Optogenetic Interrogation of Functional Synapse Formation by Corticospinal Tract Axons in the Injured Spinal Cord

To restore function after injury to the CNS, axons must be stimulated to extend into denervated territory and, critically, must form functional synapses with appropriate targets. We showed previously that forced overexpression of the transcription factor Sox11 increases axon growth by corticospinal tract (CST) neurons after spinal injury. However, behavioral outcomes were not improved, raising the question of whether the newly sprouted axons are able to form functional synapses. Here we developed an optogenetic strategy, paired with single-unit extracellular recordings, to assess the ability of Sox11-stimulated CST axons to functionally integrate in the circuitry of the cervical spinal cord. Initial time course experiments established the expression and function of virally expressed Channelrhodopsin (ChR2) in CST cell bodies and in axon terminals in cervical spinal cord. Pyramidotomies were performed in adult mice to deprive the left side of the spinal cord of CST input, and the right CST was treated with adeno-associated virus (AAV)–Sox11 or AAV–EBFP control, along with AAV–ChR2. As expected, Sox11 treatment caused robust midline crossing of CST axons into previously denervated left spinal cord. Clear postsynaptic responses resulted from optogenetic activation of CST terminals, demonstrating the ability of Sox11-stimulated axons to form functional synapses. Mapping of the distribution of CST-evoked spinal activity revealed overall similarity between intact and newly innervated spinal tissue. These data demonstrate the formation of functional synapses by Sox11-stimulated CST axons without significant behavioral benefit, suggesting that new synapses may be mistargeted or otherwise impaired in the ability to coordinate functional output. SIGNIFICANCE STATEMENT As continued progress is made in promoting the regeneration of CNS axons, questions of synaptic integration are increasingly prominent. Demonstrating direct synaptic integration by regenerated axons and distinguishing its function from indirect relay circuits and target field plasticity have presented technical challenges. Here we force the overexpression of Sox11 to stimulate the growth of corticospinal tract axons in the cervical spinal cord and then use specific optogenetic activation to assess their ability to directly drive postsynaptic activity in spinal cord neurons. By confirming successful synaptic integration, these data illustrate a novel optogenetic-based strategy to monitor and optimize functional reconnection by newly sprouted axons in the injured CNS

Plastic Adaptation: A Neuronal Imperative Capable of Confounding the Goals of Stem Cell Replacement Therapy for either Huntington’s or Parkinson’s Disease

Although stem cell transplant therapy offers considerable promise for deteriorative diseases, the efficacy of its application may be mitigated by endogenous compensatory mechanisms in the host brain. Plastic compensation follows neurodegeneration, beginning at its very onset and minimizing early symptom expression. As researchers attempt to correlate symptom remission with the ability of transplanted cells to adopt specific cell phenotypes, they need to be vigilant of the possibility that competing, local compensatory effects may be altering the outcome. Clearly plastic compensatory mechanisms could confound desired transplant-derived improvements by supplanting the beneficial contributions of the transplants. As circuit-level adaptations occur, more explicit explorations of their relevance to neuronal transplantation success are needed. Conceptual models of undirected transplanted cells adopting preconceived appropriate roles require revision. The notion that newly transplanted neuronal precursors will incorporate themselves into host circuitry with mutual cooperation across both parties (i.e., transplant and host) without some symbiosis-promoting mechanism is naïve. Undirected local circuits could react to newly transplanted additions as intruders. We advocate that appropriate signaling from transplanted cells to the host environment is required to optimize the therapeutic relevance of transplantation. This review surveys critical signaling mechanisms that might promote symbiotic interdependence between the host and new transplants

Effect of Different Method of Rice Establishment and Weed Management Options on Yield and Economics of Paddy

A field experiment was conducted during rabi 2022 at Zonal Agricultural and Horticultural Research Station, Brahmavara, Udupi, Keladi Shivappa Nayaka University of Agricultural and Horticultural Sciences, Shivamogga, on sandy loam soil to study the effect of different method of rice establishment and weed management options on yield and economics of paddy. The experiment was laid out in Factorial Randomized Complete Block Design with broadcasting and drum seeder method of establishment and five treatment combinations, replicated thrice. The study revealed that, the weed free treatment maintained by hand weeding recorded highest growth parameters and rice grain yield. The sequential application of pre-emergence herbicide pendimethalin 38.7 % CS @ 750 g a.i. ha-1 at 0-3 DAS (fb) early post-emergence application of bispyribac sodium 10 % SC @ 25 g a.i ha-1 at 13-15 DAS, recorded lowest total weed density (36.92, 31.73 and 40.45 No. m-2)  at 15, 30 and 45 DAS, respectively and lower weed index (7.23%) under drum seeder method of establishment . The yield and yield attributing parameters like number of tillers (291.33 m-2), panicle length (19 cm), filled grains (89.33 panicle-1), grain yield (4221 kg ha-1) and straw yield (5387 kg ha-1) were observed in sequential application of pre-emergence herbicide pendimethalin 38.7 % CS @ 750 g a.i. ha-1 at 0-3 DAS (fb) early post-emergence application of bispyribac sodium 10 % SC @ 25 g a.i ha-1 at 13-15 DAS under the drum seeder method of establishment. The highest net return (₹ 82586 ha-1) and B:C ratio (2.81) was also recorded in the same treatment

Use of piezoelectric actuators for thrust vectoring in ion engines: conceptual design and preliminary analysis

Nowadays, Ion propulsion systems are reliable enough to promise future space systems with high operational efficiencies. Conventionally, to control the thrust vector, ion engines are mounted on gimbals and oriented as a whole. To date, several studies and experiments have been conducted mounting compact thrust-vectoring systems within the thruster itself to reduce overall system mass. In this sense, gridded ion thruster is one of the most reliable propulsion systems with comparably higher operational efficiency, which allows for such vectoring techniques. The use of a microelectromechanical system combined with piezoelectric actuators for this process is promising. The paper presents a study for a possible implementation of these actuators in an Ion-Engine thrust vectoring system. A preliminary application is studied, and a proof of concept model is developed. Finite element analyses carried out in the present research show that the feasibility of the proposed design is demonstrated by adopting the piezoelectric actuation coupled with suitable compliant structures or adopting existing actuators as microelectromechanical piezoelectric systems. The proposed design, in theory, can eliminate the use of existing complex gimbal systems and thereby reduce the overall thrust vectoring system mass considerably

Towards enhanced functionality of vagus neuroprostheses through in silico optimized stimulation

Abstract Bioelectronic therapies modulating the vagus nerve are promising for cardiovascular, inflammatory, and mental disorders. Clinical applications are however limited by side-effects such as breathing obstruction and headache caused by non-specific stimulation. To design selective and functional stimulation, we engineered VaStim, a realistic and efficient in-silico model. We developed a protocol to personalize VaStim in-vivo using simple muscle responses, successfully reproducing experimental observations, by combining models with trials conducted on five pigs. Through optimized algorithms, VaStim simulated the complete fiber population in minutes, including often omitted unmyelinated fibers which constitute 80% of the nerve. The model suggested that all Aα-fibers across the nerve affect laryngeal muscle, while heart rate changes were caused by B-efferents in specific fascicles. It predicted that tripolar paradigms could reduce laryngeal activity by 70% compared to typically used protocols. VaStim may serve as a model for developing neuromodulation therapies by maximizing efficacy and specificity, reducing animal experimentation