Chronic cocaine exposure in both human addicts and in rodent models of addiction reduces prefrontal cortical activity, which subsequently dysregulates reward processing and higher order executive function. The net effect of this impaired gating of behavior is enhanced vulnerability to relapse. Previously we have shown that cocaine-induced increases in brain-derived neurotrophic factor (BDNF) expression in the medial prefrontal cortex (PFC) is a neuroadaptive mechanism that blunts the reinforcing efficacy of cocaine. As BDNF is known to affect neuronal survival and synaptic plasticity, we tested the hypothesis that abstinence from cocaine self-administration would lead to alterations in neuronal morphology and synaptic density in the PFC. Using a novel technique, array tomography and Golgi staining, morphological changes in the rat PFC were analyzed following 14 days of cocaine self-administration and 7 days of forced abstinence. Our results indicate that overall dendritic branching and total synaptic density are significantly reduced in the rat PFC. In contrast, the density of thin dendritic spines are significantly increased on layer V pyramidal neurons of the PFC. These findings indicate that dynamic structural changes occur during cocaine abstinence that may contribute to the observed hypo-activity of the PFC in cocaine-addicted individuals.

Purpose: The graft site microenvironment has a profound effect on alloimmunity and graft survival. We aimed to study the kinetics and phenotype of trafficking antigen-presenting cells (APC) to the draining lymph nodes (DLNs) in a mouse model of corneal transplantation, and to evaluate the homing mechanisms through which graft site inflammation controls APC trafficking. Methods: Allogeneic donor corneas were transplanted onto inflamed or quiescent graft beds. Host- (YAe⁺) and donor (CD45.1⁺ or eGFP⁺)-derived APCs were analyzed by flow cytometry. Protein and mRNA expression of the CC chemokine receptor (CCR)7 ligands CCL19 and CCL21 were assessed using ELISA and Real-Time qPCR, respectively. Transwell migration assay was performed to assess the effect of DLNs isolated from hosts with inflamed graft beds on mature bone marrow–derived dendritic cells (BMDCs). Results: We found that inflamed graft sites greatly promote the trafficking of both recipient- and graft-derived APCs, in particular mature CCR7⁺ CD11c⁺ dendritic cells (DC). CCL19 and CCL21 were expressed at significantly higher levels in the DLNs of recipients with inflamed graft beds. The supernatant of DLNs from recipients with inflamed graft beds induced a marked increase in mature DC migration compared with supernatant from recipients with quiescent graft beds in a transwell assay. This effect was abolished by neutralizing CCL19 or CCL21. These data suggest that graft site inflammation increases the expression of CCR7 ligands in the DLNs, which promote mature DC homing and allorejection. Conclusions: We conclude that the graft site microenvironment plays a critical role in alloimmunity by determining DC trafficking through the CCR7-CCL19/21 axis.

Objective evaluation of people with amyotrophic lateral sclerosis (PALS) in free-living settings is challenging. The introduction of portable digital devices, such as wearables and smartphones, may improve quantifying disease progression and hasten therapeutic development. However, there is a need for tools to characterize upper limb movements in neurologic disease and disability. Twenty PALS wore a wearable accelerometer, ActiGraph Insight Watch, on their wrist for six months. They also used Beiwe, a smartphone application that collected self-entry ALS Functional Rating Scale-Revised (ALSFRS-RSE) survey responses every 1-4 weeks. We developed several measures that quantify count and duration of upper limb movements: flexion, extension, supination, and pronation. New measures were compared against ALSFRS-RSE total score (Q1-12), and individual responses to specific questions related to handwriting (Q4), cutting food (Q5), dressing and performing hygiene (Q6), and turning in bed and adjusting bed clothes (Q7). Additional analysis considered adjusting for total activity counts (TAC). At baseline, PALS with higher Q1-12 performed more upper limb movements, and these movements were faster compared to individuals with more advanced disease. Most upper limb movement metrics had statistically significant change over time, indicating declining function either by decreasing count metrics or by increasing duration metric. All count and duration metrics were significantly associated with Q1-12, flexion and extension counts were significantly associated with Q6 and Q7, supination and pronation counts were also associated with Q4. All duration metrics were associated with Q6 and Q7. All duration metrics retained their statistical significance after adjusting for TAC. Wearable accelerometer data can be used to generate digital biomarkers on upper limb movements and facilitate patient monitoring in free-living environments. The presented method offers interpretable monitoring of patients' functioning and versatile tracking of disease progression in the limb of interest. Mitsubishi-Tanabe Pharma Holdings America, Inc.