Stimulation of the subparafascicular thalamic nucleus modulates dopamine release in the inferior colliculus of rats.

Although dopamine is commonly studied for its role in incentive motivation, cognition, and various neuropsychiatric disorders, evidence from Parkinson's disease (PD) patients that present auditory deficits suggest that dopamine is also involved in central auditory processing. It has been recently discovered that the subparafascicular thalamic nucleus (SPF) sends dopaminergic projections to the inferior colliculus (IC), an important convergence hub for the ascending and descending auditory pathways. In the present study, our aim was to provide neurochemical evidence that activation of SPF neurons evokes dopamine release in the IC of anesthetized rats using fast-scan cyclic and paired pulse voltammetry in combination with carbon fiber microelectrodes.

Antiviral Protection via RdRP-Mediated Stable Activation of Innate Immunity.

For many emerging and re-emerging infectious diseases, definitive solutions via sterilizing adaptive immunity may require years or decades to develop, if they are even possible. The innate immune system offers alternative mechanisms that do not require antigen-specific recognition or a priori knowledge of the causative agent. However, it is unclear whether effective stable innate immune system activation can be achieved without triggering harmful autoimmunity or other chronic inflammatory sequelae.

Wireless control of intraspinal microstimulation in a rodent model of paralysis.

Object: Despite a promising outlook, existing intraspinal microstimulation (ISMS) techniques for restoring functional motor control after spinal cord injury are not yet suitable for use outside a controlled laboratory environment. Thus, successful application of ISMS therapy in humans will require the use of versatile chronic neurostimulation systems. The objective of this study was to establish proof of principle for wireless control of ISMS to evoke controlled motor function in a rodent model of complete spinal cord injury.

Frequency-dependent functional neuromodulatory effects on the motor network by ventral lateral thalamic deep brain stimulation in swine.

Thalamic deep brain stimulation (DBS) is an FDA-approved neurosurgical treatment for medication-refractory essential tremor. Its therapeutic benefit is highly dependent upon stimulation frequency and voltage parameters. We investigated these stimulation parameter-dependent effects on neural network activation by performing functional magnetic resonance imaging (fMRI) during DBS of the ventral lateral (VL) thalamus and comparing the blood oxygenation level-dependent (BOLD) signals induced by multiple stimulation parameter combinations in a within-subject study of swine.

A neurochemical closed-loop controller for deep brain stimulation: toward individualized smart neuromodulation therapies.

Current strategies for optimizing deep brain stimulation (DBS) therapy involve multiple postoperative visits. During each visit, stimulation parameters are adjusted until desired therapeutic effects are achieved and adverse effects are minimized. However, the efficacy of these therapeutic parameters may decline with time due at least in part to disease progression, interactions between the host environment and the electrode, and lead migration.

Implementation of a chronic unilateral intraparenchymal drug delivery system in a swine model.

Background: Systemic delivery of pharmacologic agents has led to many significant advances in the treatment of neurologic and psychiatric conditions. However, this approach has several limitations, including difficulty penetrating the blood-brain barrier and enzymatic degradation prior to reaching its intended target. Here, we describe the testing of a system allowing intraparenchymal (IPa) infusion of therapeutic agents directly to the appropriate anatomical targets, in a swine model.

Large animal model for development of functional restoration paradigms using epidural and intraspinal stimulation.

Restoration of movement following spinal cord injury (SCI) has been achieved using electrical stimulation of peripheral nerves and skeletal muscles. However, practical limitations such as the rapid onset of muscle fatigue hinder clinical application of these technologies. Recently, direct stimulation of alpha motor neurons has shown promise for evoking graded, controlled, and sustained muscle contractions in rodent and feline animal models while overcoming some of these limitations.

Quantitative trait loci analysis reveals candidate genes implicated in regulating functional deficit and CNS vascular permeability in CD8 T cell-initiated blood-brain barrier disruption.

Background: Blood-brain barrier (BBB) disruption is an integral feature of numerous neurological disorders. However, there is a relative lack of knowledge regarding the underlying molecular mechanisms of immune-mediated BBB disruption. We have previously shown that CD8 T cells and perforin play critical roles in initiating altered permeability of the BBB in the peptide-induced fatal syndrome (PIFS) model developed by our laboratory.

Wireless neurochemical monitoring in humans.

Electrochemical techniques have long been utilized to investigate chemical changes in the neuronal microenvironment. Preclinical models have demonstrated the successful monitoring of changes in various neurotransmitter systems in vivo with high temporal and spatial resolution. The expansion of electrochemical recording to humans is a critical yet challenging goal to elucidate various aspects of human neurophysiology and to create future therapies.

A novel and selective poly (ADP-ribose) polymerase inhibitor ameliorates chemotherapy-induced painful neuropathy.

Background: Chemotherapy-induced neuropathy is the principle dose limiting factor requiring discontinuation of many chemotherapeutic agents, including cisplatin and oxaliplatin. About 30 to 40% of patients receiving chemotherapy develop pain and sensory changes. Given that poly (ADP-ribose) polymerase (PARP) inhibition has been shown to provide neuroprotection, the current study was developed to test whether the novel PARP inhibitor compound 4a (analog of ABT-888) would attenuate pain in cisplatin and oxaliplatin-induced neuropathy in mice.

Therapeutics to promote CNS repair: a natural human neuron-binding IgM regulates membrane-raft dynamics and improves motility in a mouse model of multiple sclerosis.

We have discovered a role for natural autoantibodies in central nervous system repair, remyelination and axon protection. These natural human antibodies are of the immunoglobulin M (IgM) isotype, and they bind to the surface of neural cells. The epitope of the antibody includes sialic acid because treatment with sialidase disrupts the binding.

Allurin, an amphibian sperm chemoattractant having implications for mammalian sperm physiology.

Eggs of many species are surrounded by extracellular coats that emit ligands to which conspecific sperm respond by undergoing chemotaxis and changes in metabolism, motility, and acrosomal status in preparation for fertilization. Here we review methods used to measure sperm chemotaxis and focus on recent studies of allurin, a 21-kDa protein belonging to the Cysteine-RIch Secretory Protein (CRISP) family that has chemoattraction activity for both amphibian and mammalian sperm. Allurin is unique in being the first extensively characterized Crisp protein found in the female reproductive tract and is the product of a newly discovered amphibian gene within a gene cluster that has been largely conserved in mammals.

Deletion of beta-2-microglobulin ameliorates spinal cord lesion load and promotes recovery of brainstem NAA levels in a murine model of multiple sclerosis.

We used genetic deletion of β2-microglobulin to study the influence of CD8(+) T cells on spinal cord demyelination, remyelination, axonal loss and brainstem N-acetyl aspartate levels during the acute and chronic phases of Theiler's murine encephalomyelitis virus (TMEV) infection. We used β2m(-/-) and β2m(+/+) B10.Q mice (of H-2(q) background) normally susceptible to TMEV-induced demyelination.

Mouse sperm exhibit chemotaxis to allurin, a truncated member of the cysteine-rich secretory protein family.

Allurin, a 21 kDa protein isolated from egg jelly of the frog Xenopus laevis, has previously been demonstrated to attract frog sperm in two-chamber and microscopic assays. cDNA cloning and sequencing has shown that allurin is a truncated member of the Cysteine-Rich Secretory Protein (CRISP) family, whose members include mammalian sperm-binding proteins that have been postulated to play roles in spermatogenesis, sperm capacitation and sperm-egg binding in mammals. Here, we show that allurin is a chemoattractant for mouse sperm, as determined by a 2.

Evidence for the role of B cells and immunoglobulins in the pathogenesis of multiple sclerosis.

The pathogenesis of multiple sclerosis (MS) remains elusive. Recent reports advocate greater involvement of B cells and immunoglobulins in the initiation and propagation of MS lesions at different stages of their ontogeny. The key role of B cells and immunoglobulins in pathogenesis was initially identified by studies in which patients whose fulminant attacks of demyelination did not respond to steroids experienced remarkable functional improvement following plasma exchange.

A human IgM signals axon outgrowth: coupling lipid raft to microtubules.

Mouse and human IgMs support neurite extension from primary cerebellar granule neurons. In this study using primary hippocampal and cortical neurons, we demonstrate that a recombinant human IgM, rHIgM12, promotes axon outgrowth by coupling membrane domains (lipid rafts) to microtubules. rHIgM12 binds to the surface of neuron and induces clustering of cholesterol and ganglioside GM1.

Swimming of Xenopus laevis sperm exhibits multiple gears and its duration is extended by egg jelly constituents.

The motility of Xenopus sperm is initiated by the osmotic shock experienced when these cells are ejaculated into low-salinity pond water. Motility is brief and is required for the sperm to penetrate the jelly layers and fertilize the egg. In this study we demonstrate that extracts of egg jelly contain factors that extend the period of sperm motility as well as providing a chemoattractant activity as previously reported.

Enhancing CNS repair in neurological disease: challenges arising from neurodegeneration and rewiring of the network.

Repair of the central nervous system (CNS) constitutes an integral part of treating neurological disease and plays a crucial role in restoring CNS architecture and function. Distinct strategies have been developed to reconstruct the damaged neural tissue, with many tested preclinically in animal models. We review cell replacement-based repair strategies.

Egg jelly proteins stimulate directed motility in Xenopus laevis sperm.

Previously we have shown that extracts from Xenopus egg jelly (egg water) increase the passage of sperm through a porous membrane in a dose-dependent manner. Although this assay has shown that sperm accumulation occurs only in the presence of an egg water gradient, it has not revealed the dynamic features of how Xenopus sperm swim in such gradients. Here, we use video microscopic observations to trace sperm trajectories in a Zigmond chamber.

Autoantibodies with enzymatic properties in human autoimmune diseases.

Immunoglobulins (Ig) or antibodies are heavy plasma proteins, with sugar chains added to amino acid residues by N-linked glycosylation and occasionally by O-linked glycosylation. The versatility of antibodies is demonstrated by the various functions that they mediate such as neutralization, agglutination, fixation with activation of complement and activation of effector cells. In addition to this plethora of functions, some antibodies express enzymatic activity.

Drosophila melanogaster: a new model to study cisplatin-induced neurotoxicity.

Platinum-based compounds are widely used and effective chemotherapeutic agents; however, sensory peripheral neuropathy is a dose-limiting and long term side effect for 20-30% of patients. A critical question is whether the mechanisms of cell death underlying clinical efficacy can be separated from the effects on neurons in order to develop strategies that prevent platinum-induced neuropathy. In rodent dorsal root ganglion neurons (DRG), cisplatin has been shown to bind and damage neuronal DNA, inducing apoptosis; however genetic manipulation in order to study mechanisms of this phenomenon in the rodent model system is costly and time-consuming.

Transgenic expression of viral capsid proteins predisposes to axonal injury in a murine model of multiple sclerosis.

We used transgenic expression of capsid antigens to Theiler's murine encephalomyelitis virus (TMEV) to study the influence of VP1, VP2 or VP2(121-130) to either protection or pathogenesis to chronic spinal cord demyelination, axonal loss and functional deficits during the acute and chronic phases of infection. We used both mice that are normally susceptible (FVB) and mice normally resistant (FVB.D(b) ) to demyelination.

The relevance of animal models in multiple sclerosis research.

Multiple Sclerosis (MS) is a complex disease with an unknown etiology and no effective cure, despite decades of extensive research that led to the development of several partially effective treatments. Researchers have only limited access to early and immunologically active MS tissue samples, and the modification of experimental circumstances is much more restricted in human studies compared to studies in animal models. For these reasons, animal models are needed to clarify the underlying immune-pathological mechanisms and test novel therapeutic and reparative approaches.

Transient Receptor Potential Vanilloid 1 is essential for cisplatin-induced heat hyperalgesia in mice.

Background: Cisplatin is primarily used for treatment of ovarian and testicular cancer. Oxaliplatin is the only effective treatment for metastatic colorectal cancer. Both are known to cause dose related, cumulative toxic effects on the peripheral nervous system and thirty to forty percent of cancer patients receiving these agents experience painful peripheral neuropathy.

Allelic variation in the Tyk2 and EGF genes as potential genetic determinants of CNS repair.

The potential for endogenous remyelination and axonal protection can be an important factor in determining disease outcome in demyelinating diseases like multiple sclerosis. In many multiple sclerosis (MS) patients CNS repair fails or is incomplete whereas in others the disease is accompanied by extensive repair of demyelinated lesions. We have described significant differences in the ability of two strains of mice to repair CNS damage following Theiler's virus-induced demyelination: FVB/NJ (FVB) mice repair damaged myelin spontaneously and completely, whereas B10.