Inhibitory medial zona incerta pathway drives exploratory behavior by inhibiting glutamatergic cuneiform neurons.

The cuneiform nucleus (CnF) regulates locomotor activity, which is canonically viewed as being primarily involved in initiating locomotion and regulating speed. Recent research shows greater context dependency in the locomotor functions of this nucleus. Glutamatergic neurons, which contain vesicular glutamate transporter 2 (vGLUT2), regulate context-dependent locomotor speed in the CnF and play a role in defensive behavior. Here, we identify projections from the medial zona incerta (mZI) to CnF vGLUT2 neurons that promote exploratory behavior. Using fiber photometry recordings in male mice, we find that mZI gamma-aminobutyric acid (GABA) neurons increase activity during periods of exploration. Activation of mZI GABAergic neurons is associated with reduced spiking of CnF neurons. Additionally, activating both retrogradely labeled mZI-CnF GABAergic projection neurons and their terminals in the CnF increase exploratory behavior. Inhibiting CnF vGLUT2 neuronal activity also increases exploratory behavior. These findings provide evidence for the context-dependent dynamic regulation of CnF vGLUT2 neurons, with the mZI-CnF circuit shaping exploratory behavior.

Mapping nanoscale carrier confinement in polycrystalline graphene by terahertz spectroscopy.

Terahertz time-domain spectroscopy (THz-TDS) can be used to map spatial variations in electrical properties such as sheet conductivity, carrier density, and carrier mobility in graphene. Here, we consider wafer-scale graphene grown on germanium by chemical vapor deposition with non-uniformities and small domains due to reconstructions of the substrate during growth. The THz conductivity spectrum matches the predictions of the phenomenological Drude-Smith model for conductors with non-isotropic scattering caused by backscattering from boundaries and line defects. We compare the charge carrier mean free path determined by THz-TDS with the average defect distance assessed by Raman spectroscopy, and the grain boundary dimensions as determined by transmission electron microscopy. The results indicate that even small angle orientation variations below 5° within graphene grains influence the scattering behavior, consistent with significant backscattering contributions from grain boundaries.

High-throughput gait acquisition system for freely moving mice.

Normal and pathological locomotion can be discriminated by analyzing an animal's gait on a linear walkway. This step is labor intensive and introduces experimental bias due to the handling involved while placing and removing the animal between trials. We designed a system consisting of a runway embedded within a larger arena, which can be traversed ad libitum by unsupervised, freely moving mice, triggering the recording of short clips of locomotor activity. Multiple body parts were tracked using DeepLabCut and fed to an analysis pipeline (GaitGrapher) to extract gait metrics. We compared the results from unsupervised against the standard experimenter-supervised approach and found that gait parameters analyzed via the new approach were similar to a previously validated approach (Visual Gait Lab). These data show the utility of incorporating an unsupervised, automated, approach for collecting kinematic data for gait analysis.NEW & NOTEWORTHY The acquisition and analysis of walkway data is a time-consuming task. Here, we provide an unmonitored approach for collecting gait metrics that reduces the handling and stress of mice and saves time. A detailed pipeline is outlined that provides for the collection and analysis of data using an integrated suite of tools.

Non-Linear Conductivity Response of Graphene on Thin-Film PET Characterized by Transmission and Reflection Air-Plasma THz-TDS.

We demonstrate that the conductivity of graphene on thin-film polymer substrates can be accurately determined by reflection-mode air-plasma-based THz time-domain spectroscopy (THz-TDS). The phase uncertainty issue associated with reflection measurements is discussed, and our implementation is validated by convincing agreement with graphene electrical properties extracted from more conventional transmission-mode measurements. Both the reflection and transmission THz-TDS measurements reveal strong non-linear and instantaneous conductivity depletion across an ultra-broad bandwidth (1-9 THz) under relatively high incident THz electrical field strengths (up to 1050 kV/cm).

Serious adverse events of special interest following mRNA COVID-19 vaccination in randomized trials in adults.

INTRODUCTION: In 2020, prior to COVID-19 vaccine rollout, the Brighton Collaboration created a priority list, endorsed by the World Health Organization, of potential adverse events relevant to COVID-19 vaccines. We adapted the Brighton Collaboration list to evaluate serious adverse events of special interest observed in mRNA COVID-19 vaccine trials. METHODS: Secondary analysis of serious adverse events reported in the placebo-controlled, phase III randomized clinical trials of Pfizer and Moderna mRNA COVID-19 vaccines in adults (NCT04368728 and NCT04470427), focusing analysis on Brighton Collaboration adverse events of special interest. RESULTS: Pfizer and Moderna mRNA COVID-19 vaccines were associated with an excess risk of serious adverse events of special interest of 10.1 and 15.1 per 10,000 vaccinated over placebo baselines of 17.6 and 42.2 (95 % CI -0.4 to 20.6 and -3.6 to 33.8), respectively. Combined, the mRNA vaccines were associated with an excess risk of serious adverse events of special interest of 12.5 per 10,000 vaccinated (95 % CI 2.1 to 22.9); risk ratio 1.43 (95 % CI 1.07 to 1.92). The Pfizer trial exhibited a 36 % higher risk of serious adverse events in the vaccine group; risk difference 18.0 per 10,000 vaccinated (95 % CI 1.2 to 34.9); risk ratio 1.36 (95 % CI 1.02 to 1.83). The Moderna trial exhibited a 6 % higher risk of serious adverse events in the vaccine group: risk difference 7.1 per 10,000 (95 % CI -23.2 to 37.4); risk ratio 1.06 (95 % CI 0.84 to 1.33). Combined, there was a 16 % higher risk of serious adverse events in mRNA vaccine recipients: risk difference 13.2 (95 % CI -3.2 to 29.6); risk ratio 1.16 (95 % CI 0.97 to 1.39). DISCUSSION: The excess risk of serious adverse events found in our study points to the need for formal harm-benefit analyses, particularly those that are stratified according to risk of serious COVID-19 outcomes. These analyses will require public release of participant level datasets.

Chemical Vapor-Deposited Graphene on Ultraflat Copper Foils for van der Waals Hetero-Assembly.

The purity and morphology of the copper surface is important for the synthesis of high-quality, large-grained graphene by chemical vapor deposition. We find that atomically smooth copper foils-fabricated by physical vapor deposition and subsequent electroplating of copper on silicon wafer templates-exhibit strongly reduced surface roughness after the annealing of the copper catalyst, and correspondingly lower nucleation and defect density of the graphene film, when compared to commercial cold-rolled copper foils. The "ultrafoils"-ultraflat foils-facilitate easier dry pickup and encapsulation of graphene by hexagonal boron nitride, which we believe is due to the lower roughness of the catalyst surface promoting a conformal interface and subsequent stronger van der Waals adhesion between graphene and hexagonal boron nitride.

Benchtop Evaluation of Miniature Percutaneous Nephrolithotomy Lithotrites.

Introduction: Percutaneous nephrolithotomy (PCNL) is the preferred treatment for kidney stones >2 cm. While PCNL has traditionally been performed using 24F to 30F access sheaths, there is a trend toward smaller sheaths and scopes to perform mini-PCNL (mPCNL). We performed benchtop assessment of multiple mPCNL lithotrites. Methods: One 1 cm3, hard Begostone phantom was placed in a cylinder with four 5.5 mm cylindrical openings to simulate the size of a 16.5F mPCNL sheath. Lithotripsy was performed with the 1.5 and 1.9 mm Trilogy, 1.83 mm ShockPulse, or a 200 µm Holmium:YAG (Ho:YAG) laser. Suction was used for the mechanical lithotrites. The Trilogy probes were set at 50% impact, 6 Hz, 80% ultrasound and 10% suction. The ShockPulse was used at high-power setting with low suction. The 1.9 mm Trilogy probe was used with a 15F mini-nephroscope. The 1.83 mm ShockPulse, 1.5 mm Trilogy and laser fiber were used with a 12F mini-nephroscope. The 120 W holmium laser was set at 0.5 J/70 Hz Moses-Distance. Ten independent runs were performed with modality. Time to complete stone clearance was recorded and mass stone clearance rates were calculated. Results: The Trilogy 1.9 mm showed superior stone clearance rate (11.69 ± 3.68 mg/s) vs the ShockPulse (SP) 1.83 mm (6.29 ± 1.37 mg/s, p = 0.003), the laser fiber (4.73 ± 0.61 mg/s, p < 0.0005), and the Trilogy 1.5 mm (6.84 ± 1.21 mg/s). The 200 µm laser fiber was inferior to all mechanical lithotrites. There was no difference between the 1.5 mm Trilogy and the 1.83 mm ShockPulse (p = 0.772). This translates to 3.9, 4.8, and 8.1 minutes less treatment time vs the 1.5 mm Trilogy, SP, and laser, respectively, for a spherical 1.5 cm diameter calcium oxalate monohydrate stone. Conclusion: Among these four commonly used mPCNL lithotripters, the Trilogy 1.9 mm demonstrated superior stone clearance rates in this benchtop model vs the Ho:YAG laser, 1.83 mm SP, and Trilogy 1.5 mm. Future clinical testing is warranted to evaluate the optimal lithotrite for mPCNL.

The Mesencephalic Locomotor Region: Beyond Locomotor Control.

The mesencephalic locomotor region (MLR) was discovered several decades ago in the cat. It was functionally defined based on the ability of low threshold electrical stimuli within a region comprising the cuneiform and pedunculopontine nucleus to evoke locomotion. Since then, similar regions have been found in diverse vertebrate species, including the lamprey, skate, rodent, pig, monkey, and human. The MLR, while often viewed under the lens of locomotion, is involved in diverse processes involving the autonomic nervous system, respiratory system, and the state-dependent activation of motor systems. This review will discuss the pedunculopontine nucleus and cuneiform nucleus that comprises the MLR and examine their respective connectomes from both an anatomical and functional angle. From a functional perspective, the MLR primes the cardiovascular and respiratory systems before the locomotor activity occurs. Inputs from a variety of higher structures, and direct outputs to the monoaminergic nuclei, allow the MLR to be able to respond appropriately to state-dependent locomotion. These state-dependent effects are roughly divided into escape and exploratory behavior, and the MLR also can reinforce the selection of these locomotor behaviors through projections to adjacent structures such as the periaqueductal gray or to limbic and cortical regions. Findings from the rat, mouse, pig, and cat will be discussed to highlight similarities and differences among diverse species.

Investigating Risk Factors for Urine Culture Contamination in Outpatient Clinics: A New Avenue for Diagnostic Stewardship.

Mixed flora in urine cultures usually occur due to pre-analytic contamination. In our outpatient urology clinic, we found a high prevalence of mixed flora (46.2%), which was associated with female sex and older age. Patient education did not impact the rate of mixed flora. Future efforts should target high-risk patients.

Hop Mice Display Synchronous Hindlimb Locomotion and a Ventrally Fused Lumbar Spinal Cord Caused by a Point Mutation in Ttc26.

Identifying the spinal circuits controlling locomotion is critical for unravelling the mechanisms controlling the production of gaits. Development of the circuits governing left-right coordination relies on axon guidance molecules such as ephrins and netrins. To date, no other class of proteins have been shown to play a role during this process. Here, we have analyzed hop mice, which walk with a characteristic hopping gait using their hindlimbs in synchrony. Fictive locomotion experiments suggest that a local defect in the ventral spinal cord contributes to the aberrant locomotor phenotype. Hop mutant spinal cords had severe morphologic defects, including the absence of the ventral midline and a poorly defined border between white and gray matter. The hop mice represent the first model where, exclusively found in the lumbar domain, the left and right components of the central pattern generators (CPGs) are fused with a synchronous hindlimb gait as a functional consequence. These defects were associated with abnormal developmental processes, including a misplaced notochord and reduced induction of ventral progenitor domains. Whereas the underlying mutation in hop mice has been suggested to lie within the Ttc26 gene, other genes in close vicinity have been associated with gait defects. Mouse embryos carrying a CRISPR replicated point mutation within Ttc26 displayed an identical morphologic phenotype. Thus, our data suggest that the assembly of the lumbar CPG network is dependent on fully functional TTC26 protein.

Comparison of Different Pulse Modulation Modes for Holmium:Yttrium-Aluminum-Garnet Laser Lithotripsy Ablation in a Benchtop Model.

Introduction: Manipulation of Holmium:Yttrium-Aluminum-Garnet laser parameters such as pulse energy (PE), frequency, and duration can impact laser lithotripsy ablation efficiency. In 2017, Lumenis introduced Moses™ Technology, which uses pulse modulation to enhance the delivery of energy from fiber to stone as well as to minimize stone retropulsion. Since the introduction of Moses Technology, other companies have brought additional pulse modulation concepts to market. The purpose of this in vitro study is to compare the pulse characteristics and stone ablation efficiency of Lumenis Moses Technology with Quanta's Vapor Tunnel™. Materials and Methods: Submerged BegoStone phantoms were systematically ablated using either the Lumenis Moses Pulse 120H or the Quanta Litho 100 clinical laser system. Two PEs (0.4 and 1 J), three fiber-stone standoff distances (SDs) (0.5, 1, 2 mm), and all available pulse duration and modulation modes for each laser were tested in combination. Fiber speed was adjusted to scan across the stone surface at either 1 or 10 pulses/mm to form single pulse craters or an ablation trough, respectively. Volumes of single craters and 1 mm trough segments were imaged and quantified using optical coherence tomography. Results: Ablation volumes decreased with decreasing PE and increasing SD. Statistically significant variability was seen between pulse types (PT) at every tested parameter set. Among pulse modulation modes, Moses Distance (MD) was superior at 0.5 mm in all testing and at 2 mm in trough testing. Vapor Tunnel (VT) was superior in 2 mm single crater testing. All modulated pulses performed similarly at 1 mm. Conclusions: In this benchtop model of laser lithotripsy, stone ablation was significantly impacted by PT. MD demonstrated superior or noninferior stone ablation at most tested parameters. VT maintained its efficacy the best as SD increased. Future work should focus on the mechanistic differences of these modes relative to other traditional laser pulse modes.

Evolution of Single-Use Urologic Endoscopy: Benchtop and Initial Clinical Assessment of a New Single-Use Flexible Cystoscope.

Introduction: Office cystoscopy is one of the most frequently performed procedures by a urologist. However, single-use cystoscopes remain quite undeveloped. Ambu® has developed single-use broncoscopes, rhinolaryngoscopes, and duodenoscopes. Recently, they released a single-use cystoscope. In this study, we performed a benchtop and an initial clinical assessment of the Ambu aScope™ (4) Cysto (aS4C) single-use cystoscope. Materials and Methods: Ten new, never-used aS4C single-use cystoscopes were assessed for optical performance, maximal tip flexion, and irrigation flow rate with empty working channel, 365 µm laser fiber, 0.035 in hydrophilic-tipped wire, 1.9F nitinol basket, and a 1.8 mm flexible stent grasper. All cystoscopes were then fully flexed 25 times in each direction, and maximal flexion angles were remeasured with and without instruments. Optical resolution, distortion, and depth of field were measured and compared with our reusable digital flexible cystoscopes. Assessment of clinical use was performed for inpatient bedside procedures using a Likert feedback survey and the NASA Task Load Index. Results: Maximal upward flexion exceeded 200° and 160° for all working instruments in upward and downward flexion. Downward flexion demonstrated different flexion between instrument groups in pre- and postcycling (p < 0.001). There was no clinical difference between the pre- and postcycling flexion. Flow rate decreased with increasing working instrument size (p < 0.001). The Olympus HD cystoscope resolution was superior at 3 and 5 mm distance, but not at other distances. The Ambu scope was superior to the Olympus SD scope at all distances except 3 mm. The aS4C had higher Likert scale survey scores for clinical use. Conclusions: The new Ambu single-use cystoscope demonstrates good flexion across instruments and comparable optics with reusable cystoscopes. In addition, initial inpatient bedside use of the aS4C and Monitor system compares favorably with the Olympus reusable cystoscope. Further testing in clinical scenarios such as hematuria, urothelial carcinoma, and operative endoscopy is warranted.

The histologic and molecular correlates of COVID-19 vaccine-induced changes in the skin.

A total of 22 patients who had developed an adverse cutaneous reaction to the Moderna or Pfizer vaccine underwent biopsies. Each patient was assessed light microscopically, and, in select biopsies, spike glycoprotein and cytokine assessment were also conducted. The patients developed self-limited cutaneous reactions often described clinically as urticarial or eczematous within 1 day to 4 weeks after receiving the first or second dose of the Pfizer or Moderna vaccine. Classic clinical and morphologic depictions of type IV cutaneous hypersensitivity with features of eczematous dermatitis, interface dermatitis, granulomatous inflammation, and/or lymphocytic vasculitic component were observed. Clinical and/or histologic features of perniosis, pityriasis rosea, pityriasis rubra pilaris, and guttate psoriasis were seen in select cases. In 2 cases the dominant picture was urticarial vasculitis, possibly reflective of an Arthus type III immune complex action. The biopsy specimens of normal skin post vaccine and of skin affected by the post-vaccine eruption showed rare deep microvessels positive for spike glycoprotein with no complement deposition contrasting with greater vascular deposition of spike protein and complement in skin biopsies from patients experiencing severe coronavirus disease 2019 (COVID-19). It is concluded that self-limited hypersensitivity reactions to the vaccine occur possibly owing to a substance found in the vaccine vehicle (eg, polyethylene glycol). An immune response that is directed against human-manufactured spike has to be considered because some of the reactions clinically and or histologically closely resemble mild COVID-19. Finally, vaccine-associated immune enhancement largely attributable to the adjuvant properties of the vaccine may unmask certain inflammatory milieus operational in psoriasis, atopic dermatitis, and subclinical hypersensitivity.

Long-term stability and tree-ring oxidation of WSe2 using phase-contrast AFM.

In this work, we use atomic force microscopy (AFM) to investigate the long-term evolution of oxidative defects of tungsten diselenide (WSe2) in ambient conditions over a period of 75 months, which is the longest such study performed on any layered material. In particular, we find that phase-imaging AFM of mechanically exfoliated WSe2 crystals provides convenient, direct identification of exposed and covered step-edges, and together with topographic thickness measurements allows complete determination of the layer arrangement in a multilayer flake. Step-edges with low or no phase-contrast consistently exhibit long-term stability in ambient conditions, indicating that they are covered and effectively protected by above-lying WSe2 layers. On the contrary, step-edges with initial high phase-contrast are clearly degraded after medium- to long-term exposure to ambient conditions (up to six months), indicating that these are not covered by other layers. Similar behaviour was observed for MoTe2 and MoS2. The correlation between phase-contrast and step order was confirmed by cross-sectional transmission electron microscopy. By comparing the phase-contrast line-traces in different locations and at different times, we find that long-term storage in ambient conditions led to evolution of a distinct ring-like pattern resembling the tree-lines arising from seasonal changes. Indeed the phase-contrast showed correlation with the average amount of sun-hours registered at the storage location. Storage in darkness slowed down the evolution of the tree-ring lines, in accordance with this explanation. Our work provides a unique dataset on long-term degradation of one of the most stable transition metal dichalcogenides, as well as insights into the conditions causing acceleration or inhibition of the degradation process.

Benchtop Assessment of a New Single-Use Flexible Ureteroscope.

Introduction: Single-use flexible ureteroscopes are an increasingly popular alternative to reusable ureteroscopes. In this study, we performed a benchtop examination of the physical and optical properties of the new Dornier Axis™ (Webling, Germany) single-use ureteroscope. Methods: Ten new, never-used Dornier Axis ureteroscopes were assessed for optical performance, maximal tip deflection, and irrigation flow rate with an empty working channel and with insertion of 200 and 365 µm laser fibers, and a 1.9F nitinol basket. All ureteroscopes were then fully deflected 100 times in each direction, and maximal deflection angles were re-measured with and without instruments in the working channel. All measurements were performed in duplicate. In vitro optical testing for resolution, image distortion, and depth of field was performed and compared vs the LithoVue™ (Boston Scientific, Marlborough, MA) single-use ureteroscope. Statistical analyses using paired Wilcoxon rank-sum tests and Kruskal-Wallis multiple-group comparison tests were performed in R. Results: Median maximal deflection angles exceeded 300° in both directions before and after 100 full deflection cycles for all groups except the 365 µm laser fiber group. After 100 deflection cycles, there was no change in the majority of working instruments, except a decrease in upward flexion with an empty channel and 200 µm Moses™ laser fiber, and downward flexion with 200 µm Flexiva™ laser fiber (all <10°). After excluding the 365 µm fiber, there was no difference in multi-group comparison for upward and downward flexion pre- and post-cycling. Median flow rate through an empty channel was 48.0 mL/min, and it decreased significantly with all used instruments (p < 0.001). Compared with the LithoVue, the Axis demonstrated superior resolution at all tested distances and less distortion. Conclusions: The new Dornier Axis single-use ureteroscope demonstrates excellent tip deflection, which remains unchanged after 100 manual flexions in each direction. The Axis also demonstrates superior optical performance compared with the LithoVue in benchtop testing.

The Use of Serum Procalcitonin in the Setting of Infected Ureteral Stones: A Prospective Observational Study.

Introduction: Infected ureteral stones are a urologic emergency and require urgent decompression. We set out to determine whether serum procalcitonin (PCT) could aid in the diagnosis of infected ureteral stones. Methods: All consecutive patients presenting to the emergency room from November 9, 2016, to November 10, 2018, with an obstructing ureteral stone were included. All patients had complete blood count, urinalysis (UA), PCT, and urine culture (UCx). Subgroup analysis was performed in a "clinically equivocal" cohort of afebrile patients defined as a leukocytosis >104/µL and UA with <50 white blood cells (WBCs) per high powered field (hpf). Patients with positive and negative UCx were compared. Results: A total of 231 patients were included, of whom 56 had a positive UCx. Of all covariates, UA WBCs with a cutoff of 9 per hpf performed best at predicting positive UCx with an area under the curve (AUC) of 0.87. PCT did not perform as well with an ideal cutoff of 0.08 ng/mL, having an AUC of 0.77, sensitivity 70.6%, specificity 73.9%, positive predictive value (PPV) 34.3%, and negative predictive value (NPV) 92.9%. When looking at the clinically equivocal cohort, UA WBCs with a cutoff of 6 per hpf appeared to perform best at predicting a positive UCx with an AUC of 0.72. PCT was less predictive in this cohort with an ideal cutoff of 0.3 ng/mL, having an AUC of 0.32, sensitivity 47.1%, specificity 85.2%, PPV 38.1%, and NPV 89.3%. Conclusion: PCT does not appear to be a superior marker for diagnosing urinary tract infection in the setting of obstructing ureterolithiasis when compared with components of the standard work-up.

Contributions of h- and Na+/K+ Pump Currents to the Generation of Episodic and Continuous Rhythmic Activities.

Developing spinal motor networks produce a diverse array of outputs, including episodic and continuous patterns of rhythmic activity. Variation in excitability state and neuromodulatory tone can facilitate transitions between episodic and continuous rhythms; however, the intrinsic mechanisms that govern these rhythms and their transitions are poorly understood. Here, we tested the capacity of a single central pattern generator (CPG) circuit with tunable properties to generate multiple outputs. To address this, we deployed a computational model composed of an inhibitory half-center oscillator (HCO). Following predictions of our computational model, we tested the contributions of key properties to the generation of an episodic rhythm produced by isolated spinal cords of the newborn mouse. The model recapitulates the diverse state-dependent rhythms evoked by dopamine. In the model, episodic bursting depended predominantly on the endogenous oscillatory properties of neurons, with Na+/K+ ATPase pump (I Pump) and hyperpolarization-activated currents (I h ) playing key roles. Modulation of either I Pump or I h produced transitions between episodic and continuous rhythms and silence. As maximal activity of I Pump decreased, the interepisode interval and period increased along with a reduction in episode duration. Decreasing maximal conductance of I h decreased episode duration and increased interepisode interval. Pharmacological manipulations of I h with ivabradine, and I Pump with ouabain or monensin in isolated spinal cords produced findings consistent with the model. Our modeling and experimental results highlight key roles of I h and I Pump in producing episodic rhythms and provide insight into mechanisms that permit a single CPG to produce multiple patterns of rhythmicity.

A dynamic role for dopamine receptors in the control of mammalian spinal networks.

Dopamine is well known to regulate movement through the differential control of direct and indirect pathways in the striatum that express D1 and D2 receptors respectively. The spinal cord also expresses all dopamine receptors; however, how the specific receptors regulate spinal network output in mammals is poorly understood. We explore the receptor-specific mechanisms that underlie dopaminergic control of spinal network output of neonatal mice during changes in spinal network excitability. During spontaneous activity, which is a characteristic of developing spinal networks operating in a low excitability state, we found that dopamine is primarily inhibitory. We uncover an excitatory D1-mediated effect of dopamine on motoneurons and network output that also involves co-activation with D2 receptors. Critically, these excitatory actions require higher concentrations of dopamine; however, analysis of dopamine concentrations of neonates indicates that endogenous levels of spinal dopamine are low. Because endogenous levels of spinal dopamine are low, this excitatory dopaminergic pathway is likely physiologically-silent at this stage in development. In contrast, the inhibitory effect of dopamine, at low physiological concentrations is mediated by parallel activation of D2, D3, D4 and α2 receptors which is reproduced when endogenous dopamine levels are increased by blocking dopamine reuptake and metabolism. We provide evidence in support of dedicated spinal network components that are controlled by excitatory D1 and inhibitory D2 receptors that is reminiscent of the classic dopaminergic indirect and direct pathway within the striatum. These results indicate that network state is an important factor that dictates receptor-specific and therefore dose-dependent control of neuromodulators on spinal network output and advances our understanding of how neuromodulators regulate neural networks under dynamically changing excitability.