Biomedical subjects

T Schallert

Publications and source records attributed to T Schallert.

At least 37 records · Page 2Linked to original sources

PubMed1999

Use-dependent exaggeration of brain injury: is glutamate involved?

Extreme overreliance on the impaired forelimb following unilateral lesions of the forelimb representation area of the rat sensorimotor cortex (FL-SMC) leads to exaggeration of the initial cortical injury. Glutamate has repeatedly been implicated in the secondary processes leading to neuronal death following traumatic insult, chiefly because of the neuroprotective properties of excitatory amino acid antagonists in a variety of animal models of brain injury. The present study investigated the possibility that NMDA receptor-mediated processes are involved in use-dependent exaggeration of neuronal injury. Rats were fitted with one-sleeved casts that immobilized the intact forelimb for the first 7 days following FL-SMC lesion, a procedure previously shown to result in use-dependent exaggeration of injury and more severe and persistent limb-use deficits. In the present investigation, administration of MK-801 (1 mg/kg ip once daily on alternate days) during the casting period spared neural tissue surrounding the lesion and enhanced functional recovery of the impaired forelimb. These results suggest a role for NMDA receptor-mediated processes in use-dependent exaggeration of injury.

Analysis of Variance↗

PubMed1999

Akinesia and postural abnormality after unilateral dopamine depletion.

Following unilateral nigrostriatal dopamine depletion rats engage in drug-induced and spontaneous turning. These asymmetric behaviors are associated with a hemispheric asymmetry in the dopamine function. Several tests of 'spontaneous' behavior have revealed other abnormalities, primarily in posture and akinesia. A test is described here which quantifies postural abnormalities, as well as difficulties in initiating and terminating movement. This test may be suitable for evaluating aspects of dopamine-mediated behaviors not addressed by drug tests and may prove valuable in evaluating the potential of new treatment strategies for Parkinson's disease.

Animals↗

PubMed1999

Cortical injury impairs contralateral forelimb immobility during swimming: a simple test for loss of inhibitory motor control.

Most animal models of focal injury to the sensorimotor cortex have been aimed at detecting non-use or impairment of the limbs in specific tasks or during spontaneous exploratory behaviors. However, the inability to hold a limb still can be an equally disabling movement disorder. The present study investigated the loss of control of limb immobility that occurs following damage to the forelimb region of the rat sensorimotor cortex (FL-SMC). When swimming forward in a tank of water, adult rats typically hold both forepaws mostly motionless underneath the chin, using primarily the hindlimbs for stroking movements. Following a unilateral FL-SMC lesion, rats hold only the non-impaired forelimb immobile under the chin, and make 'immature' stroking movements with the impaired forelimb. We have devised a simple means of assessing and quantifying this deficit. While the criterion for most tests of motor recovery involves appropriate movement of an impaired limb, this test depends on adequate inhibition of movement as the norm, and may be a useful way to assess the loss of inhibitory motor control and the efficacy of potential restorative interventions.

Animals↗

PubMed1999

The hippocampus is not necessary for a place response but may be necessary for pliancy.

Rats with kainate-colchicine hippocampal lesions (HL) and controls (C) were initially trained in the Morris water maze with procedures that deterred their prepotent thigmotaxic response. Training began with an escape platform that occupied nearly the entire pool. The area to which the rats could escape was made smaller by substituting smaller platforms as training progressed. In contrast to standard procedures, HL rats and C rats showed comparable performance during acquisition and preferentially searched the goal quadrant on probe trials during which the platform was removed. In a follow-up experiment, the platform was moved to a random position along the wall, which required a switch to a thigmotaxic response for most effective escape. HL rats that were thigmotaxic before place training did not switch to a thigmotaxic response as readily as did controls, behavior consistent with the view that hippocampal damage reduces pliancy.

Animals↗

PubMed1999

Differential effects of glial cell line-derived neurotrophic factor (GDNF) in the striatum and substantia nigra of the aged Parkinsonian rat.

Injection of an adenoviral (Ad) vector encoding human glial cell line-derived neurotrophic factor (GDNF) protects dopaminergic (DA) neurons in the substantia nigra (SN) of young rats. As Parkinson's disease occurs primarily in aged populations, we examined whether chronic biosynthesis of GDNF, achieved by adenovirus-mediated delivery of a GDNF gene (AdGDNF), can protect DA neurons and improve DA-dependent behavioral function in aged (20 months) rats with progressive 6-OHDA lesions of the nigrostriatal projection. Furthermore, the differential effects of injecting AdGDNF either near DA cell bodies in the SN or at DA terminals in the striatum were compared. AdGDNF or control vector was injected unilaterally into either the striatum or SN. One week later, rats received a unilateral intrastriatal injection of 6-OHDA on the same side as the vector injection. AdGDNF injection into either the striatum or SN significantly reduced the loss of FG labelled DA neurons 5 weeks after lesion (P </= 0.05). However, only striatal injections of AdGDNF protected against the development of behavioral deficits characteristic of unilateral DA depletion. Striatal AdGDNF injections also reduced tyrosine hydroxylase fiber loss and increased amphetamine-induced striatal Fos expression. These results demonstrate that increased levels of striatal, but not nigral, GDNF biosynthesis prevents DA neuronal loss and protects DA terminals from 6-OHDA-induced damage, thereby maintaining DA function in the aged rat.

Adenoviridae↗

PubMed1998

Use-dependent exacerbation of brain damage occurs during an early post-lesion vulnerable period.

For a period of time after unilateral brain injury, surviving neural tissue surrounding the lesion may be vulnerable to extremely high behavioral demand. Previously, we found that lesions of the forelimb representation area of the sensorimotor cortex (FL-SMC) in rats increase in size substantially when the intact forelimb is immobilized with a plaster of paris cast during the first 15 days after surgery, which forces overuse of the impaired forelimb. The present study was designed to determine whether the adult brain is more vulnerable to forced overuse of the impaired forelimb during the first 7 days post-lesion than during the second 7 days post-lesion. Using behavioral tests of forelimb use and stereological analysis of remaining tissue volume 40 days after FL-SMC lesions, we found that forced overuse of the impaired forelimb during the first 7 days after the initial damage caused expansion of neural injury and greatly interfered with restoration of function. In contrast, forced overuse of the impaired forelimb during the second 7 days had no significant effect on lesion size but nevertheless interfered with restoration of function. Thus, surviving neural tissue in the damaged hemisphere and recovery of function appear to be vulnerable to prolonged forced overuse of the impaired forelimb throughout the first 15 days, but tissue loss was detectable only when the animal was forced to use the impaired forelimb during the first 7 days after injury.

Animals↗

PubMed1998

Behavioral and cellular protection of rat dopaminergic neurons by an adenoviral vector encoding glial cell line-derived neurotrophic factor.

Previously, we observed that an adenoviral (Ad) vector encoding human glial cell line-derived neurotrophic factor (GDNF), injected near the rat substantia nigra (SN), protects SN dopaminergic (DA) neuronal soma from 6-hydroxydopamine (6-OHDA)-induced degeneration. In the present study, the effects of Ad GDNF injected into the striatum, the site of DA nerve terminals, were assessed in the same lesion model. So that effects on cell survival could be assessed without relying on DA phenotypic markers, fluorogold (FG) was infused bilaterally into striatae to retrogradely label DA neurons. Ad GDNF or control treatment (Ad mGDNF, encoding a deletion mutant GDNF, Ad lacZ, vehicle, or no injection) was injected unilaterally into the striatum near one FG site. Progressive degeneration of DA neurons was initiated 7 days later by unilateral injection of 6-OHDA at this FG site. At 42 days after 6-OHDA, Ad GDNF prevented the death of 40% of susceptible DA neurons that projected to the lesion site. Ad GDNF prevented the development of behavioral asymmetries which depend on striatal dopamine, including limb use asymmetries during spontaneous movements along vertical surfaces and amphetamine-induced rotation. Both behavioral asymmetries were exhibited by control-treated, lesioned rats. Interestingly, these behavioral protections occurred in the absence of an increase in the density of DA nerve fibers in the striatum of Ad GDNF-treated rats. ELISA measurements of transgene proteins showed that nanogram quantities of GDNF and lacZ transgene were present in the striatum for 7 weeks, and picogram quantities of GDNF in the SN due to retrograde transport of vector and/or transgene protein. These studies demonstrate that Ad GDNF can sustain increased levels of biosynthesized GDNF in the terminal region of DA neurons for at least 7 weeks and that this GDNF slows the degeneration of DA neurons and prevents the appearance of dopamine dependent motor asymmetries in a rat model of Parkinson's disease (PD). GDNF gene therapy targeted to the striatum, a more surgically accessible site than the SN, may be clinically applicable to humans with PD.

Adenoviridae↗

PubMed1998

Relationship between dendritic pruning and behavioral recovery following sensorimotor cortex lesions.

A unilateral injury to the forelimb area of the sensorimotor cortex results in an increase in dendritic arborization in the contralateral homotopic cortex which is followed by a pruning back of these dendritic arbors. The increase in arborization is due to an increase in the use of the unimpaired forelimb for postural-motor support; whereas, the dendritic pruning is related, in time, to the return to more symmetrical limb use, but is not prevented by the maintenance of asymmetrical limb use. Dendritic pruning can be prevented by administering an NMDA receptor antagonist (such as MK801 or ethanol) during the pruning phase. This manipulation also coincides with the chronic reinstatement of behavioral deficits. The purpose of this study was to see whether removing the antagonism of the NMDA receptor results in the eventual return of dendritic pruning and behavioral recovery. Therefore, MK801 was administered to lesioned animals starting at post-lesion day 18. One group received MK801 injections until day 60 (Lesion + MK60) and another lesioned group received MK801 until day 30 after which the injections were changed to saline until day 60 (Lesion + MK30). Lesion + MK60 animals showed a prevention of dendritic pruning as well as a chronic reinstatement of forelimb deficits. Lesion + MK30 animals also showed a prevention of dendritic pruning, however, they showed behavioral recovery. These findings suggest that pruning of dendritic arbors may not be directly related to behavioral recovery.

Animals↗

PubMed1998

Comparison of local and systemic ethanol effects on extracellular dopamine concentration in rat nucleus accumbens by microdialysis.

To determine the site of action of systemic ethanol on dopaminergic function in the nucleus accumbens, we compared the effect of intraperitoneal (i.p.) and local administration of ethanol on interstitial dopamine concentration using microdialysis in freely moving rats. The i.p. administration of 1 g/kg of ethanol significantly increased the dialysate dopamine (DA) concentrations (approximately 40% above basal), compared with saline treatment. The concentration-time profile of DA and ethanol in dialysates was similar after two ethanol injections 4 hr apart. Local perfusion with several ethanol concentrations showed that 510 and 860 mM of ethanol caused a significant concentration-related increase in extracellular DA concentrations in the nucleus accumbens (510 mM, 28% increase; 860 mM, 62% increase). However, lower ethanol concentrations, 170 mM or below, failed to change basal DA concentrations. Stimulation with high potassium (50 mM) in artificial cerebrospinal fluid preceding local ethanol treatment increased dialysate DA concentrations to 523 +/- 83% of basal levels, confirming that the DA terminals were responsive to pharmacological manipulation. Basal DA levels in dialysates were approximately 70% calcium-dependent when tested at the end of the local perfusion experiments. Stereological examination of the nucleus accumbens revealed probe-induced damage, but did not detect additional damage by local perfusion of ethanol. When ethanol concentrations in the DA sampling area around the probe are taken into account in both systemic and local administration experiments, this study suggests that concentrations of ethanol associated with moderate intoxication do not directly affect the function of DA terminals in the nucleus accumbens. Therefore, the systemic effects of ethanol on nucleus accumbens DAergic function is more likely due to an interaction with sites other than the nucleus accumbens.

Alcoholic Intoxication↗

PubMed1997

Ethanol consumption following recovery from unilateral damage to the forelimb area of the sensorimotor cortex: reinstatement of deficits and prevention of dendritic pruning.

Unilateral injury to the forelimb-representation area of the sensorimotor cortex (FL-SMC) in adult rats results in use-dependent proliferation of dendritic processes, followed by partial pruning, of layer V pyramidal neurons of the contralateral homotopic cortex. In development, 'exuberant' growth of neurons is often followed by pruning, a process that has been associated with a glutamatergic-NMDA receptor mechanism. A related mechanism may play a role in injury-related pruning of dendrites in adults. The N-methyl-D-aspartate (NMDA) receptor antagonist MK801, administered throughout the pruning phase to adult animals with FL-SMC lesions, prevents dendritic pruning and disrupts behavioral recovery. Ethanol (ETOH) also acts as an NMDA receptor antagonist. It has been shown to reduce NMDA-active ion currents, inhibit NMDA-evoked electrophysiological responses, and decrease glutamate-binding in the hippocampus and cortex. ETOH also affects neuromorphology in the developing and adult cerebellum, hippocampus, and cortex. Ethanol's involvement with NMDA receptor function and its influence on dendritic morphology led us to examine its effect on dendritic pruning and behavioral recovery following unilateral FL-SMC lesions. Lesioned animals were exposed to moderate doses of ethanol in a liquid diet only during the period of dendritic pruning. As with MK801, ETOH prevented pruning and reinstated chronic behavioral asymmetries.

Animals↗

PubMed1997

Intracisternal basic fibroblast growth factor enhances functional recovery and up-regulates the expression of a molecular marker of neuronal sprouting following focal cerebral infarction.

Focal cerebral infarction (stroke) due to unilateral occlusion of the middle cerebral artery in mature rats produces deficits in sensorimotor function of the contralateral limbs that recover partially over time. We found that biweekly intracisternal injection of basic fibroblast growth factor (bFGF; 0.5 microg/injection), a potent neurotrophic polypeptide, markedly enhanced recovery of sensorimotor function of the contralateral limbs during the first month after stroke without apparent adverse side effects. Immunostaining for growth-associated protein 43 (GAP-43), a molecular marker of axonal sprouting, showed a selective increase in GAP-43 immunoreactivity in the intact sensorimotor cortex contralateral to cerebral infarcts following bFGF treatment. These results show that bFGF treatment can enhance functional recovery after stroke, and that the mechanism may include stimulation of neuronal sprouting in the intact brain.

Animals↗

PubMed1997

Blind rats are not profoundly impaired in the reference memory Morris water maze and cannot be clearly discriminated from rats with cognitive deficits in the cued platform task.

The Morris water maze is commonly used to test cognitive function in rodent models of neurological disorders including age-related cognitive deficits. It is often assumed that the most profoundly impaired aged rats may be blind due to retinal degeneration, and it has been reported that animals with visual sensory deficits can be identified based on their performance in a cued platform task. The results of the present study demonstrate that blind rats can perform surprisingly well in the reference memory version of the Morris water maze, and that blind rats cannot be selectively excluded based on performance in the cued platform task since atropine-treated rats also perform poorly in the cued platform task. Future studies may be able to develop screening procedures that help to eliminate subjects with non-cognitive deficits, but the present results do not support the use of the cued platform or straight swim task as screening procedures. Experimenters must be careful to consider the role that visual sensory function and other non-cognitive factors may have in performance of the spatial learning Morris water maze, and also the role that severe cognitive deficits may have in performance of the cued platform task.

Animals↗

PubMed1997

Effect of ethanol on extracellular dopamine in rat striatum by direct perfusion with microdialysis.

The concentration-related effects of ethanol on extracellular dopamine (DA) in rat striatum were studied by direct perfusion through microdialysis probes in freely moving rats. Two sets of three ethanol concentrations were separately tested using a Latin square experimental design. Potassium stimulation with high potassium (50 mM) in artificial CSF (ACSF) preceding ethanol treatment confirmed the neuronal function of dopaminergic cells by increasing DA concentrations to 200-1,500% of basal levels. The perfusion with calcium-free ACSF applied at the end of each experiment confirmed the calcium dependency of the basal levels of extracellular DA by decreasing basal DA levels by 70%. The striatal volume measurement to examine the possible brain damage by direct ethanol perfusion suggested that ethanol did not increase the damage caused by the probe implantation at any ethanol concentration tested in this study. The 30-min direct perfusion of 510 and 860 mM ethanol resulted in a significant concentration-related stimulatory effect on the extracellular DA concentration in rat striatum (510 mM, 29% increase, p < 0.05; 860 mM, 66% increase, p < 0.05). However, there was no significant effect of ethanol at low concentrations, < or = 170 mM. Considering the effective ethanol concentration in tissue areas in which DA is sampled, the data suggest that concentrations of ethanol associated with moderate intoxication do not directly affect the extracellular concentration of DA in the striatum. Therefore, the systemic effects of ethanol on striatal DA found in previous studies may be caused by the interaction with sites other than the striatum.

Animals↗

PubMed1997

Use-dependent structural events in recovery of function.

We described research suggesting that forelimb use is essential for marked neural growth in the intact cortex after unilateral forelimb-cortical lesions. Although unilateral brain injury can cause severe functional impairment, the injury may be capable of mobilizing potent resources for compensatory changes such as dendritic arborization in the noninjured hemisphere, but only for a limited period of time and only with appropriate behavioral pressure. Unexpectedly, surviving tissue in the injured hemisphere may be fatally vulnerable to excessive behavioral demand. If the impaired limb is overused because the nonimpaired limb is restricted by a one-sleeve cast, injury size is greatly increased and recovery of function is severely disrupted. It is hypothesized that behaviorally driven neurotransmitter release relating to forced use of the forelimb may be toxic to surviving tissue that has been partially traumatized by the lesion. These data and hypotheses are summarized in Fig. 7. The "use-it-or-lose-it" rehabilitative approach is popular, but perhaps a less aggressive strategy should be adopted for optimal restoration of function in the injured hemisphere. Whereas traditional experiments on mechanisms of recovery of function are designed specifically to determine potentially compensatory neural changes that might mediate behavioral outcome, these experiments support a quite different view of the interplay between neural and behavioral events: behavioral changes may directly alter anatomical events.

Animals↗

PubMed1996

Use-dependent exaggeration of neuronal injury after unilateral sensorimotor cortex lesions.

Unilateral injury to the forelimb representation area of the sensorimotor cortex (FL-SMC) in adult rats causes over-reliance on the unimpaired forelimb for postural-motor movements, as well as overgrowth of layer V pyramidal cell dendrites in the homotopic cortex of the noninjured hemisphere. The overgrowth appears to be use-dependent because it can be prevented by restricting movements of the unimpaired forelimb. Additionally, restricting the unimpaired forelimb in animals with FL-SMC damage results in significantly greater behavioral dysfunction when examined 2 d after cast removal (compared to that after impaired-limb immobilization, or no limb immobilization). In the present study, the long-term behavioral and anatomical effects of limb immobilization were examined. Animals with FL-SMC lesions were fitted with casts immediately after the lesion that immobilized the impaired forelimb, the unimpaired forelimb, or neither forelimb for 15 d. Immobilization of the nonimpaired forelimb resulted in chronic prevention of dendritic growth and severe and chronic behavioral deficits. In addition, immobilization of the nonimpaired forelimb resulted in a dramatic exaggeration of the neuronal injury, presumably attributable to forced overuse of the impaired limb. Immobilization of the impaired forelimb resulted in no detectable neural changes and in only slightly increased and longer-lasting behavioral asymmetries (compared to nonimmobilized, lesioned animals), presumably attributable to mild disuse of the impaired limb. Immobilization of a single forelimb in nonlesioned rats resulted in no significant behavioral or anatomical changes. Together, these results suggest that although behavioral experience can enhance neural growth after brain injury, the region surrounding the injury may be vulnerable to behavioral pressure during the early postlesion period.

Animals↗

PubMed1996

Anticholinergic effects on acquisition of place learning in the Morris water task: spatial mapping deficit or inability to inhibit nonplace strategies?

The role of central cholinergic blockage in spatial learning was examined by testing atropine sulfate-treated (50 mg/kg) rats and saline-injected controls in the Morris water task using training procedures designed to promote the use of a spatial search strategy. First, constraints used in early trials deterred thigmotaxis. Second, an originally oversized hidden platform that nearly occupied the entire pool was effectively "shrunk" into the southwest quadrant of the pool by substituting smaller platforms over trials, a procedure intended to focus attention on the hidden platform in relation to extramaze cues. Task acquisition did not differ between groups, and on the probe trial both groups increased distance and latency and swam preferentially in the previously correct quadrant. Impairments caused by atropine sulfate may be the result of deficits in ability to inhibit nonefficient escape strategies.

Animals↗

PubMed1995

Implantation of encapsulated catecholamine and GDNF-producing cells in rats with unilateral dopamine depletions and parkinsonian symptoms.

Studies in rodents suggest that PC12 cells, encapsulated in semipermeable ultrafiltration membranes and implanted in the striatum, have some potential efficacy for the treatment of age- and 6-OHD-induced sensorimotor impairments (22, 70, 71, 74). The objectives of this study were to: (1) determine if baby hamster kidney cells engineered to secrete glial cell line-derived neurotrophic factor (BHK-GDNF) would survive encapsulation and implantation in a dopamine-depleted rodent striatum, (2) compare polymer-encapsulated PC12 and PC12A cells in terms of their ability to survive and produce catecholamines in vivo in a dopamine-depleted striatum, and (3) determine if BHK-GDNF, PC12, or PC12A cells reduce parkinsonian symptoms in a rodent model of Parkinson's disease. Capsules with BHK-GDNF or PC12 cells contained viable cells after 90 days in vivo, with little evidence of host tissue damage/gliosis. In rats with tyrosine hydroxylase (TH)-positive fibers remaining in the lesioned striatum, there was TH-positive fiber ingrowth into the membranes of the BHK-GDNF capsules. PC12-containing capsules had higher basal release of both dopamine and L-DOPA after 90 days in vivo than before implantation, while basal release of both dopamine and L-DOPA decreased in the PC12A-containing capsules. Both encapsulated PC12 and PC12A cells, but not encapsulated BHK-GDNF cells, decreased apomorphine-induced rotations. Parkinsonian symptoms (akinesia, freezing/bracing, sensorimotor neglect) related to the extent of dopamine depletion were evident even in rats with dopamine depletions of only 25%. Evidence that encapsulated cells may attenuate these parkinsonian symptoms was not detected but most of the rats were more severely depleted of dopamine than Parkinson's patients (less than 2% dopamine remaining in the entire striatum), and these tests were not sensitive to differences between rats with less than 10% dopamine remaining. These results suggest that cell encapsulation technology can safely provide site-specific delivery of dopaminergic agonists or growth factors within the CNS, without requiring suppression of the immune system, and without using fetal tissue. Of the three types of encapsulated cells examined in the present study, PC12 cells seem to offer the most therapeutic potential in rats with severe dopamine depletions.

Animals↗

PubMed1994

Use-dependent growth of pyramidal neurons after neocortical damage.

Unilateral damage to the forelimb representation area of the sensorimotor cortex in adult rats increases dendritic arborization of layer V pyramidal neurons of the contralateral homotopic cortex. Arbor size was maximum at approximately 18 d postlesion, following which there was a partial elimination, or pruning, of dendritic processes. These neural changes were closely associated with behavioral events. The overgrowth of dendrites was related in time to disuse of the contralateral (to the lesion) forelimb and over-reliance on the ipsilateral forelimb for postural and exploratory movements. The pruning of dendrites was related to a return to more symmetrical use of the forelimbs. To investigate the possibility that lesion-induced asymmetries in motor behavior contributed to dendritic arborization changes, movements of the forelimb ipsilateral to the lesion were restricted during the period of dendritic overgrowth through the use of one-holed vests. This interfered with the increase in dendritic arborization. In contrast, animals that were allowed to use both forelimbs, or only the forelimb ipsilateral to the lesion, showed the expected increases. When sham-operated rats were forced to use only one forelimb, no significant increases in arborization were found. Therefore, neither a lesion nor asymmetrical limb use alone could account for the dendritic overgrowth--it depended on a lesion-behavior interaction. Furthermore, greater sensorimotor impairments were found when the dendritic growth was blocked, suggesting that the neural growth and/or associated limb-use behavior were related to functional recovery from the cortical damage. Finally, in a second experiment, immobilization of the impaired limb during the pruning period did not prevent the elimination of processes. Thus, the pruning of neural processes was not related simply to the recovery of more symmetrical forelimb use. There may be a period early after brain damage during which marked neural structural changes can occur in the presence of adequate behavioral demand.

Animals↗