Godfrey, N. | Search bioRxiv

bioRxiv2021

Activation of LH GABAergic inputs counteracts fasting-induced changes in tVTA/RMTG neurons.

Dopamine neurons in the ventral tegmental area (VTA) are strongly innervated by GABAergic neurons in the tail of the VTA (tVTA), also known as the rostralmedial tegmental nucleus (RMTg). Disinhibition of dopamine neurons through firing of the GABAergic neurons projecting from the lateral hypothalamus (LH) leads to reward seeking and consumption through dopamine release in the nucleus accumbens. VTA dopamine neurons respond to changes in motivational state, yet less is known of whether tVTA/RMTg GABAergic neurons or the LH GABAergic neurons that project to them are also affected by changes in motivational state, such as fasting. An acute 16 h overnight fast decreased the excitability of tVTA/RMTg GABAergic neurons of male and female mice. In addition, fasting decreased synaptic strength at LH GABA to tVTA/RMTg GABAergic synapses, indicated by reduced amplitude of optically evoked currents, decreased readily releasable pool (RRP) size and replenishment. Optical stimulation of LH GABA terminals suppressed evoked action potentials of tVTA/RMTg GABAergic neurons in unfasted mice, but this effect decreased following fasting. Furthermore, during fasting, LH GABA inputs to tVTA/RMTg neurons maintained functional connectivity during depolarization, as depolarization block was reduced following fasting. Taken together, inhibitory synaptic transmission from LH GABA inputs onto tVTA/RMTg GABAergic neurons decreases following fasting, however ability to functionally inhibit tVTA/RMTg GABAergic neurons is preserved, allowing for possible disinhibition of dopamine neurons and subsequent foraging. Key PointsO_LIWhile dopamine neuronal activity changes with motivational state, it is unknown if fasting influences tVTA/RMTg GABAergic neurons, a major inhibitory input to VTA dopamine neurons. C_LIO_LIIn unfasted mice, there were sex differences in inhibitory synaptic transmission onto tVTA/RMTg GABAergic neurons. C_LIO_LIActivation of LH GABAergic neurons decreases firing of tVTA/RMTg GABAergic neurons through a monosynaptic input. C_LIO_LIAn acute fast decreased the excitability of tVTA/RMTg GABAergic neurons. C_LIO_LIAn acute fast decreases inhibitory synaptic transmission of the LH GABA input to tVTA/RMTg GABAergic neurons in both male and female mice. C_LI

neuroscience↗

bioRxiv2020

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

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

neuroscience↗