Nature Neuroscience Major Publication – How Leptin Receptor Neurons in the Hypothalamus Counteract Anxiety and Regulate Adaptive Behavior

1. Academic Background: The Dynamic Balance Between Anxiety and Survival Behaviors

Anxiety is a protective emotional state that prevents individuals from exposure to potential danger and maintains safety. However, anxiety is a “double-edged sword”; it can also interfere with the fulfillment of other essential physiological needs—such as feeding, exploration, and adaptation. Especially when the external environment is full of threats, how animals or humans strike a dynamic balance between anxiety and survival behaviors remains a major unsolved mystery in neuroscience.

In fact, anxiety disorders and eating disorders (such as anorexia nervosa) are highly comorbid, with both intertwining to affect mental health and impair adaptive behaviors. Existing studies have shown that the hormone leptin, secreted by adipocytes, not only participates in energy balance and feeding regulation but also influences emotional behaviors such as anxiety and depression. Neurons in the lateral hypothalamus (LH) expressing the leptin receptor (Lepr) play a central role in various need-based behaviors, such as feeding, exploration, and social interactions, but their specific circuitry mechanisms in anxiety adaptation remain unclear.

This study sought to answer the following key questions: 1. When animals face threats or anxiogenic stimuli, do Lepr-expressing neurons in the LH endow them with the capacity to overcome anxiety and achieve adaptive behaviors? 2. How do these neurons regulate behavior in health and disease states (such as anorexia nervosa)? 3. What regulatory role does the prefrontal cortex (PFC) play in LH neurons? Is its signaling involved in the dynamic regulation of anxiety-behavior processes?

2. Article Information and Research Team

This research manuscript, titled “A lateral hypothalamic neuronal population expressing leptin receptors counteracts anxiety to enable adaptive behavioral responses”, was published in the top neuroscience journal Nature Neuroscience (Nature Neuroscience | volume 28 | November 2025 | 2262–2272).

Leading authors include Rebecca Figge-Schlensok, Anne Petzold, Nele Hugger, Alisa Bakhareva, and others, primarily affiliated with the Institute for Systems Physiology, Faculty of Medicine, University of Cologne, the CECAD Cluster of Excellence, European Neuroscience Institute, and other internationally renowned research institutions, with the University of Cologne as the central hub. They published this result online in November 2025 (doi:10.1038/s41593-025-02078-y), marking a new era of exploration in this field.

3. Detailed Research Workflow

1. Overall Experimental Design and Innovative Methods

To systematically dissect how LH leptin receptor-expressing neurons (LeprLH cells) help animals overcome anxiety and achieve adaptive behaviors such as exploration and feeding, the authors employed several innovative techniques: - Single-cell calcium imaging: Using GCaMP6m/GCaMP8m calcium indicators to track the real-time activity of LeprLH neurons in freely behaving mice. - Targeted optogenetics and chemogenetics manipulation: Activating target neurons with Channelrhodopsin-2 (ChR2) or Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to evaluate the effect of LeprLH cell activation on anxiety behaviors. - Neural circuit tracing and parallel imaging: Combining optogenetic stimulation from the PFC to the LH with LeprLH neuron imaging to elucidate the functional coupling of cortical-hypothalamic circuits. - Single-cell transcriptomic analysis and in situ hybridization: Parsing out the molecular subpopulation structure of LeprLH neurons and identifying expression profiles of genes associated with anxiety and anorexia risk.

2. Subjects and Experimental Models

The main experimental subjects were adult mice aged 12-16 weeks, including Lepr-Cre, Nts-Cre (neurotensin-expressing), and C57Bl/6 (wild-type) strains. Both sexes were used, and groupings were randomized to ensure representativeness and reproducibility of sample selection. Key sample sizes included: - Single-cell calcium imaging: LeprLH neurons (n=193 cells, 16 mice, 10 females); NtsLH neurons (n=226 cells, 4 mice). - Optogenetic and chemogenetic manipulations: 7–11 animals per group depending on the experimental design. - PFC projection fiber imaging: n=9 mice. - Molecular analysis: Transcriptomic datasets involved thousands of neuronal cells.

3. Behavioral and Neurophysiological Experimental Procedures

(1) Assessment of Anxiety Adaptation Behaviors

Animals were required to explore safe (closed arms) and exposed (open arms) spaces in the Elevated Plus Maze (EPM), producing natural anxiety responses. The study recorded the Ca2+ signal peaks in LeprLH neurons upon entry into open arms, comparing neuronal activity and behavioral parameters (e.g., open arm time, entry counts) between high- and low-anxiety groups.

(2) Optogenetic and Chemogenetic Activation of LeprLH Neurons

In the EPM and Open Field (OF) tests, LeprLH cells were activated either optogenetically (ChR2) or chemogenetically (DREADD-hM3Dq), with behavior changes tracked in parallel. Experimental mice showed significant increases in open arm exploration and reduced anxiety compared to controls, with no increase in total locomotor activity, indicating that behavioral changes were related to anxiety rather than motor capability.

(3) Interaction Experiments Between PFC-LH Circuit and LeprLH Neurons

Optogenetic technology was used to stimulate PFC-originating projections in the LH, with concurrent analysis of LeprLH neuronal responses. Findings demonstrated that PFC→LH inputs were active during exploration of novel environments and significantly inhibited LeprLH neurons, with suppression strength positively correlated with the animal’s anxiety level—especially notable in high-anxiety mice. Subsequent behavioral experiments revealed that activation of the PFC-LH circuit reduced exploratory drive in exposed zones and heightened anxiety responses, indicating that the PFC exerts a negative regulatory effect on the hypothalamic anxiety adaptation circuit.

(4) Regulation of Feeding Behavior Under Anxiogenic Context

Using the Novelty-Suppressed Feeding Task (NSFT), food was placed in a brightly lit, novel environment, challenging hungry mice with simultaneous anxiogenic stimulus. Imaging data showed significant activation of LeprLH neurons when animals approached novel food, and the degree of activation predicted whether anxious individuals could successfully initiate feeding. Low-anxiety animals’ LeprLH responses distinctly differentiated among anxiogenic spatial stimuli, whereas high-anxiety animals’ responses overlapped and lacked such discrimination. Experimental activation of LeprLH neurons promoted feeding initiation, specifically effective under high-anxiety/novel contexts, helping to relieve adaptive impairment in animals with anxiety disorders.

(5) Anorexia Animal Model and Adaptive Behavior

An Activity-Based Anorexia (ABA) model was used, where restricted-time feeding combined with voluntary running wheel access induced mouse behaviors analogous to human anorexia. The study found a tight association between running wheel activity and anxiety level in the ABA model. In the restriction phase, LeprLH neurons responded strongly to running wheel stimulation, with group activation levels related to anxiety state. In low-anxiety animals, LeprLH activation by wheel running was rapid and robust, whereas high-anxiety animals required longer exercise to reach comparable activation. Chemogenetic activation of LeprLH cells effectively blocked anxiety-driven over-exercise in the ABA model and promoted energy-saving adaptive behaviors.

(6) Exploration of Molecular Mechanisms and Genetic Risk Analysis

Single-cell transcriptomics and in situ hybridization characterized LeprLH neuronal subpopulations, revealing cohorts expressing anxiety and anorexia risk genes (such as EBF1 and OPCML). High-anxiety animals had significantly reduced EBF1 expression in LeprLH cells. Furthermore, principal component analysis and multi-omics data identified molecular mechanisms of adaptive behaviors involving subgroups such as Gal+, Tac1+, and Htr2c+.

4. Main Findings and Scientific Significance

1. LeprLH neurons are specifically activated by anxiogenic stimuli, drive animals to overcome anxiety for exploration and feeding, and display adaptive behaviors.

• Regardless of sex, LeprLH cells exhibited significant increases in Ca2+ signals during open arm exploration in the EPM, with the degree of activation highly correlated with exploratory behavior and open zone time.
• Optogenetic and chemogenetic activation of LeprLH neurons significantly improved adaptive exploration and reduced anxiety without affecting total locomotion.
• Removal of leptin receptor expression in LeprLH cells impaired adaptive behaviors, demonstrating the central role of this subpopulation in behavioral regulation.

2. The PFC-LH circuit negatively regulates LeprLH neurons, promotes anxiety states, and affects transitions in adaptive behavior.

• PFC output to LH increased during exploration of novel environments or feeding initiation, generating strong inhibition of LeprLH cells, especially prominent in high-anxiety animals, as reflected by reduced open zone exploration and heightened anxiety.

3. LeprLH neurons have high discriminative capacity for anxiogenic spatial and food stimuli; their activation helps restore feeding in animals with anxiety disorders.

• LeprLH activity predicted whether high-anxiety animals could successfully feed in novel environments; chemogenetic activation significantly reduced feeding latency, effective only in anxiety-inducing scenarios.

4. In the Activity-Based Anorexia (ABA) model, LeprLH activation by exercise helps animals overcome anxiety barriers, prevents excessive exercise and energy expenditure—advancing understanding of the anxiety-exercise comorbidity mechanism in human anorexia.

• Activation of LeprLH effectively averted anxiety-driven over-exercise, manifesting energy-protective adaptive behaviors.
• Single-cell imaging and trajectory analyses revealed that group responses of LeprLH predict adaptive performance in animals with different anxiety levels.

5. At the molecular level, LeprLH subpopulations express EBF1, OPCML, and other genes associated with anxiety and anorexia risk, with expression inversely correlating with anxiety presentation.

• LeprLH neuronal cohorts with higher EBF1 expression correspond to low-anxiety states. Molecular profile data provide new evidence for the genetic regulation mechanisms underlying anxiety and eating disorders.

5. Research Conclusions and Applied Value

This study is the first to systematically reveal that leptin receptor-expressing neurons in the LH area adaptively modulate core survival behaviors such as exploration, feeding, and exercise by counteracting anxiogenic stimuli. Activation of LeprLH cells is the neural core of overcoming anxiety and promoting adaptive behavior, particularly showing crucial functions in animal models of psychiatric disorders like anorexia nervosa. The prefrontal cortex inhibits the LH anxiety adaptation circuit to promote anxiety and behavioral disorders, providing new targets for anxiety intervention via its negative regulatory mechanisms.

This research proposes a neural circuit model of the dynamic balance between anxiety and basic survival behaviors (such as feeding and exercise), provides a mechanistic basis for understanding psychiatric comorbidity (such as anxiety and anorexia), and may offer new methodological solutions for the clinical treatment of anxiety and eating disorders (e.g., using leptin-based drugs or circuit-targeted interventions).

6. Research Highlights and Innovation

• Multimodal single-cell real-time imaging, finely parsing neuronal activity across diverse behavioral contexts;
• Innovative combination of optogenetic/chemogenetic techniques, allowing for real-time manipulation of specific neuron groups and causal behavioral chain determination;
• First revelation of a hierarchical negative regulatory mechanism by PFC cortex over the LH anxiety-adaptation circuit;
• Precise molecular profiling, discovering LeprLH subpopulation molecular features linked to psychiatric risk genes, building a bridge from gene to behavior to neurobiology;
• Behavioral models encompass both healthy and pathological states, simultaneously innovating in disease application scenarios and basic science.

7. Outlook

Future research could focus on the function of LeprLH circuit genetic risk subgroups, the potential for pharmacological intervention, and preclinical translational studies, particularly providing precision medicine clues for groups with anxiety and eating disorder comorbidity. This will also expand theoretical understanding and technical perspectives for studies of neural circuits and dynamic regulatory mechanisms in brain health.

This work reported by Nature Neuroscience uncovers, through multi-scale neural circuits and molecular mechanisms, key answers to how life achieves adaptive balance between anxiety and survival needs; it has major implications for both fundamental neuroscience and clinical translation in mental disorders.