The orbital prefrontal cortex (PFo) operates as part of a network involved in reward-based learning and goal-directed behavior. To test whether the PFo is necessary for guiding behavior based on the value of expected reward outcomes, we compared four rhesus monkeys with two-stage bilateral PFo removals and six unoperated controls for their responses to reinforcer devaluation, a task that assesses the monkeys' abilities to alter choices of objects when the value of the underlying food has changed. For comparison, the same monkeys were tested on a standard test of flexible stimulus-reward learning, namely object reversal learning. Relative to controls, monkeys with bilateral PFo removals showed a significant attenuation of reinforcer devaluation effects on each of two separate assessments, one performed shortly after surgery and the other ϳ19 months after surgery; the operated monkeys were also impaired on object reversal learning. The same monkeys, however, were unimpaired in acquisition of object discrimination learning problems and responded like controls when allowed to choose foods alone, either on a food preference test among six different foods or after selective satiation. Thus, satiety mechanisms and the ability to assign value to familiar foods appear to be intact in monkeys with PFo lesions. The pattern of results suggests that the PFo is critical for response selection based on predicted reward outcomes, regardless of whether the value of the outcome is predicted by affective signals (reinforcer devaluation) or by visual signals conveying reward contingency (object reversal learning).

The present study examines the effects of bilateral orbital prefrontal cortex (PFo) lesions on monkeys' emotional responses in two different contexts: in the presence of a rubber snake and in the presence of a human intruder. For comparison, we also assessed the responses of rhesus monkeys with selective amygdala lesions on these same tasks. Monkeys with PFo lesions, like those with amygdala lesions, displayed blunted emotional responses to the fake snake. Unlike monkeys with amygdala lesions, however, monkeys with PFo lesions displayed more mild aggression than controls in the presence of a human intruder. The findings support the idea that the PFo helps integrate sensory signals in the service of choosing among competing responses. In addition, they point to a divergence of the roles of the PFo and amygdala in responding to a social stimulus, the human intruder.

Cells with osteogenic potential can be found in a variety of tissues. Here we show that circulating osteogenic precursor (COP) cells, a bone marrow-derived type I collagen+/CD45+ subpopulation of mononuclear adherent cells, are present in early pre-osseous fibroproliferative lesions in patients with fibrodysplasia ossificans progressiva (FOP) and nucleate heterotopic ossification (HO) in a murine in vivo implantation assay. Blood samples from FOP patients with active episodes of HO contain significantly higher numbers of clonally-derived COP cell colonies than patients with stable disease or unaffected individuals. The highest level of COP cells was found in a patient just prior to the clinical onset of an HO exacerbation. Our studies show that even COP cells derived from an unaffected individual can contribute to HO in genetically susceptible host tissue. The possibility that circulating, hematopoietic-derived cells with osteogenic potential can seed inflammatory sites has tremendous implications and, to our knowledge, represents the first example of their involvement in clinical HO. Thus, bone formation is not limited to cells of the mesenchymal lineage, and circulating cells of hematopoietic origin can also serve as osteogenic precursors at remote sites of tissue inflammation.

SummaryOsteoporosis and the associated risk of fracture are major clinical challenges in the elderly. Telomeres shorten with age in most human tissues, including bone, and because telomere shortening is a cause of cellular replicative senescence or apoptosis in cultured cells, including mesenchymal stem cells (MSCs) and osteoblasts, it is hypothesized that telomere shortening contributes to the aging of bone. Osteoporosis is common in the Werner (Wrn) and dyskeratosis congenita premature aging syndromes, which are characterized by telomere dysfunction.

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