Accumbens D2-MSN hyperactivity drives antipsychotic-induced behavioral supersensitivity

Antipsychotic-induced dopamine supersensitivity, or behavioral supersensitivity, is a problematic consequence of long-term antipsychotic treatment characterized by the emergence of motor abnormalities, refractory symptoms, and rebound psychosis. The underlying mechanisms are unclear and no approaches exist to prevent or reverse these unwanted effects of antipsychotic treatment. Here we demonstrate that behavioral supersensitivity stems from long-lasting pre, post and perisynaptic plasticity, including insertion of Ca2+-permeable AMPA receptors and loss of D2 receptor-dependent inhibitory postsynaptic currents (IPSCs) in D2 receptor-expressing medium spiny neurons (D2-MSNs) in the nucleus accumbens core (NAcore). The resulting hyperexcitability, prominent in a subpopulation of D2-MSNs (21%), caused locomotor sensitization to cocaine and was associated with behavioral endophenotypes of antipsychotic treatment resistance and substance use disorder, including disrupted extinction learning and augmented cue-induced cocaine-seeking behavior. Chemogenetic restoration of IPSCs in D2-MSNs in the NAcore was sufficient to prevent antipsychotic-induced supersensitivity, pointing to an entirely novel therapeutic direction for overcoming this condition

Cancer Stem Cells in Neuroblastoma: Expanding the Therapeutic Frontier

Neuroblastoma (NB) is the most common extracranial solid tumor often diagnosed in childhood. Despite intense efforts to develop a successful treatment, current available therapies are still challenged by high rates of resistance, recurrence and progression, most notably in advanced cases and highly malignant tumors. Emerging evidence proposes that this might be due to a subpopulation of cancer stem cells (CSCs) or tumor-initiating cells (TICs) found in the bulk of the tumor. Therefore, the development of more targeted therapy is highly dependent on the identification of the molecular signatures and genetic aberrations characteristic to this subpopulation of cells. This review aims at providing an overview of the key molecular players involved in NB CSCs and focuses on the experimental evidence from NB cell lines, patient-derived xenografts and primary tumors. It also provides some novel approaches of targeting multiple drivers governing the stemness of CSCs to achieve better anti-tumor effects than the currently used therapeutic agents

Outcomes of Mechanical Thrombectomy for Patients With Stroke Presenting With Low Alberta Stroke Program Early Computed Tomography Score in the Early and Extended Window

Importance: Limited data are available about the outcomes of mechanical thrombectomy (MT) for real-world patients with stroke presenting with a large core infarct. Objective: To investigate the safety and effectiveness of MT for patients with large vessel occlusion and an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 2 to 5. Design, setting, and participants: This retrospective cohort study used data from the Stroke Thrombectomy and Aneurysm Registry (STAR), which combines the prospectively maintained databases of 28 thrombectomy-capable stroke centers in the US, Europe, and Asia. The study included 2345 patients presenting with an occlusion in the internal carotid artery or M1 segment of the middle cerebral artery from January 1, 2016, to December 31, 2020. Patients were followed up for 90 days after intervention. The ASPECTS is a 10-point scoring system based on the extent of early ischemic changes on the baseline noncontrasted computed tomography scan, with a score of 10 indicating normal and a score of 0 indicating ischemic changes in all of the regions included in the score. Exposure: All patients underwent MT in one of the included centers. Main outcomes and measures: A multivariable regression model was used to assess factors associated with a favorable 90-day outcome (modified Rankin Scale score of 0-2), including interaction terms between an ASPECTS of 2 to 5 and receiving MT in the extended window (6-24 hours from symptom onset). Results: A total of 2345 patients who underwent MT were included (1175 women [50.1%]; median age, 72 years [IQR, 60-80 years]; 2132 patients [90.9%] had an ASPECTS of ≥6, and 213 patients [9.1%] had an ASPECTS of 2-5). At 90 days, 47 of the 213 patients (22.1%) with an ASPECTS of 2 to 5 had a modified Rankin Scale score of 0 to 2 (25.6% [45 of 176] of patients who underwent successful recanalization [modified Thrombolysis in Cerebral Ischemia score ≥2B] vs 5.4% [2 of 37] of patients who underwent unsuccessful recanalization; P = .007). Having a low ASPECTS (odds ratio, 0.60; 95% CI, 0.38-0.85; P = .002) and presenting in the extended window (odds ratio, 0.69; 95% CI, 0.55-0.88; P = .001) were associated with worse 90-day outcome after controlling for potential confounders, without significant interaction between these 2 factors (P = .64). Conclusions and relevance: In this cohort study, more than 1 in 5 patients presenting with an ASPECTS of 2 to 5 achieved 90-day functional independence after MT. A favorable outcome was nearly 5 times more likely for patients with low ASPECTS who had successful recanalization. The association of a low ASPECTS with 90-day outcomes did not differ for patients presenting in the early vs extended MT window

Association of Noncontrast Computed Tomography and Perfusion Modalities With Outcomes in Patients Undergoing Late-Window Stroke Thrombectomy

Importance: There is substantial controversy with regards to the adequacy and use of noncontrast head computed tomography (NCCT) for late-window acute ischemic stroke in selecting candidates for mechanical thrombectomy. Objective: To assess clinical outcomes of patients with acute ischemic stroke presenting in the late window who underwent mechanical thrombectomy stratified by NCCT admission in comparison with selection by CT perfusion (CTP) and diffusion-weighted imaging (DWI). Design, setting, and participants: In this multicenter retrospective cohort study, prospectively maintained Stroke Thrombectomy and Aneurysm (STAR) database was used by selecting patients within the late window of acute ischemic stroke and emergent large vessel occlusion from 2013 to 2021. Patients were selected by NCCT, CTP, and DWI. Admission Alberta Stroke Program Early CT Score (ASPECTS) as well as confounding variables were adjusted. Follow-up duration was 90 days. Data were analyzed from November 2021 to March 2022. Exposures: Selection by NCCT, CTP, or DWI. Main outcomes and measures: Primary outcome was functional independence (modified Rankin scale 0-2) at 90 days. Results: Among 3356 patients, 733 underwent late-window mechanical thrombectomy. The median (IQR) age was 69 (58-80) years, 392 (53.5%) were female, and 449 (65.1%) were White. A total of 419 were selected with NCCT, 280 with CTP, and 34 with DWI. Mean (IQR) admission ASPECTS were comparable among groups (NCCT, 8 [7-9]; CTP, 8 [7-9]; DWI 8, [7-9]; P = .37). There was no difference in the 90-day rate of functional independence (aOR, 1.00; 95% CI, 0.59-1.71; P = .99) after adjusting for confounders. Symptomatic intracerebral hemorrhage (NCCT, 34 [8.6%]; CTP, 37 [13.5%]; DWI, 3 [9.1%]; P = .12) and mortality (NCCT, 78 [27.4%]; CTP, 38 [21.1%]; DWI, 7 [29.2%]; P = .29) were similar among groups. Conclusions and relevance: In this cohort study, comparable outcomes were observed in patients in the late window irrespective of neuroimaging selection criteria. Admission NCCT scan may triage emergent large vessel occlusion in the late window

Activity Dynamics of the Nucleus Accumbens Neurons During Natural and Drug Reward Seeking

The nucleus accumbens core (NAc) represents a major neural substrate of reward encoding that has been found to play a role in differentially regulating natural and drug rewards, including cocaine. Its constituent D1- and D2- receptor expressing medium spiny neurons (MSN) are alternatively hypothesized to have either opposing effects on reward seeking or a shared role in forming encoding “ensembles” – a sparsely activated population of neurons that encode reward associations- that coordinate behavioral responding to rewards and cues predicting reward availability. Previous methods used to study these neuronal populations failed to temporal quantify the cell-type specific activity in reward seeking tasks. To conjoin the functional dichotomy and ensemble hypotheses, we leveraged the use of single-cell calcium imaging of D1- and D2-MSN in freely behaving mice during active sucrose and cocaine self-administration, cued seeking and extinction. In the first part of the dissertation, we show that reinforced cocaine and sucrose seeking are associated with the recruitment of time-locked excitatory and inhibitory ensembles from both cell types. The seeking ensemble of excited D1-MSN showed high stability within- and across- multiple sessions for both reward types, while the stable recruitment of D2-MSN was only identified with cocaine self-administration. The balance between stability and dynamicity of D1- and D2-MSN ensembles, respectively, may be a consequential aspect of how NAcore encodes natural reward seeking. The second part of my dissertation aimed to determine if D1- and D2-MSN differentially encode cocaine seeking and sucrose seeking behavior in cued non-reinforced seeking tasks. Previous reports have shown drug-specific synaptic potentiation of the nucleus accumbens core associated with cued seeking after abstinence that is not seen with natural reward seeking. We show that D1-MSN, but not D2-MSN, were found to differentially encode cocaine seeking over sucrose seeking through stable and consistently recruited excitatory ensembles during cued seeking after forced abstinence or extinction training. Interestingly, I show that different ensembles are recruited during cued seeking before and after extinction. Together, my data reveal a unique neuronal signature of D1-MSN associated with relapse to cocaine

Abstract Number ‐ 144: Rescue Endovascular Treatment of Patients with Emergent Large Vessel Occlusion Due to Intracranial Atherosclerosis: Meta‐analysis

Introduction Acute stroke patients presenting with large vessel occlusion secondary to intracranial atherosclerosis (ICAS‐LVO) may require rescue therapy (RT) in addition to mechanical thrombectomy (MT) to achieve and maintain successful recanalization. We performed a systematic review and meta‐analysis of comparative studies that reported outcomes of RT in ICAS‐LVO patients to evaluate its safety and efficacy. Methods Databases searched include PubMed, CINAHL Complete, and Scopus from database date of inception through August 17, 2021. We included comparative studies that reported the outcomes of ICAS‐LVO RT compared to outcomes of ICAS‐LVO patients who did not undergo RT or to those presenting with embolic LVO patients (non‐ICAS LVO). Meta‐analysis using the random effects model was used to combine estimates reporting odds ratios (OR) and 95% confidence intervals (CI). Results Total of 9 nonrandomized studies were included: 5 studies in ICAS‐LVO RT vs. ICAS‐LVO non‐RT analysis and 5 ICAS‐LVO RT vs. non‐ICAS LVO analysis. Rescue treatments included intra‐arterial antiplatelets, angioplasty, stenting or combination of treatments. Compared to non‐RT ICAS LVO, RT was associated with increased favorable 90‐day outcome (OR 3.19, 95% CI 1.91‐5.32, I2 14%) and decreased 90‐day mortality (OR 0.35, 95% CI 0.16‐0.76, I2 21%) (Figure 1). In the analysis of ICAS LVO vs embolic LVO, the incidence of favorable 90‐day outcome and 90‐day mortality did not differ between the ICAS‐LVO RT and non‐ICAS LVO (OR 0.97, 95% CI 0.58‐1.64, I2 50%) and (OR 1.22, 95% CI 0.90‐1.66, I2 0%), respectively. Conclusions Rescue treatment is associated with better outcomes in ICAS‐LVO patients. The outcomes of ICAS‐LVO patients who receive RT may be comparable to embolic LVO patients (non‐ICAS LVO)

Nitrous Oxide Induces Prominent Cell Proliferation in Adult Rat Hippocampal Dentate Gyrus

The identification of distinct and more efficacious antidepressant treatments is highly needed. Nitrous oxide (N2O) is an N-methyl-D-aspartic acid (NMDA) antagonist that has been reported to exhibit antidepressant effects in treatment-resistant depression (TRD) patients. Yet, no studies have investigated the effects of sub-anesthetic dosages of N2O on hippocampal cell proliferation and neurogenesis in adult brain rats. In our study, adult male Sprague-Dawley rats were exposed to single or multiple exposures to mixtures of 70% N2O and 30% oxygen (O2). Sham groups were exposed to 30% O2 and the control groups to atmospheric air. Hippocampal cell proliferation was assessed by bromodeoxyuridine (BrdU) incorporation, and BrdU-positive cells were counted in the dentate gyrus (DG) using confocal microscopy. Results showed that while the rates of hippocampal cell proliferation were comparable between the N2O and sham groups at day 1, levels increased by 1.4 folds at day 7 after one session exposure to N2O. Multiple N2O exposures significantly increased the rate of hippocampal cell proliferation to two folds. Therefore, sub-anesthetic doses of N2O, similar to ketamine, increase hippocampal cell proliferation, suggesting that there will ultimately be an increase in neurogenesis. Future studies should investigate added N2O exposures and their antidepressant behavioral correlates

Rescue Endovascular Treatment of Patients With Emergent Large Vessel Occlusion Attributed to Intracranial Atherosclerosis: A Systematic Review and Meta‐Analysis

Background Patients with acute stroke presenting with large vessel occlusion secondary to intracranial atherosclerosis (ICAS‐LVO) may require rescue therapy (RT) in addition to mechanical thrombectomy to achieve and maintain successful recanalization. We performed a systematic review and meta‐analysis of comparative studies that reported outcomes of RT in patients with ICAS‐LVO to evaluate its safety and efficacy. Methods Databases searched include PubMed, CINAHL Complete, and Scopus from database date of inception through August 17, 2021. We included comparative studies that reported the outcomes of ICAS‐LVO RT compared with outcomes of patients with ICAS‐LVO who did not undergo RT or to those patients presenting with embolic large vessel occlusion (non–ICAS‐LVO). Meta‐analysis using the random‐effects model was used to combine estimates reporting odds ratios (ORs) and 95% CIs. Results A total of 9 nonrandomized studies were included: 5 studies in ICAS‐LVO RT versus ICAS‐LVO non‐RT analysis and 5 in ICAS‐LVO RT versus non‐ICAS LVO analysis. Rescue treatments included intra‐arterial antiplatelets, angioplasty, stenting, or a combination of treatments. Compared with non‐RT ICAS‐LVO, RT was associated with an increased favorable 90‐day outcome (OR, 3.19 [95% CI, 1.91–5.32]; I2 = 14%) and decreased 90‐day mortality (OR, 0.35 [95% CI, 0.16–0.76]; I2 = 21%). In the analysis of ICAS‐LVO RT versus embolic LV, the incidence of favorable 90‐day outcome and 90‐day mortality did not differ between ICAS‐LVO RT and non–ICAS‐LVO (OR, 0.97 [95% CI, 0.58–1.64; I2 = 50%]; and OR, 1.22 [95% CI, 0.90–1.66; I2 = 0%], respectively). Conclusions Rescue treatment is likely associated with better outcomes in patients with ICAS‐LVO. The outcomes of patients with ICAS‐LVO who receive RT may be comparable with patients with embolic large vessel occlusion (non–ICAS‐LVO)

Sphere-Formation Assay: Three-Dimensional in vitro Culturing of Prostate Cancer Stem/Progenitor Sphere-Forming Cells

Cancer Stem Cells (CSCs) are a sub-population of cells, identified in most tumors, responsible for the initiation, recurrence, metastatic potential, and resistance of different malignancies. In prostate cancer (PCa), CSCs were identified and thought to be responsible for the generation of the lethal subtype, commonly known as Castration-Resistant Prostate Cancer (CRPC). In vitro models to investigate the properties of CSCs in PCa are highly required. Sphere-formation assay is an in vitro method commonly used to identify CSCs and study their properties. Here, we report the detailed methodology on how to generate and propagate spheres from PCa cell lines and from murine prostate tissue. This model is based on the ability of stem cells to grow in non-adherent serum-free gel matrix. We also describe how to use these spheres in histological and immuno-fluorescent staining assays to assess the differentiation potential of the CSCs. Our results show the sphere-formation Assay (SFA) as a reliable in vitro assay to assess the presence and self-renewal ability of CSCs in different PCa models. This platform presents a useful tool to evaluate the effect of conventional or novel agents on the initiation and self-renewing properties of different tumors. The effects can be directly evaluated through assessment of the sphere-forming efficiency (SFE) over five generations or other downstream assays such as immuno-histochemical analysis of the generated spheres