Browsing by Author "Lindsay, Carolina B."

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    A Multivariate Assessment of Age-Related Cognitive Impairment in Octodon degus
    (2021) Rivera, Daniela S.; Lindsay, Carolina B.; Oliva, Carolina A.; Bozinovic, Francisco; Inestrosa, Nibaldo C.
    Aging is a progressive functional decline characterized by a gradual deterioration in physiological function and behavior. The most important age-related change in cognitive function is decline in cognitive performance (i.e., the processing or transformation of information to make decisions that includes speed of processing, working memory, and learning). The purpose of this study is to outline the changes in age-related cognitive performance (i.e., short-term recognition memory and long-term learning and memory) in long-lived Octodon degus. The strong similarity between degus and humans in social, metabolic, biochemical, and cognitive aspects makes it a unique animal model for exploring the mechanisms underlying the behavioral and cognitive deficits related to natural aging. In this study, we examined young adult female degus (12- and 24-months-old) and aged female degus (38-, 56-, and 75-months-old) that were exposed to a battery of cognitive-behavioral tests. Multivariate analyses of data from the Social Interaction test or Novel Object/Local Recognition (to measure short-term recognition memory), and the Barnes maze test (to measure long-term learning and memory) revealed a consistent pattern. Young animals formed a separate group of aged degus for both short- and long-term memories. The association between the first component of the principal component analysis (PCA) from short-term memory with the first component of the PCA from long-term memory showed a significant negative correlation. This suggests age-dependent differences in both memories, with the aged degus having higher values of long-term memory ability but poor short-term recognition memory, whereas in the young degus an opposite pattern was found. Approximately 5% of the young and 80% of the aged degus showed an impaired short-term recognition memory; whereas for long-term memory about 32% of the young degus and 57% of the aged degus showed decreased performance on the Barnes maze test. Throughout this study, we outlined age-dependent cognitive performance decline during natural aging in degus. Moreover, we also demonstrated that the use of a multivariate approach let us explore and visualize complex behavioral variables, and identified specific behavioral patterns that allowed us to make powerful conclusions that will facilitate further the study on the biology of aging. In addition, this study could help predict the onset of the aging process based on behavioral performance.
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    Age-Dependent Behavioral and Synaptic Dysfunction Impairment Are Improved with Long-Term Andrographolide Administration in Long-Lived Female Degus (Octodon degus)
    (2023) Oliva, Carolina A.; Rivera, Daniela S.; Torres, Angie K.; Lindsay, Carolina B.; Tapia-Rojas, Cheril; Bozinovic, Francisco; Inestrosa, Nibaldo C.
    In Octodon degus, the aging process is not equivalent between sexes and worsens for females. To determine the beginning of detrimental features in females and the ways in which to improve them, we compared adult females (36 months old) and aged females (72 months old) treated with Andrographolide (ANDRO), the primary ingredient in Andrographis paniculata. Our behavioral data demonstrated that age does not affect recognition memory and preference for novel experiences, but ANDRO increases these at both ages. Sociability was also not affected by age; however, social recognition and long-term memory were lower in the aged females than adults but were restored with ANDRO. The synaptic physiology data from brain slices showed that adults have more basal synaptic efficiency than aged degus; however, ANDRO reduced basal activity in adults, while it increased long-term potentiation (LTP). Instead, ANDRO increased the basal synaptic activity and LTP in aged females. Age-dependent changes were also observed in synaptic proteins, where aged females have higher synaptotagmin (SYT) and lower postsynaptic density protein-95 (PSD95) levels than adults. ANDRO increased the N-methyl D-aspartate receptor subtype 2B (NR2B) at both ages and the PSD95 and Homer1 only in the aged. Thus, females exposed to long-term ANDRO administration show improved complex behaviors related to age-detrimental effects, modulating mechanisms of synaptic transmission, and proteins.
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    Andrographolide Reduces Neuroinflammation and Oxidative Stress in Aged Octodon degus
    (SPRINGER, 2020) Lindsay, Carolina B.; Zolezzi, Juan M.; Rivera, Daniela S.; Cisternas, Pedro; Bozinovic, Francisco; Inestrosa, Nibaldo C.
    Alzheimer's disease (AD) is a devastating neurodegenerative disorder in which superior brain functions, such as memory and cognition, are impaired. Currently, no effective treatment is available for AD. Although andrographolide (ANDRO), a compound extracted from the herb Andrographis paniculata, has shown interesting effects in models of several diseases, including AD, its effects on other molecular changes observed in AD, such as neuroinflammation and oxidative stress, have not yet been studied. To evaluate the impact of ANDRO-based intervention on the levels of amyloid-beta (A beta) and neuroinflammatory and oxidative stress markers in the brains of aged Octodon degus, a Chilean rodent, fifty-six-month-old O. degus were treated intraperitoneally with 2 or 4 mg/kg ANDRO. Vehicle-injected and 12-month-old O. degus were used as positive controls. Then, the protein levels of selected markers were assessed via immunohistochemistry and immunoblotting. ANDRO significantly reduced the total A beta burden as well as astrogliosis and interleukin-6 levels. Moreover, ANDRO significantly reduced the levels of 4-hydroxynonenal and N-tyrosine adducts, suggesting a relevant reduction in oxidative stress within aged O. degus brain. Considering that O. degus has been proposed as a potential "natural" model for sporadic AD due to the development of neuropathological markers that resemble this pathology, our results suggest that ANDRO should be further studied to establish its potential as a therapeutic drug for AD.
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    Effects of long-lasting social isolation and re-socialization on cognitive performance and brain activity: a longitudinal study in Octodon degus
    (2020) Rivera, Daniela S.; Lindsay, Carolina B.; Oliva, Carolina A.; Francisco Codocedo, Juan; Bozinovic, Francisco; Inestrosa, Nibaldo C.
    Social isolation is considered a stressful situation that results in increased physiological reactivity to novel stimuli, altered behaviour, and impaired brain function. Here, we investigated the effects of long-term social isolation on working memory, spatial learning/memory, hippocampal synaptic transmission, and synaptic proteins in the brain of adult female and male Octodon degus. The strong similarity between degus and humans in social, metabolic, biochemical, and cognitive aspects, makes it a unique animal model that can be highly applicable for further social, emotional, cognitive, and aging studies. These animals were socially isolated from post-natal and post-weaning until adulthood. We also evaluated if re-socialization would be able to compensate for reactive stress responses in chronically stressed animals. We showed that long-term social isolation impaired the HPA axis negative feedback loop, which can be related to cognitive deficits observed in chronically stressed animals. Notably, re-socialization restored it. In addition, we measured physiological aspects of synaptic transmission, where chronically stressed males showed more efficient transmission but deficient plasticity, as the reverse was true on females. Finally, we analysed synaptic and canonical Wnt signalling proteins in the hypothalamus, hippocampus, and prefrontal cortex, finding both sex-and brain structure-dependent modulation, including transient and permanent changes dependent on stress treatment.
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    Is L-methionine a trigger factor for Alzheimer’s-like neurodegeneration?: Changes in Aβ oligomers, tau phosphorylation, synaptic proteins, Wnt signaling and behavioral impairment in wild-type mice
    (2015) Tapia Rojas, Cheril Cecilia; Lindsay, Carolina B.; Montecinos Oliva, Carla; Arrazola Tello, Macarena Soledad.; Retamales, Rocio M.; Inestrosa Cantín, Nibaldo; Bunout, Daniel; Hirsch, Sandra.
    Abstract Background L-methionine, the principal sulfur-containing amino acid in proteins, plays critical roles in cell physiology as an antioxidant and in the breakdown of fats and heavy metals. Previous studies suggesting the use of L-methionine as a treatment for depression and other diseases indicate that it might also improve memory and propose a role in brain function. However, some evidence indicates that an excess of methionine can be harmful and can increase the risk of developing Type-2 diabetes, heart diseases, certain types of cancer, brain alterations such as schizophrenia, and memory impairment. Results Here, we report the effects of an L-methionine-enriched diet in wild-type mice and emphasize changes in brain structure and function. The animals in our studypresented 1) higher levels of phosphorylated tau protein, 2) increased levels of amyloid-β (Aβ)-peptides, including the formation of Aβ oligomers, 3) increased levels of inflammatory response,4) increased oxidative stress, 5) decreased level of synaptic proteins, and 6) memory impairment and loss. We also observed dysfunction of the Wnt signaling pathway. Conclusion Taken together, the results of our study indicate that an L-methionine-enriched diet causes neurotoxic effects in vivo and might contribute to the appearance of Alzheimer’s-like neurodegeneration.
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    "Live together, die alone": The effect of re-socialization on behavioural performance and social-affective brain-related proteins after a long-term chronic social isolation stress
    (2021) Rivera, Daniela S.; Lindsay, Carolina B.; Oliva, Carolina A.; Bozinovic, Francisco; Inestrosa, Nibaldo C.
    Loneliness affects group-living mammals triggering a cascade of stress-dependent physiological disorders. Indeed, social isolation stress is a major risk factor for several neuropsychiatric disorders including anxiety and depression. Furthermore, social isolation has a negative impact on health and fitness. However, the neurobiological consequences of long-term chronic social isolation stress (LTCSIS) manifested during the adulthood of affected individuals are not fully understood. Our study assessed the impact of LTCSIS and social buffering (re-socialization) on the behavioural performance and social-affective brain-related proteins in diurnal, social, and long-lived Octodon degus (degus). Thereby, anxiety-like and social behaviour, and social recognition memory were assessed in male and female animals subjected to a variety of stress-inducing treatments applied from postnatal and post-weaning until their adulthood. Additionally, we evaluated the relationship among LTCSIS, Oxytocin levels (OXT), and OXT-Ca2+-signalling proteins in the hypothalamus, the hippocampus, and the prefrontal cortex. Our findings suggest that LTCSIS induces anxiety like-behaviour and impairs social novelty preference whereas sociability is unaffected. On the other hand, re-socialization can revert both isolation-induced anxiety and social memory impairment. However, OXT and its signalling remained reduced in the abovementioned brain areas, suggesting that the observed changes in OXT-Ca2+ pathway proteins were permanent in male and female degus. Based on these findings, we conclude degus experience social stress differently, suggesting the existence of sex-related mechanisms to cope with specific adaptive challenges.
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    Long-term social isolation stress exacerbates sex-specific neurodegeneration markers in a natural model of Alzheimer's disease
    (2023) Oliva, Carolina A.; Lira, Matias; Jara, Claudia; Catenaccio, Alejandra; Mariqueo, Trinidad A.; Lindsay, Carolina B.; Bozinovic, Francisco; Cavieres, Grisel; Inestrosa, Nibaldo C.; Tapia-Rojas, Cheril; Rivera, Daniela S.
    Social interactions have a significant impact on health in humans and animal models. Social isolation initiates a cascade of stress-related physiological disorders and stands as a significant risk factor for a wide spectrum of morbidity and mortality. Indeed, social isolation stress (SIS) is indicative of cognitive decline and risk to neurodegenerative conditions, including Alzheimer's disease (AD). This study aimed to evaluate the impact of chronic, long-term SIS on the propensity to develop hallmarks of AD in young degus (Octodon degus), a long-lived animal model that mimics sporadic AD naturally. We examined inflammatory factors, bioenergetic status, reactive oxygen species (ROS), oxidative stress, antioxidants, abnormal proteins, tau protein, and amyloid-beta (A beta) levels in the hippocampus of female and male degus that were socially isolated from post-natal and post-weaning until adulthood. Additionally, we explored the effect of re-socialization following chronic isolation on these protein profiles. Our results showed that SIS promotes a pro-inflammatory scenario more severe in males, a response that was partially mitigated by a period of re-socialization. In addition, ATP levels, ROS, and markers of oxidative stress are severely affected in female degus, where a period of re-socialization fails to restore them as it does in males. In females, these effects might be linked to antioxidant enzymes like catalase, which experience a decline across all SIS treatments without recovery during re-socialization. Although in males, a previous enzyme in antioxidant pathway diminishes in all treatments, catalase rebounds during re-socialization. Notably, males have less mature neurons after chronic isolation, whereas phosphorylated tau and all detectable forms of A beta increased in both sexes, persisting even post re-socialization. Collectively, these findings suggest that long-term SIS may render males more susceptible to inflammatory states, while females are predisposed to oxidative states. In both scenarios, the accumulation of tau and A beta proteins increase the individual susceptibility to early-onset neurodegenerative conditions such as AD.
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    Long-Term, Fructose-Induced Metabolic Syndrome-Like Condition Is Associated with Higher Metabolism, Reduced Synaptic Plasticity and Cognitive Impairment in Octodon degus
    (2018) Rivera, Daniela S.; Lindsay, Carolina B.; Codocedo Henríquez, Juan Francisco; Carreño, Laura E.; Cabrera, Daniel; Arrese Jiménez, Marco; Vio Lagos, Carlos P.; Bozinovic Kuscevic, Francisco; Inestrosa Cantín, Nibaldo
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    Quercetin Exerts Differential Neuroprotective Effects Against H2O2 and A beta Aggregates in Hippocampal Neurons: the Role of Mitochondria
    (2017) Godoy, Juan A.; Lindsay, Carolina B.; Quintanilla, Rodrigo A.; Carvajal Cachaña, Francisco Javier; Cerpa Nebott, Waldo Francisco; Inestrosa Cantín, Nibaldo
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    The increased potassium intake improves cognitive performance and attenuates histopathological markers in a model of Alzheimer's disease
    (2015) Cisternas, Pedro; Lindsay, Carolina B.; Salazar, Paulina; Silva Álvarez, Carmen; Retamales, Rocio M.; Serrano, Felipe G.; Vio Lagos, Carlos P.; Inestrosa Cantín, Nibaldo
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    Wnt5a modulates dendritic spine dynamics through the regulation of Cofilin via small Rho GTPase activity in hippocampal neurons
    (2021) Vallejo, Daniela; Lindsay, Carolina B.; Gonzalez-Billault, Christian; Inestrosa, Nibaldo C.
    Dendritic spines are small, actin-rich protrusions that act as the receiving sites of most excitatory inputs in the central nervous system. The remodeling of the synapse architecture is mediated by actin cytoskeleton dynamics, a process precisely regulated by the small Rho GTPase family. Wnt ligands exert their presynaptic and postsynaptic effects during formation and consolidation of the synaptic structure. Specifically, Wnt5a has been identified as an indispensable synaptogenic factor for the regulation and organization of the postsynaptic side; however, the molecular mechanisms through which Wnt5a induces morphological changes resulting from actin cytoskeleton dynamics within dendritic spines remain unclear. In this work, we employ primary rat hippocampal cultures and HT22 murine hippocampal neuronal cell models, molecular and pharmacological tools, and fluorescence microscopy (laser confocal and epifluorescence) to define the Wnt5a-induced molecular signaling involved in postsynaptic remodeling mediated via the regulation of the small Rho GTPase family. We report that Wnt5a differentially regulates the phosphorylation of Cofilin in neurons through both Ras-related C3 botulinum toxin substrate 1 and cell division cycle 42 depending on the subcellular compartment and the extracellular calcium levels. Additionally, we demonstrate that Wnt5a increases the density of dendritic spines and promotes their maturation via Ras-related C3 botulinum toxin substrate 1. Accordingly, we find that Wnt5a requires the combined activation of small Rho GTPases to increase the levels of filamentous actin, thus promoting the stability of actin filaments. Altogether, these results provide evidence for a new mechanism by which Wnt5a may target actin dynamics, thereby regulating the subsequent morphological changes in dendritic spine architecture.