Animals assess the values of rewards to learn and choose the best possible outcomes. We studied how single neurons in the primate amygdala coded reward magnitude, an important variable determining the value of rewards. A single, Pavlovian-conditioned visual stimulus predicted fruit juice to be delivered with one of three equiprobable volumes (P = 1/3). A population of amygdala neurons showed increased activity after reward delivery, and almost one half of these responses covaried with reward magnitude in a monotonically increasing or decreasing fashion. A subset of the reward responding neurons were tested with two different probability distributions of reward magnitude; the reward responses in almost one half of them adapted to the predicted distribution and thus showed reference-dependent coding. These data suggest parametric reward value coding in the amygdala as a characteristic component of its function in reinforcement learning and economic decision making.

PURPOSE. To evaluate the effect of Conditioned Medium from human uterine cervical stem cells (CM-hUCESCs) on corneal epithelial healing in a rat model of dry eye after alkaline corneal epithelial ulcer. We also tested the bactericide effect of CM-hUCESCs. METHODS. Dry eye was induced in rats by extraocular lacrimal glands excision, and corneal ulcers were produced using NaOH. Corneal histological evaluation was made with hematoxylin-eosin (H&E) staining. Real-time PCR was used to evaluate mRNA expression levels of pro-inflammatory cytokines. We also studied the bactericide effect of CM-hUCESCs in vitro and on infected corneal contact lenses (CLs) using Escherichia coli (E. coli) and Staphylococcus epidermidis (S. epidermidis) bacteria. In addition, in order to investigate proteins from CM-hUCESCs that could mediate these effects, we carried out a human cytokine antibody array. RESULTS. After injury, dry eyes treated with CM-hUCESCs significantly improved epithelial regeneration, and showed reduced corneal MIP-1α and TNF-α mRNA expression, as compared to untreated eyes and eyes treated with culture medium or sodium hyaluronate ophthalmic drops. In addition, we found in CM-hUCESCs high levels of proteins, such as tissue inhibitors of metalloproteinases -1 and -2, fibroblast growth factor -6 and -7, urokinase receptor, and hepatocyte growth factor, that could mediate these effects. In vitro, CM-hUCESCs showed a clear bactericide effect on both E. coli and S. epidermidis, and CLs infected with S. epidermidis. Analyses of CM-hUCESCs showed elevated levels of proteins that could be involved in the bactericide effect, such as the chemokine (C-X-C motif) ligands -1, -6, -8, -10, and the chemokine (C-C motif) ligands -5, and -20. CONCLUSIONS. Treatment with CM-hUCESCs improved wound healing of alkali-injured corneas and showed a strong bactericide effect on CLs. Patients using CLs and suffering dry eye, allergies induced by commercial solutions, or small corneal injuries could benefit from this treatment.

Evidences indicate that tumor development and progression towards a malignant phenotype depend not only on cancer cells themselves, but are also deeply influenced by tumor stroma reactivity. The present study uses mesenchymal stem cells from normal human uterine cervix (hUCESCs), isolated by the minimally invasive method of routine Pap cervical smear, to study their effect on the three main cell types in a tumor: cancer cells, fibroblasts and macrophages. Administration of hUCESCs-conditioned medium (CM) to a highly invasive breast cancer MDA-MB-231 cell line and to human breast tumors with high cell proliferation rates had the effect of reducing cell proliferation, modifying the cell cycle, inducing apoptosis, and decreasing invasion. In a xenograft mouse tumor model, hUCESCs-CM reduced tumor growth and increased overall survival. In cancer-associated fibroblasts, administration of hUCESCs-CM resulted in reduced cell proliferation, greater apoptosis and decreased invasion. In addition, hUCESCs-CM inhibited and reverted macrophage differentiation. The analysis of hUCESCs-CM (fresh and lyophilized) suggests that a complex paracrine signaling network could be implicated in the anti-tumor potential of hUCESCs.

Prediction about outcomes constitutes a basic mechanism underlying informed economic decision making. A stimulus constitutes a reward predictor when it provides more information about the reward than the environmental background. Reward prediction can be manipulated in two ways, by varying the reward paired with the stimulus, as done traditionally in neurophysiological studies, and by varying the background reward while holding stimulus-reward pairing constant. Neuronal mechanisms involved in reward prediction should also be sensitive to changes in background reward independently of stimulus-reward pairing. We tested this assumption on a major brain structure involved in reward processing, the central and basolateral amygdala. In a 2 × 2 design, we examined the influence of rewarded and unrewarded backgrounds on neuronal responses to rewarded and unrewarded visual stimuli. Indeed, responses to the unchanged rewarded stimulus depended crucially on background reward in a population of amygdala neurons. Elevating background reward to the level of the rewarded stimulus extinguished these responses, and lowering background reward again reinstated the responses without changes in stimulus-reward pairing. None of these neurons responded specifically to an inhibitory stimulus predicting less reward compared with background (negative contingency). A smaller group of amygdala neurons maintained stimulus responses irrespective of background reward, possibly reflecting stimulus-reward pairing or visual sensory processes without reward prediction. Thus in being sensitive to background reward, the responses of a population of amygdala neurons to phasic stimuli appeared to follow the full criteria for excitatory reward prediction (positive contingency) rather than reflecting simple stimulus-reward pairing (contiguity).

Sensitivity to time, including the time of reward, guides the behaviour of all organisms. Recent research suggests that all major reward structures of the brain process the time of reward occurrence, including midbrain dopamine neurons, striatum, frontal cortex and amygdala. Neuronal reward responses in dopamine neurons, striatum and frontal cortex show temporal discounting of reward value. The prediction error signal of dopamine neurons includes the predicted time of rewards. Neurons in the striatum, frontal cortex and amygdala show responses to reward delivery and activities anticipating rewards that are sensitive to the predicted time of reward and the instantaneous reward probability. Together these data suggest that internal timing processes have several well characterized effects on neuronal reward processing.