The missing link: inhibitory interneurons as the core of anxiety and depression comorbidity

Descripción del proyecto

Estudiar la relación entre la ansiedad y la depresión

Cada vez más personas en todo el mundo luchan contra la depresión y la ansiedad. Estos dos trastornos mentales suelen aparecer juntos, siendo la ansiedad la que suele aparecer primero. A pesar de su impacto generalizado, los científicos aún no comprenden del todo qué las causa ni por qué se relacionan. Sin este conocimiento, los tratamientos siguen siendo limitados, lo que deja a millones de personas sin un alivio eficaz. En este contexto, el equipo del proyecto ZoomINs, financiado por el CEI, pretende descubrir la conexión biológica entre la ansiedad y la depresión. Los investigadores se centrarán en unas células encefálicas especiales llamadas interneuronas GABAérgicas (IN) y en cómo interactúan con unas células inmunitarias conocidas como microglía. Mediante técnicas avanzadas como la secuenciación genética y la obtención de imágenes encefálicas, el equipo del proyecto espera revelar nuevos conocimientos que puedan conducir a mejores tratamientos.

Objetivo

Rates of depression and anxiety are constantly surging, resulting in a growing global mental health crisis. These two disorders have a remarkably high prevalence of comorbidity, with anxiety generally preceding depression. However, the biological basis of these disorders and their comorbidity is poorly understood, leaving millions of patients with inadequate treatments and thus an urgent need for improved medications. Accumulating evidence suggests that both disorders involve GABAergic deficits, but the nature of these deficits is undefined and may be the holy grail for cracking the mysteries of depression and anxiety comorbidity. Here, I will apply cutting-edge technologies to focus on hippocampal GABAergic interneurons (INs) and propose a data-driven hypothesis for the cellular and molecular basis of anxiety and depression comorbidity. I suggest that INs selectively recruit microglia to reshape inhibition in the depressed brain. This hypothesis may provide the missing link between major hallmarks of depression: GABAergic deficits, synaptic loss, and neuroinflammation. I seek to unravel the molecular adaptations of INs to stress that lead to microglia recruitment and connect them with anxiety preceding depression. Finally, I will elucidate a novel model for innate anxiolysis mediated by local dendritic translation in INs. I will combine, for the first time, the robustness of two analytical methods: translating ribosome sequencing and spatial transcriptomics to identify the involved genes, the INs subtypes expressing them, and their hippocampal location. These data will be complemented by calcium imaging, behavioral tests, imaging, connectomics, and electrophysiology. ZoomINs targets an urgent public health concern by providing a novel hypothesis for a long-standing question: what causes anxiety and depression comorbidity? The results of this ambitious project will set the ground for the development of INs-targeting medications, giving hope to millions worldwide.