Lesion-induced Asymmetry Research Articles

Androgens exacerbate motor asymmetry in male rats with unilateral 6-hydroxydopamine lesion

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by dopamine neuron loss in the nigrostriatal pathway that shows greater incidence in men than women. The mechanisms underlying this gender bias remain elusive, although one possibility is that androgens may increase dopamine neuronal vulnerability to oxidative stress. Motor impairment can be modeled in rats receiving a unilateral injection of 6-hydroxydopamine (6-OHDA), a neurotoxin producing nigrostriatal degeneration. To investigate the role of androgens in PD, we compared young (2months) and aged (24months) male rats receiving gonadectomy (GDX) and their corresponding intact controls. One month after GDX, rats were unilaterally injected with 6-OHDA, and their motor impairment and asymmetry were assessed 2weeks later using the cylinder test and the amphetamine-induced rotation test. Plasma samples were also collected to assess the concentration of testosterone and advanced oxidation protein products, a product of oxidative stress. GDX decreased lesion-induced asymmetry along with oxidative stress and increased amphetamine-induced rotations. These results show that GDX improves motor behaviors by decreasing motor asymmetry in 6-OHDA-treated rats, an effect that may be ascribed to increased release of striatal dopamine and decreased oxidative stress. Collectively, the data support the hypothesis that androgens may underlie the gender bias observed in PD.

Relationship between Behavioral Recovery from Unilateral 6-OHDA Lesion of the Substania Nigra and Changes in the Tuberomammillary-Striatal Projection as Measured by HRP-Labelling

The tuberomammillary nucleus (TM) is the only known neuronal cell group in the brain which contains histamine. There is evidence for a reciprocal relationship between the effects of histamine and dopamine on behavior. A unilateral lesion of dopamine cells in the Substantia Nigra (SN) results in asymmetrical behavior, and recovery from this asymmetry was previously found to be associated with asymmetrical changes in the nigro-striatal projection as determined by anatomical tracing technique. In view of the apparent opposing interaction between the TM and the SN, we examined whether the tuberomammillary-striatal projection also shows changes after a unilateral lesion of the SN. Rats had 6-OHDA injected into one substantia nigra and were tested for behavioral asymmetry over a 15 day period. Horseradish peroxidase (HRP) was then deposited in the caudate-putamen (CPU) ipsilateral to the lesion. Controls devoid of a lesion had the tracer deposited in either the right of left CPU. More HRP-labeled cells were found in the anterior part of TM ipsilateral to the lesion in the animals which failed to recover from lesion-induced asymmetry in turning behavior, as compared to normal controls or animals which showed behavioral recovery. The labeled cells in the anterior part of the ipsilateral TM were smaller in animals examined 15 days after the lesions than in the control animals. The results indicate an increase in HRP uptake or transport in the anterior part of the tuberomammillary-striatal projection predominantly ipsilateral to the lesion in animals which failed to recover from lesion induced asymmetry. Previously, we had found an opposite effect in the nigro-striatal projection, namely an increase in HRP uptake or transport only in animals which recovered from their lesion induced asymmetry. The results are discussed in terms of the evidence for a reciprocal relationship between the TM- and SN-striatal systems.

Behavioral correlates of transneuronal degeneration of substantia nigra reticulata neurons are reversed by ablation of the subthalamic nucleus

In rats, acute injury of neurons in the caudate nucleus (CN) and globus pallidus (GP) by local injection of ibotenic acid (IA) or by transient forebrain ischemia has caused transneuronal cell death of neurons in the substantia nigra reticulata (SNr) weeks after the initial injury. Recently transient expression of an immediate early gene c-fos was induced specifically in neurons of the subthalamic nucleus (STN) and SNr at 36–48 h after the IA-lesions, prior to the delayed degeneration of SNr neurons. These cellular and molecular events may alter the level of inhibitory output from the basal ganglia and lead to movement disorders. To test (i) whether movement disorders occur in the early period after unilateral lesions of the CN and GP by IA-injection, and (ii) whether ablation of the STN reverses the early movement disorders, we used a modified version of Porsolt forced swim test in which the lesion-induced asymmetry of motor function becomes apparent as rotation when the animals are forced to swim. Following unilateral IA-lesions of the right CN and GP in rats, rapid contraversive rotation appeared transiently 36–48 h after the lesions, and, in turn, slow ipsiversive rotation appeared at 3–5 days postlesion. Prior ablation of the ipsilateral STN reversed these early movement disorders produced by the unilateral IA-lesions of the CN and GP and instead created persistent contraversive rotation 7–10 days after the lesions. Each phase of the dominant rotation behavior was dependent on asymmetrical limb motor activity; decreased left limb activity caused contraversive rotation, and increased left limb activity caused ipsiversive rotation. Reversal of these early movement disorders suggests that ablatin of the STN prevents the transneuronal degeneration of the SNr.

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.

Changes in the nigrostriatal projection associated with recovery from lesion-induced behavioral asymmetry

Possible neuronanatomical changes correlated with recovery from lesion-induced behavioral asymmetry were examined. Rats, with 6-OHDA injected into the substantia nigra (SN) on one side, were either assigned to a group with a 48-hour survival period, or one with a 15-day recovery period. Control groups, without a lesion, were also included. All animals were tested for behavioral asymmetry and, at the end of the survival period, had horseradish peroxidase (HRP) deposited in the caudate-putamen (CPU) ipsilateral to the lesion (right or left CPU in the controls). Both substantia nigrae of all animals were examined for HRP-labeled cells. Animals given a 15-day recovery period had more HRP-labeled cells in the SN ipsilateral to the HRP deposition site than those given a 1-day recovery period. Also animals which showed behavioral recovery had more HRP-labeled cells in their ipsilateral SN than either those which showed no recovery or those which were not given time to recover. Thus, our results suggested that behavioral recovery from lesion-induced asymmetry was associated with an increase in HRP uptake and retrograde transport by the remaining nigrostriatal terminals. Animals which recovered showed the expected decrease in ipsiversive, and increase in contraversive turning with time. Unexpectedly, animals which did not recover exhibited an increase in ipsiversive, and a decrease in contraversive turning with time.

Graft-derived recovery from 6-OHDA lesions: specificity of ventral mesencephalic graft tissues.

A series of experiments have been conducted to assess the specificity of recovery from motor asymmetries that is provided by dopamine-rich grafts in the neostriatum of rats with unilateral dopamine-depleting lesions produced by injection of 6-hydroxydopamine into the ascending nigrostriatal pathway. Grafts of embryonic tissue taken from the substantia nigra (rich in dopamine neurons could provide a complete recovery of methamphetamine-induced rotation and a partial recovery of apomorphine-induced rotation, whereas no recovery was seen in rats with grafts of tissue rich in another monoamine (serotonin, dissected from the mesencephalic raphe) or of tissue appropriate to the target (dissected from the striatal eminence). 6-Hydroxydopamine lesions of dopamine cells in the grafts of recovered animals reinstated the initial lesion-induced asymmetry. Dopamine-rich grafts implanted into the intact neostriatum did not induce any "supernormal" asymmetry in the rats, but did provide a "prophylactic" protection against subsequent lesions of the intrinsic ipsilateral dopamine nigrostriatal system. Post-mortem biochemical assays indicated that the extent of dopamine depletion in the neostriatum of lesioned rats correlated highly with both methamphetamine and apomorphine turning rates. Similarly, both drug rotation tests correlated significantly with the extent of dopamine restoration in the dorsal striatum of rats with dopamine-rich grafts, the correlation being significantly higher for the methamphetamine than for the apomorphine test.

Effect of forebrain commissurotomy on recovery from unilateral 6-OHDA lesions of the substantia nigra and circling induced by apomorphine

We studied the influence of transection of the interhemispheric fiber systems between the anterior and posterior commissures on recovery from turning behavior induced by a unilateral substantia nigra lesion in rats. It has been argued that the crossed nigrostriatal projection is involved in this recovery, and its site of crossing has been suggested to lie within the region split. Animals which received this transection did not differ from controls with respect to time-course and extent of recovery from lesion-induced asymmetries within the 7 postlesion days examined. Additionally, the commissurotomy did not prevent apomorphine-induced contraversive circling.

On the role of vestibulo-ocular reflex plasticity in recovery after unilateral peripheral vestibular lesions.

Although adaptive plasticity is a well-known feature of the vestibulo-ocular reflex (VOR), deficits in VOR performance after unilateral labyrinthectomy are poorly compensated in a large percentage of cats. To assess whether VOR plastic capabilities are affected by labyrinthectomy, forced oscillation in front of a patterned surround was imposed in unilaterally labyrinthectomized cats. This experimental paradigm has been shown to be very effective in inducing adaptive VOR gain changes in intact animals. We demonstrate that plasticity of VOR gain is still present both in acute and chronic stages following vestibular lesions. By contrast, forced oscillation did not significantly alter the lesion-induced asymmetry of responses. We conclude that VOR gain control mechanisms are not used to their fullest possible extent in a large percentage of animals suffering unilateral vestibular damage.

The effects of denervation and chronic haloperidol treatment on neostriatal dopamine receptor density are not additive in the rat

The effects of combined denervation and chronic haloperidol treatment on neostriatal D-2 receptor density were examined, and a lack of additivity was found. In the first experiment, haloperidol treatment for 14 days initiated on day 4 after the unilateral intracerebral injection of 6-hydroxydopamine (6-OHDA) abolished the lesion-induced asymmetry of [ 3H]spiroperidol binding by elevating the density of sites in the intact striatum. These results were replicated in the second experiment, in which the drug treatment was begun 4–5 weeks after 6-OHDA. In both experiments the apomorphine-induced rotation did not differ significantly between lesioned rats treated with haloperidol or its vehicle.

Effects of reducing sensory-motor feedback on the appearance of crossed nigro-thalamic projections and recovery from turning induced by unilateral substantia nigra lesions

This experiment addressed the question of whether the increase in interhemispheric nigro-thalamic projections, found after unilateral lesions of the substantia nigra (SN), is related to recovery from the lesion-induced sensory-motor asymmetry. We examined the effects of diminished information feedback about the animals' own behavior on recovery from turning induced by unilateral substantia nigra lesions, and the appearance of an increase in number of crossed nigro-thalamic projections. The animals received unilateral 6-hydroxydopamine lesions and were placed in a hammock for the next 7 days. Thus, they were prevented from engaging in turning behavior. They were then implanted with horseradish peroxidase (HRP) in the thalamus ipsilateral to the lesion. No HRP-labeled cells were found in the SN contralateral to the HRP implantation in these animals. In rats, which were allowed 7 days normal interaction with the environment subsequent to unilateral SN damage, labeled cells were found in the undamaged SN when HRP was implanted in the thalamus ipsilateral to the lesion. Animals which were kept in the hammock and subsequently allowed a week of normal interactipn with the environment showed the same pattern of recovery from turning behavior as the animals which were allowed to recover normally immediately after the unilateral SN lesion. It was concluded that the relationship between the appearance of the nigro-thalamic projections and the cessation of turning behavior is not fortuitious. Also, it would appear that some form of sensory-motor learning is involved in the recovery of function after unilateral SN lesions. Thus, the results substantiate the idea that these cross-projections form part of a physical basis of recovery from unilateral lesion-induced asymmetries.

The spontaneous firing patterns of forebrain neurons. III. Prevention of induced asymmetries in caudate neuronal firing rates by unilateral thalamic lesions

Unilateral lesions interrupting striatal outputs and inputs (MFB lesions) produce a marked slowing of neuronal firing in the caudate nucleus contralateral to the side of the lesions without affecting neuronal firing in the ipsilateral caudate nucleus. Although the MFB lesion also interrupts the nigrostriatal pathway and depletes the ipsilateral striatum of dipamine and its associated enzymes, the slowing of unit firing rates is apparently due to interruption of striatal outputs rather than inputs. Unilateral thalamic lesions palced ipsilateral to MFB lesions in iether the ventral anterior-ventrolateral nuclei (VA-VL) or in the center median-parafascicular nuclei (CM-PF) prevent the MFB lesion-induced asymmetry in caudate neuronal firing rates. These thalamic lesions do not, however, restore the striatal dopamine content depleted by the MFB lesion. Unilateral CM-PF lesions in otherwise intact cats do not alter caudate unit firing rates nor do they affect striatal dopamine. VA-VL lesions in otherwise intact cats produce a bilateral slowing in the spontaneous firing of neurons in the caudate nuclei, again, whithout altering caudate dopamine concentrations. These results provide further evidence that caudate dopamine concentration per se does not appear to be a potent variable in controlling the spontaneous firing rates of striatal neurons.