ResearchPad - research-article:-new-research https://www.researchpad.co Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[Vitamin D Supplementation Rescues Aberrant NF-κB Pathway Activation and Partially Ameliorates Rett Syndrome Phenotypes in <i>Mecp2</i> Mutant Mice]]> https://www.researchpad.co/article/elastic_article_13342 Rett syndrome (RTT) is a severe, progressive X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MECP2. We previously identified aberrant NF-κB pathway upregulation in brains of Mecp2-null mice and demonstrated that genetically attenuating NF-κB rescues some characteristic neuronal RTT phenotypes. These results raised the intriguing question of whether NF-κB pathway inhibitors might provide a therapeutic avenue in RTT. Here, we investigate whether the known NF-κB pathway inhibitor vitamin D ameliorates neuronal phenotypes in Mecp2-mutant mice. Vitamin D deficiency is prevalent among RTT patients, and we find that Mecp2-null mice similarly have significantly reduced 25(OH)D serum levels compared with wild-type littermates. We identify that vitamin D rescues aberrant NF-κB pathway activation and reduced neurite outgrowth of Mecp2 knock-down cortical neurons in vitro. Further, dietary supplementation with vitamin D in early symptomatic male Mecp2 hemizygous null and female Mecp2 heterozygous mice ameliorates reduced neocortical dendritic morphology and soma size phenotypes and modestly improves reduced lifespan of Mecp2-nulls. These results elucidate fundamental neurobiology of RTT and provide foundation that NF-κB pathway inhibition might be a therapeutic target for RTT.

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<![CDATA[Reduced TUBA1A Tubulin Causes Defects in Trafficking and Impaired Adult Motor Behavior]]> https://www.researchpad.co/article/elastic_article_8074 Newly born neurons express high levels of TUBA1A α-tubulin to assemble microtubules for neurite extension and to provide tracks for intracellular transport. In the adult brain, Tuba1a expression decreases dramatically. A mouse that harbors a loss-of-function mutation in the gene encoding TUBA1A (Tuba1aND/+) allows us to ask whether TUBA1A is important for the function of mature neurons. α-Tubulin levels are about half of wild type in juvenile Tuba1aND/+ brains, but are close to normal in older animals. In postnatal day (P)0 cultured neurons, reduced TUBA1A allows for assembly of less microtubules in axons resulting in more pausing during organelle trafficking. While Tuba1aND/+ mouse behavior is indistinguishable from wild-type siblings at weaning, Tuba1aND/+ mice develop adult-onset ataxia. Neurons important for motor function in Tuba1aND/+ remain indistinguishable from wild-type with respect to morphology and number and display no evidence of axon degeneration. Tuba1aND/+ neuromuscular junction (NMJ) synapses are the same size as wild-type before the onset of ataxia, but are reduced in size in older animals. Together, these data indicate that the TUBA1A-rich microtubule tracks that are assembled during development are essential for mature neuron function and maintenance of synapses over time.

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<![CDATA[Induction of LTM following an Insulin Injection]]> https://www.researchpad.co/article/elastic_article_8071 The pond snail Lymnaea stagnalis learns conditioned taste aversion (CTA) and consolidates it into long-term memory (LTM). One-day food-deprived snails (day 1 snails) show the best CTA learning and memory, whereas more severely food-deprived snails (5 d) do not express good memory. However, previous studies showed that CTA-LTM was indeed formed in 5-d food-deprived snails (day 5 snails), but its recall was prevented by the effects of food deprivation. CTA-LTM recall in day 5 snails was expressed following 7 d of feeding and then 1 d of food deprivation (day 13 snails). In the present study, we thus hypothesized that memory recall occurs because day 13 snails are in an optimal internal state. One day of food deprivation before the memory test in day 13 snails increased the mRNA level of molluscan insulin-related peptide (MIP) in the CNS. Thus, we further hypothesized that an injection of insulin into day 5 snails following seven additional days with access to food (day 12 snails) activates CTA neurons and mimics the food deprivation state before the memory test in day 13 snails. Day 12 snails injected with insulin could recall the memory. In addition, the simultaneous injection of an anti-insulin receptor antibody and insulin into day 12 snails did not allow memory recall. Insulin injection also decreased the hemolymph glucose concentration. Together, the results suggest that an optimal internal state (i.e., a spike in insulin release and specific glucose levels) are necessary for LTM recall following CTA training in snails.

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<![CDATA[Biophysical Basis of Alpha Rhythm Disruption in Alzheimer’s Disease]]> https://www.researchpad.co/article/elastic_article_8069 Occipital alpha is a prominent rhythm (∼10 Hz) detected in electroencephalography (EEG) during wakeful relaxation with closed eyes. The rhythm is generated by a subclass of thalamic pacemaker cells that burst at the alpha frequency, orchestrated by the interplay of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) and calcium channels in response to elevated levels of ambient acetylcholine (ACh). These oscillations are known to have a lower peak frequency and coherence in the early stages of Alzheimer’s disease (AD). Interestingly, calcium signaling, HCN channel expression and ACh signaling, crucial for orchestrating the alpha rhythm, are also known to be aberrational in AD. In a biophysically detailed network model of the thalamic circuit, we investigate the changes in molecular signaling and the causal relationships between them that lead to a disrupted thalamic alpha in AD. Our simulations show that lowered HCN expression leads to a slower thalamic alpha, which can be rescued by increasing ACh levels, a common therapeutic target of AD drugs. However, this rescue is possible only over a limited range of reduced HCN expression. The model predicts that lowered HCN expression can modify the network activity in the thalamic circuit leading to increased GABA release in the thalamus and disrupt the calcium homeostasis. The changes in calcium signaling make the network more susceptible to noise, causing a loss in rhythmic activity. Based on our results, we propose that reduced frequency and coherence of the occipital alpha rhythm seen in AD may result from downregulated HCN expression, rather than modified cholinergic signaling.

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<![CDATA[EGFR Signaling Causes Morphine Tolerance and Mechanical Sensitization in Rats]]> https://www.researchpad.co/article/elastic_article_8067 The safety and efficacy of opioids are compromised as analgesic tolerance develops. Opioids are also ineffective against neuropathic pain. Recent reports have suggested that inhibitors of the epidermal growth factor receptor (EGFR), a receptor tyrosine kinase (RTK), may have analgesic effects in cancer patients suffering from neuropathic pain. It has been shown that the platelet-derived growth factor receptor-β (PDGFR-β), an RTK that has been shown to interact with the EGFR, mediates opioid tolerance but does not induce analgesia. Therefore, we sought to determine whether EGFR signaling was involved in opioid tolerance and whether EGFR and PDGFR signaling could induce pain in rats. We found that gefitinib, an EGFR antagonist, eliminated morphine tolerance. In addition, repeated EGF administration rendered animals unresponsive to subsequent analgesic doses of morphine, a phenomenon we call “pre-tolerance.” Using a nerve injury model, we found that gefitinib alone was not analgesic. Rather, it reversed insensitivity to morphine analgesia (pre-tolerance) caused by the release of EGF by injured nerves. We also showed that repeated, but not acute EGF or PDGF-BB administration induced mechanical hypersensitivity in rats. EGFR and PDGFR-β signaling interacted to produce this sensitization. EGFR was widely expressed in primary sensory afferent cell bodies, demonstrating a neuroanatomical substrate for our findings. Taken together, our results suggest a direct mechanistic link between opioid tolerance and mechanical sensitization. EGFR antagonism could eventually play an important clinical role in the treatment of opioid tolerance and neuropathic pain that is refractory to opioid treatment.

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<![CDATA[Chronic Activation of Gp1 mGluRs Leads to Distinct Refinement of Neural Network Activity through Non-Canonical p53 and Akt Signaling]]> https://www.researchpad.co/article/elastic_article_8065 Group 1 metabotropic glutamate receptors (Gp1 mGluRs), including mGluR1 and mGluR5, are critical regulators for neuronal and synaptic plasticity. Dysregulated Gp1 mGluR signaling is observed with various neurologic disorders, including Alzheimer’s disease, Parkinson’s disease, epilepsy, and autism spectrum disorders (ASDs). It is well established that acute activation of Gp1 mGluRs leads to elevation of neuronal intrinsic excitability and long-term synaptic depression. However, it remains unknown how chronic activation of Gp1 mGluRs can affect neural activity and what molecular mechanisms might be involved. In the current study, we employed a multielectrode array (MEA) recording system to evaluate neural network activity of primary mouse cortical neuron cultures. We demonstrated that chronic activation of Gp1 mGluRs leads to elevation of spontaneous spike frequency while burst activity and cross-electrode synchronization are maintained at the baseline. We further showed that these neural network properties are achieved through proteasomal degradation of Akt that is dependent on the tumor suppressor p53. Genetically knocking down p53 disrupts the elevation of spontaneous spike frequency and alters the burst activity and cross-electrode synchronization following chronic activation of Gp1 mGluRs. Importantly, these deficits can be restored by pharmacologically inhibiting Akt to mimic inactivation of Akt mediated by p53. Together, our findings reveal the effects of chronic activation of Gp1 mGluRs on neural network activity and identify a unique signaling pathway involving p53 and Akt for these effects. Our data can provide insights into constitutively active Gp1 mGluR signaling observed in many neurologic and psychiatric disorders.

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<![CDATA[Linking Motoneuron PIC Location to Motor Function in Closed-Loop Motor Unit System Including Afferent Feedback: A Computational Investigation]]> https://www.researchpad.co/article/elastic_article_8062 The goal of this study is to investigate how the activation location of persistent inward current (PIC) over motoneuron dendrites is linked to motor output in the closed-loop motor unit. Here, a physiologically realistic model of a motor unit including afferent inputs from muscle spindles was comprehensively analyzed under intracellular stimulation at the soma and synaptic inputs over the dendrites during isometric contractions over a full physiological range of muscle lengths. The motor output of the motor unit model was operationally assessed by evaluating the rate of force development, the degree of force potentiation and the capability of self-sustaining force production. Simulations of the model motor unit demonstrated a tendency for a faster rate of force development, a greater degree of force potentiation, and greater capacity for self-sustaining force production under both somatic and dendritic stimulation of the motoneuron as the PIC channels were positioned farther from the soma along the path of motoneuron dendrites. Interestingly, these effects of PIC activation location on force generation significantly differed among different states of muscle length. The rate of force development and the degree of force potentiation were systematically modulated by the variation of PIC channel location for shorter-than-optimal muscles but not for optimal and longer-than-optimal muscles. Similarly, the warm-up behavior of the motor unit depended on the interplay between PIC channel location and muscle length variation. These results suggest that the location of PIC activation over motoneuron dendrites may be distinctively reflected in the motor performance during shortening muscle contractions.

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<![CDATA[Impaired Motor Recycling during Action Selection in Parkinson’s Disease]]> https://www.researchpad.co/article/elastic_article_8059 Behavioral studies have shown that the human motor system recycles motor parameters of previous actions, such as movement amplitude, when programming new actions. Shifting motor plans toward a new action forms a particularly severe problem for patients with Parkinson’s disease (PD), a disorder that, in its early stage, is dominated by basal ganglia dysfunction. Here, we test whether this action selection deficit in Parkinson’s patients arises from an impaired ability to recycle motor parameters shared across subsequent actions. Parkinson’s patients off dopaminergic medication (n = 16) and matched healthy controls (n = 16) performed a task that involved moving a handheld dowel over an obstacle in the context of a sequence of aiming movements. Consistent with previous research, healthy participants continued making unnecessarily large hand movements after clearing the obstacle (defined as “hand path priming effect”), even after switching movements between hands. In contrast, Parkinson’s patients showed a reduced hand path priming effect, i.e., they performed biomechanically more efficient movements than controls, but only when switching movements between hands. This effect correlated with disease severity, such that patients with more severe motor symptoms had a smaller hand path priming effect. We propose that the basal ganglia mediate recycling of movement parameters across subsequent actions.

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<![CDATA[Propagating Activity in Neocortex, Mediated by Gap Junctions and Modulated by Extracellular Potassium]]> https://www.researchpad.co/article/N979ce65e-e257-454f-9667-068464737f71

Abstract

Parvalbumin-expressing interneurons in cortical networks are coupled by gap junctions, forming a syncytium that supports propagating epileptiform discharges, induced by 4-aminopyridine. It remains unclear, however, whether these propagating events occur under more natural states, without pharmacological blockade. In particular, we investigated whether propagation also happens when extracellular K+ rises, as is known to occur following intense network activity, such as during seizures. We examined how increasing [K+]o affects the likelihood of propagating activity away from a site of focal (200–400 μm) optogenetic activation of parvalbumin-expressing interneurons. Activity was recorded using a linear 16-electrode array placed along layer V of primary visual cortex. At baseline levels of [K+]o (3.5 mm), induced activity was recorded only within the illuminated area. However, when [K+]o was increased above a threshold level (50th percentile = 8.0 mm; interquartile range = 7.5–9.5 mm), time-locked, fast-spiking unit activity, indicative of parvalbumin-expressing interneuron firing, was also recorded outside the illuminated area, propagating at 59.1 mm/s. The propagating unit activity was unaffected by blockade of GABAergic synaptic transmission, but it was modulated by glutamatergic blockers, and was reduced, and in most cases prevented altogether, by pharmacological blockade of gap junctions, achieved by any of the following three different drugs: quinine, mefloquine, or carbenoxolone. Washout of quinine rapidly re-established the pattern of propagating activity. Computer simulations show qualitative differences between propagating discharges in high [K+]o and 4-aminopyridine, arising from differences in the electrotonic effects of these two manipulations. These interneuronal syncytial interactions are likely to affect the complex electrographic dynamics of seizures, once [K+]o is raised above this threshold level.

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<![CDATA[The Epileptor Model: A Systematic Mathematical Analysis Linked to the Dynamics of Seizures, Refractory Status Epilepticus, and Depolarization Block]]> https://www.researchpad.co/article/N538242ca-4a1f-4816-abe7-9afbd7e687e4

Abstract

One characteristic of epilepsy is the variety of mechanisms leading to the epileptic state, which are still largely unknown. Refractory status epilepticus (RSE) and depolarization block (DB) are other pathological brain activities linked to epilepsy, whose patterns are different and whose mechanisms remain poorly understood. In epileptogenic network modeling, the Epileptor is a generic phenomenological model that has been recently developed to describe the dynamics of seizures. Here, we performed a detailed qualitative analysis of the Epileptor model based on dynamical systems theory and bifurcation analysis, and investigate the dynamic evolution of “normal” activity toward seizures and to the pathological RSE and DB states. The mechanisms of the transition between states are called bifurcations. Our detailed analysis demonstrates that the generic model undergoes different bifurcation types at seizure offset, when varying some selected parameters. We show that the pathological and normal activities can coexist within the same model under some conditions, and demonstrate that there are many pathways leading to and away from these activities. We here archive systematically all behaviors and dynamic regimes of the Epileptor model to serve as a resource in the development of patient-specific brain network models, and more generally in epilepsy research.

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<![CDATA[Aging But Not Age-Related Hearing Loss Dominates the Decrease of Parvalbumin Immunoreactivity in the Primary Auditory Cortex of Mice]]> https://www.researchpad.co/article/N025967a7-fa74-44ba-a9c0-fbe5dd9d3ed0 <![CDATA[Extraretinal Spike Normalization in Retinal Ganglion Cell Axons]]> https://www.researchpad.co/article/N92f187e4-0ba5-480d-a35a-41421c5a2bec

Abstract

Spike conduction velocity characteristically differs between myelinated and unmyelinated axons. Here we test whether spikes of myelinated and unmyelinated paths differ in other respects by measuring rat retinal ganglion cell (RGC) spike duration in the intraretinal, unmyelinated nerve fiber layer and the extraretinal, myelinated optic nerve and optic chiasm. We find that rapid spike firing and illumination broaden spikes in intraretinal axons but not in extraretinal axons. RGC axons thus initiate spikes intraretinally and normalize spike duration extraretinally. Additionally, we analyze spikes that were recorded in a previous study of rhesus macaque retinogeniculate transmission and find that rapid spike firing does not broaden spikes in optic tract. The spike normalization we find reduces the number of spike properties that can change during RGC light responses. However, this is not because identical spikes fire in all axons. Instead, our recordings show that different subtypes of RGC generate axonal spikes of different durations and that the differences resemble spike duration increases that alter neurotransmitter release from other neurons. Moreover, previous studies have shown that RGC spikes of shorter duration can fire at higher maximum frequencies. These properties should facilitate signal transfer by different mechanisms at RGC synapses onto subcortical target neurons.

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<![CDATA[An Unexpected Dependence of Cortical Depth in Shaping Neural Responsiveness and Selectivity in Mouse Visual Cortex]]> https://www.researchpad.co/article/N267cf9ce-5fe0-4735-a374-0629094d3f1d

Abstract

Two-photon imaging studies in mouse primary visual cortex (V1) consistently report that around half of the neurons respond to oriented grating stimuli. However, in cats and primates, nearly all neurons respond to such stimuli. Here we show that mouse V1 responsiveness and selectivity strongly depends on neuronal depth. Moving from superficial layer 2 down to layer 4, the percentage of visually responsive neurons nearly doubled, ultimately reaching levels similar to what is seen in other species. Over this span, the amplitude of neuronal responses also doubled. Moreover, stimulus selectivity was also modulated, not only with depth but also with response amplitude. Specifically, we found that orientation and direction selectivity were greater in stronger responding neurons, but orientation selectivity decreased with depth whereas direction selectivity increased. Importantly, these depth-dependent trends were found not just between layer 2/3 and layer 4 but at different depths within layer 2/3 itself. Thus, neuronal depth is an important factor to consider when pooling neurons for population analyses. Furthermore, the inability to drive the majority of cells in superficial layer 2/3 of mouse V1 with grating stimuli indicates that there may be fundamental differences in the micro-circuitry and role of V1 between rodents and other mammals.

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<![CDATA[Cerebral Contribution to the Execution, But Not Recalibration, of Motor Commands in a Novel Walking Environment]]> https://www.researchpad.co/article/N939577c6-9a69-47b0-8b76-b37814c63e4e

Abstract

Human movements are flexible as they continuously adapt to changes in the environment. The recalibration of corrective responses to sustained perturbations (e.g., constant force) altering one’s movement contributes to this flexibility. We asked whether the recalibration of corrective actions involve cerebral structures using stroke as a disease model. We characterized changes in muscle activity in stroke survivors and control subjects before, during, and after walking on a split-belt treadmill moving the legs at different speeds. The recalibration of corrective muscle activity was comparable between stroke survivors and control subjects, which was unexpected given the known deficits in feedback responses poststroke. Also, the intact recalibration in stroke survivors contrasted their limited ability to adjust their muscle activity during steady-state split-belt walking. Our results suggest that the recalibration and execution of motor commands are partially dissociable: cerebral lesions interfere with the execution, but not the recalibration, of motor commands on novel movement demands.

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<![CDATA[Zona Incerta GABAergic Output Controls a Signaled Locomotor Action in the Midbrain Tegmentum]]> https://www.researchpad.co/article/Nd948430f-4158-4075-a037-146b558e6bcc

Abstract

The zona incerta is a subthalamic nucleus proposed to link sensory stimuli with motor responses to guide behavior, but its functional role is not well established. Using mice of either sex, we studied the effect of manipulating zona incerta GABAergic cells on the expression of a signaled locomotor action, known as signaled active avoidance. We found that modulation of GABAergic zona incerta cells, but not of cells in the adjacent thalamic reticular nucleus (NRT), fully controls the expression of signaled active avoidance responses. Inhibition of zona incerta GABAergic cells drives active avoidance responses, while excitation of these cells blocks signaled active avoidance mainly by inhibiting cells in the midbrain pedunculopontine tegmental nucleus (PPT). The zona incerta regulates signaled locomotion in the midbrain.

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<![CDATA[MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System]]> https://www.researchpad.co/article/N6eb84382-0fcb-491e-9b59-8d50a4912c9a

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<![CDATA[Collapsin Response Mediator Protein 4 (CRMP4) Facilitates Wallerian Degeneration and Axon Regeneration following Sciatic Nerve Injury]]> https://www.researchpad.co/article/Nd379ba60-5a3b-45b0-8bd6-4e69e83b3b46

Abstract

In contrast to neurons in the CNS, damaged neurons from the peripheral nervous system (PNS) regenerate, but this process can be slow and imperfect. Successful regeneration is orchestrated by cytoskeletal reorganization at the tip of the proximal axon segment and cytoskeletal disassembly of the distal segment. Collapsin response mediator protein 4 (CRMP4) is a cytosolic phospho-protein that regulates the actin and microtubule cytoskeleton. During development, CRMP4 promotes growth cone formation and dendrite development. Paradoxically, in the adult CNS, CRMP4 impedes axon regeneration. Here, we investigated the involvement of CRMP4 in peripheral nerve injury in male and female Crmp4−/− mice following sciatic nerve injury. We find that sensory axon regeneration and Wallerian degeneration are impaired in Crmp4−/− mice following sciatic nerve injury. In vitro analysis of dissociated dorsal root ganglion (DRG) neurons from Crmp4−/− mice revealed that CRMP4 functions in the proximal axon segment to promote the regrowth of severed DRG neurons and in the distal axon segment where it facilitates Wallerian degeneration through calpain-dependent formation of harmful CRMP4 fragments. These findings reveal an interesting dual role for CRMP4 in proximal and distal axon segments of injured sensory neurons that coordinately facilitate PNS axon regeneration.

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<![CDATA[Signal Propagation via Open-Loop Intrathalamic Architectures: A Computational Model]]> https://www.researchpad.co/article/N1c2c9ddc-5e2b-4a19-bb34-af8dd965a2e9

Abstract

Propagation of signals across the cerebral cortex is a core component of many cognitive processes and is generally thought to be mediated by direct intracortical connectivity. The thalamus, by contrast, is considered to be devoid of internal connections and organized as a collection of parallel inputs to the cortex. Here, we provide evidence that “open-loop” intrathalamic pathways involving the thalamic reticular nucleus (TRN) can support propagation of oscillatory activity across the cortex. Recent studies support the existence of open-loop thalamo-reticulo-thalamic (TC-TRN-TC) synaptic motifs in addition to traditional closed-loop architectures. We hypothesized that open-loop structural modules, when connected in series, might underlie thalamic and, therefore cortical, signal propagation. Using a supercomputing platform to simulate thousands of permutations of a thalamocortical network based on physiological data collected in mice, rats, ferrets, and cats and in which select synapses were allowed to vary both by class and individually, we evaluated the relative capacities of closed-loop and open-loop TC-TRN-TC synaptic configurations to support both propagation and oscillation. We observed that (1) signal propagation was best supported in networks possessing strong open-loop TC-TRN-TC connectivity; (2) intrareticular synapses were neither primary substrates of propagation nor oscillation; and (3) heterogeneous synaptic networks supported more robust propagation of oscillation than their homogeneous counterparts. These findings suggest that open-loop, heterogeneous intrathalamic architectures might complement direct intracortical connectivity to facilitate cortical signal propagation.

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<![CDATA[Proportional Downscaling of Glutamatergic Release Sites by the General Anesthetic Propofol at Drosophila Motor Nerve Terminals]]> https://www.researchpad.co/article/Nc0336880-ed08-4635-a960-a7179c1caa22

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<![CDATA[Does Birth Trigger Cell Death in the Developing Brain?]]> https://www.researchpad.co/article/Nfa4540d2-9af3-4aa5-96be-bf988fcc6bde

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