Kmiec, G. | bioRxiv Science

bioRxiv2025

Loss of excitatory inputs and decreased tonic and evoked activity of locus coeruleus neurons in aged P301S mice

Tau pathology in the locus coeruleus (LC) is associated with several neurodegenerative conditions including Alzheimers disease and frontotemporal dementia. Phosphorylated tau accumulates in the LC and results in inflammation, synaptic loss, and eventually cell death as the disease progresses. Loss of LC neurons and noradrenergic innervation is thought to contribute to the symptoms of cognitive decline later in disease. While loss and degeneration of LC neurons has been well studied, less is known about changes in LC physiology at advanced stages of tau pathology that precedes neurodegeneration. In this study, we investigated the ex vivo electrophysiological properties of LC neurons in male and female mice from the P301S mouse model of tauopathy at 9 months of age, a time-point when significant tau accumulation, cell death, and cognitive impairments are observed. We found a reduction in excitatory inputs and changes in excitatory post-synaptic current kinetics in male and female P301S. There was also a decrease in spontaneous discharge of LC neurons and an increase in AP threshold in P301S mice of both sexes. Finally, we observed a decrease in excitability and increase in rheobase current in P301S mice. Despite the decrease in LC activity in slice, we did not identify differences in total tissue norepinephrine (NE) or NE metabolites in prefrontal cortex or hippocampus. Together these findings demonstrate reductions in the activity and excitability of LC neurons at late stages of tau accumulation. However, compensatory mechanisms may maintain normal NE levels in LC projection regions in vivo.

neuroscience↗

bioRxiv2023

Oral Fentanyl Consumption Alters Sleep Rhythms, Promotes Avoidance Behaviors, and Impairs Fear Extinction Learning in Male and Female Mice

The number of opioid overdose deaths has increased over the past several years, mainly driven by an increase in the availability of highly potent synthetic opioids, like fentanyl, in the un-regulated drug supply. Over the last few years, changes in the drug supply, and in particular the availability of counterfeit pills containing fentanyl, have made oral use of opioids a more common route of administration. Here, we used a drinking in the dark (DiD) paradigm to model oral fentanyl self-administration using increasing fentanyl concentrations in male and female mice over 5 weeks. Fentanyl consumption peaked in both female and male mice at the 30 {micro}g/mL dose, with female mice consuming significantly more fentanyl than male mice. Mice consumed sufficient fentanyl such that withdrawal was precipitated with naloxone, with males having more withdrawal symptoms, despite lower pharmacological exposure. We also performed behavioral assays to measure avoidance behavior and reward-seeking during fentanyl abstinence. Female mice displayed reduced avoidance behaviors in the open field assay, whereas male mice showed increased avoidance in the light/dark box assay. Female mice also exhibited increased reward-seeking in the sucrose preference test. Fentanyl-consuming mice of both sexes showed impaired cued fear extinction learning following fear conditioning and increased excitatory synaptic drive and increased excitability of BLA principal neurons. Our experiments demonstrate that long-term oral fentanyl consumption results in wide-ranging physiological and behavioral disruptions. This model could be useful to further study fentanyl withdrawal syndrome and behaviors and neuroplasticity associated with protracted fentanyl withdrawal.

neuroscience↗