Eye-opening and control of visual synapse development in the mouse superior colliculus

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Brain and Cognitive Sciences, 2007."June 2007."Includes bibliographical references.The mammalian superior colliculus (SC) coordinates visual, somatosensory, and auditory stimuli to guide animal behavior. The superficial layers (sSC) receive visual information via two major afferent projections: 1) A direct retinal projection and 2) an indirect projection from Layer V visual cortex. The retinal projection reaches the rat sSC by embryonic day 16, is topographic, and refines to form a high resolution map of visual space early in development, before eye-opening in rodents (-P12-P14). The cortical projection is delayed by about eight days, just reaching the sSC around P4, and does not complete its topographic refinement until around the time of eye-opening. These afferents compete for synaptic space during a time when patterns of spontaneous and evoked activity are rapidly changing. I have used the mouse sSC as a model system to test the role of new activity patterns due to the initial onset of visual experience after eye-opening in visual synaptic development. I have described the organization of retinal and cortical afferents and the laminar organization of the mouse sSC in Chapter 3. Previous work demonstrated eye-opening (EO) induces the appearance of dendritic PSD-95 and LTP in the sSC within 2-4 hours.(cont.) I provide evidence that EO-induced PSD-95 trafficking is required for the stabilization of new synapses in vivo as a result of patterned visual experience after eye-opening. mEPSC frequency recorded in a vertical neuronal subtype of the mid-SGS increases at least three-fold after eye-opening, indicating a rapid synaptogenesis that does not occur in PSD95KO mice, or in age-matched littermates deprived of initial visual experience. A structural analysis of these neurons revealed caliber-specific patterns of spine and filopodia development that depend on EO and the projection from visual cortex. Between P11 and P13, dendrites post-synaptic to cortical axons undergo an EO-independent tripling of filopodial density and an EO-dependent maintenance of dendritic spine density. These data suggest that rapid vision-induced trafficking of PSD-95 enables long-term potentiation and stabilization of newly formed cortico-collicular synapses in response to patterned visual stimuli. Furthermore, these data suggest that cortical inputs are sensitive to pattern vision deprivation between P12 and P13, but retinal inputs are not.by Marnie A. Phillips.Ph.D

Sensory hypo-excitability in a rat model of fetal development in Fragile X Syndrome

Fragile X syndrome (FXS) is characterized by sensory hyper-sensitivity, and animal models suggest that neuronal hyper-excitability contributes to this phenotype. To understand how sensory dysfunction develops in FXS, we used the rat model (FMR-KO) to quantify the maturation of cortical visual responses from the onset of responsiveness prior to eye-opening, through age equivalents of human juveniles. Rather than hyper-excitability, visual responses before eye-opening had reduced spike rates and an absence of early gamma oscillations, a marker for normal thalamic function at this age. Despite early hypo-excitability, the developmental trajectory of visual responses in FMR-KO rats was normal, and showed the expected loss of visually evoked bursting at the same age as wild-type, two days before eye-opening. At later ages, during the third and fourth post-natal weeks, signs of mild hyper-excitability emerged. These included an increase in the visually-evoked firing of regular spiking, presumptive excitatory, neurons, and a reduced firing of fast-spiking, presumptive inhibitory, neurons. Our results show that early network changes in the FMR-KO rat arise at ages equivalent to fetal humans and have consequences for excitability that are opposite those found in adults. This suggests identification and treatment should begin early, and be tailored in an age-appropriate manner

PSD95 Suppresses Dendritic Arbor Development in Mature Hippocampal Neurons by Occluding the Clustering of NR2B-NMDA Receptors

Considerable evidence indicates that the NMDA receptor (NMDAR) subunits NR2A and NR2B are critical mediators of synaptic plasticity and dendritogenesis; however, how they differentially regulate these processes is unclear. Here we investigate the roles of the NR2A and NR2B subunits, and of their scaffolding proteins PSD-95 and SAP102, in remodeling the dendritic architecture of developing hippocampal neurons (2–25 DIV). Analysis of the dendritic architecture and the temporal and spatial expression patterns of the NMDARs and anchoring proteins in immature cultures revealed a strong positive correlation between synaptic expression of the NR2B subunit and dendritogenesis. With maturation, the pruning of dendritic branches was paralleled by a strong reduction in overall and synaptic expression of NR2B, and a significant elevation in synaptic expression of NR2A and PSD95. Using constructs that alter the synaptic composition, we found that either over-expression of NR2B or knock-down of PSD95 by shRNA-PSD95 augmented dendritogenesis in immature neurons. Reactivation of dendritogenesis could also be achieved in mature cultured neurons, but required both manipulations simultaneously, and was accompanied by increased dendritic clustering of NR2B. Our results indicate that the developmental increase in synaptic expression of PSD95 obstructs the synaptic clustering of NR2B-NMDARs, and thereby restricts reactivation of dendritic branching. Experiments with shRNA-PSD95 and chimeric NR2A/NR2B constructs further revealed that C-terminus of the NR2B subunit (tail) was sufficient to induce robust dendritic branching in mature hippocampal neurons, and suggest that the NR2B tail is important in recruiting calcium-dependent signaling proteins and scaffolding proteins necessary for dendritogenesis.National Institutes of Health (U.S.) (Grant EY014074

A Synaptic Strategy for Consolidation of Convergent Visuotopic Maps

The mechanisms by which experience guides refinement of converging afferent pathways are poorly understood. We describe a vision-driven refinement of corticocollicular inputs that determines the consolidation of retinal and visual cortical (VC) synapses on individual neurons in the superficial superior colliculus (sSC). Highly refined corticocollicular terminals form 1–2 days after eye-opening (EO), accompanied by VC-dependent filopodia sprouting on proximal dendrites, and PSD-95 and VC-dependent quadrupling of functional synapses. Delayed EO eliminates synapses, corticocollicular terminals, and spines on VC-recipient dendrites. Awake recordings after EO show that VC and retina cooperate to activate sSC neurons, and VC light responses precede sSC responses within intervals promoting potentiation. Eyelid closure is associated with more protracted cortical visual responses, causing the majority of VC spikes to follow those of the colliculus. These data implicate spike-timing plasticity as a mechanism for cortical input survival, and support a cooperative strategy for retinal and cortical coinnervation of the sSC.National Institutes of Health (U.S.) (Grant EY006039

Women in Health Data Science and Statistics

Opportunities are expanding for women interested in health data science. This panel of leading professionals from academia and industry will highlight the accomplishments, perspectives and varied roles available for data professionals in the healthcare sector. Learn how to leverage your skills and talents into this expanding and dynamic field. Presentation: 58:4

The National Early Warning Score and its subcomponents recorded within ±24 hours of emergency medical admission are poor predictors of hospital-acquired acute kidney injury

YesBackground: Hospital-acquired Acute Kidney Injury (H-AKI) is a common cause of avoidable morbidity and mortality. Aim: To determine if the patients’ vital signs data as defined by a National Early Warning Score (NEWS), can predict H-AKI following emergency admission to hospital. Methods: Analyses of emergency admissions to York hospital over 24-months with NEWS data. We report the area under the curve (AUC) for logistic regression models that used the index NEWS (model A0), plus age and sex (A1), plus subcomponents of NEWS (A2) and two-way interactions (A3). Likewise for maximum NEWS (models B0,B1,B2,B3). Results: 4.05% (1361/33608) of emergency admissions had H-AKI. Models using the index NEWS had the lower AUCs (0.59 to 0.68) than models using the maximum NEWS AUCs (0.75 to 0.77). The maximum NEWS model (B3) was more sensitivity than the index NEWS model (A0) (67.60% vs 19.84%) but identified twice as many cases as being at risk of H-AKI (9581 vs 4099) at a NEWS of 5. Conclusions: The index NEWS is a poor predictor of H-AKI. The maximum NEWS is a better predictor but seems unfeasible because it is only knowable in retrospect and is associated with a substantial increase in workload albeit with improved sensitivity.The Health Foundatio

Thalamocortical function in developing sensory circuits.

© 2018 Elsevier Ltd Thalamocortical activity patterns, both spontaneous and evoked, undergo a dramatic shift in preparation for the onset of rich sensory experience (e.g. birth in humans; eye-opening in rodents). This change is the result of a switch from thalamocortical circuits tuned for transmission of spontaneous bursting in sense organs, to circuits capable of high resolution, active sensory processing. Early ‘pre-sensory’ tuning uses amplification generated by corticothalamic excitatory feedback and early-born subplate neurons to ensure transmission of bursts, at the expense of stimulus discrimination. The switch to sensory circuits is due, at least in part, to the coordinated remodeling of inhibitory circuits in thalamus and cortex. Appreciation of the distinct rules that govern early circuit function can, and should, inform translational studies of genetic and acquired developmental dysfunction

Thalamocortical function in developing sensory circuits

© 2018 Elsevier Ltd Thalamocortical activity patterns, both spontaneous and evoked, undergo a dramatic shift in preparation for the onset of rich sensory experience (e.g. birth in humans; eye-opening in rodents). This change is the result of a switch from thalamocortical circuits tuned for transmission of spontaneous bursting in sense organs, to circuits capable of high resolution, active sensory processing. Early ‘pre-sensory’ tuning uses amplification generated by corticothalamic excitatory feedback and early-born subplate neurons to ensure transmission of bursts, at the expense of stimulus discrimination. The switch to sensory circuits is due, at least in part, to the coordinated remodeling of inhibitory circuits in thalamus and cortex. Appreciation of the distinct rules that govern early circuit function can, and should, inform translational studies of genetic and acquired developmental dysfunction