Regulation of Brain Primary Cilia Length by MCH Signaling: Evidence from Pharmacological, Genetic, Optogenetic, and Chemogenic Manipulations

Abstract

The melanin-concentrating hormone (MCH) system is involved in numerous functions, including energy homeostasis, food intake, sleep, stress, mood, aggression, reward, maternal behavior, social behavior, and cognition. MCH acts on a G protein-coupled receptor MCHR1, which expresses ubiquitously in the brain and localizes to neuronal primary cilia. Cilia act as cells' antennas and play crucial roles in cell signaling to detect and transduce external stimuli to regulate cell differentiation and migration. Cilia are highly dynamic in terms of their length and morphology; however, it is not known if cilia length is causally regulated by MCH system activation in-vivo. In the current work, we examined the effects of activation and inactivation of MCH system on cilia lengths by using different methodologies, including pharmacological (MCHR1 agonist and antagonist GW803430), germline and conditional genetic deletion of MCHR1 and MCH, optogenetic, and chemogenetic (Designer Receptors Exclusively Activated by Designer Drugs (DREADD)) approaches. We found that stimulation of MCH system either directly through MCHR1 activation, or indirectly through optogenetic and chemogenetic-mediated excitation of MCH neurons, causes cilia shortening. In contrast, inactivation of MCH signaling through pharmacological MCHR1 blockade or through genetic manipulations -germline deletion of MCHR1 and conditional ablation of MCH neurons -induces cilia lengthening. Our study is the rst to uncover the causal effects of the MCH system in the regulation of the length of brain neuronal primary cilia. These ndings place MCH system at a unique position in the ciliary signaling in physiological and pathological conditions, and implicate cilia MCHR1 as a potential therapeutic target for the treatment of pathological conditions characterized by impaired cilia function.

The melanin-concentrating hormone system as a target for the treatment of sleep disorders

“…It has also recently been recognized that MCH is an important regulator of ciliary growth and function. MCHR1 is widely expressed on both neuronal primary cilia, which may function like “antennae” during neurotransmission ( Alhassen et al, 2022 ), and ependymal cilia within the walls of the cerebral ventricles. By enhancing ciliary beating, ventricularly transmitted MCH may augment volume transmission of a variety of chemical signals and metabolic factors within the CNS ( Conductier et al, 2013 ), which may be of physiological and clinical relevance.…”

Neuronal cilia in energy homeostasis

“…MCHR1 localizes to cilia in many areas of the mouse and rat brain, including the olfactory bulb, hippocampus, amygdala, hypothalamus, and spinal cord ( Niño-Rivero et al, 2019 ; Diniz et al, 2020 ; Brewer et al, 2022 ). Using optogenetics, and chemogenetics, activation and inhibition of the MCH pathway causes cilia shortening and lengthening, respectively, in the brain as measured with ADCY3s staining ( Alhassen et al, 2022 ). Interestingly, MCHR1 ligand, MCH, expression changes based on feeding status.…”

Relationships between the Mini-InDel Variants within the Goat CFAP43 Gene and Body Traits

“…Additionally, when cilia Animals 2022, 12, 3447 2 of 9 are present in the digestive system, they manipulate and collect food in liquids [4]. The melanin-concentrating hormone system is heavily localized to the primary cilia of neurons and is engaged in a number of areas, including energy balance and food intake [5]; thus, cilia are also important for food intake and energy metabolism.…”