Faculty Bibliography

A major component of perception is hedonic valence: perceiving stimuli as pleasant or unpleasant. Here, we used early olfactory experiences that shape odor preferences and aversions to explore developmental plasticity in circuits mediating odor hedonics. We used 2-deoxyglucose autoradiographic mapping of neural activity to identify circuits differentially activated by biologically relevant preferred and avoided odors across rat development. We then further probed this system by increasing or decreasing hedonic value. Using both region of interest and functional connectivity analyses, we identified regions within primary olfactory, amygdala/hippocampal, and prefrontal cortical networks that were activated differentially by maternal and male odors. Although some activated regions remained stable across development (postnatal days 7-23), there was a developmental emergence of others that resulted in an age-dependent elaboration of hedonic-response-specific circuitry despite stable behavioral responses (approach/avoidance) to the odors across age. Hedonic responses to these biologically important odors were modified through diet suppression of the maternal odor and co-rearing with a male. This allowed assessment of hedonic circuits in isolation of the specific odor quality and/or intensity. Early experience significantly modified odor-evoked circuitry in an age-dependent manner. For example, co-rearing with a male, which induced pup attraction to male odor, reduced activity in amygdala regions normally activated by the unfamiliar avoided male odor, making this region more consistent with maternal odor. Understanding the development of odor hedonics, particularly within the context of altered early life experience, provides insight into the development of sensory processes, food preferences, and the formation of social affiliations, among other behaviors. SIGNIFICANCE STATEMENT: Odor hedonic valence controls approach-avoidance behaviors, but also modulates ongoing behaviors ranging from food preferences and social affiliation with the caregiver to avoidance of predator odors. Experiences can shape hedonic valence. This study explored brain circuitry involved in odor hedonic encoding throughout development using maternal and predator odors and assessed the effects of early life experience on odor hedonic encoding by increasing/decreasing the hedonic value of these odors. Understanding the role of changing brain circuitry during development and its impact on behavioral function is critical for understanding sensory processing across development. These data converge with exciting literature on the brain's hedonic network and highlight the significant role of early life experience in shaping the neural networks of highly biologically relevant stimuli.

To date most pain studies have focused on spinal cord or peripheral pathways. However, a complete understanding of pain mechanisms requires the study of neocortex. Using an animal model of acute pain, we investigate neural codes for pain at both single-cell and population levels. We propose a statistical framework, rooted in state space analysis, for analyzing neural ensembles recorded from the rat primary somatosensory cortex (S1) and anterior cingulate cortex (ACC) during a laser pain stimulation protocol. The state space analysis allows us to uncover a latent state process that drives the observed ensemble spike activity, and to further detect the "neuronal threshold" for pain on a single or multiple-trial basis.

Fatigue is a severe problem for many people living with Parkinson's disease (PD). Best estimates suggest that more than 50% of patients experience this debilitating symptom. Little is known about its etiology or treatment, making the understanding of fatigue a true unmet need. As part of the Parkinson's Disease Foundation Community Choice Research Program, patients, caregivers, and scientists attended a symposium on fatigue on 16 and 17 October 2014. We present a summary of that meeting, reviewing what is known about the diagnosis and treatment of fatigue, its physiology, and what we might learn from multiple sclerosis (MS), depression, and cancer-disorders in which fatigue figures prominently too. We conclude with focused recommendations to enhance our understanding and treatment of this prominent problem in PD.

Introduction: Delayed sleep and meal timing promote metabolic dysregulation and obesity. Altered coordination of sleep and eating may impact food reward valuation in the brain; yet the independent and collective contribution of sleep and meal times remains unknown. This pilot, randomized crossover study manipulates both sleep and meal times while preserving normal sleep duration (8 h time in bed for 5 nights) to test how misalignment of sleeping and eating behaviors affects intrinsic functional connectivity (iFC) across reward and interoception-related brain circuitry. Methods: Resting state functional MRI scans (3T Siemens Skyra; TR = 2.5s; 2 x ~5-minute runs) were obtained for 4 participants (3 males; 25.3 +/- 4.6 years) who completed all 4 phases (normal sleep/normal meal; late sleep/normal meal; normal sleep/late meal; late sleep/late meal). Normal meal times were 1, 5, 11, and 12.5 h after awakening and late meal times were 4.5, 8.5, 14.5 and 16 h after awakening. For a priori selected regions-of-interest (seeds) relevant to food reward and interoception, each seed's iFC was calculated as the correlation between its time-series and that of every voxel, and then contrasted between conditions. Standard preprocessing and seed-based correlations used the Configurable Pipeline for the Analysis of Connectomes v0.3.9. Results: Statistically significant (p late) additionally significantly modulated iFC between left ventral striatum and precuneus. Other significant iFC modulations of components of reward and interoception circuitry will also be presented. Conclusion: These pilot findings provide support that misalignment of sleep and food timing alters iFC in regions relevant to food reward and interoception, motivating examination in a larger sample

Introduction: Post-ablation scarring is used as a method to uncouple and/or silence pro-arrhythmic circuits. It has been previously suggested that circulating bone marrow derived cells (BMDC) are capable of homing into myocardial infarction scars. It is possible that intercellular junctions form between myocytes and BMDCs and may contribute to ablation failure and recurrence of arrhythmias. Methods: We tested whether BMDCs populate an ablation scars and contribute to functional coupling between the scar and surrounding myocardium. Wild type C57BI/6 mice (n=17) underwent radiation-induced myeloablation and subsequent transplantation with bone marrow progenitors obtained from fetal Cx43 WT (bmcWT) or Cx43 deficient (bmcKO) mice. Results: All donor cells constitutively expressed mCherry protein. Right ventricular ablation was carried out thirty days post transplantation and hearts were studied 30 day post ablation. Cells expressing mCherry and vimentin were observed throughout the scar suggesting donor cells differentiated into a mesenchymal lineage. Coupling between the uninjured myocardium and the scar was assayed with optical mapping. Suction electrode was placed on uninjured myocardium next to the scar to deliver current pulses. Conclusions: Changes in membrane voltage were measured optically at three different sites: Uninjured myocardium, Scar and Remote area (see figure). These data demonstrate that BMDCs can couple to the surrounding myocardium and contribute to the electrophysiological properties of ablation scar tissue. Delivery of modified BMDCs could be used to modifythe post-ablation scar electrophysiological properties. (Figure Presented)

To identify determinants of respiratory disease progression in late-onset Pompe disease (LOPD), we studied relationships between pulmonary function, respiratory muscle strength, gas exchange, and respiratory control. Longitudinal evaluation of 22 LOPD patients (mean age 38 years) was performed at 6-month intervals for 6-24 months. Measurements included vital capacity (VC), maximum inspiratory pressure (MIP), maximum expiratory pressure (MEP), tidal volume (VT), dead space (VD), and ventilatory response to CO2. Although reduction in VC correlated with MIP and MEP (p < 0.0001), some patients had normal VC despite reduced MIP and MEP (5 [23%] and 9 [41%] patients, respectively). Daytime hypercapnia was associated with reduced VC (<60% predicted) and MIP (<40% predicted). Moreover, chronic hypercapnia was associated with elevated VD/VT (>/=0.44) due to falling VT ( approximately 300 ml), compatible with reduced efficiency of CO2 clearance. The presence of hypercapnia and/or ventilatory support was associated with reduced ventilatory responsiveness to CO2 (