Faculty Bibliography

INTRODUCTION/BACKGROUND:The long-standing cholinergic hypothesis posits that cholinergic signaling is uniformly deficient in Alzheimer's disease (AD) and Down syndrome (DS). We tested the hypothesis that this deficiency occurs primarily late in disease, while early stages involve excessive cholinergic signaling, with distinct implications for memory. METHODS:Tg2576 (AD model; n = 38), Ts65Dn (DS model; n = 14), and wild-type (WT; n = 17) mice at young (3 to 4 months) and old (>14 months) ages received treatments to reduce cholinergic signaling (medial septum chemogenetic inhibition, muscarinic antagonist scopolamine) or enhance it (acetylcholinesterase inhibitor donepezil). Memory assessments used novel object recognition. RESULTS:Anticholinergic manipulations restored memory in young Tg2576 and Ts65Dn mice but impaired age-matched WT mice. Conversely, donepezil improved the memory of old Tg2576, Ts65Dn, and WT but not young Tg2576 and Ts65Dn animals. DISCUSSION/CONCLUSIONS:These findings refine and challenge the cholinergic hypothesis, revealing for the first time a functional shift from cholinergic hyperactivity driving early cognitive impairment to late-stage degeneration requiring enhancement.

BACKGROUND:The obesity epidemic in the United States affects not only adults, but children and adolescents. SOURCES OF MATERIAL/UNASSIGNED:An extensive review of the literature including 85 articles has been completed with the aim of providing the most current definitions and recommendations for this chronic condition. ABSTACT OF FINDINGS/UNASSIGNED:This article reviews the definition of pediatric obesity, the increasing prevalence of obesity in children and adolescents, genetic and environmental risk factors, as well as the unique aspects and implications of this condition and its associated comorbidities for this population in comparison to adults. Current management recommendations are also discussed which include Intensive Health Behavioral and Lifestyle Treatment (IHBLT), metabolic surgery, and pharmacologic therapy including glucago-like peptide-1 receptor agonists (GLP-1RAs). CONCLUSION/CONCLUSIONS:Childhood obesity is a unique condition in its progression and management requirements, and should be approached with a focus on prevention as well as on the high-risk individual.

PURPOSE OF REVIEW/OBJECTIVE:Medullary sponge kidney (MSK) is a congenital disorder of the distal nephron, characterized by cystic dilatation of the papillary and medullary tubules. It commonly presents with recurrent calcium nephrolithiasis and often, severe, life-altering chronic pain syndromes, often independent of urinary obstruction and of uncertain etiology. Management focuses on stone prevention and symptomatic care, but these measures are frequently inadequate. No studies of management of this pain syndrome in these patients have been performed. There are essentially no studies evaluating renal denervation in MSK specifically, although the technique has been utilized with some benefit in other disorders, underscoring a major therapeutic gap. In this review, we describe patients with MSK and chronic pain syndrome and review the role of renal denervation as a potential therapy. RECENT FINDINGS/RESULTS:Renal denervation may represent a promising strategy for chronic kidney pain syndrome. It could provide pain relief and improve quality of life in affected patients. SUMMARY/CONCLUSIONS:The optimal management strategy for chronic pain in MSK has not been elucidated. Renal denervation has recently been utilized and approved for the management of blood pressure. It could be useful for managing chronic kidney pain in this condition as well.

Active avoidance responses (ARs) are instrumental behaviors that prevent harm. Adaptive ARs may contribute to active coping, whereas maladaptive avoidance habits are implicated in anxiety and obsessive-compulsive disorders. The AR learning mechanism has remained elusive, as successful avoidance trials produce no obvious reinforcer. We used a novel outcome-devaluation procedure in rats to show that ARs are positively reinforced by response-produced feedback cues that develop into safety signals during training. Males were sensitive to feedback devaluation after moderate training, but not overtraining, consistent with a transition from goal-directed to habitual avoidance. Using chemogenetics and feedback devaluation, we also show that goal-directed vs. habitual ARs depend on dorsomedial vs. dorsolateral striatum, suggesting a significant overlap between the mechanisms of avoidance and rewarded instrumental behavior. Females were insensitive to feedbackdevaluation due to a remarkable context-dependence of counterconditioning. However, degrading the contingency between avoidance and feedback suggests that both sexes rely on safety signals to perform goal-directed ARs.

Speech production entails several processing steps that encode linguistic and articulatory structure, but whether these computations correspond to spatiotemporally discrete patterns of neural activity is unclear. To address this issue, we use electrocorticography to directly measure the brains of neurosurgical participants performing an interactive speech paradigm. We observe a broad range of cortical modulation profiles, and subsequent clustering analyses establish that responses comprised distinct classes associated with sensory perception, planning, motor execution, and task-related suppression. These activity classes are also localized to separate neural substrates, indicating their status as specialized networks. We then parse dynamics in the planning and motor networks using unsupervised dimensionality reduction, which reveals subnetworks that are sequentially active throughout preparation and articulation. These results therefore support and extend a localizationist model of speech production where cortical activity "flows" within and across discrete pathways during language use.

The cardiac conduction system (CCS) has a vital role in initiating and coordinating nearly 3 billion heartbeats throughout a person's lifetime. The CCS comprises two primary tissue types: the impulse-generating, slow-conducting nodes and the fast-conducting components of the ventricular conduction system. Dysfunction in this system can give rise to a spectrum of clinical symptoms, including palpitations, syncope, heart failure and even sudden cardiac death. Owing to the limited therapeutic options other than electronic pacemakers, substantial research efforts have been aimed at uncovering the root causes of conduction system disorders. A comprehensive investigative approach integrating genetics, transcriptomics and proteomics has been used to unravel the complex biology of these diseases. Advances in single-cell genomic and transcriptomic technologies, together with spatial transcriptomics, are offering new insights into the cellular microenvironments that govern conduction system function. In this Review, we examine the latest progress in understanding the biology of the CCS, situating new findings within both established and emerging scientific paradigms. Additionally, we discuss how these insights can be leveraged to improve clinical risk assessment, expand drug discovery efforts, accelerate technology aimed at promoting CCS regeneration and foster the development of innovative therapies, including biological pacemakers.

OBJECTIVE:We sought to apply a previously developed transimpedance (TIM) heatmap pattern classification scheme in patients with no known risk factors for cochlear anomalies, in addition to patients implanted in the revision setting, to better understand the incidence of pattern variants, and potential clinical implications. STUDY DESIGN/METHODS:Single-center retrospective review. SETTING/METHODS:Tertiary referral centre. PATIENTS/METHODS:Patients older than 6 months of age who underwent cochlear implantation between June 2020 and June 2024 with normal gross cochlear anatomy and no concern for fibrosis that had intraoperative TIM testing completed. Patients undergoing revision implantation were also included as a separate cohort. INTERVENTION/METHODS:None. MAIN OUTCOME MEASURES/METHODS:The number of patients with normal and variant TIM patterns was evaluated for each cohort. TIM patterns were subsequently compared with the electrode position found on intraoperative x-ray. RESULTS:There were 321 ears that underwent implantation and subsequent intraoperative TIM assessment meeting inclusion criteria. Of these, 310 (96.6%) were in the primary surgery setting, and 11 (3.4%) were in the revision surgical setting. In the primary surgical setting, 86.4% (n=268) of the implants demonstrated a normal TIM heatmap. Compared with the primary surgical setting, where only 45.5% (n=5) of revision surgery TIM heatmaps were interpreted as normal. One patient in the revision setting had a newly identified "double X" pattern corresponding to a normal electrode position on x-ray. CONCLUSIONS:There is a decreased incidence of previously developed TIM heatmap pattern variants in CI recipients with normal gross cochlear anatomy.

Adult neurogenesis in the subgranular zone (SGZ) has been implicated in cognitive and affective functions. The role of neuroinflammation and reactive microglia in SGZ neurogenesis is not well understood. TGF-β signaling is critical to maintaining microglia homeostasis in the adult brain. To investigate the role of microglia in SGZ neurogenesis, using microglia-specific inducible knockout (iKO) mice for TGF-β1 ligand or receptor (Alk5 or Tgfbr2), here we show that TGF-β-deficient microglia increase adult neurogenesis in the SGZ, accompanied by altered anxiety-like behavior in KO mice. Single-cell RNAseq (ScRNAseq) analysis shows decreased PTEN signaling, and immunohistochemistry shows increased mTOR activity in DCX+ newly born neuroblasts at the SGZ in iKO mice. Inhibition of mTOR signaling by rapamycin reverses the heightened SGZ neurogenesis in iKO mice. This study reveals the role of microglia in regulating hippocampal adult neurogenesis via the PTEN-mTOR pathway and its potential implications for behavioral and affective functions.