👤 Melvin Samsom

Deep brain stimulation (DBS) has emerged as a prospective treatment for psychiatric disorders; for example, DBS targeting the nucleus accumbens (NAc) abolishes addictive behaviors. However, neither the core pathway nor the cellular mechanisms underlying these therapeutic effects are known. Here, morphine-induced conditioned place preference (CPP) in mice as an addiction model and NAc-DBS combined with adeno-associated virus gene delivery for activity-dependent tagging, transgenic and chemogenetic manipulation of recruited neuronal networks are used. It is reported that a cortical-accumbal pathway and local fibroblast growth factor 1 (FGF1) signaling in the medial prefrontal cortex (mPFC) are critical for NAc-DBS to be effective in altering morphine CPP. It is shown that NAc-DBS retrogradely activates mPFC neurons projecting to the NAc, and chemogenetic activation/inhibition of these DBS-activated neuron ensembles in the mPFC reproduces the NAc-DBS effects on CPP. Sustained therapeutic effects accompany reductions in local FGF1 binding to fibroblast growth factor receptor 1 (FGFR1) in these neurons. Additionally, overexpressing FGF1 in the mPFC-NAc pathway abolishes the therapeutic effects of NAc-DBS. These results demonstrate that the mPFC-NAc pathway forms a top-down motif to regulate the therapeutic effects of subcortical DBS on addiction. These results support the potential for addiction treatments involving FGF1 signaling and highlight the mPFC as a target for noninvasive brain stimulation. Show less

Duodenal signaling affects esophageal motility and perception, both pathophysiological factors in gastroesophageal reflux disease (GERD). Duodenal gene expression abnormalities, contributing to altered esophageal sensorimotor function, have not been reported to date. To identify differentially expressed genes in GERD patients' duodenum. Twenty GERD patients (total 24-h acid exposure 6-12%, SAP ≥95%) and ten healthy controls (HC) were included. Two weeks prior to duodenal biopsy collection, ten patients discontinued proton pump inhibitor (PPI) treatment and ten took maximum dose PPI. RNA was profiled on an Affymetrix Human Genome U133 Plus 2.0 array (Affymetrix, Santa Clara, CA, USA). Genes exhibiting a fold change ≥ 1.4 (t test p value <1E-4) were considered differentially expressed. A subset of 21 differentially expressed genes was selected for confirmatory TaqMan low-density array RT-PCR. Mucosal apolipoprotein A-IV (apoA-IV) and cholecystokinin (CCK) concentrations were determined by ELISA and RIA, respectively. In GERD patients off PPI, 23 up- and 23 down-regulated genes relative to HC were found. In GERD patients on PPI, 33 and five genes were higher, respectively, lower expressed. The majority of up-regulated genes were associated with lipid absorption, particularly triglyceride resynthesis and intracellular vesicular transport, rate-limiting processes for chylomicron production and secretion. Differential expression of 11 genes was confirmed by RT-PCR. Mucosal apoA-IV and CCK concentrations (signaling proteins released upon chylomicron secretion) were similar in GERD patients and HC. The identified mRNA expression differences suggest that in GERD patients' duodenum, the chylomicron production and secretion potential is elevated, and may underlie a mechanism by which postprandial duodenal signaling contributes to GERD symptom generation. Show less