Sex differences in the effect of acute fasting on excitatory and inhibitory synapses onto ventral tegmental area dopamine neurons

Abstract

Dopamine neurons in the ventral tegmental area (VTA) are important for energizing goal directed behaviour towards food and are sensitive to changes in metabolic states. Fasting increases the incentive motivation for food, mobilization of energy stores and have sex-dependent effects. However, it is unknown how acute fasting alters excitatory or inhibitory synaptic transmission onto VTA dopamine neurons. An acute 16h overnight fast induced increased food seeking behaviour that was more predominant in male mice. Fasting increased miniature excitatory postsynaptic current (mEPSC) frequency and amplitude in male, but not female mice. This effect was not due to altered release probability as there was no change in the paired pulse ratio, nor was it due to an altered postsynaptic response as there was no change in the AMPAR/NMDA ratio or response to glutamate uncaging. However, this effect was consistent with an increase in the number of release sites. In addition, depolarization-induced-suppression of excitation (DSE), a measure of short-term endocannabinoid-mediated plasticity, was enhanced in female but not male fasted mice. There were no fasting-induced changes at inhibitory synapses onto dopamine neurons of male or female mice. Taken together, these results demonstrate that fasting influences excitatory synapses differentially in male and female mice, but preserves inhibitory synapses onto dopamine neurons, indicating that the mesolimbic circuit of male and female mice respond differently to acute energy deprivation. Key PointsO_LIFasting can increase motivation for food and can energize reward-seeking. C_LIO_LIVentral tegmental area (VTA) dopamine neurons respond to motivationally relevant information and fasting can influence mesolimbic dopamine concentration. C_LIO_LIAn acute overnight fast differentially alters food approach behaviours and excitatory synaptic transmission onto VTA dopamine neurons of male or female mice. C_LIO_LIWhile inhibitory synapses onto VTA dopamine neurons are not altered by fasting in male or female mice, male mice had strengthened excitatory synapses whereas female mice had increased endocannabinoid-mediated short term plasticity at excitatory synapses. C_LIO_LIThese results help us understand how fasting differentially influences excitatory synaptic transmission onto dopamine neurons and may inform different strategies for fasting-induced food seeking by male and female mice. C_LI