RbAp48 Protein Is a Critical Component of GPR158/OCN Signaling and Ameliorates Age-Related Memory Loss

Precisely deciphering the molecular mechanisms of age-related memory loss is crucial to create appropriate therapeutic interventions. We have previously shown that the histone-binding protein RbAp48/Rbbp4 is a molecular determinant of Age-Related Memory Loss. By exploring how this protein regulates the genomic landscape of the hippocampal circuit, we find that RbAp48 controls the expression of BDNF and GPR158 proteins, both critical components of osteocalcin (OCN) signaling in the mouse hippocampus. We show that inhibition of RbAp48 in the hippocampal formation inhibits OCN’s beneficial functions in cognition and causes deficits in discrimination memory. In turn, disruption of OCN/GPR158 signaling leads to the downregulation of RbAp48 protein, mimicking the discrimination memory deficits observed in the aged hippocampus. We also show that activation of the OCN/GPR158 pathway increases the expression of RbAp48 in the aged dentate gyrus and rescues age-related memory loss

Sex Differences in Remote Contextual Fear Generalization in Mice

The generalization of fear is adaptive in that it allows an animal to respond appropriately to novel threats that are not identical to previous experiences. In contrast, the overgeneralization of fear is maladaptive and is a hallmark of post-traumatic stress disorder (PTSD), a psychiatric illness that is characterized by chronic symptomatology and a higher incidence in women compared to men. Therefore, understanding the neural basis of fear generalization at remote time-points in female animals is of particular translational relevance. However, our understanding of the neurobiology of fear generalization is largely restricted to studies employing male mice and focusing on recent time-points (i.e., within 24–48 h following conditioning). To address these limitations, we examined how male and female mice generalize contextual fear at remote time intervals (i.e., 3 weeks after conditioning). In agreement with earlier studies of fear generalization at proximal time-points, we find that the test order of training and generalization contexts is a critical determinant of generalization and context discrimination, particularly for female mice. However, tactile elements that are present during fear conditioning are more salient for male mice. Our study highlights long-term sex differences in defensive behavior between male and female mice and may provide insight into sex differences in the processing and retrieval of remote fear memory observed in humans

Gpr158 mediates osteocalcin's regulation of cognition

That osteocalcin (OCN) is necessary for hippocampal-dependent memory and to prevent anxiety-like behaviors raises novel questions. One question is to determine whether OCN is also sufficient to improve these behaviors in wild-type mice, when circulating levels of OCN decline as they do with age. Here we show that the presence of OCN is necessary for the beneficial influence of plasma from young mice when injected into older mice on memory and that peripheral delivery of OCN is sufficient to improve memory and decrease anxiety-like behaviors in 16-mo-old mice. A second question is to identify a receptor transducing OCN signal in neurons. Genetic, electrophysiological, molecular, and behavioral assays identify Gpr158, an orphan G protein-coupled receptor expressed in neurons of the CA3 region of the hippocampus, as transducing OCN's regulation of hippocampal-dependent memory in part through inositol 1,4,5-trisphosphate and brain-derived neurotrophic factor. These results indicate that exogenous OCN can improve hippocampal-dependent memory in mice and identify molecular tools to harness this pathway for therapeutic purposes

Radial probe endobronchial ultrasound assisted conventional transbronchial needle aspiration in the diagnosis of solitary peribronchial pulmonary lesion located in the segmental bronchi

Background: The diagnosis of peribronchial pulmonary lesions located in the tertiary bronchi, also known as segmental bronchi, as well as, the 4th order and 5th order segmental bronchi is very difficult. Histopathological specimens cannot be easily obtained by endobronchial biopsies (EBBX) due to the patent but small segmental bronchial lumen. The aim of the present study was to evaluate the diagnostic accuracy and safety of the novel technique with radial probe endobronchial ultrasound (R-EBUS) assisted conventional transbronchial needle aspiration (C-TBNA) in the diagnosis of solitary peribronchial pulmonary lesions located in segmental bronchi from 3th to 5th order. Methods: From December 2014 to December 2015, 16 patients with solitary peribronchial pulmonary lesions in the segmental bronchi from 3th to 5th order confirmed by computed tomography (CT) were enrolled. The lesions were located using radial probe endobronchial ultrasound (R-EBUS) to determine the sites of conventional transbronchial needle aspiration (C-TBNA), then, histopathological specimens were obtained using the technique of C-TBNA. The final pathological diagnosis was made based on the findings from the surgical specimens. Statistical analyses were performed for specimen results and complications. Results: On pathological evaluation, 14 of the 16 specimens were malignant, including 8 adenocarcinomas, 4 squamous cell carcinomas, and 2 small cell carcinomas, while 2 were non-malignant diseases. The diagnostic accuracy rate, sensitivity and missed diagnosis rates were 87.5%, 87.5% and 12.5%, respectively. When Combined the results of cytology with histologic samples obtained from C-TBNA the total diagnostic accuracy rate, sensitivity and missed diagnosis rate were 93.75%, 93.75% and 6.25%, respectively. There were 2 cases of bleeding complications \u3e5 mL after C-TBNA, and both were resolved with endobronchial management. Conclusions: The combination of R-EBUS with C-TBNA was advantageous and safe for the diagnosis of solitary peribronchial pulmonary lesions located in the segmental bronchi. However, possible bleeding complications should be anticipated with needle aspiration. Further verification of this combined application should be investigated in larger clinical trials

CyclinD2-mediated regulation of neurogenic output from the retinal ciliary margin is perturbed in albinism

In albinism, aberrations in the ipsi-/contralateral retinal ganglion cell (RGC) ratio compromise the functional integrity of the binocular circuit. Here, we focus on the mouse ciliary margin zone (CMZ), a neurogenic niche at the embryonic peripheral retina, to investigate developmental processes regulating RGC neurogenesis and identity acquisition. We found that the mouse ventral CMZ generates predominantly ipsilaterally projecting RGCs, but this output is altered in the albino visual system because of CyclinD2 downregulation and disturbed timing of the cell cycle. Consequently, albino as well as CyclinD2-deficient pigmented mice exhibit diminished ipsilateral retinogeniculate projection and poor depth perception. In albino mice, pharmacological stimulation of calcium channels, known to upregulate CyclinD2 in other cell types, augmented CyclinD2-dependent neurogenesis of ipsilateral RGCs and improved stereopsis. Together, these results implicate CMZ neurogenesis and its regulators as critical for the formation and function of the mammalian binocular circuit.This work was funded by NIH R01 EY015290, R01 EY12736, António Champalimaud Vision Award, Simons Foundation Senior Fellow award, and Vision of Children (C.A.M.); Fight for Sight and a Georgakopoulos Family Fellowship (N.S.); NIH R01 EY032062, R01 EY032507, and Precision Medicine Initiative at Columbia University (S.W.M.J.); R01 NS105477 (M.E.R.); Vision Core grant P30 EY019007; and NIH/NCI Cancer Center Support grant P30CA013696, and National Center for Advancing Translational Sciences, National Institutes of Health through grant no. UL1TR001873 (Sulzberger Genome Center).Peer reviewe

Study of pproteins regulating iron in the nervous system: role of iron in neurodegenerative disorders

Iron is one of the major elements for the preservation of life , but also capable for the destruction of it, since alterations in its balance does not cope with the proper function of the cell. Iron can be found in several states and in different protein complexes. This ability made him a vital elements of many biological complexes and pathways. The most common protein that stores iron is ferritin.Alterations in the homoistasis of iron and ferritin have dentrimental effects in the cell. One of the common tissues that is affected from the abnormalities in the iron metabolism is the neuronal tissue and especially the brain. The iron is located commonly in the basal gaglia of the brain and the quantitity is approximately the same with the amount of iron found in the liver. Iron is also present in the cells of the C.N.S. such us oligodendrocytes kai cells that produce myelin. The increase of iron in neurons, astrocytes and glia is being more obvious with increase of age. Specifically, regions such as hippocampus and substantia nigra accumulate iron normally but are susceptible in neuropathological changes that can be found in diseases, Alzheimers, Parkinson e.tc. In the present study we investigate the differential distribution of ferritin subunits in brain and we presented data showing that the redistribution of ferritin is age related. We show that in iron homoiostasis the secretoty pathway in conjuction with the proteasome pathway have vitla roles. We demonstrated that the the expression of ferritin subunits is essential for life since their disruption leads to leathality. Brian cells have different ways of handling iron and any intervention in their function can cause various defects such as neurodegeneration and movement disorders. Finally, we generated a model system for the study of iron metabolism and the relation with the neurodegeneration processes. The accumulation of hyperphosphorylated tau has been related to a group of dementing neurodegenerative diseases, known as Tauopathies. The six possible tau isoforms, products of alternative splicing of a unique transcript, are distributed mainly in the axons of central nervous system (CNS) neurons. Tau associates with microtubules and regulates their organization, stability and function including intraneuronal transport. With the exception of the familial disease Frontotemporal 372 dementia with parkinsonism linked to chromosome 17, which is associated with gene mutations, other tauopathies like Pick‘s and Alzheimer‘s disease, among others, are characterized by aggregates of hyperphosphorylated, at specific epitopes, normal tau isoforms. The hyperphosphorylated form of tau has reduced ability to bind to microtubules. As a result, it accumulates in the cytoplasm and aggregates into NFTs (neurofibrilar tanges), a characteristic pathological hallmark of many tauopathies. The heterogeneous clinical and cognitive profiles of tauopathies suggest differences in vulnerability of neuronal populations to tau levels, phosphorylation and mutations. ......................................................................

Cell type-specific processing of human Tau proteins in Drosophila

AbstractAccumulation of hyperphosphorylated Tau is associated with a number of neurodegenerative diseases collectively known as tauopathies. Differences in clinical and cognitive profiles among them suggest differential sensitivity of neuronal populations to Tau levels, phosphorylation and mutations. We used tissue specific expression of wild type and mutant human tau transgenes to demonstrate differential phosphorylation and stability in a cell type-specific manner, which includes different neuronal types and does not correlate with the level of accumulated protein. Rather, they likely reflect the spatial distribution or regulation of Tau-targeting kinases and phosphatases

Early life stress delays hippocampal development and diminishes the adult stem cell pool in mice

Contains fulltext : 202018.pdf (publisher's version ) (Open Access

MicroRNA-22 Gates Long-Term Heterosynaptic Plasticity in Aplysia through Presynaptic Regulation of CPEB and Downstream Targets

The maintenance phase of memory-related long-term facilitation (LTF) of synapses between sensory and motor neurons of the gill-withdrawal reflex of Aplysia depends on a serotonin (5-HT)-triggered presynaptic upregulation of CPEB, a functional prion that regulates local protein synthesis at the synapse. The mechanisms whereby serotonin regulates CPEB levels in presynaptic sensory neurons are not known. Here, we describe a sensory neuron-specific microRNA 22 (miR-22) that has multiple binding sites on the mRNA of CPEB and inhibits it in the basal state. Serotonin triggers MAPK/Erk-dependent downregulation of miR-22, thereby upregulating the expression of CPEB, which in turn regulates, through functional CPE elements, the presynaptic expression of atypical PKC (aPKC), another candidate regulator of memory maintenance. Our findings support a model in which the neurotransmitter-triggered downregulation of miR-22 coordinates the regulation of genes contributing synergistically to the long-term maintenance of memory-related synaptic plasticity