Brain Reward Circuitry And Hypocretin Projections

Reward Circuitry

Figure 1: Schematic representation of interactions between the hypocretinergic system and the brain reward circuitry. Hypocretin (Hcrt) neurons project to several key structures involved in the regulation of motivated behaviors, namely the ventral tegmental area (VTA), the nucleus accumbens (NAcc), the amygdala and the laterodorsal tegmentum (LDT)/pedoculonpontine tegmentum (PPT). Abbreviations: Ach, acetylcholine; DA, dopamine; Glu, glutamate; LH, lateral hypothalamus

Figure 1: Schematic representation of interactions between the hypocretinergic system and the brain reward circuitry. Hypocretin (Hcrt) neurons project to several key structures involved in the regulation of motivated behaviors, namely the ventral tegmental area (VTA), the nucleus accumbens (NAcc), the amygdala and the laterodorsal tegmentum (LDT)/pedoculonpontine tegmentum (PPT). Abbreviations: Ach, acetylcholine; DA, dopamine; Glu, glutamate; LH, lateral hypothalamus

It is well accepted that the mesolimbic dopamine system is a key regulator of brain reward function. The ventral tegmental area (VTA) contains cell bodies of dopaminergic neurons projecting to the nucleus accumbens, the amygdala, the hippocampus and the prefrontal cortex. These neurons are critically implicated in mechanisms of reward, reinforcement and emotional arousal,64 and their activity has been closely correlated to the availability of primary rewards such as food, water and sex.65 The mesolimbic dopamine system receives glutamatergic input from cortical structures including the medial and occipital prefrontal cortex and the amygdala, it receives also GABAergic inputs from striatal sources and cholinergic inputs from the brainstem.66 LHSS is thought to be rewarding in part because it activates cholinergic neurons in laterodorsal tegmental (LDT) and the pedoculopontine tegmental (PPT) nuclei that activates consequently dopaminergic neurons in the VTA.67-70 However, the brain circuitry involved in the LDT/PPT activation is unknown. Interestingly, hypocretins act synergistically with glutamatergic afferents to depolarize cholinergic neurons in the LDT area, which is thought to coordinate the activation of the entire ascending reticular activating system,16

and drive dopamine release in the nucleus accumbens by exciting dopaminergic neurons in the VTA.67 Furthermore, Hcrt-1 and Hcrt-2 have been shown to depolarize cholinergic and non-cholinergic neurons in the LDT area.16'71'72 It has been also shown that hypocretin neurons excite directly dopamine fibers in the VTA,21'73'74 and that the VTA dopaminergic system is critically involved in hypocretin-induced hyperlocomotion and stereotypy.20 Finally, hypocretin-immunoreactive fibers have been shown in the nucleus accumbens1 and hcrt peptides hyperpolarize GABAergic neurons in this nucleus.75 Hence, the hypocretin system could participate to the neuronal network involved in the regulation of the brain reward function.

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