Molecular characterization of PI*Q0la palma, a new alpha-1-antitrypsin null allele that combines two defective genetic variants

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A novel RAD21 variant associated with intrafamilial phenotypic variation in Cornelia de Lange syndrome – review of the literature

In a patient with CdLS (IV.16) we identifed a novel single basepair deletion (c.704delG) in RAD21, which encodes a cohesin pathway protein. The variant is predicted to result in a premature stop codon [p.(Ser235Ilefs*19)] and hereby would have a deleterious effect. RAD21 variants have previously been described only in five cases with cohesinopathies (b). Notably, the deletion was found in the mother and the two aunts of the index patient, and none of them had been suspected of having CdLS or a cohesinopathy prior to this study (a). The index patient can be classified as mild CdLS, but the other family members do not fulfill the diagnostic criteria of CdLS. This study together with previous reports suggests incomplete penetrance associated with RAD21 variants and these individuals may therefore be underdiagnosed.

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Intraspinal microstimulation and diaphragm activation following cervical spinal cord injury

Intraspinal microstimulation (ISMS), using implanted electrodes, can evoke locomotor movements after spinal cord injury (SCI), but has not been explored in the context of respiratory motor output. An advantage over epidural and direct muscle stimulation is the potential of ISMS to selectively stimulate components of the spinal respiratory network. The present study tested the hypothesis that medullary respiratory activity could be used to trigger mid-cervical ISMS and diaphragm motor unit activation in rats with cervical SCI. Studies were conducted after acute (hours) and subacute (5-21 days) C2 hemisection (C2Hx) injury in adult rats. Inspiratory bursting in the genioglossus (tongue) muscle was used to trigger a 250 ms train stimulus (100 Hz, 100-200 µA) to the ventral C4 spinal cord, targeting the phrenic motor nucleus. After both acute and subacute injury, genioglossus EMG activity effectively triggered ISMS and activated diaphragm motor units during the inspiratory phase. The ISMS paradigm also evoked short-term potentiation of spontaneous inspiratory activity in the previously paralyzed hemidiaphragm (i.e., bursting persisting beyond the stimulus period) in approximately 70% of the C2Hx animals. We conclude that medullary inspiratory output can be used to trigger cervical ISMS and diaphragm activity after SCI. Further refinement of this method may enable "closed loop like" ISMS approaches to sustain ventilation after severe SCI.

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Neuronal Pattern Separation of Motion-Relevant Input in LIP Activity

In various regions of the brain, neurons discriminate sensory stimuli by decreasing the similarity between ambiguous input patterns. Here we examine whether this process of pattern separation may drive the rapid discrimination of visual motion stimuli in the lateral intraparietal area (LIP). Starting with a simple mean-rate population model that captures neuronal activity in LIP, we show that overlapping input patterns can be reformatted dynamically to give rise to separated patterns of neuronal activity. The population model predicts that a key ingredient of pattern separation is the presence of heterogeneity in the response of individual units. Furthermore, the model proposes that pattern separation relies upon heterogeneity in the temporal dynamics of neural activity and not merely in the mean firing rates of individual neurons over time. We confirm these predictions in recordings of macaque LIP neurons and show that the accuracy of pattern separation is a strong predictor of behavioral performance. Overall, results propose that LIP relies on neuronal pattern separation to facilitate decision-relevant discrimination of sensory stimuli.

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Maintenance of neuronal size gradient in MNTB requires sound-evoked activit

The medial nucleus of the trapezoid body (MNTB) is an important source of inhibition during the computation of sound location. It transmits fast and precisely timed action potentials at high frequencies; this requires an efficient calcium clearance mechanism, in which the plasma membrane calcium ATPase 2 (PMCA2) is a key component. Deafwaddler (dfw^2J) mutant mice have a null mutation in PMCA2 causing deafness in homozygotes (dfw^2J/dfw^2J) and high frequency hearing loss in heterozygotes (+/dfw^2J). Despite the deafness phenotype, no significant differences in MNTB volume or cell number were observed in dfw^2J homozygous mutants, suggesting PMCA2 is not required for MNTB neuron survival. The MNTB tonotopic axis encodes high to low sound frequencies across the medial to lateral dimension. We discovered a cell size gradient along this axis: lateral neuronal somata are significantly larger than medially located somata. This size gradient is decreased in +/dfw^2J and absent in dfw^2J/dfw^2J. The lack of acoustically driven input suggests that sound-evoked activity is required for maintenance of the cell size gradient. This hypothesis was corroborated by selective elimination of auditory hair cell activity using either hair cell elimination in Pou4f3 DTR mice or inner ear tetrodotoxin (TTX) treatment. The change in soma size was reversible and recovered within 7 days of TTX treatment, suggesting that regulation of the gradient is dependent on synaptic activity, and that these changes are plastic rather than permanent.

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Contextual Effects of Noise on Vocalization Encoding in Primary Auditory Cortex

Robust auditory perception plays a pivotal function for processing behaviorally relevant sounds, particularly with distractions from the environment. The neuronal coding enabling this ability, however, is still not well understood. In this study we recorded single-unit activity from the primary auditory cortex (A1) of awake marmoset monkeys (Callithrix jacchus) while delivering conspecific vocalizations degraded by two different background noises: broadband white noise and vocalization babble. Noise effects on neural representation of target vocalizations were quantified by measuring the responses' similarity to those elicited by natural vocalizations as a function of signal-to-noise ratio. A clustering approach was used to describe the range of response profiles by reducing the population responses to a summary of four response classes (robust, balanced, insensitive, and brittle) under both noise conditions. This clustering approach revealed that on average about two-thirds of the neurons change their response class when encountering different noises. Therefore, the distortion induced by one particular masking background in single-unit responses is not necessarily predictable from that induced by another, suggesting the low likelihood of a unique group of noise-invariant neurons across different background conditions in A1. Regarding noise influence on neural activities, the brittle response group showed addition of spiking activity both within and between phrases of vocalizations relative to clean vocalizations, while the other groups generally showed spiking activity suppression within phrases, and the alteration between phrases was noise-dependent. Overall, the variable single-unit responses yet consistent response types imply that primate A1 performs scene analysis through the collective activity of multiple neurons.

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Using noise to shape motor learning

Each of our movements is selected from any number of alternative movements. Some studies have shown evidence that the central nervous system (CNS) chooses to make the specific movements that are least affected by motor noise. Previous results that the CNS has the natural tendency to minimize the effects of noise make the direct prediction that if the relationship between movements and noise were to change, the specific movements people learn to make would also change in a predictable manner. Indeed, this has been shown for well-practiced movements such as reaching. Here, we artificially manipulated the relationship between movements and visuomotor noise by adding noise to a motor task in a novel redundant geometry such that there arose a single control policy that minimized the noise. This allowed us to see if, for a novel motor task, people could learn the specific control policy that minimized noise, or if they would need to employ other compensation strategies to overcome the added noise. As predicted, subjects were able to learn movements that were biased towards the specific ones that minimized the noise, suggesting not only that the CNS can learn to minimize the effects of noise in a novel motor task but also that using artificial visuomotor noise can be a useful tool for teaching people to make specific movements. Using noise as a teaching signal promises to be useful for rehabilitative therapies and movement training with human-machine interfaces.

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