Biology subjects

Lopez, M. F.

Publications and source records attributed to Lopez, M. F..

7 recordsLinked to original sources

bioRxiv2025

Tirzepatide attenuates dopamine reward signaling and suppresses alcohol drinking and relapse-like behaviors in rodents

Alcohol use disorder (AUD) remains a major public health problem, with few effective medications currently available. However, peptides of the gut-brain axis appear to offer promising therapeutic targets for AUD as they influence the mesolimbic reward circuitry. Here, we examined the effects of tirzepatide, a long-acting dual glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) agonist approved for diabetes and obesity, using behavioral assays, alcohol intake paradigms, and molecular analyses in rodents. First, tirzepatide effectively attenuated the rewarding properties of alcohol, measured through locomotor stimulation, conditioned place preference, and accumbal dopamine release. Subsequently, this GLP-1R/GIPR agonist dose-dependently reduced voluntary alcohol consumption, prevented binge and relapse-like drinking, and maintained efficacy during repeated administration. Finally, tirzepatide induced sustained synaptic depression in the lateral septum and further altered histone regulatory proteins in this region, suggesting a potential neural substrate for its effects. Moreover, the GLP-1R/GIPR agonist affected metabolic parameters including body weight, adipose tissue mass, hepatic triglycerides and circulating pro-inflammatory cytokines. Together, our findings suggest tirzepatide modulates alcohol-related behaviors through reward-related mechanisms while also affecting physiological consequences associated with long-term alcohol use. Given tirzepatides established clinical use and the consistency of effects observed here, these results support further investigation for treating AUD and associated complications. SIGNIFICANCE STATEMENTExisting treatments for alcohol use disorder show limited effectiveness, leaving patients without viable therapeutic options. We demonstrate that tirzepatide, a long-acting gut peptide-based drug already approved for diabetes and obesity, substantially reduces alcohol consumption and prevents relapse-like behavior across multiple preclinical models. Tirzepatide appears to work by influencing brain reward systems while simultaneously affecting metabolic complications common in alcohol disorders. Given tirzepatides clinical availability, these findings suggest repurposing a recently approved drug to tackle one of medicines more persistent treatment challenges.

neuroscience↗

bioRxiv2022

Flexible IrOx Neural Electrode for Mouse Vagus Nerve Stimulation

Vagus nerve stimulation (VNS) is being actively explored as a treatment for multiple conditions as part of bioelectronic medicine research. Reliable and safe VNS in mouse models is a critical need for understanding mechanisms of these. We report on the development and evaluation of a microfabricated cuff electrode (MouseFlex) constructed of polyimide (PI) and with iridium oxide (IrOx) electrodes that is thermoformed to 86 {micro}m {+/-} 12 {micro}m radius to interface the mouse cervical vagus nerve (r {approx} 50 {micro}m). Innovative bench-top methods were used to evaluated the stimulation stability and electrochemical properties of electrodes. Our aggressive stimulation stability (Stim-Stab) test utilized 1 billion pulses at a 1000 Hz with a current density of 6.28 A/cm2 (1.51 mC/cm2/phase) to evaluate electrode lifetimes, and all electrodes remained functional. We also investigated the effects of thermoforming on their impedance, charge storage capacity (CSC), and charge injection capacity (CIC). The modest changes in electrochemical properties indicate that the thermoforming process was well tolerated. Thermoformed electrode safety and efficacy were evaluated in-vivo by performing acute VNS in mice and monitoring their heart and respiration rate as biomarkers. Their electrochemical properties were also measured before, during and after VNS. Bradycardia and bradypnea were reliably induced at stimulation currents of 100 to 200 {micro}A, well below the in-vivo CIC of ~1250 {micro}A (~0.5 mC/cm2), supporting their safety and efficacy. The electrode impedance increased and CIC decreased during in-vivo use, but largely reversed these changes in in-vitro testing after enzymatic cleaning, supporting their tolerance for surgical use.

bioengineering↗

bioRxiv2022

Transcriptome analysis of alcohol dependence and stress interactions in the nucleus of the solitary tract

Stress exposure contributes to the development of drug and alcohol use disorders. In animal models, stress exacerbates escalations in alcohol consumption in alcohol-dependent animals. The nucleus of the solitary tract (NTS) is a critical brainstem region for integrating and relaying peripheral signals to regulate stress responses. To define the molecular adaptions within this brain region that may contribute to stress-induced alcohol drinking, we exposed animals to chronic intermittent bouts of ethanol vapor (CIE), forced swim stress (FSS), or both (CIE + FSS) and then transcriptionally profiled the NTS at three different timepoints after the last vapor exposure (0-hr, 72-hr, and 186-hr). We identified interferon (IFN) signaling as a critical gene network correlated with alcohol consumption levels. Using a likelihood ratio test, we identified genes that were differentially expressed across time and between groups. Clustering analysis of these genes to identify unique expression patterns identified a subset of genes that fail to normalize in the CIE + FSS group, but not the others. These genes were enriched for cell-to-cell interaction and cellular movement pointing to long-term structural and functional changes in this brain region caused by the unique interaction of alcohol dependence and stress. Specific genes of interest identified in this group include Aqp4, Il16, Reln, Grm4, Gabrd, and Gabra6. We also compared gene expression changes in the NTS to the PFC and found a significant overlap of genes between the two brain regions. Overlapping NTS/PFC genes in the CIE + FSS group were enriched for type I IFN signaling. Finally, we tested the hypothesis that activation of type I IFN signaling increases alcohol consumption based on the three lines of evidence identifying type I IFN signaling as critical for escalations in alcohol intake. Mice treated with recombinant IFN{beta} showed significantly elevated levels of alcohol intake in a two-bottle choice procedure compared to saline-treated controls. Overall, these results define the transcriptomic changes across time in the NTS that may be critical to the development of stress-induced increases in alcohol consumption and alcohol dependence.

molecular biology↗

bioRxiv2021

Selective Vulnerability of Tripartite Synapses in Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder. Separate lines of evidence suggest that synapses and astrocytes play a role in the pathological mechanisms underlying ALS. Given that astrocytes make specialised contacts with some synapses, called tripartite synapses, we hypothesise that tripartite synapses could act as the fulcrum of disease in ALS. To test this hypothesis, we have performed an extensive microscopy-based investigation of synapses and tripartite synapses in the spinal cord of ALS model mice and post-mortem human tissue from ALS cases. We reveal widescale synaptic changes at the early symptomatic stages of the SOD1G93a mouse model. Super-resolution microscopy reveals that large complex postsynaptic structures are lost in ALS mice. Most surprisingly, tripartite synapses are selectively lost while non-tripartite synapses remain in equal number to healthy controls. Finally, we also observe a similar selective loss of tripartite synapses in human post-mortem ALS spinal cords. From these data we conclude that tripartite synaptopathy is a key hallmark of ALS.

neuroscience↗

bioRxiv2021

High-Stability Polyimide-based Flexible Electrodes with IrOx to Interface the Mouse Vagus Nerve

ObjectiveWe developed robust and cost-effective cuff Flex electrodes to facilitate bioelectronic medicine research in mouse models. They utilize polyimide (PI) as a dielectric insulation and iridium oxide (IrOx) for the electrodes, and are designed to interface small autonomic and somatic nerves (e.g. mouse vagus nerve). ApproachFlex electrodes were made using micro-fabrication technology, and innovative integration processes were developed to enable reliable acute and chronic vagus nerve interfaces. The electrochemical properties of Flex electrodes were characterized. Moreover, accelerated aging at 57 {degrees}C and stimulation-stability (Stim-Stab) testing (109 pulses at [~] 1.59 mC/cm2/phase) were performed to evaluate the lifetime of the PI encapsulation and IrOx electrodes, respectively. Flex electrodes efficacy was demonstrated by stimulating the mouse vagus nerve ([~]100 {micro}m) and measuring heart and respiratory rate changes as biomarkers. ResultsCost effective and robust lead and connector integration strategies were demonstrated, including small helical leads that improved the lead elongation by > 7x. PI encapsulation had stable impedance spectra for at least 336 days for interdigitated electrodes. Stim-Stab testing using an aggressive paradigm and rigorous optical and electrical characterization, revealed that half of electrodes showed less than minor damage at the endpoints. A trend of decreasing respiratory rate with stimulation current reached statistical significance at 500 {micro}A, demonstrating efficacy for Flex electrodes. SignificanceFlex electrodes offer demonstrated efficacy, low impedance (443 {+/-} 32 {Omega} at 103 Hz), excellent bench test stability, and cost-effective fabrication. Acute devices are easy to integrate, and mechanically robust chronic devices will be investigated in vivo in future studies. These characteristics make the electrodes well-positioned to advance bioelectronics medicine research by 1) enabling reliable studies with statistically relevant populations of acute mouse models, and 2) offering the potential for a technology that can be used in chronic studies, which scales to very small nerves.

bioengineering↗

bioRxiv2019

Kcnn3 as a target for treating aberrant behaviors in stressed, ethanol-dependent mice

Anxiety and mood disorders are often comorbid with alcohol use disorder (AUD) and are considered critical in the development, maintenance, and reinstatement of alcohol dependence and harmful alcohol-seeking behaviors. Because of this high comorbidity, it is necessary to determine shared and unique genetic factors driving heavy ethanol drinking and anxiety-related behaviors. We used a model of stress-induced escalation of drinking in ethanol dependent C57BL/6J mice to measure anxiety-like behaviors on the marble burying and novelty-suppressed feeding task (NSFT) during abstinence. In order to identify novel pharmacogenetic targets that may lead to more effective treatment, a targeted bioinformatics analysis was used to quantify the expression of K+ channel genes in the amygdala that covary with anxiety-related phenotypes in the well phenotyped and fully sequenced family of BXD strains. A pharmacological approach was used to validate the key bioinformatics finding in ethanol-dependent, stressed C57BL/6J mice during the NSFT. Amygdalar expression of Kcnn3 correlated significantly with just over 40 anxiety-associated phenotypes. Further examination of Kcnn3 expression revealed a strong eigentrait for anxiety-like behaviors in this family. Kcnn3 expression in the amygdala correlated negatively with binge-like and voluntary ethanol drinking. C57BL/6J mice treated with chronic intermittent ethanol exposure and repeated swim stress consumed more ethanol in their home cages and showed hypophagia on the NSFT during prolonged abstinence. Pharmacologically targeting KCNN3 protein with the KCa2 channel positive modulator 1-EBIO decreased ethanol drinking and reduced latency to approach food during the NSFT in ethanol-dependent, stressed mice. Collectively these validation studies provide central nervous system mechanistic links into to the covariance of stress, anxiety, and AUD in the BXD strains. Further this analytical approach is effective in defining targets for treating alcohol dependence and comorbid mood and anxiety disorders.

neuroscience↗

bioRxiv2019

Brain Regional Gene Expression Network Analysis Identifies Unique Interactions Between Chronic Ethanol Exposure and Consumption

Progressive increases in ethanol consumption is a hallmark of alcohol use disorder (AUD). Persistent changes in brain gene expression are hypothesized to underlie the altered neural signaling producing abusive consumption in AUD. To identify brain regional gene expression networks contributing to progressive ethanol consumption, we performed microarray and scale-free network analysis of expression responses in a C57BL/6J mouse model utilizing chronic intermittent ethanol by vapor chamber (CIE) in combination with limited access oral ethanol consumption. This model has previously been shown to produce long-lasting increased ethanol consumption, particularly when combining oral ethanol access with repeated cycles of intermittent vapor exposure. The interaction of CIE and oral consumption was studied by expression profiling and network analysis in medial prefrontal cortex, nucleus accumbens, hippocampus, bed nucleus of the stria terminalis, and central nucleus of the amygdala. Brain region expression networks were analyzed for ethanol-responsive gene expression, correlation with ethanol consumption and functional content using extensive bioinformatics studies. In all brain-regions studied the largest number of changes in gene expression were seen when comparing ethanol naive mice to those exposed to CIE and drinking. In the prefrontal cortex, however, unique patterns of gene expression were seen compared to other brain-regions. Network analysis identified modules of co-expressed genes in all brain regions. The prefrontal cortex and nucleus accumbens showed the greatest number of modules with significant correlation to drinking behavior. Across brain-regions, however, many modules with strong correlations to drinking, both baseline intake and amount consumed after CIE, showed functional enrichment for synaptic transmission and synaptic plasticity.

genomics↗