Molecular Neurobiology

, Volume 46, Issue 2, pp 332–348 | Cite as

The Brain's Response to an Essential Amino Acid-Deficient Diet and the Circuitous Route to a Better Meal

  • Dorothy W. Gietzen
  • Susan M. Aja


The essential (indispensable) amino acids (IAA) are neither synthesized nor stored in metazoans, yet they are the building blocks of protein. Survival depends on availability of these protein precursors, which must be obtained in the diet; it follows that food selection is critical for IAA homeostasis. If even one of the IAA is depleted, its tRNA becomes quickly deacylated and the levels of charged tRNA fall, leading to disruption of global protein synthesis. As they have priority in the diet, second only to energy, the missing IAA must be restored promptly or protein catabolism ensues. Animals detect and reject an IAA-deficient meal in 20 min, but how? Here, we review the molecular basis for sensing IAA depletion and repletion in the brain's IAA chemosensor, the anterior piriform cortex (APC). As animals stop eating an IAA-deficient meal, they display foraging and altered choice behaviors, to improve their chances of encountering a better food. Within 2 h, sensory cues are associated with IAA depletion or repletion, leading to learned aversions and preferences that support better food selection. We show neural projections from the APC to appetitive and consummatory motor control centers, and to hedonic, motivational brain areas that reinforce these adaptive behaviors.


Nutrient sensing Anterior piriform cortex Hypothalamus Feeding circuits Essential amino acids Foraging Learned aversion Learned preference GCN2 



Medial agranular (supplementary motor) cortex




Area postrema


Anterior piriform cortex


Activating transcription factor


Basal ganglia




Calcium sensing receptor


Calcium calmodulin kinase II




Conditioned taste aversion


Circumventricular organ





D1or 2

Dopamine receptor categories 1or 2


Dorsolateral perifornical lateral hypothalamus


Dorsomedial hypothalamus


Eukaryotic initiation factor 2


Extracellular signal-related kinase


General amino acid control non-derepressing kinase 2


Globus pallidus


Glutamate receptor 1




Horseradish peroxidase


Indispensable (essential in the diet) amino acid


Insular (taste) cortex




Lateral hypothalamic area


Mitogen-activated protein kinase


2-Methylamino isobutyric acid


Mammalian target of rapamycin


Nucleus accumbens




Nucleus of the tractus solitarius


Orbitofrontal cortex


Parabrachial nucleus


Paraventricular nucleus of the hypothalamus


Phosphatidylinositol 3 kinase


Prefrontal cortex


Reticular thalamus


Sulfur-containing amino acid


Sodium-coupled neutral amino acid transporter


Striatum (caudate + putamen)


Transfer ribonucleic acid

vent TEG

Ventral tegmentum


Ventromedial hypothalamus


Ventral pallidum


Zona incerta



The tract-tracing work of Dr. Aja was supported by National Institutes of Health (NIH) grant DK 09271. DWG had support from NIH grants DK42274, NS 043210, and NS 33347, and from Ajinomoto Co., Inc., Tokyo. We extend particular thanks to Dr. Kunio Torii for his kind advice and collaboration. The authors are grateful to the many students and postdoctoral fellows and technicians in the Food Intake Laboratory at the University of California, Davis, who provided assistance with the animal and biochemical studies (to all those who weighed spill papers, special thanks). The authors extend our profound apologies to those whose volumes of work could not be included due to space limitations.


  1. 1.
    Geiger E (1947) Experiments with delayed supplementation of incomplete amino acid mixtures. J Nutr 34(1):97–111PubMedGoogle Scholar
  2. 2.
    Peters JC, Harper AE (1984) Influence of dietary protein level on protein self-selection and plasma and brain amino acid concentrations. Physiol Behav 33(5):783–790PubMedCrossRefGoogle Scholar
  3. 3.
    Sorensen A, Mayntz D, Raubenheimer D, Simpson SJ (2008) Protein-leverage in mice: the geometry of macronutrient balancing and consequences for fat deposition. Obesity (Silver Spring) 16(3):566–571. doi: 10.1038/oby.2007.58 CrossRefGoogle Scholar
  4. 4.
    Tome D (2004) Protein, amino acids and the control of food intake. Br J Nutr 92(Suppl 1):S27–S30PubMedCrossRefGoogle Scholar
  5. 5.
    Harper AE, Benevenga NJ, Wohlhueter RM (1970) Effects of ingestion of disproportionate amounts of amino acids. Physiol Rev 50(3):428–558PubMedGoogle Scholar
  6. 6.
    White BD, He B, Dean RG, Martin RJ (1994) Low protein diets increase neuropeptide Y gene expression in the basomedial hypothalamus of rats. J Nutr 124(8):1152–1160PubMedGoogle Scholar
  7. 7.
    Riggs AJ, White BD, Gropper SS (2007) Changes in energy expenditure associated with ingestion of high protein, high fat versus high protein, low fat meals among underweight, normal weight, and overweight females. Nutr J 6:40. doi: 10.1186/1475-2891-6-40 PubMedCrossRefGoogle Scholar
  8. 8.
    Du F, Higginbotham DA, White BD (2000) Food intake, energy balance and serum leptin concentrations in rats fed low-protein diets. J Nutr 130(3):514–521PubMedGoogle Scholar
  9. 9.
    Galef BG (2000) Is there a specific appetite for protein? In: Berthoud HR, Seeley RJ (eds) Neural and metabolic control of macronutrient intake. CRC Press, Boca Raton, pp 19–28Google Scholar
  10. 10.
    Morrison CD, Reed SD, Henagan TM (2012) Homeostatic regulation of protein intake: in search of a mechanism. Am J Physiol Regul Integr Comp Physiol 302(8):R917–R928. doi: 10.1152/ajpregu.00609.2011 Google Scholar
  11. 11.
    DiBattista D, Mercier S (1999) Role of learning in the selection of dietary protein in the golden hamster (Mesocricetus auratus). Behav Neurosci 113(3):574–586PubMedCrossRefGoogle Scholar
  12. 12.
    Gibson EL, Wainwright CJ, Booth DA (1995) Disguised protein in lunch after low-protein breakfast conditions food-flavor preferences dependent on recent lack of protein intake. Physiol Behav 58(2):363–371PubMedCrossRefGoogle Scholar
  13. 13.
    Gibson EL, Booth DA (1986) Acquired protein appetite in rats: dependence on a protein-specific need state. Experientia 42(9):1003–1004PubMedCrossRefGoogle Scholar
  14. 14.
    Hansen BS, Vaughan MH, Wang L (1972) Reversible inhibition by histidinol of protein synthesis in human cells at the activation of histidine. J Biol Chem 247(12):3854–3857PubMedGoogle Scholar
  15. 15.
    Hao S, Sharp JW, Ross-Inta CM, McDaniel BJ, Anthony TG, Wek RC, Cavener DR, McGrath BC, Rudell JB, Koehnle TJ, Gietzen DW (2005) Uncharged tRNA and sensing of amino acid deficiency in mammalian piriform cortex. Science 307(5716):1776–1778. doi: 10.1126/science.1104882 PubMedCrossRefGoogle Scholar
  16. 16.
    Leung PM, Rogers QR, Harper AE (1968) Effect of amino acid imbalance in rats fed ad libitum, interval-fed or force-fed. J Nutr 95(3):474–482PubMedGoogle Scholar
  17. 17.
    Hrupka BJ, Lin YM, Gietzen DW, Rogers QR (1997) Small changes in essential amino acid concentrations alter diet selection in amino acid-deficient rats. J Nutr 127(5):777–784PubMedGoogle Scholar
  18. 18.
    Hinnebusch AG, Natarajan K (2002) Gcn4p, a master regulator of gene expression, is controlled at multiple levels by diverse signals of starvation and stress. Eukaryot Cell 1(1):22–32PubMedCrossRefGoogle Scholar
  19. 19.
    Wek RC, Jiang HY, Anthony TG (2006) Coping with stress: EIF2 kinases and translational control. Biochem Soc Trans 34(Pt 1):7–11. doi: 10.1042/BST20060007 PubMedGoogle Scholar
  20. 20.
    Kilberg MS, Shan J, Su N (2009) ATF4-dependent transcription mediates signaling of amino acid limitation. Trends Endocrinol Metab 20(9):436–443. doi: 10.1016/j.tem.2009.05.008 PubMedCrossRefGoogle Scholar
  21. 21.
    Kilberg MS, Balasubramanian M, Fu L, Shan J (2012) The transcription factor network associated with the amino acid response in mammalian cells. Adv Nutr 3(3):295–306. doi: 10.3945/an.112.001891 PubMedGoogle Scholar
  22. 22.
    Koehnle TJ, Russell MC, Morin AS, Erecius LF, Gietzen DW (2004) Diets deficient in indispensable amino acids rapidly decrease the concentration of the limiting amino acid in the anterior piriform cortex of rats. J Nutr 134(9):2365–2371PubMedGoogle Scholar
  23. 23.
    Leung PM, Rogers QR (1971) Importance of prepyriform cortex in food-intake response of rats to amino acids. Am J Physiol 221(3):929–935PubMedGoogle Scholar
  24. 24.
    Rogers QR, Leung PM (1973) The influence of amino acids on the neuroregulation of food intake. Fed Proc 32(6):1709–1719PubMedGoogle Scholar
  25. 25.
    Gietzen DW (1993) Neural mechanisms in the responses to amino acid deficiency. J Nutr 123(4):610–625PubMedGoogle Scholar
  26. 26.
    Noda K, Chikamori K (1976) Effect of ammonia via prepyriform cortex on regulation of food intake in the rat. Am J Physiol 231(4):1263–1266PubMedGoogle Scholar
  27. 27.
    Firman JD, Kuenzel WJ (1988) Neuroanatomical regions of the chick brain involved in monitoring amino acid deficient diets. Brain Res Bull 21(4):637–642PubMedCrossRefGoogle Scholar
  28. 28.
    Beverly JL, Gietzen DW, Rogers QR (1990) Effect of dietary limiting amino acid in prepyriform cortex on meal patterns. Am J Physiol 259(4 Pt 2):R716–R723PubMedGoogle Scholar
  29. 29.
    Beverly JL, Gietzen DW, Rogers QR (1990) Effect of dietary limiting amino acid in prepyriform cortex on food intake. Am J Physiol 259(4 Pt 2):R709–R715PubMedGoogle Scholar
  30. 30.
    Monda M, Sullo A, De Luca V, Pellicano MP, Viggiano A (1997) L-threonine injection into PPC modifies food intake, lateral hypothalamic activity, and sympathetic discharge. Am J Physiol 273(2 Pt 2):R554–R559PubMedGoogle Scholar
  31. 31.
    Hasan Z, Woolley DE, Gietzen DW (1998) Responses to indispensable amino acid deficiency and replenishment recorded in the anerior piriform cortex of the behaving rat. Nutr Neurosci 1:373–381Google Scholar
  32. 32.
    Rudell JB, Rechs AJ, Kelman TJ, Ross-Inta CM, Hao S, Gietzen DW (2011) The anterior piriform cortex is sufficient for detecting depletion of an indispensable amino acid, showing independent cortical sensory function. J Neurosci 31(5):1583–1590. doi: 10.1523/JNEUROSCI.4934-10.2011 PubMedCrossRefGoogle Scholar
  33. 33.
    Gietzen DW (2000) Amino acid recognition in the central nervous system. In: Berthoud HR, Seeley RJ (eds) Neural and metabolic control of macronutrient intake. CRC Press, Boca Raton, pp 339–357Google Scholar
  34. 34.
    Gietzen DW, Hao S, Anthony TG (2007) Mechanisms of food intake repression in indispensable amino acid deficiency. Annu Rev Nutr 27:63–78. doi: 10.1146/annurev.nutr.27.061406.093726 PubMedCrossRefGoogle Scholar
  35. 35.
    Gietzen DW, Rogers QR (2006) Nutritional homeostasis and indispensable amino acid sensing: a new solution to an old puzzle. Trends Neurosci 29(2):91–99. doi: 10.1016/j.tins.2005.12.007 PubMedCrossRefGoogle Scholar
  36. 36.
    Rowe TB, Macrini TE, Luo ZX (2011) Fossil evidence on origin of the mammalian brain. Science 332(6032):955–957. doi: 10.1126/science.1203117 PubMedCrossRefGoogle Scholar
  37. 37.
    Shepherd G (1979) Olfactory cortex. In: The synaptic organization of the brain, 2nd edn. Oxford University Press, New York, pp 289–307Google Scholar
  38. 38.
    Kanter ED, Haberly LB (1990) NMDA-dependent induction of long-term potentiation in afferent and association fiber systems of piriform cortex in vitro. Brain Res 525(1):175–179PubMedCrossRefGoogle Scholar
  39. 39.
    Suzuki N, Bekkers JM (2010) Inhibitory neurons in the anterior piriform cortex of the mouse: classification using molecular markers. J Comp Neurol 518(10):1670–1687. doi: 10.1002/cne.22295 PubMedCrossRefGoogle Scholar
  40. 40.
    Cummings SL, Truong BG, Gietzen DW (1998) Neuropeptide Y and somatostatin in the anterior piriform cortex alter intake of amino acid-deficient diets. Peptides 19(3):527–535PubMedCrossRefGoogle Scholar
  41. 41.
    Jung MW, Larson J, Lynch G (1990) Role of NMDA and non-NMDA receptors in synaptic transmission in rat piriform cortex. Exp Brain Res 82(2):451–455PubMedCrossRefGoogle Scholar
  42. 42.
    Sharp JW, Ross-Inta CM, Hao S, Rudell JB, Gietzen DW (2006) Co-localization of phosphorylated extracellular signal-regulated protein kinases 1/2 (ERK1/2) and phosphorylated eukaryotic initiation factor 2alpha (eIF2alpha) in response to a threonine-devoid diet. J Comp Neurol 494(3):485–494. doi: 10.1002/cne.20817 PubMedCrossRefGoogle Scholar
  43. 43.
    Gale K, Zhong P, Miller LP, Murray TF (1992) Amino acid neurotransmitter interactions in 'area tempestas': an epileptogenic trigger zone in the deep prepiriform cortex. Epilepsy Res Suppl 8:229–234PubMedGoogle Scholar
  44. 44.
    Ekstrand JJ, Domroese ME, Johnson DM, Feig SL, Knodel SM, Behan M, Haberly LB (2001) A new subdivision of anterior piriform cortex and associated deep nucleus with novel features of interest for olfaction and epilepsy. J Comp Neurol 434(3):289–307PubMedCrossRefGoogle Scholar
  45. 45.
    Koehnle TJ, Russell MC, Gietzen DW (2003) Rats rapidly reject diets deficient in essential amino acids. J Nutr 133(7):2331–2335PubMedGoogle Scholar
  46. 46.
    Gietzen DW, Ross CM, Hao S, Sharp JW (2004) Phosphorylation of eIF2alpha is involved in the signaling of indispensable amino acid deficiency in the anterior piriform cortex of the brain in rats. J Nutr 134(4):717–723PubMedGoogle Scholar
  47. 47.
    Maurin AC, Jousse C, Averous J, Parry L, Bruhat A, Cherasse Y, Zeng H, Zhang Y, Harding HP, Ron D, Fafournoux P (2005) The GCN2 kinase biases feeding behavior to maintain amino acid homeostasis in omnivores. Cell Metab 1(4):273–277. doi: 10.1016/j.cmet.2005.03.004 PubMedCrossRefGoogle Scholar
  48. 48.
    Mitsuda T, Hayakawa Y, Itoh M, Ohta K, Nakagawa T (2007) ATF4 regulates gamma-secretase activity during amino acid imbalance. Biochem Biophys Res Commun 352(3):722–727. doi: 10.1016/j.bbrc.2006.11.075 PubMedCrossRefGoogle Scholar
  49. 49.
    Truong BG, Magrum LJ, Gietzen DW (2002) GABA(A) and GABA(B) receptors in the anterior piriform cortex modulate feeding in rats. Brain Res 924(1):1–9PubMedCrossRefGoogle Scholar
  50. 50.
    Leung PM, Larson DM, Rogers QR (1972) Food intake and preference of olfactory bulbectomized rats fed amino acid imbalanced or deficient diets. Physiol Behav 9(4):553–557PubMedCrossRefGoogle Scholar
  51. 51.
    Choi GB, Stettler DD, Kallman BR, Bhaskar ST, Fleischmann A, Axel R (2011) Driving opposing behaviors with ensembles of piriform neurons. Cell 146(6):1004–1015. doi: 10.1016/j.cell.2011.07.041 PubMedCrossRefGoogle Scholar
  52. 52.
    Rogers QR, Leung PMB (1977) The control of food intake: when and how are amino acids involved? In: Kare MR, Maller O (eds) The chemical senses and nutrition. Academic Press. Inc., New York, pp 213–249Google Scholar
  53. 53.
    Feurte S, Tome D, Gietzen DW, Even PC, Nicolaidis S, Fromentin G (2002) Feeding patterns and meal microstructure during development of a taste aversion to a threonine devoid diet. Nutr Neurosci 5(4):269–278PubMedCrossRefGoogle Scholar
  54. 54.
    Koehnle TJ, Gietzen DW (2005) Modulation of feeding behavior by amino acid-deficient diets: present findings and future directions. In: Lieberman HR, Kanarek RB, Prasad C (eds) Nutritional neuroscience. Taylor and Francis Group/CRC Press, Boca Raton, pp 147–161Google Scholar
  55. 55.
    Gietzen DW, Leung PM, Rogers QR (1989) Dietary amino acid imbalance and neurochemical changes in three hypothalamic areas. Physiol Behav 46(3):503–511PubMedCrossRefGoogle Scholar
  56. 56.
    Price JL, Slotnick BM, Revial MF (1991) Olfactory projections to the hypothalamus. J Comp Neurol 306(3):447–461. doi: 10.1002/cne.903060309 PubMedCrossRefGoogle Scholar
  57. 57.
    Avruch J, Long X, Ortiz-Vega S, Rapley J, Papageorgiou A, Dai N (2009) Amino acid regulation of TOR complex 1. Am J Physiol Endocrinol Metab 296(4):E592–E602. doi: 10.1152/ajpendo.90645.2008 PubMedCrossRefGoogle Scholar
  58. 58.
    Hao S, Ross-Inta CM, Gietzen DW (2010) The sensing of essential amino acid deficiency in the anterior piriform cortex, that requires the uncharged tRNA/GCN2 pathway, is sensitive to wortmannin but not rapamycin. Pharmacol Biochem Behav 94(3):333–340. doi: 10.1016/j.pbb.2009.09.014 PubMedCrossRefGoogle Scholar
  59. 59.
    Lynch CJ (2001) Role of leucine in the regulation of mTOR by amino acids: revelations from structure-activity studies. J Nutr 131(3):861S–865SPubMedGoogle Scholar
  60. 60.
    Goto S, Nagao K, Bannai M, Takahashi M, Nakahara K, Kangawa K, Murakami N (2010) Anorexia in rats caused by a valine-deficient diet is not ameliorated by systemic ghrelin treatment. Neuroscience 166(1):333–340. doi: 10.1016/j.neuroscience.2009.12.013 PubMedCrossRefGoogle Scholar
  61. 61.
    Palacin M, Estevez R, Bertran J, Zorzano A (1998) Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev 78(4):969–1054PubMedGoogle Scholar
  62. 62.
    Blais A, Huneau JF, Magrum LJ, Koehnle TJ, Sharp JW, Tome D, Gietzen DW (2003) Threonine deprivation rapidly activates the system A amino acid transporter in primary cultures of rat neurons from the essential amino acid sensor in the anterior piriform cortex. J Nutr 133(7):2156–2164PubMedGoogle Scholar
  63. 63.
    Mackenzie B, Erickson JD (2004) Sodium-coupled neutral amino acid (system N/A) transporters of the SLC38 gene family. Pflugers Arch 447(5):784–795. doi: 10.1007/s00424-003-1117-9 PubMedCrossRefGoogle Scholar
  64. 64.
    Gietzen DW, Magrum LJ (2001) Molecular mechanisms in the brain involved in the anorexia of branched-chain amino acid deficiency. J Nutr 131(3):851S–855SPubMedGoogle Scholar
  65. 65.
    Sharp JW, Magrum LJ, Gietzen DW (2002) Role of MAP kinase in signaling indispensable amino acid deficiency in the brain. Brain Res Mol Brain Res 105(1–2):11–18PubMedCrossRefGoogle Scholar
  66. 66.
    Sharp JW, Ross CM, Koehnle TJ, Gietzen DW (2004) Phosphorylation of Ca2+/calmodulin-dependent protein kinase type II and the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor in response to a threonine-devoid diet. Neuroscience 126(4):1053–1062. doi: 10.1016/j.neuroscience.2004.03.066 PubMedCrossRefGoogle Scholar
  67. 67.
    Koehnle TJ, Stephens AL, Gietzen DW (2004) Threonine-imbalanced diet alters first-meal microstructure in rats. Physiol Behav 81(1):15–21. doi: 10.1016/j.physbeh.2003.11.009 PubMedCrossRefGoogle Scholar
  68. 68.
    Haberly LB, Price JL (1978) Association and commissural fiber systems of the olfactory cortex of the rat. J Comp Neurol 178(4):711–740. doi: 10.1002/cne.901780408 PubMedCrossRefGoogle Scholar
  69. 69.
    Aja SM (1999) Neurotransmitters and neural circuitry supporting aminoprivic feeding. Dissertation, University of California, DavisGoogle Scholar
  70. 70.
    Price JL, Carmichael T, Haberly LB (1991) Olfactory input to the prefrontal cortex. In: Davis JL, Eichenbaum H (eds) Olfaction a model system for computational neuroscience. MIT Press, London, pp 101–120Google Scholar
  71. 71.
    Neafsey EJ, Bold EL, Haas G, Hurley-Gius KM, Quirk G, Sievert CF, Terreberry RR (1986) The organization of the rat motor cortex: a microstimulation mapping study. Brain Res 396(1):77–96PubMedCrossRefGoogle Scholar
  72. 72.
    Sul JH, Jo S, Lee D, Jung MW (2011) Role of rodent secondary motor cortex in value-based action selection. Nat Neurosci 14(9):1202–1208. doi: 10.1038/nn.2881 PubMedCrossRefGoogle Scholar
  73. 73.
    Rolls ET (1993) The neural control of feeding in primates. In: Booth DA (ed) Neurophysiology of ingestion. Pergamon Press, Oxford, pp 137–169Google Scholar
  74. 74.
    Rolls ET (2011) Chemosensory learning in the cortex. Front Syst Neurosci 5:78. doi: 10.3389/fnsys.2011.00078 PubMedCrossRefGoogle Scholar
  75. 75.
    Krettek JE, Price JL (1977) Projections from the amygdaloid complex to the cerebral cortex and thalamus in the rat and cat. J Comp Neurol 172(4):687–722. doi: 10.1002/cne.901720408 PubMedCrossRefGoogle Scholar
  76. 76.
    Karnani MM, Apergis-Schoute J, Adamantidis A, Jensen LT, de Lecea L, Fugger L, Burdakov D (2011) Activation of central orexin/hypocretin neurons by dietary amino acids. Neuron 72(4):616–629. doi: 10.1016/j.neuron.2011.08.027 PubMedCrossRefGoogle Scholar
  77. 77.
    Blevins JE, Dixon KD, Hernandez EJ, Barrett JA, Gietzen DW (2000) Effects of threonine injections in the lateral hypothalamus on intake of amino acid imbalanced diets in rats. Brain Res 879(1–2):65–72PubMedCrossRefGoogle Scholar
  78. 78.
    Russell MC, Koehnle TJ, Barrett JA, Blevins JE, Gietzen DW (2003) The rapid anorectic response to a threonine imbalanced diet is decreased by injection of threonine into the anterior piriform cortex of rats. Nutr Neurosci 6(4):247–251PubMedCrossRefGoogle Scholar
  79. 79.
    Tabuchi E, Ono T, Nishijo H, Torii K (1991) Amino acid and NaCl appetite, and LHA neuron responses of lysine-deficient rat. Physiol Behav 49(5):951–964PubMedCrossRefGoogle Scholar
  80. 80.
    Sinnamon HM (1993) Preoptic and hypothalamic neurons and the initiation of locomotion in the anesthetized rat. Prog Neurobiol 41(3):323–344PubMedCrossRefGoogle Scholar
  81. 81.
    Jordan LM (1998) Initiation of locomotion in mammals. Ann N Y Acad Sci 860:83–93PubMedCrossRefGoogle Scholar
  82. 82.
    Wang Y, Cummings SL, Gietzen DW (1996) Temporal-spatial pattern of c-Fos expression in the rat brain in response to indispensable amino acid deficiency. II. The learned taste aversion. Brain Res Mol Brain Res 40(1):35–41PubMedCrossRefGoogle Scholar
  83. 83.
    Wang Y, Cummings SL, Gietzen DW (1996) Temporal-spatial pattern of c-Fos expression in the rat brain in response to indispensable amino acid deficiency. I. The initial recognition phase. Brain Res Mol Brain Res 40(1):27–34PubMedCrossRefGoogle Scholar
  84. 84.
    Bellinger LL, Evans JF, Gietzen DW (1998) Dorsomedial hypothalamic lesions alter intake of an imbalanced amino acid diet in rats. J Nutr 128(7):1213–1217PubMedGoogle Scholar
  85. 85.
    Bellinger LL, Evans JF, Tillberg CM, Gietzen DW (1999) Effects of dorsomedial hypothalamic nuclei lesions on intake of an imbalanced amino acid diet. Am J Physiol 277(1 Pt 2):R250–R262PubMedGoogle Scholar
  86. 86.
    Hernandez L, Hoebel BG (1988) Feeding and hypothalamic stimulation increase dopamine turnover in the accumbens. Physiol Behav 44(4–5):599–606PubMedCrossRefGoogle Scholar
  87. 87.
    Mark GP, Blander DS, Hoebel BG (1991) A conditioned stimulus decreases extracellular dopamine in the nucleus accumbens after the development of a learned taste aversion. Brain Res 551(1–2):308–310PubMedCrossRefGoogle Scholar
  88. 88.
    Yamamoto T, Ueji K (2011) Brain mechanisms of flavor learning. Front Syst Neurosci 5:76. doi: 10.3389/fnsys.2011.00076 PubMedCrossRefGoogle Scholar
  89. 89.
    Aja SM, Chan P, Barrett JA, Gietzen DW (1999) DA1 receptor activity opposes anorectic responses to amino acid-imbalanced diets. Pharmacol Biochem Behav 62(3):493–498PubMedCrossRefGoogle Scholar
  90. 90.
    Wang CX, Erecius LF, Beverly JL 3rd, Gietzen DW (1999) Essential amino acids affect interstitial dopamine metabolites in the anterior piriform cortex of rats. J Nutr 129(9):1742–1745PubMedGoogle Scholar
  91. 91.
    Hoebel BG (1975) Brain reward and aversion systems in the control of feeding and sexual behavior. Nebr Symp Motiv 22:49–112PubMedGoogle Scholar
  92. 92.
    Derjean D, Moussaddy A, Atallah E, St-Pierre M, Auclair F, Chang S, Ren X, Zielinski B, Dubuc R (2010) A novel neural substrate for the transformation of olfactory inputs into motor output. PLoS Biol 8(12):e1000567. doi: 10.1371/journal.pbio.1000567 PubMedCrossRefGoogle Scholar
  93. 93.
    Scott TR (2011) Learning through the taste system. Front Syst Neurosci 5:87. doi: 10.3389/fnsys.2011.00087 PubMedCrossRefGoogle Scholar
  94. 94.
    Stellar E (1954) The physiology of motivation. Psychol Rev 61(1):5–22PubMedCrossRefGoogle Scholar
  95. 95.
    Blevins JE, Truong BG, Gietzen DW (2004) NMDA receptor function within the anterior piriform cortex and lateral hypothalamus in rats on the control of intake of amino acid-deficient diets. Brain Res 1019(1–2):124–133. doi: 10.1016/j.brainres.2004.05.089 PubMedCrossRefGoogle Scholar
  96. 96.
    Barone FC, Cheng JT, Wayner MJ (1994) GABA inhibition of lateral hypothalamic neurons: role of reticular thalamic afferents. Brain Res Bull 33(6):699–708PubMedCrossRefGoogle Scholar
  97. 97.
    Rozin P (1967) Specific aversions as a component of specific hungers. J Comp Physiol Psychol 64(2):237–242PubMedCrossRefGoogle Scholar
  98. 98.
    Sodersten P, Nergardh R, Bergh C, Zandian M, Scheurink A (2008) Behavioral neuroendocrinology and treatment of anorexia nervosa. Front Neuroendocrinol 29(4):445–462. doi: 10.1016/j.yfrne.2008.06.001 PubMedCrossRefGoogle Scholar
  99. 99.
    Magrum LJ, Teh PS, Kreiter MR, Hickman MA, Gietzen DW (2002) Transfer ribonucleic acid charging in rat brain after consumption of amino acid-imbalanced diets. Nutr Neurosci 5(2):125–130PubMedCrossRefGoogle Scholar
  100. 100.
    Kadowaki M, Kanazawa T (2003) Amino acids as regulators of proteolysis. J Nutr 133(6 Suppl 1):2052S–2056SPubMedGoogle Scholar
  101. 101.
    Simson PC, Booth DA (1973) Olfactory conditioning by association with histidine-free or balanced amino acid loads in rats. Q J Exp Psychol 25(3):354–359. doi: 10.1080/14640747308400356 PubMedCrossRefGoogle Scholar
  102. 102.
    Fromentin G, Feurte S, Nicolaidis S (1998) Spatial cues are relevant for learned preference/aversion shifts due to amino-acid deficiencies. Appetite 30(2):223–234. doi: 10.1006/appe.1997.0132 PubMedCrossRefGoogle Scholar
  103. 103.
    Booth DA, Simson PC (1971) Food preferences acquired by association with variations in amino acid nutrition. Q J Exp Psychol 23(1):135–145. doi: 10.1080/00335557143000149 PubMedCrossRefGoogle Scholar
  104. 104.
    Fromentin G, Gietzen DW, Nicolaidis S (1997) Aversion-preference patterns in amino acid- or protein-deficient rats: a comparison with previously reported responses to thiamin-deficient diets. Br J Nutr 77(2):299–314PubMedCrossRefGoogle Scholar
  105. 105.
    Gietzen DW, McArthur LH, Theisen JC, Rogers QR (1992) Learned preference for the limiting amino acid in rats fed a threonine-deficient diet. Physiol Behav 51(5):909–914PubMedCrossRefGoogle Scholar
  106. 106.
    Garcia J, Kimeldorf DJ, Koelling RA (1955) Conditioned aversion to saccharin resulting from exposure to gamma radiation. Science 122(3160):157–158PubMedGoogle Scholar
  107. 107.
    Simson PC, Booth DA (1973) Effect of CS-US interval on the conditioning of odour preferences by amino acid loads. Physiol Behav 11(6):801–808PubMedCrossRefGoogle Scholar
  108. 108.
    Rogers QR, Wigle AR, Laufer A, Castellanos VH, Morris JG (2004) Cats select for adequate methionine but not threonine. J Nutr 134(8 Suppl):2046S–2049SPubMedGoogle Scholar
  109. 109.
    Meliza LL, Leung PM, Rogers QR (1981) Effect of anterior prepyriform and medial amygdaloid lesions on acquisition of taste-avoidance and response to dietary amino acid imbalance. Physiol Behav 26(6):1031–1035PubMedCrossRefGoogle Scholar
  110. 110.
    Gietzen DW, Erecius LF, Rogers QR (1998) Neurochemical changes after imbalanced diets suggest a brain circuit mediating anorectic responses to amino acid deficiency in rats. J Nutr 128(4):771–781PubMedGoogle Scholar
  111. 111.
    Dardou D, Datiche F, Cattarelli M (2006) Fos and Egr1 expression in the rat brain in response to olfactory cue after taste-potentiated odor aversion retrieval. Learn Mem 13(2):150–160. doi: 10.1101/lm.148706 PubMedCrossRefGoogle Scholar
  112. 112.
    Inui-Yamamoto C, Yoshioka Y, Inui T, Sasaki KS, Ooi Y, Ueda K, Seiyama A, Ohzawa I (2010) The brain mapping of the retrieval of conditioned taste aversion memory using manganese-enhanced magnetic resonance imaging in rats. Neuroscience 167(2):199–204. doi: 10.1016/j.neuroscience.2010.02.027 PubMedCrossRefGoogle Scholar
  113. 113.
    Riley AL, Tuck DL (1985) Conditioned food aversions: a bibliography. Ann N Y Acad Sci 443:381–437PubMedCrossRefGoogle Scholar
  114. 114.
    Aja S, Sisouvong S, Barrett JA, Gietzen DW (2000) Basolateral and central amygdaloid lesions leave aversion to dietary amino acid imbalance intact. Physiol Behav 71(5):533–541PubMedCrossRefGoogle Scholar
  115. 115.
    Fromentin G, Feurte S, Nicolaidis S, Norgren R (2000) Parabrachial lesions disrupt responses of rats to amino acid devoid diets, to protein-free diets, but not to high-protein diets. Physiol Behav 70(3–4):381–389PubMedCrossRefGoogle Scholar
  116. 116.
    Overmann SR, Woolley DE, Bornschein RL (1980) Hippocampal potentials evoked by stimulation of olfactory basal forebrain and lateral septum in the rat. Brain Res Bull 5(4):437–449PubMedCrossRefGoogle Scholar
  117. 117.
    Leung PM, Rogers QR (1979) Effects of hippocampal lesions on adaptive intake of diets with disproportionate amounts of amino acids. Physiol Behav 23(1):129–136PubMedCrossRefGoogle Scholar
  118. 118.
    Beverly JL 3rd, Gietzen DW, Rogers QR (1991) Protein synthesis in the prepyriform cortex: effects on intake of an amino acid-imbalanced diet by sprague-dawley rats. J Nutr 121(5):754–761PubMedGoogle Scholar
  119. 119.
    Torii K, Kondoh T, Mori M, Ono T (1998) Hypothalamic control of amino acid appetite. Ann N Y Acad Sci 855:417–425PubMedCrossRefGoogle Scholar
  120. 120.
    Markison S, Gietzen DW, Spector AC (1999) Essential amino acid deficiency enhances long-term intake but not short-term licking of the required nutrient. J Nutr 129(8):1604–1612PubMedGoogle Scholar
  121. 121.
    Nelson G, Chandrashekar J, Hoon MA, Feng L, Zhao G, Ryba NJ, Zuker CS (2002) An amino-acid taste receptor. Nature 416(6877):199–202. doi: 10.1038/nature726 PubMedCrossRefGoogle Scholar
  122. 122.
    Yasumatsu K, Ogiwara Y, Takai S, Yoshida R, Iwatsuki K, Torii K, Margolskee RF, Ninomiya Y (2011) Umami taste in mice uses multiple receptors and transduction pathways. J Physiol 590(Pt 5):1155–1170. doi: 10.1113/jphysiol.2011.211920 Google Scholar
  123. 123.
    Contreras RJ, Beckstead RM, Norgren R (1982) The central projections of the trigeminal, facial, glossopharyngeal and vagus nerves: an autoradiographic study in the rat. J Auton Nerv Syst 6(3):303–322PubMedCrossRefGoogle Scholar
  124. 124.
    Norgren R, Leonard CM (1973) Ascending central gustatory pathways. J Comp Neurol 150(2):217–237. doi: 10.1002/cne.901500208 PubMedCrossRefGoogle Scholar
  125. 125.
    Iwatsuki K, Uneyama H (2012) Sense of taste in the gastrointestinal tract. J Pharmacol Sci 118(2):123–128PubMedCrossRefGoogle Scholar
  126. 126.
    Negri R, Morini G, Greco L (2011) From the tongue to the gut. J Pediatr Gastroenterol Nutr 53(6):601–605. doi: 10.1097/MPG.0b013e3182309641 PubMedGoogle Scholar
  127. 127.
    Roper SD (2007) Signal transduction and information processing in mammalian taste buds. Pflugers Arch 454(5):759–776. doi: 10.1007/s00424-007-0247-x PubMedCrossRefGoogle Scholar
  128. 128.
    Chaudhari N, Roper SD (2010) The cell biology of taste. J Cell Biol 190(3):285–296. doi: 10.1083/jcb.201003144 PubMedCrossRefGoogle Scholar
  129. 129.
    Cota D, Proulx K, Smith KA, Kozma SC, Thomas G, Woods SC, Seeley RJ (2006) Hypothalamic mTOR signaling regulates food intake. Science 312(5775):927–930. doi: 10.1126/science.1124147 PubMedCrossRefGoogle Scholar
  130. 130.
    Inoki K, Kim J, Guan KL (2012) AMPK and mTOR in cellular energy homeostasis and drug targets. Annu Rev Pharmacol Toxicol 52:381–400. doi: 10.1146/annurev-pharmtox-010611-134537 PubMedCrossRefGoogle Scholar
  131. 131.
    Hundal HS, Taylor PM (2009) Amino acid transceptors: gate keepers of nutrient exchange and regulators of nutrient signaling. Am J Physiol Endocrinol Metab 296(4):E603–E613. doi: 10.1152/ajpendo.91002.2008 PubMedCrossRefGoogle Scholar
  132. 132.
    Hyde R, Taylor PM, Hundal HS (2003) Amino acid transporters: roles in amino acid sensing and signalling in animal cells. Biochem J 373(Pt 1):1–18PubMedCrossRefGoogle Scholar
  133. 133.
    Ljungdahl PO (2009) Amino-acid-induced signalling via the SPS-sensing pathway in yeast. Biochem Soc Trans 37(Pt 1):242–247. doi: 10.1042/BST0370242 PubMedCrossRefGoogle Scholar
  134. 134.
    Palii SS, Thiaville MM, Pan YX, Zhong C, Kilberg MS (2006) Characterization of the amino acid response element within the human sodium-coupled neutral amino acid transporter 2 (SNAT2) system A transporter gene. Biochem J 395(3):517–527. doi: 10.1042/BJ20051867 PubMedCrossRefGoogle Scholar
  135. 135.
    Conigrave AD, Hampson DR (2010) Broad-spectrum amino acid-sensing class C G-protein coupled receptors: molecular mechanisms, physiological significance and options for drug development. Pharmacol Ther 127(3):252–260. doi: 10.1016/j.pharmthera.2010.04.007 PubMedCrossRefGoogle Scholar
  136. 136.
    Liou AP, Sei Y, Zhao X, Feng J, Lu X, Thomas C, Pechhold S, Raybould HE, Wank SA (2011) The extracellular calcium-sensing receptor is required for cholecystokinin secretion in response to L-phenylalanine in acutely isolated intestinal I cells. Am J Physiol Gastrointest Liver Physiol 300(4):G538–G546. doi: 10.1152/ajpgi.00342.2010 PubMedCrossRefGoogle Scholar
  137. 137.
    Conigrave AD, Mun HC, Lok HC (2007) Aromatic l-amino acids activate the calcium-sensing receptor. J Nutr 137(6 Suppl 1):1524S–1527S, discussion 1548SPubMedGoogle Scholar
  138. 138.
    Albers A, Broer A, Wagner CA, Setiawan I, Lang PA, Kranz EU, Lang F, Broer S (2001) Na+ transport by the neural glutamine transporter ATA1. Pflugers Arch 443(1):92–101. doi: 10.1007/s004240100663 PubMedCrossRefGoogle Scholar
  139. 139.
    Armano S, Coco S, Bacci A, Pravettoni E, Schenk U, Verderio C, Varoqui H, Erickson JD, Matteoli M (2002) Localization and functional relevance of system A neutral amino acid transporters in cultured hippocampal neurons. J Biol Chem 277(12):10467–10473. doi: 10.1074/jbc.M110942200 PubMedCrossRefGoogle Scholar
  140. 140.
    Gietzen DW, Jhanwar-Uniyal M (1996) Alpha 2 noradrenoceptors in the anterior piriform cortex decline with acute amino acid deficiency. Brain Res Mol Brain Res 35(1–2):41–46PubMedCrossRefGoogle Scholar
  141. 141.
    Sanahuja JC, Harper AE (1962) Effect of amino acid imbalance on food intake and preference. Am J Physiol 202:165–170PubMedGoogle Scholar
  142. 142.
    Naito-Hoopes M, McArthur LH, Gietzen DW, Rogers QR (1993) Learned preference and aversion for complete and isoleucine-devoid diets in rats. Physiol Behav 53(3):485–494PubMedCrossRefGoogle Scholar
  143. 143.
    Elizalde G, Sclafani A (1990) Flavor preferences conditioned by intragastric polycose infusions: a detailed analysis using an electronic esophagus preparation. Physiol Behav 47(1):63–77PubMedCrossRefGoogle Scholar
  144. 144.
    Hrupka BJ, Lin Y, Gietzen DW, Rogers QR (1999) Lysine deficiency alters diet selection without depressing food intake in rats. J Nutr 129(2):424–430PubMedGoogle Scholar
  145. 145.
    Murphy ME, Pearcy SD (1993) Dietary amino acid complementation as a foraging strategy for wild birds. Physiol Behav 53(4):689–698PubMedCrossRefGoogle Scholar
  146. 146.
    Roth FX, Meindl C, Ettle T (2006) Evidence of a dietary selection for methionine by the piglet. J Anim Sci 84(2):379–386PubMedGoogle Scholar
  147. 147.
    Fortes-Silva R, Rosa PV, Zamora S, Sanchez-Vazquez FJ (2012) Dietary self-selection of protein-unbalanced diets supplemented with three essential amino acids in Nile tilapia. Physiol Behav 105(3):639–644. doi: 10.1016/j.physbeh.2011.09.023 PubMedCrossRefGoogle Scholar
  148. 148.
    Wilson DA, Kadohisa M, Fletcher ML (2006) Cortical contributions to olfaction: plasticity and perception. Semin Cell Dev Biol 17(4):462–470. doi: 10.1016/j.semcdb.2006.04.008 PubMedCrossRefGoogle Scholar
  149. 149.
    Gloaguen M, Le Floc'h N, Corrent E, Primot Y, van Milgen J (2012) Providing a diet deficient in valine but with excess leucine results in a rapid decrease in feed intake and modifies the postprandial plasma amino acid and alpha-keto acid concentrations in pigs. J Anim Sci. doi: 10.2527/jas.2011-4956
  150. 150.
    Bellinger LL, Williams FE, Rogers QR, Gietzen DW (1996) Liver denervation attenuates the hypophagia produced by an imbalanced amino acid diet. Physiol Behav 59(4–5):925–929PubMedCrossRefGoogle Scholar
  151. 151.
    Harper AE (1965) Effect of variations in protein intake on enzymes of amino acid metabolism. Can J Biochem 43(9):1589–1603PubMedCrossRefGoogle Scholar
  152. 152.
    Sikalidis AK, Stipanuk MH (2010) Growing rats respond to a sulfur amino acid-deficient diet by phosphorylation of the alpha subunit of eukaryotic initiation factor 2 heterotrimeric complex and induction of adaptive components of the integrated stress response. J Nutr 140(6):1080–1085. doi: 10.3945/jn.109.120428 PubMedCrossRefGoogle Scholar
  153. 153.
    Hasek BE, Stewart LK, Henagan TM, Boudreau A, Lenard NR, Black C, Shin J, Huypens P, Malloy VL, Plaisance EP, Krajcik RA, Orentreich N, Gettys TW (2010) Dietary methionine restriction enhances metabolic flexibility and increases uncoupled respiration in both fed and fasted states. Am J Physiol Regul Integr Comp Physiol 299(3):R728–R739. doi: 10.1152/ajpregu.00837.2009 PubMedCrossRefGoogle Scholar
  154. 154.
    Nagao K, Bannai M, Seki S, Kawai N, Mori M, Takahashi M (2010) Voluntary wheel running is beneficial to the amino acid profile of lysine-deficient rats. Am J Physiol Endocrinol Metab 298(6):E1170–E1178. doi: 10.1152/ajpendo.00763.2009 PubMedCrossRefGoogle Scholar
  155. 155.
    Baumeister A, Hawkins WF, Cromwell RL (1964) Need states and activity level. Psychol Bull 61:438–453PubMedCrossRefGoogle Scholar
  156. 156.
    Elshorbagy AK, Valdivia-Garcia M, Mattocks DA, Plummer JD, Smith AD, Drevon CA, Refsum H, Perrone CE (2011) Cysteine supplementation reverses methionine restriction effects on rat adiposity: significance of stearoyl-coenzyme A desaturase. J Lipid Res 52(1):104–112. doi: 10.1194/jlr.M010215 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of Anatomy, Physiology and Cell Biology, School of Veterinary MedicineUniversity of California, DavisDavisUSA
  2. 2.Department of NeuroscienceJohns Hopkins University School of MedicineBaltimoreUSA

Personalised recommendations