Restoration of Visual Function by Enhancing Conduction in Regenerated Axons.

Although a number of repair strategies have been shown to promote axon outgrowth following neuronal injury in the mammalian CNS, it remains unclear whether regenerated axons establish functional synapses and support behavior. Here, in both juvenile and adult mice, we show that either PTEN and SOCS3 co-deletion, or co-overexpression of osteopontin (OPN)/insulin-like growth factor 1 (IGF1)/ciliary neurotrophic factor (CNTF), induces regrowth of retinal axons and formation of functional synapses in the superior colliculus (SC) but not significant recovery of visual function. Further analyses suggest that regenerated axons fail to conduct action potentials from the eye to the SC due to lack of myelination. Consistent with this idea, administration of voltage-gated potassium channel blockers restores conduction and results in increased visual acuity. Thus, enhancing both regeneration and conduction effectively improves function after retinal axon injury.

Brillouin spectroscopy via an atomic line monochromator.

Brillouin spectrometers, used for characterizing material mechanical properties, traditionally employ etalons such as Fabry-Pérot interferometers and virtually imaged phased arrays (VIPA) that use spatial dispersion of the spectrum for measurement. Here, we introduce what we believe to be a novel approach to Brillouin spectroscopy using hot atomic vapors. Using laser induced circular dichroism of the rubidium D2 line in a ladder-type configuration, we developed a narrow-band monochromator for Brillouin analysis. Unlike etalon-based spectrometers, atomic line monochromators operate in free-space, facilitating Brillouin spectroscopy integration with microscopy instruments. We report the transmission and spectral resolution performances of the spectrometer and demonstrate Brillouin spectra measurements in liquids.

Artemin promotes functional long-distance axonal regeneration to the brainstem after dorsal root crush.

Recovery after a spinal cord injury often requires that axons restore synaptic connectivity with denervated targets several centimeters from the site of injury. Here we report that systemic artemin (ARTN) treatment promotes the regeneration of sensory axons to the brainstem after brachial dorsal root crush in adult rats. ARTN not only stimulates robust regeneration of large, myelinated sensory axons to the brainstem, but also promotes functional reinnervation of the appropriate target region, the cuneate nucleus. ARTN signals primarily through the RET tyrosine kinase, an interaction that requires the nonsignaling coreceptor GDNF family receptor (GFRα3). Previous studies reported limited GFRα3 expression on large sensory neurons, but our findings demonstrate that ARTN promotes robust regeneration of large, myelinated sensory afferents. Using a cell sorting technique, we demonstrate that GFRα3 expression is similar in myelinated and unmyelinated adult sensory neurons, suggesting that ARTN likely induces long-distance regeneration by binding GFRα3 and RET. Although ARTN is delivered for just 2 wk, regeneration to the brainstem requires more than 3 mo, suggesting that brief trophic support may initiate intrinsic growth programs that remain active until targets are reached. Given its ability to promote targeted functional regeneration to the brainstem, ARTN may represent a promising therapy for restoring sensory function after spinal cord injury.

SAD kinases control the maturation of nerve terminals in the mammalian peripheral and central nervous systems.

Axons develop in a series of steps, beginning with specification, outgrowth, and arborization, and terminating with formation and maturation of presynaptic specializations. We found previously that the SAD-A and SAD-B kinases are required for axon specification and arborization in subsets of mouse neurons. Here, we show that following these steps, SAD kinases become localized to synaptic sites and are required within presynaptic cells for structural and functional maturation of synapses in both peripheral and central nervous systems. Deleting SADs from sensory neurons can perturb either axonal arborization or nerve terminal maturation, depending on the stage of deletion. Thus, a single pair of kinases plays multiple, sequential roles in axonal differentiation.

Hepatopulmonary syndrome with large pulmonary arteriovenous malformations: CT findings with emphasis on its association with a mosaic pattern of the lung parenchyma.

We present a case of a 54-year-old patient with cirrhosis, progressive dyspnea, and platypnea. Thoracic computed tomography (CT) showed multiple pulmonary arteriovenous malformations (PAVM), confirming the diagnosis of hepatopulmonary syndrome (HPS). Besides precisely identifying the number and location of PAVM, CT also demonstrated a striking mosaic pattern of the lung parenchyma, characterized by the presence of alternating geographic areas of low attenuation (showing pulmonary vessels with a decreased diameter) with regions of relatively increased attenuation (showing pulmonary vessels with a normal diameter). This mosaic pattern of the lung parenchyma has scarcely been described in patients with HPS since it is not always present and usually requires a post-processing of the CT images in order to increase the contrast between the low attenuation areas (representing hypoperfused regions) and the areas with a relatively increased attenuation (representing better perfused regions). The decision was made to embolize the major PAVM, achieving an improvement of both the oxygen partial pressure and the patient's symptoms. This improvement allowed the patient to become an acceptable candidate for liver transplantation. We believe that, unlike other radiological signs of HPS, the mosaic pattern has not been sufficiently described in the scientific literature. If the association of the mosaic pattern on CT with HPS is confirmed in larger studies, it could become a useful sign for detecting hypoperfused pulmonary areas related to small nonvisible PAVM.

Dynamics of a diffusive model for cancer stem cells with time delay in microRNA-differentiated cancer cell interactions and radiotherapy effects.

Understand the dynamics of cancer stem cells (CSCs), prevent the non-recurrence of cancers and develop therapeutic strategies to destroy both cancer cells and CSCs remain a challenge topic. In this paper, we study both analytically and numerically the dynamics of CSCs under radiotherapy effects. The dynamical model takes into account the diffusion of cells, the de-differentiation (or plasticity) mechanism of differentiated cancer cells (DCs) and the time delay on the interaction between microRNAs molecules (microRNAs) with DCs. The stability of the model system is studied by using a Hopf bifurcation analysis. We mainly investigate on the critical time delay τ c , that represents the time for DCs to transform into CSCs after the interaction of microRNAs with DCs. Using the system parameters, we calculate the value of τ c for prostate, lung and breast cancers. To confirm the analytical predictions, the numerical simulations are performed and show the formation of spatiotemporal circular patterns. Such patterns have been found as promising diagnostic and therapeutic value in management of cancer and various diseases. The radiotherapy is applied in the particular case of prostate model. We calculate the optimum dose of radiation and determine the probability of avoiding local cancer recurrence after radiotherapy treatment. We find numerically a complete eradication of patterns when the radiotherapy is applied before a time t < τ c . This scenario induces microRNAs to act as suppressors as experimentally observed in prostate cancer. The results obtained in this paper will provide a better concept for the clinicians and oncologists to understand the complex dynamics of CSCs and to design more efficacious therapeutic strategies to prevent the non-recurrence of cancers.

Area-Selective Growth of Zinc Oxide Nanowire Arrays for Piezoelectric Energy Harvesting.

In this work, we present the area-selective growth of zinc oxide nanowire (NW) arrays on patterned surfaces of a silicon (Si) substrate for a piezoelectric nanogenerator (PENG). ZnO NW arrays were selectively grown on patterned surfaces of a Si substrate using a devised microelectromechanical system (MEMS)-compatible chemical bath deposition (CBD) method. The fabricated devices measured a maximum peak output voltage of ~7.9 mV when a mass of 91.5 g was repeatedly manually placed on them. Finite element modeling (FEM) of a single NW using COMSOL Multiphysics at an applied axial force of 0.9 nN, which corresponded to the experimental condition, resulted in a voltage potential of -6.5 mV. The process repeated with the same pattern design using a layer of SU-8 polymer on the NWs yielded a much higher maximum peak output voltage of ~21.6 mV and a corresponding peak power density of 0.22 µW/cm3, independent of the size of the NW array. The mean values of the measured output voltage and FEM showed good agreement and a nearly linear dependence on the applied force on a 3 × 3 µm2 NW array area in the range of 20 to 90 nN.

Topographically specific regeneration of sensory axons in the spinal cord.

Artemin, a member of the glial-derived neurotrophic factor family, promotes robust regeneration of sensory axons after dorsal root crush. We report here that several classes of sensory axons regenerate to topographically appropriate regions of the dorsal horn with artemin treatment. Projections of regenerated muscle and cutaneous myelinated sensory afferents are restricted to the correct spinal segments and to appropriate regions within spinal gray matter. Regenerated unmyelinated axons expressing calcitonin gene-related peptide project only to superficial laminae of the dorsal horn, where uninjured nociceptive afferents project normally. In contrast, intraventricular infusion of a soluble form of the Nogo receptor that blocks the action of several myelin-associated inhibitory proteins promotes relatively unrestricted regeneration of sensory axons throughout the dorsal white and gray matter of the spinal cord. These results demonstrate that cues capable of guiding regenerating axons to appropriate spinal targets persist in the adult mammalian cord, but only some methods of stimulating regeneration allow the use of these cues by growing axons.

Current ARTs, Virologic Failure, and Implications for AIDS Management: A Systematic Review.

Antiretroviral therapies (ARTs) have revolutionized the management of human immunodeficiency virus (HIV) infection, significantly improved patient outcomes, and reduced the mortality rate and incidence of acquired immunodeficiency syndrome (AIDS). However, despite the remarkable efficacy of ART, virologic failure remains a challenge in the long-term management of HIV-infected individuals. Virologic failure refers to the persistent detectable viral load in patients receiving ART, indicating an incomplete suppression of HIV replication. It can occur due to various factors, including poor medication adherence, drug resistance, suboptimal drug concentrations, drug interactions, and viral factors such as the emergence of drug-resistant strains. In recent years, extensive efforts have been made to understand and address virologic failure in order to optimize treatment outcomes. Strategies to prevent and manage virologic failure include improving treatment adherence through patient education, counselling, and supportive interventions. In addition, the regular monitoring of viral load and resistance testing enables the early detection of treatment failure and facilitates timely adjustments in ART regimens. Thus, the development of novel antiretroviral agents with improved potency, tolerability, and resistance profiles offers new options for patients experiencing virologic failure. However, new treatment options would also face virologic failure if not managed appropriately. A solution to virologic failure requires a comprehensive approach that combines individualized patient care, robust monitoring, and access to a range of antiretroviral drugs.

The role of muscle spindles in the development of the monosynaptic stretch reflex.

Muscle sensory axons induce the development of specialized intrafusal muscle fibers in muscle spindles during development, but the role that the intrafusal fibers may play in the development of the central projections of these Ia sensory axons is unclear. In the present study, we assessed the influence of intrafusal fibers in muscle spindles on the formation of monosynaptic connections between Ia (muscle spindle) sensory axons and motoneurons (MNs) using two transgenic strains of mice. Deletion of the ErbB2 receptor from developing myotubes disrupts the formation of intrafusal muscle fibers and causes a nearly complete absence of functional synaptic connections between Ia axons and MNs. Monosynaptic connectivity can be fully restored by postnatal administration of neurotrophin-3 (NT-3), and the synaptic connections in NT-3-treated mice are as specific as in wild-type mice. Deletion of the Egr3 transcription factor also impairs the development of intrafusal muscle fibers and disrupts synaptic connectivity between Ia axons and MNs. Postnatal injections of NT-3 restore the normal strengths and specificity of Ia-motoneuronal connections in these mice as well. Severe deficits in intrafusal fiber development, therefore, do not disrupt the establishment of normal, selective patterns of connections between Ia axons and MNs, although these connections require the presence of NT-3, normally supplied by intrafusal fibers, to be functional.

Chondrogenesis by chemotactic homing of synovium, bone marrow, and adipose stem cells in vitro.

Cell transplantation has been well explored for cartilage regeneration. We recently showed that the entire articular surface of a synovial joint can regenerate by endogenous cell homing and without cell transplantation. However, the sources of endogenous cells that regenerate articular cartilage remain elusive. Here, we studied whether cytokines not only chemotactically recruit adipose stem cells (ASCs), mesenchymal stem cells (MSCs), and synovium stem cells (SSCs) but also induce chondrogenesis of the recruited cells. Recombinant human transforming growth factor-ß3 (TGF-ß3; 100 ng) and/or recombinant human stromal derived factor-1ß (SDF-1ß; 100 ng) was control released into an acellular collagen sponge cube with underlying ASCs, MSCs, or SSCs in monolayer culture. Although all cell types randomly migrated into the acellular collagen sponge cube, TGF-ß3 and/or SDF-1ß recruited significantly more cells than the cytokine-free control group. In 6 wk, TGF-ß3 alone recruited substantial numbers of ASCs (558±65) and MSCs (302±52), whereas codelivery of TGF-ß3 and SDF-1ß was particularly chemotactic to SSCs (400±120). Proliferation of the recruited cells accounted for some, but far from all, of the observed cellularity. TGF-ß3 and SDF-1ß codelivery induced significantly higher aggrecan gene expression than the cytokine-free group for ASCs, MSCs, and SSCs. Type II collagen gene expression was also significantly higher for ASCs and SSCs by SDF-1 and TGF-ß3 codelivery. Remarkably, the expression of aggrecan and type II collagen was detected among all cell types. Thus, homing of multiple stem/progenitor cell populations may potentially serve as an alternative or adjunctive approach to cell transplantation for cartilage regeneration.

Persistent restoration of sensory function by immediate or delayed systemic artemin after dorsal root injury.

Dorsal root injury results in substantial and often irreversible loss of sensory functions as a result of the limited regenerative capacity of sensory axons and the inhibitory barriers that prevent both axonal entry into and regeneration in the spinal cord. Here, we describe previously unknown effects of the growth factor artemin after crush injury of the dorsal spinal nerve roots in rats. Artemin not only promoted re-entry of multiple classes of sensory fibers into the spinal cord and re-establishment of synaptic function and simple behavior, but it also, surprisingly, promoted the recovery of complex behavior. These effects occurred after a 2-week schedule of intermittent, systemic administration of artemin and persisted for at least 6 months following treatment, suggesting a substantial translational advantage. Systemic artemin administration produced essentially complete and persistent restoration of nociceptive and sensorimotor functions, and could represent a promising therapy that may effectively promote sensory neuronal regeneration and functional recovery after injury.

Potential of Azadirachta indica as a Capping Agent for Antiviral Nanoparticles against SARS-CoV-2.

A rare type of pneumonia later on referred to as COVID-19 was reported in China in December 2019. Investigations revealed that this disease is caused by a coronavirus previously identified as SARS-CoV-2, and since then, it has become a global pandemic with new strains emerging rapidly as a result of genetic mutations. Various therapeutic options are being explored in order to eradicate this pandemic even though approved vaccine candidates are being currently rolled out globally. Most medicinal plant extracts have astonishing properties, and they can therefore be used in the biosynthesis of effective antiviral nanoparticles. In this systematic review, we aimed to highlight the specific attributes that make Azadirachta indica (neem plant) a suitable candidate for the biosynthesis of anti-SARS-CoV-2 nanoparticles. A systematic investigation was therefore carried out in PubMed, Scopus, Web of Science, and AJOL databases with the keywords "Nanoparticles," "Biosynthesis," "Antivirals," "SARS-CoV-2," and "Azadirachta indica." 1216 articles were retrieved by the 21st of February 2022, but we screened studies that reported data on biomedical and antimicrobial assessment of Azadirachta indica extracts. We also screened studies that were reporting nanoparticles possessing antiviral properties against SARS-C0V-2, narrowing our results to 98 reports. Herein, the SARS-CoV-2 viral structure is briefly discussed with nanoparticles of biomedical importance in the design of SARS-CoV-2 antivirals. Most importantly, we focused on the biomedical and antiviral properties of Azadirachta indica extracts that could be of importance in the design of potential anti-SARS-CoV-2 nanoformulations.

Multiple features that distinguish unilateral incongruity and self-incompatibility in the tomato clade.

Wild tomato species in Solanum Section Lycopersicon often exhibit two types of reproductive barriers: self-incompatibility (SI) and unilateral incompatibility or incongruity (UI), wherein the success of an inter-specific cross depends on the direction of the cross. UI pollen rejection often follows the 'SI × SC' rule, i.e. pistils of SI species reject the pollen of SC (self-compatible) species but not vice versa, suggesting that the SI and UI pollen rejection mechanisms may overlap. In order to address this question, pollen tube growth was measured after inter-specific crosses using wild tomato species as the female parents and pollen from cultivated tomato (Solanum lycopersicum). Two modes of UI pollen rejection, early and late, were observed, and both differed from SI pollen rejection. The structure and expression of known stylar SI genes were evaluated. We found that S-RNase expression is not required for either the early or late mode of UI pollen rejection. However, two HT family genes, HT-A and HT-B, map to a UI QTL. Surprisingly, we found that a gene previously implicated in SI, HT-B, is mutated in both SI and SC S. habrochaites accessions, and no HT-B protein could be detected. HT-A genes were detected and expressed in all species examined, and may therefore function in both SI and UI. We conclude that there are significant differences between SI and UI in the tomato clade, in that pollen tube growth differs between these two rejection systems, and some stylar SI factors, including S-RNase and HT-B, are not required for UI.

Axon guidance in the spinal cord: choosin' by exclusion.

A critical step in the formation of correct patterns of sensory inputs to the spinal cord is the guidance of specific subsets of sensory axons to their appropriate target regions. Yoshida et al. demonstrate in this issue of Neuron that a repulsive interaction between plexinA1 and sema6C/6D prevents the growth of proprioceptive sensory axons into the superficial laminae of the dorsal horn where cutaneous sensory axons terminate.

Blockade of Nogo receptor ligands promotes functional regeneration of sensory axons after dorsal root crush.

A major impediment for regeneration of axons within the CNS is the presence of multiple inhibitory factors associated with myelin. Three of these factors bind to the Nogo receptor, NgR, which is expressed on axons. Administration of exogenous blockers of NgR or NgR ligands promotes the regeneration of descending axonal projections after spinal cord hemisection. A more detailed analysis of CNS regeneration can be made by examining the growth of specific classes of sensory axons into the spinal cord after dorsal root crush injury. In this study, we assessed whether administration of a soluble peptide fragment of the NgR (sNgR) that binds to and blocks all three NgR ligands can promote regeneration after brachial dorsal root crush in adult rats. Intraventricular infusion of sNgR for 1 month results in extensive regrowth of myelinated sensory axons into the white and gray matter of the dorsal spinal cord, but unmyelinated sensory afferents do not regenerate. In concert with the anatomical growth of sensory axons into the cord, there is a gradual restoration of synaptic function in the denervated region, as revealed by extracellular microelectrode recordings from the spinal gray matter in response to stimulation of peripheral nerves. These positive synaptic responses are correlated with substantial improvements in use of the forelimb, as assessed by paw preference, paw withdrawal to tactile stimuli and the ability to grasp. These results suggest that sNgR may be a potential therapy for restoring sensory function after injuries to sensory roots.

Complete Genomic Analysis of VRE From a Cattle Feedlot: Focus on 2 Antibiotic Resistance.

Practices in intensive animal farming such as the extensive use of antimicrobials have significant impacts on the genetic make-up of bacterial communities, especially on that of human/animal commensals. In this report, whole genome sequencing of two vancomycin-resistant enterococci (VRE) isolates from a cattle feedlot in the North West Province, South Africa, was used to highlight the threats that extensive antimicrobial usage in intensive animal rearing represents for environmental microbiomes and the food chain. The genomic DNA of the studied strains was extracted using a DNA extraction kit. Whole-genome sequencing was performed through next-generation sequencing. The genomes of Enterococcus durans strain NWUTAL1 and Enterococcus gallinarum strain S52016 consisted of 3,279,618 and 2,374,946 bp, respectively with G + C contents of 40.76 and 43.13%, respectively. Antibiotic resistance genes (ARG), plasmids and virulence factors (involved in biofilm formation, colonization and copper/silver efflux system), were detected in the genomes of both strains. The presence of these genetic determinants in the studied strains is a cause for concern as they may disseminate and find their way into the food chain via horizontal gene transfer amongst bacteria of the different ecological niches. Issues of this nature cannot be undermined and are relevant as far as food safety is concerned.

Detection of Virulence Genes in Multidrug Resistant Enterococci Isolated from Feedlots Dairy and Beef Cattle: Implications for Human Health and Food Safety.

The misuse/abuse of antibiotics in intensive animal rearing and communities led to the emergence of resistant isolates such as vancomycin-resistant enterococci (VREs) worldwide. This has become a major source of concern for the public health sector. The aim of this study was to report the antibiotic resistance profiles and to highlight the presence of virulence genes in VREs isolated from feedlots cattle of the North-West Province of South Africa. 384 faecal samples, 24 drinking troughs water, and 24 soil samples were collected aseptically from 6 registered feedlots. Biochemical and molecular methods were used to identify and categorise the enterococci isolates. Their antibiotic resistance profiles were assessed and genotypic methods were used to determine their antibiotic resistance and their virulence profiles. 527 presumptive isolates were recovered, out of which 289 isolates were confirmed as Enterococcus sp. Specifically, E. faecalis (9%), E. faecium (10%), E. durans (69%), E. gallinarum (6%), E. casseliflavus (2%), E. mundtii (2%), and E. avium (2%) were screened after molecular assays. VanA (62%), vanB (17%), and vanC (21%) resistance genes were detected in 176 Enterococcus sp., respectively. Moreover, tetK (26), tetL (57), msrA/B (111), and mefA (9) efflux pump genes were detected in 138 VRE isolates. Multiple antibiotic resistances were confirmed in all the VRE isolates of this study; the most common antibiotic resistance phenotype was TETR-AMPR-AMXR-VANR-PENR-LINR-ERYR. CylA, hyl, esp, gelE, and asa1 virulence genes were detected in 86 VREs with the exception of vancomycin-resistant E. mundtii isolates that did not display any virulence factor. Most VRE isolates had more than one virulence genes but the most encountered virulence profile was gelE-hyl. Potentially pathogenic multidrug resistant VREs were detected in this study; this highlights the impact of extensive usage of antimicrobials in intensive animal rearing and its implications on public health cannot be undermined.

Virulence profiles of vancomycin-resistant enterococci isolated from surface and ground water utilized by humans in the North West Province, South Africa: a public health perspective.

Vancomycin-resistant enterococci (VRE) have been responsible for numerous outbreaks of serious infections in humans worldwide. Enterococcus faecium and Enterococcus faecalis are the principal species that are frequently associated with vancomycin resistance determinants, thus usually implicated in hospital- and community-acquired infections in humans. The study aim was to determine the antibiotic resistance and virulence profiles of VREs isolated from surface and groundwater samples that are used by humans in the North West Province, South Africa. A total of 170 water samples were collected and analyzed. Eighty-one potential isolates were screened for characteristics of Enterococcus species using preliminary biochemical tests, PCR assays and sequence analysis. The antimicrobial resistance profiles of the isolates against nine antibiotics were determined and a dendrogram was generated to access the relatedness of the isolates. The isolates were screened for the presence of antibiotic resistance and virulence genes by multiplex PCR analysis. A total of 56 isolates were confirmed as Enterococcus species and the proportion of E. faecium (46.9%) was higher than E. faecalis (29%) and E. saccharolyticus (1.2%). Sequence data of E. faecium, E. faecalis, and E. saccharolyticus isolates revealed 97 to 98% similarities to clinical strains deposited in NCBI Genbank. Large proportions (44; 78.6%) of the isolates were resistant to vancomycin while 16 and 3.6% of the isolates possessed the vanA and vanB genes respectively. The MAR phenotype Vancomycin-Nalidixic Acid-Streptomycin-Chloramphenicol-Ampicillin-Oxytetracycline-Gentamycin-Nitrofurantoin-Sulphamethoxazole indicated that some isolates were resistant to all of the nine antibiotics tested. Cluster analysis of antibiotic resistance data revealed two major clusters. Sixteen (36.4%), 14 (27.3%), 3 (6.8%), and 2 (4.5%) of the VRE isolates possessed the gel, asa1, hyl, and esp virulence genes respectively while the cylA gene was not detected in the study. Multiple antibiotic-resistant enterococci were also resistant to vancomycin and possessed virulence determinants indicating that they can pose severe public health complications on individuals who consume contaminated water.

Prenatal exposure to elevated NT3 disrupts synaptic selectivity in the spinal cord.

Monosynaptic connections between muscle spindle (Ia) afferents and motoneurons (MNs), the central portion of the stretch reflex circuit, are highly specific, but the mechanisms underlying this specificity are primarily unknown. In this study, we report that embryonic overexpression of neurotrophin-3 (NT3) in muscles disrupts the development of these specific Ia-MN connections, using transgenic (mlc/NT3) mice that express elevated levels of NT3 in muscles during development. In mlc/NT3 mice, there is a substantial increase in the amplitudes of monosynaptic EPSPs evoked by Ia afferents in MNs as measured with extracellular recordings from ventral roots. Despite this increased functional projection of Ia afferents, there is no obvious change in the anatomical density of Ia projections into the ventral horn of the spinal cord. Intracellular recordings from MNs revealed a major disruption in the pattern of Ia-MN connections. In addition to the normal connections between Ia afferents and MNs supplying the same muscle, there were also strong monosynaptic inputs from Ia afferents supplying unrelated muscles, which explains the increase seen in extracellular recordings. There was also a large variability in the strength of Ia input to individual MNs, both from correct and incorrect Ia afferents. Postnatal muscular administration of NT3 did not cause these changes in connectivity. These results indicate that prenatal exposure to elevated levels of NT3 disrupts the normal mechanisms responsible for synaptic selectivity in the stretch reflex circuit.