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-OR-stimulating microinjections have long been known to increase feeding when placed sub-cortically in regions of rat nucleus accumbens, neostriatum, or amygdala . 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 . Further, in a smaller 8 mm3 ‘hedonic hotspot’ within rat anteromedial OFC, DAMGO microinjections enhance taste-reactivity ‘liking’ reactions to sweetness . 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 mm3 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 food-seeking behavior  and chemogenetic stimulation suppresses food bingeing and motor impulsivity . 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 bolstered by ligand-PET studies in humans showing µ-OR changes in homologous cortical regions related to obesity, eating disorders, and impulsivity (reviewed in ). Yet, µ-opioid peptides may be only one exemplar of a broad category of peptide modulators (including ones yet undiscovered) that profoundly impact cortical function. Indeed, already there is evidence that the peptide, orexin/hypocretin, produces many of the same motivation/hedonic effects in cortex as do opioids, including in hedonic hotspots . Future work may identify novel players that can usher in a new era of peptide pharmaceuticals with which to manipulate cortical function.
Berridge KC, Ho CY, Richard JM, DiFeliceantonio AG. The tempted brain eats: pleasure and desire circuits in obesity and eating disorders. Brain Res. 2010;1350:43–64.
Mena JD, Sadeghian K, Baldo BA. Induction of hyperphagia and carbohydrate intake by mu-opioid receptor stimulation in circumscribed regions of frontal cortex. J Neurosci. 2011;31:3249–60.
Castro DC, Berridge KC. Opioid and orexin hedonic hotspots in rat orbitofrontal cortex and insula. Proc Natl Acad Sci USA. 2017;114:E9125–E34.
Giacomini JL, Geiduschek E, Selleck RA, Sadeghian K, Baldo BA. Dissociable control of mu-opioid-driven hyperphagia vs. food impulsivity across subregions of medial prefrontal, orbitofrontal, and insular cortex. Neuropsychopharmacology. 2021; https://doi.org/10.1038/s41386-021-01068-5.
Anastasio NC, Stutz SJ, Price AE, Davis-Reyes BD, Sholler DJ, Ferguson SM, et al. Convergent neural connectivity in motor impulsivity and high-fat food binge-like eating in male Sprague-Dawley rats. Neuropsychopharmacology. 2019;44:1752–61.
Baldo BA. Prefrontal cortical opioids and dysregulated motivation: a network hypothesis. Trends Neurosci. 2016;39:366–77.
This work was supported by NIH grant MH074723 from the National Institute for Mental Health to BAB, and MH063649 & DA015188 to KCB.
The authors declare no competing interests.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Baldo, B.A., Berridge, K.C. Mapping causal generators of appetitive motivation-hedonic functions in frontal cortex. Neuropsychopharmacol. 47, 415–416 (2022). https://doi.org/10.1038/s41386-021-01154-8