Development of associative and innate neural circuits : from olfactory piriform cortex to hypothalamic hunger and thirst centers

Neurodevelopment is a dynamic process during which neurons mature as individual cells and the architecture of networks emerges from the connectivity between such cells. Such processes involve a combination of molecular cues guiding neurite and synapse growth and activity-dependent mechanisms driving synapse strengthening and physiological maturation of neurons. Given different neural circuits underlie different computations, it is not surprising that their maturation processes and timelines differ as well. Here, I present two projects investigating the development of distinct types of circuits: one recurrently connected associative circuit that remains highly plastic throughout life as an animal encounters new stimuli, and a second circuit driving innate behaviors that stabilizes in its representation early in life. In Chapter 1, I discuss our use of Targeted Recombination in Active Neurons (TRAP) to identify regions of early active neurons that may facilitate activity-dependent developmental processes. By using TRAP in embryonic mice, we found that primary olfactory (piriform) cortex contained the most active neurons in the developing cortex. Because piriform cortex is implicated in olfaction and olfaction is necessary for neonatal survival, we investigated the role of these embryonically active population in neonatally-relevant olfactory behaviors. In addition, piriform cortex depends on its highly recurrent connectivity to stabilize odor representations in the adult brain, but little is known about the development of this recurrent connectivity. Thus, we also investigated the role of this embryonically active population in the development of the recurrent piriform network. Using a combination of ex vivo patch-clamp electrophysiology and in vivo single-unit population recordings, we found that this embryonically active population demonstrated hub-like properties during early postnatal life. These neurons were both broadly connected to the piriform network and had high interconnectivity between members of embryonically active population. While these neurons did not tune towards neonatally-relevant odors, they led spontaneous synchronized population activity during odor-free epochs. Lastly, selective optogenetic activation of this population during neonatal stages increased recurrent connectivity strength within piriform. Together, these findings suggest that embryonically active piriform neurons are a hub-like population whose activity promotes recurrent connectivity in neonates. In Chapter 2, I discuss our investigation into the development of hunger- and thirst-responsive circuits in the neonatal mouse brain. Because neonates sate both hunger and thirst by consuming maternal milk over the first 2--3 postnatal weeks, it is unclear whether these two drives are differentially represented at these early development stages. It has also been difficult to isolate these homeostatic drives in neonates due to the reliance on maternal milk to sate both. To address this, we developed a continuous feeding system using implanted cannulae in neonatal mice. By feeding mice with hyperosmolar food or water, we were able to isolate hunger or thirst in neonates. We found that hunger- and thirst-responding regions are selectively responsive to food and water deprivation within the first postnatal week. Within brain regions that responded to both hunger and thirst, subpopulations of neurons responded consistently to one or the other drive, with little overlap in the population responding across different needs. Feeding an animal a liquid food diet into adulthood did not alter this distinct neural response to hunger and thirst. Thus, activation in these of hunger- and thirst-sensing regions become distinct early in life and remain robust to environmental changes in food and water source.

Keywords: Humanities and Sciences.
Biology.
Advisor: Ding Jun
Luo Liqun
Monje-Deisseroth Michelle
Shatz Carla