Adolescence is a developmental stage of life broadly viewed as a transitional period between juvenility and adulthood. This stage is characterized by sexual maturation and physical growth in addition to specific behavioral phenotypes, such as increased exploration, risk-taking, and impulsivity. Concurrent with these behavioral changes, the frontal cortex continues to develop throughout adolescence. Some of the physiological changes in the frontal cortex during adolescence mirror those that occur in sensory cortices at earlier ages, when certain sensory functions undergo a “critical period” of development. During a critical period, neurophysiological changes facilitate the emergence of specialized neural functioning, and developmental disruptions during a critical period can result in irreparable deficits in neural function. It has been postulated that there may be critical, or “sensitive”, periods for behavioral functions in addition to neural functions. However, it remains unclear how the concept of a critical or sensitive period may translate from the sensory cortices to the functions of and emergent behaviors involving the frontal cortex. In this dissertation, I explore the possibility of an adolescent sensitive period for encoding of task-related information in the dorsomedial region of the prefrontal cortex of mice.
In Chapter 1, I describe the developmental changes that occur over the course of adolescence. I focus on anatomical and neurophysiological remodeling in the dorsomedial prefrontal cortex at the cellular level and give a brief overview of a subset of the existing literature examining adolescent behavior. There are many classes of behavioral tasks employed in adolescent studies, but I describe only those related to response inhibition, a behavior of relevance to the research herein. In Chapter 2, I outline the mechanisms of critical period onset from previous work in sensory cortices and demonstrate how these mechanisms are reflected in the frontal cortex during adolescence. I construct the hypothesis that, if adolescence does indeed represent a sensitive period for frontal cortical function, we may expect to see greater encoding of environmentally relevant information in the adolescent frontal cortex compared to the adult. I then present my work examining learning of a go/no-go task and encoding of task information in the dorsomedial prefrontal cortex of adolescent and adult mice. I show that adolescent mice learn the task faster and run more during the task than adults. Moreover, adolescent frontal cortex encodes certain task variables with greater specificity at the population level, but not at the single-cell level, than adult frontal cortex. I argue that this evidence, supported by previous literature documenting the development of the dorsomedial prefrontal cortex, lends credence to the concept of an adolescent sensitive period. This chapter contains material in preparation for publication with co-authors Hongli Wang, Lung-Hao Tai, Albert Qü, Mei Murphy, and Linda Wilbrecht.
In Chapter 3, I discuss methodologies for investigating catecholamine neuromodulation in the brain. I emphasize that while recent advances in fluorescent sensors have enabled unprecedented access to catecholamine dynamics in animal models, few studies have employed optical techniques in the adolescent brain, possibly due to limitations of existing tools. In this chapter, I present research that documents first steps toward expanding the repertoire of available imaging methods. This research leverages the fluorescent properties of single-walled carbon nanotubes to develop a functionalized optical fiber capable of detecting nanomolar concentrations of dopamine in vitro in small volumes of biological fluids and ex vivo in mouse brain tissue. This form factor bypasses the need for genetic integration of a fluorescent protein, potential permitting greater translatability. I also introduce the development of a dual-near-infrared mobile fiber photometry rig that permits flexible use of our tool. I discuss the utility of this tool in its current form and outline potential future applications. This chapter contains material in preparation for publication with co-authors Rigney Miller, Linda Wilbrecht, and Markita Landry.
Finally, in Chapter 4, I return to the discussion of the adolescent sensitive period. I reiterate some of the major changes developing in the adolescent frontal cortex and suggest potential mechanisms of action for their contributions to the onset of a sensitive period. I explore the possibility that mechanisms of sensitive period onset beyond those observed in sensory cortices are at play in the frontal cortex and suggest future directions of research. I conclude by stressing the importance of research on the adolescent brain from a public health perspective. Overall, this dissertation aims to communicate the possibility of an adolescent sensitive period for the development of the frontal cortex, introduce a new potential tool for investigation of catecholamine dynamics, and advocate for greater attention to the adolescent brain.