Faculty Bibliography

BACKGROUND: Rare gene variants are important sources of schizophrenia vulnerability that likely interact with polygenic susceptibility loci. This study examined if novel or rare missense coding variants in any of four different signaling genes in sporadic schizophrenia cases were associated with clinical phenotypes in an exceptionally well-characterized sample. METHOD: Structured interviews, cognition, symptoms and life course features were assessed in 48 ethnically-diverse cases with psychosis who underwent targeted exome sequencing of PTPRG (Protein Tyrosine Phosphatase, Receptor Type G), SLC39A13 (Solute Carrier Family 39 (Zinc Transporter) Member 13), TGM5 (transglutaminase 5) and ARMS/KIDINS220 (Ankyrin repeat-rich membrane spanning protein or Kinase D-Interacting Substrate of 220kDa). Cases harboring rare missense coding polymorphisms or novel mutations in one or more of these genes were compared to other cases not carrying any rare missense coding polymorphisms or novel mutations in these genes and healthy controls. FINDINGS: Fifteen of 48 cases (31.25%) carried rare or novel missense coding variants in one or more of these genes. The subgroups significantly differed in important features, including specific working memory deficits for PTPRG (n=5); severe negative symptoms, global cognitive deficits and poor educational attainment, suggesting a developmental disorder, for SLC39A13 (n=4); slow processing speed, childhood attention deficit disorder and milder symptoms for TGM5 (n=4); and global cognitive deficits with good educational attainment suggesting neurodegeneration for ARMS/KIDINS220 (n=5). Case vignettes are included in the appendix. INTERPRETATION: Genes prone to missense coding polymorphisms and/or mutations in sporadic cases may highlight influential genes for psychosis and illuminate heterogeneous pathways to schizophrenia. Ethnicity appears less important at the level of genetic variability. The sequence variations that potentially alter the function of specific genes or their signaling partners may contribute to particular subtypes of psychosis. This approach may be applicable to other complex disorders.

The zebra finch brain features a set of clearly defined and hierarchically arranged motor nuclei that are selectively responsible for producing singing behavior. One of these regions, a critical forebrain structure called HVC, contains premotor neurons that are active at precise time points during song production. However, the neural representation of this behavior at a population level remains elusive. We used two-photon microscopy to monitor ensemble activity during singing, integrating across multiple trials by adopting a Bayesian inference approach to more precisely estimate burst timing. Additionally, we examined spiking and motor-related synaptic inputs using intracellular recordings during singing. With both experimental approaches, we find that premotor events do not occur preferentially at the onsets or offsets of song syllables or at specific subsyllabic motor landmarks. These results strongly support the notion that HVC projection neurons collectively exhibit a temporal sequence during singing that is uncoupled from ongoing movements.

Although the two pathological hallmarks of Alzheimer's disease (AD), senile plaques composed of amyloid-beta (Abeta) peptides and neurofibrillary tangles (NFTs) consisting of hyperphosphorylated tau, have been studied extensively in postmortem AD and relevant animal and cellular models, the pathogenesis of AD remains unknown, particularly in the early stages of the disease where therapies presumably would be most effective. We and others have demonstrated that Abeta plaques and NFTs are present in varying degrees before the onset and throughout the progression of dementia. In this regard, aged people with no cognitive impairment (NCI), mild cognitive impairment (MCI, a presumed prodromal AD transitional state), and AD all present at autopsy with varying levels of pathological hallmarks. Cognitive decline, a requisite for the clinical diagnosis of dementia associated with AD, generally correlates better with NFTs than Abeta plaques. However, correlations are even higher between cognitive decline and synaptic loss. In this review, we illustrate relevant clinical pathological research in preclinical AD and throughout the progression of dementia in several areas including Abeta and tau pathobiology, single population expression profiling of vulnerable hippocampal and basal forebrain neurons, neuron plasticity, neuroimaging, cerebrospinal fluid (CSF) biomarker studies and their correlation with antemortem cognitive endpoints. In each of these areas, we provide evidence for the importance of studying the pathological hallmarks of AD not in isolation, but rather in conjunction with other molecular, cellular, and imaging markers to provide a more systematic and comprehensive assessment of the multiple changes that occur during the transition from NCI to MCI to frank AD.

Mild traumatic brain injury (mTBI), also commonly referred to as concussion, affects millions of Americans annually. Although computed tomography is the first-line imaging technique for all traumatic brain injury, it is incapable of providing long-term prognostic information in mTBI. In the past decade, the amount of research related to magnetic resonance (MR) imaging of mTBI has grown exponentially, partly due to development of novel analytical methods, which are applied to a variety of MR techniques. Here, evidence of subtle brain changes in mTBI as revealed by these techniques, which are not demonstrable by conventional imaging, will be reviewed. These changes can be considered in three main categories of brain structure, function, and metabolism. Macrostructural and microstructural changes have been revealed with three-dimensional MR imaging, susceptibility-weighted imaging, diffusion-weighted imaging, and higher order diffusion imaging. Functional abnormalities have been described with both task-mediated and resting-state blood oxygen level-dependent functional MR imaging. Metabolic changes suggesting neuronal injury have been demonstrated with MR spectroscopy. These findings improve understanding of the true impact of mTBI and its pathogenesis. Further investigation may eventually lead to improved diagnosis, prognosis, and management of this common and costly condition. ((c)) RSNA, 2016.

Pyramidal neurons recorded from the rat hippocampus and entorhinal cortex, such as place and grid cells, have diverse receptive fields, which are either unimodal or multimodal. Spiking activity from these cells encodes information about the spatial position of freely foraging rat. At fine timescales, a neuron's spike activity also depends significantly on its own spike history. However, due to limitations of current parametric modeling approaches, it remains a challenge to estimate complex, multimodal neuronal receptive fields with additional spike history dependence. Furthermore, efforts to decode the rat's trajectory in one- or two-dimensional space from hippocampal ensemble spiking activity have mainly focused on spike history-independent neuronal encoding models. In this letter, we address these two important issues by extending a recently introduced nonparametric neural encoding framework that allows modeling both complex spatial receptive fields and spike history dependencies. Using this extended nonparametric approach, we develop novel algorithms for decoding a rat's trajectory using a full encoding model that jointly characterizes both spatial position and history dependencies in hippocampal place cells and entorhinal grid cells. Results show that both encoding and decoding models with spike history dependence derived from our new method performed significantly better than state-of-the-art encoding and decoding models on 6 minutes of test data. In addition, our model's performance remains invariant to the apparent modality of the neuron's receptive field.

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.

We measured saccadic latencies in a large sample (total n = 459) of individuals with amblyopia or risk factors for amblyopia, e.g., strabismus or anisometropia, and normal control subjects. We presented an easily visible target randomly to the left or right, 3.5 degrees from fixation. The interocular difference in saccadic latency is highly correlated with the interocular difference in LogMAR (Snellen) acuity-as the acuity difference increases, so does the latency difference. Strabismic and strabismic-anisometropic amblyopes have, on average, a larger difference between their eyes in LogMAR acuity than anisometropic amblyopes and thus their interocular latency difference is, on average, significantly larger than anisometropic amblyopes. Despite its relation to LogMAR acuity, the longer latency in strabismic amblyopes cannot be attributed either to poor resolution or to reduced contrast sensitivity, because their interocular differences in grating acuity and in contrast sensitivity are roughly the same as for anisometropic amblyopes. The correlation between LogMAR acuity and saccadic latency arises because of the confluence of two separable effects in the strabismic amblyopic eye-poor letter recognition impairs LogMAR acuity while an intrinsic sluggishness delays reaction time. We speculate that the frequent microsaccades and the accompanying attentional shifts, made while strabismic amblyopes struggle to maintain fixation with their amblyopic eyes, result in all types of reactions being irreducibly delayed.

Local inhibitory neurons control the timing of neural activity in many circuits. To understand how inhibition controls timing, it is important to understand the dynamics of activity in populations of local inhibitory interneurons, as well as the mechanisms that underlie these dynamics. Here we describe thein vivoresponse dynamics of a large population of inhibitory local neurons (LNs) in theDrosophila melanogasterantennal lobe, the analog of the vertebrate olfactory bulb, and we dissect the network and intrinsic mechanisms that give rise to these dynamics. Some LNs respond to odor onsets ("ON" cells) and others to offsets ("OFF" cells), whereas still others respond at both times. Moreover, different LNs signal odor concentration fluctuations on different timescales. Some respond rapidly, and can track rapid concentration fluctuations. Others respond slowly, and are best at tracking slow fluctuations. We found a continuous spectrum of preferred stimulation timescales among LNs, as well as a continuum of ON-OFF behavior. Usingin vivowhole-cell recordings, we show that the timing of an LN's response (ON vs OFF) can be predicted from the interplay of excitatory and inhibitory synaptic currents that it receives. Meanwhile, the preferred timescale of an LN is related to its intrinsic properties. These results illustrate how a population of inhibitory interneurons can collectively encode bidirectional changes in stimulus intensity on multiple timescales, and how this can arise via an interaction between synaptic and intrinsic mechanisms. SIGNIFICANCE STATEMENT: Most neural circuits contain diverse populations of inhibitory interneurons. The way inhibition shapes network activity will depend on the spiking dynamics of the interneuron population. Here we describe the dynamics of activity in a large population of inhibitory interneurons in the first brain relay of the fruit fly olfactory system. Because odor plumes fluctuate on multiple timescales, the drive to this circuit can vary over a range of frequencies. We show how synaptic and cellular mechanisms interact to recruit different interneurons at different times, and in response to different temporal features of odor stimuli. As a result, inhibition is recruited over a range of conditions, and there is the potential to tune the timing of inhibition as the environment changes.

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