Decoding neuropeptide function in inhibitory amygdala microcircuits

Descripción del proyecto

El papel de los neuropéptidos en el comportamiento adaptativo

Cada vez hay más pruebas de que diversos trastornos psiquiátricos implican procesos de aprendizaje inadaptados. Se cree que los neuropéptidos, conocidos por favorecer la comunicación neuronal y la plasticidad, especialmente en situaciones de estrés, desempeñan un papel clave en este sentido. Sin embargo, su función precisa en los circuitos cerebrales sigue siendo poco conocida. El equipo del proyecto DecodeNP, financiado por el CEI, pretende descubrir cómo afectan los neuropéptidos al miedo y la ansiedad. El equipo de investigación se centrará en neuronas especializadas de la amígdala, la parte del cerebro profundamente implicada en el procesamiento de las emociones. Mediante imágenes avanzadas y perfiles moleculares, estudiarán exactamente cuándo se liberan los neuropéptidos y cómo influyen en la actividad neuronal. En última instancia, en el proyecto se espera arrojar luz sobre los mecanismos biológicos que subyacen al comportamiento relacionado con la supervivencia y ayudar a comprender cómo se desarrollan los trastornos de ansiedad.

Objetivo

Adaptive behaviour to ever-changing environments is crucial for an animal’s survival in conditions of immediate threat. Meanwhile, there is growing evidence that psychiatric conditions, including anxiety disorders, are at least partly based on maladaptive learning. Neuropeptide signalling plays a key role in regulating synaptic plasticity and hence learning in a state-dependent manner, and dysregulated peptide signalling has been observed in patients suffering from psychiatric disorders. Due to specific expression of peptides and their receptors in distinct cell types and microcircuits, they can contribute to the specificity of neural communication on both temporal and spatial scales. However, the signalling mechanisms and behavioural roles of neuropeptides in individual circuit elements are not well understood.
In this proposal, we will use a multimodal approach to determine the role of neuropeptides in innate and learned fear and anxiety states. We will focus on microcircuits of the amygdala, more specifically on distinct interneuron types, which co-release different peptides with their common main transmitter GABA. Using state-of-the-art technology, we will analyse under which conditions neuropeptides are released from interneurons, and probe their causal contribution to fear learning and anxiety states with intersectional genetic interrogations. Large-scale, longitudinal in vivo calcium imaging combined with novel spatial transcriptomics will further reveal peptide impact on circuit computations. As both amygdala circuitry and function as well as neuropeptide expression are evolutionarily conserved, we expect that this proposal will unravel fundamental mechanisms of neural circuit functions for survival. This research will not only provide novel insights into the neural mechanisms of fear and anxiety, but will also hold significant clinical relevance for understanding the underlying pathophysiological processes that contribute to psychiatric disorders.