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...

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...

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 GABAB receptors (GABABRs) 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 GABABR-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 functio...

Galanin-expressing neurons in the ventrolateral preoptic area (VLPOgalanin) are active during sleep and play an important role in regulating non-rapid eye movement (NREM) sleep. It is generally believed that VLPOgalanin neurons promote sleep via inhibitory actions in arousal-promoting regions of the brain. Histaminergic neurons are a population of wake-active neurons that receive strong projections from the sleep-active VLPOgalanin neurons. However, the ability of galanin to influence the activity of histaminergic neurons has received limited attention. Here, using whole-cell patch-clamp electrophysiological recordings from genetically identified histaminergic neurons in male mice, we explore the mechanisms by which galanin influences histaminergic neuron electrical excitability. Our results reveal that galanin is a powerful inhibitor of histaminergic neuron activity and demonstrate that the inhibitory effects of galanin are mediated by galanin receptor 1 (GALR1) and the subsequent opening of G-protein-cou...

Neurite outgrowth is essential for neural circuit formation and is tightly regulated by secreted factors and their receptors. The secreted extracellular domain of the amyloid precursor protein (sAPPα) has been shown to modulate neurite outgrowth. Recently, the gamma amino butyric acid receptor type-B subunit 1a (GABABR1a) was identified as an sAPPα binding partner that mediates its effects on synaptic transmission. Here, we investigated whether this interaction also regulates neurite outgrowth. In mouse primary hippocampal neurons of either sex, the GABABR agonist baclofen reduced axon length; whereas its antagonist CGP54626 increased axon length in primary hippocampal neurons. Moreover, GABABR1a knock-out increased axon length and abolished the effect of baclofen. Application of sAPPα reduced axon length, an effect that required the presence of both GABABR1a and the extension domain of sAPPα, which mediates its binding to GABABR1a. Similarly, the APP 17mer peptide, which is sufficient to bind GABABR1a and...

Blocking is a key statistical method introduced almost a century ago by Ronald Fisher. Blocking controls the effect of “nuisance” variables that are not of direct interest but introduce unwanted variation into the experimental response. Block factors, such as cage, litter, or time, are used to group experimental units into homogeneous subsets. There are two types of block designs: complete and incomplete. In complete block designs every treatment appears in every block. Examples include the Randomized Complete Block Design (RCBD) with a single block factor, and variants such as Latin square and Graeco-Latin square designs with multiple block factors. RCBDs are simple, flexible, and the most widely used. Replicated and nested Latin square designs allow more rigorous control of complex nuisance structures with minimal sample size. Incomplete block designs are extremely useful when practical constraints (e.g., caging density or varying litter sizes) restrict complete treatment replication across all blocks. B...

Behavioral neuroscientists are in the business of linking neuron function to behavior. Historically, single-unit recording has done much of the heavy lifting in this work. Nobel Prize-winning work on the visual system came from experiments such as Hubel and Wiesel (1962), in which 303 cortical neurons were painstakingly recorded across 40 subjects. Single-neuron firing was examined under a wide range of visual conditions. Careful evaluation of single-neuron firing, combined with anatomy and connectivity, uncovered the functional organization of the visual system. “What is my neuron doing?” is one of the most important and powerful questions in behavioral neuroscience. Modern neuroscience has seen a torrent of new tools for monitoring neural activity. Single-unit recording can now track hundreds of neurons per session (Steinmetz et al., 2021; Song et al., 2024). Emerging voltage indicators are providing direct optical readouts of membrane potential in behaving subjects (Hao et al., 2024). Yet no technique ...

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...

Microglia, resident immune sentinels in the brain, are crucial in responding to tissue damage, infection, damage signals like purines (ATP/ADP), and clearing cellular debris. It is currently unknown how microglial reactivity progresses and contributes to seizure development following Theiler's murine encephalomyelitis virus (TMEV) infection. Previously, it has been demonstrated that purinergic signaling in microglia is disrupted in the hippocampus of TMEV-infected mice. However, whether reactive cortical microglia also exhibit changes in purinergic signaling, cytokine levels, and purinergic receptors is unknown. Thus, we seek to evaluate region-based differences in microglial reactivity in the TMEV model. We employed a custom triple transgenic mouse line expressing tdTomato and GCaMP6f under a CX3CR1 Cre promoter and exogenously applied ATP/ADP to acute brain slice preparations from TMEV-infected mice and controls of either sex. Interestingly and in contrast to what is observed in the hippocampus, we found...

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 condi...