The effects of fasting on the physiology of ventral tegmental area neurons of male and female mice
Date
2022-01
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Abstract
The activity of dopamine neurons in the VTA controls release of dopamine in the striatum, amygdala, and cortical regions to signal reward predictions in response to an environmental cue, and to activate behaviour for reward acquisition and consumption. The activity of dopamine neurons is controlled by both GABA and glutamate inputs to the VTA. Release of dopamine at terminal regions occurs in response to firing of dopamine neurons, induced by prolonged depolarization, typically due to NMDA receptor activation by an excitatory input. Furthermore, dopamine neurons in the VTA are strongly innervated by tVTA/RMTg GABA neurons that act as inhibitory interneurons to inhibit the firing of dopamine. Removal of this inhibition can also lead to firing of dopamine neurons and release of dopamine. GABA neurons from the lateral hypothalamus (LH) send a strong projection to tVTA/RMTg GABA neurons, providing disinhibition of dopamine neurons, release of dopamine in terminal regions, and reward acquisition and consumption. VTA dopamine neurons are responsive to external factors including stress, satiety, and food restriction. However, an understanding of how synaptic inputs to these neurons change in response to acute energy deprivation is unknown. The first aim of my thesis seeks to understand how both excitatory and inhibitory synapses to VTA dopamine neurons changes in response to a 16 hour, dark-cycle fast. I found that acute fasting increases food approach and consumption of high-fat food in a sex dependent manner. These behavioural changes were paralleled by an increase in excitatory synaptic strength in males, and stronger endocannabinoid-mediated short-term synaptic depression in females. The second aim of my thesis focuses on the LH GABA input to GABA neurons in the tVTA/RMTg and how a 16 hour, dark-cycle fast affects synaptic transmission from this input and the general excitability of tVTA/RMTg GABA neurons. I found that fasting decreased the excitability of tVTA/RMTg GABA neurons. In addition, fasting decreased the strength of the LH GABA input to tVTA/RMTg GABA neurons in both males and females and decreased the probability of release at these synapses in females but not males. The knowledge gained from this research will be instrumental in understanding how acute energy deprivation affects the underlying neuronal circuits that control motivation and will aide in the development of more effective treatments for obesity and eating disorders.
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Keywords
Dopamine, GABA, Ventral Tegmental Area, VTA, Fasting, Hunger, Anorexia Nervosa, Motivation, Plasticity
Citation
Godfrey, N. (2022). The effects of fasting on the physiology of ventral tegmental area neurons of male and female mice (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.