Precision mouse models with expanded tropism for human pathogens

A major limitation of current humanized mouse models is that they primarily enable the analysis of human-specific pathogens that infect hematopoietic cells. However, most human pathogens target other cell types, including epithelial, endothelial and mesenchymal cells. Here, we show that implantation of human lung tissue, which contains up to 40 cell types, including nonhematopoietic cells, into immunodeficient mice (lung-only mice) resulted in the development of a highly vascularized lung implant. We demonstrate that emerging and clinically relevant human pathogens such as Middle East respiratory syndrome coronavirus, Zika virus, respiratory syncytial virus and cytomegalovirus replicate in vivo in these lung implants. When incorporated into bone marrow/liver/thymus humanized mice, lung implants are repopulated with autologous human hematopoietic cells. We show robust antigen-specific humoral and T-cell responses following cytomegalovirus infection that control virus replication. Lung-only mice and bone marrow/liver/thymus-lung humanized mice substantially increase the number of human pathogens that can be studied in vivo, facilitating the in vivo testing of therapeutics

The Decerebrate Cat Generates the Essential Features of the Force Constraint Strategy

Cats actively respond to horizontal perturbations of the supporting surface according to the force constraint strategy. In this strategy, the force responses fall into two groups oriented in either rostral and medial directions or caudal and lateral directions, rather than in strict opposition to the direction of perturbation. When the distance between forelimbs and hindlimbs is decreased, the responses are less constrained and directed more in line with the perturbation. We have recently shown that electromyographic responses from limb muscles of the decerebrate cat resemble those obtained in the intact animal. Our objectives here were to determine whether the decerebrate cat preparation would also exhibit the force constraint strategy and whether that strategy would exhibit the characteristic dependence on limb position on the strategy. Horizontal support surface perturbations were delivered and three-dimensional exerted forces were recorded from all four limbs. Clustered force responses were generated by all four limbs and were found to be statistically indistinguishable between animals decerebrated using two different levels of transection. The directionality of the force responses was preserved throughout successive time epochs during the perturbations. In addition, the clustering of force responses increased with distance between forelimbs and hindlimbs. These results indicate that the force constraint strategy used by terrestrial animals to maintain stability can be generated without the assistance of the cerebral cortices and without prior training. This suggests an important role for the lower brain stem and spinal cord in generating an appropriate strategy to maintain stability

Electromyographic Responses From the Hindlimb Muscles of the Decerebrate Cat to Horizontal Support Surface Perturbations

The sensory and neural mechanisms underlying postural control have received much attention in recent decades but remain poorly understood. Our objectives were 1) to establish the decerebrate cat as an appropriate model for further research into the sensory mechanisms of postural control and 2) to observe what elements of the postural response can be generated by the brain stem and spinal cord. Ten animals were decerebrated using a modified premammillary technique, which consists of a premammillary decerebration that is modified with a vertical transection near the subthalamic nucleus to eliminate spontaneous locomotion. Horizontal support surface perturbations were applied to all four limbs and electromyographic recordings were collected from 14 muscles of the right hindlimb. Muscle activation was quantified with tuning curves, which compared increases and decreases in muscle activity to background and graphed the difference against perturbation direction. Parallels were drawn between these tuning curves, which were further quantified with a principal direction and breadth (range of directions of muscle activation), and data collected by other researchers from the intact animal. We found a strong similarity in the direction and breadth of the tuning curves generated in the decerebrate and intact cat. These results support our hypothesis that directionally specific tuning of muscles in response to support surface perturbations does not require the cortex, further indicating a strong role for the brain stem and spinal cord circuits in mediating directionally appropriate muscle activation patterns

Instruction-dependent modulation of the long-latency stretch reflex is associated with indicators of startle

Long-latency responses elicited by postural perturbation are modulated by how a subject is instructed to respond to the perturbation, yet the neural pathways responsible for this modulation remain unclear. The goal of this study was to determine whether instruction-dependent modulation is associated with activity in brainstem pathways contributing to startle. Our hypothesis was that elbow perturbations can evoked startle, indicated by activity in the sternocleidomastoid muscle (SCM). Perturbation responses were compared to those elicited by a loud acoustic stimulus, known to elicit startle. Postural perturbations and startling acoustic stimuli both evoked SCM activity, but only when a ballistic elbow extension movement was planned. Both stimuli triggered SCM activity with the same probability. When SCM activity was present, there was an associated early onset of triceps electromyographic (EMG), as required for the planned movement. This early EMG onset occurred at a time often attributed to long-latency stretch reflexes (75-100 ms). The nature of the perturbation-triggered EMG (excitatory or inhibitory) was independent of the perturbation direction (flexion or extension) indicating that it was not a feedback response appropriate for returning the limb to its original position. The net EMG response to perturbations delivered after a movement had been planned could be explained as the sum of a stretch reflex opposing the perturbation and a startle-evoked response associated with the prepared movement. These results demonstrate that rapid perturbations can trigger early release of a planned ballistic movement, and that this release is associated with activity in the brainstem pathways contributing to startle reflexes

Evidence for startle as a measurable behavioral indicator of motor learning

<div><p>The ability of the classic startle reflex to evoke voluntarily prepared movement involuntarily has captured the attention of neuroscientists for its wide-ranging functional utility and potential uses in patient populations. To date, there is only one documented task resistant to the startReact phenomenon–index finger abduction. Previous reports have suggested the lack of startReact is due to different neural mechanisms driving individuated finger movement and more proximal joint control (e.g. elbow, wrist movement). However, an alternative hypothesis exists. Though not particularly difficult to execute, isolated index finger abduction is rarely performed during activities of daily living and is not a natural correlate to common individuated finger tasks. We propose that startReact can be evoked during individuated finger movements but only during tasks that are highly trained or familiar. The objective of this study was to determine the impact of a 2-week training regimen on the ability to elicit startReact. We found evidence in support of our hypothesis that following training, individuated movements of the hands (specifically index finger abduction) become susceptible to startReact. This is significant not only because it indicates that individuated finger movements are in fact amenable to startReact, but also that startle has differential response characteristics in novel tasks compared to highly trained tasks suggesting that startle is a measurable behavioral indicator of motor learning.</p></div

Task illustration.

<p>Subjects performed index finger abduction with their right hand when directed by the auditory GO cue.</p

Group results.

<p>Comparisons of FDI onset latencies between SCM+ and SCM- trials. **<i>P <</i> 0.01, SE error bars.</p

Experiment schedule.

<p>Subjects practiced index finger abduction over 10 daily training sessions. Stimulus trials were included on Day 1, 5 and 10. Auditory feedback based on previous day’s performance was administered on Day 2–10.</p