Within the context of a rapidly aging world, the incidence of brain injuries and age-associated neurodegenerative diseases, often characterized by axonal pathology, is rising. In the context of aging, we suggest the killifish visual/retinotectal system as a model to explore central nervous system repair, with a focus on axonal regeneration. Our initial description in killifish concerns an optic nerve crush (ONC) model designed to induce and study the degeneration and regeneration of retinal ganglion cells (RGCs) and their axons. Subsequently, we compile diverse strategies for mapping the progressive steps of the regenerative process—axonal regrowth and synapse reformation—through the use of retrograde and anterograde tracing techniques, (immuno)histochemical analysis, and morphometric assessment.
The modern societal trend of an increasing elderly population emphasizes the crucial role of a well-designed and pertinent gerontology model. Specific cellular characteristics, cataloged by Lopez-Otin and his colleagues, allow for the mapping and analysis of aging tissue. Recognizing that the presence of individual aging attributes doesn't necessarily indicate aging, we present several (immuno)histochemical strategies for examining several hallmark processes of aging—specifically, genomic damage, mitochondrial dysfunction/oxidative stress, cellular senescence, stem cell depletion, and altered intercellular communication—morphologically in the killifish retina, optic tectum, and telencephalon. Through the application of this protocol, along with molecular and biochemical analyses of these aging hallmarks, a complete picture of the aged killifish central nervous system can be ascertained.
Age-related visual impairment is a significant phenomenon, and the loss of sight is often deemed the most valuable sensory function to be deprived of. In our aging population, the central nervous system (CNS) deteriorates with age, alongside neurodegenerative diseases and head traumas, frequently impacting visual function and performance. We present two behavioral assays focused on vision to evaluate visual performance in fast-aging killifish exhibiting aging or central nervous system damage. To initiate the examination, the optokinetic response (OKR) scrutinizes the reflexive eye movement in response to visual field motion to determine visual acuity. Using overhead light input, the second assay, the dorsal light reflex (DLR), defines the swimming angle. The OKR, in assessing visual acuity changes due to aging, as well as the recovery and improvement in vision following rejuvenation treatments or visual system injury or disease, holds a significant role, whereas the DLR is particularly useful in assessing the functional repair after a unilateral optic nerve crush.
Defects in the Reelin and DAB1 signaling cascades, brought about by loss-of-function mutations, result in improper neuron positioning in both the cerebral neocortex and the hippocampus, despite the underlying molecular mechanisms remaining a mystery. SBI-115 Heterozygous yotari mice, carrying a single autosomal recessive yotari Dab1 mutation, displayed a thinner neocortical layer 1 compared to wild-type mice on postnatal day 7. A birth-dating study revealed, however, that the observed reduction was not caused by the failure of neuronal migration. In utero electroporation-mediated sparse labeling identified a pattern in which superficial layer neurons from heterozygous yotari mice showed a preference for extending their apical dendrites within layer 2 compared to layer 1. Additionally, the caudo-dorsal hippocampus's CA1 pyramidal cell layer displayed a splitting phenotype in heterozygous yotari mice; a birth-dating investigation indicated a correlation between this splitting and the migration deficit of late-born pyramidal neurons. SBI-115 Sparse labeling with adeno-associated virus (AAV) yielded the finding that many pyramidal cells within the split cell displayed an misalignment of their apical dendrites. Reelin-DAB1 signaling pathways' regulation of neuronal migration and positioning displays unique dependencies on Dab1 gene dosage across distinct brain regions, as suggested by these findings.
The behavioral tagging (BT) hypothesis provides a framework for comprehending the complex process of long-term memory (LTM) consolidation. The experience of novelty in the brain represents a crucial stage in the activation of the molecular mechanisms responsible for memory creation. Using different neurobehavioral tasks, several studies have validated BT, yet open field (OF) exploration has remained the only consistent novel component in each A key experimental paradigm, environmental enrichment (EE), is instrumental in delving into the fundamental workings of the brain. Recent research findings have illuminated the influence of EE on enhancing cognition, fortifying long-term memory, and facilitating synaptic plasticity. We sought to explore, in this study, the effects of different types of novelty on long-term memory consolidation and plasticity-related protein synthesis, using the behavioral task (BT) phenomenon. Male Wistar rats participated in novel object recognition (NOR) as the learning task, where open field (OF) and elevated plus maze (EE) environments constituted the novel experiences. Our research indicates that LTM consolidation is effectively achieved by EE exposure, leveraging the BT phenomenon. Exposure to EE notably elevates protein kinase M (PKM) synthesis specifically in the hippocampus of the rat brain. Although exposed to OF, a notable enhancement of PKM expression did not occur. Subsequently, the hippocampus exhibited no alterations in BDNF expression levels following exposure to both EE and OF. Thus, it is ascertained that differing novelties contribute to the BT phenomenon with identical behavioral implications. However, the diverse novelties' effects might vary drastically at the molecular underpinnings.
Solitary chemosensory cells (SCCs) are found inhabiting the nasal epithelium. Peptidergic trigeminal polymodal nociceptive nerve fibers innervate SCCs, which exhibit expression of bitter taste receptors and taste transduction signaling components. Therefore, nasal squamous cell carcinomas exhibit responsiveness to bitter compounds, including those produced by bacteria, which in turn trigger protective respiratory reflexes and inherent immune and inflammatory reactions. SBI-115 Our study, employing a custom-built dual-chamber forced-choice device, sought to determine if SCCs are associated with aversive reactions to specific inhaled nebulized irritants. Careful records were kept and analyzed, focusing on the duration mice spent in individual chambers, providing behavioral insights. In wild-type mice, an aversion to 10 mm denatonium benzoate (Den) and cycloheximide was evident, resulting in a greater preference for the saline control chamber. Knockout mice lacking the SCC-pathway did not show any aversion. WT mice demonstrated a bitter avoidance behavior that was positively correlated with both the heightened concentration of Den and the number of exposures they experienced. Bitter-ageusia P2X2/3 double knockout mice exhibited an aversion to nebulized Den, a reaction independent of taste mechanisms, suggesting a critical role for squamous cell carcinoma in this aversive response. It is noteworthy that SCC-pathway KO mice demonstrated an attraction towards greater concentrations of Den; however, chemical ablation of the olfactory epithelium eliminated this attraction, presumably connected to the perceptible odor of Den. By activating SCCs, a rapid aversive response to certain irritant categories is elicited, wherein olfaction plays a pivotal role in subsequent avoidance behavior while gustation does not. A noteworthy defensive tactic against inhaling noxious chemicals is the avoidance behavior orchestrated by the SCC.
Human lateralization patterns often involve a consistent preference for employing one arm rather than the other when engaging in a diverse array of physical movements. A comprehensive understanding of the computational aspects of movement control, and how this leads to varied skills, is absent. Predictive and impedance control mechanisms are postulated to be employed differently by the dominant and nondominant arms. However, prior research presented obstacles to definitive conclusions, whether contrasting performance across two disparate groups or using a design allowing for asymmetrical limb-to-limb transfer. In order to address these concerns, we examined a reaching adaptation task, during which healthy volunteers performed movements utilizing their right and left arms in a randomized pattern. We conducted two trials. The 18 participants in Experiment 1 focused on adapting to the presence of a disruptive force field (FF), whereas the 12 participants in Experiment 2 concentrated on rapid adjustments in feedback responses. The left and right arm's randomization resulted in concurrent adaptation, enabling a study of lateralization in single individuals, exhibiting symmetrical limb function with minimal transfer. This design's findings emphasized participants' capacity to adapt control of both arms, yielding consistent performance across both. While the non-dominant arm began with a slightly less impressive showing, it attained a similar performance level to the dominant arm by the conclusion of the trials. During adaptation to the force field perturbation, the nondominant arm exhibited a control strategy distinct from the dominant arm, exhibiting compatibility with robust control. The EMG data suggests that variations in control were unrelated to differences in co-contraction strength across each arm. Consequently, rather than postulating discrepancies in predictive or reactive control mechanisms, our findings reveal that, within the framework of optimal control, both limbs are capable of adaptation, with the non-dominant limb employing a more resilient, model-free strategy, potentially compensating for less precise internal models of movement dynamics.
Cellular function is dependent on a proteome that exhibits a delicate balance, coupled with a high degree of dynamism. Mitochondrial protein import dysfunction results in cytosolic buildup of precursor proteins, disrupting cellular proteostasis and initiating a mitoprotein-triggered stress response.