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Biomedical subjects

David J Anderson

Publications and source records attributed to David J Anderson.

At least 19 recordsLinked to original sources

Synthesis and structure-activity relationships of 3,8-diazabicyclo[4.2.0]octane ligands, potent nicotinic acetylcholine receptor agonists.

A series of potent neuronal nicotinic acetylcholine receptor (nAChR) ligands based on a 3,8-diazabicyclo[4.2.0]octane core have been synthesized and evaluated for affinity and agonist efficacy at the human high affinity nicotine recognition site (halpha4beta2) and in a rat model of persistent nociceptive pain (formalin model). Numerous analogs in this series exhibit picomolar affinity in radioligand binding assays and nanomolar agonist potency in functional assays, placing them among the most potent nAChR ligands known for the halpha4beta2 receptor. Several of the compounds reported in this study (i.e., 24, 25, 28, 30, 32, and 47) exhibit equivalent or greater affinity for the halpha4beta2 receptor relative to epibatidine, and like epibatidine, many exhibit robust analgesic efficacy in the rat formalin model of persistent pain.

Analgesics↗

The transcription factor NFIA controls the onset of gliogenesis in the developing spinal cord.

The mechanisms controlling the transition from neurogenesis to gliogenesis in the vertebrate CNS are incompletely understood. We identified a family of transcription factors, called NFI genes, which are induced throughout the spinal cord ventricular zone (VZ) concomitantly with the induction of GLAST, an early marker of gliogenesis. NFIA is both necessary and sufficient for GLAST induction in the VZ. Unexpectedly, NFIA is also essential for the continued inhibition of neurogenesis in VZ progenitors. This function is mediated by the requirement of NFIA for the expression of HES5, a Notch effector. However, Notch effectors are unable to promote glial-fate specification in the absence of NFIA. Thus, NFIA links the abrogation of neurogenesis to a generic program of gliogenesis, in both astrocyte and oligodendrocyte VZ progenitors. At later stages, NFIA promotes migration and differentiation of astrocyte precursors, a function that is antagonized in oligodendrocyte precursors by Olig2.

Animals↗

Antidromic activation reveals tonotopically organized projections from primary auditory cortex to the central nucleus of the inferior colliculus in guinea pig.

The inferior colliculus (IC) is highly modulated by descending projections from higher auditory and nonauditory centers. Traditionally, corticofugal fibers were believed to project mainly to the extralemniscal IC regions. However, there is some anatomical evidence suggesting that a substantial number of fibers from the primary auditory cortex (A1) project into the IC central nucleus (ICC) and appear to be tonotopically organized. In this study, we used antidromic stimulation combined with other electrophysiological techniques to further investigate the spatial organization of descending fibers from A1 to the ICC in ketamine-anesthetized guinea pigs. Based on our findings, corticofugal fibers originate predominantly from layer V of A1, are amply scattered throughout the ICC and only project to ICC neurons with a similar best frequency (BF). This strict tonotopic pattern suggests that these corticofugal projections are involved with modulating spectral features of sound. Along the isofrequency dimension of the ICC, there appears to be some differences in projection patterns that depend on BF region and possibly isofrequency location within A1 and may be indicative of different descending coding strategies. Furthermore, the success of the antidromic stimulation method in our study demonstrates that it can be used to investigate some of the functional properties associated with corticofugal projections to the ICC as well as to other regions (e.g., medial geniculate body, cochlear nucleus). Such a method can address some of the limitations with current anatomical techniques for studying the auditory corticofugal system.

Acoustic Stimulation↗

Electrophysiological validation of a human prototype auditory midbrain implant in a guinea pig model.

The auditory midbrain implant (AMI) is a new treatment for hearing restoration in patients with neural deafness or surgically inaccessible cochleae who cannot benefit from cochlear implants (CI). This includes neurofibromatosis type II (NF2) patients who, due to development and/or removal of vestibular schwannomas, usually experience complete damage of their auditory nerves. Although the auditory brainstem implant (ABI) provides sound awareness and aids lip-reading capabilities for these NF2 patients, it generally only achieves hearing performance levels comparable with a single-channel CI. In collaboration with Cochlear Ltd. (Lane Cove, Australia), we developed a human prototype AMI, which is designed for electrical stimulation along the well-defined tonotopic gradient of the inferior colliculus central nucleus (ICC). Considering that better speech perception and hearing performance has been correlated with a greater number of discriminable frequency channels of information available, the ability of the AMI to effectively activate discrete frequency regions within the ICC may enable better hearing performance than achieved by the ABI. Therefore, the goal of this study was to investigate if our AMI array could achieve low-threshold, frequency-specific activation within the ICC, and whether the levels for ICC activation via AMI stimulation were within safe limits for human application. We electrically stimulated different frequency regions within the ICC via the AMI array and recorded the corresponding neural activity in the primary auditory cortex (A1) using a multisite silicon probe in ketamine-anesthetized guinea pigs. Based on our results, AMI stimulation achieves lower thresholds and more localized, frequency-specific activation than CI stimulation. Furthermore, AMI stimulation achieves cortical activation with current levels that are within safe limits for central nervous system stimulation. This study confirms that our AMI design is sufficient for ensuring safe and effective activation of the ICC, and warrants further studies to translate the AMI into clinical application.

Acoustic Stimulation↗

Antisense knockdown of the rat alpha7 nicotinic acetylcholine receptor produces spatial memory impairment.

Selective and brain penetrating pharmacological antagonists for use in clarifying a role of alpha7 nicotinic acetylcholine receptors (nAChR) in behavioral paradigms are presently unavailable. Studies in alpha7 knock-out mice (KO) have not revealed convincing changes in behavioral phenotype, in particular measures of cognition that include contextual fear conditioning and spatial memory, which may be due to compensatory developmental changes. Therefore, an antisense oligonucleotide (aON) targeted toward the 3'- and 5'-UTR coding regions of the rat alpha7 nicotinic acetylcholine receptor was used. Following central injection of aON into the lateral ventricle of Long Evans rats for 6 days, treated rats exhibited a significant 42% and 25% decrease in alpha7 nAChR densities in hippocampus and cortex, respectively, as measured by [(3)H]-methyllycaconitine (MLA) binding. There was no change in alpha4beta2 densities measured by [(3)H]-cytisine binding. Acquisition of Morris Water Maze (MWM) performance, a measure of spatial memory, was impaired in aON-treated rats. In addition, a reduction in target platform crossings during a subsequent probe-trial was observed. These data demonstrate the ability of this aON to reduce hippocampal and cortical alpha7 nicotinic receptor densities associated with impaired MWM performance and support the specific involvement of the alpha7 nAChR in spatial learning and memory, a phenotype not affected in alpha7 KO mice.

Aconitine↗

Involvement of DRG11 in the development of the primary afferent nociceptive system.

During development, dorsal root ganglia (DRG) neurons differentiate in various subpopulations, nociceptive neurons belonging in the small-diameter class. This study addresses the role played by DRG11, a transcription factor expressed in the spinal area of projection of small-diameter DRG neurons, in the development of the primary afferent system. The various subclasses of DRG neurons were compared between wild-type and Drg11(-/-) mice at embryonic and postnatal life. In Drg11(-/-) mice, numbers of small peptidergic and non-peptidergic DRG neurons were decreased at P7 concomitant with abnormal cell death. Innervation by small DRG neurons was impaired in cutaneous, visceral and deep tissues. Large DRG neurons were not affected. The data point to a role for DRG11 in early postnatal survival of normally generated small primary afferent neurons innervating various kinds of peripheral tissues, which would explain the nociceptive deficits observed in Drg11-null mutant mice.

Animals↗

(L)-Phenylglycine, but not necessarily other alpha2delta subunit voltage-gated calcium channel ligands, attenuates neuropathic pain in rats.

Gabapentin and pregabalin have been demonstrated, both in animal pain models and clinically, to be effective analgesics particularly for the treatment of neuropathic pain. The precise mechanism of action for these two drugs is unknown, but they are generally believed to function via initially binding to the alpha2delta subunit of voltage-gated Ca2+ channels. In this study, we used a pharmacological approach to test the hypothesis whether high affinity interactions with the alpha2delta subunit alone could lead to attenuation of neuropathic pain in rats. The anti-allodynic effects of gabapentin and pregabalin, along with three other compounds--(L)-phenylglycine, m-chlorophenylglycine and 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (ABHCA)--discovered to be potent alpha2delta ligands, were tested in the rat spinal nerve ligation model of neuropathic pain. Gabapentin (Ki = 120 nM), pregabalin (180 nM) and (L)-phenylglycine (180 nM) were shown to be anti-allodynic, with respective ED50 values of 230, 90 and 80 micromol/kg (p.o.). (L)-Phenylglycine was as potent as pregabalin and equi-efficacious in reversing mechanical allodynia. In contrast, two ligands with comparable or superior alpha2delta binding affinities, m-chlorophenylglycine (Ki = 54 nM) and ABHCA (150 nM), exhibited no anti-allodynic effects at doses of 30-300 micromol/kg (p.o.), although these compounds achieved substantial brain levels. The data demonstrate that, at least in the rat spinal nerve ligation model of neuropathic pain, (L)-phenylglycine has an anti-allodynic effect, but two equally potent alpha2delta subunit ligands do not. These results suggest that additional mechanisms, besides alpha2delta interactions, may contribute to the effects of compounds like gabapentin, pregabalin and (L)-phenylglycine in neuropathic pain.

Analgesics↗

Auditory cortical responses to electrical stimulation of the inferior colliculus: implications for an auditory midbrain implant.

The success and limitations of cochlear implants (CIs) along with recent advances in deep brain stimulation and neural engineering have motivated the development of a central auditory prosthesis. In this study, we investigated the effects of electrical stimulation of the inferior colliculus central nucleus (ICC) on primary auditory cortex (A1) activity to determine the potential benefits of an auditory midbrain implant (AMI). We recorded multiunit activity in A1 of ketamine-anesthetized guinea pigs in response to single-pulse (200 micros/phase) monopolar stimulation of the ICC using multisite silicon-substrate probes. We then compared measures of threshold, dynamic range, and tonotopic spread of activation for ICC stimulation with that of published data for CI stimulation. Our results showed that compared with cochlear stimulation, ICC stimulation achieved: 1) thresholds about 8 dB lower; 2) dynamic ranges > or = 4 dB greater; and 3) more localized, frequency-specific activation, even though frequency specificity was partially lost at higher stimulus levels for low-frequency ICC regions. Our results also showed that stimulation of rostral ICC regions elicited lower thresholds but with greater activation spread along the tonotopic gradient of A1 than did stimulation of more caudal regions. These results suggest that an AMI may improve frequency and level coding with lower energy requirements compared with CIs. However, a trade-off between lower perceptual thresholds and better frequency discrimination may exist that depends on location of stimulation along the caudorostral dimension of the ICC. Overall, this study provides the foundation for future AMI research and development.

Acoustic Stimulation↗

Development of NG2 neural progenitor cells requires Olig gene function.

In the adult central nervous system, two distinct populations of glial cells expressing the chondroitin sulfate proteoglycan NG2 have been described: bipolar progenitor cells and more differentiated "synantocytes." These cells have diverse neurological functions, including critical roles in synaptic transmission, repair, and regeneration. Despite their potential importance, the genetic factors that regulate NG2 cell development are poorly understood, and the relationship of synantocytes to the oligodendroglial lineage, in particular, remains controversial. Here, we show that >90% of embryonic and adult NG2 cells express Olig2, a basic helix-loop-helix transcription factor required for oligodendrocyte lineage specification. Analysis of mice lacking Olig function demonstrates a failure of NG2 cell development at embryonic and perinatal stages that can be rescued by addition of a transgene containing the human OLIG2 locus. These findings show a general requirement for Olig function in NG2 cell development and highlight further roles for Olig transcription factors in neural progenitor cells.

Animals↗

Allocrine modulation of feeding behavior by the Sex Peptide of Drosophila.

Mating elicits a dramatic reprogramming of female behavior in numerous insect species. In Drosophila, this postmating response (PMR) comprises increased egg-laying rate and reduced sexual receptivity and is controlled by the products of the male accessory glands, a family of approximately 80 small peptides transferred in the male seminal fluid . Here, we show that copulation strongly stimulates female food intake. Remarkably, this change is abolished if the males lack a single, small seminal protein, the Sex Peptide (SP). Ectopic expression of SP in virgin females mimics the effect of mating on feeding behavior, demonstrating that SP is the main agent controlling this behavioral paradigm. Our observations identify enhanced feeding behavior as a novel component of the Drosophila PMR and suggest that SP represents a molecular link between energy acquisition and reproductive investment.

Animals↗

Improved signal and reduced noise in neural recordings from close-spaced electrode arrays using independent component analysis as a preprocessor.

Noise can greatly complicate the isolation of individual cell action potential waveforms for the sake of electrophysiological analysis. For an experiment involving recording in the thalamus/subthalamus areas of a rat brain, a hybrid hardware/software method was utilized to improve the signal-to-noise quality of the recorded signal on each recording channel. The procedure uses closely spaced recording electrode arrays and independent component analysis (ICA) to fortify the signal energy of a single spike by combining input from several channels, and concurrently to reduce the noise on each channel by isolating common mode components such as artifacts, slow waves, and correlated distant spike activation. In the next step, a wavelet denoising-based signal-to-noise assessment is used to quantify the improvement in data quality for each data record. The data presented here demonstrate that this method, which can be applied off-line as a preprocessor to other time domain or transform domain spike sorting methods, is consistently effective at improving data quality and facilitating subsequent detection and classification of neurons.

Action Potentials↗

Olig2+ neuroepithelial motoneuron progenitors are not multipotent stem cells in vivo.

Neurons and glia are thought to arise from multipotent and self-renewing stem cells, which comprise the majority of neuroepithelial cells in the ventricular zone (VZ) of the early embryonic CNS. However, this idea remains to be tested rigorously, because CNS stem cells have been identified only by using in vitro assays, from which their abundance in vivo cannot be directly inferred. In the hematopoietic system, stem cells are characterized by using prospective isolation and direct in vivo transplantation. Here we have used this approach to ask whether most VZ progenitors behave as stem cells in vivo. The best-studied region of the embryonic CNS for addressing this problem is, arguably, the ventral spinal cord, within which progenitors in the motoneuron progenitor (pMN) domain sequentially generate motoneurons (MNs) and oligodendrocyte precursors (OPs). Virtually all VZ cells in pMN express the transcription factor Olig2. If most of these cells are stem cells, then they should maintain neurogenic potential, even at later, gliogenic stages. To test this hypothesis, we have prospectively isolated Olig2(+) cells from murine embryonic day (E)9.5 and E13.5 spinal cord and directly transplanted them to E2 chick spinal cord. Transplanted E9.5 cells generate both neurons, including MNs and OPs, whereas E13.5 cells generate. The observation that most Olig2(+) progenitors do not maintain neurogenic potential into the period of gliogenesis argues that they do not self-renew. These results do not support the commonly held view that most neuroepithelial cells in the embryonic CNS VZ are stem cells in vivo.

Animals↗

Magnetic resonance compatibility of multichannel silicon microelectrode systems for neural recording and stimulation: design criteria, tests, and recommendations.

Magnetic resonance (MR) compatibility of biomedical implants and devices represents a challenge for designers and potential risks for users. This paper addresses these problems and presents the first MR-compatible multichannel silicon chronic microelectrode system, used for recording and electrical stimulation of the central nervous system for animal models. A standard chronic assembly, from the Center for Neural Communication Technology at the University of Michigan, was tested on a 2 Tesla magnet to detect forces, heating, and image distortions, and modified to minimize or eliminate susceptibility artifacts, tissue damage, and electrode displacement, maintaining good image quality and safety to the animals. Multiple commercial connectors were tested for MR compatibility and several options for the reference electrode were also tested to minimize image artifacts and provide a stable biocompatible reference for shortand long-term neural recordings. Different holding screws were tested to anchor the microelectrode assembly on the top of the skull. The final selection of this part was based on MR-compatibility, biocompatibility, durability, and mechanical and chemical stability. The required adaptor to interconnect the MR-compatible microelectrode with standard data acquisition systems was also designed and fabricated. The final design is fully MR-compatible and has been successfully tested on guinea pigs.

Animals↗

A-85380: a pharmacological probe for the preclinical and clinical investigation of the alphabeta neuronal nicotinic acetylcholine receptor.

A-85380 [3-(2(s)-azetidinylmethoxy) pyridine] is a neuronal nicotinic acetylcholine receptor (nAChR) agonist that has been a useful tool in the investigation of the function of nAChRs in both preclinical and clinical studies. Amongst nAChR subtypes, A-85380 shows selectivity for the alpha(4)beta(2) vs. the alpha(7) or alpha(1)beta(1)deltagamma nAChRs. In functional in vitro cation flux assays, A-85380 is a potent and full agonist. A-85380 has a broad-spectrum analgesic profile with efficacy in acute, persistent, and neuropathic pain models. As demonstrated using selective nAChR antagonists or alpha(4) antisense, the alpha(4)beta(2) nAChR mediates the analgesic effects of A-85380. Interestingly, the site of action depends upon the type of pain as antinociception is mediated by descending inhibition into the spinal cord whereas anti-allodynia in neuropathic pain is mediated at both central and peripheral sites. Radiolabelled forms of A-85380 have been developed and shown to be safe for use in vivo in humans. In clinical studies using positron and photon emission tomography, marked decreases in alpha(4)beta(2) nAChRs have been seen in patients with Parkinson's and Alzheimer's disease. Although not developed as a therapeutic agent, A-85380 has proven to be an important component in the development of novel nAChR ligands for the treatment of pain and other disorders.

Animals↗

Albatross species demonstrate regional differences in North Pacific marine contamination.

Recent concern about negative effects on human health from elevated organochlorine and mercury concentrations in marine foods has highlighted the need to understand temporal and spatial patterns of marine pollution. Seabirds, long-lived pelagic predators with wide foraging ranges, can be used as indicators of regional contaminant patterns across large temporal and spatial scales. Here we evaluate contaminant levels, carbon and nitrogen stable isotope ratios, and satellite telemetry data from two sympatrically breeding North Pacific albatross species to demonstrate that (1) organochlorine and mercury contaminant levels are significantly higher in the California Current compared to levels in the high-latitude North Pacific and (2) levels of organochlorine contaminants in the North Pacific are increasing over time. Black-footed Albatrosses (Phoebastria nigripes) had 370-460% higher organochlorine (polychlorinated biphenyls [PCBs], dichlorodiphenyltrichloroethanes [DDTs]) and mercury body burdens than a closely related species, the Laysan Albatross (P. immutabilis), primarily due to regional segregation of their North Pacific foraging areas. PCBs (the sum of the individual PCB congeners analyzed) and DDE concentrations in both albatross species were 130-360% higher than concentrations measured a decade ago. Our results demonstrate dramatically high and increasing contaminant concentrations in the eastern North Pacific Ocean, a finding relevant to other marine predators, including humans.

Animals↗

Acute rhabdomyolysis following acute compartment syndrome of upper arm.

Compartment syndromes of the upper arm are rare, and patients presenting with suspected problem in this region may not have physical signs as obvious as those presenting with symptoms of forearm and lower extremity. This case report describes the aetiology, diagnosis and the management of compartment syndrome that presented in upper arm.

Acute Disease↗

The origin and diversification of Galapagos mockingbirds.

Evolutionary radiations of colonists on archipelagos provide valuable insight into mechanisms and modes of speciation. The apparent diversification of Galapagos mockingbirds (Nesomimus) provoked Darwin's initial conception of adaptive radiation, but the monophyly of this historically important exemplar has not been evaluated with molecular data. Additionally, as with most Galapagos organisms, we have a poor understanding of the temporal pattern of diversification of the mockingbirds following colonization(s) from source populations. Here we present a molecular phylogeny of Galapagos and other mockingbird populations based on mitochondrial sequence data. Monophyly of Galapagos mockingbirds was supported, suggesting a single colonization of the archipelago followed by diversification. Our analyses also indicate that Nesomimus is nested within the traditional genus Mimus, making the latter paraphyletic, and that the closest living relatives of Galapagos mockingbirds appear to be those currently found in North America, northern South America, and the Caribbean, rather than the geographically nearest species in continental Ecuador. Thus, propensity for over-water dispersal may have played a more important role than geographic proximity in the colonization of Galapagos by mockingbirds. Within Galapagos, four distinct mitochondrial DNA clades were identified. These four clades differ from current taxonomy in several important respects. In particular, mockingbirds in the eastern islands of the archipelago (Española, San Cristóbal, and Genovesa) have very similar mitochondrial DNA sequences, despite belonging to three different nominal species, and mockingbirds from Isabela, in the west of the archipelago, are more phylogenetically divergent than previously recognized. Consistent with current taxonomy is the phylogenetic distinctiveness of the Floreana mockingbird (N. trifasciatus) and close relationships among most mockingbirds from the central and northern region of the archipelago (currently considered conspecific populations of N. parvulus). Overall, phylogeographic patterns are consistent with a model of wind-based dispersal within Galapagos, with colonization of more northerly islands by birds from more southern populations, but not the reverse. Further radiation in Galapagos would require coexistence of multiple species on individual islands, but this may be prevented by relatively limited morphological divergence among mockingbirds and by lack of sufficient habitat diversity in the archipelago to support more than one omnivorous mimid.

Animals↗