Faculty Bibliography

Physical exercise improves motor performance in individuals with Parkinson's disease and elevates mood in those with depression. Although underlying factors have not been identified, clues arise from previous studies showing a link between cognitive benefits of exercise and increases in brain-derived neurotrophic factor (BDNF). Here, we investigated the influence of voluntary wheel-running exercise on BDNF levels in the striatum of young male wild-type (WT) mice, and on the striatal release of a key motor-system transmitter, dopamine (DA). Mice were allowed unlimited access to a freely rotating wheel (runners) or a locked wheel (controls) for 30 d. Electrically evoked DA release was quantified in ex vivo corticostriatal slices from these animals using fast-scan cyclic voltammetry. We found that exercise increased BDNF levels in dorsal striatum (dStr) and increased DA release in dStr and in nucleus accumbens core and shell. Increased DA release was independent of striatal acetylcholine (ACh), and persisted after a week of rest. We tested a role for BDNF in the influence of exercise on DA release using mice that were heterozygous for BDNF deletion (BDNF^+/-). In contrast to WT mice, evoked DA release did not differ between BDNF^+/- runners and controls. Complementary pharmacological studies using a tropomyosin receptor kinase B (TrkB) agonist in WT mouse slices showed that TrkB receptor activation also increased evoked DA release throughout striatum in an ACh-independent manner. Together, these data support a causal role for BDNF in exercise-enhanced striatal DA release and provide mechanistic insight into the beneficial effects of exercise in neuropsychiatric disorders, including Parkinson's, depression, and anxiety.SIGNIFICANCE STATEMENT Exercise has been shown to improve movement and cognition in humans and rodents. Here, we report that voluntary exercise for 30 d leads to an increase in evoked DA release throughout the striatum and an increase in BDNF in the dorsal (motor) striatum. The increase in DA release appears to require BDNF, indicated by the absence of DA release enhancement with running in BDNF^+/- mice. Activation of BDNF receptors using a pharmacological agonist was also shown to boost DA release. Together, these data support a necessary and sufficient role for BDNF in exercise-enhanced DA release and provide mechanistic insight into the reported benefits of exercise in individuals with dopamine-linked neuropsychiatric disorders, including Parkinson's disease and depression.

The nucleus accumbens (NAc) is considered a hub of reward processing and a growing body of evidence has suggested its crucial role in the pathophysiology of major depressive disorder (MDD). However, inconsistent results have been reported by studies on reward network-focused resting-state functional MRI (rs-fMRI). In this study, we examined functional alterations of the NAc-based reward circuits in patients with MDD via meta- and mega-analysis. First, we performed a coordinated-based meta-analysis with a new SDM-PSI method for all up-to-date rs-fMRI studies that focused on the reward circuits of patients with MDD. Then, we tested the meta-analysis results in the REST-meta-MDD database which provided anonymous rs-fMRI data from 186 recurrent MDDs and 465 healthy controls. Decreased functional connectivity (FC) within the reward system in patients with recurrent MDD was the most robust finding in this study. We also found disrupted NAc FCs in the DMN in patients with recurrent MDD compared with healthy controls. Specifically, the combination of disrupted NAc FCs within the reward network could discriminate patients with recurrent MDD from healthy controls with an optimal accuracy of 74.7%. This study confirmed the critical role of decreased FC in the reward network in the neuropathology of MDD. Disrupted inter-network connectivity between the reward network and DMN may also have contributed to the neural mechanisms of MDD. These abnormalities have potential to serve as brain-based biomarkers for individual diagnosis to differentiate patients with recurrent MDD from healthy controls.

PURPOSE/OBJECTIVE:To elucidate long-term sequelae of radiation therapy (RT) in head and neck cancer (HNC) patients, a multi-center prospective study, Clinical Registry of Dental Outcomes in Head and Neck Cancer Patients (OraRad), was established with tooth failure as its primary outcome. We report tooth failure and associated risk factors. METHODS:Demographics, cancer and dental disease characteristics were documented in 572 HNC patients at baseline and 6, 12, 18, and 24 months after RT. Eligible patients were age 18 or older, diagnosed with HNC, and receiving RT to treat HNC. Tooth failure during follow-up was defined as losing a tooth or having a tooth deemed hopeless. Analyses of time to first tooth-failure event and number of teeth that failed used Kaplan-Meier estimators, Cox regression, and generalized linear models. RESULTS:At 2 years, the estimated fraction of tooth failure was 17.8% (95% confidence interval [CI]: 14.3%-21.3%). Number of teeth that failed was higher for those with fewer teeth at baseline (p<0.0001), greater reduction in salivary flow rate (p=0.013), and non-compliance with daily oral hygiene (p=0.03). Patients with dental caries at baseline had higher risk of tooth failure with decreased salivary flow. Patients who were oral hygiene non-compliant at baseline but compliant at all follow-up visits had the fewest teeth that failed; greatest tooth failure occurred in participants who were non-compliant at baseline and follow-up. CONCLUSION/CONCLUSIONS:Despite pre-RT dental management, substantial tooth failure occurs within 2 years after RT for HNC. Identified factors may help to predict or reduce risk of post-RT tooth failure.

Resolving glial contributions to Alzheimer's disease (AD) is necessary because changes in neuronal function, such as reduced synaptic density, altered electrophysiological properties, and degeneration, are not entirely cell autonomous. To improve understanding of transcriptomic heterogeneity in glia during AD, we used single-nuclei RNA sequencing (snRNA-seq) to characterize astrocytes and oligodendrocytes from apolipoprotein (APOE) Ɛ2/3 human AD and age- and genotype-matched non-symptomatic (NS) brains. We enriched astrocytes before sequencing and characterized pathology from the same location as the sequenced material. We characterized baseline heterogeneity in both astrocytes and oligodendrocytes and identified global and subtype-specific transcriptomic changes between AD and NS astrocytes and oligodendrocytes. We also took advantage of recent human and mouse spatial transcriptomics resources to localize heterogeneous astrocyte subtypes to specific regions in the healthy and inflamed brain. Finally, we integrated our data with published AD snRNA-seq datasets, highlighting the power of combining datasets to resolve previously unidentifiable astrocyte subpopulations.

Sarcolemmal/plasmalemmal ATP-sensitive K⁺ (K_ATP) channels have key roles in many cell types and tissues. Hundreds of studies have described how the K_ATP channel activity and ATP sensitivity can be regulated by changes in the cellular metabolic state, by receptor signaling pathways and by pharmacological interventions. These alterations in channel activity directly translate to alterations in cell or tissue function, that can range from modulating secretory responses, such as insulin release from pancreatic β-cells or neurotransmitters from neurons, to modulating contractile behavior of smooth muscle or cardiac cells to elicit alterations in blood flow or cardiac contractility. It is increasingly becoming apparent, however, that K_ATP channels are regulated beyond changes in their activity. Recent studies have highlighted that K_ATP channel surface expression is a tightly regulated process with similar implications in health and disease. The surface expression of K_ATP channels is finely balanced by several trafficking steps including synthesis, assembly, anterograde trafficking, membrane anchoring, endocytosis, endocytic recycling and degradation. This review aims to summarize the physiological and pathophysiological implications of K_ATP channel trafficking and mechanisms that regulate K_ATP channel trafficking. A better understanding of this topic has potential to identify new approaches to develop therapeutically useful drugs to treat K_ATP channel-related diseases.

OBJECTIVE:To investigate a new surgical and signal processing technique that provides apical stimulation of the cochlea using a cochlear implant without extending the length of the electrode array. PATIENTS/METHODS:Three adult patients who underwent cochlear implantation using this new technique. INTERVENTIONS/METHODS:The patients received a cochlear implant. The surgery differed from the standard approach in that a ground electrode was placed in the cochlear helicotrema via an apical cochleostomy rather than in its typical location underneath the temporalis muscle. Clinical fitting was modified such that low frequencies were represented using the apically placed electrode as a ground. MAIN OUTCOME MEASURES/METHODS:Pitch scaling and speech recognition. RESULTS:All surgeries were successful with no complications. Pitch scaling demonstrated that use of the apically placed electrode as a ground lowered the perceived pitch of electric stimulation relative to monopolar stimulation. Speech understanding was improved compared with preoperative scores. CONCLUSIONS:The new surgical approach and clinical fitting are feasible. A lower pitch is perceived when using the apically placed electrode as a ground relative to stimulation using an extracochlear ground (i.e., monopolar mode), suggesting that stimulation can be provided more apically without the use of a longer electrode array. Further work is required to determine potential improvements in outcomes and optimal signal processing for the new approach.

We developed a "gut-brain-axis questionnaire" (GBAQ) to obtain standardized person-specific "review of systems" data for microbiome-gut-brain-axis studies. Individual items were compared to PANSS symptom measures using dimensional, transdiagnostic and traditional categorical approaches.

Dynamic interactions within and across brain areas underlie behavioral and cognitive functions. To understand the basis of these processes, the activities of distributed local circuits inside the brain of a behaving animal must be synchronously recorded while the inputs to these circuits are precisely manipulated. Even though recent technological advances have enabled such large-scale recording capabilities, the development of the high-spatiotemporal-resolution and large-scale modulation techniques to accompany those recordings has lagged. A novel neural probe is presented in this work that enables simultaneous electrical monitoring and optogenetic manipulation of deep neuronal circuits at large scales with a high spatiotemporal resolution. The "hectoSTAR" micro-light-emitting-diode (μLED) optoelectrode features 256 recording electrodes and 128 stimulation μLEDs monolithically integrated on the surface of its four 30-µm thick silicon micro-needle shanks, covering a large volume with 1.3-mm × 0.9-mm cross-sectional area located as deep as 6 mm inside the brain. The use of this device in behaving mice for dissecting long-distance network interactions across cortical layers and hippocampal regions is demonstrated. The recording-and-stimulation capabilities hectoSTAR μLED optoelectrodes enables will open up new possibilities for the cellular and circuit-based investigation of brain functions in behaving animals.

Aggregation of the tau protein is thought to be responsible for the neurodegeneration and subsequent functional impairments in diseases that are collectively named tauopathies. Alzheimer's disease is the most common tauopathy, but the group consists of over 20 different diseases, many of which have tau pathology as their primary feature. The development of tau therapies has mainly focused on preventing the formation of and/or clearing these aggregates. Of these, immunotherapies that aim to either elicit endogenous tau antibodies or deliver exogenous ones are the most common approach in clinical trials. While their mechanism of action can involve several pathways, both extra- and intracellular, pharmaceutical companies have primarily focused on antibody-mediated clearance of extracellular tau. As we have pointed out over the years, this is rather surprising because it is well known that most of pathological tau protein is found intracellularly. It has been repeatedly shown by several groups over the past decades that antibodies can enter neurons and that their cellular uptake can be enhanced by various means, particularly by altering their charge. Here, we will briefly describe the potential extra- and intracellular mechanisms involved in antibody-mediated clearance of tau pathology, discuss these in the context of recent failures of some of the tau antibody trials, and finally provide a brief overview of how the intracellular efficacy of tau antibodies can potentially be further improved by certain modifications that aim to enhance tau clearance via specific intracellular degradation pathways.

OBJECTIVE:To compare the frequency of stone-related events among subgroups of high-risk patients with and without 24-hour urine testing before PPT prescription. While recent studies show, on average, no benefit to a selective approach to preventive pharmacological therapy (PPT) for urinary stone disease (USD), there could be heterogeneity in treatment effect across patient subgroups. MATERIALS AND METHODS/METHODS:Using medical claims data from working-age adults and their dependents with USD (2008-2019), we identified those with a prescription fill for a PPT agent (thiazide diuretic, alkali therapy, or allopurinol). We then stratified patients into subgroups based on the presence of a concomitant condition or other factors that raised their stone recurrence risk. Finally, we fit multivariable regression models to measure the association between stone-related events (emergency department visit, hospitalization, and surgery) and 24-hour urine testing before PPT prescription by high-risk subgroup. RESULTS:Overall, 8,369 adults with USD had a concomitant condition that raised their recurrence risk. Thirty-three percent (n=2,722) of these patients were prescribed PPT after 24-hour urine testing (median follow-up, 590 days), and 67% (n=5,647) received PPT empirically (median follow-up, 533 days). Compared to patients treated empirically, those with a history of recurrent USD had a significantly lower hazard of a subsequent stone-related event if they received selective PPT (hazard ratio, 0.83; 95% CI, 0.71-0.96). No significant associations were noted for selective PPT in the other high-risk subgroups. CONCLUSIONS:Patients with a history of recurrent USD benefit from PPT when guided by findings from 24-hour urine testing.