Effect of insulin on excitatory synaptic transmission onto dopamine neurons of the ventral tegmental area in a mouse model of hyperinsulinemia

Obesity has drastically increased over the last few decades. Obesity is associated with elevated insulin levels, which can gain access to the brain, including into dopamine neurons of the ventral tegmental area (VTA), a brain region critical for mediating reward-seeking behavior. Synaptic plasticity of VTA dopamine neurons is associated with altered motivation to obtain reinforcing substances such as food and drugs of abuse. Under physiological circumstances, insulin in the VTA can suppress excitatory synaptic transmission onto VTA dopamine neurons and reduce aspects of palatable feeding behavior. However, it is unknown how insulin modulates excitatory synaptic transmission in pathological circumstances such as hyperinsulinemia. Using patch-clamp electrophysiology, we demonstrate that, in a hyperinsulinemic mouse model, insulin has reduced capacity to cause a synaptic depression of VTA dopamine neurons, although both low-frequency stimulation-induced long-term depression and cannabinoid-induced depression were normal. These results suggest that insulin action in the VTA during pathological hyperinsulinemia is disrupted and may lead to increased feeding behavior.