Drosophila Corazonin Neurons as a Hub for Regulating Growth, Stress Responses, Ethanol-Related Behaviors, Copulation Persistence and Sexually Dimorphic Reward Pathways

Abstract

The neuronal mechanisms by which complex behaviors are coordinated and timed often involve neuropeptidergic regulation of stress and reward pathways. Recent studies of the neuropeptide Corazonin (Crz), a homolog of the mammalian Gonadotrophin Releasing Hormone (GnRH), have suggested its crucial role in the regulation of growth, internal states and behavioral decision making. We focus this review on Crz neurons with the goal to (1) highlight the diverse roles of Crz neuron function, including mechanisms that may be independent of the Crz peptide, (2) emphasize current gaps in knowledge about Crz neuron functions, and (3) propose exciting ideas of novel research directions involving the use of Crz neurons. We describe the different developmental fates of distinct subsets of Crz neurons, including recent findings elucidating the molecular regulation of apoptosis. Crz regulates systemic growth, food intake, stress responses and homeostasis by interacting with the short Neuropeptide F (sNPF) and the steroid hormone ecdysone. Additionally, activation of Crz neurons is shown to be pleasurable by interacting with the Neuropeptide F (NPF) and regulates reward processes such as ejaculation and ethanol-related behaviors in a sexually dimorphic manner. Crz neurons are proposed to be a motivational switch regulating copulation duration using a CaMKII-dependent mechanism described as the first neuronal interval timer lasting longer than a few seconds. Lastly, we propose ideas to use Crz neuron-induced ejaculation to study the effects of fictive mating and sex addiction in flies, as well as to elucidate dimorphic molecular mechanisms underlying reward behaviors and feeding disorders.

Keywords: addiction; alcoholism; dimorphism; eating disorder; growth; insect disease model; neuropeptide.

Figure 1

Diagram showing the populations of Corazonin (Crz) expressing neurons in the nervous systems of third-instar larvae and adult flies. In third-instar larvae, one dorsomedial (DM) neuron and three dorsolateral (DL) neurons are present in either hemisphere of the brain, and eight pairs of neurons (vCrz) are present on either side of the ventral nerve cord. DH31-R1 and DH44-R1 expression is present in all of these cells, while sNPF is only present in the DM and DL neurons, but not the vCrz neurons [21]. In adults, 6–8 dorso-latero-posterior (DLP) neurons are present on either hemisphere of the brain, and 4–6 Abg-Crz neurons are present in the abdominal ganglion in males only. DH31-R1, sNPF, and DH44-R1 expression is present in the DLP cells but not the AbgCrz neurons. Cells that also express Gr43a are indicated in cyan, however it should be noted that the number and locations of these cells vary. General regions in the adult and larval nervous system that contain Crz receptors (CrzR) are indicated in blue, while regions containing IPC neurons are indicated in magenta. The specific locations of additional neurons in the fly neurosecretory system (such as sNFP or IPCs) has been recently reviewed [11]. Relative locations of larval CrzR neurons are based on [15,16]. It is worth mentioning that different observations have been reported for CrzR expression in the adult brain. Whereas Zer-Krispil et al. (2018) [8] reported CrzR expression in numerous fat cells that surround the brain, a recent study by Zandawala et al. (2021) [17] showed expression of CrzR in brain neurons.

Figure 2

DL-Crz regulation of basal ecdysone production as well as the two pathways leading to vCrz apoptosis and one regarding the clearance of the resulting neural debris. Beginning at the left of the figure, DL-Crz neurons express octopamine receptors and innervate PTTH cells to modulate basal ecdysone production in the prothoracic gland. In the middle and right portion of the figure, basal ecdysone acts on the fat body to inhibit insulin signaling, thereby negatively controlling systemic growth. When ecdysone levels peak, it binds to either Astro-like or cortex glial cells at the EcR-B receptor to trigger the production of Myo, which binds to the Babo-A receptor in vCrz neurons causing apoptosis via TGF-β signaling. Ecdysone also binds to the EcR-B/Usp receptor complex which transforms astrocyte-like cells only into phagocytes which clear neural debris produced by Crz neuron apoptosis. Finally, peak ecdysone can also act on vCrz neurons directly via the EcR-B/Usp receptor complex to cause apoptosis through the major and the two minor death genes, grim and sickle (skl)/reaper (rpr), respectively [55,58].