Role of Human Premotor Dorsal Region in Learning a Conditional Visuo-Motor Task

Conditional learning is an important component of our everyday activities, e.g. handling a phone or sorting work files and requires identification of the arbitrary stimulus, accurate selection of the motor response, monitoring of the response, and storing in memory the stimulus-response association for future recall. Learning this type of conditional visuo-motor task appears to engage the premotor dorsal region (PMd). However, the extent to which PMd might be involved in specific or all processes of conditional learning is not well understood. Using transcranial magnetic stimulation (TMS), we demonstrate the role of human PMd in specific stages of learning of a novel conditional visuo-motor task that required subjects to identify object center of mass using a color cue, and apply appropriate torque on the object at lift onset to minimize tilt. TMS over PMd, but not vertex, increased error in torque exerted on the object during the learning trials. Analyses of digit position and forces further revealed that the slowing in conditional visuo-motor learning resulted from impaired monitoring of the object orientation during lift, rather than stimulus identification, thus compromising the ability to accurately reduce performance error across trials. Importantly, TMS over PMd did not alter production of torque based on the recall of learned color-torque associations. We conclude that the role of PMd for conditional learning is highly sensitive to the stage of learning visuo-motor associations.

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Calcium dynamics and regulation in horizontal cells of the vertebrate retina: lessons from teleosts

Horizontal cells (HCs) are inhibitory interneurons of the vertebrate retina. Unlike typical neurons, HCs are chronically depolarized in the dark, leading to a constant influx of Ca²⁺. Therefore, mechanisms of Ca²⁺ homeostasis in HCs must differ from neurons elsewhere in the central nervous system, which undergo excitotoxicity when they are chronically depolarized or stressed with Ca²⁺. Horizontal cells are especially well characterized in teleost fish, and have been used to unlock mysteries of the vertebrate retina for over a century. More recently, mammalian models of the retina have been increasingly informative for HC physiology. We draw from both teleost and mammalian models in this review, using a comparative approach to examine what is known about Ca²⁺ pathways in vertebrate HCs. We begin with a survey of Ca²⁺-permeable ion channels, exchangers, and pumps, and summarize Ca²⁺ influx and efflux pathways, buffering, and intracellular stores. This includes evidence for Ca²⁺-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs), and for voltage-gated Ca²⁺ channels. Special attention is given to interactions between ion channels, to differences between species, and in which subtypes of HCs these channels have been found. We then discuss a number of unresolved issues pertaining to Ca²⁺ dynamics in HCs, including: a potential role for Ca²⁺ in feedback to photoreceptors, the role for Ca²⁺-induced Ca²⁺ release, and the properties and functions of Ca²⁺-based action potentials. This review aims to highlight the unique Ca²⁺ dynamics in HCs, as these are inextricably tied to retinal function.

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Neuromuscular responses differ between slip-induced falls and recoveries in older adults

How does the robust control of walking and balance break down during a fall? As a first step in identifying the neuromuscular determinants of falls, we tested the hypothesis that falls and recoveries are characterized by differences in neuromuscular responses. Using muscle synergy analysis, conventional onset latencies, and peak activity, we identified differences in muscle coordination between older adults who fell and those who recovered from a laboratory-induced slip. We found that subjects who fell recruited fewer muscle synergies than those who recovered, suggesting a smaller motor repertoire. During slip trials subjects who fell had delayed knee flexor and extensor onset times in the leading/slip leg, as well as different muscle synergy structure involving those muscles. Therefore, the ability to coordinate muscle activity around the knee in a timely manner may be critical to avoiding falls from slips. Unique to subjects who fell during slip trials were greater bilateral muscle activation, and the recruitment of a muscle synergy with excessive co-activation. These differences in muscle coordination between subjects who fell and those who recovered could not be explained by differences in gait-related variables at slip onset (i.e. initial motion state) nor variations in slip difficulty. This suggests that differences in muscle coordination likely reflected differences in the neural control of movement rather than biomechanical constraints imposed by perturbation or walking mechanics. These results are the first step in determining the causation of falls from the perspective of muscle coordination. They suggest that there may be a neuromuscular basis for falls.

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Contrast sensitivity, V1 neural activity, and natural vision

Contrast sensitivity is fundamental to natural visual processing and an important tool for characterizing both visual function and clinical disorders. We simultaneously measured contrast sensitivity and neural contrast response functions and compared measurements in common laboratory conditions with naturalistic conditions. In typical experiments, a subject holds fixation and a stimulus is flashed on, whereas in natural vision saccades bring stimuli into view. Motivated by our previous V1 findings, we tested the hypothesis that perceptual contrast sensitivity is lower in natural vision and that this effect is associated with corresponding changes in V1 activity. We find that contrast sensitivity and V1 activity are correlated and that the relationship is similar in laboratory and naturalistic paradigms. However, in the more natural situation, contrast sensitivity is reduced up to 25% compared to a standard fixation paradigm, particularly at lower spatial frequencies, and this effect correlates with significant reductions in V1 responses. Our results suggest that these reductions in natural vision result from fast adaptation on one fixation that lowers the response on a subsequent fixation. This is the first demonstration of rapid, natural-image adaptation that carries across saccades, a process that appears to constantly influence visual sensitivity in natural vision.

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Psychosocial stress alters the strength of reticulospinal input to the human upper trapezius

Psychosocial stress has been shown to influence several aspects of human motor control associated with the fight-or-flight response, including augmentation of upper trapezius muscle activity. Given the established role of the reticular formation in arousal, this study investigated the contribution of reticulospinal activation to trapezius muscle activity during exposure to an acute psychosocial stressor. Twenty-five healthy adults were exposed to startling acoustic stimuli (SAS) while performing a motor task during periods of low and high psychosocial stress. Acoustic startle reflexes (ASRs) were recorded in the upper trapezius during low-intensity contractions using both surface and intramuscular electromyography. Exposure to the stressor increased subjective and physiologic measures of arousal (p<0.01). The majority of participants demonstrated inhibitory ASRs, whereas a small subgroup with significantly higher trait anxiety (N=5) demonstrated excitatory ASRs in the low stress condition. Changes in synaptic input for inhibitory ASRs were confirmed by decreases in the discharge rate of single motor units in response to the SAS. ASRs decreased in magnitude for all participants during exposure to the acute psychosocial stressor. These findings suggest that the reticular formation has predominately inhibitory effects on the human upper trapezius during an ongoing motor task, and that disinhibition caused by psychosocial stress may contribute to augmentation of trapezius muscle activity. Further research is required to investigate mechanisms underlying the complex ASRs characterized by this study, particularly the phase reversal to excitatory responses observed among more anxious individuals.

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Caveolin-1 Regulation of Disrupted-in-Schizophrenia-1 as a Potential Therapeutic Target for Schizophrenia

Background: Schizophrenia is a debilitating psychiatric disorder manifested in early adulthood. Disrupted-In-Schizophrenia-1 (DISC1) is a susceptible gene for schizophrenia (54, 76, 101) implicated in neuronal development, brain maturation and neuroplasticity (12, 20). Therefore, DISC1 is a promising candidate gene for schizophrenia, but the molecular mechanisms underlying its role in the pathogenesis of the disease are still poorly understood. Interestingly, Caveolin-1 (Cav-1), a cholesterol binding and scaffolding protein, regulates neuronal signal transduction and promotes neuroplasticity. Here we examined the role of Cav-1 in mediating DISC1 expression in neurons in vitro and the hippocampus in vivo. Methods and Results: Overexpressing Cav-1 specifically in neurons using a neuron specific synapsin promoter (SynCav1) increased expression of DISC1 and proteins involved in synaptic plasticity (PSD95, synaptobrevin, synaptophysin, neurexin, and syntaxin-1). Similarly, SynCav1-transfected differentiated human neurons derived from induced pluripotent stem cells (hiPSCs) exhibited increased expression of DISC1 and markers of synaptic plasticity. Conversely, hippocampi from Cav-1 knockout (KO) exhibited decreased expression of DISC1 and proteins involved in synaptic plasticity. Finally, SynCav1 delivery to the hippocampus of Cav-1 KO mice and Cav-1 KO neurons in culture restored expression of DISC1 and markers of synaptic plasticity. Furthermore, we found that Cav-1 co-immunoprecipitated with DISC1 in brain tissues. Conclusion: These findings suggest an important role by which neuronal Cav-1 regulates DISC1 neurobiology with implications for synaptic plasticity. Therefore, SynCav1 might be a potential therapeutic target for restoring neuronal function in schizophrenia.

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Go-activation endures following the presentation of a stop-signal: Evidence from startle

It has been proposed that in a stop-signal task (SST), independent go- and stop-processes "race" to control behaviour. If the go-process wins, an overt response is produced, while if the stop-process wins, the response is withheld. One prediction that follows from this proposal is that if the activation associated with one process is enhanced, it is more likely to win the race. We looked to determine whether these initiation and inhibition processes (and thus response outcome) could be manipulated by using a startling acoustic stimulus (SAS), which has been shown to provide additional response activation. In the present study participants were to respond to a visual go-stimulus; however, if a subsequent stop-signal appeared they were to inhibit the response. The stop-signal was presented at a delay corresponding to a probability of responding of 0.4 (determined from a baseline block of trials). On stop-trials a SAS was presented either simultaneous with the go-signal or stop-signal, or 100, 150, or 200 ms following the stop-signal. Results showed that presenting a SAS during stop-trials led to an increase in probability of responding when presented with or following the stop-signal. The latency of SAS responses at the stop-signal+150 ms and stop-signal+200 ms probe times suggests they would have been voluntarily inhibited but instead were involuntarily initiated by the SAS. Thus, results demonstrate that go-activation endures even 200 ms following a stop-signal and remains accessible well after the response has been inhibited, providing evidence against a winner take all race between independent go- and stop-processes.

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