Neuronal circuits, neurophysiology and optogenetic approaches, Neuronal excitability

Publication date: 24/12/2025

Authors: Ducrocq F, Delwel L, Papavoine N, Brouwer E, Kooij KL, Wolterink-Donselaar IG, Drost L, Hak J, Veendijk M, Luijendijk M, Meye FJ & Adan RA

Journal: Nature Communications

Commentary: Ducrocq and colleagues offer a mechanistic advance in the neurobiology of anorexia nervosa by exploiting an animal model that captures its core phenotypes, as self-starvation, excessive physical activity, and susceptibility to severe weight loss. Using the activity-based anorexia (ABA) paradigm in female mice, the authors identify a specific inhibitory circuit mechanism within the ventral tegmental area (VTA) that links negative energy balance to pathological hyperactivity. The central finding is that ABA exposure selectively increases the firing rate of VTA dopamine neurons without altering their intrinsic membrane properties, indicating that synaptic rather than cell-autonomous changes underlie this effect. The study demonstrates that this hyperdopaminergic state arises from weakened local GABAergic control: VTA GABA neurons exhibit reduced excitability and decreased action potential–dependent GABA release onto dopamine neurons, resulting in functional disinhibition. These alterations are precisely characterized using ex vivo patch-clamp recordings, paired-pulse analyses of inhibitory synapses, and optogenetic stimulation of local GABA projections. Crucially, the functional relevance of this circuit mechanism is established through chemogenetic experiments in behaving animals. Selective activation of midbrain GABA neurons during ABA exposure suppresses light-phase running activity and limits body weight loss, whereas their inhibition accelerates hyperactivity and exacerbates starvation. These bidirectional manipulations directly link VTA GABA neuron activity to both behavioral and metabolic outcomes, identifying this population as a key regulator of maladaptive energy expenditure. Future work will need to determine whether similar mechanisms operate across sexes and disease stages, and how VTA GABA dysfunction interacts with stress, hormonal signals, and feeding-related circuits. Overall, this study reframes hyperactivity in anorexia nervosa because of impaired inhibitory control over midbrain dopamine signaling and highlights VTA GABA neurons as a promising circuit-level target for therapeutic intervention.

Commented by: Francesca Mottarlini

DOI: https://doi.org/10.1038/s41467-025-67897-w