Biology subjects

Murdaugh, L. B.

Publications and source records attributed to Murdaugh, L. B..

3 recordsLinked to original sources

bioRxiv2025

Projection-defined ventral tegmental area neurons exhibit distinct fentanyl-induced molecular and functional adaptations that differentially support drug-context associations

RationaleSynthetic opioids like fentanyl are contributing to unprecedented overdose rates, yet the neural circuitry underlying fentanyl-associated behaviors remains poorly understood. The ventral tegmental area (VTA) projects to both the nucleus accumbens (NAc) and prefrontal cortex (PFC), forming distinct pathways that are implicated in drug-cue associations, though their specific roles in fentanyl-context encoding are not well defined. ObjectivesThis study aimed to determine how VTA-NAc and VTA-PFC circuits contribute to fentanyl-context associations, and to assess the role of downstream dopamine receptor signaling in fentanyl context-seeking. MethodsMale and female mice underwent fentanyl conditioned place preference (CPP; 0.2 mg/kg). We locally inhibited dopamine D1 or D2 receptors in NAc or PFC during CPP expression. We used fiber photometry calcium imaging to measure activity in VTA-NAc and VTA-PFC projection neurons, and chemogenetic inhibition to suppress activity during CPP expression. ResultsFentanyl CPP expression was attenuated by blocking D1 but not D2 receptors in PFC, and D2 but not D1 receptors in NAc. We found both VTA-NAc and VTA-PFC exhibited increased calcium activity during fentanyl exposure and during entries to the fentanyl-paired context. We further identified a functional role for VTA-NAc, as chemogenetic inhibition of VTA-NAc, but not VTA-PFC, reduced fentanyl context-seeking. ConclusionsWhile both VTA-NAc and VTA-PFC pathways are recruited by fentanyl exposure, fentanyl context-seeking relies on different downstream dopamine receptors in NAc vs PFC. Further, activity in VTA-NAc functionally supports the expression of fentanyl CPP. Together, these findings indicate that VTA circuits differentially contribute to fentanyl context-seeking.

neuroscience↗

bioRxiv2024

12/15-Lipoxygenases mediate neuropathic-like pain hypersensitivity in female mice

It is estimated that chronic neuropathic pain conditions exhibit up to 10% prevalence in the general population, with increased incidence in females. However, nonsteroidal inflammatory drugs (NSAIDs) are ineffective, and currently indicated prescription treatments such as opioids, anticonvulsants, and antidepressants provide only limited therapeutic benefit. In the current work, we extended previous studies in male rats utilizing a paradigm of central Toll-like receptor 4 (TLR4)-dependent, NSAID-unresponsive neuropathic-like pain hypersensitivity to male and female C57BL/6N mice, uncovering an unexpected hyperalgesic phenotype in female mice following intrathecal (IT) LPS. In contrast to previous reports in female C57BL/6J mice, female C57BL/6N mice displayed tactile and cold allodynia, grip force deficits, and locomotor hyperactivity in response to IT LPS. Congruent with our previous observations in male rats, systemic inhibition of 12/15-Lipoxygenases (12/15-LOX) in female B6N mice with selective inhibitors - ML355 (targeting 12-LOX-p) and ML351 (targeting 15-LOX-1) - completely reversed allodynia and grip force deficits. We demonstrate here that 12/15-LOX enzymes also are expressed in mouse spinal cord and that 12/15-LOX metabolites produce tactile allodynia when administered spinally (IT) or peripherally (intraplantar in the paw, IPLT) in a hyperalgesic priming model, similar to others observations with the cyclooxygenase (COX) metabolite Prostaglandin E2 (PGE2). Surprisingly, we did not detect hyperalgesic priming following IT administration of LPS, indicating that this phenomenon likely requires peripheral activation of nociceptors. Collectively, these data suggest that 12/15-LOX enzymes contribute to neuropathic-like pain hypersensitivity in rodents, with potential translatability as druggable targets across sexes and species using multiple reflexive and non-reflexive outcome measures.

pharmacology and toxicology↗

bioRxiv2024

Examining Cognitive Performance in Mice using the Open-Source Operant Feeding Device FED3

Cognitive impairments are prevalent in various neurological disorders, including chronic pain conditions, and pose significant therapeutic challenges. Preclinical rodent models serve as valuable tools for investigating the underlying mechanisms of and treatments for cognitive dysfunction. However, factors such as stress, age, sex, and disease duration present challenges to reliably capturing cognitive deficits in rodents. Here, we present a comprehensive and high-throughput protocol utilizing the open-source operant Feeding Experimentation Device 3 (FED3) for assessing cognitive performance in mice. We developed a data pipeline to streamline data compilation and analysis, and established operating conditions for a six-test cognitive battery which can be completed in as few as 20 days. We validated our testing procedures using bilateral orbitofrontal cortical lesions to capture deficits in executive function, and demonstrated the feasibility of assessing cognitive function in aged mice of both sexes to identify genotypic and sex-specific effects. Overall, our findings demonstrate that the FED3 is a versatile tool for evaluating cognitive function in mice, offering a low-cost, high-throughput approach for preclinical studies of neurological disorders. We anticipate that this protocol will facilitate broader implementation of cognitive testing in rodent models and contribute to the understanding and treatment of cognitive dysfunction in neurological diseases.

neuroscience↗