Searching for principles of neural circuit evolution, connectivity, and function [electronic resource]

The human brain is the most complex entity in the known universe, whose capabilities and shortcomings are the result of billions of years of evolving life on earth. The nervous system is charged with myriad tasks, from sensing features of the environment to homeostatic control of the body to complex social behaviors. These decisions emerge from computations at many levels: from receptors to cells to circuits to networks. In this dissertation, I take disparate but complementary approaches to search for underlying principles of brain structure and function: (1) a circuit-level analysis of the anatomy and function of the serotonin system in mice and (2) a search for genomic events that caused human-specific nervous system connectivity. In addition to classic excitatory and inhibitory transmission, information flow through the nervous system can be powerfully altered by neuromodulatory signaling (Bargmann and Marder, 2013). Serotonin is perhaps the most famous of these neuromodulators, as it is the target of ubiquitous yet imperfect psychiatric drugs (Nester et al, 2009). Despite its importance in mental health, remarkably little is known about the basic organization of the serotonin system. In Section 2 of this dissertation, we apply rabies-based tracing and electrophysiological techniques to assemble a circuit diagram of the long-range and local inputs to serotonergic and their neighboring GABAergic neurons in the Dorsal Raphe Nucleus (DR). We find that both subtypes receive remarkably similar, diverse inputs, with some interesting differences. In addition to creating a valuable anatomical foundation for future research, we find evidence for heterogeneity within these populations, and that there is a striking spatial organization of local connectivity within the DR. Based on this information, we next sought to study the heterogeneity of these populations in more detail, and to ask what information is being conveyed by DR subtypes, and how that information is encoded in their spatiotemporal patterns of activity. We therefore established a broadly applicable technique to perform in vivo calcium imaging in the DR. In Section 3, we describe this technique, and present preliminary data showing that individual serotonin neurons are remarkably heterogeneous in their responses to positive and aversive stimuli, and that there appears to be some logic to these responses across experiments. Ultimately, the nervous system is the result of natural selection. It can therefore be argued that its organization and logic only make sense in that context, and that by understanding both the selective pressures and the mechanisms by which selection shapes nervous systems, we have the best chance of glimpsing governing principles. In a separate project, unrelated to the serotonin system, we sought to discover genomic events that caused human-specific changes in the connectivity of neural circuits. We hypothesized that the loss of a cis-regulatory element for a gene involved in neural development -- particularly at the level of axon guidance or synapse formation -- could dramatically change patterns of peripheral innervation or central circuit architecture and be a driving force for nervous system evolution. In Section 4, we describe separate human-specific deletions of highly conserved sequence (from McLean et al, 2011) near the neurodevelopmental genes Close homologue of L1 (CHL1), Teneurin 2 (TEN2), and Teneurin 4 (TEN4). We find that a deletion near CHL1 removes two widely expressed transcripts, and that a deletion upstream of TEN4 removes a cis-regulatory element that drives expression in the nail bed of the developing digits. These serve as two examples of ways in which genomic changes drive evolution via modular modifications to gene function.

Keywords: Biology.
Advisor: Luo Liqun
Kingsley David M. (David Mark) advisor. Thesis advisor
Malenka Robert C.
Shen Kang