bluuebunny/crossref_metadata_2025_split huggingface dataset:
PtenRegulates Retinal Amacrine Cell Number by Modulating Akt, Tgfβ, and Erk Signaling
Authors: Tachibana Nobuhiko , Cantrup Robert , Dixit Rajiv , Touahri Yacine , Kaushik Gaurav , Zinyk Dawn , Daftarian Narsis , Biernaskie Jeff , McFarlane Sarah , Schuurmans Carol 
Published: September 2016

All tissues are genetically programmed to acquire an optimal size that is defined by total cell number and individual cellular dimensions. The retina contains stereotyped proportions of one glial and six neuronal cell types that are generated in overlapping waves. How multipotent retinal progenitors know when to switch from making one cell type to the next so that appropriate numbers of each cell type are generated is poorly understood. Pten is a phosphatase that controls progenitor cell proliferation and differentiation in several lineages. Here, using a conditional loss-of-function strategy, we found thatPtenregulates retinal cell division and is required to produce the full complement of rod photoreceptors and amacrine cells in mouse. We focused on amacrine cell number control, identifying three downstream Pten effector pathways. First, phosphoinositide 3-kinase/Akt signaling is hyperactivated inPtenconditional knock-out (cKO) retinas, and misexpression of constitutively active Akt (Akt-CA) in retinal explants phenocopies the reduction in amacrine cell production observed inPtencKOs. Second, Akt-CA activates Tgfβ signaling in retinal explants, which is a negative feedback pathway for amacrine cell production. Accordingly, Tgfβ signaling is elevated inPtencKO retinas, and epistatic analyses placed Pten downstream of TgfβRII in amacrine cell number control. Finally,Ptenregulates Raf/Mek/Erk signaling levels to promote the differentiation of all amacrine cell subtypes, which are each reduced in number inPtencKOs.Ptenis thus a positive regulator of amacrine cell production, acting via multiple downstream pathways, highlighting its diverse actions as a mediator of cell number control.SIGNIFICANCE STATEMENTDespite the importance of size for optimal organ function, how individual cell types are generated in correct proportions is poorly understood. There are several ways to control cell number, including readouts of organ function (e.g., secreted hormones reach functional levels when enough cells are made) or counting of cell divisions or cell number. The latter applies to the retina, where cell number is regulated by negative feedback signals, which arrest differentiation of particular cell types at threshold levels. Herein, we show thatPtenis a critical regulator of amacrine cell number in the retina, acting via multiple downstream pathways. Our studies provide molecular insights into howPTENloss in humans may lead to uncontrolled cell division in several pathological conditions.
A Corticocortical Circuit Directly Links Retrosplenial Cortex to M2 in the Mouse
Authors: Yamawaki Naoki , Radulovic Jelena , Shepherd Gordon M.G. 
Published: September 2016

Retrosplenial cortex (RSC) is a dorsomedial parietal area involved in a range of cognitive functions, including episodic memory, navigation, and spatial memory. Anatomically, the RSC receives inputs from dorsal hippocampal networks and in turn projects to medial neocortical areas. A particularly prominent projection extends rostrally to the posterior secondary motor cortex (M2), suggesting a functional corticocortical link from the RSC to M2 and thus a bridge between hippocampal and neocortical networks involved in mnemonic and sensorimotor aspects of navigation. We investigated the cellular connectivity in this RSC→M2 projection in the mouse using optogenetic photostimulation, retrograde labeling, and electrophysiology. Axons from RSC formed monosynaptic excitatory connections onto M2 pyramidal neurons across layers and projection classes, including corticocortical/intratelencephalic neurons (reciprocally and callosally projecting) in layers 2–6, pyramidal tract neurons (corticocollicular, corticopontine) in layer 5B, and, to a lesser extent, corticothalamic neurons in layer 6. In addition to these direct connections, disynaptic connections were made via posterior parietal cortex (RSC→PPC→M2) and anteromedial thalamus (RSC→AM→M2). In the reverse direction, axons from M2 monosynaptically excited M2-projecting corticocortical neurons in the RSC, especially in the superficial layers of the dysgranular region. These findings establish an excitatory RSC→M2 corticocortical circuit that engages diverse types of excitatory projection neurons in the downstream area, suggesting a basis for direct communication from dorsal hippocampal networks involved in spatial memory and navigation to neocortical networks involved in diverse aspects of sensorimotor integration and motor control.SIGNIFICANCE STATEMENTCorticocortical pathways interconnect cortical areas extensively, but the cellular connectivity in these pathways remains largely uncharacterized. Here, we show that a posterior part of secondary motor cortex receives corticocortical axons from the rostral retrosplenial cortex (RSC) and these form monosynaptic excitatory connections onto a wide spectrum of excitatory projection neurons in this area. Our results define a cellular basis for direct communication from RSC to this medial frontal area, suggesting a direct link from dorsal hippocampal networks involved in spatial cognition and navigation (the “map”) to sensorimotor networks involved the control of movement (the “motor”).
Maternal Rest/Nrsf Regulates Zebrafish Behavior throughsnap25a/b
Authors: Moravec Cara E. , Samuel John , Weng Wei , Wood Ian C. , Sirotkin Howard I. 
Published: September 2016

During embryonic development, regulation of gene expression is key to creating the many subtypes of cells that an organism needs throughout its lifetime. Recent work has shown that maternal genetics and environmental factors have lifelong consequences on diverse processes ranging from immune function to stress responses. The RE1-silencing transcription factor (Rest) is a transcriptional repressor that interacts with chromatin-modifying complexes to repress transcription of neural-specific genes during early development. Here we show that in zebrafish, maternally suppliedrestregulates expression of target genes during larval development and has lifelong impacts on behavior. Larvae deprived of maternalrestare hyperactive and show atypical spatial preferences. Adult male fish deprived of maternalrestpresent with atypical spatial preferences in a novel environment assay. Transcriptome sequencing revealed 158 genes that are repressed by maternalrestin blastula stage embryos. Furthermore, we found that maternalrestis required for target gene repression until at least 6 dpf. Importantly, disruption of the RE1 sites in eithersnap25aorsnap25bresulted in behaviors that recapitulate the hyperactivity phenotype caused by absence of maternalrest. Both maternalrestmutants andsnap25aRE1 site mutants have altered primary motor neuron architecture that may account for the enhanced locomotor activity. These results demonstrate that maternalrestrepressessnap25a/bto modulate larval behavior and that early Rest activity has lifelong behavioral impacts.SIGNIFICANCE STATEMENTMaternal factors deposited in the oocyte have well-established roles during embryonic development. We show that, in zebrafish, maternalrest(RE1-silencing transcription factor) regulates expression of target genes during larval development and has lifelong impacts on behavior. The Rest transcriptional repressor interacts with chromatin-modifying complexes to limit transcription of neural genes. We identify several synaptic genes that are repressed by maternal Rest and demonstrate thatsnap25a/bare key targets of maternalrestthat modulate larval locomotor activity. These results reveal that zygoticrestis unable to compensate for deficits in maternally supplied rest and uncovers novel temporal requirements for Rest activity, which has implications for the broad roles of Rest-mediated repression during neural development and in disease states.
Anti-Inflammatory Modulation of Microglia via CD163-Targeted Glucocorticoids Protects Dopaminergic Neurons in the 6-OHDA Parkinson's Disease Model
Authors: Tentillier Noemie , Etzerodt Anders , Olesen Mads N. , Rizalar F. Sila , Jacobsen Jan , Bender Dirk , Moestrup Søren K. , Romero-Ramos Marina 
Published: September 2016

Increasing evidence supports a decisive role for inflammation in the neurodegenerative process of Parkinson's disease (PD). The immune response in PD seems to involve, not only microglia, but also other immune cells infiltrated into the brain. Indeed, we observed here the infiltration of macrophages, specifically CD163+ macrophages, into the area of neurodegeneration in the 6-hydroxydopamine (6-OHDA) PD model. Therefore, we investigated the therapeutic potential of the infiltrated CD163+ macrophages to modulate local microglia in the brain to achieve neuroprotection. To do so, we designed liposomes targeted for the CD163 receptor to deliver dexamethasone (Dexa) into the CD163+ macrophages in the 6-OHDA PD model. Our data show that a fraction of the CD163-targeted liposomes were carried into the brain after peripheral intravenous injection. The 6-OHDA-lesioned rats that received repeated intravenous CD163-targeted liposomes with Dexa for 3 weeks exhibited better motor performance than the control groups and had minimal glucocorticoid-driven side effects. Furthermore, these animals showed better survival of dopaminergic neurons in substantia nigra and an increased number of microglia expressing major histocompatibility complex II. Therefore, rats receiving CD163-targeted liposomes with Dexa were partially protected against 6-OHDA-induced dopaminergic neurodegeneration, which correlated with a distinctive microglia response. Altogether, our data support the use of macrophages for the modulation of brain neurodegeneration and specifically highlight the potential of CD163-targeted liposomes as a therapeutic tool in PD.SIGNIFICANCE STATEMENTThe immune response now evident in the progression of Parkinson's disease comprises both local microglia and other immune cells. We provide evidence that CD163+ macrophages can be a target to modulate brain immune response to achieve neuroprotection in the 6-hydroxydopamine model. To do so, we targeted the CD163+ population, which to a low but significant extent infiltrated in the neurodegenerating area of the brain. Specially designed liposomes targeted for the CD163 receptor were loaded with glucocorticoids and injected peripherally to modify the infiltrated CD163 cells toward an anti-inflammatory profile. This modification of the CD163 population resulted in a distinctive microglial response that correlated with decreased dopaminergic cell death and better motor performance.
Reactivation of Rate Remapping in CA3
Authors: Schwindel C. Daniela , Navratilova Zaneta , Ali Karim , Tatsuno Masami , McNaughton Bruce L. 
Published: September 2016

The hippocampus is thought to contribute to episodic memory by creating, storing, and reactivating patterns that are unique to each experience, including different experiences that happen at the same location. Hippocampus can combine spatial and contextual/episodic information using a dual coding scheme known as “global” and “rate” remapping. Global remapping selects which set of neurons can activate at a given location. Rate remapping readjusts the firing rates of this set depending on current experience, thus expressing experience-unique patterns at each location. But can the experience-unique component be retrieved spontaneously? Whereas reactivation of recent, spatially selective patterns in hippocampus is well established, it is never perfect, raising the issue of whether the experiential component might be absent. This question is key to the hypothesis that hippocampus can assist memory consolidation by reactivating and broadcasting experience-specific “index codes” to neocortex. In CA3, global remapping exhibits attractor-like dynamics, whereas rate remapping apparently does not, leading to the hypothesis that only the former can be retrieved associatively and casting doubt on the general consolidation hypothesis. Therefore, we studied whether the rate component is reactivated spontaneously during sleep. We conducted neural ensemble recordings from CA3 while rats ran on a circular track in different directions (in different sessions) and while they slept. It was shown previously that the two directions of running result in strong rate remapping. During sleep, the most recent rate distribution was reactivated preferentially. Therefore, CA3 can retrieve patterns spontaneously that are unique to both the location and the content of recent experience.SIGNIFICANCE STATEMENTThe hippocampus is required for memory of events and their spatial contexts. The primary correlate of hippocampal activity is location in space, but multiple memories can occur in the same location. To be useful for distinguishing these memories, the hippocampus must be able, not only to express, but also to retrieve both spatial and nonspatial information about events. Whether it can retrieve nonspatial information has been challenged recently. We exposed rats to two different experiences (running in different directions) in the same locations and showed that even the nonspatial components of hippocampal cell firing are reactivated spontaneously during sleep, supporting the conclusion that both types of information about a recent experience can be retrieved.
Increasing the GluN2A/GluN2B Ratio in Neurons of the Mouse Basal and Lateral Amygdala Inhibits the Modification of an Existing Fear Memory Trace
Authors: Holehonnur Roopashri , Phensy Aarron J. , Kim Lily J. , Milivojevic Milica , Vuong Dat , Daison Delvin K. , Alex Saira , Tiner Michael , Jones Lauren E. , Kroener Sven , Ploski Jonathan E. 
Published: September 2016

Reconsolidation updating is a form of memory modification in which an existing memory can become destabilized upon retrieval and subsequently be modified via protein-synthesis-dependent reconsolidation. However, not all memories appear to destabilize upon retrieval and thus are not modifiable via reconsolidation updating approaches and the neurobiological basis for this remains poorly understood. Here, we report that auditory fear memories created with 10 tone–shock pairings are resistant to retrieval-dependent memory destabilization and are associated with an increase in the synaptic GluN2A/GluN2B ratio in neurons of the basal and lateral amygdala (BLA) compared with weaker fear memories created via one or three tone–shock pairings. To increase the GluN2A/GluN2B ratio after learning, we generated a line of mice that expresses an inducible and doxycycline-dependent GFP-GluN2A transgene specifically in α-CaMKII-positive neurons. Our findings indicate that increasing the GluN2A/GluN2B ratio in BLA α-CaMKII-positive neurons after a weak fear memory has consolidated inhibits retrieval-dependent memory destabilization and modification of the fear memory trace. This was associated with a reduction in retrieval-dependent AMPA receptor trafficking, as evidenced by a reduction in retrieval-dependent phosphorylation of GluR1 at serine-845. In addition, we determined that increasing the GluN2A/GluN2B ratio before fear learning significantly impaired long term memory consolidation, whereas short-term memory remained unaltered. An increase in the GluN2A/GluN2B ratio after fear learning had no influence on fear extinction or expression. Our results underscore the importance of NMDAR subunit composition for memory destabilization and suggest a mechanism for why some memories are resistant to modification.SIGNIFICANCE STATEMENTMemory modification using reconsolidation updating is being examined as one of the potential treatment approaches for attenuating maladaptive memories associated with emotional disorders. However, studies have shown that, whereas weak memories can be modified using reconsolidation updating, strong memories can be resistant to this approach. Therefore, treatments targeting the reconsolidation process are unlikely to be clinically effective unless methods are devised to enhance retrieval-dependent memory destabilization. Currently, little is known about the cellular and molecular events that influence the induction of reconsolidation updating. Here, we determined that an increase in the GluN2A/GluN2B ratio interferes with retrieval-dependent memory destabilization and inhibits the initiation of reconsolidation updating.
Glial Cell Calcium Signaling Mediates Capillary Regulation of Blood Flow in the Retina
Authors: Biesecker Kyle R. , Srienc Anja I. , Shimoda Angela M. , Agarwal Amit , Bergles Dwight E. , Kofuji Paulo , Newman Eric A. 
Published: September 2016

The brain is critically dependent on the regulation of blood flow to nourish active neurons. One widely held hypothesis of blood flow regulation holds that active neurons stimulate Ca2+increases in glial cells, triggering glial release of vasodilating agents. This hypothesis has been challenged, as arteriole dilation can occur in the absence of glial Ca2+signaling. We address this controversy by imaging glial Ca2+signaling and vessel dilation in the mouse retina. We find that sensory stimulation results in Ca2+increases in the glial endfeet contacting capillaries, but not arterioles, and that capillary dilations often follow spontaneous Ca2+signaling. In IP3R2−/−mice, where glial Ca2+signaling is reduced, light-evoked capillary, but not arteriole, dilation is abolished. The results show that, independent of arterioles, capillaries actively dilate and regulate blood flow. Furthermore, the results demonstrate that glial Ca2+signaling regulates capillary but not arteriole blood flow.SIGNIFICANCE STATEMENTWe show that a Ca2+-dependent glial cell signaling mechanism is responsible for regulating capillary but not arteriole diameter. This finding resolves a long-standing controversy regarding the role of glial cells in regulating blood flow, demonstrating that glial Ca2+signaling is both necessary and sufficient to dilate capillaries. While the relative contributions of capillaries and arterioles to blood flow regulation remain unclear, elucidating the mechanisms that regulate capillary blood flow may ultimately lead to the development of therapies for treating diseases where blood flow regulation is disrupted, including Alzheimer's disease, stroke, and diabetic retinopathy. This finding may also aid in revealing the underlying neuronal activity that generates BOLD fMRI signals.
Diphtheria Toxin-Induced Cell Death Triggers Wnt-Dependent Hair Cell Regeneration in Neonatal Mice
Authors: Hu Lingxiang , Lu Jingrong , Chiang Hao , Wu Hao , Edge Albert S. B. , Shi Fuxin 
Published: September 2016

Cochlear hair cells (HCs), the sensory cells that respond to sound, do not regenerate after damage in adult mammals, and their loss is a major cause of deafness. Here we show that HC regeneration in newborn mouse ears occurred spontaneously when the original cells were ablated by treatment with diphtheria toxin (DT) in ears that had been engineered to overexpress the DT receptor, but was not detectable when HCs were ablatedin vivoby the aminoglycoside antibiotic neomycin. A variety of Wnts (Wnt1, Wnt2, Wnt2b, Wnt4, Wnt5a, Wnt7b, Wnt9a, Wnt9b, and Wnt11) and Wnt pathway component Krm2 were upregulated after DT damage. Nuclear β-catenin was upregulated in HCs and supporting cells of the DT-damaged cochlea. Pharmacological inhibition of Wnt decreased spontaneous regeneration, confirming a role of Wnt signaling in HC regeneration. Inhibition of Notch signaling further potentiated supporting cell proliferation and HC differentiation that occurred spontaneously. The absence of new HCs in the neomycin ears was correlated to less robust Wnt pathway activation, but the ears subjected to neomycin treatment nonetheless showed increased cell division and HC differentiation after subsequent forced upregulation of β-catenin. These studies suggest, first, that Wnt signaling plays a key role in regeneration, and, second, that the outcome of a regenerative response to damage in the newborn cochlea is determined by reaching a threshold level of Wnt signaling rather than its complete absence or presence.SIGNIFICANCE STATEMENTSensory HCs of the inner ear do not regenerate in the adult, and their loss is a major cause of deafness. We found that HCs regenerated spontaneously in the newborn mouse after diphtheria toxin (DT)-induced, but not neomycin-induced, HC death. Regeneration depended on activation of Wnt signaling, and regeneration in DT-treated ears correlated to a higher level of Wnt activation than occurred in nonregenerating neomycin-treated ears. This is significant because insufficient regeneration caused by a failure to reach a threshold level of signaling, if true in the adult, has the potential to be exploited for development of clinical approaches for the treatment of deafness caused by HC loss.
Perception and Processing of Faces in the Human Brain Is Tuned to Typical Feature Locations
Authors: de Haas Benjamin , Schwarzkopf D. Samuel , Alvarez Ivan , Lawson Rebecca P. , Henriksson Linda , Kriegeskorte Nikolaus , Rees Geraint 
Published: September 2016

Faces are salient social stimuli whose features attract a stereotypical pattern of fixations. The implications of this gaze behavior for perception and brain activity are largely unknown. Here, we characterize and quantify a retinotopic bias implied by typical gaze behavior toward faces, which leads to eyes and mouth appearing most often in the upper and lower visual field, respectively. We found that the adult human visual system is tuned to these contingencies. In two recognition experiments, recognition performance for isolated face parts was better when they were presented at typical, rather than reversed, visual field locations. The recognition cost of reversed locations was equal to ∼60% of that for whole face inversion in the same sample. Similarly, an fMRI experiment showed that patterns of activity evoked by eye and mouth stimuli in the right inferior occipital gyrus could be separated with significantly higher accuracy when these features were presented at typical, rather than reversed, visual field locations. Our findings demonstrate that human face perception is determined not only by the local position of features within a face context, but by whether features appear at the typical retinotopic location given normal gaze behavior. Such location sensitivity may reflect fine-tuning of category-specific visual processing to retinal input statistics. Our findings further suggest that retinotopic heterogeneity might play a role for face inversion effects and for the understanding of conditions affecting gaze behavior toward faces, such as autism spectrum disorders and congenital prosopagnosia.SIGNIFICANCE STATEMENTFaces attract our attention and trigger stereotypical patterns of visual fixations, concentrating on inner features, like eyes and mouth. Here we show that the visual system represents face features better when they are shown at retinal positions where they typically fall during natural vision. When facial features were shown at typical (rather than reversed) visual field locations, they were discriminated better by humans and could be decoded with higher accuracy from brain activity patterns in the right occipital face area. This suggests that brain representations of face features do not cover the visual field uniformly. It may help us understand the well-known face-inversion effect and conditions affecting gaze behavior toward faces, such as prosopagnosia and autism spectrum disorders.