Shreesh P. Mysore

Activity-regulated N-cadherin endocytosis.

Enduring forms of synaptic plasticity are thought to require ongoing regulation of adhesion molecules, such as N-cadherin, at synaptic junctions. Little is known about the activity-regulated trafficking of adhesion molecules. Here we demonstrate that surface N-cadherin undergoes a surprisingly high basal rate of internalization. Upon activation of NMDA receptors (NMDAR), the rate of N-cadherin endocytosis is significantly reduced, resulting in an accumulation of N-cadherin in the plasma membrane. Beta-catenin, an N-cadherin binding partner, is a primary regulator of N-cadherin endocytosis. Following NMDAR stimulation, beta-catenin accumulates in spines and exhibits increased binding to N-cadherin. Overexpression of a mutant form of beta-catenin, Y654F, prevents the NMDAR-dependent regulation of N-cadherin internalization, resulting in stabilization of surface N-cadherin molecules. Furthermore, the stabilization of surface N-cadherin blocks NMDAR-dependent synaptic plasticity. These results indicate that NMDAR activity regulates N-cadherin endocytosis, providing a mechanistic link between structural plasticity and persistent changes in synaptic efficacy.

A shared inhibitory circuit for both exogenous and endogenous control of stimulus selection.

The mechanisms by which the brain suppresses distracting stimuli to control the locus of attention are unknown. We found that focal, reversible inactivation of a single inhibitory circuit in the barn owl midbrain tegmentum, the nucleus isthmi pars magnocellularis (Imc), abolished both stimulus-driven (exogenous) and internally driven (endogenous) competitive interactions in the optic tectum (superior colliculus in mammals), which are vital to the selection of a target among distractors in behaving animals. Imc neurons transformed spatially precise multisensory and endogenous input into powerful inhibitory output that suppressed competing representations across the entire tectal space map. We identified a small, but highly potent, circuit that is employed by both exogenous and endogenous signals to exert competitive suppression in the midbrain selection network. Our findings reveal, to the best of our knowledge, for the first time, a neural mechanism for the construction of a priority map that is critical for the selection of the most important stimulus for gaze and attention.

Global Inhibition and Stimulus Competition in the Owl Optic Tectum

Stimulus selection for gaze and spatial attention involves competition among stimuli across sensory modalities and across all of space. We demonstrate that such cross-modal, global competition takes place in the intermediate and deep layers of the optic tectum, a structure known to be involved in gaze control and attention. A variety of either visual or auditory stimuli located anywhere outside of a neurons receptive field (RF) were shown to suppress or completely eliminate responses to a visual stimulus located inside the RF in nitrous oxide sedated owls. The essential mechanism underlying this stimulus competition is global, divisive inhibition. Unlike the effect of the classical inhibitory surround, which decreases with distance from the RF center and shapes neuronal responses to individual stimuli, global inhibition acts across the entirety of space and modulates responses primarily in the context of multiple stimuli. Whereas the source of this global inhibition is as yet unknown, our data indicate that different networks mediate the classical surround and global inhibition. We hypothesize that this global, cross-modal inhibition, which acts automatically in a bottom-up manner even in sedated animals, is critical to the creation of a map of stimulus salience in the optic tectum.

The role of a midbrain network in competitive stimulus selection.

A midbrain network interacts with the well-known frontoparietal forebrain network to select stimuli for gaze and spatial attention. The midbrain network, containing the superior colliculus (SC; optic tectum, OT, in non-mammalian vertebrates) and the isthmic nuclei, helps evaluate the relative priorities of competing stimuli and encodes them in a topographic map of space. Behavioral experiments in monkeys demonstrate an essential contribution of the SC to stimulus selection when the relative priorities of competing stimuli are similar. Neurophysiological results from the owl OT demonstrate a neural correlate of this essential contribution of the SC/OT. The multi-layered, spatiotopic organization of the midbrain network lends itself to the analysis and modeling of the mechanisms underlying stimulus selection for gaze and spatial attention.

Signaling of the Strongest Stimulus in the Owl Optic Tectum

Essential to the selection of the next target for gaze or attention is the ability to compare the strengths of multiple competing stimuli (bottom-up information) and to signal the strongest one. Although the optic tectum (OT) has been causally implicated in stimulus selection, how it computes the strongest stimulus is unknown. Here, we demonstrate that OT neurons in the barn owl systematically encode the relative strengths of simultaneously occurring stimuli independently of sensory modality. Moreover, special “switch-like” responses of a subset of neurons abruptly increase when the stimulus inside their receptive field becomes the strongest one. Such responses are not predicted by responses to single stimuli and, indeed, are eliminated in the absence of competitive interactions. We demonstrate that this sensory transformation substantially boosts the representation of the strongest stimulus by creating a binary discrimination signal, thereby setting the stage for potential winner-take-all target selection for gaze and attention.

Stimulus-driven competition in a cholinergic midbrain nucleus.

The mechanisms by which the brain selects a particular stimulus as the next target for gaze are poorly understood. A cholinergic nucleus in the owls midbrain exhibits functional properties that suggest its role in bottom-up stimulus selection. Neurons in the nucleus isthmi pars parvocellularis (Ipc) responded to wide ranges of visual and auditory features, but they were not tuned to particular values of those features. Instead, they encoded the relative strengths of stimuli across the entirety of space. Many neurons exhibited switch-like properties, abruptly increasing their responses to a stimulus in their receptive field when it became the strongest stimulus. This information propagates directly to the optic tectum, a structure involved in gaze control and stimulus selection, as periodic (25–50 Hz) bursts of cholinergic activity. The functional properties of Ipc neurons resembled those of a salience map, a core component in computational models for spatial attention and gaze control.

Effects of N-Cadherin Disruption on Spine Morphological Dynamics

Structural changes at synapses are thought to be a key mechanism for the encoding of memories in the brain. Recent studies have shown that changes in the dynamic behavior of dendritic spines accompany bidirectional changes in synaptic plasticity, and that the disruption of structural constraints at synapses may play a mechanistic role in spine plasticity. While the prolonged disruption of N-cadherin, a key synaptic adhesion molecule, has been shown to alter spine morphology, little is known about the short-term regulation of spine morphological dynamics by N-cadherin. With time-lapse, confocal imaging in cultured hippocampal neurons, we examined the progression of structural changes in spines following an acute treatment with AHAVD, a peptide known to interfere with the function of N-cadherin. We characterized fast and slow timescale spine dynamics (minutes and hours, respectively) in the same population of spines. We show that N-cadherin disruption leads to enhanced spine motility and reduced length, followed by spine loss. The structural effects are accompanied by a loss of functional connectivity. Further, we demonstrate that early structural changes induced by AHAVD treatment, namely enhanced motility and reduced length, are indicators for later spine fate, i.e., spines with the former changes are more likely to be subsequently lost. Our results thus reveal the short-term regulation of synaptic structure by N-cadherin and suggest that some forms of morphological dynamics may be potential readouts for subsequent, stimulus-induced rewiring in neuronal networks.

Machinery Fault Diagnosis and Prognosis: Application of Advanced Signal Processing Techniques

Abstract Machinery health prediction based on process models and/or process parameters is an important function in automated manufacturing set-ups. Sensor data is collected and used to indirectly model the equipment. Due to the short response times required it is important to investigate robust sensor data representation schemes. Traditional Fourier Analysis is not sufficient to preserve the information in both frequency and time domains. In this paper we describe the use of wavelets, both continuous and discrete, for equipment diagnosis and prognosis. We detail wavelet-based techniques for gear fault diagnosis and prognosis.

Flexible Categorization of Relative Stimulus Strength by the Optic Tectum

Categorization is the process by which the brain segregates continuously variable stimuli into discrete groups. We report that patterns of neural population activity in the owl optic tectum (OT) categorize stimuli based on their relative strengths into “strongest” versus “other.” The category boundary shifts adaptively to track changes in the absolute strength of the strongest stimulus. This population-wide categorization is mediated by the responses of a small subset of neurons. Our data constitute the first direct demonstration of explicit categorization of stimuli by a neural network based on relative stimulus strength or salience. The finding of categorization by the population code relaxes constraints on the properties of downstream decoders that might read out the location of the strongest stimulus. These results indicate that the ensemble neural code in the OT could mediate bottom-up stimulus selection for gaze and attention, a form of stimulus categorization in which the category boundary often shifts within hundreds of milliseconds.

N-cadherin, spine dynamics, and synaptic function

Dendritic spines are one-half (the postsynaptic half) of most excitatory synapses. Ever since the direct observation over a decade ago that spines can continually change size and shape, spine dynamics has been of great research interest, especially as a mechanism for structural synaptic plasticity. In concert with this ongoing spine dynamics, the stability of the synapse is also needed to allow continued, reliable synaptic communication. Various cell-adhesion molecules help to structurally stabilize a synapse and its proteins. Here, we review the effects of disrupting N-cadherin, a prominent trans-synaptic adhesion molecule, on spine dynamics, as reported in Mysore et al. (2007). We highlight the novel method adopted therein to reliably detect even subtle changes in fast and slow spine dynamics. We summarize the structural, functional, and molecular consequences of acute N-cadherin disruption, and tie them in, in a working model, with longer-term effects on spines and synapses reported in the literature.