Sex, stress, and fear: individual differences in conditioned learning.

It has long been recognized that humans vary in their conditionability, yet the factors that contribute to individual variation in emotional learning remain to be delineated. The goal of the present study was to investigate the relationship among sex, stress hormones, and fear conditioning in humans. Forty-five healthy adults (22 females) underwent differential delay conditioning, using fear-relevant conditioned stimuli and a shock unconditioned stimulus. Salivary cortisol samples were taken at baseline and after acquisition training and a 24-h-delayed retention test. The results showed that acquisition of conditioning significantly correlated with postacquisition cortisol levels in males, but not in females. This sex-specific relationship was found despite similar overall levels of conditioning, unconditioned responding, and cortisol. There was no effect of postacquisition cortisol on consolidation of fear learning in either sex. These findings have implications for the understanding of individual differences in fear acquisition and risk factors for the development of affective disorders.

Emotional enhancement of perceptual priming is preserved in aging and early-stage Alzheimer's disease.

Perceptual priming for emotionally-negative and neutral scenes was tested in early-stage Alzheimer's disease (AD) patients and healthy younger, middle-aged and older adults. In the study phase, participants rated the scenes for their arousal properties. In the test phase, studied and novel scenes were initially presented subliminally, and the exposure duration was gradually increased until a valence categorization was made. The difference in exposure duration required to categorize novel versus studied items was the dependent measure of priming. Aversive content increased the magnitude of priming, an effect that was preserved in healthy aging and AD. Results from an immediate recognition memory test showed that the priming effects could not be attributable to enhanced explicit memory for the aversive scenes. These findings implicate a dissociation between the modulatory effect of emotion across implicit and explicit forms of memory in aging and early-stage AD.

Impact of healthy aging on awareness and fear conditioning.

Fear conditioning has provided a useful model system for studying associative emotional learning, but the impact of healthy aging has gone relatively unexplored. The present study investigated fear conditioning across the adult life span in humans. A delay discrimination task was employed using visual conditioned stimuli and an auditory unconditioned stimulus. Awareness of the reinforcement contingencies was assessed in a postexperimental interview. Compared with young adult participants, middle-aged and older adults displayed reductions in unconditioned responding, discriminant conditioning, and contingency awareness. When awareness and overall arousability were taken into consideration, there were no residual effects of aging on conditioning. These results highlight the importance of considering the influence of declarative knowledge when interpreting age-associated changes in discriminative conditioned learning.

Effect of T cell subset dose on outcome of T cell-depleted bone marrow transplantation.

T cell depletion using the murine monoclonal antibody (moAb) T10B9 is unique in that the T cell receptor (TCR)gamma delta bearing subset is relatively spared compared to the TCR alpha beta + subset. We evaluated the probabilities of engraftment, acute and chronic graft-versus-host disease (GVHD), relapse, and survival in 273 recipients of marrow T cell depleted using T10B9. Sixty-two patients received marrow from an HLA-identical sibling, 54 patients received partially matched related donor marrow and 157 patients received unrelated donor marrow. Limiting dilution analysis (LDA) was used to estimate total clonable T cell dose in all patients and a modified LDA using moAb-coated immunomagnetic beads was used to estimate TCR alpha beta +, CD4+, and CD8+ T cells in a subset of patients. TCR gamma delta + cell dose was estimated by flow cytometry. Cox proportional hazards regression models were used to assess the impact of T cell subset dose/kg of body weight on outcome. We found a significant association of TCR gamma delta + T cell dose (P = 0.004), but not TCR alpha beta + T cell dose or total clonable T cell dose, with the probability of engraftment. TCR alpha beta +, CD4+, CD8+ and total clonable T cell dose were significantly associated (P < 0.001) with the risks of grade 2-4 acute GVHD in recipients of marrow from related donors but not in recipients of marrow from unrelated donors. Neither total clonable T cell dose nor any T cell subset dose was found to be significantly associated with chronic GVHD, relapse or survival. The results confirm preclinical studies showing TCR gamma delta + T cells promote engraftment. TCR gamma delta + T cells are not associated with an increased risk of acute GVHD while TCR alpha beta T cells are associated with acute GVHD but not engraftment in recipients of marrow grafts T cell depleted using T10B9. These findings support the hypothesis that T cell subsets differentially contribute to alloengraftment and GVHD.

A new limiting dilution culture system for the detection of T cell subsets in T cell-depleted marrow grafts.

T cell depletion (TCD) has been achieved using techniques that cause the inactivation, lysis, or physical removal of T cells from the donor marrow. The clinical results of TCD reflect, in part, the degree of TCD achieved and the subsets that are removed. To better evaluate TCD using the monoclonal antibody (mAb) T10B9, we have performed a series of flow cytometry and mAb blocking studies and have developed a new limiting dilution assay (LDA) that allows the detection of T cell subsets that survive treatment. T cell growth was stimulated with PHA, rIL-2, and irradiated feeder PBMC in a total well volume of 20 microliters. Growth was scored by microscopic examination on days 14-16 of incubation. Immunomagnetic beads coated with mAb were added to the growing wells and incubated, then the plates were fixed to a template of samarium cobalt magnets before washing away nonadherent cells. Wells in which > 50 cells bound > or = 2 beads were scored as positive. Flow cytometry indicated that T10B9 recognized all T cells, but complement-mediated lysis spared a significant proportion of the TCR gamma delta + subset. The epitope recognized by T10B9 on TCR gamma delta + cells appears to be differentially expressed compared with TCR alpha beta + T cells based on antibody blocking studies. In contrast to antibodies to CD3 epsilon, T10B9 binds less well to TCR gamma delta + cells, possibly resulting in incomplete complement-mediated lysis of this subset. The relative sparing of TCR gamma delta + cells was found in marrow and peripheral blood. Subset LDA confirmed that the TCR gamma delta + cells detected by flow cytometry were capable of growth and further showed that OKT3 did not spare TCR gamma delta + cells. The subset LDA should prove useful in helping to assess the role of T cell subsets in clinical events post-TCD bone marrow transplantation.