The unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease by improving synaptic function and proteostasis.

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol-requiring enzyme-1 (IRE1) operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-box binding protein 1 (XBP1). To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in the brain. Overexpression of XBP1 in the nervous system using transgenic mice reduced the load of amyloid deposits and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an 5xFAD mice using adeno-associated vectors improved different AD features. XBP1 expression corrected a large proportion of the proteomic alterations observed in the AD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

mGluR-dependent plasticity in rodent models of Alzheimer's disease.

Long-term potentiation (LTP) and depression (LTD) are currently the most comprehensive models of synaptic plasticity models to subserve learning and memory. In the CA1 region of the hippocampus LTP and LTD can be induced by the activation of either NMDA receptors or mGluR5 metabotropic glutamate receptors. Alterations in either form of synaptic plasticity, NMDAR-dependent or mGluR-dependent, are attractive candidates to contribute to learning deficits in conditions like Alzheimer's disease (AD) and aging. Research, however, has focused predominantly on NMDAR-dependent forms of LTP and LTD. Here we studied age-associated changes in mGluR-dependent LTP and LTD in the APP/PS1 mouse model of AD and in Octodon degu, a rodent model of aging that exhibits features of AD. At 2 months of age, APP/PS1 mouse exhibited robust mGluR-dependent LTP and LTD that was completely lost by the 8th month of age. The expression of mGluR protein in the hippocampus of APP/PS1 mice was not affected, consistent with previous findings indicating the uncoupling of the plasticity cascade from mGluR5 activation. In O. degu, the average mGluR-LTD magnitude is reduced by half by the 3 rd year of age. In aged O. degu individuals, the reduced mGluR-LTD correlated with reduced performance in a radial arm maze task. Altogether these findings support the idea that the preservation of mGluR-dependent synaptic plasticity is essential for the preservation of learning capacity during aging.

Unfolded protein response IRE1/XBP1 signaling is required for healthy mammalian brain aging.

Aging is a major risk factor to develop neurodegenerative diseases and is associated with decreased buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway activated to cope with endoplasmic reticulum (ER) stress, in the functional deterioration of the mammalian brain during aging. We report that genetic disruption of the ER stress sensor IRE1 accelerated age-related cognitive decline. In mouse models, overexpressing an active form of the UPR transcription factor XBP1 restored synaptic and cognitive function, in addition to reducing cell senescence. Proteomic profiling of hippocampal tissue showed that XBP1 expression significantly restore changes associated with aging, including factors involved in synaptic function and pathways linked to neurodegenerative diseases. The genes modified by XBP1 in the aged hippocampus where also altered. Collectively, our results demonstrate that strategies to manipulate the UPR in mammals may help sustain healthy brain aging.

Multiscale entropy analysis of retinal signals reveals reduced complexity in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is one of the most significant health challenges of our time, affecting a growing number of the elderly population. In recent years, the retina has received increased attention as a candidate for AD biomarkers since it appears to manifest the pathological signatures of the disease. Therefore, its electrical activity may hint at AD-related physiological changes. However, it is unclear how AD affects retinal electrophysiology and what tools are more appropriate to detect these possible changes. In this study, we used entropy tools to estimate the complexity of the dynamics of healthy and diseased retinas at different ages. We recorded microelectroretinogram responses to visual stimuli of different nature from retinas of young and adult, wild-type and 5xFAD-an animal model of AD-mice. To estimate the complexity of signals, we used the multiscale entropy approach, which calculates the entropy at several time scales using a coarse graining procedure. We found that young retinas had more complex responses to different visual stimuli. Further, the responses of young, wild-type retinas to natural-like stimuli exhibited significantly higher complexity than young, 5xFAD retinas. Our findings support a theory of complexity-loss with aging and disease and can have significant implications for early AD diagnosis.

Scalable and accurate method for neuronal ensemble detection in spiking neural networks.

We propose a novel, scalable, and accurate method for detecting neuronal ensembles from a population of spiking neurons. Our approach offers a simple yet powerful tool to study ensemble activity. It relies on clustering synchronous population activity (population vectors), allows the participation of neurons in different ensembles, has few parameters to tune and is computationally efficient. To validate the performance and generality of our method, we generated synthetic data, where we found that our method accurately detects neuronal ensembles for a wide range of simulation parameters. We found that our method outperforms current alternative methodologies. We used spike trains of retinal ganglion cells obtained from multi-electrode array recordings under a simple ON-OFF light stimulus to test our method. We found a consistent stimuli-evoked ensemble activity intermingled with spontaneously active ensembles and irregular activity. Our results suggest that the early visual system activity could be organized in distinguishable functional ensembles. We provide a Graphic User Interface, which facilitates the use of our method by the scientific community.

Gender inequality in Latin American Neuroscience community.

Gender bias in Science, Technology, Engineering, and Mathematics (STEM) has been identified since a long time ago. However, gender imbalance in neuroscience has not yet been adequately explored worldwide. Here we report the first study on the development of the careers of men and women neuroscientists in Latin America in relation to family life and their perceptions of obstacles to success. Apart from revealing gender inequality in the neuroscience field, distinctive Latin American traits have become evident, thus providing novel insights into the global comprehension of gender imbalance in the region, which is required for guiding future actions, including the design of public policies in the region.

Ocular Health of Octodon degus as a Clinical Marker for Age-Related and Age-Independent Neurodegeneration.

The aging process and age-related diseases such as Alzheimer's disease (AD), are very heterogeneous and multifactorial, making it challenging to diagnose the disease based solely on genetic, behavioral tests, or clinical history. It is yet to be explained what ophthalmological tests relate specifically to aging and AD. To this end, we have selected the common degu (Octodon degus) as a model for aging which develops AD-like signs to conduct ophthalmological screening methods that could be clinical markers of aging and AD. We investigated ocular health using ophthalmoscopy, fundus photography, intraocular pressure (IOP), and pupillary light reflex (PLR). The results showed significant presence of cataracts in adult degus and IOP was also found to increase significantly with advancing age. Age had a significant effect on the maximum pupil constriction but other pupil parameters changed in an age-independent manner (PIPR retention index, resting pupil size, constriction velocity, redilation plateau). We concluded that degus have underlying factors at play that regulate PLR and may be connected to sympathetic, parasympathetic, and melanopsin retinal ganglion cell (ipRGC) deterioration. This study provides the basis for the use of ocular tests as screening methods for the aging process and monitoring of neurodegeneration in non-invasive ways.

Retinal Ganglion Cells Functional Changes in a Mouse Model of Alzheimer's Disease Are Linked with Neurotransmitter Alterations.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent form of dementia worldwide. This neurodegenerative syndrome affects cognition, memory, behavior, and the visual system, particularly the retina. OBJECTIVE: This work aims to determine whether the 5xFAD mouse, a transgenic model of AD, displays changes in the function of retinal ganglion cells (RGCs) and if those alterations are correlated with changes in the expression of glutamate and gamma-aminobutyric acid (GABA) neurotransmitters. METHODS: In young (2-3-month-old) and adult (6-7-month-old) 5xFAD and WT mice, we have studied the physiological response, firing rate, and burst of RGCs to various types of visual stimuli using a multielectrode array system. RESULTS: The firing rate and burst response in 5xFAD RGCs showed hyperactivity at the early stage of AD in young mice, whereas hypoactivity was seen at the later stage of AD in adults. The physiological alterations observed in 5xFAD correlate well with an increase in the expression of glutamate in the ganglion cell layer in young and adults. GABA staining increased in the inner nuclear and plexiform layer, which was more pronounced in the adult than the young 5xFAD retina, altering the excitation/inhibition balance, which could explain the observed early hyperactivity and later hypoactivity in RGC physiology. CONCLUSION: These findings indicate functional changes may be caused by neurochemical alterations of the retina starting at an early stage of the AD disease.

Alzheimer's Disease, Neural Plasticity, and Functional Recovery.

Alzheimer's disease (AD) is the most common and devastating neurodegenerative condition worldwide, characterized by the aggregation of amyloid-ß and phosphorylated tau protein, and is accompanied by a progressive loss of learning and memory. A healthy nervous system is endowed with synaptic plasticity, among others neural plasticity mechanisms, allowing structural and physiological adaptations to changes in the environment. This neural plasticity modification sustains learning and memory, and behavioral changes and is severely affected by pathological and aging conditions, leading to cognitive deterioration. This article reviews critical aspects of AD neurodegeneration as well as therapeutic approaches that restore neural plasticity to provide functional recoveries, including environmental enrichment, physical exercise, transcranial stimulation, neurotrophin involvement, and direct electrical stimulation of the amygdala. In addition, we report recent behavioral results in Octodon degus, a promising natural model for the study of AD that naturally reproduces the neuropathological alterations observed in AD patients during normal aging, including neuronal toxicity, deterioration of neural plasticity, and the decline of learning and memory.

Pannexin Channel Regulation of Cell Migration: Focus on Immune Cells.

The role of Pannexin (PANX) channels during collective and single cell migration is increasingly recognized. Amongst many functions that are relevant to cell migration, here we focus on the role of PANX-mediated adenine nucleotide release and associated autocrine and paracrine signaling. We also summarize the contribution of PANXs with the cytoskeleton, which is also key regulator of cell migration. PANXs, as mechanosensitive ATP releasing channels, provide a unique link between cell migration and purinergic communication. The functional association with several purinergic receptors, together with a plethora of signals that modulate their opening, allows PANX channels to integrate physical and chemical cues during inflammation. Ubiquitously expressed in almost all immune cells, PANX1 opening has been reported in different immunological contexts. Immune activation is the epitome coordination between cell communication and migration, as leukocytes (i.e., T cells, dendritic cells) exchange information while migrating towards the injury site. In the current review, we summarized the contribution of PANX channels during immune cell migration and recruitment; although we also compile the available evidence for non-immune cells (including fibroblasts, keratinocytes, astrocytes, and cancer cells). Finally, we discuss the current evidence of PANX1 and PANX3 channels as a both positive and/or negative regulator in different inflammatory conditions, proposing a general mechanism of these channels contribution during cell migration.

Evidence of Synaptic and Neurochemical Remodeling in the Retina of Aging Degus.

Accumulation of amyloid-beta (Aß) peptides is regarded as the hallmark of neurodegenerative alterations in the brain of Alzheimer's disease (AD) patients. In the eye, accumulation of Aß peptides has also been suggested to be a trigger of retinal neurodegenerative mechanisms. Some pathological aspects associated with Aß levels in the brain are synaptic dysfunction, neurochemical remodeling and glial activation, but these changes have not been established in the retina of animals with Aß accumulation. We have employed the Octodon degus in which Aß peptides accumulated in the brain and retina as a function of age. This current study investigated microglial morphology, expression of PSD95, synaptophysin, Iba-1 and choline acetyltransferase (ChAT) in the retina of juvenile, young and adult degus using immunolabeling methods. Neurotransmitters glutamate and gamma-aminobutyric acid (GABA) were detected using immunogold labeling and glutamate receptor subunits were quantified using Western blotting. There was an age-related increase in presynaptic and a decrease in post-synaptic retinal proteins in the retinal plexiform layers. Immunolabeling showed changes in microglial morphology characteristic of intermediate stages of activation around the optic nerve head (ONH) and decreasing activation toward the peripheral retina. Neurotransmitter expression pattern changed at juvenile ages but was similar in adults. Collectively, the results suggest that microglial activation, synaptic remodeling and neurotransmitter changes may be consequent to, or parallel to Aß peptide and phosphorylated tau accumulation in the retina.

Chromatic pupillometry for the characterization of the pupillary light reflex in Octodon degus.

The common degu (Octodon degus) is an emerging model in biomedical science research due to its longevity and propensity to develop human-like conditions. However, there is a lack of standardized techniques for this non-traditional laboratory animal. In an effort to characterize the model, we developed a chromatic pupillometry setup and analysis protocol to characterize the pupillary light reflex (PLR) in our animals. The PLR is a biomarker to detect early signs for central nervous system deterioration. Chromatic pupillometry is a non-invasive and anesthesia-free method that can evaluate different aspects of the PLR, including the response of intrinsically photosensitive retinal ganglion cells (ipRGCs), the disfunction of which has been linked to various disorders. We studied the PLR of 12 degus between 6 and 48 months of age to characterize responses to LEDs of 390, 450, 500, 525 and 605 nm, and used 5 with overall better responses to establish a benchmark for healthy PLR (PLR+) and deteriorated PLR (PLR-). Degu pupils contracted up to 65% of their horizontal resting size before reaching saturation. The highest sensitivity was found at 500 nm, with similar sensitivities at lower tested intensities for 390 nm, coinciding with the medium wavelength and short wavelength cones of the degu. We also tested the post-illumination pupillary response (PIPR), which is driven exclusively by ipRGCs. PIPR was largest in response to 450 nm light, with the pupil preserving 48% of its maximum constriction 9 s after the stimulus, in contrast with 24% preserved in response to 525 nm, response driven mainly by cones. PLR- animals showed maximum constriction between 40% and 50% smaller than PLR+, and their PIPR almost disappeared, pointing to a disfunction of the iPRGCs rather than the retinal photoreceptors. Our method thus allows us to non-invasively estimate the condition of experimental animals before attempting other procedures.

Speed-Selectivity in Retinal Ganglion Cells is Sharpened by Broad Spatial Frequency, Naturalistic Stimuli.

Motion detection represents one of the critical tasks of the visual system and has motivated a large body of research. However, it remains unclear precisely why the response of retinal ganglion cells (RGCs) to simple artificial stimuli does not predict their response to complex, naturalistic stimuli. To explore this topic, we use Motion Clouds (MC), which are synthetic textures that preserve properties of natural images and are merely parameterized, in particular by modulating the spatiotemporal spectrum complexity of the stimulus by adjusting the frequency bandwidths. By stimulating the retina of the diurnal rodent, Octodon degus with MC we show that the RGCs respond to increasingly complex stimuli by narrowing their adjustment curves in response to movement. At the level of the population, complex stimuli produce a sparser code while preserving movement information; therefore, the stimuli are encoded more efficiently. Interestingly, these properties were observed throughout different populations of RGCs. Thus, our results reveal that the response at the level of RGCs is modulated by the naturalness of the stimulus - in particular for motion - which suggests that the tuning to the statistics of natural images already emerges at the level of the retina.

Characterization of Retinal Functionality at Different Eccentricities in a Diurnal Rodent.

Although the properties of the neurons of the visual system that process central and peripheral regions of the visual field have been widely researched in the visual cortex and the LGN, they have scarcely been documented for the retina. The retina is the first step in integrating optical signals, and despite considerable efforts to functionally characterize the different types of retinal ganglion cells (RGCs), a clear account of the particular functionality of cells with central vs. peripheral fields is still wanting. Here, we use electrophysiological recordings, gathered from retinas of the diurnal rodent Octodon degus, to show that RGCs with peripheral receptive fields (RF) are larger, faster, and have shorter transient responses. This translates into higher sensitivity at high temporal frequencies and a full frequency bandwidth when compared to RGCs with more central RF. We also observed that imbalances between ON and OFF cell populations are preserved with eccentricity. Finally, the high diversity of functional types of RGCs highlights the complexity of the computational strategies implemented in the early stages of visual processing, which could inspire the development of bio-inspired artificial systems.

Publisher Correction: Electrical coupling between A17 cells enhances reciprocal inhibitory feedback to rod bipolar cells.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Electrical coupling between A17 cells enhances reciprocal inhibitory feedback to rod bipolar cells.

A17 amacrine cells are an important part of the scotopic pathway. Their synaptic varicosities receive glutamatergic inputs from rod bipolar cells (RBC) and release GABA onto the same RBC terminal, forming a reciprocal feedback that shapes RBC depolarization. Here, using patch-clamp recordings, we characterized electrical coupling between A17 cells of the rat retina and report the presence of strongly interconnected and non-coupled A17 cells. In coupled A17 cells, evoked currents preferentially flow out of the cell through GJs and cross-synchronization of presynaptic signals in a pair of A17 cells is correlated to their coupling degree. Moreover, we demonstrate that stimulation of one A17 cell can induce electrical and calcium transients in neighboring A17 cells, thus confirming a functional flow of information through electrical synapses in the A17 coupled network. Finally, blocking GJs caused a strong decrease in the amplitude of the inhibitory feedback onto RBCs. We therefore propose that electrical coupling between A17 cells enhances feedback onto RBCs by synchronizing and facilitating GABA release from inhibitory varicosities surrounding each RBC axon terminal. GJs between A17 cells are therefore critical in shaping the visual flow through the scotopic pathway.

IRE1 signaling exacerbates Alzheimer's disease pathogenesis.

Altered proteostasis is a salient feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress and abnormal protein aggregation. ER stress triggers the activation of the unfolded protein response (UPR), a signaling pathway that enforces adaptive programs to sustain proteostasis or eliminate terminally damaged cells. IRE1 is an ER-located kinase and endoribonuclease that operates as a major stress transducer, mediating both adaptive and proapoptotic programs under ER stress. IRE1 signaling controls the expression of the transcription factor XBP1, in addition to degrade several RNAs. Importantly, a polymorphism in the XBP1 promoter was suggested as a risk factor to develop AD. Here, we demonstrate a positive correlation between the progression of AD histopathology and the activation of IRE1 in human brain tissue. To define the significance of the UPR to AD, we targeted IRE1 expression in a transgenic mouse model of AD. Despite initial expectations that IRE1 signaling may protect against AD, genetic ablation of the RNase domain of IRE1 in the nervous system significantly reduced amyloid deposition, the content of amyloid ß oligomers, and astrocyte activation. IRE1 deficiency fully restored the learning and memory capacity of AD mice, associated with improved synaptic function and improved long-term potentiation (LTP). At the molecular level, IRE1 deletion reduced the expression of amyloid precursor protein (APP) in cortical and hippocampal areas of AD mice. In vitro experiments demonstrated that inhibition of IRE1 downstream signaling reduces APP steady-state levels, associated with its retention at the ER followed by proteasome-mediated degradation. Our findings uncovered an unanticipated role of IRE1 in the pathogenesis of AD, offering a novel target for disease intervention.

Genetic variants associated with neurodegenerative Alzheimer disease in natural models.

The use of transgenic models for the study of neurodegenerative diseases has made valuable contributions to the field. However, some important limitations, including protein overexpression and general systemic compensation for the missing genes, has caused researchers to seek natural models that show the main biomarkers of neurodegenerative diseases during aging. Here we review some of these models-most of them rodents, focusing especially on the genetic variations in biomarkers for Alzheimer diseases, in order to explain their relationships with variants associated with the occurrence of the disease in humans.

Metabotropic Glutamate Receptors Induce a Form of LTP Controlled by Translation and Arc Signaling in the Hippocampus.

Activity-dependent bidirectional modifications of excitatory synaptic strength are essential for learning and storage on new memories. Research on bidirectional synaptic plasticity has largely focused on long-term potentiation (LTP) and long-term depression (LTD) mechanisms that rely on the activation of NMDA receptors. In principle, metabotropic glutamate receptors (mGluRs) are also suitable to convert synaptic activity into intracellular signals for synaptic modification. Indeed, dysfunction of a form of LTD that depends on Type I mGluRs (mGluR-LTD), but not NMDARs, has been implicated in learning deficits in aging and mouse models of several neurological conditions, including Fragile X syndrome and Alzheimer's disease. To determine whether mGluR activation can also induce LTP in the absence of NMDAR activation, we examined in hippocampal slices from rats and mice, an NMDAR-independent form of LTP previously characterized as dependent on voltage-gated Ca(2+) channels. We found that this form of LTP requires activation of Type I mGluRs and, like mGluR-LTD but unlike NMDAR-dependent plasticity, depends crucially on protein synthesis controlled by fragile X mental retardation protein and on Arc signaling. Based on these observations, we propose the coexistence of two distinct activity-dependent systems of bidirectional synaptic plasticity: one that is based on the activity of NMDARs and the other one based on the activation of mGluRs. SIGNIFICANCE STATEMENT: Bidirectional changes of synaptic strength are crucial for the encoding of new memories. Currently, the only activity-dependent mechanism known to support such bidirectional changes are long-term potentiation (LTP) and long-term depression (LTD) forms that relay on the activation of NMDA receptors. Metabotropic glutamate receptors (mGluRs) are, in principle, also suitable to trigger bidirectional synaptic modifications. However, only the mGluR-dependent form of LTD has been characterized. Here we report that an NMDAR-independent form of LTP, initially characterized as dependent on voltage-gated Ca(2+) channels, also requires the activation of mGluRs. These finding suggest the coexistence of two distinct activity-dependent systems of bidirectional synaptic plasticity: one that is based on the activity of NMDARs and the other one based on the activation of mGluRs.

Regulation of Memory Formation by the Transcription Factor XBP1.

Contextual memory formation relies on the induction of new genes in the hippocampus. A polymorphism in the promoter of the transcription factor XBP1 was identified as a risk factor for Alzheimer's disease and bipolar disorders. XBP1 is a major regulator of the unfolded protein response (UPR), mediating adaptation to endoplasmic reticulum (ER) stress. Using a phenotypic screen, we uncovered an unexpected function of XBP1 in cognition and behavior. Mice lacking XBP1 in the nervous system showed specific impairment of contextual memory formation and long-term potentiation (LTP), whereas neuronal XBP1s overexpression improved performance in memory tasks. Gene expression analysis revealed that XBP1 regulates a group of memory-related genes, highlighting brain-derived neurotrophic factor (BDNF), a key component in memory consolidation. Overexpression of BDNF in the hippocampus reversed the XBP1-deficient phenotype. Our study revealed an unanticipated function of XBP1 in cognitive processes that is apparently unrelated to its role in ER stress.