Biology subjects

Yackle, K.

Publications and source records attributed to Yackle, K..

5 recordsLinked to original sources

bioRxiv2026

Reciprocal control of the stomach and intestine by viscerosensory neurons in caudal brainstem

Digestion requires precisely timed transit of food through the gastrointestinal tract. Here we show that emptying of food from the stomach occurs in discrete pulses, separated by pauses that allow the proximal duodenum to clear before the next bolus arrives. By combining X-ray fluoroscopy of the gut with calcium imaging of the brainstem, we identify a population of neurons defined by expression of neuropeptide FF (NPFF) that tracks these duodenal dynamics. Stimulation of NPFF neurons induces a coordinated response that inhibits gastric emptying and accelerates intestinal transit, thereby clearing the proximal intestine for the next bolus of food. These neurons also bidirectionally control food intake through cholinergic signaling in the gut. These findings reveal a mechanism by which brainstem transforms the sensory detection of nutrients in the duodenum into the opposing control of the stomach and intestine. They also establish an experimental approach for dissecting gut-brain signaling in behaving animals.

neuroscience↗

bioRxiv2023

The breath shape controls intonation of mouse vocalizations

Intonation in speech is the control of vocal pitch to layer expressive meaning to communication, like increasing pitch to indicate a question. Also, stereotyped patterns of pitch are used to create distinct sounds with different denotations, like in tonal languages and, perhaps, the ten sounds in the murine lexicon. A basic tone is created by exhalation through a constricted laryngeal voice box, and it is thought that more complex utterances are produced solely by dynamic changes in laryngeal tension. But perhaps, the shifting pitch also results from altering the swiftness of exhalation. Consistent with the latter model, we describe that intonation in most vocalization types follows deviations in exhalation that appear to be generated by the re-activation of the cardinal breathing muscle for inspiration. We also show that the brainstem vocalization central pattern generator, the iRO, can create this breath pattern. Consequently, ectopic activation of the iRO not only induces phonation, but also the pitch patterns that compose most of the vocalizations in the murine lexicon. These results reveal a novel brainstem mechanism for intonation.

neuroscience↗

bioRxiv2021

A novel reticular oscillator in the brainstem synchronizes neonatal crying with breathing

Human speech can be divided into short, rhythmically-timed elements, similar to syllables within words. Even our cries and laughs, as well as the vocalizations of other species, are periodic. However, the cellular and molecular mechanisms underlying the tempo of mammalian vocalizations remain unknown. Here we describe rhythmically-timed neonatal mouse vocalizations that occur within single breaths, and identify a brainstem node that structures these cries, which we name the intermediate reticular oscillator (iRO). We show that the iRO acts autonomously and sends direct inputs to key muscles in order to coordinate neonatal vocalizations with breathing, as well as paces and patterns these cries. These results reveal that a novel mammalian brainstem oscillator embedded within the conserved breathing circuitry plays a central role in the production of neonatal vocalizations.

neuroscience↗

bioRxiv2020

β2-Arrestin germline knockout does not attenuate opioid respiratory depression

Opioids are perhaps the most effective analgesics in medicine. However, from 1999 to 2018, they also killed more than 400,000 people in the United States by suppressing breathing, a common side-effect known as opioid induced respiratory depression. This doubled-edged sword has inspired the dream of developing novel therapeutics that provide opioid-like analgesia without respiratory depression. One such approach has been to develop so-called biased agonists that activate some, but not all pathways downstream of the {micro}-opioid receptor (MOR), the target of morphine and other opioid analgesics. This hypothesis stems from a study suggesting that MOR-mediated activation of {beta}2-Arrestin is the downstream signaling pathway responsible for respiratory depression, whereas inhibition of adenylyl cyclase produces analgesia. To further verify this model, which represents the motivation for the biased agonist approach, we examined respiratory behavior in mice lacking the gene for {beta}2-Arrestin. Contrary to previous findings, we find no correlation between {beta}2-Arrestin function and opioid-induced respiratory depression, suggesting that any effect of biased agonists must be mediated through an as-yet to be identified signaling mechanism.

neuroscience↗

bioRxiv2019

Opioids depress breathing through two small brainstem sites

The rates of opioid overdose in the United States quadrupled between 1999 and 2017, reaching a staggering 130 deaths per day. This health epidemic demands innovative solutions that require uncovering the key brain areas and cell types mediating the cause of overdose--opioid respiratory depression. Here, we identify two primary changes to breathing after administering opioids. These changes implicate the brainstems breathing circuitry which we confirm by locally eliminating the -Opiate receptor. We find the critical brain site is the origin of the breathing rhythm, the preBotzinger Complex, and use genetic tools to reveal that just 70-140 neurons in this region are responsible for its sensitivity to opioids. Future characterization of these neurons may lead to novel therapies that prevent respiratory depression while sparing analgesia.

physiology↗