eNeuro最新文献

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 sociability remained entirely normal. Changes in social novelty preference were completely independent of individual differences in spatial memory and unrelated to anxiety or sensorimotor function. Notably, neuromodulation via TMS enhanced social novelty preference selectively in aged rats that exhibited a social introversion phenotype before treatment, consistent with the possibility that this aging condition reflects a distinct and modifiable neural network state. Together, the results establish a valuable preclinical framework for developing a comprehensive neurobiology of social cognition in aging.

Cognitive flexibility, a mental process crucial for adaptive behavior, involves multiscale functioning across several neuronal organization levels. While its neural underpinnings have been studied for decades, limited knowledge exists about the structure and age-related differentiation of the white matter (WM) subserving brain regions implicated in cognitive flexibility. This study investigated the population-level relationship between cognitive flexibility and WM properties across two periods of human adulthood, aiming to discern how these associations vary over different life stages and brain tracts among men and women. We propose a novel framework to study age effects in brain structure-function associations. First, a meta-analysis was conducted to identify neural regions associated with cognitive flexibility. Next, projections of these neural regions were traced through the Human Connectome Project tractography template to identify the subserving WM associated with cognitive flexibility. Then, a cohort analysis was performed to characterize myelin-related macromolecular features using a subset of the UK Biobank magnetic resonance imaging (MRI) data, which has a companion functional/behavioral dataset. We found that (1) the wiring of cognitive flexibility is defined by a subset of brain tracts, which present undifferentiated features early in adulthood and significantly differentiated types in later life. (2) These MRI-derived properties are correlated with individual subprocesses of cognition closely related to cognitive flexibility. (3) In late life, homogeneity of specific WM tracts implicated in cognitive flexibility declines with age, a phenomenon not observed in early life. Our findings support the age-related differentiation of WM implicated in cognitive flexibility as a natural substrate of adaptive cognitive function.

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 molecular diversity and specialization of Nrxns.

Natural environments contain behaviorally relevant information along many stimulus dimensions, each of which sensory systems must encode in order to guide behaviors. For example, the mammalian visual cortex encodes features of visual scenes such as spatial information related to object identity and temporal information about the motion of those objects in space. In order to reliably encode these behaviorally relevant visual features, neural representations should be robust to changes in environmental conditions. Further, information about changes in environmental conditions, such as the luminance changes that occur over the course of a day, is also important for guiding behaviors. In this study, we asked whether mouse primary visual cortex (V1) jointly represents the spatial properties of visual stimuli along with changes in the mean luminance of the visual scene. We find that while V1 neurons, in mice of either sex, encode spatial aspects of visual information in an invariant manner across luminance conditions, the V1 population response also contains a robust representation of luminance. Importantly, V1 populations encode changes in stimulus orientation and mean luminance along orthogonal axes in the neural response space, such that a change in one stimulus variable is encoded independently from the other.

Dementia-causing diseases, including Alzheimer's disease (AD), are one of the greatest health concerns facing the aging world population. A key feature of AD is excessive accumulation of amyloid-beta, leading to synapse and cell loss in brain structures, such as the hippocampus. This neurodegeneration is preceded by impaired neuron function, notably reduced synaptic inhibition. Metabotropic GABA_B receptors (GABA_BRs) may be modulated by amyloid precursor protein (APP) and are reported to be progressively lost from neuronal membranes of hippocampal pyramidal neurons. However, it remains unknown whether functional GABA_BR-mediated signaling changes over aging and whether or not pharmacological intervention can prevent receptor loss. In this study, we combine electrophysiological and biochemical analysis of hippocampal neurons in the Amyloid Precursor Protein/Presenilin-1 (APP/PS1) mouse model of AD from acute brain slices and organotypic slice cultures prepared from male and female mice to determine if functional GABA_BRs are lost and the effect of pharmacological modulation. Overall, we found that GABA_BR expression decreased with age, independent of genotype, with no evidence for postsynaptic GABA_BR loss in CA1 pyramidal cells at any age. We did observe a genotype-dependent reorganization of postsynaptic GABA_BR-mediated IPSCs, which was independent of age. Presynaptic GABA_BR-mediated inhibition was impaired in APP/PS1 mice, also independent of age. We observed that chronic GABA_BR modulation differentially regulated function but was independent of genotype. Overall, our data show that functional GABA_BR signaling is altered in APP/PS1 mice, independent of age, increasing our understanding of amyloidopathy-induced dysfunction.

The dorsomedial striatum (DMS) is critical for both motivating and inhibiting behavioral responses. The region integrates inputs from the cortex, thalamus, and other subcortical structures including midbrain dopamine neurons. Though less studied, serotonin neurons from the dorsal raphe nucleus also richly innervate the DMS, which expresses nearly all 14 serotonin receptor subtypes. Slice electrophysiology shows that the serotonin 1B receptor (5-HT1BR) impacts DMS physiology and plasticity, and behavioral experiments show that 5-HT1BR expression modulates impulsivity and other DMS-dependent reward-related behaviors. In these studies, our goal was to investigate the effects of 5-HT1BR on the DMS in vivo. Using a genetic 5-HT1BR loss-of-function mouse model, we examined calcium activity of individual medium spiny neurons (MSNs) in the DMS of both males and females during operant tasks focusing on responses to actions, reward, and waiting. We found that knock-out of 5-HT1BRs resulted in different effects on MSN calcium activity depending on behavioral state. Specifically, mice lacking 5-HT1BRs showed significantly more inhibition of MSN calcium activity during the rewards, but more cells with excitatory calcium responses during the delay period of the trial. This suggests that serotonin, acting via 5-HT1BRs, may recruit MSN activity in response to reward but inhibit MSN activity during waiting. These results highlight the importance of in vivo studies for understanding the functional role of DMS serotonin in reward-related behavior. Overall our results demonstrate that serotonin can modulate the DMS in a behavioral state-specific manner, potentially providing a mechanism for how serotonin effects on behavior are context dependent.

Gamma oscillations (40-140 Hz) play a fundamental role in neural coordination and cognitive functions in the medial entorhinal cortex (mEC). While previous studies suggest that pyramidal-interneuron network gamma (PING) and interneuron network gamma (ING) mechanisms contribute to these oscillations, the precise role of inhibitory circuits remains unclear. Using optogenetic stimulation and whole-cell electrophysiology in acute mouse brain slices, we examined synaptic input and spike timing in neurons across layer II/III mEC. We found that fast-spiking interneurons exhibited robust gamma-frequency firing, while excitatory neurons engaged in gamma cycle skipping. Stellate and pyramidal cells received minimal recurrent excitation, whereas fast-spiking interneurons received strong excitatory input. Both excitatory neurons and fast-spiking interneurons received gamma-frequency inhibition, emphasizing the role of recurrent inhibition in gamma rhythms. Gamma activity was reduced but persisted after AMPA/kainate receptor blockade, indicating that interneurons can sustain oscillations via an ING mechanism. Selective activation of PV+ interneurons confirmed their ability to sustain fast gamma inhibition autonomously. To further assess the interplay of excitation and inhibition, we developed computational network models constrained by our experimental data. Simulations revealed that weak excitatory input to interneurons supports fast ING-dominated rhythms (∼100-140 Hz) while strengthening excitatory drive induces a transition to slower PING-dominated oscillations (60-100 Hz), although this regime shift was not observed consistently after AMPA/kainate receptor block. These findings highlight the dominant role of inhibitory circuits in sustaining gamma rhythms, demonstrate how excitation strength tunes the oscillatory regime, and refine models of entorhinal gamma oscillations critical for spatial memory processing.

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 shear stress varied across age and AD models. Mean velocity and pulsatility index varied across age and AD. Liquid chromatography-mass spectrometry of brain tissue revealed several lipids that were statistically different between age and AD, and matrix-assisted laser desorption/ionization MS imaging revealed region-specific differences between groups. Combining both ultrasound and mass spectrometry, we were able to detect significant changes in the vascular biomechanics of neck vasculature prior to observing significant changes in the brain biochemistry. Our work revealed significant vascular differences in the 3xTg compared with controls and, to our knowledge, is the first to study vascular biomechanics via ultrasound in the 3xTg AD mouse model.

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 differential effects on externally guided and self-generated timing.