Effects of withdrawal from ethanol drinking in chronic intermittent ethanol vapor (CIE)-exposed dependent rats and air-exposed nondependent rats on proliferation and survival of progenitor cells in the hippocampus and the medial prefrontal cortex (mPFC) were investigated. Rats were injected with 5′-Bromo 2-deoxyuridine 72 h post-CIE to measure proliferation (2 h-old cells) and survival (29-day-old cells) of progenitors born during a time-point previously reported to elicit a proliferative burst in the hippocampus. Hippocampal and mPFC brain-derived neurotrophic factor (BDNF) and tropomyosin-related kinase B receptor (TrkB) expression were measured 3 h or 21d post-CIE to evaluate neurotrophic signaling during a time point preceding the proliferative burst and survival of newly born progenitors. CIE rats demonstrated elevated drinking compared to nondependent rats and CIE rats maintained elevated drinking following protracted abstinence. Withdrawal from CIE increased BDNF levels in the hippocampus and mPFC, and subsequently increased proliferation in the hippocampus and mPFC compared to nondependent rats and controls. Protracted abstinence from CIE reduced BDNF expression to control levels, and subsequently reduced neurogenesis compared to controls and nondependent rats in the hippocampus. In the mPFC, protracted abstinence reduced BDNF expression to control levels, whereas increased oligodendrogenesis in dependent rats compared to nondependent rats and controls. These results suggest a novel relationship between BDNF and progenitors in the hippocampus and mPFC, in which increased ethanol drinking may alter hippocampal and cortical function in alcohol dependent subjects by altering the cellular composition of newly born progenitors in the hippocampus and mPFC.
Adult neurogenesis in the dentate gyrus (DG) is strongly influenced by drug taking behavior and may have a role in the etiology of drug seeking behavior. However, mechanistic studies on the relationship of neurogenesis on drug seeking are limited. Outbred Wistar rats experienced extended access methamphetamine self-administration and individual differences in drug taking defined animals with higher preferred and lower preferred levels of drug intake. Forced abstinence from higher preferred levels of drug taking enhanced neurogenesis and neuronal activation of granule cell neurons (GCNs) in the DG and produced compulsive-like drug reinstatement. Systemic treatment with the drug Isoxazole-9 (a synthetic small molecule known to modulate neurogenesis in adult rodent brain) during abstinence blocked compulsive-like context-driven methamphetamine reinstatement. Isoxazole-9 modulated neurogenesis, neuronal activation and structural plasticity of GCNs, and expression of synaptic proteins associated with learning and memory in the DG. These findings identify a subset of newly born GCNs within the DG that could directly contribute to drug-seeking behavior. Taken together, these results support a direct role for the importance of adult neurogenesis during abstinence in compulsive-like drug reinstatement.
In rodents, chronic intermittent ethanol vapor exposure (CIE) produces alcohol dependence, alters the structure and activity of pyramidal neurons and decreases the number of oligodendroglial progenitors in the medial prefrontal cortex (mPFC). In this study, adult Wistar rats were exposed to seven weeks of CIE and were withdrawn from CIE for 21 days (protracted abstinence; PA) and tissue enriched in the mPFC was processed for Western blot analysis and Golgi-Cox staining to investigate the long-lasting effects of CIE on structure of mPFC neurons and levels of myelin associated proteins. PA increased dendritic arborization within apical dendrites of pyramidal neurons and these changes occurred concurrently with hypophosphorylation of the NMDA receptor 2B (NR2B) at Tyr-1472. PA increased myelin basic protein (MBP) levels that occurred concurrently with hypophosphorylation of the premyelinating oligodendrocyte bHLH transcription factor Olig2 in the mPFC. Given that PA is associated with increased sensitivity to stress and hypothalamic-pituitary-adrenal (HPA) axis dysregulation, and stress alters oligodendrocyte expression as a function of glucocorticoid receptor (GR) activation, the levels of total GR and phosphorylated GR were also evaluated. PA produces hypophosphorylation of the GR at Ser-232 without affecting expression of total protein. These findings demonstrate persistent and compensatory effects of ethanol in the mPFC long after cessation of CIE, including enhanced myelin production and impaired GR function. Collectively, these results suggest a novel relationship between oligodendrocytes and GR in the mPFC, in which stress may alter frontal cortex function in alcohol dependent subjects by promoting hypermyelination, thereby altering the cellular composition and white matter structure in the mPFC.
Introduction Sinus infections are a common reason patients seek medical care. However, the intended meaning of the term sinus infection among patients and otolaryngologists is incompletely understood. Methods In this multi‐institutional cross‐sectional study, a semantics‐based questionnaire was provided to consecutive patients presenting to otolaryngology clinics at six academic centers from June 2020 until May 2021. The primary outcome was respondent definitions for sinus infection from a list of 28 proposed terms covering six general categories. Secondary outcome measures included differences between geographic regions. Results Responses were obtained from 560 patients (54% female, mean age 48.9 years) and 29 otolaryngologists (42% female, mean age 37.4 years). Patients and otolaryngologists selected a median of 10 and 11 terms, respectively, to define a sinus infection. Among patients the most frequently selected symptom categories were mucus (500, 89.3%), pressure/pain (480, 85.7%), and airflow (468, 83.6%). Compared to patients, clinicians selected with greater frequency the symptom categories of pressure/pain (14.3% difference; 95% CI, 7.6% to 22.5%), mucus (10.7% difference; 95% CI, 4.7% to 18.3%) and airflow (13.0% difference; 95% CI, 4.8% to 21.7%). Multiple categories were selected by 96% of patients and 100% of providers. Conclusion The definition of sinus infection appears variable for both patients and otolaryngologists, though patients appear to apply a broader range of symptoms to the term sinus infection. There were no pronounced geographic differences in the description of a sinus infection in this US sample population. Patients commonly described sinus infection in the context of pain‐related symptoms. Appreciation of these semantic differences may enable more effective patient‐clinician communication.
Objective To assess the perceived symptoms caused by the sinuses as defined by otolaryngology patients and clinicians. Study Design Multi‐institutional cross‐sectional study. Setting Six academic outpatient otolaryngology practices. Methods We performed a multi‐institutional, cross‐sectional study using a semantics‐based questionnaire. Consecutive patients were enrolled at 6 academic otolaryngology centers from June 2020 to May 2021. The primary outcome examined patient and provider definitions for the symptoms caused by the sinuses from a list of 28 proposed terms covering 6 general categories. These data were also collected from otolaryngology faculty at the same institutions. Results Responses were obtained from 451 patients (54% female, mean age 48.3 years) and 29 otolaryngologists (38% female, mean age 37.4 years). Patients selected a median of 12 terms, compared to 8.5 for otolaryngologists. Among patients, the most frequently selected symptom domains were mucus (419, 92.9%), airflow (412, 91.4%), and pain (389, 86.3%). Compared to clinicians, patients more frequently selected symptoms related to the ear (difference, 48.3%; 95% confidence interval [CI], 34.8%‐59.3%), throat (difference, 35.7%, 95% CI, 22.0%‐47.5%), systemic (difference, 34.4%, 95% CI, 21.2%‐46.0%), mucus (difference, 20.5%, 95% CI, 10.2%‐30.6%), and airflow domains (difference, 19.0%, 95% CI, 8.4%‐29.3%). Multiple domains were selected by 98% of patients and 79% of providers. Conclusion Semantic differences exist between patients and clinicians regarding the symptoms caused by the sinus with patients having a broader range of perceived symptoms. These differences may provide clues to improve communication between otolaryngologists and their patients.
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