The cerebellum is well established in subsecond motor timing, but its role in suprasecond interval timing remains unclear. Here, we investigated how cerebellar output influences time estimation over longer timescales. Male rats performed a nose-poke interval timing task in which reward availability could be predicted either from a fixed 2.5 s auditory cue (cued trials) or had to be estimated internally during uncued 3.5 s trials that demanded self-timing. Chemogenetic inhibition of the lateral cerebellar nucleus (LCN) produced bidirectional effects: delayed action initiation in predictable trials and premature (∼100–160 ms) responses when self-timing was required. Despite a slowing of movement, overall task success rates remained unchanged. Because motor slowing is likely to lead to later, not earlier, action initiation, these results implicate the LCN in computing internal time estimates. These findings demonstrate that the cerebellum integrates motor and cognitive processes for suprasecond timing, with d...

There is a critical need for robust and reliable preclinical models for posttraumatic stress disorder (PTSD) to better understand pathophysiological mechanisms and support the development of novel treatments. The single prolonged stress (SPS) model has been previously utilized to investigate various acute behavioral effects and stress hormone changes in rodents. This study paired anxiety-like and social behavioral evaluations with corticosterone assessment as a complementary physiological biomarker to determine the presence of robust and intervenable phenotypes following SPS. Sprague Dawley rats ( N  = 36, 30 male and 6 female) received SPS model induction (e.g., restraint with odorant, forced-swim, diethyl ether exposure, and isolation) or control handling. Serum corticosterone and behavioral assessments, including the open field test (OFT) and a social motivation test (SMT), were investigated at 1 and 2 weeks following SPS induction. This SPS model did not induce anxiety-like or locomotive differences as...

Age-related vascular changes accompany or precede the development of Alzheimer's disease (AD) pathology. The comorbidity of AD and arterial stiffening suggests that vascular changes have a pathogenic role. Carotid artery mechanics and hemodynamics have been associated with age-related cognitive decline. However, the impact of hemodynamics and vascular mechanics on regional vulnerability within the brain has not been thoroughly explored. Compared with the arterial system, brain venous circulation in cognitive impairment is less understood despite the venous system's role in transport. To study vasculature impact on biochemistry in AD models, we must first establish the differences in vasculature mechanics and hemodynamics in a common AD model compared with healthy controls. With this baseline data, future studies on manipulating vasculature integrity in mice become feasible. Young and aged female 3xTg mice and age-matched controls were imaged using a combination of ultrasound and mass spectrometry. Wall she...

Social cognition, central to emotional and cognitive well-being, is particularly vulnerable to aging, where impairments can lead to isolation and functional decline. Despite compelling evidence that altered social behavior is associated with cognitive decline and dementia risk, experimental strategies for testing causative links remain scarce. To address this gap, we aimed to establish a rat model for research on social neurocognitive aging. We conducted a large-scale behavioral study in 169 male young (6 months) and aged (24–25 months) Long–Evans rats. In order to explore potential relationships among aging outcomes, we first documented individual differences in a widely validated water maze test of hippocampal learning and memory. Sociability and social novelty were then evaluated in the same subjects using the three-chamber social interaction test. Aging induced a selective shift in social novelty preference, marked by a striking familiarity bias in a substantial subpopulation of old rats, while sociabi...

Spastin is a conserved microtubule-severing enzyme mutated in hereditary spastic paraplegia. The role that spastin plays in the cell biology of axon regeneration and degeneration has recently been investigated in Drosophila . We show that the C. elegans spastin ortholog, spas-1 , is expressed in GABA motor neurons, in addition to the known expression in touch receptor neurons (TRNs) and that it is required for axon regeneration in the GABA motor neurons after in vivo laser axotomy. We identified no neuronal developmental defects in the GABA motor neurons and only minor branching variations in the TRNs. However, we show that spas-1 is required for the long-term maintenance of TRN axons in C. elegans , as older spas-1 null C. elegans show a significant increase in specific axonal morphological defects compared with the wild type as identified by confocal microscopy in aged animals. Together, our results suggest that spastin is required for regrowth and maintenance of axons in C. elegans , consistent with pre...

Dopaminergic inputs to various brain regions, such as the striatum, orbitofrontal cortex, and amygdala, play a critical role in processing reward acquisition information. While reward-related activity is also observed more broadly in motor, parietal, and hippocampal regions, the functional significance and potential hierarchy of reward-related representation across these latter areas remain unclear. We investigated this by quantifying neural predictive power using machine learning. Specifically, neural activity was examined in six brain areas—the primary and secondary motor cortices (M1 and M2), posterior parietal cortex (PPC), dorsal and ventral CA1 (dCA1 and vCA1), and lateral entorhinal cortex (LEC)—in male rats performing a self-initiated left–right choice task. Machine learning models classified rewarded versus nonrewarded trials based on neuronal firing properties significantly above chance for all regions. Crucially, classification revealed a clear performance gradient, forming a functional hierarch...

Neurexins (Nrxns) are presynaptic cell adhesion molecules essential for synapse development and function. Of the many neurexin isoforms, only β-Nrxns contain the histidine-rich domain (HRD). While the HRD has been implicated in several pathological contexts, its normal physiological role remains unclear. To address this, we used a CRISPR-Cas9 method to generate a new mouse line expressing in-frame truncated Nrxn1β lacking the HRD. We found that HRD deletion did not affect mouse viability, gross brain development, or general behavior of either sex. However, loss of the HRD significantly altered neuroligin-1-dependent excitatory, but not inhibitory, presynaptic differentiation in primary cultured neurons. Moreover, this deletion affected presynaptic short-term plasticity, but not basal synaptic transmission, at hippocampal Schaffer collateral→CA1 synapses. These findings identify the Nrxn1β HRD as a potential contributor to excitatory presynaptic organization and function, providing new insight into the mole...

Vestibular dysfunction constitutes a major medical concern, and regeneration of hair cells (HCs) is a primary target of gene therapy aimed at restoring vestibular functions. Thus far, therapeutic trials in animal models targeting vestibular loss associated with genetic diseases have yielded variable and partial results, and the functional identity and quantity of HCs required to restore minimal or normal vestibular function remain undefined. Indeed, direct comparisons between structural pathology and quantitative assessments of vestibular dysfunctions are lacking in humans and are rather limited in animal models, representing a significant gap in current knowledge. Here, we present an innovative methodology to bridge the gap between HC integrity and functional vestibular loss in individual mice of either sex. Gradual vestibular deficits were induced through a dose-dependent ototoxic lesion, quantified with canal or utricular-specific vestibulo-ocular reflex tests, and were then correlated in all individual...

Measuring neurite length is crucial in neurobiology because it provides valuable insights into the growth, development, and function of neurons. In particular, neurite length is fundamental to study neuronal development and differentiation, neurons responses to drugs, neurodegenerative diseases and neuronal plasticity. Surprisingly, there is currently a lack of tools for high-throughput neurite analysis. In this article, we present CABaNe, as an open-source, high-throughput, rule-based ImageJ macro for cell analysis, including their neurite length. This macro possesses a graphical interface, metadata production, as well as verification means before and after analysis. Rule-based and machine learning-based programming have been tested for cell identification. Cell tested were N2A, a mouse neuroblastoma cell line. After testing, we had better precision and adaptability using rule-based cell identification. We challenged CABaNe with currently used techniques, which are manual or assisted. When tested on a sma...

There are a wide variety of commercially available antibodies for labeling microglial cells based on different protein targets, as well as antibodies for the same protein target made in different species. While this array of targets and hosts allows for flexibility in immunohistochemical experiments, it is important to validate that different antibodies provide comparable and accurate immunodetection prior to experimental data collection. We found that a commercially available anti-Iba1 antibody, made in goat, produces irregular staining patterns in specific regions of the mouse brain in both sexes, prompting a further investigation into the phenomenon. This Iba1-goat antibody displayed increased numbers of labeled cells when compared with expression of a CX3CR1-GFP reporter and IHC detection of P2RY12, two common microglial markers. Furthermore, immunodetection by other common anti-Iba1 antibodies made in rabbit and chicken did not display the excessive cell labeling when compared with the CX3CR1-GFP repo...