Biology subjects

Bonaventura, J.

Publications and source records attributed to Bonaventura, J..

6 recordsLinked to original sources

bioRxiv2024

Dopamine dynamics in chronic pain: music-induced sex-dependent behavioral effects in mice

1Chronic pain is a debilitating disease that is usually comorbid to anxiety and depression. Current treatment approaches primarily rely on analgesics, but they often neglect emotional aspects. Non-pharmacological interventions have been incorporated into clinics to provide a more comprehensive management of chronic pain. Among these interventions, listening to music is a well-accepted and cost-effective option. However, the underlying mechanisms of music-mediated pain relief remain insufficiently understood. Here, our aim was to evaluate the effects of music exposure in an animal model of chronic pain. First, we injected mice with the inflammatory agent complete Freunds adjuvant (CFA) into the hind paw and housed them for 14 days with background music during their active period (Mozart K.205, overnight), or silence. The impact of music exposure on nociception and anxiety-like and depression-like behaviors was evaluated through different paradigms, including the hot plate, Von Frey, elevated plus maze, splash, and tail suspension tests. Additionally, we investigated whether music influences dopamine dynamics in the nucleus accumbens (NAcc), a pivotal region involved in pain processing, anhedonia, and reward. Our findings indicate that music exposure prevents the decreased NAcc activity observed in CFA-injected mice, linking with a sex-dependent reduction of allodynia, anxiety- and depression-like behaviors. Thus, females were more sensitive to music exposure. Collectively, our findings provide compelling evidence for the integration of music listening as a non-pharmacological intervention in chronic pain conditions. Moreover, the observed impact on the NAcc suggests its potential as a therapeutic target for addressing chronic pain and its associated symptoms.

neuroscience↗

bioRxiv2023

In vivo photopharmacology with light-activated opioid drugs

Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed PhOX and PhNX, photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry during chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action. HighlightsA photoactivatable opioid agonist (PhOX) and antagonist (PhNX) for in vivo photopharmacology. Systemic pro-drug delivery followed by local photoactivation in the brain. In vivo photopharmacology produces behavioral changes within seconds of photostimulation. In vivo photopharmacology enables all-optical pharmacology and physiology.

neuroscience↗

bioRxiv2022

Backscattering Mueller Matrix polarimetry on whole brain specimens shows promise for minimally invasive mapping of microstructural orientation features

Understanding microscale physiology and microstructural cellular features of the brain is key to understanding the mechanisms of neurodegenerative diseases and injury, as well as the prominent changes that neurons and glia in the brain undergo in development and aging which reflect functional state. Non-invasive imaging modalities sensitive to the microscale - especially diffusion magnetic resonance imaging (dMRI) - are extremely promising for three-dimensional mapping of cellular microstructure of brain tissues and brain connectivity via tractography; however, there is a need for robust validation techniques to verify and improve the biological accuracy of fiber orientation information derived from these techniques. Recent advances in dMRI acquisition and modeling have moved toward probing of the more complex grey matter architecture, challenging current validation techniques, which are largely based on ex vivo staining and microscopy focusing on white matter. Polarized light imaging (PLI) has been shown to be a successful technique for high resolution, direct, microstructural imaging and has been applied to dMRI validation with clear advantages over conventional staining and microscopy techniques. Conventionally, PLI is applied to thin, sectioned samples in transmission mode, but unlike histologic staining, PLI can be extended to operate with high sensitivity in reflectance mode and even extended to 3D imaging to bridge the gap toward in vivo validation of dMRI measurements of orientation features in both gray and white matter of the brain. In this report we investigate the use of backscattering Mueller Matrix polarimetry to characterize the microstructural content of intact Ferret brain specimens. The experimental results show that backscattering polarimetry can probe white matter fiber coherence and fiber orientation in whole brain specimens, and show promise for probing grey matter microstructure. Ultimately, these preliminary results motivate further study to fully understand how backscattering polarimetry can best be used for validation of in vivo microstructural imaging of the brain.

bioengineering↗

bioRxiv2022

The SARS-CoV-2 spike protein binds and modulates estrogen receptors

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike (S) protein binds angiotensin-converting enzyme 2 (ACE2) at the cell surface, which constitutes the primary mechanism driving SARS-CoV-2 infection. Molecular interactions between the transduced S and endogenous proteins likely occur post-infection, but such interactions are not well understood. We used an unbiased primary screen to profile the binding of full-length S against >9,000 human proteins and found significant S-host protein interactions, including one between S and human estrogen receptor alpha (ER). After confirming this interaction in a secondary assay, we used bioinformatics, supercomputing, and experimental assays to identify a highly conserved and functional nuclear receptor coregulator (NRC) LXD-like motif on the S2 subunit and an S-ER binding mode. In cultured cells, S DNA transfection increased ER cytoplasmic accumulation, and S treatment induced ER-dependent biological effects and ACE2 expression. Noninvasive multimodal PET/CT imaging in SARS-CoV-2-infected hamsters using [18F]fluoroestradiol (FES) localized lung pathology with increased ER lung levels. Postmortem experiments in lung tissues from SARS-CoV-2-infected hamsters and humans confirmed an increase in cytoplasmic ER expression and its colocalization with S protein in alveolar macrophages. These findings describe the discovery and characterization of a novel S-ER interaction, imply a role for S as an NRC, and are poised to advance knowledge of SARS-CoV-2 biology, COVID-19 pathology, and mechanisms of sex differences in the pathology of infectious disease.

immunology↗

bioRxiv2020

Zinc potentiates dopamine neurotransmission and cocaine seeking

Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn2+ concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn2+ content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn2+ concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn2+ were dependent on the Zn2+ transporter 3 (ZnT3), a neuronal Zn2+ transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn2+. ZnT3 KO mice showed significantly lower electrically-evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn2+ deficiency in mice resulted in decreased striatal Zn2+ content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn2+ release and turnover/metabolism in the striatum, and that synaptically-released Zn2+ potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaines pharmacological mechanism of action and suggest that Zn2+ may serve as an environmentally-derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.

neuroscience↗

bioRxiv2018

Chemogenetic ligands for translational neurotheranostics

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a popular chemogenetic technology for manipulation of neuronal activity in uninstrumented awake animals with potential for precision medicine-based clinical theranostics. DREADD ligands developed to date are not appropriate for such translational applications. The prototypical DREADD agonist clozapine N-oxide (CNO) lacks brain entry and converts to clozapine. The second-generation DREADD agonist, Compound 21 (C21), was developed to overcome these limitations. We found that C21 has low brain penetrance, weak affinity, and low in vivo DREADD occupancy. To address these drawbacks, we developed two new DREADD agonists, JHU37152 and JHU37160, and the first dedicated positron emission tomography (PET) DREADD radiotracer, [18F]JHU37107. JHU37152 and JHU37160 exhibit high in vivo DREADD potency. [18F]JHU37107 combined with PET allows for DREADD detection in locally-targeted neurons and at their long-range projections, enabling for the first time, noninvasive and longitudinal neuronal projection mapping and potential for neurotheranostic applications.

neuroscience↗