Biology subjects

Schmidt, M. F.

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

5 recordsLinked to original sources

bioRxiv2024

Presynapses are mitophagy pit stops that prevent axon degeneration

Defects in neuronal mitophagy have been linked to neurodegenerative diseases including Parkinsons disease. However, despite the importance of mitophagy in neuronal homeostasis, the mechanistic basis for neurodegeneration when mitophagy is defective is unclear. Here, using human neurons, we discover that presynapses are mitophagy pit stops for damaged axonal mitochondria. We show that while mitochondrial damage and PINK1/Parkin activation events are distributed throughout axons, mitophagy initiation and autophagosome formation are restricted to presynapses, which we show contain the machineries required for mitophagy. Being the primary sites of axonal mitophagy, presynapses were vulnerable when PINK1/Parkin mitophagy was defective. We observed local cytochrome c release within presynapses from an accumulation of damaged mitochondria. This resulted in downstream degradative caspase activation, defining a mechanism for neurodegeneration. Pharmacological rescue of axon degeneration was achieved through synthetic upregulation of receptor mediated mitophagy with the clinically approved compound Roxadustat, revealing a potential therapeutic avenue for disease.

cell biology↗

bioRxiv2024

Molecular insights into G protein specificity and biased agonism at the β2-adrenergic receptor

G protein coupled receptors (GPCRs) exhibit varying degrees of selectivity for different G protein isoforms. Despite the abundant structures of GPCR-G protein complexes, little is known about the mechanism of G protein coupling specificity. The {beta}2-adrenergic receptor is an example of GPCR with high selectivity for Gs, the stimulatory G protein for adenylyl cyclase, and much weaker for the Gi family of G proteins inhibiting adenylyl cyclase. By developing a Gi-biased agonist (LM189), we provide structural and biophysical evidence supporting that distinct conformations at ICL2 and TM6 are required for coupling of the different G protein subtypes Gs and Gi. These results deepen our understanding of G protein specificity and bias and can accelerate the design of ligands that select for preferred signaling pathways.

molecular biology↗

bioRxiv2021

Cohesion in male singing behavior predicts group reproductive output in a social songbird

All social groups require organization to function optimally. Group organization is often shaped by social rules, which function to manage conflict, discourage cheating, or promote cooperation1-5. If social rules promote effective social living, then the ability to learn and follow these rules may be expected to influence individual and group-level fitness. However, such links can rarely be tested, due to the complexity of the factors mediating social systems and the difficulty of gathering data across multiple groups. Songbirds offer an opportunity to investigate the link between social rules and reproductive output because most of their social interactions are mediated by song, a well-studied and readily quantifiable behavior6,7. Using observations from 19 groups of brown-headed cowbirds (Molothrus ater) studied across 15 years, we find evidence for a previously undocumented social rule: cohesive group transitions between dominance- and courtship-related singing. Comparing across groups, the degree of cohesion in male singing behavior predicts the reproductive output of their group. Experimental manipulation of group structure via the introduction of juvenile males to captive flocks reduced group cohesion and adult male reproductive success. Taken together, these results demonstrate that cohesion in group behavioral states can affect both individual and group-level reproductive success, suggesting that selection can act not only on individual-level traits, but also on an individuals ability and opportunity to participate effectively in organized social interactions. Social cohesion could therefore be an unappreciated force affecting social evolution in many diverse systems.

evolutionary biology↗

bioRxiv2021

Variation in female songbird state determines signal state needed to evoke copulation

Female preferences for male signals largely determine courtship success. In most songbirds, females control reproduction via the copulation solicitation display (CSD), an innate, stereotyped posture produced in direct response to male displays. In some species, CSD can be elicited under controlled experimental conditions, allowing CSD production to be used as a bioassay for the underlying mechanics of courtship, however historically our ability to measure variability in CSD was limited. Using computer vision approaches to precisely quantify the trajectory of CSD in female brown-headed cowbirds (Molothrus ater), we show that song potency (how often a song elicits CSD) and female responsivity (how likely a female is to produce CSD) each predict whether a female produces CSD in response to a given presentation. Within elicited CSD, potency and responsivity also predict the duration and onset latency of the displays. By modeling and testing two alternative hypotheses of preference formation, we show that changes in response rates are consistent with a shifting receiver response threshold, suggesting that the song quality required to evoke the copulatory posture in a particular female will vary over time. These results establish a novel framework for exploring CSD and emphasize the importance of the internal state of receivers in determining behavioral responses and suggest that female responsivity acts in conjunction with male signal strength to determine the efficacy of male courtship signaling.

animal behavior and cognition↗

bioRxiv2017

Regulation of vocal precision by local noradrenergic modulation of a motor nucleus

Recent theories of norepinephrine (NE) function suggest that NE modulates the transition between stereotyped, goal-directed behavior and more variable exploratory behaviors that facilitate learning and adaptation. We provide evidence for context dependent switching by NE that is analogous to this explore/exploit strategy in the vocal system of the zebra finch (Taeniopygia guttata). Stimulation of the locus coeruleus, the major source of norepinephrine in the brain, decreases song trial-to-trial variability transforming the variable, exploratory \"undirected\" song into song that resembles the more stereotyped, exploitative \"directed\" song males sing to females. This behavioral switch is mediated by NE acting directly on a cortical motor nucleus that integrates inputs from a premotor cortical nucleus and a basal ganglia circuit necessary for vocal motor learning. These findings suggest that norepinephrine can act directly on the motor system to influence the transition between exploratory and exploitative behavioral strategies.

neuroscience↗