Konstantinos Meletis

Emotions guide humans and animals in the selection of behavioral strategies to optimize outcomes and promote well-being. Repeated or unexpected strong negative stimuli such as stressors impair the processing of emotions and lead to the development of mood disorders such as depression and anxiety. Understanding how individuals control their emotions and cope with stressful events has become a major clinical challenge for the development of new treatments. This project aims to define the circuit mechanisms that control emotional regulation. I will focus on a brain region key in emotional regulation, namely the lateral habenula (LHb). Over the past decades, clinical and preclinical studies have identified the LHb as a major hub in the regulation of negative emotions and in the induction of mood disorders. Recent studies have highlighted that lateral hypothalamic (LHA) excitatory inputs to the LHb drive negative emotions (i.e., aversion) and may play a role in depression. However, how the LHb integrates diverse types of inputs to promote negative emotions remains unknown. The main hypothesis of the project is that the complex regulation of emotions is defined by a discrete organization of inputs to LHb that underlies maladaptive circuit-specific dysfunction in models of stress. I will investigate here the molecular and functional properties of the LHb neurons based on their discrete inputs from the LHA. I will use a multidisciplinary approach combining cutting-edge spatial transcriptomics, neuronal tracing and optogenetics to define for the first time the role of the molecularly-defined discrete LHA-LHb pathways in normal and disease-related behaviours. This project will provide key insights about the regulation of mood by the lateral habenula and how the inputs from the lateral hypothalamus are key in the pathophysiology of depression and anxiety disorders.

Action selection, decision-making and cognitive flexibility are critical brain functions for humans and other animals in order to thrive and survive in a complex environment. The frontal cortex and the basal ganglia are thought to control selection of appropriate actions, evaluate their outcome, and update behaviors accordingly. Degeneration of the dopamine system is a hallmark of Parkinson’s disease (PD), and in the prodromal phases of the disease, cognitive and emotional behaviors are affected before the emergence of severe motor dysfunction. We hypothesize that motor and non-motor/motivated behaviors are shaped by the activity of distinct dopamine subtypes, where discrete aspects of motivated behaviors are regulated by different dopamine neuron subtypes and their interactions with striatal compartments and neuron types. In this project, we will investigate the function of Anxa1+ dopamine neurons for learning new motor skills, particularly fine motor actions like reaching and grasping, and cognitive flexibility during choice tasks – and define their role in the manifestation of cognitive and motor learning impairments in prodromal PD. Our aim is to define how specialized interactions between neurons subtypes in the dopamine system and the striatum control motivated behaviors and learning, with the long-term aim to establish a mechanistic understanding of how the organized connectivity between molecularly defined subregions and neuron types shapes complex behaviors.