Faculty Bibliography

Bilateral cortical circuits are not necessarily symmetrical. Asymmetry, or cerebral lateralization, allows functional specialization of bilateral brain regions and has been described in humans for such diverse functions as perception, memory and emotion. There is also evidence for asymmetry in the human olfactory system, though evidence in non-human animal models is lacking. Here, we took advantage of the known changes in olfactory cortical local field potentials that occur over the course of odor discrimination training to test for functional asymmetry in piriform cortical activity during learning. Both the right and left piriform cortex local field potential activities were recorded. The results demonstrate robust inter-hemispheric asymmetry in anterior piriform cortex activity that emerges during specific stages of odor discrimination learning, with a transient bias toward the left hemisphere. This asymmetry is not apparent during error trials. Furthermore, functional connectivity (coherence) between the bilateral anterior piriform cortices is learning- and context-dependent. Steady-state inter-hemispheric anterior piriform cortex coherence is reduced during initial stages of learning and then recovers as animals acquire competent performance. The decrease in coherence is seen relative to bilateral coherence expressed in the home cage, which remains stable across conditioning days. Similarly, transient, trial-related inter-hemispheric coherence increases with task competence. Together the results demonstrate transient asymmetry in piriform cortical function during odor discrimination learning until mastery, and suggests that each PCX may contribute something unique to odor memory

The Research Domain Criteria (RDoC) adopts a dimensional approach for examining pathophysiological processes underlying categorically defined psychiatric diagnoses. We used this framework to examine relationships among symptom dimensions, diagnostic categories, and resting state connectivity in behaviorally and emotionally dysregulated youth selected from the Longitudinal Assessment of Manic Symptoms study (n=42) and healthy control youth (n=18). Region of interest analyses examined relationships among resting state connectivity, symptom dimensions (behavioral and emotional dysregulation measured with the Parent General Behavior Inventory-10 Item Mania Scale [PGBI-10M]; dimensional severity measures of mania, depression, anxiety), and diagnostic categories (Bipolar Spectrum Disorders, Attention Deficit Hyperactivity Disorder, Anxiety Disorders, and Disruptive Behavior Disorders). After adjusting for demographic variables, two dimensional measures showed significant inverse relationships with resting state connectivity, regardless of diagnosis: 1) PGBI-10M with amygdala-left posterior insula/bilateral putamen; and 2) depressive symptoms with amygdala-right posterior insula connectivity. Diagnostic categories showed no significant relationships with resting state connectivity. Resting state connectivity between amygdala and posterior insula decreased with increasing severity of behavioral and emotional dysregulation and depression; this suggests an intrinsic functional uncoupling of key neural regions supporting emotion processing and regulation. These findings support the RDoC dimensional approach for characterizing pathophysiologic processes that cut across different psychiatric disorders.

BACKGROUND: Borderline personality disorder (BPD) is a prevalent psychiatric disorder associated with significant distress, dysfunction, and treatment utilization. Though, theoretically, BPD is posited to arise from a combination of trait and environmental risk factors, few studies have tested trait-by-environment interactions in BPD. We investigated the roles of rejection sensitivity (RS) and childhood emotional neglect and abuse (ENA) as well as their interaction in BPD. SAMPLING AND METHODS: Eighty-five adults with a lifetime mood disorder who were recruited for outpatient studies in a psychiatric clinic were assessed for ENA using the Childhood Trauma Questionnaire and for RS with the Adult Rejection Sensitivity Questionnaire. BPD diagnoses were made by consensus using data collected on the Structured Clinical Interview for DSM-IV. Hierarchical logistic regression was used to test associations between RS, ENA, their interaction and BPD. RESULTS: RS and ENA interacted to predict co-occurring BPD in our sample of mood-disordered patients, with the strength of the relationship between RS and BPD depending on the severity of ENA. In the context of little or no ENA, RS and BPD were more strongly related than when ENA was more severe. CONCLUSIONS: Our results extend previous findings suggesting RS and ENA are risk factors for BPD. They also provide preliminary support for contemporary theories of BPD positing trait-by-environment interactions in the development of BPD. Prospective studies are needed to confirm these findings. (c) 2014 S. Karger AG, Basel.

Learning of a complex olfactory discrimination (OD) task results in acquisition of rule learning after prolonged training. Previously, we demonstrated enhanced synaptic connectivity between the piriform cortex (PC) and its ascending and descending inputs from the olfactory bulb (OB) and orbitofrontal cortex (OFC) following OD rule learning. Here, using recordings of evoked field postsynaptic potentials in behaving animals, we examined the dynamics by which these synaptic pathways are modified during rule acquisition. We show profound differences in synaptic connectivity modulation between the 2 input sources. During rule acquisition, the ascending synaptic connectivity from the OB to the anterior and posterior PC is simultaneously enhanced. Furthermore, post-training stimulation of the OB enhanced learning rate dramatically. In sharp contrast, the synaptic input in the descending pathway from the OFC was significantly reduced until training completion. Once rule learning was established, the strength of synaptic connectivity in the 2 pathways resumed its pretraining values. We suggest that acquisition of olfactory rule learning requires a transient enhancement of ascending inputs to the PC, synchronized with a parallel decrease in the descending inputs. This combined short-lived modulation enables the PC network to reorganize in a manner that enables it to first acquire and then maintain the rule.

Background: Corpus callosum (CC) size and shape have been previously studied in Alzheimer's disease (AD) with the majority of studies having been cross-sectional. Due to the large variance in normal CC morphology, cross-sectional studies are limited in statistical power. Determining individual rates of change requires longitudinal data. Physiological changes are particularly relevant in mild cognitive impairment (MCI), in which CC morphology has not been previously studied longitudinally. Objective: To study temporal rates of change in CC morphology in MCI patients over a one-year period, and to determine whether these rates differ between MCI subjects who converted to AD (MCI-C) and those who did not (MCI-NC) over an average (+/-SD) observation period of 5.4 (+/-1.6) years. Methods: We used a novel multi-atlas based algorithm to segment the mid-sagittal cross-sectional area of the CC in longitudinal MRI scans. Rates of change of CC circularity, total area, and five sub-areas were compared between 57 MCI-NC and 81 MCI-C subjects. Results: The CC became less circular (-0.89% per year in MCI-NC, -1.85% per year in MCI-C) with time, with faster decline in MCI-C (p = 0.0002). In females, atrophy rates were higher in MCI-C relative to MCI-NC in total CC area (p = 0.0006), genu/rostrum (p = 0.005), and splenium (0.002). In males, these rates did not differ between groups. Conclusion: A greater than normal decline in CC circularity was shown to be an indicator of prodromal AD in MCI subjects. This measure is potentially useful as an imaging biomarker of disease and a therapeutic target in clinical trials.

The mossy fiber (MF) pathway is critical to hippocampal function and influenced by gonadal hormones. Physiological data are limited, so we asked whether basal transmission and long-term potentiation (LTP) differed in slices of adult male and female rats. The results showed small sex differences in basal transmission but striking sex differences in opioid receptor sensitivity and LTP. When slices were made from females on proestrous morning, when serum levels of 17beta-estradiol peak, the nonspecific opioid receptor antagonist naloxone (1 mum) enhanced MF transmission but there was no effect in males, suggesting preferential opioid receptor-dependent inhibition in females when 17beta-estradiol levels are elevated. The mu-opioid receptor (MOR) antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP; 300 nm) had a similar effect but the delta-opioid receptor (DOR) antagonist naltrindole (NTI; 1 mum) did not, implicating MORs in female MF transmission. The GABAB receptor antagonist saclofen (200 mum) occluded effects of CTOP but the GABAA receptor antagonist bicuculline (10 mum) did not. For LTP, a low-frequency (LF) protocol was used because higher frequencies elicited hyperexcitability in females. Proestrous females exhibited LF-LTP but males did not, suggesting a lower threshold for synaptic plasticity when 17beta-estradiol is elevated. NTI blocked LF-LTP in proestrous females, but CTOP did not. Electron microscopy revealed more DOR-labeled spines of pyramidal cells in proestrous females than males. Therefore, we suggest that increased postsynaptic DORs mediate LF-LTP in proestrous females. The results show strong MOR regulation of MF transmission only in females and identify a novel DOR-dependent form of MF LTP specific to proestrus.