Lateral Hypothalamic Projections to the Rat Ventral Tegmental Area: Potential Anatomical Substrates for Adaptive Integration of Behaviors Mediated by Ascending Dopamine Systems

Complex motor behaviors enable mammals to adapt to their internal and external environments. The lateral hypothalamic area (LHA) contributes importantly to autonomic and endocrine regulation, behavioral states, and energy balance. Orexin (Orx) neuropeptides, produced exclusively by LHA cells, are crucial in the integration of sleep and arousal. The LHA projects densely to the ventral tegmental area (VTA), a dopamine (DA) region that is essential for modulating goal-directed behaviors. Extensive investigations of reward function implicate the LHA-VTA connectivity, an arrangement not yet characterized in detail at the ultrastructural level. The present research sought to clarify the precise interactions of LHA axons with VTA cells. Considering reported physiological responses of VTA cells to LHA stimulation and Orx actions, we hypothesized that both projections interact heavily with DA and GABA cell groups in the VTA, and that LHA axons provide a predominant inhibitory innervation. We used immunocytochemistry to visualize DA or GABA neurons in combination with 1) tract tracer identification of LHA axons or 2) immunolabeling for Orx. Electron microscopic analysis of the VTA revealed that, while the bulk of LHA and Orx projections pass through the VTA, their connections with DA and GABA neurons are a complementary mixture of excitatory and inhibitory synapses. The details of morphology herein suggest many different mechanisms of signal transmission by which LHA axons might contribute information concerning interoceptive state to the adaptive performance of complex motor behaviors modulated by the VTA. x xi PREFACE I would like to thank the members of my thesis committee for their valuable guidance. I especially want to thank Dr. Susan Sesack, my advisor, for teaching me about the many fine details of neuroanatomy, science, and life in general. Much appreciation to past and present members of the Sesack Lab, for all their patience and insight in training me in the methodology of electron microscopy. My family and friends give precious meaningfulness to this accomplishment. Thank you for your loving support and understanding: my husband and favorite person in the world, Nic Pedicino-thank you for caring for me the way you do every day; my parents, Drs. Arthur and Amelia Balcita; my brother, Arnel Balcita; Connie and Janeanne Lopes, my mother and sister in-law; my best buddy, Layla Banihashemi. This thesis is dedicated to my dearest nephew Qai Balcita. The perspective of the present research comes not from the question of whether lateral hypothalamic area (LHA)-ventral tegmental area (VTA) connections are …