Biology subjects

Cushman, J. D.

Publications and source records attributed to Cushman, J. D..

9 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↗

bioRxiv2026

Immune receptor LAG3 regulates microglia function duringAlzheimer's disease

Alzheimers Disease (AD) remains the leading cause of dementia globally, yet the exact etiology is not well defined and effective treatments remain unavailable. Here, we report that deletion of the immune checkpoint receptor lymphocyte activation gene 3 (Lag3) in a familial AD mouse model, 5xFAD+, can rescue molecular, cellular and behavioral phenotypes of neurodegeneration. Specifically, we demonstrate that amyloidosis and microgliosis in the 5xFAD+ mice are significantly reduced by Lag3 deletion. Moreover, we show that Lag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes in the 5xFAD+ mice. Transcriptional profiling reveals that Lag3 deletion suppresses aberrant overexpression of disease associated microglia (DAM) genes in 5xFAD+ microglia, effectively restoring homeostatic transcriptional programs. Finally, we observe reduced CD8+ T cell infiltration in the brain of 5xFAD+ animals after Lag3 deletion which likely mediates molecular, cellular and behavioral effects resulting from microglia DAM gene activation. Our results highlight a previously unrecognized role for Lag3 in AD as a critical regulator of microglia function and suggest Lag3 might be a viable target for novel AD therapeutic interventions. HighlightsO_LIImmune receptor Lag3 deletion ameliorates amyloidosis and microgliosis during AD C_LIO_LILag3 deletion attenuates deficits in neurodegeneration-related behavioral phenotypes C_LIO_LILag3 deletion reverses aberrant activation of DAM genes and restores microglia homeostasis C_LIO_LILag3 inhibition presents a viable approach for novel AD therapeutic interventions C_LI

neuroscience↗

bioRxiv2023

FiPhA: An Open-Source Platform for Fiber Photometry Analysis

SignificanceFiber photometry is a widely used technique in modern behavioral neuroscience, employing genetically encoded fluorescent sensors to monitor neural activity and neurotransmitter release in awake-behaving animals, However, analyzing photometry data can be both laborious and time-consuming. AimWe propose the FiPhA (Fiber Photometry Analysis) app, which is a general-purpose fiber photometry analysis application. The goal is to develop a pipeline suitable for a wide range of photometry approaches, including spectrally resolved, camera-based, and lock-in demodulation. ApproachFiPhA was developed using the R Shiny framework and offers interactive visualization, quality control, and batch processing functionalities in a user-friendly interface. ResultsThis application simplifies and streamlines the analysis process, thereby reducing labor and time requirements. It offers interactive visualizations, event-triggered average processing, powerful tools for filtering behavioral events and quality control features. ConclusionsFiPhA is a valuable tool for behavioral neuroscientists working with discrete, event-based fiber photometry data. It addresses the challenges associated with analyzing and investigating such data, offering a robust and user-friendly solution without the complexity of having to hand-design custom analysis pipelines. This application thus helps standardize an approach to fiber photometry analysis.

neuroscience↗

bioRxiv2023

Partial or complete loss of norepinephrine differentially alters contextual fear and catecholamine release dynamics in hippocampal CA1

Contextual fear learning is heavily dependent on the hippocampus. Despite evidence that catecholamines contribute to contextual encoding and memory retrieval, the precise temporal dynamics of their release in the hippocampus during behavior is unknown. In addition, new animal models are required to probe the effects of altered catecholamine synthesis on release dynamics and contextual learning. Utilizing GRABNE and GRABDA sensors, in vivo fiber photometry, and two new mouse models of altered locus coeruleus norepinephrine (LC-NE) synthesis, we investigate norepinephrine (NE) and dopamine (DA) release dynamics in dorsal hippocampal CA1 during contextual fear conditioning. We report that aversive foot-shock increases both NE and DA release in dorsal CA1, while freezing behavior associated with recall of fear memory is accompanied by decreased release. Partial loss of LC-NE synthesis reveals that NE release dynamics are modulated by sex. Moreover, we find that recall of recent fear memory is sensitive to both partial and complete loss of LC-NE synthesis throughout prenatal and postnatal development, similar to prior observations of mice with global loss of NE synthesis beginning postnatally. In contrast, remote recall is compromised only by complete loss of LC-NE synthesis beginning prenatally. Overall, these findings provide novel insights into the role of NE in contextual fear and the precise temporal dynamics of both NE and DA during freezing behavior, and highlight a complex relationship between genotype, sex, and NE signaling.

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↗

bioRxiv2021

Hippocampal representations of distance, space, and direction and their plasticity predict navigational performance

The hippocampus is implicated in episodic memory and allocentric spatial navigation. However, spatial selectivity is insufficient to navigate; one needs information about the distance and direction to the reward on a specific journey. The nature of these representations, whether they are expressed in an episodic-like sequence, and their relationship with navigational performance are unknown. We recorded single units from dorsal CA1 of the hippocampus while rats navigated to an unmarked reward zone defined solely by distal visual cues, similar to the classic water maze. The allocentric spatial selectivity was substantially weaker than in typical real world tasks, despite excellent navigational performance. Instead, the majority of cells encoded path distance from the start of trials. Cells also encoded the rats allocentric position and head angle. Often the same cells multiplexed and encoded path distance, head direction and allocentric position in a sequence, thus encoding a journey-specific episode. The strength of neural activity and tuning strongly correlated with performance, with a temporal relationship indicating neural responses influencing behavior and vice versa. Consistent with computational models of associative Hebbian learning, neural responses showed increasing clustering and became better predictors of behaviorally relevant variables, with neurometric curves exceeding and converging to psychometric curves. These findings demonstrate that hippocampal neurons multiplex and exhibit highly plastic, task- and experience-dependent tuning to path-centric and allocentric variables to form an episode, which could mediate navigation.

neuroscience↗

bioRxiv2020

Mutations on a novel brain-specific isoform of PGC1α leads to extensive upregulation of neurotransmitter-related genes and sexually dimorphic motor deficits in mice

The peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC1) is known as a transcriptional co-activator in peripheral tissues but its function in the brain remains poorly understood. Various brain-specific Pgc1 isoforms have been reported in mice and humans, including transcripts derived from a novel promoter about [~]580 Kb upstream from the reference gene. These isoforms incorporate repetitive sequences from the simple sequence repeat (SSR) and short interspersed nuclear element (SINE) classes and are predicted to give rise to proteins with distinct amino-termini. In this study, we show that a SINE-containing isoform is the predominant form of Pgc1 expressed in neurons. We then generated a mouse carrying a mutation within the SINE to study its functional role in the brain. By combining genomics, biochemical and behavioural approaches, we show that this mutation leads to impaired motor coordination in females, but not male mice, associated with the upregulation of hundreds of cerebellar genes. Moreover, our analysis suggests that known nuclear receptors interact with this isoform of PGC1 in the brain to carry out the female transcriptional program. These data expand our knowledge on the role of Pgc1 in the brain and help explain its conflicting roles in neurological disease and behavioural outcomes.

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↗

bioRxiv2019

A role for the locus coeruleus in the modulation of feeding

Recent data suggest that LC-NE neurons play a role in fear-induced suppression of feeding, but their endogenous activity in naturally behaving animals has not been explored. We found that endogenous activity of LC-NE neurons was enhanced during food approach and suppressed during food consumption, and that these food-evoked LC-NE responses were attenuated in sated mice. Interestingly, visual-evoked LC-NE activity was also attenuated in sated mice, demonstrating that internal satiety state modulates LC-NE encoding of multiple behavioral states. We also found that food intake could be attenuated by brief or longer durations of LC-NE activation. Lastly, we demonstrated that activation of LC neurons suppresses feeding and enhances avoidance and anxiety-like responding through a projection to the lateral hypothalamus. Collectively, our data suggest that LC-NE neurons modulate feeding by integrating both external cues (e.g., anxiogenic environmental cues) and internal drives (e.g., nutritional state).

neuroscience↗