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...

Auditory-evoked EEG signals contain rich temporal and cognitive features that reflect both the identity of individuals and their neural response to external stimuli. Traditional unimodal approaches often fail to fully leverage this multidimensional information fully, limiting their effectiveness in real-world biometric and neurocognitive applications. This study aims to develop a unified deep learning model capable of jointly performing biometric identification, auditory stimulus language classification, and device modality recognition, thereby exploiting both physiological and cognitive dimensions of auditory-evoked EEG. We introduce TriNet-MTL (Triple-Task Neural Transformer for Multitask Learning), a multi-branch deep learning framework composed of a shared temporal encoder and a transformer-based sequence modeling unit, trained and validated on auditory-evoked EEG data from 20 human participants (16 males and 4 females). The architecture is designed to simultaneously learn task-specific features via th...

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...

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 ...

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 re...

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...

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 MS...

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 Image J 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 sm...