Faculty Bibliography

Developmental ethanol exposure can lead to long-lasting cognitive impairment, hyperactivity, and emotional dysregulation among other problems. In healthy adults, sleep plays an important role in each of these behavioral manifestations. Here we explored circadian rhythms (activity, temperature) and slow-wave sleep in adult mice that had received a single day of ethanol exposure on postnatal day 7 and saline littermate controls. We tested for correlations between slow-wave activity and both contextual fear conditioning and hyperactivity. Developmental ethanol resulted in adult hyperactivity within the home cage compared to controls but did not significantly modify circadian cycles in activity or temperature. It also resulted in reduced and fragmented slow-wave sleep, including reduced slow-wave bout duration and increased slow-wave/fast-wave transitions over 24 hour periods. In the same animals, developmental ethanol exposure also resulted in impaired contextual fear conditioning memory. The impairment in memory was significantly correlated with slow-wave sleep fragmentation. Furthermore, ethanol treated animals did not display a post-training modification in slow-wave sleep which occurred in controls. In contrast to the memory impairment, sleep fragmentation was not correlated with the developmental ethanol-induced hyperactivity. Together these results suggest that disruption of slow-wave sleep and its plasticity are a secondary contributor to a subset of developmental ethanol exposure's long-lasting consequences.

Allosteric regulation promises to open up new therapeutic avenues by increasing drug specificity at G-protein-coupled receptors (GPCRs). However, drug discovery efforts are at present hampered by an inability to precisely control the allosteric site. Herein, we describe the design, synthesis, and testing of PhotoETP, a light-activated positive allosteric modulator of the glucagon-like peptide-1 receptor (GLP-1R), a class B GPCR involved in the maintenance of glucose homeostasis in humans. PhotoETP potentiates Ca(2+) , cAMP, and insulin responses to glucagon-like peptide-1 and its metabolites following illumination of cells with blue light. PhotoETP thus provides a blueprint for the production of small-molecule class B GPCR allosteric photoswitches, and may represent a useful tool for understanding positive cooperativity at the GLP-1R.

Oxytocin promotes social interactions and recognition of conspecifics that rely on olfaction in most species. The circuit mechanisms through which oxytocin modifies olfactory processing are incompletely understood. Here, we observed that optogenetically induced oxytocin release enhanced olfactory exploration and same-sex recognition of adult rats. Consistent with oxytocin's function in the anterior olfactory cortex, particularly in social cue processing, region-selective receptor deletion impaired social recognition but left odor discrimination and recognition intact outside a social context. Oxytocin transiently increased the drive of the anterior olfactory cortex projecting to olfactory bulb interneurons. Cortical top-down recruitment of interneurons dynamically enhanced the inhibitory input to olfactory bulb projection neurons and increased the signal-to-noise of their output. In summary, oxytocin generates states for optimized information extraction in an early cortical top-down network that is required for social interactions with potential implications for sensory processing deficits in autism spectrum disorders.

Motor axons approach muscles that are prepatterned in the prospective synaptic region. In mice, prepatterning of acetylcholine receptors requires Lrp4, a LDLR family member, and MuSK, a receptor tyrosine kinase. Lrp4 can bind and stimulate MuSK, strongly suggesting that association between Lrp4 and MuSK, independent of additional ligands, initiates prepatterning in mice. In zebrafish, Wnts, which bind the Frizzled (Fz)-like domain in MuSK, are required for prepatterning, suggesting that Wnts may contribute to prepatterning and neuromuscular development in mammals. We show that prepatterning in mice requires Lrp4 but not the MuSK Fz-like domain. In contrast, prepatterning in zebrafish requires the MuSK Fz-like domain but not Lrp4. Despite these differences, neuromuscular synapse formation in zebrafish and mice share similar mechanisms, requiring Lrp4, MuSK, and neuronal Agrin but not the MuSK Fz-like domain or Wnt production from muscle. Our findings demonstrate that evolutionary divergent mechanisms establish muscle prepatterning in zebrafish and mice.

Proper development of the nervous system requires a temporally and spatially orchestrated set of events including differentiation, synapse formation and neurotransmission. NGF acting through the TrkA neurotrophin receptor regulates many of these events. However, the molecular mechanisms responsible for NGF-regulated secretion are not completely understood. Here, we describe a new signaling pathway involving TrkA, ARMS/Kidins220, Synembryn-B, and Rac1 in NGF-mediated secretion in PC12 cells. Whereas overexpression of ARMS/Kidins220 blocked NGF-mediated secretion, without affecting basal secretion, a decrease in ARMS/Kidins220 resulted in potentiation. Similar effects were observed with Synembryn-B, a protein that interacts directly with ARMS/Kidins220. Downstream of ARMS/Kidins220 and Synembryn-B are Galphaq and Trio proteins, which modulate the activity of Rac1 in response to NGF. Expression of a dominant negative of Rac1 rescued the secretion defects of cells overexpressing ARMS/Kidins220 or Synembryn-B. Thus this neurotrophin pathway represents a new mechanism responsible for NGF-regulated secretion.

Background: Impulsivity is a core feature of substance use disorders. Temporal discounting (TD) paradigms provide a modelbased approach to studying the dynamics of impulsive decisionmaking as drug-addicted individuals undergo treatment. Here we examine (1) how TD changes as opioid use disorder (OUD) subjects stabilize on maintenance therapy; and (2) how TD is predicted by (or is predictive of) relevant clinical outcomes. Methods: 30 individuals initiating treatment for OUD and 29 matched community controls (CC) were assessed weekly (up to 15 weeks) on a TD task. Drug use was monitored by urine toxicology and chart review. We analyzed the data with a hyperbolic discounting model and derived subject-specific parameters forTD rate, and the non-parametric proportion of immediate choices. Results: OUD subjects showed higher TD rates than CC (Means: 0.039 versus 0.139 respectively, p = 0.005). Although this measure had high test-retest reliability, OUD subjects exhibited more variability across the repeated measures. Subjects in the initial phase of treatment showed a progressive decrease of TD (p = 0.007). Recent heroin use predicted subjects' level of impulsivity: positive use in the previous week correlated with a significantly higher proportion of immediate choices (p = 0.02). We did not And a predictive effect of TD on heroin use the following week. Conclusions: These results suggest that TD greatly fluctuates in treatment-seeking heroin users, in contrast to its stability in CC. TD is both sensitive to the initial phase of treatment for OUD and to recent heroin use, but not predictive of future use in this population

Online imaging requires that the reconstruction of current frame only depends on the previous frames, and real time imaging is the desired case. In this work, we propose a novel scheme for real time dynamic magnetic resonance imaging (dMRI) reconstruction. Different from previous methods, the reconstructions of the second frame to the last frame are independent in our scheme, which only require the first frame as the reference image. Therefore, this scheme can be naturally implemented in parallel. After the first frame is reconstructed, all the later frames can be processed as soon as the k-space data are acquired. As an extension of the conventional spatial total variation, a new online model called dynamic total variation is used to exploit the sparsity on both spatial and temporal domains in dMRI. In real time dMRI, each frame is required to be reconstructed very fast. We then design a novel reweighted least squares algorithm to solve the challenging problem. Motivated by the special structure of partial Fourier transform in sparse MRI, this algorithm is accelerated by the preconditioned conjugate gradient descent method. The proposed method is compared with 4 state-of-the-art online and offline methods on two in-vivo cardiac dMRI datasets. The experimental results show that our method significantly outperforms previous online methods, and is comparable to the offline methods in terms of reconstruction accuracy.

Determining the cellular basis of brain growth is an important problem in developmental neurobiology. In the mammalian brain, the cerebellum is particularly amenable to studies of growth because it contains only a few cell types, including the granule cells, which are the most numerous neuronal subtype. Furthermore, in the mouse cerebellum granule cells are generated from granule cell precursors (gcps) in the external granule layer (EGL), from 1 day before birth until about 2 weeks of age. The complexity of the underlying cellular processes (multiple cell behaviors, three spatial dimensions, time-dependent changes) requires a quantitative framework to be fully understood. In this paper, a differential equation-based model is presented, which can be used to estimate temporal changes in granule cell numbers in the EGL. The model includes the proliferation of gcps and their differentiation into granule cells, as well as the process by which granule cells leave the EGL. Parameters describing these biological processes were derived from fitting the model to histological data. This mathematical model should be useful for understanding altered gcp and granule cell behaviors in mouse mutants with abnormal cerebellar development and cerebellar cancers.

Background: Oxytocin is essential for social interactions and maternal behavior. However, little is known about how oxytocin modulates neural circuits to improve social and maternal outcomes. We describe a synaptic mechanism by which oxytocin enhances signal-to-noise ratio in left primary auditory cortex to improve mouse maternal behavior. Methods: We performed electrophysiological recordings, and used anatomical, optogenetic and behavioral techniques to examine the role of oxytocin in maternal behavior in wild-type C57BL/6 and Oxytocin-IRES-Cre mice. Results: Virgins females, who do not initially retrieve distressed pups, rapidly expressed retrieval behavior after receiving oxytocin under dam and pups co-housing conditions. Retrieval onset was accelerated in 20/36 mice receiving systemic oxytocin and in 5/7 mice receiving optogenetic stimulation (P=0.03, 0.05, respectively; Fisher's two-tailed exact test). To confirm regional sites of action subserving improved maternal behavior, we generated novel antibodies that bind to the mouse oxytocin receptor. Oxytocin receptors were preferentially expressed in the left auditory cortex (19% left cells, 14% right cells, n=21, P=0.001). Finally, we utilitzed in vivo whole-cell recordings to measure spiking/synaptic responses to pup calls. Pup call responses were lateralized, with co-tuned/temporally-precise responses in left auditory cortex of maternally-experienced but not maternal-naive adults. Pairing calls with oxytocin enhanced call-evoked responses in virgin dams by balancing the magnitude/ timing of inhibition with excitation, transitioning the auditory cortex from a virgin-like state to a maternal state. Conclusions: Our study provides a biological basis for the lateralization of vocal processing and emergence of experience-based social learning. These studies inform behavioral therapies involving oxytocin administration