Rewarded Maze Training Increases Approach Behavior in Rats Through Neurogenesis-Dependent Growth of Ventral Hippocampus-Prelimbic Circuits.

Background: Learning complex navigation routes increases hippocampal volume in humans, but it is not clear whether this growth impacts behaviors outside the learning situation or what cellular mechanisms are involved. Methods: We trained rats with pharmacogenetic suppression of adult neurogenesis and littermate controls in 3 mazes over 3 weeks and tested novelty approach behavior several days after maze exposure. We then measured hippocampus and prelimbic cortex volumes using magnetic resonance imaging and assessed neuronal and astrocyte morphology. Finally, we investigated the activation and behavioral role of the ventral CA1 (vCA1)-to-prelimbic pathway using immediate-early genes and DREADDs (designer receptors exclusively activated by designer drugs). Results: Maze training led to volume increase of both the vCA1 region of the hippocampus and the prelimbic region of the neocortex compared with rats that followed fixed paths. Growth was also apparent in individual neurons and astrocytes in these 2 regions, and behavioral testing showed increased novelty approach in maze-trained rats in 2 different tests. Suppressing adult neurogenesis prevented the effects on structure and approach behavior after maze training without affecting maze learning itself. The vCA1 neurons projecting to the prelimbic area were more activated by novelty in maze-trained animals, and suppression of this pathway decreased approach behavior. Conclusions: Rewarded navigational learning experiences induce volumetric and morphologic growth in the vCA1 and prelimbic cortex and enhance activation of the circuit connecting these 2 regions. Both the structural and behavioral effects of maze training require ongoing adult neurogenesis, suggesting a role for new neurons in experience-driven increases in novelty exploration.

Aging mice show impaired memory updating in the novel OUL updating paradigm.

Memories do not persist in a permanent, static state but instead must be dynamically modified in response to new information. Although new memory formation is typically studied in a laboratory setting, most real-world associations are modifications to existing memories, particularly in the aging, experienced brain. To date, the field has lacked a simple behavioral paradigm that can measure whether original and updated information is remembered in a single test session. To address this gap, we have developed a novel memory updating paradigm, called the Objects in Updated Locations (OUL) task that is capable of assessing memory updating in a non-stressful task that is appropriate for both young and old rodents. We first show that young mice successfully remember both the original memory and the updated information in OUL. Next, we demonstrate that intrahippocampal infusion of the protein synthesis inhibitor anisomycin disrupts both the updated information and the original memory at test, suggesting that memory updating in OUL engages the original memory. To verify this, we used the Arc CatFISH technique to show that the OUL update session reactivates a largely overlapping set of neurons as the original memory. Finally, using OUL, we show that memory updating is impaired in aging, 18-m.o. mice. Together, these results demonstrate that hippocampal memory updating is impaired with aging and establish that the OUL paradigm is an effective, sensitive method of assessing memory updating in rodents.

New neurons restore structural and behavioral abnormalities in a rat model of PTSD.

Post-traumatic stress disorder (PTSD) has been associated with anxiety, memory impairments, enhanced fear, and hippocampal volume loss, although the relationship between these changes remain unknown. Single-prolonged stress (SPS) is a model for PTSD combining three forms of stress (restraint, swim, and anesthesia) in a single session that results in prolonged behavioral effects. Using pharmacogenetic ablation of adult neurogenesis in rats, we investigated the role of new neurons in the hippocampus in the long-lasting structural and behavioral effects of SPS. Two weeks after SPS, stressed rats displayed increased anxiety-like behavior and decreased preference for objects in novel locations regardless of the presence or absence of new neurons. Chronic stress produced by daily restraint for 2 or 6 hr produced similar behavioral effects that were also independent of ongoing neurogenesis. At a longer recovery time point, 1 month after SPS, rats with intact neurogenesis had normalized, showing control levels of anxiety-like behavior. However, GFAP-TK rats, which lacked new neurons, continued to show elevated anxiety-like behavior and enhanced serum corticosterone response to anxiogenic experience. Volume loss in ventral CA1 region of the hippocampus paralleled increases in anxiety-like behavior, occurring in all rats exposed to SPS at the early time point and only rats lacking adult neurogenesis at the later time point. In chronic stress experiments, volume loss occurred broadly throughout the dentate gyrus and CA1 after 6-hr daily stress but was not apparent in any hippocampal subregion after 2-hr daily stress. No effect of SPS was seen on cell proliferation in the dentate gyrus, but the survival of young neurons born a week after stress was decreased. Together, these data suggest that new neurons are important for recovery of normal behavior and hippocampal structure following a strong acute stress and point to the ventral CA1 region as a potential key mediator of stress-induced anxiety-like behavior.

Epigenetic regulation of the circadian gene Per1 contributes to age-related changes in hippocampal memory.

Aging is accompanied by impairments in both circadian rhythmicity and long-term memory. Although it is clear that memory performance is affected by circadian cycling, it is unknown whether age-related disruption of the circadian clock causes impaired hippocampal memory. Here, we show that the repressive histone deacetylase HDAC3 restricts long-term memory, synaptic plasticity, and experience-induced expression of the circadian gene Per1 in the aging hippocampus without affecting rhythmic circadian activity patterns. We also demonstrate that hippocampal Per1 is critical for long-term memory formation. Together, our data challenge the traditional idea that alterations in the core circadian clock drive circadian-related changes in memory formation and instead argue for a more autonomous role for circadian clock gene function in hippocampal cells to gate the likelihood of long-term memory formation.

Context and Auditory Fear are Differentially Regulated by HDAC3 Activity in the Lateral and Basal Subnuclei of the Amygdala.

Histone acetylation is a fundamental epigenetic mechanism that is dynamically regulated during memory formation. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) compete to modulate histone acetylation, allowing for rapid changes in acetylation in response to a learning event. HDACs are known to be powerful negative regulators of memory formation, but it is not clear whether this function depends on HDAC enzymatic activity per se. Here, we tested whether the enzymatic activity of an individual Class I HDAC, HDAC3, has a role in fear memory formation in subregions of the hippocampus and amygdala. We found that fear conditioning drove expression of the immediate early genes cFos and Nr4a2 in the hippocampus, which coincided with reduced HDAC3 occupancy at these promoters. Using a dominant-negative, deacetylase-dead point mutant virus (AAV-HDAC3(Y298H)-v5), we found that selectively blocking HDAC3 deacetylase activity in either the dorsal hippocampus or basal nucleus of the amygdala enhanced context fear without affecting tone fear. Blocking HDAC3 activity in the lateral nucleus of the amygdala, on the other hand, enhanced tone, but not context fear memory. These results show for the first time that the enzymatic activity of HDAC3 functions to negatively regulate fear memory formation. Further, HDAC3 activity regulates different aspects of fear memory in the basal and lateral subregions of the amygdala. Thus, the deacetylase activity of HDAC3 is a powerful negative regulator of fear memory formation in multiple subregions of the fear circuit.

Novel Oral Therapies for Opioid-induced Bowel Dysfunction in Patients with Chronic Noncancer Pain.

Opioid analgesics are frequently prescribed and play an important role in chronic pain management. Opioid-induced bowel dysfunction, which includes constipation, hardened stool, incomplete evacuation, gas, and nausea and vomiting, is the most common adverse event associated with opioid use. Mu-opioid receptors are specifically responsible for opioid-induced bowel dysfunction, resulting in reduced peristaltic and secretory actions. Agents that reverse these actions in the bowel without reversing pain control in the central nervous system may be preferred over traditional laxatives. The efficacy and safety of these agents in chronic noncancer pain were assessed from publications identified through Ovid and PubMed database searches. Trials that evaluated the safety and efficacy of oral agents for opioid-induced constipation or opioid-induced bowel dysfunction, excluding laxatives, were reviewed. Lubiprostone and naloxegol are approved in the United States by the Food and Drug Administration for use in opioid-induced constipation. Axelopran (TD-1211) and sustained-release naloxone have undergone phase 2 and phase 1 studies, respectively, for the same indication. Naloxegol and axelopran are peripherally acting µ-opioid receptor antagonists. Naloxone essentially functions as a peripherally acting µ-opioid receptor antagonist when administered orally in a sustained-release formulation. Lubiprostone is a locally acting chloride channel (CIC-2) activator that increases secretions and peristalsis. All agents increase spontaneous bowel movements and reduce other bowel symptoms compared with placebo in patients with noncancer pain who are chronic opioid users. The most common adverse events were gastrointestinal in nature, and none of the drugs were associated with severe adverse or cardiovascular events. Investigations comparing these agents to regimens using standard laxative and combination therapy and trials in special populations and patients with active cancer are needed to further define their role in therapy.

Congenital coronary arteriopathy and myocardial infarctions occur with tricuspid atresia.

Sinusoids and coronary arterial fistulae are well described in fetuses and infants with single ventricles. Coronary arteriopathy is well described as a cause of myocardial infarction in adults and in children with familial hypercholesterolemias. To the best of our knowledge, pathologic alterations in coronary arteries (coronary arteriopathy) have only twice before been described as the cause of infarction in neonates. We present the case of a newborn with perinatal myocardial infarctions and death in the setting of extensive coronary arteriopathy and tricuspid atresia. The child had a pulseless arrest immediately after birth. Autopsy showed multiple areas of infarction ranging in age from acute to >10 days old.

Molecular epidemiology of carbapenem-nonsusceptible Acinetobacter baumannii in the United States.

Acinetobacter baumannii is emerging as an important nosocomial pathogen worldwide. We report molecular epidemiology of 65 carbapenem-nonsusceptible A. baumannii isolates identified from hospitals in New York, Pennsylvania, Florida, Missouri, Nevada, and California between 2008 and 2009. All isolates were subjected to pulsed-field gel electrophoresis (PFGE). Select isolates then underwent multilocus sequence typing (MLST). While the PFGE patterns tended to cluster within each hospital, sequence types (STs) belonging to the clonal complex 92 (CC92) and the pan-European clonal lineage II (EUII; worldwide clonal lineage 2) were predominant in all hospitals. Of them, ST122 and ST208 were the most common and were found in four of the six hospitals. Isolates belonging to the pan-European clonal lineages I and III were identified in one hospital each. Carbapenemase-encoding genes bla(OXA-23) and/or ISAba1-bla(OXA-51-like) were present among the majority of isolates. These findings suggest that carbapenem-nonsusceptible A. baumannii isolates found in U.S. hospitals constitute part of the global epidemic driven by CC92, but have unique STs other than ST92, which may be spreading by means of patient transfer between health care facilities within the United States.

Video rigid laryngeal endoscopy compared to laryngeal mirror examination: an assessment of patient comfort and clinical visualization.

OBJECTIVES: To determine whether there are differences in patient preference and extent of laryngeal visualization between video rigid (30 degree endoscope) laryngoscopy (VRL) and laryngeal mirror examination (LME). STUDY DESIGN: A prospective comparison by patients undergoing laryngeal examination by both VRL and LME conducted by two examiners experienced in both mirror and rigid video endoscopy. METHODS: Forty-three patients had laryngeal examination by both VRL and LME in alternating order. Patients were instructed to observe their exam on a monitor screen during the rigid exam. At the conclusioon of both laryngeal examinations, patients were asked to rank comfort and level of gagging on a 1 to 10 scale for both VRL and LME, as well as preference between the two methods and whether seeing their laryngeal examination on the video screen was helpful. The extent of laryngeal visualization by the clinician was recorded for each examination. RESULTS: Patient comfort level was greater with VRL (P < .001) and gagging was significantly less with VRL (P < .001) compared to LME. VRL provided a more complete examination of the larynx by the clinician (P < .001) compared to LME. Patient preference significantly favored VRL (79.1%) compared to LME (18.4%) and 2.3% had no preference (P < .001) A total of 83.7% found visualization of laryngeal exam on the monitor during the VRL helpful. CONCLUSIONS: VRL is superior to LME for most patients based on comfort, extent of laryngeal examination by the clinician, and patient preference. The majority of patients found visualization of their laryngeal examination during VRL to be helpful.

Incidence of aortic root dilatation in pectus excavatum and its association with Marfan syndrome.

OBJECTIVE: To investigate the incidence of aortic root dilatation in pectus excavatum. DESIGN: Retrospective medical record review and echocardiographic reanalysis. SETTING: Morgan Stanley Children's Hospital of New York-Presbyterian. PARTICIPANTS: Surgical candidates with pectus excavatum (n = 37) and age-matched controls (n = 44) referred for an echocardiogram from 1994 to 2002. INTERVENTIONS: Two-dimensional and color Doppler transthoracic echocardiograms. OUTCOME MEASURES: The aortic annulus and root were measured and z scores were calculated and compared. Medical records were reviewed for genetic evaluation. RESULTS: Patients with pectus excavatum and age-matched controls were reanalyzed. There was no difference in age, weight, height, or body surface area between patients and controls. There were no differences in the mean aortic annulus diameter, mean aortic annulus z score, or mean aortic root measurements. However, the aortic root z score was significantly higher in the pectus excavatum group compared with the controls: 0.9 (SD, 1.06) vs 0.0 (SD, 1.25) (P = .001). There were more patients with an aortic root z score of 2 or greater in the pectus excavatum group (9 of 37 patients) than in the control group (0 of 43 controls), with a calculated odds ratio of 29.7 (95% confidence interval, 1.10-1.59). Genetic evaluation was performed in 5 patients with a pectus excavatum and dilated aortic root; 2 of them received diagnoses of Marfan syndrome. CONCLUSIONS: Aortic root dilatation is more common in patients with pectus excavatum than in a control population. Echocardiographic screening may be useful in the identification of aortic root dilatation in patients with isolated pectus excavatum.

Efficacy of sinonasal simulator in teaching endoscopic nasal skills.

OBJECTIVES/HYPOTHESIS: To develop a nasal model (NM) which accurately simulates human texture and anatomy and to study the effect of training with NM on performance of video rigid nasal endoscopy and video flexible laryngoscopy. At the conclusion of this presentation, the participants should be able to demonstrate that training with nasal endoscopic simulation enhances efficiency and may improve comfort to the patient. STUDY DESIGN: A randomized blinded control trial. METHODS: Twenty medical students without prior endoscopic experience, stratified by prior video game experience, were randomized to training or no training on NM. All participants viewed a 15-minute video instruction on endoscopy. Students randomized to training then practiced on the NM for 15 minutes. All students were tested within 90 minutes of the initial instruction with a timed identification of structures on NM followed by a timed flexible laryngoscopy on a human volunteer who ranked comfort/discomfort on a visual analogue scale. RESULTS: The students in the training group had a significantly shorter procedure time on NM using rigid nasal endoscopy compared with untrained students (61 seconds vs. 104 seconds, P = .025). The trained students showed a trend, which did not reach statistical significance, toward faster flexible laryngoscopy on the model (23 seconds vs. 32 seconds, P = .085). The trained students had average lower discomfort scores (0.89 vs. 1.33) compared with untrained students, but this did not reach statistical significance. CONCLUSIONS: Our NM accurately simulates human texture and anatomy and provides an opportunity for endoscopic training without concern of bloodborne pathogens and expense of cadavers. Further development of the NM is warranted to expand the training utility.

Co-occurrence of problem behaviors in South Korean adolescents: findings from Korea Youth Panel Survey.

Study findings showed problem behaviors can be observed in clusters in South Korean adolescents. Prevention programs targeting problem behavior clusters may have a greater impact on adolescents at risk for more than one problem behavior than programs targeting only a portion of the cluster.