Sex difference effects of acute starvation on excitatory and inhibitory synapses on dopamine neurons

Abstract

Background: The aim of this study is to assess the influence of acute fasting on synaptic properties in the ventral tegmental area (VTA) with regards to the sex-dependent differences by use of male and female mice. The study aimed to unravel the intricate interplay between fasting, synaptic plasticity, and behavioural changes to enhance our understanding of the underlying mechanisms. Methods: This study carried out at a tertiary care centre, employed a 16-hour overnight fasting protocol in female rodents and male rodents to examine the effects on physiological parameters, feeding behaviour, and neuronal attributes in the VTA. Various assays, including measurements of blood glucose, ketones, corticosterone (CORT) levels, locomotor activity, and electrophysiological recordings of synaptic currents, were conducted to assess the physiological and synaptic responses to acute fasting. Results: The study found that acute fasting induced significant metabolic changes, including body mass decrease by about 10%. Altered food-seeking behaviour was evident, with male mice exhibiting a pronounced increase. Moreover, neuronal attributes in the midbrain or VTA showed gender-dependent responses: males displayed substantial 20% increase in the frequency of mEPSC onto the dopaminergic neurons in the midbrain post fasting, while females exhibited a 13% elevation in CORT levels, accompanied by a transient period of depression at stimulatory synapses onto dopaminergic neurons which was mediated by endocannabinoids. Notably, no significant changes were observed at restraining synapses in rodents of both genders. These findings highlight the nuanced influence of short-term fasting/starvation on the VTA's synaptic plasticity, emphasizing sex-specific responses and providing valuable insights into potential mechanisms influencing gender differences in neuropsychiatric conditions. Conclusions: The study reveals that acute fasting induces sex-specific synaptic changes in the VTA, shedding light on the intricate relationship between metabolism, food-seeking behaviour, and neural plasticity. These findings emphasize the importance of considering gender-specific responses in studies exploring the neurobiological effects of fasting and their relevance to mental health.