Eat, explore, rest: a leptin-sensing brain circuit helps overcome anxiety to meet vital needs

How do mammals manage to eat in situations that cause anxiety, step into exposed spaces, or slow down when anxiety drives them to keep moving? A new study pinpoints a leptin-sensitive circuit in the lateral hypothalamus that helps to overcome anxiety to perform essential behaviours such as exploring, feeding, and limiting maladaptive hyperactivity. Leptin is a hormone that acts in the brain, regulating energy balance, influencing appetite and eating behaviour. Leptin is sensed by neurons which have leptin receptors. Many of these neurons are located in the lateral hypothalamus, the brain region where metabolic signals come together. It is responsible for the regulation of eating behaviour. The study “A lateral hypothalamic neuronal population expressing leptin receptors counteracts anxiety to enable adaptive behavioral responses”, headed by Professor Dr Tatiana Korotkova, director of the University of Cologne’s Institute for Systems Physiology and Principal Investigator at the CECAD Cluster of Excellence on Aging Research, has appeared in Nature Neuroscience.

Anxiety is a protective state that helps us to avoid harmful conditions. Yet, anxiety can also block us from pursuing vital needs like eating and, in some cases, can even lead to maladaptive behaviours such as excessive exercise in anorexia nervosa. Because the hypothalamus and its core circuitry are evolutionarily conserved between mice and humans, delineating leptin-sensitive lateral hypothalamic mechanisms could provide a foundation for clinical translation and drug development. In the mouse model, the team shows that activity in leptin-sensing lateral hypothalamic neurons predicts an individual’s anxiety state and can be tuned to restore adaptive choices even under conditions that cause anxiety.

The researchers used tiny microscopes to visualize the activity of individual neurons while the mice freely explored different environments and engaged in various spontaneous behaviours. “We imaged the activity of leptin-sensing neurons while mice faced situations that might cause anxiety. We saw that these neurons get activated whenever animals overcame anxiety and freely explored exposed areas or approached food within them,” says Rebecca Figge-Schlensok, a doctoral researcher at the University of Cologne. “When we boosted this activity, mice explored more and were able to eat in challenging contexts – clear signs that this circuit helps push past anxiety to support adaptive, goal-directed behaviour.”

The researchers further observed increased input from the prefrontal cortex – a region that mediates cognitive control – in more anxious animals. This input supressed the activity of anxiety-reducing cells, thereby preventing relief from anxiety. This demonstrates a role of cognitive control in the regulation of emotional states. “What excited us is that the activity of these leptin-sensing neurons doesn’t just track state – it predicts which individual will be more or less anxious in a challenging situation,” notes Dr Anne Petzold, co-first author, currently a group leader at the European Neuroscience Institute, Göttingen. “Increased input from the prefrontal cortex provided a mechanistic handle for why more anxious individuals fail to recruit this anxiety-reducing circuit.”

Anxiety has clear clinical intersections, notably with anorexia nervosa. To investigate the therapeutic potential of the anxiety-relieving, leptin-sensitive neurons for the treatment of anorexia nervosa, the team turned to a preclinical anorexia nervosa disease model: the activity-based anorexia model. In this paradigm, mice with scheduled access to food and a freely accessible running wheel spontaneously develop excessive exercise levels. This symptom, often observed in anorexia nervosa patients, can transiently relieve anxiety, but worsens negative energy balance. Boosting the activity of leptin-sensing lateral hypothalamic neurons reduced excessive exercise to baseline levels, uncoupling anxiety from compensatory running.

This observation points to an anxiety-reducing, energy-preserving mechanism: “Anxiety and anorexia nervosa often go hand in hand – and anorexia has the highest mortality rate of any psychiatric disorder, with no effective pharmacological treatment to date,” says senior author Tatiana Korotkova. “By identifying a leptin-sensitive hypothalamic node that restrains anxiety-driven locomotion without suppressing normal activity, we begin to understand how emotional state and energy balance intersect in the brain. The next step is to test whether pharmacological modulation of these neurons could help treat anxiety and eating disorders.”

This research was supported by the ERC Consolidator Grant HypFeedNet, the German Research Foundation (DFG), the Cluster of Excellence on Aging Research (CECAD), Collaborative Research Centre 1451 “Key Mechanisms of Motor Control in Health and Disease”, and the Center for Molecular Medicine Cologne (CMMC).

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