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Experimental neurology [journal]
- Combined SCI and TBI: Recovery of forelimb function after unilateral cervical spinal cord injury (SCI) is retarded by contralateral traumatic brain injury (TBI), and ipsilateral TBI balances the effects of SCI on paw placement. [JOURNAL ARTICLE]
- Exp Neurol 2013 Jun 12.
A significant proportion (estimates range from 16-74%) of patients with spinal cord injury (SCI) have concomitant traumatic brain injury (TBI), and the combination often produces difficulties in planning and implementing rehabilitation strategies and drug therapies. For example, many of the drugs used to treat SCI may interfere with cognitive rehabilitation, and conversely drugs that are used to control seizures in TBI patients may undermine locomotor recovery after SCI. The current paper presents an experimental animal model for combined SCI and TBI to help drive mechanistic studies of dual diagnosis. Rats received a unilateral SCI (75 kdyn) at C5 vertebral level, a unilateral TBI (2.0mm depth, 4.0m/s velocity impact on the forelimb sensori-motor cortex), or both SCI+TBI. TBI was placed either contralateral or ipsilateral to the SCI. Behavioral recovery was examined using paw placement in a cylinder, grooming, open field locomotion, and the IBB cereal eating test. Over 6weeks, in the paw placement test, SCI+contralateral TBI produced a profound deficit that failed to recover, but SCI+ipsilateral TBI increased the relative use of the paw on the SCI side. In the grooming test, SCI+contralateral TBI produced worse recovery than either lesion alone even though contralateral TBI alone produced no observable deficit. In the IBB forelimb test, SCI+contralateral TBI revealed a severe deficit that recovered in 3weeks. For open field locomotion, SCI alone or in combination with TBI resulted in an initial deficit that recovered in 2weeks. Thus, TBI and SCI affected forelimb function differently depending upon the test, reflecting different neural substrates underlying, for example, exploratory paw placement and stereotyped grooming. Concurrent SCI and TBI had significantly different effects on outcomes and recovery, depending upon laterality of the two lesions. Recovery of function after cervical SCI was retarded by the addition of a moderate TBI in the contralateral hemisphere in all tests, but forepaw placements were relatively increased by an ipsilateral TBI relative to SCI alone, perhaps due to the dual competing injuries influencing the use of both forelimbs. These findings emphasize the complexity of recovery from combined CNS injuries, and the possible role of plasticity and laterality in rehabilitation, and provide a start towards a useful preclinical model for evaluating effective therapies for combine SCI and TBI.
- A non-cholinergic neuronal loss in the pedunculopontine nucleus of toxin-evoked Parkinsonian rats. [JOURNAL ARTICLE]
- Exp Neurol 2013 Jun 13.
The pedunculopontine nucleus (PPN) controls various physiological functions, whilst being deemed a suitable target for low-frequency stimulation therapy for alleviating aspects of Parkinson's disease (PD). Previous studies showed that the PPN contains mainly cholinergic, γ-aminobutyric acid (GABA)ergic and glutamatergic neurons. Here we report on the total number of PPN neurons in laboratory rats, a species frequently used as an experimental model for simulating aspects of human PD. Moreover, the study reports that the number of PPN neurons decrease under toxic conditions that mimic in animals the core pathology seen in human PD. Immunohistochemical detection methods combined with unbiased stereology served to estimate that the PPN of healthy rats unilaterally contain ~19,028 NeuN-immunopositive neurons. The identified neurons revealed a distinct distribution pattern consisting of high cell density in the most rostral and caudal sections of the PPN nucleus, contrasting with lower densities in the medial segments. Our data also show a significant loss which affected PPN non-cholinergic cells, but not cholinergic ones in rats lesioned unilaterally in the Substantia Nigra pars compacta (SNpc) with a single injection of 6-hydroxydopamine (6-OHDA) compared to control animals. This result differs from previous studies which reported a substantial cholinergic cell loss in the PPN of post-mortem PD brains and in 6-OHDA-lesioned monkeys. Since a noted demise of dopaminergic neurons residing in the SN was confirmed in the 6-OHDA-lesioned rats, the current study suggest that a "dying-back" mechanism may underlie the cell death affecting non-cholinergic PPN neurons.
- Early cognitive changes due to whole body γ- irradiation: A behavioral and diffusion tensor imaging study in mice. [JOURNAL ARTICLE]
- Exp Neurol 2013 Jun 11.
Radiation-induced aberration in the neuronal integrity and cognitive functions are well known. However, there is a lacuna between sparsely reported immediate effects and the well documented delayed effects of radiation on cognitive functions. The present study was aimed at investigating the radiation-dose dependent incongruities in the early cognitive changes, employing two approaches, behavioral functions and diffusion tensor imaging (DTI). 6 month old female C57BL/6 mice were exposed to a whole-body dose of 2, 5 and 8Gy of γ-radiation and 24hrs after exposure, the stress and anxiety levels were examined in the open-field test (OFT). 48hrs after irradiation, the hippocampal dependent recognition memory was observed by the novel object recognition task (NORT), and the cognitive functions related to memory processing and recall were tested using the elevated plus maze (EPM). Magnetic resonance imaging, including diffusion tensor imaging (DTI) was done at 48-hour post-irradiation to visualize microstructural damage in brain parenchyma. Our results indicate a complex dose independent effect on the cognitive functions immediately after exposure to gamma rays. Radiation exposure caused short-term memory dysfunctions at lower doses, which were seen to be abrogated at higher doses, but the long-term memory processing was disrupted at higher doses. The hippocampus emerged as one of the sensitive regions to be affected by whole-body exposure to gamma rays, which led to profound immediate alterations in cognitive functions. Furthermore, the results indicate a cognitive recovery process, which might be dependent on the extent of damage to the hippocampal region. The present study also emphasizes the importance of further research to unravel the complex pattern of neurobehavioral responses immediately following ionizing radiation exposure.
- Reduced subventricular zone proliferation and white matter damage in juvenile ferrets with kaolin-induced hydrocephalus. [JOURNAL ARTICLE]
- Exp Neurol 2013 Jun 12.
Hydrocephalus is a neurological condition characterized by altered cerebrospinal fluid (CSF) flow with enlargement of ventricular cavities in the brain. A reliable model of hydrocephalus in gyrencephalic mammals is necessary to test preclinical hypotheses. Our objective was to characterize the behavioral, structural, and histological changes in juvenile ferrets following induction of hydrocephalus. Fourteen-day old ferrets were given an injection of kaolin (aluminum silicate) into the cisterna magna. Two days later and repeated weekly until 56days of age, magnetic resonance (MR) imaging was used to assess ventricle size. Behavior was examined thrice weekly. Compared to age-matched saline-injected controls, severely hydrocephalic ferrets weighed significantly less, their postures were impaired, and they were hyperactive prior to extreme debilitation. They developed significant ventriculomegaly and displayed white matter destruction. Reactive astroglia and microglia detected by glial fibrillary acidic protein (GFAP) and Iba-1 immunostaining were apparent in white matter, cortex, and hippocampus. There was a hydrocephalus-related increase in activated caspase 3 labeling of apoptotic cells (7.0 vs. 15.5%) and a reduction in Ki67 labeling of proliferating cells (23.3 vs. 5.9%) in the subventricular zone (SVZ). Reduced Olig2 immunolabeling suggests a depletion of glial precursors. GFAP content was elevated. Myelin basic protein (MBP) quantitation and myelin biochemical enzyme activity showed early maturational increases. Where white matter was not destroyed, the remaining axons developed myelin similar to the controls. In conclusion, the hydrocephalus-induced periventricular disturbances may involve developmental impairments in cell proliferation and glial precursor cell populations. The ferret should prove useful for testing hypotheses about white matter damage and protection in the immature hydrocephalic brain.
- The challenges of axon survival: Introduction to the special issue on axonal degeneration. [EDITORIAL]
- Exp Neurol 2013 Jun 12.
Early axon loss is a common feature of many neurodegenerative disorders. It renders neurons functionally inactive, or less active if axon branches are lost, in a manner that is often irreversible. In the CNS, there is no long-range axon regeneration and even peripheral nerve axons are unlikely to reinnervate their targets while the cause of the problem persists. In most disorders, axon degeneration precedes cell death so it is not simply a consequence of it, and it is now clear that axons have at least one degeneration mechanism that differs from that of the soma. It is important to understand these degeneration mechanisms and their contribution to axon loss in neurodegenerative disorders. In this way, it should become possible to prevent axon loss as well as cell death. This special edition considers the roles and mechanisms of axon degeneration in amyotrophic lateral sclerosis, Charcot-Marie-Tooth disease, hereditary spastic paraplegia, ischemic injury, traumatic brain injury, Alzheimer's disease, glaucoma, Huntington's disease and Parkinson's disease. Using examples from these and other disorders, this introduction considers some of the reasons for axon vulnerability. It also illustrates how molecular genetics and studies of Wallerian degeneration have contributed to our understanding of axon degeneration mechanisms.
- Hibernation: The search for treatments to prevent disuse-induced skeletal muscle atrophy. [JOURNAL ARTICLE]
- Exp Neurol 2013 Jun 12.
Loss of skeletal muscle mass is a serious consequence of multiple diseases and conditions for which there is limited treatment options. Disuse-induced muscle atrophy occurs as the result of both reduced mechanical loading and decreased neural activity. Hibernation represents a unique physiological state where skeletal muscles are protected from unloading, inactivity and nutritional deprivation. A recent study published in Experimental Neurology (Xu et al., 2013) utilized the thirteen-lined ground squirrel, a natural hibernator, to specifically examine whether peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1-α (PGC-1α) and its associated upstream and downstream signaling partners were increased during hibernation. The results showed an increase in PGC-1α expression as well as increases in mitochondrial biogenesis, oxidative capacity, and antioxidant capacity in hibernating animals. It was suggested that upregulation of PCG-1α could be a viable strategy for the treatment of disuse-induced atrophy in humans. This commentary discusses the results of Xu et al. in the context of other studies that have examined muscle sparing in hibernating mammals, and compares these findings to what is known about disuse-induced atrophy in nonhibernating rodents and humans.
- AAV2-mediated striatum delivery of human CDNF prevents the deterioration of midbrain dopamine neurons in a 6-hydroxydopamine induced parkinsonian rat model. [JOURNAL ARTICLE]
- Exp Neurol 2013 Jun 10.
Parkinson's disease (PD) is an aging-associated neurodegenerative disorder with progressive pathology involving the loss of midbrain dopaminergic neurons. Neurotrophic factors are promising for PD gene therapy; they are integrally involved in the development of the nigrostriatal system. Cerebral dopamine neurotrophic factor (CDNF) was recently discovered to be more selective and potent on preserving dopaminergic neurons than other known trophic factors. The present study examined the neuroprotective and functional restorative effects of CDNF overexpression in the striatum via recombinant adeno-associated virus type 2 (AAV2.CDNF) in 6-hydroxydopamine (6-OHDA) injected rats. Striatal delivery of AAV2.CDNF was able to recover 6-OHDA-induced behavior deficits and resulted in a significant restoration of tyrosine hydroxylase immunoreactive (TH-ir) neurons in the substantia nigra pars compacta (SNpc) and TH-ir fiber density in the striatum. PET analyses with [(11)C]-2β-carbomethoxy-3β-(4-fluorophenyl)-tropane ([(11)C]β-CFT) probes suggested functional recovery of dopaminergic (DA) neurons. Our results indicate that striatal administration of AAV2.CDNF was able to provide effective neuro-restoration in the 6-OHDA-lesioned nigrostriatal system and that it may be considered for future clinical applications in PD therapy.
- Oscillatory activity in the human basal ganglia: More than just beta, more than just Parkinson's disease. [JOURNAL ARTICLE]
- Exp Neurol 2013 Jun 10.
The implantation of deep brain stimulators in different structures of the basal ganglia to treat neurological and psychiatric diseases has allowed the recording of local field potential activity in these structures. The analysis of these signals has helped our understanding of basal ganglia physiology in health and disease. However, there remain some major challenges and questions for the future. In a recent work, Tan et al. (Tan, H., Pogosyan, A., Anam, A., Foltynie, T., Limousin, P., Zrinzo, L., et al. 2013. Frequency specific activity in subthalamic nucleus correlates with hand bradykinesia in Parkinson's disease. Exp. Neurol. 240,122-129) take profit of these recordings to study the changes in subthalamic oscillatory activity during the hold and release phases of a grasping paradigm, and correlate the changes in different frequency bands with performance parameters. They found that beta activity was related to the release phase, while force maintenance related most to theta and gamma/HFO activity. There was no significant effect of the motor state of the patient on this latter association. These findings suggest that the alterations in the oscillatory activity of the basal ganglia in Parkinson's disease are not limited to the beta band, and they involve aspects different from movement preparation and initiation. Additionally, these results highlight the usefulness of the combination of well-designed paradigms with recordings in off and on motor states (in Parkinson's disease), or in different pathologies, in order to understand not only the pathophysiology of the diseases affecting the patients recorded, but also the normal physiology of the basal ganglia.
- Endogenous descending facilitation and inhibition differ in control of formalin intramuscularly induced persistent muscle nociception. [JOURNAL ARTICLE]
- Exp Neurol 2013 Jun 10.
In conscious rats, intramuscular injection of 2.5% formalin into the gastrocnemius muscle, at volumes between 25 and 200μl, evoked dose-dependent biphasic persistent flinching activities: phase 1 (0-10min) and phase 2 (10-60min). During this intramuscular formalin-induced ipsilateral muscle nociception, bilateral secondary mechanical hyperalgesia and heat hypoalgesia assessed by measuring thresholds of paw withdrawal reflex to noxious mechanical and heat stimuli were observed (P<0.05). Lesion of either the ipsilateral dorsal funiculus (DF) or contralateral thalamic mediodorsal (MD) nucleus significantly alleviated the formalin-induced flinches in both phase 1 and phase 2 of the behavioral response, and blocked the occurrence of secondary mechanical hyperalgesia, but not heat hypoalgesia. By contrast, lesion of the ipsilateral dorsal lateral funiculus (DLF) or contralateral thalamic ventromedial (VM) nucleus markedly enhanced the formalin induced flinching behavior in the late part (30-60min) of phase 2 alone; phase 1 and early part (10-30min) of phase 2 response were unaffected. Heat hypoalgesia, but not mechanical hyperalgesia, was markedly attenuated by this treatment (P<0.05). Microinjection of GABA (0.1μg/0.5μl) into the thalamic MD nucleus significantly depressed the intramuscular formalin-induced biphasic persistent nociception, and the occurrence of bilateral secondary mechanical hyperalgesia was significantly delayed (P<0.05). By contrast, microinjection of GABA into the thalamic VM nucleus significantly enhanced the formalin-induced nociceptive behavior in the late part (30-60min) of phase 2, and the bilateral secondary heat hypoalgesia was temporarily prevented (P<0.05). The present study demonstrates that intramuscular formalin evokes biphasic muscle nociception, and that bilateral secondary mechanical hyperalgesia and heat hypoalgesia are differentially controlled by endogenous descending facilitation and inhibition respectively. It is further suggested that thalamic MD nucleus and VM nucleus constitute an endogenous discriminative, modulatory system that exerts, via pathways in the DF and DLF, descending facilitatory and inhibitory actions on responses to peripheral afferent activity evoked by noxious mechanical and heat stimulation.
- Effective long-term immunosuppression in rats by subcutaneously implanted sustained-release tacrolimus pellet: Effect on spinally grafted human neural precursor survival. [JOURNAL ARTICLE]
- Exp Neurol 2013 Jun 5.
Achievement of effective, safe and long-term immunosuppression represents one of the challenges in experimental allogeneic and xenogeneic cell and organ transplantation. The goal of the present study was to develop a reliable, long-term immunosuppression protocol in Sprague-Dawley (SD) rats by: 1) comparing the pharmacokinetics of four different subcutaneously delivered/implanted tacrolimus (TAC) formulations, including: i) caster oil/saline solution, ii) unilamellar or multilamellar liposomes, iii) biodegradable microspheres, and iv) biodegradable 3-month lasting pellets; and 2) defining the survival and immune response in animals receiving spinal injections of human neural precursors at 6weeks to 3months after cell grafting. In animals implanted with TAC pellets (3.4mg/kg/day), a stable 3-month lasting plasma concentration of TAC averaging 19.1±4.9ng/ml was measured. Analysis of grafted cell survival in SOD+ or spinal trauma-injured SD rats immunosuppressed with 3-month lasting TAC pellets (3.4-5.1mg/kg/day) showed the consistent presence of implanted human neurons with minimal or no local T-cell infiltration. These data demonstrate that the use of TAC pellets can represent an effective, long-lasting immunosuppressive drug delivery system that is safe, simple to implement and is associated with a long-term human neural precursor survival after grafting into the spinal cord of SOD+ or spinal trauma-injured SD rats.