Intracellular mechanisms underlying modulation of inhibitory synaptic transmission by appetite-related peptides in the insular cortex

Background: The insular cortex (IC) integrates multimodal sensory inputs, including gustatory, visceral, nociceptive, and oral somatosensory information, and is widely regarded as the primary gustatory cortex. These functions are closely associated with feeding behaviors such as mastication, swallowing, and digestion, which are affected by appetite- and energy balance-related peptides. Highlight: Orexin, leptin, and insulin have received particular attention because of their effects on IC circuits. Orexin, produced in the hypothalamus, activates postsynaptic phospholipase C, thereby inducing IP₃ and elevating intracellular calcium levels. This effect facilitates inhibitory transmission to pyramidal neurons and promotes an excitatory drive onto interneurons. Leptin, secreted by adipocytes, facilitates inhibitory transmission from fast-spiking interneurons to pyramidal neurons via the presynaptic JAK2–PI3K–Akt signaling pathway. Similarly, insulin increases GABA release from fast spiking interneurons to pyramidal neurons in a PI3K–Akt-dependent manner. This collective peptidergic modulation leads to a net facilitation of inhibition within IC circuits, potentially reducing cortical excitability and output. Conclusions: Given the involvement of the IC in the processing of sensory, interoceptive, and reward-related information, this peptidergic regulation likely influences a range of behaviors, including feeding, pain perception, and addiction. Elucidating these intricate mechanisms could facilitate the development of novel therapeutic interventions for disorders such as obesity, chronic pain, and substance dependence.