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Customer Research Highlight | PNAS | Yunfeng Zhang, Yiqun Yu, and Minghong Ma Teams Reveal How the VTA–mOT Dopaminergic Pathway Regulates Odor-Guided Insect Predation in Mice

Release time：2025-11-27 16:55:41
Foraging and food consumption are fundamental for animal survival. In natural environments, wild rodents feed on insects such as moth larvae, and evaluating potential food sources through olfaction is a key step in initiating feeding behavior. Odor cues from food sources provide predators with critical information about nutritional quality and palatability. Rodents likely assess the nutritional status of food resources via olfactory signals to decide whether to initiate feeding. However, the mechanisms underlying this process remain largely unclear.

On October 10, 2025, a collaborative team led by Yunfeng Zhang from the Institute of Zoology, Chinese Academy of Sciences, Yiqun Yu from Fudan University, and Minghong Ma from the University of Pennsylvania published a research article titled “A midbrain-to-ventral-striatum dopaminergic pathway orchestrates odor-guided insect predation in mice” in PNAS.

Using a laboratory predator–prey system built with mice and Helicoverpa armigera larvae, the study combined multiple techniques to show that mice prefer to consume larvae that have fed (nutrient-rich larvae). This preference depends on the main olfactory system: mice are attracted to linoleic acid (LA) emitted from the larval surface while avoiding (Z)-9-tricosene ((Z)-9-TE).

This odor-guided preference is precisely regulated by a dopaminergic pathway from the ventral tegmental area (VTA) to the medial olfactory tubercle (mOT). Inhibiting this pathway abolishes the preference for LA, whereas activating it can reverse preference direction. Moreover, D1 and D2 neurons in the mOT mediate attraction to LA and aversion to (Z)-9-TE, respectively. These findings reveal a neurobiological system in rodents that uses chemical cues to support insect predation.

The Main Olfactory System Is Essential for Larval Preference in Mice

To investigate the feeding preferences of mice for H. armigera larvae, the researchers conducted semi-natural foraging assays and two-choice feeding tests. Compared with unfed larvae, both fasted and non-fasted mice showed a stronger preference for larvae that had fed, with fasted mice consuming more overall. When larval movement was controlled by fixing them in place, mice still preferred fed larvae, indicating that larval mobility plays little role and the preference likely reflects enhanced nutritional quality.

Figure 1. Fasted and non-fasted mice prefer fed larvae over unfed larvae.
 
To identify sensory cues underlying this preference, the researchers used wire-mesh cups wrapped in gauze (blocking visual and tactile cues while allowing odor diffusion) for a two-choice test. Both fasted and non-fasted mice showed spatial preference for fed larvae. However, after methimazole treatment (which ablates the main olfactory epithelium), this preference disappeared. This demonstrates that an intact main olfactory system is required for the larval feeding preference.

Figure 2. The olfactory system plays a key role in determining feeding preference for larvae.
 

Linoleic Acid (LA) and (Z)-9-Tricosene ((Z)-9-TE) Mediate Feeding Preferences in Mice

The researchers analyzed the surface volatiles of fed and unfed larvae using gas chromatography–mass spectrometry (GC-MS). They found that fed larvae contained significantly higher levels of LA and lower levels of (Z)-9-TE compared to unfed larvae. In two-choice olfactory preference tests, mice showed a strong spatial preference for LA while avoiding (Z)-9-TE (with no significant difference in locomotion under specific fasted/non-fasted conditions). Direct comparison confirmed that mice preferred LA more strongly, and functional reversal tests demonstrated that adding these two molecules to larvae could reverse the mice’s preference. These results indicate that LA and (Z)-9-TE are key molecules mediating mouse feeding preference and dominating the olfactory environment.

Figure 3. Mice prefer LA while avoiding (Z)-9-TE.
 
To investigate whether this odor preference is conserved across rodent species, the researchers performed two-choice olfactory preference tests using laboratory C57BL/6 mice and two wild rodents: Rattus norvegicus (brown rat) and Microtus fortis (reed vole). The results showed that the wild rodents displayed similar attraction to LA and avoidance of (Z)-9-TE as laboratory mice. This suggests that the preference for LA and aversion to (Z)-9-TE are widespread among rodents, highlighting their potential ecological significance in foraging and feeding behaviors.

Figure 4. Non-fasted reed voles and brown rats show preference for LA and avoidance of (Z)-9-TE.
 

VTA–mOT Dopaminergic Pathway Regulates Preferences for LA and (Z)-9-TE

The VTA is rich in dopaminergic neurons, and the VTA–mOT dopaminergic pathway is known to play a key role in mediating olfactory preferences in mice. To investigate whether this pathway regulates mice’s preference for LA and avoidance of (Z)-9-TE, the researchers used chemogenetic techniques to inhibit or activate the pathway and tracked the behavior of non-fasted mice in two-choice olfactory preference tests.

The results showed that inhibiting the VTA–mOT pathway abolished the preference for LA over (Z)-9-TE, while activating the pathway reversed this preference, making mice more likely to approach (Z)-9-TE. This demonstrates that the VTA–mOT dopaminergic pathway plays a critical role in regulating preferences for LA and (Z)-9-TE, likely through D1 and/or D2 spiny projection neurons (SPNs) in the mOT.、

Figure 5. Chemogenetic manipulation of the VTA–mOT dopaminergic pathway alters non-fasted mice’s preference for LA versus (Z)-9-TE.
 

D1 and D2 Spiny Projection Neurons in the mOT Mediate Attraction to LA and Avoidance of (Z)-9-TE, Respectively

To further clarify the role of D1 and D2 SPNs in olfactory preference, the researchers locally infused saline or selective dopamine receptor antagonists into the mOT and tracked mice in two-choice olfactory tests.
D1 receptor antagonist (SCH23390) abolished mice’s preference for LA.
D2 receptor antagonist (eticlopride) reversed avoidance of (Z)-9-TE into preference.
Fiber photometry calcium imaging revealed that D1 SPNs in the mOT responded strongly to LA, whereas D2 SPNs showed stronger responses to (Z)-9-TE. These findings indicate that D1 and D2 SPNs mediate attraction to LA and avoidance of (Z)-9-TE, respectively.

Figure 6. Dopamine D1 and D2 receptor antagonism in the medial olfactory tubercle modulates responses to LA and (Z)-9-TE.

Summary

This study uncovers a “seesaw” mechanism in rodents, linking olfactory perception (main olfactory system) → chemical signal recognition (LA/(Z)-9-TE) → neural circuit regulation (VTA–mOT–D1/D2 SPNs) to orchestrate insect predation behavior. The findings provide a microscopic mechanism for understanding interspecies predation and energy flow in ecosystems and lay a theoretical foundation for developing rodent control strategies targeting conserved olfactory pathways.

Figure 7. Operational model of VTA–mOT dopaminergic pathway regulating foraging behavior via the “seesaw” mechanism.
 
 

The viral tools used in this study were provided by
Brain Case Biotech（bd@ebraincase.com) 
Product Category Number Product Name
Fluorescent Protein BC-0016 rAAV-EF1α-DIO-mCherry
Chemogenetic Inhibition BC-0626 rAAV-hSyn-DIO-hM4D(Gi)-P2A-EGFP
BC-0143 rAAV-hSyn-DIO-hM3D(Gq)-mCherry
Calcium indicator BC-0238 rAAV-hSyn-DIO-GCaMP6s
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