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NBT(IF=68) Li Yulong's team at Peking University developed a highly sensitive and spatiotemporal resolution oxytocin release sensor

 Last Update: 2023-02-03
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iNature

Oxytocin (OT) is a peptide hormone and neuromodulator involved in a variety of physiological and pathophysiological processes
in the central nervous system and peripherals.
However, the regulatory and functional sequences of spatial OT release in the brain are still poorly
understood.

On January 2, 2023, Li Yulong's research group of Peking University published a report entitled "A genetically encoded sensor measures temporal oxytocin release from different neuronal compartments" in the journal Nature Biotechnology This study developed a highly sensitive GPCR activation-based (GRAB) sensor, GRAB_{OT1.
0 (OT1.
0}).

The study not only uses this sensor in vitro to identify the mechanism
of OT release in different brain regions.
Sensors of behavioral mice were also imaged and found OT release in specific regions in terms of discreteness of mating behavior in male mice
.
Together, this work expands the toolbox of neurotransmitter and neuromodulator gene-coding sensors to elucidate the mechanisms
of peptide energy signaling in the brain.

Neuronal communication is often described as a unidirectional process in which dendrites receive and integrate input information, and somatic cells convert signals into action potentials, which then propagate to axon terminals to release neurotransmitters
.
However, in addition to the classical axonal release, some neurochemicals, such as GABA (γ-aminobutyric acid), dopamine, and neuropeptides, also undergo growth dendritic release to mutually regulate surrounding neurons and regulate important physiological functions
。 Evolutionarily, ancient large cellular neurosecretory cells (MNCs) in the paraventricular and supraoptic (SON) nuclei have made extensive contributions to the understanding of neurosecretory mechanisms and have been shown to release oxytocin (OT) or arginine from the axonal and somal dendritic regions vasopressin，AVP)
。 OT is thought to regulate a range of physiological processes
in the peripheral and central nervous systems.
In the mammalian brain, OT is mainly produced
by neurons located in the PVN, SON and paranucleus of the hypothalamus.
OT synthesized in these brain regions is released from the posterior pituitary gland into the blood circulation as a hormone that regulates labor and breastfeeding through OT receptors (OTRs), which are highly expressed
in the uterus and mammary glands, respectively.
In addition to projecting to the pituitary gland, OT neurons also send axons throughout the brain, with axon-released OT regulating food intake, fear, aggression, socialization, sexuality and maternal behavior in rodents, while growth dendritic OT release is associated
with autocrine function during lactation and uterine contractions.
Consistent with the various physiological effects of OT, alterations in OT signaling regulation are associated with a variety of negative emotional states and conditions, such as stress, social amnesia, autism spectrum disorder, and schizophrenia
.
OT release from different brain regions shows different functions, and OT release of somatic dendrites can also be initiated by intracellular^Ca2+ mobilization, however OT release of axons has not been reported
.
Therefore, OT is likely to be released
independently of each compartment.
However, even though several methods have been developed to measure OT release, the molecular mechanisms of OT release chamber control are largely unclear
.
For example, microdialysis has been used for decades to monitor extracellular OT
in free-moving animals.
Cell-based OT assays use exogenous "sniffing cells" expressing OTRs to "sniff" OT and report increased
levels of their intracellular^Ca2+.
The recently developed genetically encoded OT sensor OTR-iTango2 uses light-induced activation of reporter gene expression to measure downstream signals, and the fluorescent OT sensor MTRIAOT has been reported
.
However, these methods do not provide sensitive, specific, and non-invasive monitoring
of OT dynamics at high temporal and spatial resolutions.
In this study, the researchers used the GRAB probe strategy (GPCR-Activation Based Sensor) to graft the cyclically rearranged green fluorescent protein cpGFP to the third intracellular loop of the oxytocin receptor OTR, and through the screening of OTRs derived from different species and the systematic optimization of the linkage peptides, finally the cattle-based oxytocin receptor development obtained a genetically encoded G protein-coupled receptor activation ( G-protein-coupled receptor activation-based (GRAB) OT sensor, called GRAB_{OT1.
0}
.
Compared to previous methods, GRABOT1.
0 is capable of imaging OT release in vivo and in vitro with appropriate sensitivity, specificity, and spatiotemporal resolution
.
Figure 1.
The development of the GRABOT sensor and the activity-dependent OT release in brain slices (Figure from Nature Biotechnology) further used the sensor to visualize the stimulation-induced OT release of specific neuronal brain regions in mouse brain slices, and found that N-type calcium channels mainly mediate axonal OT release, while L-type calcium channels mediate growth dendritic OT release
。 In addition, in acute mouse brain slices, the researchers found that OT1.
0 could detect OT release from specific neuronal brain regions, namely axonal OT release in VTA and growth dendritic OT release
in PVN.
Using this tool, differential molecular mechanisms
for OT release in axonal and growth dendritic neuronal brain regions were identified.
Finally, a series of fiberophotometer-based experiments in freely active male mice showed differences
in OT release from different brain regions at specific stages of mating behavior.
Figure 2.
Model showing the molecular basis of axon and growth dendritic OT release (Image from Nature Biotechnology) Overall, the study reports the development and characterization
of a genetically encoded fluorescent indicator for monitoring extracellular OT in vitro and in vivo.
The OT1.
0 sensor has a wide dynamic range, good sensitivity and selectivity for OT compared to other neurotransmitters and neuropeptides, high spatial and temporal resolution, and negligible downstream coupling
.
OT1.
0 provides insights
into the role of brain region OT release in physiological and behavioral functions.
Professor Li Yulong of the School of Life Sciences of Peking University is the corresponding author of this paper, Qian Tongrui, doctoral student of Peking University School of Life Sciences, Wang Huan, a doctoral graduate, and Dr.
Wang Peng of Beijing Chaoyang Hospital affiliated to Capital Medical University are the co-first authors of this paper, and doctoral students Geng Lan and Wang Lei of Peking University have made important contributions
to the paper.

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