Intact Recognition Memory and Altered Hippocampal Glucocorticoid Receptor Signaling in Fkbp5-deficient Mice Following Acute Uncontrollable Stress.

The FK506 binding protein 5 (FKBP5) is a co-chaperone that regulates the activity of the glucocorticoid receptor (GR) and has been reported to mediate stress resilience. This study aimed to determine the effects of Fkbp5 deletion on acute stress-induced recognition memory impairment and hippocampal GR signaling. Wild-type and Fkbp5-knockout mice were subjected to acute uncontrollable stress induced by restraint and electrical tail shock. First, we assessed the cognitive status of mice using a novel object recognition task. Next, we measured plasma corticosterone, GR levels, and the levels of GR phosphorylation at serine 211 in the hippocampus. Wild-type mice exhibited stress-induced memory impairments, whereas Fkbp5-knockout mice did not. Plasma corticosterone and GR levels did not differ between the non-stressed wild-type and Fkbp5-knockout mice, but the levels of phosphorylated GR were lower in Fkbp5-knockout mice than in wild-type mice. Wild-type and Fkbp5-knockout mice showed increased nuclear GR levels following stress, indicating GR translocation. However, cytosolic phosphorylated GR levels were lower in the hippocampi of Fkbp5-knockout mice following stress than in those of wild-type mice. These results suggest that FKBP5 deficiency increases resilience to acute stress by altering GR signaling.

Chemogenetic modulation of the medial prefrontal cortex regulates resistance to acute stress-induced cognitive impairments.

The medial prefrontal cortex (mPFC) has been implicated in regulating resistance to the effects of acute uncontrollable stress. We previously showed that mPFC-lesioned animals exhibit impaired object recognition memory after acute exposure to a brief stress that had no effect in normal animals. Here, we used designer receptors exclusively activated by designer drugs to determine how modulating mPFC activity affects recognition-memory performance under stressful conditions. Specifically, animals with chemogenetic excitation or inhibition of the mPFC underwent either a brief ineffective stress (20-min restraint + 20 tail shocks) or a prolonged effective stress (60-min restraint + 60 tail shocks). Subsequent recognition memory tests showed that animals with chemogenetic mPFC inhibition exposed to brief stress showed impairment in an object recognition memory task, whereas those with chemogenetic mPFC excitation exposed to prolonged stress did not. Thus, the present findings the decreased mPFC activity exacerbates acute stress effects on memory function whereas increased mPFC activity counters these stress effects provide evidence that the mPFC bidirectionally modulates stress resistance.

Peroxiredoxin 2 deletion impairs hippocampal-dependent memory via exacerbating transient ischemia-induced oxidative damage.

Peroxiredoxin 2 (Prx2) regulates oxidative stress response in neuronal injury. The present study examined the effects of Prx2 deletion on transient global ischemia-induced hippocampal-dependent memory impairment. First, 20-min bilateral common carotid artery occlusion (BCCAO)-reperfusion and sham-operated control procedures were conducted in 6- or 7-month-old Prx2 knockout and wild-type mice. The cognitive status of these mice was assessed using the Morris water maze task with a hidden platform and a novel object recognition task 7 days after the 20-min BCCAO. Next, to evaluate neuronal degeneration and oxidative stress in the CA1 subregion of the hippocampus critical for learning and memory, we measured immunoreactive Fluoro-jade C (FJC)-positive signals and 4-hydroxy-2-trans-nonenal (4-HNE) levels, respectively. The 20-min BCCAO induced cognitive impairments and increased the intensity of FJC-positive signals and 4-HNE levels of CA1 in Prx2 knockout mice but not in wild-type mice. These results suggest that Prx2 deficiency reduces resilience to transient global ischemia.

Optimal application of compressive palatal stents following mesiodens removal in pediatric patients: A Randomized Controlled Trial / Aplicación óptima de stents palatinos de compresión después de la extracción del mesiodens en pacientes pediátricos: un ensayo controlado aleatorio

Background: There is no scientific evidence supporting the choice of a palatal stent in patients who underwentremoval of an impacted supernumerary tooth. We aimed to investigate the effects of palatal stents in patients whounderwent supernumerary tooth removal through a palatal approach and to suggest the optimal stent thicknessand material.Material and Methods: We recruited 144 patients who underwent extraction of a supernumerary tooth between themaxillary anterior teeth. Subjects were assigned to a control group (CG) or one of four compressive palatal stentgroups (CPSGs) classified by the thickness and material of the thermoplastic acrylic stent used. Palatal gingivalswelling and objective indices (healing, oral hygiene, gingival, and plaque) were evaluated before surgery and onpostoperative days (PODs) 3, 7, and 14; pain/discomfort and the Child Oral Health Impact Profile (COHIP) wereassessed as subjective indices of the effects of the stent.Results: The CPSGs showed faster healing than did the CG on PODs 7 (P<0.001) and 14 (P=0.043); swelling wasmeasured by 1.64±0.88 mm and 4.52±0.39 mm, respectively. Although swelling was least in the 4-mm hard group(0.92±0.33 mm), the difference compared with that in the 2-mm hard group (1.01±0.18 mm) was not significant(P=0.077). The CPSGs showed better COHIP (P<0.001-0.036) and pain scores (P<0.001) than did the CG onPODs 1-3. Conclusions: Compressive palatal stents reduce discomfort by decreasing pain and alleviating swelling. Althougha stent is effective regardless of its thickness and material, 2-mm hard stents maximized such positive effects withminimal discomfort.(AU)

Engagement of lateral habenula in the extinction of the appetitive conditioned responses.

Following the association of a neutral stimulus (conditioned stimulus, CS) with a biologically significant stimulus (unconditioned stimulus, US), CS-alone presentations generate extinction: a decline in the conditioned response. Many studies have revealed the neural substrates of fear extinction; however, a few have identified the brain regions responsible for appetitive extinction. Midbrain dopamine neurons are activated by presenting a reward or predictable reward cue, whereas the cue signaling the absence of reward activates the lateral habenula (LHb) neurons. We examined the engagement of the LHb in appetitive extinction. In the first phase, rats first received pairings of a CS (light) with US delivery (food pellets). In the second phase, rats in the CS-alone group underwent four CS-alone presentations, whereas those in the paired group received four pairings of light with food pellets. We also included a comparison group for CS-alone presentations: rats were placed in the training box without CS or US exposures in the first phase and received four CS-alone presentations in the second phase. Thirty minutes after the second phase, c-Fos levels in the ventral tegmental area (VTA), substantia nigra pars compacta (SNc), and LHb in these groups were measured. c-Fos levels in the LHb were higher in the paired-CS-alone group than in the paired-paired and comparison groups, while those in the VTA and SNc were significantly higher in the paired-paired group than in the other groups. On examination of LHb neurotoxic lesion effects on the decline of conditioned food-cup responses when a CS was repeatedly presented with no US, LHb lesions decelerated the decline in conditioned food-cup responses, suggesting a crucial role of LHb in appetitive extinction.

SGK1 knockdown in the medial prefrontal cortex reduces resistance to stress-induced memory impairment.

Down-regulation of serum and glucocorticoid-regulated kinase1 (SGK1) expression has been reported in the postmortem prefrontal cortex (PFC) of subjects with post-traumatic stress disorder. Furthermore, experimental treatments that reduce SGK1 function in the medial prefrontal cortex (mPFC) cause depressive-like behaviors and synaptic dysfunction. Therefore, we examined the effect of SGK1 down-regulation in the mPFC on resistance to stress-induced cognitive impairment. Rats with viral-mediated knockdown of SGK1 in the mPFC were subjected to either a brief 20-min restraint plus 20 intermittent tail shocks or a prolonged 60-min restraint plus 60 intermittent tail shocks, after which their performance in an object recognition task was assessed. Recognition memory remained intact in control rats following the brief stress, but was impaired in rats with SGK1 knockdown in the mPFC. Prolonged stress impaired recognition memory in both control rats and rats with SGK1 knockdown. Our findings indicate that altered mPFC SGK1 signaling is a potential mechanism for resistance to stress-induced cognitive impairment.

Altered Mitochondrial Functions and Morphologies in Epithelial Cells Are Associated With Pathogenesis of Chronic Rhinosinusitis With Nasal Polyps.

PURPOSE: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a complex inflammatory disease of the nasal and paranasal sinus mucosa. The disease is associated with mitochondrial dysfunction, structural changes in the mitochondria, and reactive oxygen species (ROS) generation. This study investigated whether there are functional and morphological changes in the mitochondria in the epithelial cells of nasal polyps (NPs) and Staphylococcus aureus enterotoxin B (SEB)-stimulated nasal epithelial cells. METHODS: In all, 30 patients with CRSwNP and 15 healthy subjects were enrolled. Mitochondrial ROS (mtROS) and changes in mitochondrial functions and structures were investigated in the uncinate tissue (UT) of healthy controls, the UT or NPs of CRSwNP patients, and human nasal epithelial cells with or without SEB stimulation. RESULTS: Oxidative phosphorylation complexes showed various responses following SEB stimulation in the nasal epithelial cells, and their expressions were significantly higher in the NPs of patients with CRSwNP than in the UT of controls. Generation of mtROS was increased following SEB exposure in nasal epithelial cells and was reduced by pretreatment with MitoTEMPO, which is used as an mtROS scavenger. In the tissues, mtROS was significantly increased in the NPs of CRSwNP patients compared to the UT of controls or CRSwNP patients. The expressions of fusion- and fission-related molecules were also significantly higher in SEB-exposed nasal epithelial cells than in non-exposed cells. In tissues, the expression of fission (fission mediator protein 1)- and fusion (membrane and mitofusin-1, and optic atrophy protein 1)-related molecules was significantly higher in the NPs of CRSwNP patients than in UT of controls or CRSwNP patients. Transmission electron microscopy revealed elongated mitochondria in SEB-exposed nasal epithelial cells and epithelial cells of NPs. CONCLUSIONS: Production of mtROS, disrupted mitochondrial function, and structural changes in nasal epithelial cells might be involved in the pathogenesis of CRSwNP.

Assessment of Cognitive Phenotyping in Inbred, Genetically Modified Mice, and Transgenic Mouse Models of Alzheimer's Disease.

Genetically modified mouse models are being used predominantly to understand brain functions and diseases. Well-designed and controlled behavioral analyses of genetically modified mice have successfully led to the identification of gene functions, understanding of brain diseases, and development of treatments. Recently, complex and higher cognitive functions have been examined in mice with genetic mutations. Therefore, research strategies for cognitive phenotyping should be sophisticated and evolve to convey the exact meaning of the findings and provide robust translational tools for testing hypotheses and developing treatments. This review addresses issues of experimental design and discusses studies that have examined cognitive function using mouse strain differences, genetically modified mice, and transgenic mice for Alzheimer's disease.