUSIONS: FIT provided program leadership with a sense of an applicant's 'fit' within this program. Interview day scores correlated with scores received during residency. Most applicants report a positive experience with FIT sessions. FIT provides a useful tool to recruit applicants who fit with the residency program.

Social worker assessment of bad news delivery by emergency medicine residents: a novel direct-observation milestone assessment.

The skill of delivering bad news is difficult to teach and evaluate. Residents may practice in simulated settings; however, this may not translate to confidence or competence during real experiences. We investigated the acceptability and feasibility of social workers as evaluators of residents' delivery of bad news during patient encounters, and assessed the attitudes of both groups regarding this process. From August 2013 to June 2014, emergency medicine residents completed self-assessments after delivering bad news. Social workers completed evaluations after observing these conversations. The Assessment tools were designed by modifying the global Breaking Bad News Assessment Scale. Residents and social workers completed post-study surveys. 37 evaluations were received, 20 completed by social workers and 17 resident self-evaluations. Social workers reported discussing plans with residents prior to conversations 90 % of the time (18/20, 95 % CI 64.5, 97.8). Social workers who had previously observed the resident delivering bad news reported that the resident was more skilled on subsequent encounters 90 % of the time (95 % CI 42.2, 99). Both social workers and residents felt that prior training or experience was important. First-year residents valued advice from social workers less than advice from attending physicians, whereas more experienced residents perceived advice from social workers to be equivalent with that of attending physicians (40 versus 2.9 %, p = 0.002). Social worker assessment of residents' abilities to deliver bad news is feasible and acceptable to both groups. This formalized self-assessment and evaluation process highlights the importance of social workers' involvement in delivery of bad news, and the teaching of this skill. This method may also be used as direct-observation for resident milestone assessment.

Sleep disturbances predict prospective declines in resident physicians' psychological well-being.

BACKGROUND: Medical residency can be a time of increased psychological stress and sleep disturbance. We examine the prospective associations between self-reported sleep quality and resident wellness across a single training year. METHODS: Sixty-nine (N=69) resident physicians completed the Brief Resident Wellness Profile (M=17.66, standard deviation [SD]=3.45, range: 0-17) and the Pittsburgh Sleep Quality Index (M=6.22, SD=2.86, range: 12-25) at multiple occasions in a single training year. We examined the 1-month lagged effect of sleep disturbances on residents' self-reported wellness. RESULTS: Accounting for residents' overall level of sleep disturbance across the entire study period, both the concurrent (within-person) within-occasion effect of sleep disturbance (B=-0.20, standard error [SE]=0.06, p=0.003, 95% confidence interval [CI]: -0.33, -0.07) and the lagged within-person effect of resident sleep disturbance (B=-0.15, SE=0.07, p=0.037, 95% CI: -0.29, -0.009) were significant predictors of decreased resident wellness. Increases in sleep disturbances are a leading indicator of resident wellness, predicting decreased well-being 1 month later. CONCLUSIONS: Sleep quality exerts a significant effect on self-reported resident wellness. Periodic evaluation of sleep quality may alert program leadership and the residents themselves to impending decreases in psychological well-being.

Implementation of the Introductory Clinician Development Series: an optional boot camp for Emergency Medicine interns.

BACKGROUND: The transition from medical student to first-year intern can be challenging. The stress of increased responsibilities, the gap between performance expectations and varying levels of clinical skills, and the need to adapt to a new institutional space and culture can make this transition overwhelming. Orientation programs intend to help new residents prepare for their new training environment. OBJECTIVE: To ease our interns' transition, we piloted a novel clinical primer course. We believe this course will provide an introduction to basic clinical knowledge and procedures, without affecting time allotted for mandatory orientation activities, and will help the interns feel better prepared for their clinical duties. METHODS: First-year Emergency Medicine residents were invited to participate in this primer course, called the Introductory Clinician Development Series (or "intern boot camp"), providing optional lecture and procedural skills instruction prior to their participation in the mandatory orientation curriculum and assumption of clinical responsibilities. Participating residents completed postcourse surveys asking for feedback on the experience. RESULTS: Survey responses indicated that the intern boot camp helped first-year residents feel more prepared for their clinical shifts in the Emergency Department. CONCLUSION: An optional clinical introductory series can allow for maintenance of mandatory orientation activities and clinical shifts while easing the transition from medical student to clinician.

Role of an audience response system in didactic attendance and assessment.

BACKGROUND: The Residency Review Committee for Emergency Medicine mandates conference participation, but tracking attendance is difficult and fraught with errors. Feedback on didactic sessions, if not collected in real time, is challenging to obtain. OBJECTIVE: We assessed whether an audience response system (ARS) would (1) encourage residents to arrive on time for lectures, and (2) increase anonymous real-time audience feedback. METHODS: The ARS (Poll Everywhere) provided date/time-stamped responses to polls from residents, including a question to verify attendance and questions to gather immediate, anonymous postconference evaluations. Fisher exact test was used to calculate proportions. RESULTS: The proportion of residents who completed evaluations prior to the institution of the ARS was 8.75, and it was 59.42 after (P < .001). The proportion of faculty who completed evaluations prior to using the ARS was 6.12, and it was 85.71 after (P < .001). The proportion of residents who reported they had attended the conference session was 55 for the 3 weeks prior to initiating the ARS, decreasing to 46.67 for the 3 weeks during which the ARS was used to take attendance (P  =  .46). The proportion of faculty who reported attending the conference was 5.56 for the 3 weeks prior to ARS initiation, decreasing to 4.44 for the 3 weeks while using the ARS (P  =  .81). CONCLUSIONS: Audience response systems are an effective way to verify attendance and tardiness, eliminating the subjective effect of attendance takers' leniency and increasing completion of evaluations for didactic sessions.

Does the experience of the writer affect the evaluative components on the standardized letter of recommendation in emergency medicine?

BACKGROUND: The Standardized Letter of Recommendation (SLOR) was developed in an attempt to standardize the evaluation of applicants to an emergency medicine (EM) residency. OBJECTIVE: Our aim was to determine whether the Global Assessment Score (GAS) and Likelihood of Matching Assessment (LOMA) of the SLOR for applicants applying to an EM residency are affected by the experience of the letter writer. We describe the distribution of GAS and LOMA grades and compare the GAS and LOMA scores to length of time an applicant knew the letter writer and number of EM rotations. METHODS: We conducted a retrospective review of all SLORs written for all applicants applying to three EM residency programs for the 2012 match. Median number of letters written the previous year were compared across the four GAS and LOMA scores using an equality of medians test and test for trend to see if higher scores on the GAS and LOMA were associated with less experienced letter writers. Distributions of the scores were determined and length of time a letter writer knew an applicant and number of EM rotations were compared with GAS and LOMA scores. RESULTS: There were 917 applicants representing 27.6% of the total applicant pool for the 2012 United States EM residency match and 1253 SLORs for GAS and 1246 for LOMA were analyzed. The highest scores on the GAS and LOMA were associated with the lowest median number of letters written the previous year (equality of medians test across groups, p < 0.001; test for trend, p < 0.001). Less than 3% received the lowest score for GAS and LOMA. Among letter writers that knew an applicant for more than 1 year, 45.3% gave a GAS score of "Outstanding" and 53.4% gave a LOMA of "Very Competitive" compared with 31.7% and 39.6%, respectively, if the letter writer knew them 1 year or less (p = 0.002; p = 0.005). Number of EM rotations was not associated with GAS and LOMA scores. CONCLUSIONS: SLORs written by less experienced letter writers were more likely to have a GAS of "Outstanding" (p < 0.001) and a LOMA of "Very Competitive" (p < 0.001) than more experienced letter writers. The overall distribution of GAS and LOMA was heavily weighted to the highest scores. The length of time a letter writer knew an applicant was significantly associated with GAS and LOMA scores.

Syndromic surveillance for influenza in the emergency department-A systematic review.

The science of surveillance is rapidly evolving due to changes in public health information and preparedness as national security issues, new information technologies and health reform. As the Emergency Department has become a much more utilized venue for acute care, it has also become a more attractive data source for disease surveillance. In recent years, influenza surveillance from the Emergency Department has increased in scope and breadth and has resulted in innovative and increasingly accepted methods of surveillance for influenza and influenza-like-illness (ILI). We undertook a systematic review of published Emergency Department-based influenza and ILI syndromic surveillance systems. A PubMed search using the keywords "syndromic", "surveillance", "influenza" and "emergency" was performed. Manuscripts were included in the analysis if they described (1) data from an Emergency Department (2) surveillance of influenza or ILI and (3) syndromic or clinical data. Meeting abstracts were excluded. The references of included manuscripts were examined for additional studies. A total of 38 manuscripts met the inclusion criteria, describing 24 discrete syndromic surveillance systems. Emergency Department-based influenza syndromic surveillance has been described worldwide. A wide variety of clinical data was used for surveillance, including chief complaint/presentation, preliminary or discharge diagnosis, free text analysis of the entire medical record, Google flu trends, calls to teletriage and help lines, ambulance dispatch calls, case reports of H1N1 in the media, markers of ED crowding, admission and Left Without Being Seen rates. Syndromes used to capture influenza rates were nearly always related to ILI (i.e. fever +/- a respiratory or constitutional complaint), however, other syndromes used for surveillance included fever alone, "respiratory complaint" and seizure. Two very large surveillance networks, the North American DiSTRIBuTE network and the European Triple S system have collected large-scale Emergency Department-based influenza and ILI syndromic surveillance data. Syndromic surveillance for influenza and ILI from the Emergency Department is becoming more prevalent as a measure of yearly influenza outbreaks.

Online research article discussion board to increase knowledge translation during emergency medicine residency.

BACKGROUND: Many clinicians have difficulties reading current best practice journal articles on a regular basis. Discussion boards are one method of online asynchronous learning that facilitates active learning and participation. We hypothesized that an online repository of best practice articles with a discussion board would increase journal article reading by emergency medicine residents. METHODS: PARTICIPANTS ANSWERED THREE QUESTIONS WEEKLY ON A DISCUSSION BOARD: What question does this study address? What does this study add to our knowledge? How might this change clinical practice? A survey regarding perceived barriers to participating was then distributed. RESULTS: Most participants completed an article summary once or twice in total (23/32, 71.9%). Only three were involved most weeks (3/32, 9.4%) whereas 5/32 (15.6%) participated monthly. The most common barriers were lack of time (20/32, 62.5%), difficulty logging on (7/32, 21.9%), and forgetting (6/32, 18.8%). CONCLUSION: Although subjects were provided weekly with an article link, email, and feedback, journal article reading frequency did not increase.

Argonaute 2 in dopamine 2 receptor-expressing neurons regulates cocaine addiction.

Cocaine is a highly addictive drug that exerts its effects by increasing the levels of released dopamine in the striatum, followed by stable changes in gene transcription, mRNA translation, and metabolism within medium spiny neurons in the striatum. The multiple changes in gene and protein expression associated with cocaine addiction suggest the existence of a mechanism that facilitates a coordinated cellular response to cocaine. Here, we provide evidence for a key role of miRNAs in cocaine addiction. We show that Argonaute 2 (Ago2), which plays an important role in miRNA generation and execution of miRNA-mediated gene silencing, is involved in regulation of cocaine addiction. Deficiency of Ago2 in dopamine 2 receptor (Drd2)-expressing neurons greatly reduces the motivation to self-administer cocaine in mice. We identified a distinct group of miRNAs that is specifically regulated by Ago2 in the striatum. Comparison of miRNAs affected by Ago2 deficiency with miRNAs that are enriched and/or up-regulated in Drd2-neurons in response to cocaine identified a set of miRNAs that are likely to play a role in cocaine addiction.