Faculty Bibliography

Early life maltreatment by the caregiver constitutes a major risk factor for the development of later-life psychopathologies, including fear-related pathologies. Here, we used an animal model of early life maltreatment induced by the Scarcity-Adversity Model of low bedding (LB) where the mother is given insufficient bedding for nest building while rat pups were postnatal days (PN) 8-12. To assess effects of maltreatment on the expression of threat-elicited defensive behaviors, animals underwent odor-shock threat conditioning at three developmental stages: late infancy (PN18), adolescence (PN45) or adulthood (>PN75) and tested the next day with odor only presentations (cue test). Results showed that in typically developing rats, the response to threat increases with maturation, although experience with maltreatment in early infancy produced enhanced responding to threat in infancy and adulthood, but a decrease in maltreated adolescents. To better understand the unique features of this decreased threat responding in adolescence, c-Fos expression was assessed within the amygdala and ventromedial prefrontal cortex (vmPFC) associated with the cued expression of threat learning. Fos counts across amygdala subregions were lower in LB rats compared to controls, while enhanced c-Fos expression was observed in the vmPFC prelimbic cortex (PL). Correlational analysis between freezing behavior and Fos revealed freezing levels were correlated with CeA in controls, although more global correlations were detected in LB-reared rats, including the BA, LA, and CeA. Functional connectivity analysis between brain regions showed that LB reared rats exhibited more diffuse interconnectivity across amygdala subnuclei, compared the more heterogeneous patterns observed in controls. In addition, functional connectivity between the IL and LA switched from positive to negative in abused adolescents. Overall, these results suggest that in adolescence, the unique developmental decrease in fear expression following trauma is associated with distinct changes in regional function and long-range connectivity, reminiscent of pathological brain function. These results suggest that early life maltreatment from the caregiver perturbs the developmental trajectory of threat-elicited behavior. Indeed, it is possible that this form of trauma, where the infant's safety signal or "safe haven" (the caregiver) is actually the source of the threat, produces distinct outcomes across development.

The dentate gyrus (DG) and its primary cell type, the granule cell (GC), are thought to be critical to many cognitive functions. A major neuronal subtype of the DG is the hilar mossy cell (MC). MCs have been considered to play an important role in cognition, but in vivo studies to understand the activity of MCs during cognitive tasks are challenging because the experiments usually involve trauma to the overlying hippocampus or DG, which kills hilar neurons. In addition, restraint typically occurs, and MC activity is reduced by brief restraint stress. Social isolation often occurs and is potentially confounding. Therefore, we used c-fos protein expression to understand when MCs are active in vivo in socially housed adult C57BL/6 mice in their home cage. We focused on c-fos protein expression after animals explored novel objects, based on previous work which showed that MCs express c-fos protein readily in response to a novel housing location. Also, MCs are required for the training component of the novel object location task and novelty-encoding during a food-related task. GluR2/3 was used as a marker of MCs. The results showed that MC c-fos protein is greatly increased after exposure to novel objects, especially in ventral DG. We also found that novel objects produced higher c-fos levels than familiar objects. Interestingly, a small subset of neurons that did not express GluR2/3 also increased c-fos protein after novel object exposure. In contrast, GCs appeared relatively insensitive. The results support a growing appreciation of the role of the DG in novelty detection and novel object recognition, where hilar neurons and especially MCs are very sensitive.

OBJECTIVE:This study evaluated changes in positive affect within cognitive-behavioral treatments (CBT) for anxiety disorders. It was hypothesized that there would be significantly greater increases in positive affect in CBT conditions compared to the waitlist, and particularly higher in the Unified Protocol (UP) than the single disorder protocols (SDP) given the UP's focus on emotions (including positive emotions) rather than symptoms. METHOD:Patients with heterogeneous anxiety disorders (N = 223) were randomly assigned to the UP, SDP or waitlist. Linear mixed model regression (intent to treat) analyses were used to compare change in positive affect, quality of life, and savoring between patients in the treatment conditions (UP and SDP) versus waitlist conditions. Between condition effect sizes were calculated to assess the magnitude of difference within conditions at post-treatment. RESULTS:Results indicated a significant Group (treatment vs. waitlist) × Time (pre- post-treatment) interaction (F(1, 154.36) = 6.75; p = .01) for positive affect in which the treatment group showed significant improvements in positive affect pre- to post-treatment (ESsg = 0.37, SEsg = 0.09, 95% CI [0.20: 0.54]) and the waitlist condition did not. There were no differences between UP and SDP conditions in positive affect at baseline or at post-treatment. CONCLUSIONS:These results suggest CBT, which typically focuses on reductions in negative affect, may also improve positive affect. The importance of future research evaluating, targeting, and improving positive affect in CBT trials is discussed. Clinicaltrials.gov Identifier: NCT01243606.

Rates of treatment utilization decline as adolescents make the transition to adulthood even though young adults are particularly vulnerable to the negative outcomes of untreated mental illness. Although a variety of factors have been explored to explain decreased treatment utilization in this age group, previous research has almost exclusively employed cross-sectional methods rather than following a group of youth as they enter adulthood. The current study aims to address this methodological limitation by assessing treatment utilization in emerging adults who began participating in a longitudinal study during childhood. One hundred and thirty seven youth who turned 18 during the 96-month follow-up period were included in the current analyses. Demographic and socioeconomic variables such as sex, race, and insurance status and clinical variables such as psychiatric diagnoses and perceptions of treatment effectiveness were investigated as factors potentially associated with outpatient treatment use before and after age 18. Prior to age 18, youth reported using outpatient services at 75% of their visits, but after age 18, outpatient treatment utilization dropped to around 50%. White race, increased parental stress, and increased parental perception of treatment usefulness were associated with greater treatment use prior to age 18, whereas only increased youth perception of symptom-related dysfunction were associated with increased treatment use after age 18. Findings point to the importance of including youth preferences and perceptions of dysfunction in treatment decisions across adolescence in order to optimize treatment use following the transition to adulthood.