Probes for INS

Oxytocin, secreted by oxytocin neurons in the hypothalamus, is an endogenous neuropeptide involved in modulating multiple sensory information processing pathways, and its roles in the brain have been associated with prosocial, maternal, and feeding-related behaviors. Visual information is necessary for initiating these behaviors, with the retina consisting of the first stage in the visual system mediating external stimulus perception. Oxytocin has been detected in the mammalian retina; however, the expression and possible function of oxytocin receptors (OxtR) in the retina remain unknown. Here, we explore the role of oxytocin in regulating visual information processing in the retina.We observed that OxtR mRNA and protein are expressed in the mouse retina. With Oxtr-Cre transgenic mice, immunostaining, and fluorescence in situ hybridization, we found that OxtRs are mainly expressed in GABAergic amacrine cells (ACs) in both the inner nuclear layer (INL) and ganglion cell layer (GCL). Further immunoreactivity studies showed that GABAergic OxtR+ neurons are mainly cholinergic and dopaminergic neurons in the INL and are cholinergic and corticotrophin-releasing hormone neurons in the GCL. Surprisingly, a high level of Oxtr mRNAs was detected in retinal dopaminergic neurons, and exogenous oxytocin application activated dopaminergic neurons to elevate the retinal dopamine level. Relying on in vivo electroretinographic recording, we found that activating retinal OxtRs reduced the activity of bipolar cells via OxtRs and dopamine receptors.These data indicate the functional expression of OxtRs in retinal GABAergic ACs, especially dopaminergic ACs, and expand the interactions between oxytocinergic and dopaminergic systems. This study suggests that visual perception, from the first stage of information processing in the retina, is modulated by hypothalamic oxytocin signaling.

Neuromodulatory substances can be released from distal afferents for communication between brain structures or produced locally to modulate neighboring circuit elements. Corticotropin-releasing hormone (CRH) from long-range neurons in the hypothalamus projecting to the medial prefrontal cortex (mPFC) has been shown to induce anxiety-like behaviors. However, the role of CRH produced in the mPFC has not been investigated. Here we demonstrate that a specific class of mPFC interneurons that express CRH (CrhINs) releases CRH upon high-frequency stimulation to enhance excitability of layer 2/3 pyramidal cells (L2/3 PCs) expressing the CRH receptors. When stimulated at low frequency, CrhINs release GABA resulting in the inhibition of oxytocin receptor-expressing interneurons (OxtrINs) and L2/3 PCs. Conditional deletion of CRH in mPFC CrhINs and chemogenetic activation of CrhINs have opposite effects on novelty exploration in male but not in female mice, and do not affect anxiety-related behaviors in either males or females. Our data reveal that CRH produced by local interneurons in the mPFC is required for sex-specific novelty exploration and suggest that our understanding of complex behaviors may require knowledge of local and remote neuromodulatory action.

Glucagon-like peptide-1 receptor (GLP-1R) is a well-studied incretin hormone receptor and target of several therapeutic drugs for type 2 diabetes (T2D), obesity and, more recently, cardiovascular disease. Some signalling pathways downstream of GLP-1R may be responsible for drug adverse effects such as nausea, while others mediate therapeutic outcomes of incretin-based T2D therapeutics. Understanding the interplay between different factors that alter signalling, trafficking, and receptor activity, including biased agonism, single nucleotide polymorphisms and structural modifications is key to develop the next-generation of personalised GLP-1R agonists. However, these interactions remain poorly described, especially for novel therapeutics such as dual and tri-agonists that target more than one incretin receptor. Comparison of GLP-1R structures in complex with G proteins and different peptide and non-peptide agonists has revealed novel insights into important agonist-residue interactions and networks crucial for receptor activation, recruitment of G proteins and engagement of specific signalling pathways. Here, we review the latest knowledge on GLP-1R structure and activation, providing structural evidence for biased agonism and delineating important networks associated with this phenomenon. We survey current biased agonists and multi-agonists at different stages of development, highlighting possible challenges in their translational potential. Lastly, we discuss findings related to non-synonymous genomic variants of GLP1R and the functional importance of specific residues involved in GLP-1R function. We propose that studies of GLP-1R polymorphisms, and specifically their effect on receptor dynamics and pharmacology in response to biased agonists, could have a significant impact in delineating precision medicine approaches and development of novel therapeutics.