Alcohol and Diet-Induced Disruptions to Vagal Circuits Regulating Insulin Function
Open Access
- Author:
- Keller, Bailey
- Graduate Program:
- Neuroscience
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- March 17, 2023
- Committee Members:
- Nicholas Graziane, Outside Unit & Field Member
Kirsteen Browning, Major Field Member
Yuval Silberman, Chair & Dissertation Advisor
Andras Hajnal, Major Field Member
Alistair Barber, Program Head/Chair - Keywords:
- Dorsal vagal complex
Alcohol use disorder
binge
GABA
pancreas
insulin
serotonin
selective serotonin reuptake inhibitor
high-fat diet - Abstract:
- Alcohol use disorder (AUD) and diet-induced obesity are highly prevalent and heterogenous conditions that can lead to increased risk of development of chronic metabolic disorders such as Type II diabetes. AUD and diet-induced obesity potentially share biological underpinnings regarding harmful consumption which may be, at least partially, mediated by neurocircuitry within the dorsal vagal complex (DVC). The DVC integrates and relays interoceptive sensory information from the peripheral organs (liver, gastrointestinal tract, pancreas etc.) to influence central processes involved in consummatory behaviors as well as parasympathetic motor control of abdominal end-organ function. Thus, the DVC may be a critical region where alcohol and high-fat diet (HFD) interact to disrupt central circuits involved in both higher order cognition to drive further consumption and dysfunctional autonomic output to organs involved in metabolic control. This dissertation explores the acute and chronic effects of alcohol and HFD on neurotransmission within subregions of the DVC including the nucleus of the tractus solitarius (NTS), the initial central site of processing for sensory signaling from the vagus nerve, and pancreatic-projecting motor neurons residing in the dorsal motor nucleus of the vagus (DMV-PP) which are shown to drive parasympathetic autonomic control of insulin secretions. In Chapter 1, we review the potential role of the DVC in AUD and discuss how the variety of neurotransmitters and neuropeptides produced by the NTS modulate hypothalamic and limbic regions involved in stress, reward and homeostatic control. In Chapter 2, present data from our findings show that acute alcohol exposure on DMV-PP neurons enhanced presynaptic GABA release resulting in decreased neuronal firing and this effect was reproduced by increasing endogenous serotonin, suggesting alcohol may inhibit pancreatic insulin secretions via presynaptic modulation of serotonin. Chapter 3 presents evidence that increasing systemic levels of serotonin through chronic oral administration of fluoxetine, a selective serotonin reuptake inhibitor, reduced alcohol consumption behaviors in mice that co-binge on alcohol and HFD, but may have worsened insulin tolerance and glucose handling in vivo which we postulate may be due to a combination of effects of fluoxetine in the periphery in addition to effects on central circuits including the DVC. In Chapter 4, we examined the effects of chronic alcohol and HFD exposure on DMV-PP and NTS neurons and found that chronic alcohol exposure may increase DVC sensitivity to subsequent alcohol exposure and increase presynaptic GABAergic inhibition from the NTS onto DMV-PP neurons which may drive further disruption of pancreatic insulin release. In Chapter 5, we summarize and discuss the main findings and provide additional considerations for future studies. Overall, examining the mechanistic role of the DVC in metabolic dysfunction associated with AUD and diet-induced obesity could lead to the development of more effective pharmacological targets for management and treatment of these conditions.