Date of Award
Doctor of Philosophy (PhD)
Elucidating the mechanisms through which brain circuits influence behavior is a fundamental tenet of Systems Neuroscience. Advancements in this field are critical to help us understand the inner workings of our brains, and eventually who we are as humans. Describing the physiologic functioning of neural circuits is also necessary to recognize their malfunctions, and to develop strategies to correct them. In many cases, however, alterations in the activity of brainwide circuits can be traced back to specific neuronal populations, and acting selectively upon these cells can restore the normal activity within the system, ultimately correcting the aberrant behavior. Thus, understanding how changes in gene expression and molecular profiles of neurons alter their function is critical to describe interneuronal dynamics within a circuit. During my graduate studies in the Friedman Laboratory at Rockefeller I had the opportunity to combine both Systems and Molecular-Cellular approaches to dissect the circuits and identify the neuronal populations involved in regulating behaviors along the broadest spectrum: from subconscious and innate behaviors (ie, control of energy homeostasis) all the way to the highest order functions (ie, anxiety and compulsive behaviors). To do so, I studied the interaction between cells, circuits and behavior in mice, an ideal model to test these conserved functions. This is because the mouse brain is evolutionarily close to the human brain, yet it is simpler and highly accessible to external manipulations with the molecular biology tools currently at our disposal. The main focus of my graduate work has been to investigate the mechanisms underlying movement control, and regulation of emotions and higher cognitive functions. This project responded to my interest, originated during my medical training, in finding commonalities and differences in neural circuits and functions between brain disorders traditionally classified as pertaining to the sphere of Neurology and Psychiatry. I thus focused on a neural network of nuclei deeply involved in these behaviors, known as the basal ganglia, and in particular on the role of the Subthalamic Nucleus (STN) in Parkinson’s Disease and Obsessive-Compulsive Disorder. I identified previously undescribed subpopulations of STN neurons, and tested their role in mediating motor, emotional and cognitive functions in mice, both in normal and pathologic state. This part of my graduate work is detailed in Chapter 1 to 6. The data I present here have important implications for the physiology and pathophysiology of movement and psychiatric disorders, with the potential for enabling further translational studies. In addition to my main study, I was fascinated by the work conducted in the Friedman Laboratory to elucidate the metabolic and nervous mechanisms that regulate energy balance in the body. I therefore collaborated with a postdoctoral fellow in the laboratory and adopted the same experimental approaches to dissect a neural circuit involved in the maintenance of body temperature in mice. The anterior hypothalamus has been the main brain area associated with thermoregulation since the 1950s. With our work, however, we found that a brainstem region known as the Dorsal Raphe Nucleus (DRN), and particularly a subpopulation of DRN neurons, can also respond selectively and powerfully to changes in external stimuli to maintain a constant body temperature. We also showed that this effect is achieved by inducing changes in both thermogenesis and locomotor activity, and mediated via projections to the anterior hypothalamus and to other brain areas known to be involved in thermoregulation. This part of my graduate work is detailed in the Appendix section. Taken together, these experiments reveal a circuit configuration that allows for the robust control of an innate homeostatic response.
Parolari, Luca, "Dissection of Neurons and Circuits Involved in Regulating Innate Behaviors, Movement and Higher Cognitive Functions in Mice" (2020). Student Theses and Dissertations. 691.