Physiological Effects of Alcohol on Crayfish Escape Circuitry

Alcohol is one of the oldest and most widely used drugs on the planet, but the cellular mechanisms by which it affects neural function are still poorly understood. Unlike other drugs of abuse, alcohol has no specific receptor in the nervous system, but is believed to operate through GABAergic and serotonergic neurotransmitter systems. Invertebrate models offer circuits of reduced numerical complexity and involve the same cell types and neurotransmitter systems as vertebrate circuits. The well-understood neural circuits controlling crayfish escape behavior offer neurons that are modulated by GABAergic inhibition, thus making tail-flip circuitry an effective circuit model to study the cellular mechanisms of acute alcohol exposure. Crayfish are capable of two stereotyped, reflexive escape behaviors known as tail-flips that are controlled by two different pairs of giant interneurons, the lateral giants (LG) and the medial giants (MG). The LG circuit has been an established model in the neuroscience field for more than 60 years and is almost completely mapped out. In contrast, the MG is still poorly understood, but has important behavioral implications in social behavior and value-based decision making. In this dissertation, I show that both crayfish tail-flip circuitry are physiologically sensitive to relevant alcohol concentrations and that this sensitivity is observable on the single cell level. I also show that this ethyl alcohol (EtOH) sensitivity in the LG can be changed by altering the crayfish’s recent social experience and by removing descending inputs to the LG. While the MG exhibits similar physiological sensitivity, its inhibitory properties have never been studied before this research. Through the use of electrophysiological and pharmacological techniques, I show that the MG exhibits many similar inhibitory properties as the LG that appear to be the result of GABA-mediated chloride currents. Finally, I present evidence that the EtOH-induced changes in the MG are blocked through pre-treatment of the potent GABAA receptor agonist, muscimol, which underlines the role of GABA in EtOH’s effects on crayfish tail-flip circuitry. The work presented here opens the way for crayfish tail-flip circuitry to be used as an effective model for EtOH’s acute effects on aggression and value-based decision making.

The relationship of early social, mental, and behavioral experiences with adult obesity and Alcohol Use Disorder

Stressful life events early in life, including symptoms of mental disorders or childhood maltreatment, may increase risk for worse mental and physical health outcomes in adulthood. The purpose of this dissertation was to examine the effects of childhood Attention Deficit Hyperactivity Disorder (ADHD) symptoms and maltreatment experience on two adult outcomes: obesity and alcohol use disorder (AUD). Mediational effects of adolescent characteristics were explored. This dissertation used Waves I, III, and IV of the National Longitudinal Study of Adolescent to Adult Health. In Paper 1 (Chapter 3), we investigated the association between multiple types of child maltreatment and adult objective (body mass index; BMI) and subjective (self-rated) obesity, as well as mediating effects by adolescent characteristics including depressive symptoms and BMI. Results showed that after adjusting for sex, race/ethnicity, and maternal education, physical maltreatment was moderately associated with adulthood obesity as measured by BMI and self-reported obesity, while sexual maltreatment was more strongly associated with the objective measure but not the subjective measure. The indirect effects of mediation of adolescent BMI and depressive symptoms were statistically significant. In Paper 2 (Chapter 4), the objective was to examine mediation by adolescent depressive symptoms, alcohol consumption, peer alcohol consumption, and delinquency in the relationship between ADHD symptoms and adult AUD. The indirect effects of mediation of adolescent delinquency, alcohol consumption, and peer alcohol consumption were statistically significant in single and multiple mediator models. In Paper 3 (Chapter 5), the objective was to assess the joint effects of maltreatment/neglect on adult AUD. After adjusting for sex, race/ethnicity, child maltreatment, and parental AUD, ADHD symptoms were significantly associated with increased odds of AUD. There was no strong evidence of multiplicative interaction by maltreatment. This association was stronger for males than females, although the interaction term was not statistically significant. This dissertation adds to the literature by examining relationships between several major public health problems: ADHD symptoms, childhood maltreatment, AUD, depressive symptoms, and obesity. This project has implications for understanding how early life stress increases risk for later physical and mental health problems, and identifying potential intervention targets for adolescents.