• 2014-2023close
• Open Access close
• Closed Access close
• Open Source close
• Other research products close
• US close
• Neuroinformatics close

Identifying and tracking cell location in long-term longitudinal studies is critical for identifying large-scale time-dependent neuronal activity variations. Population cell tracking across multiple sessions is complicated by non-rigid transformations induced by noise, cell movement and imaging field shifts. In this text we develop SCOUT (Single-Cell SpatiOtemporal LongitUdinal Tracking), a fast, robust cell tracking method utilizing multiple cell-cell similarity metrics, probabilistic inference, and an adaptive clustering methodology to perform cell identification across multiple calcium imaging sessions. We then apply SCOUT to study variations of firing activity coincident with contextual discrimination and neural circuit negation. Next, we investigate the relationship between firing activity and transcriptomics in a single cell type, showing that transcriptional gradients can be associated to subtle variations in neuronal firing activity, which then motivates the development of scGradient, a machine learning algorithm for identifying continuous transcriptional gradients across and within cell types.

Metastasis of ovarian carcinoma to the central nervous system occurs in <2% of cases and classically localizes within the brain parenchyma. Moreover, leptomeningeal spread of these tumors is an exceedingly rare phenomenon. Here, we conduct a systematic review of the current literature on the natural history, treatment options, and proposed pathogenic mechanisms of leptomeningeal carcinomatosis in ovarian carcinoma. We also report a case of a 67-year-old female with stage IV metastatic ovarian serous carcinoma initially confined to the peritoneal cavity with a stable disease burden over the course of three years. Follow-up imaging demonstrated an intracranial lesion, which was resected via craniotomy, and pathology was consistent with the original diagnosis. Three months after surgery, she developed rapidly progressive dizziness, generalized weakness, fatigue, and ataxia. Repeat MRI demonstrated interval development of extensive and diffusely enhancing dural nodularity, numerous avidly enhancing supratentorial and infratentorial lesions, enhancement of the bilateral trigeminal nerves, internal auditory canals, and exit wound from the surgical site into the posterior aspect of the right-sided neck musculature consistent with diffuse leptomeningeal dissemination. The present case highlights that leptomeningeal dissemination of ovarian carcinoma is a potential yet rare consequence following surgical resection of an ovarian parenchymal metastasis. Progressive clinical symptomatology that develops postoperatively in this patient population should prompt urgent workup to rule out leptomeningeal disease and an expedited radiation oncology consultation if identified. Published version

Functional imaging of neural cell populations at mesoscale is criticalfor mapping intra- and inter-regional network dynamics across the dorsal neocortex. Past lab members produced a flexible work flow for producing high quality segmentations of functional structure across neocortex utilizing Independent Component Analysis (ICA). This unsupervised machine learning decomposition of densely sampled recordings of cortical calcium dynamics, results in a collection of components comprised of neuronal signal sources distinct from optical, movement, and vascular artifacts. In this body of work, I built a supervised learning classifier that automatically separates neural activity and artifact components, using a set of extracted spatial and temporal metrics that characterize the respective components. Control data recorded in glial cell reporter and non-fluorescent mouse lines validates human and machine identification of functional component class.Utilizing the insight from the machine learning analysis, I processed alarge dataset from three different transgenic mouse lines expressing calcium indicators in distinct sub-population of neurons: pan-neuronal, upper, and lower layer specific excitatory neuronal subpopulations. I was able to create domain maps to discretize the cortex into functional units and observe how each domain behaves. The application of this data-driven method ultimately reduced the number of time series, while maintaining the informative structure at a mesoscale. From all these animals, I gain insight into the developing structural changes of circuitry based on age-related functional changes observed in these domain maps.

Castration is a common management procedure employed in North American cattle production and is known to cause a pain response. The present study was designed to investigate the effect of unmitigated surgical castration on the electroencephalography (EEG) responses and plasma substance P (SP) concentrations in calves of different ages under the same experimental conditions. Thirty male Holstein calves in three age categories [<6 weeks (6W); 3 months (3M); 6 months (6M); 10 calves per age group] were used in the study. Calves were subjected to a simulated castration session (SHAM) followed 24 h later by surgical castration (CAST) without analgesia. An EEG analysis was performed before the procedure (i.e., baseline), at treatment, and 0–5, 5–10, and 10–20 min post-treatment for both SHAM and CAST, respectively. Blood samples were collected immediately prior to both treatments (time 0) and again at 1, 2, 4, 8, and 12 h after both treatments. The EEG results showed a three-way interaction between treatment, age, and time for delta and beta absolute power, beta relative power, total power, and median frequency (p = 0.004, p = 0.04, p = 0.04, p = 0.03, and p = 0.008, respectively). Following CAST, EEG total power decreased, and median frequency increased relative to SHAM in 6W and 3M calves only following treatment. For 6W and 3M calves, delta and beta absolute power increased at CAST and at later time points relative to SHAM. Marginal evidence for two-way interactions was noted between time and treatment and between age and treatment on the concentration of SP (p = 0.068 and p = 0.066, respectively). Substance P concentrations decreased in CAST treatment compared to SHAM at the later times (8 h: p = 0.007; 12 h: p = 0.048); 6W calves showed lower SP concentration at CAST relative to SHAM (p = 0.017). These findings indicate variation in EEG responses and in SP concentrations following unmitigated surgical castration in calves and that these responses may be age specific. These EEG findings have implications for supporting the perception of the pain associated with surgical castration in young calves and emphasize the urgency of pain mitigation strategies during routine husbandry practices such as castration, as typically implemented in North American cattle management. Published version

The plant glutamate-like receptor homologs (GLRs) are homologs of mammalian ionotropic glutamate receptors (iGluRs) which were discovered more than 10 years ago, and are hypothesized to be potential amino acid sensors in plants. Although initial progress on this gene family has been hampered by gene redundancy and technical issues such as gene toxicity; genetic, pharmacological, and electrophysiological approaches are starting to uncover the functions of this protein family. In parallel, there has been tremendous progress in elucidating the structure of animal glutamate receptors (iGluRs), which in turn will help understanding of the molecular mechanisms of plant GLR functions. In this review, we will summarize recent progress on the plant GLRs. Emerging evidence implicates plant GLRs in various biological processes in and beyond N sensing, and implies that there is some overlap in the signaling mechanisms of amino acids between plants and animals. Phylogenetic analysis using iGluRs from metazoans, plants, and bacteria showed that the plant GLRs are no more closely related to metazoan iGluRs as they are to bacterial iGluRs, indicating the separation of plant, other eukaryotic, and bacterial GLRs might have happened as early on as the last universal common ancestor. Structural similarities and differences with animal iGluRs, and the implication thereof, are also discussed.

N-methyl-D-Aspartate (NMDA) receptor-mediated Hebbian learning is related to NMDA excitatory postsynaptic current (epsc) duration via calcium-threshold for the induction of long-term potentiation (LTP). Decreasing epsc duration decreases total calcium influx and hence makes it harder to elicit LTP. This model explains developmental decrease in susceptibility to LTP with decreases in epsc duration, and genetic enhancement of learning by overexpressing NR2B, which increased epsc duration. However there are additional data that do not fit in this threshold model. NR2A knockout mice have reduced LTP and learning in spite of the fact that the lack of NR2A subunit increases epsc decay time. Furthermore, aged dementia patients undergoing treatment with memantine, which decreases NMDA epsc duration, showed improvement in learning and memory. In an effort to resolve these inconsistencies, we formulated a model of NMDA receptor-mediated temporal correlation learning. Assuming temporal coincidence of epscs is the physiological basis of associative learning we obtained an expression for learning in terms of NMDA epsc duration. We find that learning is an inverted-U function of NMDA epsc duration. Optimal epsc duration is ~250 msec, which gives maximal LTP of 200%.

Mapping presents a compelling way to demystify complex data and concepts into useful visual information that most people can understand regardless of language, level of literacy, or culture. These maps can also be shared instantaneously with the world via the Internet. Interactive community mapping (ICM) is one method of information and communication technology (ICT)-enabled participatory mapping. In the development context, ICM can be a useful approach in helping community members, members of civil society organizations (CSOs), governments, and development partners to better picture and assess the needs and concerns of the mapped communities and adjust development plans, activities, and policies accordingly. This note is aimed at providing step-by-step guidance on the design and implementation of the ICM process to achieve an evidence-based and increasingly participatory decision-making approach for development projects. Relying on good practice examples from Kenya and Tanzania, this note seeks to provide a better understanding of how the potential benefits of ICM can be translated into tangible results. The note outlines some of the available ICM technology, delineate the enabling environment for ICM, and provide step-by-step guidance on how to effectively design and implement ICM in projects.

In humans, high-grade gliomas may infiltrate across the corpus callosum resulting in bihemispheric lesions that may have symmetrical, winged-like appearances. This particular tumor manifestation has been coined a “butterfly” glioma (BG). While canine and human gliomas share many neuroradiological and pathological features, the BG morphology has not been previously reported in dogs. Here, we describe the magnetic resonance imaging (MRI) characteristics of BG in three dogs and review the potential differential diagnoses based on neuroimaging findings. All dogs presented for generalized seizures and interictal neurological deficits referable to multifocal or diffuse forebrain disease. MRI examinations revealed asymmetrical (2/3) or symmetrical (1/3), bihemispheric intra-axial mass lesions that predominantly affected the frontoparietal lobes that were associated with extensive perilesional edema, and involvement of the corpus callosum. The masses displayed heterogeneous T1, T2, and fluid-attenuated inversion recovery signal intensities, variable contrast enhancement (2/3), and mass effect. All tumors demonstrated classical histopathological features of glioblastoma multiforme (GBM), including glial cell pseudopalisading, serpentine necrosis, microvascular proliferation as well as invasion of the corpus callosum by neoplastic astrocytes. Although rare, GBM should be considered a differential diagnosis in dogs with an MRI evidence of asymmetric or symmetric bilateral, intra-axial cerebral mass lesions with signal characteristics compatible with glioma. Immunohistochemical reagents and studies were funded in part by: CA139099/CA/NCI NIH HHS and Brain Tumor Center of Excellence at Wake Forest School of Medicine. Published version

Fragile X Syndrome (FXS) is a neurodevelopmental disorder and the leading known genetic cause of autism spectrum disorder (ASD). Approximately 96% of individuals with ASD and FXS experience improper processing of sensory stimuli. Possible mechanisms attributed to this hyperarousal state include altered excitatory and inhibitory balance and impaired synaptic development. How these developmental changes impair sensory processing, neural responses and functions remain unclear. The major goal of my dissertation project is to identify the developmental mechanisms underlying the pathophysiology of FXS. Our previous studies have shown that elevated levels of Matrix Metalloproteinase-9 (MMP-9) contribute to the hyper-responsiveness of auditory cortex in Fmr1 KO mice by affecting perineuronal net (PNN) formation around parvalbumin (PV)-expressing inhibitory interneurons. Abnormal development of PV neurons most likely contributes to abnormal electroencephalography (EEG)-based phenotypes of auditory hypersensitivity in the Fmr1 KO mice that are remarkably similar to those seen in humans with FXS. However, how the expression of Fmr1 in different cell types shapes normal cortical responses during circuit development is not known.Therefore, I investigated whether the disruption of communication between excitatory neurons and inhibitory PV cells was sufficient to trigger abnormal phenotypes using several mouse models. In the first part of this study, cell-specific deletion of Fmr1 was achieved in cortical excitatory neurons during early embryonic development. I demonstrated that embryonic deletion of Fmr1 from cortical excitatory neurons did indeed trigger PV cell loss, abnormal cortical responses, and behavioral phenotypes in the auditory cortex of Fmr1 KO mice. In the second part of this study, I examined whether conditional deletion (cOFF) or re-expression (cON) of Fmr1 in excitatory neurons during the critical postnatal day (P)14-P21 period of PV cell development is sufficient to trigger or prevent abnormal phenotypes. Our results indicate that postnatal deletion or re-expression of FMRP in excitatory neurons is sufficient to elicit or ameliorate structural and functional cortical deficits as well as abnormal behavioral phenotypes in mice, informing future gene re-expression studies about appropriate treatment window and providing a new insight into the mechanism of cortical circuit dysfunctions in FXS. Lastly, with the discovery of FMRP in astrocytes, coupled with a role of astrocytes in synaptic function and inhibition in particular, it is possible that astrocytes contribute, in some capacity, to the impaired inhibition and circuit hyperexcitability seen in FXS. Therefore, in the third part of this study, I aimed to determine whether astrocyte-specific deletion of Fmr1 during critical developmental period of inhibitory circuit maturation would alter GABAergic signaling and PV cell development leading to cortical hyperexcitability and behavioral alterations. Our results demonstrate a profound role of astrocytic FMRP in the development of inhibitory circuits and shaping normal inhibitory responses.

Anxiety disorders are highly prevalent and disabling but seem particularly tractable to investigation with translational neuroscience methodologies. Neuroimaging has informed our understanding of the neurobiology of anxiety disorders, but research has been limited by small sample sizes and low statistical power, as well as heterogenous imaging methodology. The ENIGMA-Anxiety Working Group has brought together researchers from around the world, in a harmonized and coordinated effort to address these challenges and generate more robust and reproducible findings. This paper elaborates on the concepts and methods informing the work of the working group to date, and describes the initial approach of the four subgroups studying generalized anxiety disorder, panic disorder, social anxiety disorder, and specific phobia. At present, the ENIGMA-Anxiety database contains information about more than 100 unique samples, from 16 countries and 59 institutes. Future directions include examining additional imaging modalities, integrating imaging and genetic data, and collaborating with other ENIGMA working groups. The ENIGMA consortium creates synergy at the intersection of global mental health and clinical neuroscience, and the ENIGMA-Anxiety Working Group extends the promise of this approach to neuroimaging research on anxiety disorders.