Light-Enhanced Startle as an Experimental Model of Withdrawal

Nicotine is extremely addictive, and the negative effects of withdrawal, such as increased anxiety, contribute to relapse. Nicotine produces significant changes in the extended amygdala, the brain regions responsible for regulating anxiety. Light-Enhanced Startle is an established method for assessing anxiety in animal models and is sensitive to drug manipulations. This thesis had two goals, Experiment 1 asked: can LES be used to investigate the anxiety of extended nicotine withdrawal following chronic nicotine administration in rats? We hypothesized that exposing rats to chronic nicotine would result in elevated LES during spontaneous withdrawal as compared to controls, and that this elevation in LES would decrease as withdrawal progressed. Adult Sprague-Dawley rats were given .40 mg/kg nicotine twice daily for 14 days, and were then tested in LES on withdrawal days 1, 3, and 5. Animals showed significantly increased anxiety on withdrawal day 1, and exhibited a pattern of decreasing but elevated LES on withdrawal days 3 and 5 consistent with our predictions. Experiment 2 built on Experiment 1, and asked: what effect will brief nicotine pre-exposure have on the anxiety of withdrawal following later administration? We hypothesized that briefly exposing animals to nicotine, followed by abstinence and then chronic exposure, would potentiate the anxiogenic effects of withdrawal, resulting in even further elevated LES during withdrawal. Adult rats were given 4 days of .40 mg/kg nicotine, followed by 10 days of abstinence, and then chronic nicotine and LES as described above. Surprisingly, animals in Experiment 2 displayed a general decrease in LES, indicating that nicotine pre-exposure has an anxiolytic effect during later withdrawal. These findings demonstrate that nicotine pre-exposure has a significant impact on how the brain responds to later nicotine, and this could be caused by a unique pattern of nAChR desensitization and upregulation resulting from pre-exposure

Emotional learning retroactively enhances item memory but distorts source attributions

An adaptive memory system should prioritize select information surrounding a powerful learning event that may prove useful for predicting future meaningful events. The behavioral tagging hypothesis provides a mechanistic framework to interpret how weak experiences persist as durable memories through temporal association with a strong experience. Importantly, memories are composed of multiple elements, and different mnemonic aspects of the same experience may be uniquely affected by mechanisms that retroactively modulate weakly encoded memory. Here we investigated how emotional learning affects item and source memory for related events encoded close in time. Participants encoded trial-unique category exemplars before, during, and after Pavlovian fear conditioning. Results showed selective retroactive enhancements in 24-hour item memory were accompanied by a bias to misattribute items to the temporal context of fear conditioning. The strength of this source memory bias correlated with participants’ retroactive item memory enhancement, and source misattribution to the emotional context predicted whether items were remembered overall. In the framework of behavioral tagging: memory attribution was biased to the temporal context of the stronger event (fear conditioning) that provided the putative source of memory stabilization for the weaker event (non-emotional learning). We additionally found that fear conditioning selectively and retroactively enhanced stimulus typicality ratings for related items, and that stimulus typicality also predicted overall item memory. Collectively, these results provide new evidence that items related to an emotional event are misattributed to the temporal context of the emotional event and judged to be more representative of their semantic category. Both processes may help facilitate memory retrieval for related events encoded close in time

The features that shape fear: how emotional intensity and threat relevance interact to guide fear generalization

The amount of fear of a potential threat is oftentimes proportional to the overlap in shared features with a known threat. An adaptive threat learning system should therefore extract the most relevant feature of a known threat to help successfully detect and appropriately respond to potential threats in the future. But what if the most salient feature of a known threat is emotionally positive? Here, we asked whether fear generalization can be guided be positive emotional features. We first paired a slightly happy (Experiment 1) or fearful (Experiment 2) face with an electrical shock. We then tested fear generalization to modified face stimuli of the same identity exhibiting more or less happiness or fear expression. Both experiments yielded biased physiological arousal to a face stimulus with the most exaggerated emotional expression. These findings suggest that overlap of positive emotional features extracted from a known threat can guide biased fear generalization

Category (Animal, Tool, Food) Stimuli

A collection of animal and tool stimuli with typicality ratings Methodology for typicality ratings described in Hennings et al., 2021. Learning & Memory (http://www.learnmem.org/cgi/doi/10.1101/lm.053371.120

A Meta-Analysis of Conditioned Fear Generalization in Anxiety-Related Disorders

Manuscript for this project is under revie

Thyroid-Stimulating Hormone, Thyroglobulin, and Thyroid Hormones and Risk of Differentiated Thyroid Carcinoma:The EPIC Study

Background Increased levels of thyroglobulin (Tg) and thyroid-stimulating hormone (TSH) are associated with differentiated thyroid carcinoma (TC) risk, but strong epidemiological evidence is lacking. Methods Three hundred fifty-seven incident TC case patients (n = 300 women and 57 men; mean age at blood collection = 51.5 years) were identified in the EPIC cohort study and matched with 2 (women) or 3 (men) control subjects using incidence density sampling. Matching included study center, sex, age, date, time, and fasting status at blood collection. Levels of total and free (f) thyroxine (T4) and triiodo-thyronine (T3), TSH, Tg, and anti-Tg antibodies (TgAb) were measured by commercially available immunoassays. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression. All statistical tests were two-sided. Results TC risk was positively associated with Tg (OR for the highest vs lowest quartile = 9.15; 95% CI = 5.28 to 15.90; P < .001) and negatively associated with TSH level (OR = 0.56; 95% CI = 0.38 to 0.81; P = .001). Odds ratios were not modified by adjustment for weight and height and were consistent across sexes, age groups, and countries. The association with Tg was stronger in follicular than papillary TC. The odds ratio for TgAb-positivity was 1.50 (95% CI = 1.05 to 2.15; P = .03). Among case patients, TSH level was stable over time, whereas Tg level was higher in proximity to TC diagnosis. Areas under the receiver operating characteristic curve were 57% and 74% for TSH and Tg level, respectively. Conclusions High Tg levels precede by up to 8 years the detection of TC, pointing to a long sojourn time of the disease. Low TSH levels may predispose to TC onset. Neither marker has sufficient accuracy to be a screening test