The data support the view that pancreatic β-cells become dedifferentiated and convert to α- and δ-"like" cells in human type 2 diabetes. The findings should prompt a reassessment of goals in the prevention and treatment of β-cell dysfunction.

In general, our results suggest that both the frequency of nicotine self-administration, as well as the dosage, are positively associated with greater delay discounting of gains. One neuropsychopharmacological explanation for this effect is that chronic nicotine intake may induce neuroadaptation of the neural circuitry involved in reward processing.

Psychopharmacologists are interested in delay and probability discounting because the tendency to discount the value of future and uncertain rewards has been linked with drug dependency. However, relatively little is known about the long-term stability of discounting measures typically studied in clinical psychopharmacology. To evaluate the stability of discounting over a 3-month period, the authors compared points of subjective equality (indifference points) with those collected from the same subjects 3 months earlier. Seven delay periods, ranging from 1 week to 25 years, and 7 probability values, ranging from .95 to .05, were assessed in an undergraduate sample (n=22, delay discounting; n=18, probability discounting). The authors examined both differential stability (stability of individual differences) and absolute stability (stability of the group mean) of delay and probability discounting measures as well as their respective indifference points. The results demonstrate that standard delay and probability discounting parameters (e.g., hyperbolic k and area under the curve) had both differential stability and absolute stability across 3 months. Moreover, most indifference points in the delay and probability discounting tasks demonstrated both differential and absolute stability. All together, these results suggest that delay and probability parameters are stable enough to predict future behavior, such as substance abuse. Additional findings indicated that a hyperbolic function fitted the data better than an exponential function and that delay and probability discounting parameters were not significantly correlated.

The neural mechanisms underlying memory regulation during sleep are not yet fully understood. We found that melanin concentrating hormone–producing neurons (MCH neurons) in the hypothalamus actively contribute to forgetting in rapid eye movement (REM) sleep. Hypothalamic MCH neurons densely innervated the dorsal hippocampus. Activation or inhibition of MCH neurons impaired or improved hippocampus-dependent memory, respectively. Activation of MCH nerve terminals in vitro reduced firing of hippocampal pyramidal neurons by increasing inhibitory inputs. Wake- and REM sleep–active MCH neurons were distinct populations that were randomly distributed in the hypothalamus. REM sleep state–dependent inhibition of MCH neurons impaired hippocampus-dependent memory without affecting sleep architecture or quality. REM sleep–active MCH neurons in the hypothalamus are thus involved in active forgetting in the hippocampus.

Whether increased serotonin (5-HT) release in the forebrain attenuates or enhances anxiety has been controversial for over 25 yr. Although there is considerable indirect evidence, there is no direct evidence that indicates a relationship between acute 5-HT release and anxiety. In particular, there is no known method that can reversibly, selectively, and temporally control serotonergic activity. To address this issue, we generated transgenic animals to manipulate the firing rates of central 5-HT neurons by optogenetic methods. Activation of serotonergic neurons in the median raphe nucleus was correlated to enhanced anxiety-like behaviour in mice, whereas activation of serotonergic neurons in the dorsal raphe nucleus had no effect on anxiety-like behaviour. These results indicate that an acute increase in 5-HT release from the median raphe nucleus enhances anxiety.

Generation of surrogate sources of insulin-producing β-cells remains a goal of diabetes therapy. While most efforts have been directed at differentiating embryonic or induced pluripotent stem (iPS) cells into β-like-cells through endodermal progenitors, we have shown that gut endocrine progenitor cells of mice can be differentiated into glucose-responsive, insulin-producing cells by ablation of transcription factor Foxo1. Here we show that FOXO1 is present in human gut endocrine progenitor and serotonin-producing cells. Using gut organoids derived from human iPS cells, we show that FOXO1 inhibition using a dominant-negative mutant or lentivirus-encoded shRNA promotes generation of insulin-positive cells that express all markers of mature pancreatic β-cells, release C-peptide in response to secretagogues, and survive in vivo following transplantation into mice. The findings raise the possibility of using gut-targeted FOXO1 inhibition or gut organoids as a source of insulin-producing cells to treat human diabetes.

Our results indicated that cotransplantation of ADSCs with islet graft promoted survival and insulin function of the graft and reduced the islet mass required for reversal of diabetes. This innovative protocol may allow "one donor to one recipient" islet transplantation.

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