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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.

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.

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. Fil: Silva, Ana. International Brain Research Organization. Latin American Regional Committee; Uruguay. Universidad de la República; Uruguay Fil: Tomassini, Cecilia. International Brain Research Organization. Latin American Regional Committee; Uruguay. Universidad de la República; Uruguay Fil: Zurbrigg, Julieta. Economic Commission for Latin America and the Caribbean in Montevideo; Uruguay Fil: Palacios, Adrian. Centro Interdisciplinario de Neurociencia de Valparaíso; Chile. International Brain Research Organization. Latin American Regional Committee; Uruguay Fil: Amarante, Verónica. Economic Commission for Latin America and the Caribbean; Uruguay Fil: Bouzat, Cecilia Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Investigaciones Bioquímicas de Bahía Blanca. Universidad Nacional del Sur. Instituto de Investigaciones Bioquímicas de Bahía Blanca; Argentina. Universidad Nacional del Sur. Departamento de Biología, Bioquímica y Farmacia; Argentina. International Brain Research Organization. Latin American Regional Committee; Uruguay

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) is an ER-located kinase and endoribonuclease that 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). A polymorphism in the XBP1 promoter has been suggested as a risk factor for AD. To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in neurons using preclinical models. Overexpression of an active form of XBP1 in the nervous system using transgenic mice significantly reduced the load of amyloid deposits in the cerebral cortex and hippocampus and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved long-term potentiation, memory performance, and dendritic spine density. Quantitative proteomics of the hippocampus revealed that XBP1 expression corrects a large proportion of the alterations observed in the 5xFAD 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.

Perhaps one of the most significant scientific challenges is to understand the human brain. Neuroscience research has had a considerable impact on individuals, families, and society. However, before we can have a real impact on public health, we need a greater understanding of biological processes that underlie the wide variety of neurological and psychiatric disorders such as Alzheimer's disease (AD), Parkinson's disease, schizophrenia, depression, traumatic brain injury, epilepsy, and many others. It is a great challenge and responsibility of science to unravel the brain's secrets through translational research and drug discovery in order to improve the lives of individuals with these devastating conditions. In the past decade, outstanding discoveries have been made that have made possible novel and multidisciplinary approaches to understanding the brain's mysteries.

Even though the retinal microcircuit organization has been described in detail at the single-cell level, little is known about how groups of retinal cells’ coordinated activity encode and process parallel information representing the spatial and temporal structure of changing environmental conditions. To describe the population dynamics of retinal neuronal ensembles, we used microelectrode array recordings that describe hundreds of retinal ganglion cells’ simultaneous activity in response to a short movie captured in the natural environment where our subject develops their visual behaviors. The vectorization of population activity allowed the identification of retinal neuronal ensembles that synchronize to specific segments of natural stimuli. These synchronous retinal neuronal ensembles were reliably activated by the same stimuli at different trials, indicating a robust population response of retinal microcircuits. The generation of asynchronous events required integrating a physiologically meaningful time window larger than 80 ms, demonstrating that retinal neuronal ensembles’ time integration filters non-structured visual information. Interestingly, individual neurons could be part of several ensembles indicating that parallel circuits could encode environmental conditions changes. We conclude that parallel neuronal ensembles could represent the functional unit of retinal computations and propose that the further study of retinal neuronal ensembles could reveal emergent properties of retinal circuits that individual cells’ activity cannot explain.

Alzheimer’s disease (AD) is the most common and devastating neurodegenerative condition worldwide, characterized by the aggregation of amyloid-β 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.

We propose a novel, scalable, and accurate automated method for detecting neuronal ensembles from a population of spiking neurons. Our approach offers a simple yet powerful tool to study ensemble activity. It allows the participation of neurons in different ensembles, has few parameters to tune and is computationally efficient. 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 is already organized in clearly distinguishable functional ensembles. 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. Additionally, we found that our method outperforms current alternative methodologies. Finally, we provide a Graphic User Interface, which aims to facilitate our method’s use by the scientific community.Author summaryNeuronal ensembles are strongly interconnected groups of neurons that tend to fire together (Hebb 1949). However, even when this concept was proposed more than 70 years ago, only recent advances in multi-electrode arrays and calcium imaging, statistical methods, and computing power have made it possible to record and analyze multiple neurons’ activities spiking simultaneously, providing a unique opportunity to study how groups of neurons form ensembles spontaneously and under different stimuli scenarios. Using our method, we found that retinal ganglion cells show a consistent stimuli-evoked ensemble activity, and, when validated with synthetic data, the method shows good performance by detecting the number of ensembles, the activation times, and the core-cells for a wide range of firing rates and number of ensembles accurately.

Brain ageing is the main risk factor to develop dementia and neurodegenerative diseases, associated with a decay in the buffering capacity of the proteostasis network. We investigated the significance of the unfolded protein response (UPR), a major signaling pathway to cope with ER stress, to the functional deterioration of the brain during aging. Genetic disruption of the ER stress sensor IRE1α accelerated cognitive and motor decline during ageing. Exogenous bolstering of the UPR by 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 indicated that XBP1s expression attenuated age-related alterations to synaptic function and pathways linked to neurodegenerative diseases. Overall, our results demonstrate that strategies to manipulate the UPR in mammals may sustain healthy brain ageing.

Aging is the major risk factor for the development of dementia and neurodegenerative disorders, and the aging brain manifests severe deficits in buffering capacity by the proteostasis network. Accordingly, we investigated the significance of the unfolded protein response (UPR), a major signaling pathway that copes with endoplasmic reticulum (ER) stress, to normal mammalian brain aging. Genetic disruption of ER stress sensor IRE1α accelerated cognitive and motor dysfunction during aging. Exogenous bolstering of the UPR by overexpressing an active form of the transcription factor XBP1 restored synaptic and cognitive function in addition to reducing cell senescence. Remarkably, proteomic profiling of hippocampal tissue indicated that XBP1s expression corrected age-related alterations in synaptic function. Collectively, our data demonstrate that strategies to manipulate the UPR sustain healthy brain aging.One Sentence SummaryThe IRE1/XBP1 pathway dictates when and how brain function declines during aging.

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.

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 β 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.

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.

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 visual step to integrate optical signals and already includes mechanisms that extract spatio-temporal features needed for animal behavior and survival. Despite considerable efforts to functionally characterize the different types of retinal ganglion cell (RGCs), a clear account of the particular functionality of cells with central vs. peripheral fields is still wanting. Here, we use electrophysiological recording, gathered from retinas of the diurnal rodent, Octodon degus, to show that RGCs with peripheral receptive fields are larger, faster and have shorter transient responses, which translates into greater sensitivity at high temporal frequencies and a full frequency bandwidth, than neurons with more central receptive fields. We also observed that imbalances between ON and OFF cell populations are preserved with eccentricity. Finally, the high diversity of functional types of RGCs in the retina highlights the complexity of the computational strategies implemented at the early stages of visual processing, which could inspire the development of bio-inspired artificial systems.

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 Ca2+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 STATEMENTBidirectional 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 Ca2+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.

Maximum entropy models (MEM) have been widely used in the last 10 years to characterize the statistics of networks of spiking neurons. A major drawback of this approach is that the number of parameters used in the statistical model increases very fast with the network size, hindering its interpretation and fast computation. Here, we present a novel framework of dimensionality reduction for generalized MEM handling spatio-temporal correlations. This formalism is based on information geometry where a MEM is a point on a large-dimensional manifold. We exploit the geometrical properties of this manifold in order to find a projection on a lower dimensional space that best captures the high-order statistics. This allows us to define a quantitative criterion that we call the “degree of compressibility” of the neuronal code. A powerful aspect of this method is that it does not require fitting the model. Indeed, the matrix defining the metric of the manifold is computed directly via the data without parameters fitting. The method is first validated using synthetic data generated by a known statistics. We then analyze a MEM having more parameters than the underlying data statistics and show that our method detects the extra dimensions. We then test it on experimental retinal data. We record retinal ganglion cells (RGC) spiking data using multi-electrode arrays (MEA) under different visual stimuli: spontaneous activity, white noise stimulus, and natural scene. Using our method, we report a dimensionality reduction up to 50% for retinal data. As we show, this is quite a huge reduction compared to a randomly generated spike train, suggesting that the neuronal code, in these experiments, is highly compressible. This additionally shows that the dimensionality reduction depends on the stimuli statistics, supporting the idea that sensory networks adapt to stimuli statistics by modifying the level of redundancy.Author SummaryMaximum entropy models (MEM) have been widely used to characterize the statistics of networks of spiking neurons. However, as the network size increases, the number of model parameters increases rapidly, hindering its interpretation and fast computation. Here, we propose a method to evaluate the dimensionality reduction of MEM, based on the geometrical properties of the manifold best capturing the network high-order statistics. Our method is validated with synthetic data using independent or correlated neural responses. Importantly, we show that dimensionality reduction depends on the stimuli statistics, supporting the idea that sensory networks adapt to stimuli statistics modifying the level of redundancy.

Motion detection represents one of the critical tasks of the visual system and has motivated a large body of research. However, is remain 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 deguswith 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.

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.

The segregated properties of the visual system processing central or peripheral regions of the visual field have been widely studied in the visual cortex and the LGN, but rarely reported in retina. The retina performs complex computational strategies to extract spatial-temporal features that are in coherence with animal behavior and survival. Even if a big effort has been done to functionally characterize different retinal ganglion cell (RGC) types, a clear account of the particular functionality of central and peripheral cells is still missing. Here, using electrophysiological data obtained with a 256-MEA recording system on female diurnal rodent retinas (Octodon degus), we evidenced that peripheral RGCs have larger receptive fields, more sustained, faster and shorter temporal responses and sensitive to higher temporal frequencies with a broader frequency bandwidth than the center. Additionally, we also compared the asymmetries between ON and OFF cell populations present in each region, reporting that these asymmetries are dependent on the eccentricity. Finally, the presence of the asymmetries here reported emphasizes even more the complexity of computational strategies performed by the retina, which could serve as inspiration for the development of artificial visual systems.

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.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of age-related dementia worldwide. Several models for AD have been developed to provide information regarding the initial changes that lead to degeneration. Transgenic mouse models recapitulate many, but not all, of the features of AD, most likely because of the high complexity of the pathology. In this context, the validation of a wild-type animal model of AD that mimics the neuropathological and behavioral abnormalities is necessary. In previous studies, we have reported that the Chilean rodent Octodon degus could represent a natural model for AD. In the present work, we further describe the age-related neurodegeneration observed in the O. degus brain. We report some histopathological markers associated with the onset progression of AD, such as glial activation, increase in oxidative stress markers, neuronal apoptosis and the expression of the peroxisome proliferative-activated receptor γ coactivator-1α (PGC-1α). With these results, we suggest that the O. degus could represent a new model for AD research and a powerful tool in the search for therapeutic strategies against AD.

To what extent can the mammalian visual system be shaped by visual behavior? Here we analyze the shape of the visual fields, the densities and distribution of cells in the retinal ganglion-cell layer and the organization of the visual projections in two species of facultative non-strictly subterranean rodents, Spalacopus cyanus and Ctenomys talarum, aiming to compare these traits with those of phylogenetically closely related species possessing contrasting diurnal/nocturnal visual habits. S. cyanus shows a definite zone of frontal binocular overlap and a corresponding area centralis, but a highly reduced amount of ipsilateral retinal projections. The situation in C. talarum is more extreme as it lacks of a fronto-ventral area of binocular superposition, has no recognizable area centralis and shows no ipsilateral retinal projections except to the suprachiasmatic nucleus. In both species, the extension of the monocular visual field and of the dorsal region of binocular overlap as well as the whole set of contralateral visual projections, appear well-developed. We conclude that these subterranean rodents exhibit, paradoxically, diurnal instead of nocturnal visual specializations, but at the same time suffer a specific regression of the anatomical substrate for stereopsis. We discuss these findings in light of the visual ecology of subterranean lifestyles Fil: Vega Zuniga, Tomas. Universidad de Chile; Chile Fil: Medina, Felipe. Universidad de Chile; Chile Fil: Marin, Gonzalo. Universidad de Chile; Chile Fil: Letelier, Juán Carlos. Universidad de Chile; Chile Fil: Palacios, Adrián G.. Universidad de Valparaíso; Chile Fil: Němec, Pavel. Charles University in Prague; República Checa Fil: Schleich, Cristian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mar del Plata. Instituto de Investigaciones Marinas y Costeras. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Instituto de Investigaciones Marinas y Costeras; Argentina Fil: Mpodozis, Jorge. Universidad de Chile; Chile

Alzheimer's disease (AD) is the most common form of dementia with progressive deterioration of memory and cognition. Complaints related to vision are common among AD patients. Several changes in the retina, lens, and in the vasculature have been noted in the AD eye that may be the cause of visual symptoms experienced by the AD patient. Anatomical changes have been detected within the eye before signs of cognitive impairment and memory loss are apparent. Unlike the brain, the eye is a unique organ that can be visualized noninvasively at the cellular level because of its transparent nature, which allows for inexpensive testing of biomarkers in a clinical setting. In this review, we have searched for candidate biomarkers that could enable diagnosis of AD, covering ocular neurodegeneration associated with functional tests. We explore the evidence that suggests that inexpensive, noninvasive clinical tests could be used to detect AD ocular biomarkers.

SummaryContextual 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.

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.

We studied the retinal photoreceptors in the mouse opossum Thylamys elegans, a nocturnal South American marsupial. A variety of photoreceptor properties and color vision capabilities have been documented in Australian marsupials, and we were interested to establish what similarities and differences this American marsupial showed. Thylamys opsin gene sequencing revealed two cone opsins, a longwave-sensitive (LWS) opsin and a shortwave-sensitive (SWS1) opsin with deduced peak sensitivities at 560 nm and 360 nm (ultraviolet), respectively. Immunocytochemistry located these opsins to separate cone populations, a majority of LWS cones (density range 1,600-5,600/mm(2)) and a minority of SWS1 cones (density range 100-690/mm(2)). With rod densities of 440,000-590,000/mm(2), the cones constituted 0.4-1.2% of the photoreceptors. This is a suitable adaptation to nocturnal vision. Cone densities peaked in a horizontally elongated region ventral to the optic nerve head. In ventral-but not dorsal-retina, roughly 40% of the LWS opsin-expressing cones occurred as close pairs (double cones), and one member of each double cone contained a colorless oil droplet. The corneal electroretinogram (ERG) showed a high scotopic sensitivity with a rod peak sensitivity at 505 nm. At mesopic light levels, the spectral ERG revealed the contributions of a UV-sensitive SWS1 cone mechanism and an LWS cone mechanism with peak sensitivities at 365 nm and 555 nm, respectively, confirming the tuning predictions from the cone opsin sequences. The two spectral cone types provide the basis for dichromatic color vision, or trichromacy if the rods contribute to color processing at mesopic light levels.

We studied the photopic spectral sensitivity in the green-backed firecrown, Sephanoides sephaniodes, a South American hummingbird, and its possible ecological relationship with preferred flowers and body colouration. Avian colour vision is in general tetrachromatic with at least four types of cones, which vary in sensitivity from the near ultraviolet (UV) to the red wavelength range. Hummingbirds represent an important family of birds, yet little is known about their eye sensitivity, especially about the role of photoreceptors and their oil droplet complements. The photopic electroretinogram shows a main sensitivity peak at 560 nm and a secondary peak in the UV, and may be explained by the presence of four single cones (λ max at ~370, 440, 508 and 560 nm), and a double cone (λ max at 560 nm) screened by oil droplets. The flowers preferred by the firecrown are those in which the red–green wavelength region predominates and have higher contrast than other flowers. The crown plumage of males is highly iridescent in the red wavelength range (peak at 650 nm) and UV; when plotted in a high-dimensional tetrachromatic space, it falls in a “red + UV” purple hue line, suggesting a potential significant communication signal for sexual differentiation.

Acetylcholine (ACh) is a major retinal neurotransmitter that modulates visual processing through a large repertoire of cholinergic receptors expressed on different retinal cell types. ACh is released from starburst amacrine cells (SACs) under scotopic conditions, but its effects on cells of the rod pathway have not been investigated. Using whole-cell patch clamp recordings in slices of rat retina, we found that ACh application triggers GABA release onto rod bipolar (RB) cells. GABA was released from A17 amacrine cells and activated postsynaptic GABAA and GABAC receptors in RB cells. The sensitivity of ACh-induced currents to nicotinic ACh receptor (nAChR) antagonists (TMPH ~ mecamylamine > erysodine > DhβE > MLA) together with the differential potency of specific agonists to mimic ACh responses (cytisine >> RJR2403 ~ choline), suggest that A17 cells express heteromeric nAChRs containing the β4 subunit. Activation of nAChRs induced GABA release after Ca(2+) accumulation in A17 cell dendrites and varicosities mediated by L-type voltage-gated calcium channels (VGCCs) and intracellular Ca(2+) stores. Inhibition of acetylcholinesterase depolarized A17 cells and increased spontaneous inhibitory postsynaptic currents in RB cells, indicating that endogenous ACh enhances GABAergic inhibition of RB cells. Moreover, injection of neostigmine or cytisine reduced the b-wave of the scotopic flash electroretinogram (ERG), suggesting that cholinergic modulation of GABA release controls RB cell activity in vivo. These results describe a novel regulatory mechanism of RB cell inhibition and complement our understanding of the neuromodulatory control of retinal signal processing.

The structural and functional similarities between Muller cells and oligodendrocytes prompted the present study of the electrophysiological properties of Muller (glia) cells obtained from the retinae of control and myelin mutant taiep rats during the postnatal developmental period (P12-P180). The whole-cell configuration of the patch-clamp technique was used to characterize the general properties and the K+ currents from dissociated Muller cells. During the first 3 weeks of life, a decrease of the membrane resistance and an increase of the membrane potential were observed in Muller cells from both control and taiep rats. However, Muller cells from taiep rats never achieved the very negative membrane potential (-50 mV vs -80 mV) and the low membrane resistance characteristic for control cells. Furthermore, Muller cells displayed increased inward and outward K+ currents during postnatal development up to P30/60 in controls; however, in taiep rats, this increase ceased at P20/30, and low-amplitude currents persisted into adulthood. These results provide first evidence of physiological changes in retinal Muller cells as a consequence of a myelin mutation causing a progressive deterioration of the central nervous system (CNS) due to a disturbance of the microtubule network of oligodendrocytes. We hypothesize that the progressive dysmyelination process of the optic nerve, accompanied by functional deficits of retinal neurons (e.g., ganglion cells), induces physiological alterations of Muller cells.

The threshold for bidirectional modification of synaptic plasticity is known to be controlled by several factors, including the balance between protein phosphorylation and dephosphorylation, postsynaptic free Ca(2+) concentration and NMDA receptor (NMDAR) composition of GluN2 subunits. Pannexin 1 (Panx1), a member of the integral membrane protein family, has been shown to form non-selective channels and to regulate the induction of synaptic plasticity as well as hippocampal-dependent learning. Although Panx1 channels have been suggested to play a role in excitatory long-term potentiation (LTP), it remains unknown whether these channels also modulate long-term depression (LTD) or the balance between both types of synaptic plasticity. To study how Panx1 contributes to excitatory synaptic efficacy, we examined the age-dependent effects of eliminating or blocking Panx1 channels on excitatory synaptic plasticity within the CA1 region of the mouse hippocampus. By using different protocols to induce bidirectional synaptic plasticity, Panx1 channel blockade or lack of Panx1 were found to enhance LTP, whereas both conditions precluded the induction of LTD in adults, but not in young animals. These findings suggest that Panx1 channels restrain the sliding threshold for the induction of synaptic plasticity and underlying brain mechanisms of learning and memory.

Nitric oxide (NO) is involved in retinal signal processing, but its cellular actions are only partly understood. An established source of retinal NO are NOACs, a group of nNOS-expressing amacrine cells which signal onto bipolar, other amacrine and ganglion cells in the inner plexiform layer. Here, we report that NO regulates glutamate responses in morphologically and electrophysiologically identified type 4 OFF cone bipolar cells through activation of the soluble guanylyl cyclase-cGMP-PKG pathway. The glutamate response of these cells consists of two components, a fast phasic current sensitive to kainate receptor agonists, and a secondary component with slow kinetics, inhibited by AMPA receptor antagonists. NO shortened the duration of the AMPA receptor-dependent component of the glutamate response, while the kainate receptor-dependent component remained unchanged. Application of 8-Br-cGMP mimicked this effect, while inhibition of soluble guanylate cyclase or protein kinase G prevented it, supporting a mechanism involving a cGMP signaling pathway. Notably, perfusion with a NOS-inhibitor prolonged the duration of the glutamate response, while the NO precursor L-arginine shortened it, in agreement with a modulation by endogenous NO. Furthermore, NO accelerated the response recovery during repeated stimulation of type 4 cone bipolar cells, suggesting that the temporal response properties of this OFF bipolar cell type are regulated by NO. These results reveal a novel cellular mechanism of NO signaling in the retina, and represent the first functional evidence of NO modulating OFF cone bipolar cells.

Several studies have shown that connexin channels play an important role in retinal neural coding in nocturnal rodents. However, the contribution of these channels to signal processing in the retina of diurnal rodents remains unclear. To gain insight into this problem, we studied connexin expression and the contribution of connexin channels to the retinal light response in the diurnal rodent Octodon degus (degu) compared to rat, using in vivo ERG recording under scotopic and photopic light adaptation. Analysis of the degu genome showed that the common retinal connexins present a high degree of homology to orthologs expressed in other mammals, and expression of Cx36 and Cx43 was confirmed in degu retina. Cx36 localized mainly to the outer and inner plexiform layers (IPLs), while Cx43 was expressed mostly in cells of the retinal pigment epithelium. Under scotopic conditions, the b-wave response amplitude was strongly reduced by 18-β-glycyrrhetinic acid (β-GA) (−45.1% in degu, compared to −52.2% in rat), suggesting that connexins are modulating this response. Remarkably, under photopic adaptation, β-GA increased the ERG b-wave amplitude in degu (+107.2%) while reducing it in rat (−62.3%). Moreover, β-GA diminished the spontaneous action potential firing rate in ganglion cells (GCs) and increased the response latency of ON and OFF GCs. Our results support the notion that connexins exert a fine-tuning control of the retinal light response and have an important role in retinal neural coding.

STUDY OBJECTIVES To determine rapid eye movement (REM) sleep phase preference in a crepuscular mammal (Octodon degus) by challenging the specific REM sleep homeostatic response during the diurnal and nocturnal anticrepuscular rest phases. DESIGN We have investigated REM sleep rebound, recovery, and documented REM sleep propensity measures during and after diurnal and nocturnal selective REM sleep deprivations. SUBJECTS Nine male wild-captured O. degus prepared for polysomnographic recordings. INTERVENTIONS Animals were recorded during four consecutive baseline and two separate diurnal or nocturnal deprivation days, under a 12:12 light-dark schedule. Three-h selective REM sleep deprivations were performed, starting at midday (zeitgeber time 6) or midnight (zeitgeber time 18). MEASUREMENTS AND RESULTS Diurnal and nocturnal REM sleep deprivations provoked equivalent amounts of REM sleep debt, but a consistent REM sleep rebound was found only after nocturnal deprivation. The nocturnal rebound was characterized by a complete recovery of REM sleep associated with an augment in REM/total sleep time ratio and enhancement in REM sleep episode consolidation. CONCLUSIONS Our results support the notion that the circadian system actively promotes REM sleep. We propose that the sleep-wake cycle of O. degus is modulated by a chorus of circadian oscillators with a bimodal crepuscular modulation of arousal and a unimodal promotion of nocturnal REM sleep

This chapter focuses on methods from statistical physics and probability theory allowing the analysis of spike trains in neural networks. Taking as an example the retina we present recent works attempting to understand how retina ganglion cells encode the information transmitted to the visual cortex via the optical nerve, by analyzing their spike train statistics. We compare the maximal entropy models used in the literature of retina spike train analysis to rigorous results establishing the exact form of spike train statistics in conductance-based Integrate-and-Fire neural networks.

Alzheimer’s disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia, and hallmark neuropathological markers, such as deposition of amyloid-β (Aβ) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aβ oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aβ oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aβ oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated.

We present a method to estimate Gibbs distributions with \textit{spatio-temporal} constraints on spike trains statistics. We apply this method to spike trains recorded from ganglion cells of the salamander retina, in response to natural movies. Our analysis, restricted to a few neurons, performs more accurately than pairwise synchronization models (Ising) or the 1-time step Markov models (\cite{marre-boustani-etal:09}) to describe the statistics of spatio-temporal spike patterns and emphasizes the role of higher order spatio-temporal interactions., Comment: To appear in J. Physiol. Paris

Alzheimer’s disease (AD) is the most common origin of dementia in the elderly. Although the cause of AD remains unknown, several factors have been identified that appear to play a critical role in the development of this debilitating disorder. In particular, amyloid precursor protein (APP), tau hyperphosphorylation, and the secretase enzymes, have become the focal point of recent research. Over the last two decades, several transgenic and non-transgenic animal models have been developed to elucidate the mechanistic aspects of AD and to validate potential therapeutic targets. Transgenic rodent models over-expressing human β-amyloid precursor protein (β-APP) and mutant forms of tau have become precious tools to study and understand the pathogenesis of AD at the molecular, cellular and behavioural levels, and to test new therapeutic agents. Nevertheless, none of the transgenic models of AD recapitulate fully all of the pathological features of the disease. Octodon degu, a South American rodent has been recently found to spontaneously develop neuropathological signs of AD in old age. This review aims to address the limitations and clinical relevance of transgenic rodent models in AD, and to highlight the potential for O. degu as a natural model for the study of AD neuropathology.

Traditionally, vision was thought to be useless for animals living in dark underground habitats, but recent studies in a range of subterranean rodent species have shown a large diversity of eye features, from small subcutaneous eyes to normal‐sized functional eyes. We analyzed the retinal photoreceptors in the subterranean hystricomorph rodents Ctenomys talarum and Ctenomys magellanicus to elucidate whether adaptation was to their near‐lightless burrows or rather to their occasional diurnal surface activity. Both species had normally developed eyes. Overall photoreceptor densities were comparatively low (95,000–150,000/mm2 in C. magellanicus, 110,000–200,000/mm2 in C. talarum), and cone proportions were rather high (10–31% and 14–31%, respectively). The majority of cones expressed the middle‐to‐longwave‐sensitive (L) opsin, and a 6–16% minority expressed the shortwave‐sensitive (S) opsin. In both species the densities of L and S cones were higher in ventral than in dorsal retina. In both species the tuning‐relevant amino acids of the S opsin indicate sensitivity in the near UV rather than the blue/violet range. Photopic spectral electroretinograms were recorded. Unexpectedly, their sensitivity profiles were best fitted by the linear summation of three visual pigment templates with λmax at 370 nm (S pigment, UV), at 510 nm (L pigment), and at 450 nm (an as‐yet unexplained mechanism). Avoiding predators and selecting food during the brief aboveground excursions may have exerted pressure to retain robust cone‐based vision in Ctenomys. UV tuning of the S cone pigment is shared with a number of other hystricomorphs. Fil: Schleich, Cristian. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Mar del Plata. Facultad de Ciencias Exactas y Naturales. Departamento de Biología. Laboratorio de Ecofisiología; Argentina Fil: Vielma, Alex. Universidad de Valparaíso; Chile Fil: Glösmann, Martin. University of Veterinary Medicine Vienna; Austria Fil: Palacios, Adrian G.. Universidad de Valparaíso; Chile Fil: Peichl, Leo. Max Planck Institute for Brain Research; Alemania

SUMMARYIt has been argued that trichromatic bees with photoreceptor spectral sensitivity peaks in the ultraviolet (UV), blue and green areas of the spectrum are blind to long wavelengths (red to humans). South American temperate forests (SATF) contain a large number of human red-looking flowers that are reported to be visited by the bumblebee Bombus dahlbomii. In the present study, B. dahlbomii's spectral sensitivity was measured through electroretinogram (ERG) recordings. No extended sensitivity to long wavelengths was found in B. dahlbomii. The spectral reflectance curves from eight plant species with red flowers were measured. The color loci occupied by these flowers in the bee color space was evaluated using the receptor noise-limited model. Four of the plant species have pure red flowers with low levels of chromatic contrast but high levels of negative L-receptor contrast. Finally, training experiments were performed in order to assess the role of achromatic cues in the detection and discrimination of red targets by B. dahlbomii. The results of the training experiments suggest that the bumblebee relies on achromatic contrast provided by the L-receptor to detect and discriminate red targets. These findings are discussed in the context of the evolutionary background under which the relationship between SATF species and their flower visitors may have evolved.