Biology subjects

Luis-Islas, J.

Publications and source records attributed to Luis-Islas, J..

3 recordsLinked to original sources

bioRxiv2023

Tesofensine, a novel antiobesity drug, silences GABAergic hypothalamic neurons

Obesity is a major global health epidemic that has adverse effects on both the people affected as well as the cost to society. Several anti-obesity drugs that target GLP-1 receptors have recently come to the market. Here we describe the effects of tesofensine, a novel anti-obesity drug that acts as a triple monoamine neurotransmitter reuptake inhibitor. We investigated its effects on weight loss and underlying neuronal mechanisms in mice and rats using various techniques. These include behavioral tasks, DeepLabCut videotaped analysis, electrophysiological ensemble recordings, optogenetic activation, and chemogenetic silencing of GABAergic neurons in the Lateral Hypothalamus (LH). We found that tesofensine induced greater weight loss in obese than lean rats, which was associated with changes in LH ensemble activity. In Vgat-ChR2 and Vgat-IRES-cre transgenic mice, we found for the first time that tesofensine inhibited a subset of LH GABAergic neurons, reducing their ability to promote feeding behavior, and chemogenetically silencing them enhanced tesofensines food-suppressing effects. Unlike phentermine, a dopaminergic appetite suppressant, tesofensine causes few, if any, head-weaving stereotypy at therapeutic doses. Most importantly, we found that tesofensine prolonged the weight loss induced by 5-HTP, a serotonin precursor, and blocked the body weight rebound that often occurs after weight loss. Behavioral studies on rats with the tastant sucrose indicated that tesofensines appetite suppressant effects are independent of taste aversion and do not directly affect the perception of sweetness or palatability of sucrose. In summary, our data provide new insights into the effects of tesofensine on weight loss and the underlying neuronal mechanisms, suggesting that tesofensine may be an effective treatment for obesity and that it may be a valuable adjunct to other appetite suppressants to prevent body weight rebound.

neuroscience↗

bioRxiv2021

Interoceptive perception of optogenetic brain stimulation

How do animals experience brain manipulations? Optogenetics has allowed us to manipulate selectively and interrogate neural circuits underlying brain function in health and disease. However, it is currently unknown whether mice could perceive arbitrary optogenetic stimulation in addition to their evoked physiological functions. To address this issue, mice were trained to report an optogenetic stimulation as a cue to obtain rewards and avoid punishments. It was found that mice could perceive optogenetic manipulations regardless of the brain area modulated, their rewarding effects, or the stimulation of glutamatergic, GABAergic, and dopaminergic cell types. We named this phenomenon optoception. Using optoception, mice could learn to execute two different sets of instructions based on the laser frequency. Importantly, optoception can occur either activating or silencing a single cell type. Our findings revealed that mices brains are capable of "monitoring" their self-activity, albeit indirectly, perhaps via interoception or as a discriminative stimulus, opening a new way to introduce information to the brain and control brain-computer interfaces.

neuroscience↗

bioRxiv2020

Lateral Hypothalamic GABAergic neurons encode and potentiate sucrose palatability

Sucrose is attractive to most species in the animal kingdom, not only because it induces a sweet taste sensation but also for its positive palatability (i.e., oromotor responses elicited by increasing sucrose concentrations). Although palatability is such an important sensory attribute, it is currently unknown which cell types encode and modulate sucroses palatability. Studies in mice have shown that activation of GABAergic LHAVgat+ neurons evokes voracious eating; however, it is not known whether these neurons would be driving consumption by increasing palatability. Using optrode recordings, we measured sucroses palatability while VGAT-ChR2 transgenic mice performed a brief access sucrose test. We found a subpopulation of LHAVgat+ neurons encodes palatability by increasing (or decreasing) their activity as a function of the increment in licking responses evoked by sucrose concentrations. Optogenetic gain of function experiments, where mice were able to choose among available water, 3%, or 18% sucrose solution, uncovered that opto-stimulation of LHAVgat+ neurons consistently promoted higher intake of the most palatable stimulus (18% sucrose). In contrast, if they self-stimulated near the less palatable stimulus, some VGAT-ChR2 mice preferred water over 18% sucrose. Unexpectedly, activation of LHAVgat+ neurons increased quinine intake but only during water deprivation, since in sated animals, they failed to promote quinine intake or tolerate an aversive stimulus. Conversely, these neurons promoted overconsumption of sucrose when it was the nearest stimulus. Also, experiments with solid foods further confirmed that these neurons increased food interaction time with the most palatable food available. We conclude that LHAVgat+ neurons increase the drive to consume, but it is potentiated by the palatability and proximity of the tastant.

neuroscience↗