Faculty Bibliography

BACKGROUND:Genetic variant interpretation contributes to testing yield differences reported for sudden unexplained death. Adapting a high-resolution variant interpretation framework, which considers disease prevalence, reduced penetrance, genetic heterogeneity, and allelic contribution to determine the maximum tolerated allele count in gnomAD, we report an evaluation of cardiac channelopathy and cardiomyopathy genes in a large, demographically diverse sudden unexplained death cohort that underwent thorough investigation in the United States' largest medical examiner's office. METHODS AND RESULTS/RESULTS:The cohort has 296 decedents: 147 Blacks, 64 Hispanics, 49 Whites, 22 Asians, and 14 mixed ethnicities; 142 infants (1 to 11 months), 39 children (1 to 17 years), 74 young adults (18 to 34 years), and 41 adults (35 to 55 years). Eighty-nine cardiac disease genes were evaluated. Using a high-resolution variant interpretation workflow, we classified 17 variants as pathogenic or likely pathogenic (2 of which were incidental findings and excluded in testing yield analysis), 46 novel variants of uncertain significance, and 130 variants of uncertain significance. Nine pathogenic or likely pathogenic variants in ClinVar were reclassified to likely benign and excluded in testing yield analysis. The yields of positive cases by ethnicity and age were 21.4% in mixed ethnicities, 10.2% Whites, 4.5% Asians, 3.1% Hispanics, and 2% Blacks; 7.7% children, 7.3% in adults, 5.4% young adults, and 2.8% infants. The percentages of uncertain cases with variants of uncertain significance by ethnicity were 45.5% in Asians, 45.3% Hispanics, 44.20% Blacks, 36.7% Whites, and 14.3% in mixed ethnicities. CONCLUSIONS:High-resolution variant interpretation provides diagnostic accuracy and healthcare efficiency. Under-represented populations warrant greater inclusion in future studies.

Epilepsy is a neurologic condition which often occurs with other neurologic and psychiatric disorders. The relation between epilepsy and these conditions is complex. Some population-based studies have identified a bidirectional relation, whereby not only patients with epilepsy are at increased risk of suffering from some of these neurologic and psychiatric disorders (migraine, stroke, dementia, autism, depression, anxiety disorders, Attention deficit hyperactivity disorder (ADHD), and psychosis), but also patients with these conditions are at increased risk of suffering from epilepsy. The existence of common pathogenic mechanisms has been postulated as a potential explanation of this phenomenon. To reassess the relationships between neurological and psychiatric conditions in general, and specifically autism, depression, Alzheimer's disease, schizophrenia, and epilepsy, a recent meeting brought together basic researchers and clinician scientists entitled "Epilepsy as a Network Disorder." This was the fourth in a series of conferences, the "Fourth International Halifax Conference and Retreat". This manuscript summarizes the proceedings on potential relations between Epilepsy on the one hand and autism and depression on the other. A companion manuscript provides a summary of the proceedings about the relation between epilepsy and Alzheimer's disease and schizophrenia, closed by the role of translational research in clarifying these relationships. The review of the topics in these two manuscripts will provide a better understanding of the mechanisms operant in some of the common neurologic and psychiatric comorbidities of epilepsy.

Cognition can be conceptualized as a set of algorithmic control functions whose real-time deployment determines how an organism stores and uses information to guide thought and action. A subset of these functions is required for goal-directed selection and amplification of sensory signals-broadly referred to as attention-and for its flexible control and its interaction with processes such as working memory and decision making. While the contribution of recurrent cortical microcircuits to cognition has been extensively studied, the role of the thalamus is just beginning to be elucidated. Here we highlight recent studies across rodents and primates showing how thalamus contributes to attentional control. In addition to high-fidelity information relay to or between cortical regions, thalamic circuits shift and sustain functional interactions within and across cortical areas. This thalamic process enables rapid coordination of spatially segregated cortical computations, thereby constructing task-relevant functional networks. Because such function may be critical for cognitive flexibility, clarifying its mechanisms will likely expand our basic understanding of cognitive control and its perturbation in disease.

Introduction: Increasing evidence suggests sleep can influence the risk for development of Alzheimer disease (AD), but the precise features of sleep architecture influencing this risk and the role of obstructive sleep apnea (OSA) in contributing to this risk remain only partially characterized. Current models of AD suggest that pathological changes, including the accumulation of proteins beta-amyloid (Ab) and tau, can occur years to even decades before clinical symptoms of memory impairment become evident. In this study, we examined the impact of OSA severity on longitudinal changes in Ab measured both in cerebrospinal fluid (CSF) and with brain PET imaging with Pittsburgh compound B (PiB). In subsets of individuals without significant OSA, we examined the impact of features of sleep architecture such as slow wave activity (SWA) and spindles on concentrations CSF Ab and tau at cross-section. Materials and Methods: 208 cognitively normal elderly subjects (68 +/- 7 years, CDR score = 0) received medical, neurological, and psychiatric evaluations, home polysomnography (PSG) for OSA severity, structural magnetic resonance imaging (MRI) scans, a lumbar puncture (LP) and/or PiB PET scans. A subset of 109 subjects completed a second LP 2.4 +/- 0.9 years after the first LP, and a subset of 34 subjects completed a second brain PiB PET scan 2.5 +/- 0.4 years after the first. A subset of 50 subjects without significant OSA (AHI4% < 15/hour) completed in-laboratory nocturnal PSG for measurements of sleep architecture. SWA was calculated using the average power density in the 0.5-4.0 Hz range at the F4- lead during full night EEG recordings. Spindles were isolated and quantified using DETOKS in which the EEG from the C3-lead was decomposed into oscillatory and non-oscillatory components. Oscillatory components were further scored for sleep spindles using threshold values in the frequency band of 11-16 Hz and time duration of 0.5 to 3 seconds. Results: OSA increased amyloid burden over the years, as a significant association was found between longitudinal decreases in CSF Ab42 and increasing OSA severity indices AHI-all (F1,88 = 4.26, p< .05) and AHI4% (F1,87 = 4.36, p< .05). This was corroborated by a trend toward longitudinal increases in brain PiB PET uptake positively associating with increasing OSA severity by AHI-all (F1,28 = 2.96, p=.09). At cross-section, in those subjects without significant OSA, low frontal SWA was significantly associated with high concentrations of CSF Ab42 and low sleep spindle counts and density were significantly associated with high levels of total and phosphorylated tau in the CSF

Oral cancer patients report severe pain during function. Inflammation plays a role in the oral cancer microenvironment; however, the role of immune cells and associated secretion of inflammatory mediators in oral cancer pain has not been well defined. In this study, we utilized two oral cancer mouse models: a cell line supernatant injection model and the 4-nitroquinoline-1-oxide (4NQO) chemical carcinogenesis model. We used the two models to study changes in immune cell infiltrate and orofacial nociception associated with oral squamous cell carcinoma (oSCC). Oral cancer cell line supernatant inoculation and 4NQO-induced oSCC resulted in functional allodynia and neuronal sensitization of trigeminal tongue afferent neurons. While the infiltration of immune cells is a prominent component of both oral cancer models, our use of immune-deficient mice demonstrated that oral cancer-induced nociception was not dependent on the inflammatory component. Furthermore, the inflammatory cytokine, tumor necrosis factor alpha (TNFa), was identified in high concentration in oral cancer cell line supernatant and in the tongue tissue of 4NQO-treated mice with oSCC. Inhibition of TNFa signaling abolished oral cancer cell line supernatant-evoked functional allodynia and disrupted T cell infiltration. With these data, we identified TNFa as a prominent mediator in oral cancer-induced nociception and inflammation highlighting the need for further investigation in neural-immune communication in cancer pain.

The entorhinal cortex (EC) is affected early in Alzheimer's disease, an illness defined by a co-occurrence of tau and amyloid-related pathologies. How the co-occurrence of these pathologies in the EC affects the hippocampal circuit remains unknown. Here we address this question by performing electrophysiological analyses of the EC circuit in mice that express mutant human amyloid precursor protein (hAPP) or tau (hTau), or both in the EC. We show that the alterations in the hippocampal circuit are divergent, with hAPP increasing but hTau decreasing neuronal/circuit excitability. Most importantly, mice co-expressing hAPP and hTau show that hTau has a dominant effect, dampening the excitatory effects of hAPP. Additionally, compensatory synaptic downscaling, in response to increased excitability in EC was observed in subicular neurons of hAPP mice. Based on simulations, we propose that EC interneuron pruning can account for both EC hyperexcitability and subicular synaptic downscaling found in mice expressing hAPP.

A remarkable example of maladaptive plasticity is the development of epilepsy after a brain insult or injury to a normal animal or human. A structure that is considered central to the development of this type of epilepsy is the dentate gyrus (DG), because it is normally a relatively inhibited structure and its quiescence is thought to reduce hippocampal seizure activity. This characteristic of the DG is also considered to be important for normal hippocampal-dependent cognitive functions. It has been suggested that the brain insults which cause epilepsy do so because they cause the DG to be more easily activated. One type of brain insult that is commonly used is induction of severe seizures (status epilepticus; SE) by systemic injection of a convulsant drug. Here we describe an alteration in the DG after this type of experimental SE that may contribute to chronic seizures that has not been described before: large folds or gyri that develop in the DG by 1 month after SE. Large gyri appeared to increase network excitability because epileptiform discharges recorded in hippocampal slices after SE were longer in duration when recorded inside gyri relative to locations outside gyri. Large gyri may also increase excitability because immature adult-born neurons accumulated at the base of gyri with time after SE, and previous studies have suggested that abnormalities in adult-born DG neurons promote seizures after SE. In summary, large gyri after SE are a common finding in adult rats, show increased excitability, and are associated with the development of an abnormal spatial distribution of adult-born neurons. Together these alterations may contribute to chronic seizures and associated cognitive comorbidities after SE.

The notion of subjective value is central to choice theories in ecology, economics, and psychology, serving as an integrated decision variable by which options are compared. Subjective value is often assumed to be an absolute quantity, determined in a static manner by the properties of an individual option. Recent neurobiological studies, however, have shown that neural value coding dynamically adapts to the statistics of the recent reward environment, introducing an intrinsic temporal context dependence into the neural representation of value. Whether valuation exhibits this kind of dynamic adaptation at the behavioral level is unknown. Here, we show that the valuation process in human subjects adapts to the history of previous values, with current valuations varying inversely with the average value of recently observed items. The dynamics of this adaptive valuation are captured by divisive normalization, linking these temporal context effects to spatial context effects in decision making as well as spatial and temporal context effects in perception. These findings suggest that adaptation is a universal feature of neural information processing and offer a unifying explanation for contextual phenomena in fields ranging from visual psychophysics to economic choice.

The Drosophila visual system has become a premier model for probing how neural diversity is generated during development. Recent work has provided deeper insight into the elaborate mechanisms that control the range of types and numbers of neurons produced, which neurons survive, and how they interact. These processes drive visual function and behavioral preferences. Other studies are beginning to provide insight into how neuronal diversity evolved in insects by adding new cell types and modifying neural circuits. Some of the most powerful comparisons have been those made to the Drosophila visual system, where a deeper understanding of molecular mechanisms allows for the generation of hypotheses about the evolution of neural anatomy and function. The evolution of new neural types contributes additional complexity to the brain and poses intriguing questions about how new neurons interact with existing circuitry. We explore how such individual changes in a variety of species might play a role over evolutionary timescales. Lessons learned from the fly visual system apply to other neural systems, including the fly central brain, where decisions are made and memories are stored. Expected final online publication date for the Annual Review of Genetics Volume 51 is November 23, 2017. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

AKT is a kinase regulating numerous cellular processes in the brain, and mutations in AKT are known to affect brain function. AKT is indirectly implicated in synaptic plasticity, but its direct role has not been studied. Moreover, three highly related AKT isoforms are expressed in the brain, but their individual roles are poorly understood. We find in Mus musculus, each AKT isoform has a unique expression pattern in the hippocampus, with AKT1 and AKT3 primarily in neurons but displaying local differences, while AKT2 is in astrocytes. We also find isoform-specific roles for AKT in multiple paradigms of hippocampal synaptic plasticity in area CA1. AKT1, but not AKT2 or AKT3, is required for L-LTP through regulating activity-induced protein synthesis. Interestingly, AKT activity inhibits mGluR-LTD, with overlapping functions for AKT1 and AKT3. In summary, our studies identify distinct expression patterns and roles in synaptic plasticity for AKT isoforms in the hippocampus.