Modulation of anxiety behavior by intranasally administered vaccinia virus complement control protein and curcumin in a mouse model of Alzheimer's disease.

Widespread neuroinflammation in the central nervous system (CNS) of Alzheimer's disease (AD) patients, involving pro-inflammatory mediators such as complement components, might be responsible for AD associated behavioral symptoms such as anxiety. Vaccinia virus complement control protein (VCP) and curcumin (Cur) are the bioactive compounds of natural origin shown to inhibit the in-vitro complement activation. In order to develop complement regulatory compounds which could be delivered to the CNS by a non-invasive route, VCP, its truncated version (tVCP), and Cur were administered to Wistar rats intranasally. The distribution of these compounds in cerebrospinal fluid (CSF) was studied using an enzyme linked immunosorbent assay (ELISA), using VCP and tVCP as antigens and a modified fluorimetric method (Cur). VCP and tVCP were also detected in the olfactory lobes of the rat brain using immunohistochemical analysis. These compounds were then compared for their ability to attenuate the anxiety levels in APPswePS1δE9 mice using an elevated plus maze (EPM) apparatus. VCP treatment significantly improved the exploratory behavior and reduced the anxiety behavior in APPswePS1δE9 mice. tVCP however showed an opposite effect to VCP, whereas Cur showed no effect on the anxiety behavior of these mice. When these mice were subsequently tested for their cognitive performance in the Morris water maze (MWM), they showed tendencies to collide with the periphery of the walls of MWM. This unusual activity was termed "kissperi" behavior. This newly defined index of anxiety was comparable to the anxiety profile of the VCP and tVCP treated groups on EPM. VCP can thus be delivered to the CNS effectively via intranasal route of administration to attenuate anxiety associated with AD.

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 Parkinson's 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 microg/4 microl). 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 Parkinson's disease.

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 electroencephalograms 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.

Early pubertal female rats are more resistant than males to 6-hydroxydopamine neurotoxicity and behavioural deficits: a possible role for trophic factors.

PURPOSE: The infusion of 6-hydroxydopamine (6-OHDA) into the nigrostriatal pathway in rats is commonly used to produce an animal model of Parkinson's disease (PD). However, most studies use male adult animals only. The present study focused on possible gender differences in vulnerability to 6-OHDA during the early pubertal period when the effects exerted by gonadal steroid hormones are unpronounced. METHODS: Young Sprague-Dawley rats, 35 days of age, were given a low vs. a higher dose of 6-OHDA in the medial forebrain bundle (MFB). Control rats received equivalent saline infusions. At 14 days post-surgery the rats were evaluated for forelimb akinesia. RESULTS: For the higher dose of 6-OHDA the female rats were less impaired than males in making adjustment steps in response to a weight shift and in a vibrissae-evoked forelimb placing test. Tyrosine hydroxylase (TH) immunoreactivity was significantly higher for the female rats. CONCLUSION: Early gender differences in cell survival factors and/or other promoters of neuroplasticity may have contributed to the beneficial outcome in the females. For example, NGF was found to be higher in the female rats following administration of DA neurotoxin. It is unclear whether gonadal steroids are involved, and if so, whether female hormones are protective or whether male hormones are prodegenerative. Determining the mechanisms for the improved outcome in the young female rats may lead to potential treatment strategies in PD.

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 microM NMDA for 2 min at 35 degrees C. 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.

Development of a method to evaluate glutamate receptor function in rat barrel cortex slices.

The rat is a nocturnal animal and uses its vibrissae extensively to navigate its environment. The vibrissae are linked to a highly organized part of the sensory cortex, called the barrel cortex which contains spiny neurons that receive whisker specific thalamic input and distribute their output mainly within the cortical column. The aim of the present study was to develop a method to evaluate glutamate receptor function in the rat barrel cortex. Long Evans rats (90-160 g) were killed by cervical dislocation and decapitated. The brain was rapidly removed, cooled in a continuously oxygenated, ice-cold Hepes buffer (pH 7.4) and sliced using a vibratome to produce 0.35 mm slices. The barrel cortex was dissected from slices corresponding to 8.6 to 4.8 mm anterior to the interaural line and divided into rostral, middle and caudal regions. Depolarization-induced uptake of 45Ca2+ was achieved by incubating test slices in a high K+ (62.5 mM) buffer for 2 minutes at 35 degrees C. Potassium-stimulated uptake of 45Ca2+ into the rostral region was significantly lower than into middle and caudal regions of the barrel cortex. Glutamate had no effect. NMDA significantly increased uptake of 45Ca2+ into all regions of the barrel cortex. The technique is useful in determining NMDA receptor function and will be applied to study differences between spontaneously hypertensive rats (SHR) that are used as a model for attention deficit disorder and their normotensive control rats.

The Effect of Head-Group on Selective Counterion Binding to Cationic Surfactants

Selectivity coefficients for the competitive adsorption of chloride, bromide, and iodide at the air/solution interface have been measured by a high accuracy ion flotation technique using the surfactant cations dodecylammonium, dodecylmethylammonium, dodecyldimethylammonium, and dodecyltrimethylammonium. Selective binding was found to depend on the nature of the head group, with selectivity increasing from primary to quaternary ammonium ions. Results are consistent with counterion binding arising from contact adsorption by mutual dehydration of head groups and counterions. Copyright 1997 Academic Press. Copyright 1997Academic Press

Kindled seizures do not affect adenosinergic inhibition of DA or ACh release in rat accumbens or PFC.

Epileptic seizures are thought to terminate largely as a result of the extracellular accumulation of the purinergic neuromodulator, adenosine, released by discharging neurons. However, the postictal surge in extracellular adenosine and its widespread inhibitory effects are limited in time to only a few minutes and cannot directly account for increased resistance to seizures and the complex behavioural and motivational effects that may persist for hours or days after a seizure. The present study examined whether kindled seizures might alter the sensitivity or efficacy of inhibitory presynaptic adenosine receptors, and thereby induce more enduring changes in downstream transmitter systems. Rats were kindled in the amygdala of the dominant cerebral hemisphere, contralateral to the preferred direction of rotation, and their brains were removed either 2 h or 28 days after completion of kindling. Inhibition of electrically stimulated release of dopamine (DA) and acetylcholine (ACh) by the A1 adenosine-receptor agonist, R-phenylisopropyladenosine (R-PIA) was then measured in the prefrontal cortex (PFC) and nucleus accumbens. R-PIA (1.0 microM) inhibited [1H]DA release from PFC and nucleus accumbens tissue, and [14C]ACh release from nucleus accumbens tissue, but release was unaffected by prior kindling, regardless of the intervening interval. These results do not support suggestions that DA or ACh might mediate the effects of seizure-induced changes in purinergic inhibitory tone so as to cause long-term shifts in seizure threshold and postictal behavior.

Effect of amygdaloid kindling on rat striatal dopamine D1- and D2-receptors.

The effect of kindling on dopaminergic (DA) neurotransmission was assessed by measuring dopamine D1- and D2-receptor binding in the dorsal and ventral striatum of rats either 2 hours (short-term) or 3-4 weeks (long-term) after the last kindled seizure. Kindling did not have any significant long-term effect on DA D2-receptor Kd or Bmax values in the dorsal or ventral striatum or on DA D1-receptor parameters in the dorsal striatum. The short-term effect of kindled seizures was to abolish the asymmetry in DA D2-receptor density observed in the dorsal striatum of control rats. DA D1-receptor density was also increased in the dorsal striatum contralateral to the kindled amygdala of short-term rats. The short-term effects support the notion that limbic seizures can modify the lateral imbalance of DA activity in the striatum.

Effect of amygdaloid kindling on [3H]dopamine and [14C]acetylcholine release from rat prefrontal cortex and striatal slices.

The involvement of the dopaminergic (DA) systems in the control of limbic kindled seizures is ill defined. The effects of kindling on DA activity may have been overlooked in the past, because of its subtle unilateral occurrence and/or the variance of the endogenous imbalance of DA activity in normal animals. In the present study rats were screened for their endogenous DA imbalance using amphetamine-induced rotational behaviour. Electrical or sham kindling was applied in the hemisphere with the higher endogenous DA activity. Sections of the bilateral prefrontal cortex and dorsal and ventral striatum were dissected either 2 hours or 21 days after the final seizure and the electrically stimulated release of [3H]DA and [14C]acetylcholine (ACh) determined. Release was also measured in the presence of quinpirole or sulpiride to assess the activity of pre- and postsynaptic DA D2-receptors. Long-term effects of kindling consisted of facilitation of ACh release in the ventral striatum contralateral to the kindled amygdala and bilateral depression of DA release in the prefrontal cortex. Kindling therefore produced area specific changes in neurotransmitter systems giving rise to increased pro-convulsive cholinergic activity in the ventral striatum and decreased anti-convulsive dopaminergic activity in the prefrontal cortex.

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.

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.

Hemispheric disconnection and rotational behaviour.

Several studies have demonstrated the existence of crossed pathways interconnecting the bilateral extrapyramidal system. The present study has evaluated the role of the thalamus in the interhemispheric control of nigrostriatal function by observing the effect of midsagittal thalamic transection on amphetamine-induced rotation in rats. The effect of thalamic transection on net rotational asymmetry did not differ from the effects of sham operations. Also, the transection did not affect the rotational asymmetry induced by subsequent lesioning of the dominant hemisphere substantia nigra. The failure to affect the rotation asymmetry by the transection suggests either that the inter-hemispheric pathway does not control extrapyramidal asymmetry or that the crossing takes place outside the thalamus. In an additional group of rats, thalamic transection did not interrupt retrograde labeling of somata in the substantia nigra and ventral tegmental area by horseradish peroxidase injected in the contralateral caudate. Thus, the crossed nigrostriatal projection does not decussate via the thalamus. It is suggested that this pathway decussates in the ventral mesencephalon.