Cypin (cytosolic postsynaptic density protein 95 interactor) is the primary guanine deaminase in the central nervous system (CNS), promoting the metabolism of guanine to xanthine, an important reaction in the purine salvage pathway. Activation of the purine salvage pathway leads to the production of uric acid (UA). UA has paradoxical effects, specifically in the context of CNS injury as it confers neuroprotection, but it also promotes pain. Since neuropathic pain is a comorbidity associated with spinal cord injury (SCI), we postulated that small molecule cypin inhibitor B9 treatment could attenuate SCI-induced neuropathic pain, potentially by interfering with UA production. However, we also considered that this treatment could hinder the neuroprotective effects of UA and, in doing so, exacerbate SCI outcomes. To address our hypothesis, we induced a moderate midthoracic contusion SCI in female mice and assessed whether transient intrathecal administration of B9, starting at 1 d postinjury (dpi) until 7 dpi,...

Biological variation is ubiquitous in nature. Despite highly standardized breeding and husbandry under controlled environmental conditions, phenotypic diversity exists in laboratory mice and rats just as it does in humans. The resulting inter-individual variability affects various characteristics of animal disease models, including the responsiveness to drugs. Thus, the common practice of averaging data within an experimental group can lead to misinterpretations in neuroscience and other research fields. In this commentary, the impact of inter-individual variation in drug responsiveness is illustrated by examples from the testing of antiseizure medications in rodent temporal lobe epilepsy models. Individual mice and rats rendered epileptic by treatment according to standardized protocols fall into groups that either do or do not respond to antiseizure medications, thus mimicking the clinical situation in patients with epilepsy. Population responses are not normally distributed, and divergent responding is ...

Alpha-synuclein has been implicated in neurodegenerative diseases such as Parkinson's disease and dementia with Lewy bodies, with A53T and A30P mutations shown to be disease causing. It has been reported that hemizygous transgenic mice with tyrosine hydroxylase promotor-driven expression of A53T/A30P mutant alpha-synuclein in dopamine neurons provide a useful preclinical model of these conditions by virtue of developing behavioral deficits. Here, we report a lack of replication of this finding. Despite detecting robust overexpression of A53T/A30P mutant alpha-synuclein in dopamine neurons, we did not observe decreased tyrosine hydroxylase immunofluorescence or behavioral deficits in these mice. Our results demonstrate that preclinical models of synucleinopathy need careful validation in the field.

Opioid use disorder (OUD) is a public health crisis currently being exacerbated by increased rates of use and overdose of synthetic opioids, primarily fentanyl. Therefore, the identification of novel biomarkers and treatment strategies to reduce problematic fentanyl use and relapse to fentanyl taking is critical. In recent years, there has been a growing body of work demonstrating that the gut microbiome can serve as a potent modulator of the behavioral and transcriptional responses to both stimulants and opioids. Here, we advance this work to define how manipulations of the microbiome drive fentanyl intake and fentanyl-seeking in a translationally relevant drug self-administration model. Depletion of the microbiome of male rats with broad spectrum antibiotics leads to increased drug administration on increased fixed ratio, progressive ratio, and drug seeking after abstinence. Utilizing 16S  sequencing of microbiome contents from these animals, specific populations of bacteria from the gut microbiome corre...

Alzheimer's disease (AD) is the most common form of dementia and results in neurodegeneration and cognitive impairment. White matter (WM) is affected in AD and has implications for neural circuitry and cognitive function. The trajectory of these changes across age, however, is still not well understood, especially at earlier stages in life. To address this, we used the AppNL∼G∼F/NL∼G∼F knock-in (APPKI) mouse model that harbors a single copy knock-in of the human amyloid precursor protein ( App ) gene with three familial AD mutations. We performed in vivo diffusion tensor imaging (DTI) to study how the structural properties of the brain change across age in the context of AD. In late age APPKI mice, we observed reduced fractional anisotropy (FA), a proxy of WM integrity, in multiple brain regions, including the hippocampus, anterior commissure, neocortex, and hypothalamus. At the cellular level, we observed greater numbers of oligodendrocytes in middle age (prior to observations in DTI) in both the anterior...

Interactions between astrocytes and microglia play an important role in the regeneration and repair of traumatic brain injury (TBI), and exosomes are involved in cell‒cell interactions. A TBI model was constructed in rats. Brain extract (Ext) was isolated 1 day after TBI. Astrocyte-derived exosomes were obtained by coculturing Ext with primary astrocytes, and the morphology of exosomes was observed by electron microscopy. The isolated exosomes were cocultured with microglia to observe phenotypic changes in M1 and M2 markers. Aberrant RNA expression was detected in necrotic brain tissue and edematous brain tissue. The role of miR-148a-3p in regulating microglial phenotype was explored by knocking down or overexpressing miR-148a-3p. Finally, the effect of miR-148a-3p on TBI was studied in a rat TBI model. Astrocyte-derived exosomes stimulated by Ext promoted the transition of microglia from the M1 phenotype to the M2 phenotype. MiR-148a-3p was highly expressed in TBI. Transfecting miR-148a-3p promoted the tr...

Estimating durations between hundreds of milliseconds and seconds is essential for several daily tasks. Explicit timing tasks, which require participants to estimate durations to make a comparison (time for perception) or to reproduce them (time for action), are often used to investigate psychological and neural timing mechanisms. Recent studies have proposed that mechanisms may depend on specific task requirements. In this study, we conducted electroencephalogram (EEG) recordings on human participants as they estimated intervals in different task contexts to investigate the extent to which timing mechanisms depend on the nature of the task. We compared the neural processing of identical visual reference stimuli in two different tasks, in which stimulus durations were either perceptually compared or motorically reproduced in separate experimental blocks. Using multivariate pattern analyses, we could successfully decode the duration and the task of reference stimuli. We found evidence for both overlapping t...

Learning and adaptation during sources of threat and safety are critical mechanisms for survival. The prelimbic (PL) and infralimbic (IL) subregions of the medial prefrontal cortex (mPFC) have been broadly implicated in the processing of threat and safety. However, how these regions regulate threat and safety during naturalistic conditions involving thermal challenge still remains elusive. To examine this issue, we developed a novel paradigm in which adult mice learned that a particular zone that was identified with visuospatial cues was associated with either a noxious cold temperature (“threat zone”) or a pleasant warm temperature (“safety zone”). This led to the rapid development of avoidance behavior when the zone was paired with cold threat or approach behavior when the zone was paired with warm safety. During a long-term test without further thermal reinforcement, mice continued to exhibit robust avoidance or approach to the zone of interest, indicating that enduring spatial-based memories were forme...

Spinal cord injury (SCI) often results in various long-term sequelae, and chronically injured spinal cords exhibit a refractory feature, showing a limited response to cell transplantation therapies. To our knowledge, no preclinical studies have reported a treatment approach with results surpassing those of treatment comprising rehabilitation alone. In this study of rats with SCI, we propose a novel combined therapy involving a semaphorin 3A inhibitor (Sema3Ai), which enhances axonal regeneration, as the third treatment element in combination with neural stem/progenitor cell transplantation and rehabilitation. This comprehensive therapeutic strategy achieved significant improvements in host-derived neuronal and oligodendrocyte differentiation at the SCI epicenter and promoted axonal regeneration even in the chronically injured spinal cord. The elongated axons established functional electrical connections, contributing to significant enhancements in locomotor mobility when compared with animals treated with ...

Stress-inducing events during pregnancy are associated with aberrant neurodevelopment resulting in adverse psychiatric outcomes, including autism spectrum disorder (ASD). While numerous preclinical models for the study of ASD are frequently generated using C57BL/6J mice, few studies have investigated the effects of prenatal stress on this genetic background. In the current manuscript, we stressed C57BL/6 dams during gestation and examined numerous behavioral and molecular endophenotypes in the adult male and female offspring to characterize the resultant phenotype as compared with offspring born from non-stressed dams. Adult mice born from prenatally restraint stressed (PRS) dams demonstrated reduced sociability and reciprocal social interaction along with increased marble burying behaviors relative to mice born from non-stressed (NS) control dams. Differential expression of genes related to excitatory and inhibitory neurotransmission was evaluated in the medial prefrontal cortex, amygdala, hippocampus, nu...