Organization of brain circuits that control motivated behaviors

Eudemonia (Greek: εὐδαιμονία) is an anthropocentric term describing the absolute well-being in the Aristotelian ethics, along with the terms “arête” (virtue) and “phronesis” (wisdom from an ethical and practical point of view). Arête and virtue will guide ones decisions to promote future eudemonia and ultimately survival. Some of the classic parameters that shape decisions across species include the ability to experience reward, the good prognosis of reward and the avoidance of events that would harm ones physiology and psychology. Such behavioral complexity is orchestrated by a plethora of brain circuits. A well-established candidate mediating reward-related behaviors is the neurotransmitter dopamine and the dopaminergic pathways. The activity of the dopaminergic pathways is influenced and modulated by cortical and subcortical areas involved in pain, mood regulation, arousal, stress and substance abuse (Hikosaka et al., 2008). These neuronal networks, affecting directly or indirectly the dopamine activity, are shaping motivated behaviors and decisionmaking. The conceptual aim of my thesis is to understand molecular, anatomical and functional features of brain reward circuits. In this thesis I will be summarizing the background literature of my projects with special references to the brain areas including the basal ganglia structures, the habenula complex and the parabrachial nucleus, in the context of motivation, anhedonia and pain. In Chapter 1, the brain-reward system will be discussed, with references to the old and new methodologies used to study its neurobiology. The diverse modulatory effects of dopamine and its implications in the prediction of reward are also described here. Chapter 2 reviews the basal ganglia literature. The neurochemistry and neuroanatomy of the main elements of basal ganglia are described here, with the main focus being on the area of striatum. The physiology and pathophysiology of striatal circuits are central in the control of motor, cognitive and limbic functions. Relevant to this chapter are the Papers I and II. The work in Paper I, describes the cell-type specific corticostriatal projections as well as the molecular discrimination of the cortical layers. It will be also examined here, the acute-cocaineexposure effect in motor and reward function on a molecular and behavioral level. During this study, an open-access pipeline was developed in order to easily identify and map neuronal features (cell bodies, axons, dendrites) on a standardized brain atlas. Paper II deals with the complexity of striatal anatomy and neurochemistry. This work describes how cell-type-dependent and cell-type-independent spaces uniquely constitute the striatum. There are special references to a newly identified striatal medium spiny projection neuron. In Chapter 3, the epithalamic structure of lateral habenula is reviewed on an anatomical and functional level. The general focus of the chapter is on how the lateral habenula is mediating anti-reward signals through its connectivity patterns and its direct effects on neuromodulatory systems. Paper III is related to this chapter. The Paper III, reveals how the lateral habenula-mediated aversive and fear behaviors are reflected on a network connectivity level. Central in this project are the adjacent populations of the basal ganglia-hypothalamus borders that are of distinct neurochemistry and connectivity and also convey differential anti-reward signals to the lateral habenula. Chapter 4, reviews the parabrachial nucleus structure and function. It is discussed here, the importance of the parabrachial activity in conveying internal and external signals (pain, fear, visceral malaise) to forebrain in order to promote decision-making. The last Paper IV (manuscript) relates to chapter 4. Paper IV, deals with the unique cytoarchitecture of the lateral parabrachial nucleus and its afferent and efferent connectivity. The main focal point in this work is the previously undescribed cholinergic subpopulation of the nucleus, which displays both classic and distinct neuroanatomical features when compared with the well-established markers of the area. In summary, this thesis captures the diversity of neuronal substrates scattered across the brain and yet function in the direction of maximizing well-being. Common substrate of these structures is their direct or indirect connections with the dopaminergic centers and the extended brain reward circuit. Paradoxically, activation of most of the areas examined here is primarily signaling aversion, fear and pain rather that reward! The combinatorial view when studying advance behavioral aspects leads to a finer comprehension of the physiological function. LIST OF SCIENTIFIC PAPERS I. An interactive framework for whole-brain maps at cellular resolution Fu ̈rth D. , Vaissière T. , Tzortzi O. , Xuan Y. , Märtin A. , Lazaridis I. , Spigolon G. , Fisone G. , Tomer R. , Deisseroth K. , Carlén M. , Miller C.A. , Rumbaugh G. , Meletis K. Nature Neuroscience. 2018 Jan;21(1):139-149. II. A spatiomolecular map of the mouse striatum Märtin A. , Calvigioni D. , Tzortzi O. , Fuzik J., Wärnberg E. , Meletis K. Cell Reports. 2019 Dec 24;29(13):4320-4333.e5. III. A hypothalamus-habenula circuit controls aversion Lazaridis I. , Tzortzi O. , Weglage M. , Märtin A. , Xuan Y. , Parent M. , Johansson Y. , Fuzik J., Furth D. , Fenno L.E. , Ramakrishanan C. , Silberberg G. , Deisseroth K. , Carlén M. , Meletis K. Molecular psychiatry. 2019 Sep;24(9):1351-1368. IV. Characterization of a cholinergic-glutamatergic population in the lateral parabrachial nucleus Tzortzi O. , Mantzafou A. , Meletis K. Manuscript CONTENTS 1. The Brain Reward System . 1 1.