Cued Reinstatement of Cocaine but Not Sucrose Seeking Is Dependent on Dopamine Signaling in Prelimbic Cortex and Is Associated with Recruitment of Prelimbic Neurons That Project to Contralateral Nucleus Accumbens Core.

Background: Drug cues recruit prelimbic cortex neurons that project to ipsilateral nucleus accumbens core. However, it is not known if the same is true for prelimbic cortex projections that decussate to innervate contralateral nucleus accumbens core. Further, a role for prelimbic cortex dopamine signaling in cued reinstatement of cocaine seeking has not been shown. Methods: We assessed Fos expression in prelimbic cortex neurons that project to contralateral nucleus accumbens core following cued reinstatement of cocaine or sucrose seeking. We also tested the effect of intra-prelimbic cortex infusions of the D1/D2 antagonist fluphenazine on cued cocaine and sucrose seeking. Results: Prelimbic cortex-contralateral nucleus accumbens core projections were activated by cocaine cues but not sucrose cues, and this activation correlated with reinstatement behavior. Blockade of prelimbic cortex dopamine signaling prevented cued reinstatement of cocaine- but not sucrose-seeking behavior. Conclusions: Cued cocaine seeking is associated with activation of the prelimbic cortex-contralateral nucleus accumbens core pathway. Prelimbic cortex dopamine signaling is necessary for cues to reinstate drug-seeking behavior.

Successful Preoperative Transjugular Intrahepatic Portosystemic Shunt for Portal Decompression in Patients With Inflammatory Bowel Disease and Cirrhosis Requiring Surgical Intervention.

Background: Colorectal surgery in patients with inflammatory bowel disease (IBD) and cirrhosis has increased morbidity, which may preclude surgery. Preoperative transjugular intrahepatic portosystemic shunt (TIPS) is postulated to reduce surgical risk. In this retrospective single-center study, we characterized perioperative outcomes in patients with IBD and cirrhosis who underwent preoperative TIPS. Methods: We identified patients with IBD and cirrhosis who had undergone preoperative TIPS for portal decompression between 2010 and 2023. All other indications for TIPS led to patient exclusion. Demographic and medical data were collected, including portal pressure measurements. Primary outcome of interest was perioperative outcomes. Results: Ten patients met the inclusion criteria. The most common surgical indications were dysplasia (50%) and refractory IBD (50%). TIPS was performed at a median of 47 days (IQR 34-80) before surgery, with reduction in portal pressures (22.5 vs. 18.5 mmHg, P < .01) and portosystemic gradient (12.5 vs. 5.5 mmHg, P < .01). Perioperative complications occurred in 80% of patients, including surgical site bleeding (30%), wound dehiscence (10%), systemic infection (30%), liver function elevation (50%), and coagulopathy (50%). No patients required re-operation, with median length of stay being 7 days (IQR 5.5-9.3). The 30-day readmission rate was 40%, most commonly for infection (75%), with 2 patients having intra-abdominal abscesses and 1 patient with concern for bowel ischemia. Ninety-day and one-year survival was 100% and 90%, respectively. Patients with primary sclerosing cholangitis (PSC)-cirrhosis were noted to have higher perioperative morbidity and a 30-day readmission rate. Conclusions: In patients with IBD and cirrhosis, preoperative TIPS facilitated successful surgical intervention despite heightened risk. Nevertheless, significant complications were noted, in particular for patients with PSC-cirrhosis.

Interferon-γ/Interleukin-27 Axis Induces Programmed Death Ligand 1 Expression in Monocyte-Derived Dendritic Cells and Restores Immune Tolerance in Central Nervous System Autoimmunity.

Antigen (Ag)-specific tolerance induction by intravenous (i. v.) injection of high-dose auto-Ags has been explored for therapy of autoimmune diseases, including multiple sclerosis (MS). It is thought that the advantage of such Ag-specific therapy over non-specific immunomodulatory treatments would be selective suppression of a pathogenic immune response without impairing systemic immunity, thus avoiding adverse effects of immunosuppression. Auto-Ag i.v. tolerance induction has been extensively studied in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and limited clinical trials demonstrated that it is safe and beneficial to a subset of MS patients. Nonetheless, the mechanisms of i.v. tolerance induction are incompletely understood, hampering the development of better approaches and their clinical application. Here, we describe a pathway whereby auto-Ag i.v. injected into mice with ongoing clinical EAE induces interferon-gamma (IFN-γ) secretion by auto-Ag-specific CD4+ T cells, triggering interleukin (IL)-27 production by conventional dendritic cells type 1 (cDC1). IL-27 then, via signal transducer and activator of transcription 3 activation, induces programmed death ligand 1 (PD-L1) expression by monocyte-derived dendritic cells (moDCs) in the central nervous system of mice with EAE. PD-L1 interaction with programmed cell death protein 1 on pathogenic CD4+ T cells leads to their apoptosis/anergy, resulting in disease amelioration. These findings identify a key role of the IFN-γ/IL-27/PD-L1 axis, involving T cells/cDC1/moDCs in the induction of i.v. tolerance.