Retinoic acid modulation of granule cell activity and spatial discrimination in the adult hippocampus.

Retinoic acid (RA), derived from vitamin A (retinol), plays a crucial role in modulating neuroplasticity within the adult brain. Perturbations in RA signaling have been associated with memory impairments, underscoring the necessity to elucidate RA's influence on neuronal activity, particularly within the hippocampus. In this study, we investigated the cell type and sub-regional distribution of RA-responsive granule cells (GCs) in the mouse hippocampus and delineated their properties. We discovered that RA-responsive GCs tend to exhibit a muted response to environmental novelty, typically remaining inactive. Interestingly, chronic dietary depletion of RA leads to an abnormal increase in GC activation evoked by a novel environment, an effect that is replicated by the localized application of an RA receptor beta (RARß) antagonist. Furthermore, our study shows that prolonged RA deficiency impairs spatial discrimination-a cognitive function reliant on the hippocampus-with such impairments being reversible with RA replenishment. In summary, our findings significantly contribute to a better understanding of RA's role in regulating adult hippocampal neuroplasticity and cognitive functions.

Maladaptation of dentate gyrus mossy cells mediates contextual discrimination deficit after traumatic stress.

Fear overgeneralization is a maladaptive response to traumatic stress that is associated with the inability to discriminate between threat and safety contexts, a hallmark feature of post-traumatic stress disorder (PTSD). However, the neural mechanisms underlying this deficit remain unclear. Here, we show that traumatic stress exposure impairs contextual discrimination between threat and safety contexts in the learned helplessness (LH) model. Mossy cells (MCs) in the dorsal hippocampus are suppressed in response to traumatic stress. Bidirectional manipulation of MC activity in the LH model reveals that MC inhibition is causally linked to impaired contextual discrimination. Mechanistically, MC inhibition increases the number of active granule cells in a given context, significantly overlapping context-specific ensembles. Our study demonstrates that maladaptive inhibition of MCs after traumatic stress is a substantial mechanism underlying fear overgeneralization with contextual discrimination deficit, suggesting a potential therapeutic target for cognitive symptoms of PTSD.

Hippocampal mossy cell involvement in behavioral and neurogenic responses to chronic antidepressant treatment.

Most antidepressants, including selective serotonin reuptake inhibitors (SSRIs), initiate their drug actions by rapid elevation of serotonin, but they take several weeks to achieve therapeutic onset. This therapeutic delay suggests slow adaptive changes in multiple neuronal subtypes and their neural circuits over prolonged periods of drug treatment. Mossy cells are excitatory neurons in the dentate hilus that regulate dentate gyrus activity and function. Here we show that neuronal activity of hippocampal mossy cells is enhanced by chronic, but not acute, SSRI administration. Behavioral and neurogenic effects of chronic treatment with the SSRI, fluoxetine, are abolished by mossy cell-specific knockout of p11 or Smarca3 or by an inhibition of the p11/AnxA2/SMARCA3 heterohexamer, an SSRI-inducible protein complex. Furthermore, simple chemogenetic activation of mossy cells using Gq-DREADD is sufficient to elevate the proliferation and survival of the neural stem cells. Conversely, acute chemogenetic inhibition of mossy cells using Gi-DREADD impairs behavioral and neurogenic responses to chronic administration of SSRI. The present data establish that mossy cells play a crucial role in mediating the effects of chronic antidepressant medication. Our results indicate that compounds that target mossy cell activity would be attractive candidates for the development of new antidepressant medications.

Ecological Momentary Assessment Using Smartphone-Based Mobile Application for Affect and Stress Assessment.

OBJECTIVES: This study aimed to describe the process of utilizing a mobile application for ecological momentary assessment (EMA) to collect data on stress and mood in daily life setting. METHODS: A mobile application for the Android operating system was developed and installed with a set of questions regarding momentary mood and stress into a smartphone of a participant. The application sets alarms at semi-random intervals in 60-minute blocks, four times a day for 7 days. After obtaining all momentary affect and stress, the questions to assess the usability of the mobile EMA application were also administered. RESULTS: The data were collected from 97 police officers working in Gyeonggi Province of South Korea. The mean completion rate was 60.0% ranging from 3.5% to 100%. The means of positive and negative affect were 18.34 of 28 and 19.09 of 63. The mean stress was 17.92 of 40. Participants responded that the mobile application correctly measured their affect (4.34 ± 0.83) and stress (4.48 ± 0.62) of 5-point Likert scale. CONCLUSIONS: Our study investigated the process of utilizing a mobile application to assess momentary affect and stress at repeated times. We found challenges regarding adherence to the research protocol, such as completion and delay of answering after alarm notification. Despite this inherent issue of adherence to the research protocol, the EMA still has advantages of reducing recall bias and assessing the actual moment of interest at multiple time points that improves ecological validity.

LPA-induced migration of ovarian cancer cells requires activation of ERM proteins via LPA1 and LPA2.

Lysophosphatidic acid (LPA) has been implicated in the pathology of human ovarian cancer. This phospholipid elicits a wide range of cancer cell responses, such as proliferation, trans-differentiation, migration, and invasion, via various G-protein-coupled LPA receptors (LPARs). Here, we explored the cellular signaling pathway via which LPA induces migration of ovarian cancer cells. LPA induced robust phosphorylation of ezrin/radixin/moesin (ERM) proteins, which are membrane-cytoskeleton linkers, in the ovarian cancer cell line OVCAR-3. Among the LPAR subtypes expressed in these cells, LPA1 and LPA2, but not LPA3, induced phosphorylation of ERM proteins at their C-termini. This phosphorylation was dependent on the Gα12/13/RhoA pathway, but not on the Gαq/Ca2+/PKC or Gαs/adenylate cyclase/PKA pathway. The activated ERM proteins mediated cytoskeletal reorganization and formation of membrane protrusions in OVCAR-3 cells. Importantly, LPA-induced migration of OVCAR-3 cells was completely abolished not only by gene silencing of LPA1 or LPA2, but also by overexpression of a dominant negative ezrin mutant (ezrin-T567A). Taken together, this study demonstrates that the LPA1/LPA2/ERM pathway mediates LPA-induced migration of ovarian cancer cells. These findings may provide a potential therapeutic target to prevent metastatic progression of ovarian cancer.

Prognostic value of psychological state in cochlear implantation.

CONCLUSION: Perioperative Minnesota Multiphasic Personality Inventory (MMPI) scores may be beneficial for predicting prognosis of cochlear implantation (CI). A positive attitude for social interaction in particular correlates with a better speech outcome. Proper perioperative psychological management may, therefore, assist in the auditory rehabilitation of CI patients. OBJECTIVE: To determine the perioperative psychological state of CI patients and its relationship with patient prognosis after CI. METHODS: This study prospectively enrolled 29 patients who underwent CI from 2005-2013. The MMPI was administered to assess psychosocial and emotional issues surrounding CI and the Korean version of the Central Institute of Deafness (K-CID) score was used to measure speech perception. RESULTS: CI resulted in a significant improvement on the MMPI Paranoia scale (p = 0.02). Patients with abnormal pre-operative and post-operative MMPI scores also had an earlier onset of deafness, longer duration of deafness, and lower K-CID scores than patients with normal MMPI scores (all p < 0.05). The post-CI K-CID score had a significant negative correlation with the pre-operative MMPI Schizophrenia score (p < 0.01) and significant negative correlations with the post-operative MMPI Paranoia (p = 0.02), Psychasthenia (p = 0.02), Schizophrenia (p = 0.04), Hypomania (p = 0.02) and Social Introversion (p = 0.03) scores.

The soluble interleukin-6 receptor is a mediator of hematopoietic and skeletal actions of parathyroid hormone.

Both PTH and IL-6 signaling play pivotal roles in hematopoiesis and skeletal biology, but their interdependence is unclear. The purpose of this study was to evaluate the effect of IL-6 and soluble IL-6 receptor (sIL-6R) on hematopoietic and skeletal actions of PTH. In the bone microenvironment, PTH stimulated sIL-6R protein levels in primary osteoblast cultures in vitro and bone marrow in vivo in both IL-6(+/+) and IL-6(-/-) mice. PTH-mediated hematopoietic cell expansion was attenuated in IL-6(-/-) compared with IL-6(+/+) bone marrow, whereas sIL-6R treatment amplified PTH actions in IL-6(-/-) earlier than IL-6(+/+) marrow cultures. Blocking sIL-6R signaling with sgp130 (soluble glycoprotein 130 receptor) inhibited PTH-dependent hematopoietic cell expansion in IL-6(-/-) marrow. In the skeletal system, although intermittent PTH administration to IL-6(+/+) and IL-6(-/-) mice resulted in similar anabolic actions, blocking sIL-6R significantly attenuated PTH anabolic actions. sIL-6R showed no direct effects on osteoblast proliferation or differentiation in vitro; however, it up-regulated myeloid cell expansion and production of the mesenchymal stem cell recruiting agent, TGF-ß1 in the bone marrow microenvironment. Collectively, sIL-6R demonstrated orphan function and mediated PTH anabolic actions in bone in association with support of myeloid lineage cells in the hematopoietic system.