Lauriston Kellaway

Stress reduces the neuroprotective effect of exercise in a rat model for Parkinson's disease.

Parkinsons disease (PD) is a progressive neurodegenerative disease of nigrostriatal dopamine (DA) neurons that project from the substantia nigra pars compacta (SNc) to the striatum. To further understand PD, researchers have developed standardized animal models of PD. In this study, Long Evans (LE) rats were unilaterally lesioned by injection of the neurotoxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle (MFB) of the left hemisphere. The rats were divided into three groups randomly; group 1 (runners) were housed in individual cages with attached running wheels, group 2 (stressed-runners) had access to individual free running wheels, except post-lesion when the rats were subjected to immobilization of the running wheel for 1 h per day for 14 days, as well as one session of 24-h food deprivation and a 7-h shift in the light/dark cycle. Group 3 (non-runnners) were housed individually in cages with attached running wheels that were permanently immobilized. Subcutaneous injection of the DA agonist, apomorphine, caused stressed-runners and non-runners to rotate vigorously away from the side of the lesion (contralaterally). Apomorphine-induced rotations provide a behavioural measure of the extent of the lesion, a depletion of more than 80% of DA neurons is required to produce vigorous contralateral rotations in response to apomorphine injection. Runners rotated significantly less than non-runners and stressed-runners. The number of rotations performed by stressed-runners was not significantly different from non-runners, suggesting that stress had cancelled the neuroprotective effect of running. Immunohistochemical staining for tyrosine hydroxylase in the SNc revealed slightly less destruction of DA neurons in the runners than in stressed-runners or non-runners, although these differences did not achieve statistical significance. The behavioural results confirm a previous finding suggesting that voluntary exercise is neuroprotective. A novel finding is that mild stressors cancel the neuroprotection afforded by voluntary exercise.

NMDA Receptor Function in the Prefrontal Cortex of a Rat Model for Attention-Deficit Hyperactivity Disorder

The spontaneously hypertensive rat (SHR) is an accepted model for attention-deficit hyperactivity disorder (ADHD) since it displays the major symptoms of ADHD (hyperactivity, impulsivity, and poor performance in tasks that require sustained attention). We have previously shown that glutamate activation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors released significantly more norepinephrine from SHR prefrontal cortex slices than control Wistar-Kyoto (WKY) rats. The aim of this study was to determine whether N-methyl-D-aspartate (NMDA) receptor function is disturbed in the prefrontal cortex of SHR. Prefrontal cortex slices were incubated with 45Ca2+ in the presence or absence of 100 μM NMDA for 2 min. Activation of NMDA receptors stimulated significantly less Ca2+ uptake into prefrontal cortex slices of SHR than control WKY (2.8 ± 0.17 vs. 3.7 ± 0.38 nmol/mg protein, respectively, P < 0.05). Basal Ca2+ uptake into SHR slices was not significantly different from WKY. These findings are consistent with suggestions that the intracellular concentration of calcium is elevated and therefore the concentration gradient that drives calcium into the cell is decreased in SHR compared to WKY. Impaired NMDA receptor function in the prefrontal cortex of SHR could give rise to impaired cognition and an inability to sustain attention.

The crossed nigrostriatal projection decussates in the ventral tegmental decussation

Horseradish peroxidase (HRP) tract-tracing techniques were used in 44 rats in order to establish the site of decussation of the crossed nigrostriatal projection. Somata in both the ipsilateral and the contralateral ventromedial mesencephalon were labelled after injection of HRP into the caudate nucleus. In agreement with previous studies, contralateral labelling constituted about 3% of the ipsilateral labelling. Midsagittal transection of the mesodiencephalic junction did not prevent the contralateral labelling. However, mid-sagittal transection of the ventral mesencephalon, or selective 6-hydroxydopamine (6-OHDA) lesions of the ventral tegmental decussation did prevent the contralateral labelling. Moreover, 6-OHDA lesions of the substantia nigra ipsilateral to the horseradish peroxidase injection also prevented contralateral labelling. We conclude that the crossed nigrostriatal projection decussates in the ventral tegmental decussation, and that this projection is susceptible to damage by standard 6-OHDA lesions located on the opposite side to the origin of the crossed pathway.

Maternal separation affects dopamine transporter function in the spontaneously hypertensive rat: an in vivo electrochemical study

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a developmental disorder characterised by symptoms of inattention, impulsivity and hyperactivity. The spontaneously hypertensive rat (SHR) is a well-characterised model of this disorder and has been shown to exhibit dopamine dysregulation, one of the hypothesised causes of ADHD. Since stress experienced in the early stages of life can have long-lasting effects on behaviour, it was considered that early life stress may alter development of the dopaminergic system and thereby contribute to the behavioural characteristics of SHR. It was hypothesized that maternal separation would alter dopamine regulation by the transporter (DAT) in ways that distinguish SHR from control rat strains.MethodsSHR and control Wistar-Kyoto (WKY) rats were subjected to maternal separation for 3 hours per day from postnatal day 2 to 14. Rats were tested for separation-induced anxiety-like behaviour followed by in vivo chronoamperometry to determine whether changes had occurred in striatal clearance of dopamine by DAT. The rate of disappearance of ejected dopamine was used as a measure of DAT function.ResultsConsistent with a model for ADHD, SHR were more active than WKY in the open field. SHR entered the inner zone more frequently and covered a significantly greater distance than WKY. Maternal separation increased the time that WKY spent in the closed arms and latency to enter the open arms of the elevated plus maze, consistent with other rat strains. Of note is that, maternal separation failed to produce anxiety-like behaviour in SHR. Analysis of the chronoamperometric data revealed that there was no difference in DAT function in the striatum of non-separated SHR and WKY. Maternal separation decreased the rate of dopamine clearance (k-1) in SHR striatum. Consistent with this observation, the dopamine clearance time (T100) was increased in SHR. These results suggest that the chronic mild stress of maternal separation impaired the function of striatal DAT in SHR.ConclusionsThe present findings suggest that maternal separation failed to alter the behaviour of SHR in the open field and elevated plus maze. However, maternal separation altered the dopaminergic system by decreasing surface expression of DAT and/or the affinity of DAT for dopamine, increasing the time to clear dopamine from the extracellular fluid in the striatum of SHR.

Maternal separation exaggerates the toxic effects of 6-hydroxydopamine in rats: Implications for neurodegenerative disorders

Many studies have shown that early life stress may lead to impaired brain development, and may be a risk factor for developing psychiatric pathologies such as depression. However, few studies have investigated the impact that early life stress might have on the onset and development of neurodegenerative disorders, such as Parkinsons disease, which is characterized in part by the degeneration of dopaminergic neurons in the nigrostriatal pathway. The present study subjected rat pups to a maternal separation paradigm that has been shown to model adverse early life events, and investigated the effects that it has on motor deficits induced by a unilateral, intrastriatal injection of 6-hydroxydopamine (12 μg/4 μl). The female rats were assessed for behavioral changes at 28 days post-lesion with a battery of tests that are sensitive to the degree of dopamine loss. The results showed that rats that had been subjected to maternal separation display significantly impaired performance in the vibrissae and single-limb akinesia test when compared to normally reared animals. In addition, there was a significant increase in the loss of tyrosine hydroxylase staining in maternally separated rats. Our results therefore suggest that adverse experiences sustained during early life contribute to making dopamine neurons more susceptible to subsequent insults occurring during more mature stages of life and may therefore play a role in the etiopathogenesis of Parkinsons disease.

Voluntary running distance is negatively correlated with striatal dopamine release in untrained rats

This study examined the relationship between voluntary running distance and glutamate- and K+-stimulated dopamine release in the striatum (nucleus accumbens and caudate-putamen) of male Long-Evans rats. Twenty-one rats were housed individually in cages with attached running-wheels for 1 week. There was a 19-fold variability between rats in voluntary running distances over this period (range = 2.3-44.6 km). The average distance completed during the week was 16 +/- 2.8 km. There was a strong positive correlation between the running distances completed during the first 24 h (day 1) and the last 24 h. Certain rats were therefore inclined to run from the start. The average daily running distance (2.4 +/- 0.4 km per day) was negatively correlated with the weight of the rat (r = -0.82). Glutamate-stimulated release of dopamine was not a significant predictor of voluntary running distance. However, the average daily running distance was negatively correlated with K+-stimulated dopamine release in the nucleus accumbens core and caudate-putamen but not the nucleus accumbens shell. The present findings suggest that decreased depolarization-induced release of striatal dopamine may be a predictor of hyperactivity. The results show, in a normal population of Long-Evans rats, that there are, at the end of the continuum, rats that display some of the neurochemical and behavioral characteristics of a rat model for attention-deficit hyperactivity disorder.

IL-4R{alpha}-responsive smooth muscle cells increase intestinal hypercontractility and contribute to resistance during acute Schistosomiasis.

Interleukin-(IL)-4 and IL-13 signal through heterodimeric receptors containing a common IL-4 receptor-alpha (IL-4Ralpha) subunit, which is important for protection against helminth infections, including schistosomiasis. Previous studies demonstrated important roles for IL-4Ralpha-responsive hematopoietic cells, including T cells and macrophages in schistosomiasis. In this study, we examined the role of IL-4Ralpha responsiveness by nonhematopoietic smooth muscle cells during experimental acute murine schistosomiasis. Comparative Schistosoma mansoni infection studies with smooth muscle cell-specific IL-4Ralpha-deficient (SM-MHC(cre)IL-4Ralpha(-/flox)) mice, heterozygous control (IL-4Ralpha(-/flox)) mice, and global IL-4Ralpha-deficient (IL-4Ralpha(-/-)) mice were conducted. S. mansoni-infected SM-MHC(cre)IL-4Ralpha(-/flox) mice showed increased weight loss and earlier mortalities compared with IL-4Ralpha(-/flox) mice, despite comparable T(H)2/type 2 immune responses. In contrast to highly susceptible IL-4Ralpha-deficient mice, increased susceptibility in SM-MHC(cre)IL-4Ralpha(-/flox) mice was not accompanied by intestinal tissue damage and subsequent sepsis. However, both susceptible mutant mouse strains failed to efficiently expel eggs, demonstrated by egg reduction in the feces compared with control mice. Reduced egg expulsion was accompanied by impaired IL-4/IL-13-mediated hypercontractile intestinal responses, which was present in the more resistant control mice. Together, we conclude that IL-4Ralpha responsiveness by smooth muscle cells and subsequent IL-4- and IL-13-mediated hypercontractility are required for host protection during acute schistosomiasis to efficiently expel S. mansoni eggs and to prevent premature mortality.

Event-related potentials, reaction time, and response selection of skilled and less-skilled cricket batsmen.

The differences in P300 latency, P300 amplitude, response selection, and reaction time between skilled and less-skilled cricket batsmen have been investigated. Eight skilled and ten less-skilled right-handed batsmen each viewed 100 in-swing, 100 out-swing, and 40 slower deliveries displayed in random sequence from projected video footage whilst their responses and electro-encephalograms were recorded. Logistic regression was used to derive a discriminative function for the P300 data. This was done to determine whether the skilled batsmen differed from the less-skilled batsmen on the basis of pooled P300 amplitude and latency data. All the batsmen were correctly characterised as being skilled or less-skilled. Logistic regression equations with reaction time and correctness of response data indicated that behavioural data do not correctly classify skilled performance. It is suggested that skilled cricket batsmen have a superior perceptual decision-making ability compared with less-skilled cricket batsmen, as measured by P300 latency and amplitude. This appears to be the first study showing a link between skill and cerebral cortical activity during a perceptual cricket batting task and it could pave the way for future studies on mental processing in cricket batsmen.

NMDA-stimulated Ca2+ uptake into barrel cortex slices of spontaneously hypertensive rats.

The spontaneously hypertensive rat (SHR) is used as a model for attention-deficit hyperactivity disorder (ADHD), since it has behavioural characteristics that resemble the behavioral disturbances of ADHD, namely hyperactivity, failure to sustain attention, and impulsiveness. The aim of this study was to establish whether N-methyl-D-aspartate (NMDA) receptor function was altered in barrel cortex slices of 4- to 6- week-old SHR compared to their normotensive Wistar-Kyoto (WKY) control rats. The barrel cortex was dissected from brain slices corresponding to antero-posterior coordinates 8.7–4.8 mm with reference to the Paxinos and Watson (1986) atlas and divided into rostral, middle, and caudal regions. 45Ca2+ uptake was stimulated by incubating test slices in buffer containing 100 μM NMDA for 2 min at 35°. Total 45Ca2+ uptake into the entire barrel cortex as well as uptake into all regions of SHR barrel cortex was lower compared to WKY. Basal uptake into the entire barrel cortex as well as uptake into rostral and caudal regions of SHR barrel cortex was lower than WKY but basal uptake into the middle region was the same for both strains. There was no difference between SHR and WKY in NMDA-stimulated 45Ca2+ uptake into barrel cortex slices except for significantly lower NMDA-stimulated uptake into the middle region of SHR barrel cortex compared to WKY. These findings suggest that calcium metabolism is disturbed in the somatosensory cortex of SHR but that NMDA receptor function is not altered.

Transient contralateral rotation following unilateral substantia nigra lesion reflects susceptibility of the nigrostriatal system to exhaustion by amphetamine

Following unilateral 6-OHDA induced SN lesion, a transient period of contralateral rotation has been reported to precede the predominant ipsilateral circling. In order to clarify the nature of this initial contralateral rotation we examined the effect of the duration of recovery period after the lesion, on amphetamine-induced rotational behavior. Three days post lesion, most rats circled predominantly contralaterally to the lesion. Such contralateral rotation may result from either degeneration-induced breakdown of the DA pool, or lesion-induced increase of DA turnover in the spared neurons. A substantial degree of contralateral preference was still evident when amphetamine was administered for the first time 24 days after lesioning, indicating involvement of spared cells in the contralateral rotation. However, regardless of the duration of recovery (and irrespective of either lesion volume, amphetamine dose, or post-lesion motor exercise), amphetamine-induced rotation tended to become gradually more ipsilateral as the observation session progressed, and all rats circled ipsilaterally to the lesion in response to further amphetamine injections. These findings suggest that amphetamine has an irreversible effect on the post-lesion DA pool contributing to contralateral rotation.