The Role of Ghrelin in Regulating Synaptic Function and Plasticity of Feeding-Associated Circuits

Abstract

Synaptic plasticity of the neuronal circuits associated with feeding behavior is regulated by peripheral signals as a response to changes in the energy status of the body. These signals include glucose, free fatty acids, leptin and ghrelin and are released into circulation, being able to reach the brain. Ghrelin, a small peptide released from the stomach, is an orexigenic hormone produced in peripheral organs, and its action regulates food intake, body weight and glucose homeostasis. Behavioral studies show that ghrelin is implicated in the regulation of both hedonic and homeostatic feeding and of cognition. Ghrelin-induced synaptic plasticity has been described in neuronal circuits associated with these behaviors. In this review, we discuss the neuromodulatory mechanisms induced by ghrelin in regulating synaptic plasticity in three main neuronal circuits previously associated with feeding behaviors, namely hypothalamic (homeostatic feeding), ventral tegmental (hedonic and motivational feeding) and hippocampal (cognitive) circuits. Given the central role of ghrelin in regulating feeding behaviors, and the altered ghrelin levels associated with metabolic disorders such as obesity and anorexia, it is of paramount relevance to understand the effects of ghrelin on synaptic plasticity of neuronal circuits associated with feeding behaviors.

Keywords: feeding; ghrelin; hippocampus; hypothalamus; synaptic plasticity; ventral tegmental area.

FIGURE 1

Scheme with the scope of this review. The mechanisms for synaptic plasticity modulated by ghrelin are discussed in three main neuronal circuits associated with feeding: the hypothalamic, the mesolimbic and the hippocampal circuits. Two energy states are represented: fasting/hunger and satiety. Fasting or hunger conditions are associated with high ghrelin and low leptin levels, while satiety is associated with low ghrelin and high leptin levels. Hypothalamic circuitry drives food intake depending on energy store levels (homeostatic feeding), while the mesolimbic circuitry drives consumption of food with elevated rewarding properties (hedonic and motivational feeding). Hippocampal circuitry integrates feeding with cognitive behavior suggesting that ghrelin is relevant for food searches in nature and can impact cognitive functions.

FIGURE 2

Effects of ghrelin on synaptic plasticity of hypothalamic circuits associated with feeding. Two energy states are represented: fasting/hunger and satiety. In the fasted state, AgRP neuronal activity and dendritic spine density are increased, while POMC neuronal activity is decreased. The AgRP neurons release NPY and GABA and the POMC neurons release POMC, which is subsequently cleaved to produce α-MSH, and targets the melanocortin receptors in the paraventricular nucleus (PVN MCR4) to regulate feeding responses. The effects of fasting on hypothalamic synaptic plasticity can be mediated directly by the activation of the GSH-R1a in AgRP neurons or indirectly by the upstream regulation of AgRP and POMC neurons. Upstream neurons include ghrelin-sensing cells that release glutamate on AgRP neurons through a mechanism dependent on the release of calcium from internal stores and subsequent activation of AMPK, therefore increasing the excitatory synaptic input onto these neurons. Simultaneously, ghrelin leads to the activation of NMDA receptors, of the SIRT1 → p53 → AMPK → PAK and of the mTORC → S6K1 → S6 pathways, which drive state-dependent excitatory synaptic plasticity in AgRP neurons. In parallel, a population of neurons release GABA onto the POMC neurons therefore increasing the inhibitory tone on these neurons. In the fed state, the balance of excitatory versus inhibitory synaptic inputs in the AgRP and POMC neurons is reversed, increasing the anorexigenic melanocortin tone. Additionally, astrocytes express GSH-R1a and its activation promotes the release of adenosine that will bind to the adenosine A1 receptors expressed in the AgRP neurons, thus, decreasing their excitation threshold.

FIGURE 3

Effects of ghrelin on synaptic plasticity in the VTA → NAc circuit of the mesolimbic system. Two energy states are represented: fasting/hunger and satiety. In the fasted state, ghrelin increases the neuronal activity and the density of excitatory synapses of dopaminergic neurons in the VTA. This increase in VTA dopaminergic activity triggers the release of dopamine onto the NAc. The ghrelin effects on the VTA synaptic plasticity may be directly mediated since the GSH-R1a is expressed in the VTA DA and GABA neurons. Indirect activation of the VTA-NAc pathway by ghrelin is mediated by orexin, which is released by upstream orexigenic neurons, and by cholinergic afferents from the laterodorsal tegmental area (LDTg), which contain both GSH-R1a and nicotinic acetylcholine receptors in cholinergic presynaptic neurons. GABAergic transmission is also involved in the ghrelin-induced effects on neuronal activity. In the fed state, the VTA neuronal activity and, subsequently, dopamine release on the NAc return to basal levels.

FIGURE 4

Effects of ghrelin on synaptic plasticity in the hippocampus. Two energy states are represented: fasting/hunger and satiety. During fasting or hunger, ghrelin increases the expression of LTP at the Schaffer collateral-CA1 synapse promoting the insertion of AMPA receptors through a mechanism dependent on PI3K, PKA and PKC activation. These functional changes are accompanied by an increase in the density of dendritic spines, as a result of an increase in the levels of filamentous actin. One potential mechanism for the effects of ghrelin on hippocampal plasticity is through activation of GSH-R1a-DR1R heteromers by dopamine, which promotes an increase in the phosphorylation of CaMKII and of AMPA receptor subunits at serine residues relevant for plasticity, leading to the synaptic incorporation of AMPA receptors in a GHS-R1a-dependent manner.