The brain's response to an essential amino acid-deficient diet and the circuitous route to a better meal

Abstract

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.

Fig. 1

The projections from the APC to brain areas important to locomotor activity are shown for Appetitive behavior in foraging. Included are: the Supplementary Motor Cortex (AGm), the Basal Ganglia (BG) outlined in dashed rectangles, the dorsolateral perifornical hypothalamus (DLLH), which projects to the AGm, and the Primary Motor Cortex, which receives the processed output for locomotor activity from the BG, via the Thalamus. Included in this segment is the inhibitory RT, which projects GABAergic signals to the DLLH, to end the meal and allow foraging. In the Consummatory behavior segment, the APC, with its normal level of inhibitory function under IAA repletion, would not activate the RT’s inhibition of the DLLH, allowing feeding to proceed. The dashed arrows show GABAergic pathways and the solid arrows indicate glutamatergic pathways. Abbreviations are: APC, anterior piriform cortex; RT, reticular thalamus; DLLH, dorsolateral perifornical hypothalamus; GP ext, globus pallidus externa; GP Int, globus pallidus interna; N, nucleus

Fig. 2

Photomicrographs of biocytin tract tracing from [69], showing: a Axons running from the globus pallidus (GP), left, crossing through the internal capsule (indicated by the single arrow at the top) to the reticular thalamus (RT) at the three arrows, on the right. b Monosynaptic axons from the highly chemosensitive region of the APC, which recognizes IAA deficiency using the GCN2 system, are shown following the internal capsule and ending in the dorsolateral perifornical LH (DLLH). Note that the internal capsule is in the same orientation in both frames. Abbreviations are OT, optic tract; LH, lateral hypothalamus

Fig. 3

The brain areas associated with the sensory, integrative, and motor output functions associated with the sensing of and responses to IAA-deficient diets. Under Sensory, the regions belonging to the olfactory cortex, with their projections, are shown on the left of the figure. Under Integration, the top box represents cortical areas, prefrontal (PFC), orbitofrontal (OFC), and supplementary motor (AGm). As subcortical structures, central and basolateral amygdala (Ce, BL AMYG) and DLLH hypothalamus are as in Fig. 1. In the dashed box, ventral pallidum (VP) and nucleus accumbens (NAcc) are members of the basal ganglia in the striatum (STR). The ventral tegmentum (vent TEG) projects to the STR in the motivation circuit (Reward); at this level the pedunculopontine nucleus (PPN) also receives input from the STR and projects to reticulospinal centers. Members of the motivation circuit are in five-sided boxes, taste association areas are in ovals. The diencephalon includes the hypothalamus (and DLLH) and thalamus (THAL), indicated in dotted cylinders, for comparison with the lamprey circuit. Under Output are the motor centers for appetitive activities such as foraging. The hippocampus (HIP) is important for spatial memory

Fig. 4

Food intake data showing feeding responses to IAA basal, imbalanced, devoid or corrected diets, are replotted, with permission from [24]. The data are taken from computerized food intake records of two individual rats eating the diets listed at the top of each panel. The top two panels represent one rat’s feeding patterns; the bottom two panels are from the second rat. Food intake is given in grams per half-hour bins. The time is plotted on the X-axis, for the first 6.5 h of each animal’s first exposure to imbalanced, devoid or corrected diets, compared with the basal control (prefeeding) diet

Fig. 5

Anatomical features of the taste-aversion or preference pathways. The Sensory pathway for taste is at the left of the figure, with cranial nerves for taste (CrN VII, IX, and X) coming in to the brainstem at the level of the nucleus tractus solitarius (NTS). The NTS projects to the parabrachial nucleus (PBN) and then to the taste relay in the thalamus (VPMpc) and finally to the insular cortex (IC). The area postrema (AP) is a circumventricular organ (CVO) allowing molecules in the blood to enter the brainstem at the level of the NTS. Other elements of the figure, for Integration with the learned aspects of the responses, are the same as in Fig. 3