Rodent Lesions Research Articles

Arousal Regulation by the External Globus Pallidus: A New Node for the Mesocircuit Hypothesis.

In the decade since its debut, the Mesocircuit Hypothesis (MH) has provided researchers a scaffolding for interpreting their findings by associating subcortical-cortical dysfunction with the loss and recovery of consciousness following severe brain injury. Here, we leverage new findings from human and rodent lesions, as well as chemo/optogenetic, tractography, and stimulation studies to propose the external segment of the globus pallidus (GPe) as an additional node in the MH, in hopes of increasing its explanatory power. Specifically, we discuss the anatomical and molecular mechanisms involving the GPe in sleep-wake control and propose a plausible mechanistic model explaining how the GPe can modulate cortical activity through its direct connections with the prefrontal cortex and thalamic reticular nucleus to initiate and maintain sleep. The inclusion of the GPe in the arousal circuitry has implications for understanding a range of phenomena, such as the effects of the adenosine (A2A) and dopamine (D2) receptors on sleep-wake cycles, the paradoxical effects of zolpidem in disorders of consciousness, and sleep disturbances in conditions such as Parkinson's Disease.

Anatomical Plasticity of Rostrally Terminating Axons as a Possible Bridging Substrate across a Spinal Injury.

Transfer of information across a spinal lesion is required for many aspects of recovery across diverse motor systems. Our understanding of axonal plasticity and which subpopulations of neurons may contribute to bridging substrates following injury, however, remains relatively incomplete. Most recently, attention has been directed to propriospinal neurons (PSNs), with research suggesting that they are capable of bridging a spinal lesion in rodents. In the current study, subpopulations of both long (C5) and short (T6, T8) PSNs-as well as a supraspinal system, the rubrospinal tract (RST)-were assessed following low thoracic (T9) hemisection in the cat using the retrograde tracer Fluoro-Gold. Acutely, within 2 weeks post-hemisection, the numbers of short and long PSNs, as well as contralateral RST neurons, with axons crossing the lesion were significantly decreased relative to uninjured controls. This decrease persisted bilaterally and was permanent in the long PSNs and the contralateral red nucleus (RN). However, by 16 weeks post-hemisection, the numbers of ipsilesional and contralesional short PSNs bridging the lesion were significantly increased. Further, the number of contralesional contributing short PSNs was significantly greater in injured animals than in uninjured animals. A significant increase over uninjured numbers also was seen in the ipsilateral (non-axotomized) RN. These findings suggest that a novel substrate of undamaged axons, which normally terminates rostral to the lesion, grows past a thoracic lesion after injury. This rostral population represents a major component of the bridging substrate seen and may represent an important anatomical target for evolving rehabilitation approaches as a substrate capable of contributing to functional recovery.

Three-dimensional motion analysis for comprehensive understanding of gait characteristics after sciatic nerve lesion in rodents

Rodent models of sciatic nerve lesion are regularly used to assess functional deficits in nerves. Impaired locomotor functions induced by sciatic nerve lesion are currently evaluated with scoring systems despite their limitations. To overcome these shortcomings, which includes low sensitivity, little significance, and the representation of only marginal components of motion profiles, some additional metrics have been introduced. However, a quantitative determination of motion deficits is yet to be established. We used a three-dimensional motion analysis to investigate gait deficits after sciatic nerve lesion in rats. This enabled us to depict the distorted gait motion using both traditional parameters and novel readouts that are specific for the three-dimensional analysis. Our results suggest that three-dimensional motion analysis facilitates a comprehensive understanding of the gait impairment specifically, but not limited to, a sciatic lesion rat model. A broad application of these methods will improve understanding and standardized motor assessment.

Lateral Entorhinal Cortex Lesions Impair Local Spatial Frameworks.

A prominent theory in the neurobiology of memory processing is that episodic memory is supported by contextually gated spatial representations in the hippocampus formed by combining spatial information from medial entorhinal cortex (MEC) with non-spatial information from lateral entorhinal cortex (LEC). However, there is a growing body of evidence from lesion and single-unit recording studies in rodents suggesting that LEC might have a role in encoding space, particularly the current and previous locations of objects within the local environment. Landmarks, both local and global, have been shown to control the spatial representations hypothesized to underlie cognitive maps. Consequently, it has recently been suggested that information processing within this network might be organized with reference to spatial scale with LEC and MEC providing information about local and global spatial frameworks respectively. In the present study, we trained animals to search for food using either a local or global spatial framework. Animals were re-tested on both tasks after receiving excitotoxic lesions of either the MEC or LEC. LEC lesioned animals were impaired in their ability to learn a local spatial framework task. LEC lesioned animals were also impaired on an object recognition (OR) task involving multiple local features but unimpaired at recognizing a single familiar object. Together, this suggests that LEC is involved in associating features of the local environment. However, neither LEC nor MEC lesions impaired performance on the global spatial framework task.

Chronic Posttraumatic Epilepsy following Neocortical Undercut Lesion in Mice.

Posttraumatic epilepsy (PTE) usually develops in a small percentage of patients of traumatic brain injury after a varying latent period. Modeling this chronic neurological condition in rodents is time consuming and inefficient, which constitutes a significant obstacle in studying its mechanism and discovering novel therapeutics for its prevention and treatment. Partially isolated neocortex, or undercut, is known to induce cortical hyperexcitability and epileptiform activity in vitro, and has been used extensively for studying the neurophysiological mechanism of posttraumatic epileptogenesis. However, whether the undercut lesion in rodents causes chronic epileptic seizures has not been systematically characterized. Here we used a miniature telemetry system to continuously monitor electroencephalography (EEG) in adult C57BL mice for up to 3 months after undercut surgery. We found that 50% of animals developed spontaneous seizures between 16–50 days after injury. The mean seizure duration was 8.9±3.6 seconds, and the average seizure frequency was 0.17±0.17 times per day. There was no progression in seizure frequency and duration over the recording period. Video monitoring revealed behavioral arrests and clonic limb movement during seizure attacks. A pentylenetetrazol (PTZ) test further showed increased seizure susceptibility in the undercut mice. We conclude that undercut lesion in mice is a model of chronic PTE that involves spontaneous epileptic seizures.

The hippocampus: a special place for time.

Many findings have demonstrated that memories of past events are temporally organized. It is well known that the hippocampus is critical for such episodic memories, but, until recently, little was known about the temporal organization of mnemonic representations in the hippocampus. Recent developments in human and animal research have revealed important insights into the role of the hippocampus in learning and retrieving sequences of events. Here, we review these findings, including lesion and single-unit recording studies in rodents, functional magnetic resonance imaging studies in humans, and computational models that link findings from these studies to the anatomy of the hippocampal circuit. The findings converge toward the idea that the hippocampus is essential for learning sequences of events, allowing the brain to distinguish between memories for conceptually similar but temporally distinct episodes, and to associate representations of temporally contiguous, but otherwise unrelated experiences.

Remodeling of the piriform cortex after lesion in adult rodents.

Denervation of the piriform cortex by bulbotomy causes a series of important cellular changes in the inhibitory interneurons of layer I and transsynaptic apoptosis of a large number of pyramidal neurons in outer layer II within 24 h. In this study, we report that following the marked loss of neurons in outer layer II, the piriform cortex is reconstituted by the addition of newly formed neurons that restore the number to a preinjury level within 30 days. We provide evidence that the number of newly divided neuronal progenitors increases after injury and further show that a population of doublecortin-positive cells that resides in the piriform cortex decreases after injury. Taken together, these findings suggest that the piriform cortex has significant neurogenic potential that is activated following sensory denervation and may contribute toward the replacement of neurons in outer layer II.

Mutation Spectra of Kras and Tp53 in Urethral and Lung Neoplasms in B6C3F1 Mice Treated with 3,3′,4,4′-Tetrachloroazobenzene

3,3',4,4'-tetrachloroazobenzene (TCAB) is a contaminant formed during manufacture of various herbicide compounds. A recent National Toxicology Program study showed B6C3F1 mice exposed to TCAB developed a treatment-related increase in lung carcinomas in the high-dose group, and urethral carcinomas, an extremely rare lesion in rodents, in all dose groups. As the potential for environmental exposure to TCAB is widespread, and the mechanisms of urethral carcinogenesis are unknown, TCAB-induced urethral and pulmonary tumors were evaluated for alterations in critical human cancer genes, Kras and Tp53. Uroplakin III, CK20, and CK7 immunohistochemistry was performed to confirm the urothelial origin of urethral tumors. TCAB-induced urethral carcinomas harbored transforming point mutations in K-ras (38%) and Tp53 (63%), and 71% displayed nuclear TP53 expression, consistent with formation of mutant protein. Transition mutations accounted for 88% of Tp53 mutations in urethral carcinomas, suggesting that TCAB or its metabolites target guanine or cytosine bases and that these mutations are involved in urethral carcinogenesis. Pulmonary carcinomas in TCAB-exposed animals harbored similar rates of Tp53 (55%) and Kras (36%) mutations as urethral carcinomas, suggesting that TCAB may induce mutations at multiple sites by a common mechanism. In conclusion, TCAB is carcinogenic at multiple sites in male and female B6C3F1 mice through mechanisms involving Tp53 and Kras mutation.

JAK2 inhibition is neuroprotective and reduces astrogliosis after quinolinic acid striatal lesion in adult mice

Quinolinic acid (QA) striatal lesion in rodents induces neuronal death, astrogliosis and migration of neuroblasts from subventricular zone to damaged striatum. These phenomena occur in some human neurodegenerative illnesses, but the underlying mechanisms are unknown. We investigated the effect of AG490, a Janus-kinase 2 (JAK2) inhibitor, on astrogliosis, neuronal loss and neurogenesis in the striatum of adult mice after unilateral infusion of QA (30nmol). Animals were given subcutaneous injections of AG490 (10mg/kg) or vehicle immediately after lesion and then once daily for six days. Brain sections were used for neuronal stereological quantification, immunohistochemical and Western Blotting analyses for GFAP and doublecortin, markers of astrocytes and neuroblasts, respectively. The total area of doublecortin-positive cells (ADPC) and the number of neurons (NN) in the lesioned (L) and contralateral (CL) sides were evaluated. Neurogenesis index (NI=ADPC(L)/ADPC(CL)) and neuronal ratio (NR=NN(L)/NN(CL)) were calculated. After QA administration, blotting for GFAP showed an ipsilateral decrease of 19% in AG490- vs vehicle-treated animals. NR was 25% higher in mice given AG490 vs controls given vehicle. NI showed a decrease of 21% in AG490- vs vehicle-treated mice. Our results indicate that JAK2 inhibition reduces QA lesion and suggest that astrogliosis may impair neuronal survival in this model.

Hemodynamic responses in amygdala and hippocampus distinguish between aversive and neutral cues during Pavlovian fear conditioning in behaving rats

Lesion and electrophysiological studies in rodents have identified the amygdala and hippocampus (HPC) as key structures for Pavlovian fear conditioning, but human functional neuroimaging studies have not consistently found activation of these structures. This could be because hemodynamic responses cannot detect the sparse neuronal activity proposed to underlie conditioned fear. Alternatively, differences in experimental design or fear levels could account for the discrepant findings between rodents and humans. To help distinguish between these alternatives, we used tissue oxygen amperometry to record hemodynamic responses from the basolateral amygdala (BLA), dorsal HPC (dHPC) and ventral HPC (vHPC) in freely-moving rats during the acquisition and extinction of conditioned fear. To enable specific comparison with human studies we used a discriminative paradigm, with one auditory cue [conditioned stimulus (CS)+] that was always followed by footshock, and another auditory cue (CS−) that was never followed by footshock. BLA tissue oxygen signals were significantly higher during CS+ than CS− trials during training and early extinction. In contrast, they were lower during CS+ than CS− trials by the end of extinction. dHPC and vHPC tissue oxygen signals were significantly lower during CS+ than CS− trials throughout extinction. Thus, hemodynamic signals in the amygdala and HPC can detect the different patterns of neuronal activity evoked by threatening vs. neutral stimuli during fear conditioning. Discrepant neuroimaging findings may be due to differences in experimental design and/or fear levels evoked in participants. Our methodology offers a way to improve translation between rodent models and human neuroimaging.

Dysregulation of the Wnt pathway inhibits timely myelination and remyelination in the mammalian CNS

The progressive loss of CNS myelin in patients with multiple sclerosis (MS) has been proposed to result from the combined effects of damage to oligodendrocytes and failure of remyelination. A common feature of demyelinated lesions is the presence of oligodendrocyte precursors (OLPs) blocked at a premyelinating stage. However, the mechanistic basis for inhibition of myelin repair is incompletely understood. To identify novel regulators of OLP differentiation, potentially dysregulated during repair, we performed a genome-wide screen of 1040 transcription factor-encoding genes expressed in remyelinating rodent lesions. We report that approximately 50 transcription factor-encoding genes show dynamic expression during repair and that expression of the Wnt pathway mediator Tcf4 (aka Tcf7l2) within OLPs is specific to lesioned-but not normal-adult white matter. We report that beta-catenin signaling is active during oligodendrocyte development and remyelination in vivo. Moreover, we observed similar regulation of Tcf4 in the developing human CNS and lesions of MS. Data mining revealed elevated levels of Wnt pathway mRNA transcripts and proteins within MS lesions, indicating activation of the pathway in this pathological context. We show that dysregulation of Wnt-beta-catenin signaling in OLPs results in profound delay of both developmental myelination and remyelination, based on (1) conditional activation of beta-catenin in the oligodendrocyte lineage in vivo and (2) findings from APC(Min) mice, which lack one functional copy of the endogenous Wnt pathway inhibitor APC. Together, our findings indicate that dysregulated Wnt-beta-catenin signaling inhibits myelination/remyelination in the mammalian CNS. Evidence of Wnt pathway activity in human MS lesions suggests that its dysregulation might contribute to inefficient myelin repair in human neurological disorders.

Best Practices for Use of Historical Control Data of Proliferative Rodent Lesions

CHARLOTTE KEENAN, SUSAN ELMORE, SABINE FRANCKE-CARROLL, RAMON KEMP, ROY KERLIN, SHYAMAL PEDDADA, JOHN PLETCHER, MATTHIAS RINKE, STEPHEN PETER SCHMIDT, IAN TAYLOR, AND DOUGLAS C. WOLF GlaxoSmithKline, King of Prussia, Pennsylvania, USA National Toxicology Program (NTP), National Institute of Environmental Health Sciences (NIEHS), Research Triangle Park, North Carolina, USA Center for Food Safety and Applied Nutrition (CFSAN), U.S. Food and Drug Administration, College Park, Maryland, USA Merck Research Laboratories, Riom, France Pfizer Inc., Groton, Connecticut, USA NIEHS, Research Triangle Park, North Carolina, USA Charles River, Frederick, Maryland, USA Bayer Schering Pharma AG, Wuppertal, Germany Huntingdon Life Sciences, Eye, United Kingdom U.S. Environmental Protection Agency, Research Triangle Park, North Carolina, USA

A Monograph on Histomorphologic Evaluation of Lymphoid Organs

Shortly after the 2005 publication of the “Society of Toxicologic Pathology (STP) Position Paper on Best Practice Guidelines for the Routine Pathology Evaluation of the Immune System” (Haley et al., 2005), the National Toxicology Program (NTP) Satellite Symposium that preceded the 2005 annual STP meeting provided an interactive forum on this topic. Using specific examples of normal and abnormal lymphoid tissue histology, both during and after the NTP Satellite Symposium, it became apparent that a set of specific examples to illustrate the STP position paper would be useful to the toxicologic pathology scientific community. The present Monograph on the Histomorphologic Evaluation of Lymphoid Organs represents that endeavor. In the process of assembling the photomicrographs to support the STP Best Practices position paper, we realized that an illustrated review of normal structure, function, and histology of lymphoid organs as well as representative examples of common spontaneous and treatment-related lesions would provide useful background reference material. This monograph consists of peer-reviewed papers covering normal structure, function, pathology, and enhanced histopathology for lymph nodes, thymus, bone marrow, spleen, and mucosa-associated lymphoid tissues. In addition there is a paper on the immunohistochemistry of lymphoid organs. Papers dealing with enhanced histopathology are grouped separately in this monograph. Hopefully, topics covered will serve to bring focus to some relevant issues such as the distinction between thymic atrophy and physiological involution and assessment of direct immunomodulatory effects versus effects secondary to stress. We have not covered methods related to collection, processing, sectioning, and staining of lymphoid tissues or recommended a uniform grading scheme for severity of tissue alterations. The monograph emphasis is on rodent lesions with occasional addition of canine and nonhuman primate examples and is intended to be a guide and atlas for the general practicing toxicologic pathologist. All images are from hematoxylin and eosin-stained slides unless otherwise noted in the legend. The majority of images are produced in grayscale to maintain reasonable publication costs. All images are available in color on a CD-ROM inserted into this Monograph issue of Toxicologic Pathology. The images on the CD are of suitable resolution for teaching purposes. The occasional redundancy between papers and between the text and legends, plus some duplication of photomicrographs is a deliberate attempt to have individual papers as well as the enclosed CD of images be sufficiently comprehensive to stand-alone as a definitive resource. There was also

Enhanced Catecholamine Synthesis in the Prefrontal Cortex after Traumatic Brain Injury: Implications for Prefrontal Dysfunction

Traumatic brain injury (TBI)--induced dysfunction of the prefrontal cortex causes many high-level cognitive deficits, including working memory (WM) dysfunction. WM lies at the core of many high-level functions, yet the cellular and molecular mechanisms underlying its dysfunction are poorly understood. Lesion and pharmacological studies in rodents have implicated the medial prefrontal cortex (mPFC), which includes the prelimbic/infralimbic (PL/IL) cortices, in WM tasks. These studies have shown that optimal levels of catecholamine neurotransmission are critical for normalcy of WM function, suggesting that alterations in their synthesis may play a role in WM dysfunction. Using the cortical impact injury model of traumatic brain injury which reproducibly causes working memory deficits in rodents, we have measured the protein levels and activity of tyrosine hydroxylase (TH), the rate-limiting enzyme for catecholamine biosynthesis, and tissue dopamine (DA) and norepinephrine (NE) levels in microdissected PL/IL tissues. Our results show that TBI increases TH protein levels, its activity and tissue DA and NE content in the PL/IL. These findings suggest that altered catecholamine signaling within the PL/IL may contribute to impaired PFC function, and may have implications in the design and implementation of strategies to alleviate prefrontal dysfunction in brain injury patients.

A new reproducible model of an epidural mass lesion in rodents. Part I: Characterization by neurophysiological monitoring, magnetic resonance imaging, and histopathological analysis.

The goal of this study was to characterize a new model of an epidural mass lesion in rodents by means of neurophysiological monitoring, magnetic resonance imaging, and histopathological analysis. Changes in intracranial pressure (ICP), cerebral perfusion pressure (CPP), and laser Doppler flowmetry (LDF) values, intraparenchymal tissue partial oxygen pressure (PtiO2), and electroencephalography (EEG) activity were evaluated in the rat during controlled, epidural expansion of a latex balloon up to a maximum ICP of 60 mm Hg. The initial balloon inflation was followed by periods of sustained inflation (30 +/- 1 minute) and reperfusion (180 +/- 5 minutes). Histopathological analysis and magnetic resonance (MR) imaging were performed to characterize the lesion. The time to maximum balloon expansion and the average balloon volume were highly reproducible. Alterations in EEG activity during inflation first appeared when the CPP decreased to 57 mm Hg, the LDF value to 66% of baseline values. and the PtiO2 to 12 mm Hg. During maximum compression, the CPP was reduced to 34 mm Hg, the LDF value to 40% of baseline, and the PtiO2 to 4 to 5 mm Hg. The EEG tracing was isoelectric during prolonged inflation and the values of LDF and PtiO2 decreased due to accompanying hypotonia. After reperfusion, the CPP was significantly decreased (p < 0.05) due to the elevation of ICP. Both the LDF value and EEG activity displayed incomplete restoration, whereas the value of PtiO2 returned to normal. Histological analysis and MR imaging revealed brain swelling with a midline shift and a combined cortical-subcortical ischemic lesion beyond the site of balloon compression. This novel model of an epidural mass lesion in rodents closely resembles the process observed in humans. Evaluation of pathophysiological and morphological changes was feasible by using neurophysiological monitoring and MR imaging.

A reproducible model of an epidural mass lesion in rodents. Part II: Characterization by in vivo magnetic resonance imaging.

The goal of this study was to characterize a novel epidural space-occupying lesion caused by balloon expansion in rodents by using sequential in vivo magnetic resonance (MR) imaging. Ten Sprague-Dawley rats were intraperitoneally sedated. A trephination was performed over the left parietal cortex to attach a balloon-expansion device, which was secured with dental cement. Measurements were performed using a 1.5-tesla MR imaging device to obtain sequential T2-weighted and diffusion-weighted (DW) sequences in the coronal plane. A three-dimensional, constructed interference in steady state sequence was used for calculation of the balloon volume. The animal's temperature, heartbeat, and the arterial percentage of oxygen saturation were monitored continuously. After a baseline examination had been performed, the balloon was inflated for a 30-minute period until it reached a maximum volume of 0.3 ml; this procedure was followed by a period of sustained inflation lasting 30 minutes, balloon deflation, and a period of reperfusion lasting 3 hours. After perfusion fixation of the animals, morphometric analysis of the lesion size and examination of the percentage of viable neurons in the hippocampus were performed. Magnetic resonance imaging allowed for the precise visualization of the extension and location of the epidural mass lesion, narrowing of the basal cisterns, and development of a midline shift. A white-matter focus of hyperintensity, consistent with brain edema, developed, predominantly in the contralateral temporal lobe. During sustained inflation the volume of the balloon did not change and comprised 5 to 7% of total intracranial volume. During the same period the white-matter edema progressed further but no increased signal was revealed on DW images. After balloon deflation the brain reexpanded to the calvaria and imaging signs of raised intracranial pressure subsided. A cortical area of hyperintensity on T2-weighted images developed in the parietal lobe in the region of the former balloon compression. This area appeared bright on DW images, a finding that corresponded to an early cytotoxic edema. After deflation white-matter vasogenic edema in the temporal lobes regressed within 3 hours after reperfusion. The cortical edema in the parietal lobe and the ipsilateral basal ganglia became sharply demarcated. The histopathological results (that is, the extent of tissue damage) corresponded with findings of the authors' companion investigation, which appears in this issue. Magnetic resonance imaging allows for a precise and sequential in vivo monitoring of a space-occupying epidural mass lesion and visualizes the time course of vasogenic and cytotoxic brain edema. This rodent model of an epidural mass lesion proved to be reproducible.

Preneoplastic and Precancerous Lesions in Rodents: Morphologic and Molecular Characteristics.

Cancer evolves through a sequential process from normal cells in many tissues of humans and animals. The natural history of tumor development can be seen histologically and by biochemical and molecular changes. There are two common basic pathways for the formation of malignant epithelial tumors; through preneoplastic foci and benign tumors (carcinoma developing in an adenoma) in parenchymal tissue or progression from intraepithelial neoplasia (IN) (atypical hyperplasia, noninvasive carcinoma, carcinoma in situ), a lesion in flat or lining epithelium. In epithelial-lining tissues of humans and rodents (e.g. cervix, mammary gland, prostate, skin), these lesions have been described as IN. In solid epithelial organs (liver, kidney, endocrine tissues) focal hyperplasia leads to adenomas. Adenomas develop foci of carcinoma, a process that is more common in rodents than in humans. These precancerous lesions in many rodent tissues often have multiple biochemical and molecular lesions which can be similar or different from those found in malignant tumors. The rodent molecular lesions include mutations in oncogenes (K-ras, H-ras) and tumor suppressor genes (p53, β-catenin, apc) or loss of heterozygosity (LOH) in tumor suppressor genes of mutant mouse models. This manuscript will review specific sequential morphologic and molecular lesions in the histopathogenesis of cancer in several rodent tissues. The significance of molecular lesions for diagnosis of rodent lesions will be discussed.

Differential expression of mRNAs of GDNF family in the striatum following 6-OHDA-induced lesion.

Changes of mRNA levels of GDNF and its recently discovered congeners persephin, neurturin, artemin in the striatum of lesioned side following 6-hydroxydopamine (6-OHDA) lesion in rodents were investigated with semi-quantitative RT-PCR. Two weeks after the lesions were made, mRNA levels of GDNF family members, except for neurturin, were significantly increased in the striatum on the side ipsilateral to the lesion compared with equivalent tissue of sham control. This increase reached a maximal level 5-7 weeks post-lesion. The marked increase of BDNF mRNA expression was also observed in the ipsilateral striatum with similar time course. These findings suggest that 6-OHDA-induced lesions can change gene expression in denervated target tissue, and that mRNA levels of GDNF family members in striatal cells may be modulated by afferent dopaminergic input in a slow-rising and long-lasting fashion.

Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons.

The neurotrophic factors ciliary neurotrophic factor and brain-derived neurotrophic factor can prevent motor neuron cell death during development and after nerve lesion in neonatal rodents. However, local and systemic application of these factors to newborn rats with damaged motor nerves rescues motor neurons only transiently during the first two weeks after axotomy. In order to test the effect of continuous delivery of these factors, the effect of localized injection of CNTF- or BDNF-transducing recombinant adenoviruses into the lesioned nerves was investigated. Under such conditions, survival of axotomized motor neurons is maintained for at least 5 weeks. This way of delivery corresponds to the physiological situation in adult rodents, under which endogenous CNTF is present in the cytosol of Schwann cells and BDNF expression is upregulated after nerve lesion, making these factors available to the damaged motor neurons. Recent results show that overexpression of muscle-derived neurotrophin-3 prevents degeneration of axons and motor endplates, but has only little effect on the number of motor neuron cell bodies in a murine animal model of motor neuron disease. Therefore, techniques suitable for tonic exposure to both nerve- and muscle-derived neurotrophic factors may have implications for the design of future therapeutic strategies against human motor neuron disease.

Relationships among petroleum refining, water and sediment contamination, and fish health

Water, sediment, and fish were sampled from three streams that were receiving or had received effluents from oil refineries. Water and sediment samples were analyzed by gas chromatography/mass spectrometry. Each stream contained aromatic carbons including substituted benzenes and naphthalenes, which are related to oil refinery operations. Fish were identified, counted, and examined for external lesions. Lengths and weights were recorded for older bullhead catfish, and their livers were examined histologically. Differences were seen in the diversity and abundance of fish among the upstream, impacted (effluent-receiving), and downstream stations. In one stream, differences in liver pathology were observed between reference bullhead, collected from an upstream station, and those collected at impacted stations with more than 50% of the bullheads taken from impacted stations having some sort of pathological change, including one with a liver clear-cell focus, which is considered a preneoplastic lesion in rodents. These data suggest a correlation between contamination of water and sediments with aromatic hydrocarbons, presumably from refinery effluents, and compromised fish health.