Mapping causal generators of appetitive motivation-hedonic functions in frontal cortex

Abstract

Pharmacological, optogenetic, and chemogenetic mapping studies of neurobehavioral causation are revealing an often-remarkable degree of cortical localization for appetitive-motivation and hedonic functions. Recent identification of spatially-localized functional nodes within frontal cortex have yielded network-level insights that were not entirely predictable a priori. These function-mapping approaches have also demonstrated heterogeneity of neurochemical effects within an anatomical locus. Hence, insights into cortical localization of specific functions have depended upon finding just the right pharmacological or neurobiologically-specific tool. One example has been the use of pharmacological microinjections that stimulate μ-opioid receptors (μ-ORs). These μ-ORstimulating microinjections have long been known to increase feeding when placed sub-cortically in regions of rat nucleus accumbens, neostriatum, or amygdala [1]. Recently, μ-opioid microinjections in specific rat frontal-cortical subregions were found to similarly elicit increases in feeding and related behaviors, appetitive effects obtained neither from other opioid-receptor subtypes, nor from cortical monoamines or amino-acid transmitters [2, 3]. A fascinating spatial heterogeneity of opioid-modulated motivation functions across the frontal cortex has been revealed. Microinjections of the μ-OR agonist, DAMGO, in anteromedial orbitofrontal cortex (OFC) reveal a corridor where DAMGO engenders motivated hyperactivity in anticipation of food and increases food intake [4]. Further, in a smaller 8 mm ‘hedonic hotspot’ within rat anteromedial OFC, DAMGO microinjections enhance taste-reactivity ‘liking’ reactions to sweetness [3]. In contrast, DAMGO at other sites in the medial prefrontal cortex (PFC) produces ‘wanting’ without ‘liking’: failing to enhance, or even instead suppressing, hedonic taste reactivity; yet increasing consummatory food intake, food-reinforced operant responding, and anticipatory hyperactivity and approach [3, 4]. Moving caudally/laterally, near primary gustatory insula, DAMGO microinjections increase consummatory food intake but not anticipatory hyperactivity. Further caudally in another 6 mm hedonic hotspot in parietal insula, DAMGO microinjection amplifies hedonic taste reactions without changing intake (‘liking’ without ‘wanting’) [3, 4]. Finally, studies of inhibitory control over food-motivated behaviors have identified a circumscribed site of ventromedial PFC where DAMGO engenders impulsive-like foodseeking behavior [4] and chemogenetic stimulation suppresses food bingeing and motor impulsivity [5]. Together, these results could suggest a network model wherein OFC serves as an interface between sensory/palatability computations in the insular cortex and more purely ‘seeking-like’, action-selection functions of medial PFC (see Fig. 1). As time goes on, this model will be further refined and extended with new manipulations. However, the findings discussed above underscore that μ-OR agonists have been powerful tools to reveal previously unappreciated localization of functions in cortex. The clinical relevance of this approach is