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Neuropeptide-mediated synaptic plasticity regulates context-dependent mating behaviors in Drosophila [1]

['Tianmu Zhang', 'Hit Center For Life Sciences', 'School Of Life Science', 'Technology', 'Harbin Institute Of Technology', 'Harbin', 'Zekun Wu', 'Yutong Song', 'Tae Hoon Ryu', 'Neurophysiology Research Group']

Date: 2025-09 

Neuropeptides play crucial roles in regulating context-dependent behaviors, but the underlying mechanisms remain elusive. We investigate the role of the neuropeptide SIFa and its receptor SIFaR in regulating two distinct mating duration behaviors in male Drosophila: Longer-Mating-Duration (LMD) and Shorter-Mating-Duration (SMD). We found that SIFaR expression in specific neurons is required for both LMD and SMD behaviors. Social context and sexual experience lead to synaptic reorganization between SIFa and SIFaR neurons, altering internal states of brain. We revealed that the SIFa-SIFaR/Crz-CrzR neuropeptide relay pathway is essential for generating distinct interval timing behaviors, with Crz neurons being responsive to the activity of SIFa neurons. Additionally, CrzR expression in glial cell population is critical for regulating LMD behavior. Our study provides insights into how neuropeptides and their receptors modulate context-dependent behaviors through synaptic plasticity and calcium signaling, with implications for understanding the neural circuitry underlying interval timing and neuropeptidergic system modulation of behavioral adaptations.

Funding: This research was supported by a University of Ottawa Startup grant 602496 to WJK, Startup funds from HIT Center for Life Science to WJK, a University of Ottawa Interdisciplinary Research Group Funding Opportunity (IRGFO stream 1 and 2) grants 148101 and 148747 to WJK, a Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grant (reference: 211406) to WJK, a University of Ottawa Brain and Mind Research Institute/Center for Neural Dynamics Open call project grant 150950 to WJK, a Mitacs Globalink Research Internship Program grant 17268 to WJK. This research was also supported by the Brain Pool Program of the National Research Foundation in Korea grant ZYM5041911 to WJK, Burroughs Wellcome Fund Collaborative Research Travel Grants (reference: 1017486) to WJK and a NVIDIA Academic Hardware Grant Program to WJK. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The mechanisms by which SIFa signaling coordinates behavior via SIFaR remain incompletely resolved. This gap persists partly because SIFaR expression is distributed widely across diverse neural populations, complicating circuit-pecific dissection. Furthermore, neuropeptide-receptor circuits are inherently less tractable than those of neuropeptide-expressing neurons due to systemic compensation, volume transmission, and pleiotropic signaling modes [ 10 , 49 – 51 ]. Conventional molecular genetics and synaptic connectomics face inherent limitations in resolving neuropeptide-receptor interactions due to SIFaR’s broad expression and non-synaptic signaling dynamics. To overcome these specific challenges in dissecting SIFa-SIFaR mechanisms, we employed targeted applications of these approaches—combining genetic perturbation with synaptic tracing to map functional connectivity within candidate pathways. Here, we report that SIFa controls two alternate interval timing behaviors through long-range neuropeptide relay signaling by SIFaR and other important neuropeptides and transmits the internal states of the male brain into decision-making.

The neuropeptide SIFa is a neuromodulator that demonstrates plasticity on a molecular and behavioral level. SIFa is expressed by four neurons located in the pars intercerebrails (PI), and they are the most widely arborizing peptidergic neurons in Drosophila [ 39 ]. SIFa is synthesized in four PI neurons and transported to the broad regions of central nervous system (CNS), including central complex via axonal projections [ 39 – 43 ]. SIFa has significant impact on various behaviors including feeding-related behavior [ 41 , 44 ], courtship [ 40 , 42 ], sleep [ 43 , 45 , 46 ], memory [ 47 ], and interval timing [ 48 ]. SIFa neurons integrate information through several inputs and form a hub to orchestrate many behaviors. The SIFa neurons receive inputs from peptidergic neurons expressing hugin-pyrokinin (PK)/myoinhibitory peptide (MIP) that mediate hunger/satiety [ 41 ], Drosophila insulin-like peptides (DILPs) that mediates feeding/fasting rhythm [ 44 ] and sleep [ 43 , 45 ]. Thus, it is anticipated that the SIFa neurons would play a crucial role in the context-dependent orchestration of multiple behaviors [ 4 ].

The dimension of time is the fundamental basis for an animal’s survival. Being able to estimate and control the time between events is crucial for all everyday activities [ 25 ]. The perception of time in the seconds-to-hours range, referred to as ‘interval timing’, is involved in foraging, decision-making, and learning via activation of cortico-striatal circuits in mammals [ 26 ]. Interval timing requires entirely different neural mechanisms from millisecond or circadian timing [ 27 – 29 ]. There is abundant psychological research on time perception because it is a universal cognitive dimension of experience and behavioral plasticity. Despite decades of research, the genetic and neural substrates of temporal information processing have not been well established except for the molecular bases of circadian timing [ 30 , 31 ]. Thus, a simple genetic model system to study interval timing is required. Fruit fly mating lasts about 20 min—a duration within the range of interval timing mechanisms. Thus, mating duration (MD) provides a relevant model for studying the neural circuits that govern time perception in Drosophila. Understanding these circuits requires insight into the neural and behavioral plasticity underlying interval timing [ 32 – 38 ].

Neuropeptide relays represent a fundamental mechanism for energy homeostasis, particularly in gut-brain communication [ 13 – 18 ]. These relays critically depend on non-synaptic transmission, where neuropeptides diffuse broadly to coordinate physiological states across tissues. While extensively documented in mammalian systems (e.g., hypothalamic integration of hunger/satiety signals via stomach, adipose, and pancreas communication [ 13 , 19 ]) and conserved in Drosophila metabolic regulation [ 1 , 14 , 20 – 24 ], the precise circuitry of central neuropeptidergic relays remains poorly characterized. This gap significantly limits our understanding of how such non-synaptic signaling modulates complex behaviors like decision-making.

Plasticity in animal behavior is dependent on the capacity to integrate external stimuli and internal states from a fluctuating environment and, as a result, to modify activity in neuronal circuits of the brain [ 1 , 2 ]. In Drosophila, many of the neural systems that are known to influence behavioral circuits in a state-dependent manner and create switches between behaviors make use of various neuropeptides or biogenic amines like serotonin, dopamine, or octopamine [ 3 – 9 ]. These neuromodulatory circuits or pathways are not always hardwired; they depend on paracrine signaling or volume transmission, which is based on non-synaptic release of an amine or neuropeptide [ 4 , 10 ]. Interorgan communication is particularly governed by neuromodulatory signaling, which operates via non-synaptic release of amines or neuropeptides. This enables both local (paracrine/volume transmission) and systemic (hormonal action via circulation) pathways to coordinate physiological responses across tissues [ 11 – 13 ].

Results

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[1] Url: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003330

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