Biology subjects

Yakel, J. L.

Publications and source records attributed to Yakel, J. L..

5 recordsLinked to original sources

bioRxiv2026

Diphenhydramine Disrupts Sleep Architecture in 5XFAD Alzheimers Disease Model and Wild-Type Mice

Sleep disruption is common in Alzheimers disease (AD). Diphenhydramine (DPH), a first-generation antihistamine with anticholinergic properties, is widely used as an over-the-counter sleep aid. We tested whether chronic DPH treatment alters sleep architecture in 5XFAD and wild-type mice. Female 5XFAD (n=16) and wild-type (WT) littermates (n=14) were implanted with wireless telemetry recording devices to measure electroencephalography (EEG), electromyography (EMG), temperature, and activity continuously. After a 24h baseline recording at 5 months of age, mice received oral DPH (10 mg/kg) or vehicle at ZT0 for one month. After this chronic treatment, sleep was recorded continuously for 48h during ongoing dosing. Sleep was scored as rapid eye movement (REM), non-rapid eye movement (NREM) 1, NREM2, or wake. A survival curve analysis was used to investigate the microarchitecture of sleep phases after chronic diphenhydramine treatment. At baseline, 5XFAD mice had more time in NREM1 than WT controls and had shorter REM and NREM2 bouts. Chronic DPH treatment fragmented NREM2 in both genotypes, reducing long NREM2 bouts. DPH increased total duration of NREM1 and REM during the active phase, which is analogous to daytime drowsiness in humans. DPH did not rescue 5XFAD sleep deficits; instead, DPH treatment exacerbated NREM2 fragmentation. Overall, chronic DPH use degrades sleep quality and increases fragmentation in both WT and AD-model mice, which questions the use of sedating anticholinergics as sleep aids, especially in AD.

neuroscience↗

bioRxiv2025

Mesoscopic analysis of GABAergic marker expression in acetylcholine neurons in the whole mouse brain

In the central nervous system, acetylcholine (ACh) neurons coordinate neural network activity required for higher brain functions, such as attention, learning, and memory, as well as locomotion. Disturbances in cholinergic signaling have been described in many diseases of the developing and mature brain. Interestingly, ACh neurons can co-transmit GABA to support essential roles in brain function. However, the contributions of ACh/GABA co-transmission to brain function remain unclear. This underscores the need to better understand the heterogeneity of ACh neurons, particularly the sub-population of ACh neurons co-expressing GABAergic markers. We used various combinations of transgenic mouse lines to systematically label ACh neuron populations positive for different GABAergic markers in the brain. We developed a workflow combining tissue clearing, light-sheet fluorescence microscopy, and machine learning to image entire mouse brain hemispheres followed by quantification of ACh neurons throughout the brain. With this approach, we assessed the role of GABA co-transmission in ACh neuron function and quantified ACh and ACh/GABA neuron sub-populations in the brain. Our results suggest that GABA co-transmission from ACh neurons is not required to maintain the regular ACh neuron count in the brain. Furthermore, we report that a large subset of ACh neurons can potentially synthesize GABA by co-expressing the marker Gad2. However, most of these ACh neurons do not express vGAT, which would enable these neurons to release GABA. Taken together, we conclude that GABA co-transmission likely occurs only from a small population of ACh neurons restricted to few brain nuclei. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/675394v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1dc5915org.highwire.dtl.DTLVardef@15c872borg.highwire.dtl.DTLVardef@1ae3993org.highwire.dtl.DTLVardef@145f32b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Proteomic Analysis of Endemic Viral Infections in Neuronsoffers Insights into Neurodegenerative Diseases

Endemic viral infections with low pathogenicity are often overlooked due to their mild symptoms, yet they can exert long-term effects on cellular function and contribute to disease pathogenesis. While viral infections have been implicated in neurodegenerative disorders, their impact on the neuronal proteome remains poorly understood. Here, we differentiated human induced pluripotent stem cells (KOLF2.1J) into mature neurons to investigate virus-induced proteomic changes following infection with five neurotropic endemic human viruses: Herpes simplex virus 1 (HSV-1), Human coronavirus 229E (HCoV-229E), Epstein-Barr virus (EBV), Varicella-Zoster virus (VZV), and Influenza A virus (H1N1). Given that these viruses can infect adults and have the potential to cross the placental barrier, their molecular impact on neurons may be relevant across the lifespan. Using mass spectrometry-based proteomics with a customized library for simultaneous detection of human and viral proteins, we confirmed successful infections and identified virus-specific proteomic signatures. Notably, virus-induced protein expression changes converged on key neuronal pathways, including those associated with neurodegeneration. Gene co-expression network analysis identified protein modules correlated with viral proteins. Pathway enrichment analysis of these modules revealed associations with the nervous system, including pathways linked to Alzheimers and Parkinsons disease. Remarkably, several viral-induced proteomic alterations overlapped with changes observed in postmortem Alzheimers patient brains, suggesting a mechanistic connection between viral exposure and neurodegenerative disease progression. These findings provide molecular insights into how common viral infections perturb neuronal homeostasis and may contribute to neurodegenerative pathology, highlighting the need to consider endemic viruses as potential environmental risk factors in neurological disorders.

neuroscience↗

bioRxiv2022

Loss of GABA co-transmission from cholinergic neurons impairs behaviors related to hippocampal, striatal, and medial prefrontal cortex functions

Altered signaling or function of acetylcholine (ACh) has been reported in various neurological diseases, including Alzheimers disease, Tourette syndrome, epilepsy among others. Many neurons that release ACh also co-transmit the neurotransmitter gamma-aminobutyrate (GABA) at synapses in the hippocampus, striatum, and medial prefrontal cortex (mPFC). Although ACh transmission is crucial for higher brain functions such as learning and memory, the role of co-transmitted GABA from ACh neurons in brain function remains unknown. Thus, the overarching goal of this study was to investigate how a systemic loss of GABA co-transmission from ACh neurons affected the behavioral performance of mice. To do this, we used a conditional knock-out mouse of the vesicular GABA transporter (vGAT) crossed with the ChAT-Cre driver line to selectively ablate GABA co-transmission at ACh synapses. In a comprehensive series of standardized behavioral assays, we compared Cre-negative control mice with Cre-positive vGAT knock-out mice of both sexes. Loss of GABA co-transmission from ACh neurons did not disrupt the animals sociability, motor skills or sensation. However, in the absence of GABA co-transmission, we found significant alterations in social, spatial and fear memory as well as a reduced reliance on striatum-dependent response strategies in a T-maze. In addition, male CKO mice showed increased locomotion. Taken together, the loss of GABA co-transmission leads to deficits in higher brain functions and behaviors. Therefore, we propose that ACh/GABA co-transmission modulates neural circuitry involved in the affected behaviors.

neuroscience↗

bioRxiv2020

Loss of α7 nicotinic acetylcholine receptors in GABAergic interneurons causes sex-dependent impairments in postnatal neurogenesis and cognitive and social behavior

Neural stem cells within the subgranular zone of the dentate gyrus (DG) generate new neurons that form the granule cell layer during embryonic development and continue to generate new neurons throughout life. The maturation process of newly generated granule cells is modulated by nicotinic acetylcholine receptors (nAChRs), which have been shown to play a role in cell survival, signal modulation, dendritic integration, and memory formation. Disrupted nAChR signaling has been implicated in neuropsychiatric and neurodegenerative disorders, potentially via alterations in DG neurogenesis. GABAergic interneurons are known to express nAChRs, particularly the 7 subunit, and have been shown to shape development, integration, and circuit reorganization of DG granule cells. Therefore, we examined the effects of conditional deletion of 7 nAChRs in GABAergic interneurons on measures of postnatal neurogenesis and behavioral outcomes. Loss of 7 nAChRs resulted in a decrease of postnatal granule cells, as indicated by reduced GFAP+ cells in the DG, specifically in male mice, as well as sex-dependent changes in several behaviors, including social recognition, object investigation, and spatial learning. Overall, these findings suggest 7 nAChRs expressed in GABAergic interneurons play an important role in regulating postnatal neurogenesis and behavior in a sex-dependent manner. This provides important insight into the mechanisms by which cholinergic dysfunction contributes to the cognitive and behavioral changes associated with neurodevelopmental and neurodegenerative disorders.

animal behavior and cognition↗