Sex difference in the bed nucleus of the stria terminalis of the human brain.

A quantitative analysis of the volume of the darkly staining region of the posteromedial bed nucleus of the stria terminalis was performed on the brains of 26 age-matched male and female human subjects. We suggest the term "darkly staining posteromedial" component of the bed nucleus of the stria terminalis (BNST-dspm) to describe this sexually dimorphic region of the human brain. The volume of the BNST-dspm was 2.47 times greater in males than in females. This region in humans appears to correspond to an area of the bed nucleus of the stria terminalis in laboratory animals that exhibits volumetric and neurochemical sexual dimorphisms, concentrates gonadal steroids, and is anatomically connected to several other sexually dimorphic nuclei. Furthermore, the bed nucleus of the stria terminalis is involved in sexually dimorphic functions, including aggressive behavior, sexual behavior, and gonadotropin secretion, which are also influenced by gonadal steroids. Therefore, it is possible that in human beings as well, gonadal hormones influence the sexual dimorphism in the BNST-dspm and that this morphological difference, in part, underlies sexually dimorphic function.     

Activating the damaged basal forebrain cholinergic system: tonic stimulation versus signal amplification

The hypothesis that the cognitive decline in senile dementia is related to the loss of cortical cholinergic afferent projections predicts that pharmacological manipulations of the remaining cholinergic neurons will have therapeutic effects. However, treatment with cholinesterase inhibitors or muscarinic agonists has been, for the most part, largely unproductive. These drugs seem to disrupt the normal patterning of cholinergic transmission and thus may block proper signal processing. An alternative pharmacological strategy which focuses on the amplification of presynaptic activity without disrupting the normal patterning of cholinergic transmission appears to be more promising. Such a strategy may make use of the normal GABAergic innervation of basal forebrain cholinergic neurons in general, and in particular of the inhibitory hyperinnervation of remaining cholinergic neurons which may develop under pathological conditions. Disinhibition of the GABAergic control of cholinergic activity is assumed to intensify presynaptic cortical cholinergic activity and to enhance cognitive processing. Although the extent to which compounds such as the benzodiazepine receptor antagonist-carboline ZK 93 426 act via the basal forebrain GABA-cholinergic link is not yet clear, the available data suggest that the beneficial behavioral effects of this compound established in animals and humans are based on indirect cholinomimetic mechanisms. It is proposed that an activation of residual basal forebrain cholinergic neurons can be achieved most physiologically via inhibitory modulation of afferent GABAergic transmission. This modulation may have a therapeutic value in treating behavioral syndromes associated with cortical cholinergic denervation.     

P^53,Bcl—2在皮肤鳞状细胞癌、基底细胞癌脂溢性角化病中联合表达的意义

目的：探讨P^53蛋白,Bcl-2蛋白在皮肤鳞状细胞癌（SCC）,基底细胞癌（BCC）及脂溢性角化病（SK）中的表达及意义。方法：采用S－P法分别对12例SCC,BCC,SK进行免疫组化P^53蛋白,Bcl－2蛋白检测。结果：12例SCC,BCC中分别有9例,11例P^53蛋白表达阳性有10例,11例Bcl-2蛋白表达阳性,12例SK中有1例P^53表达阳性,11例Bcl-2表达阳性,P^53蛋白在SCC,BCC中表达显著高于SK（P＜0．01）。结论：P53蛋白基因突变和Bcl-2蛋白的过度表达（即细胞凋亡机制）在皮肤恶性肿瘤的发生,发展中起重要促进作用。     

Effect of nerve growth factor and GM1 ganglioside on the recovery of cholinergic neurons after a lesion of the nucleus basalis in aging rats

Summary A unilateral ibotenic acid lesion was placed in the nucleus basalis magnocellularis of 3- and 18-month-old rats. In the lesioned aging rats, the number of choline acetyltransferase-immunoreactive neurons of the nucleus basalis magnocellularis was markedly reduced in the ipsilateral side and to a lesser extent in the contralateral side. Twenty-one days after the lesion, the activity of choline acetyltransferase in the ipsilateral cortex was reduced by 40% in both groups of rats and by 24% in the contralateral frontal cortex of the aging rats. Intracerebroventricular administration of nerve growth factor (10 g, twice a week) to aging lesioned rats for 3 weeks after surgery resulted in a complete recovery in the number of choline acetyltransferase-immunoreactive neurons in the nucleus basalis of both sides, and choline acetyltransferase activity in the contralateral cortex, with little effect on the ipsilateral cortex. No potentiation was seen after the concurrent administration of GM1 ganglioside and nerve growth factor. Complete recovery in cortical choline acetyltransferase activity was only observed in the lesioned rats treated with nerve growth factor for 1 week before and 3 weeks after lesioning. Nerve growth factor treatment, both after the lesion, and before and after the lesion, improved the passive avoidance performance disrupted by the lesion. In young lesioned rats daily intraperitoneal administration of GM1 (30 mg/kg) for 21 days after surgery promoted both the recovery of choline acetyltransferase activity and passive avoidance performance. In aging rats GM1, even at a dose twice as large, failed to reverse the biochemical and morphological deficits and behavioral impairment induced by the lesion. Only when GM1 administration was started 3 days before the lesion, were a complete recovery in choline acetyltransferase activity in the contralateral cortex and a partial recovery in the ipsilateral cortex obtained.Our results indicate that nerve growth factor and, to some extent, GM1 facilitate the recovery of the cholinergic neurons after a lesion of the nucleus basalis in aging rats, but their efficacy is reduced. The lower efficacy of GM1 as compared to NGF might be due to the different routes of administration used.     

Basal glucose turnover inPsammomys obesus

The aim of this study was to examine wholebody glucose turnover and glucose uptake into individual tissues inPsammomys obesus. The animals were classi-fied according to the level of circulating glucose and insulin in the fed state: group A was normoglycaemic and normoinsulinaemic (glucose <8.0 mmol/l, insulin <150 mU/l), group B was normoglycaemic and hyperinsulinaemic (glucose <8.0 mmol/l, insulin 150 mU/l), and group C was hyperglycaemic and hyperinsulinaemic (glucose 8.0 mmol/l, insulin 150 mU/l). The animals were deprived of food for 6 h, after which they were anaesthetized and cannulated, using the jugular vein for infusions and the carotid artery for blood sampling. Whole-body glucose turnover was measured using a primed-continuous infusion of 6-[³H]-glucose and saline to quantitatively assess hepatic glucose production (HGP), glucose disposal (Rd), and the metabolic clearance rate of glucose (MCR). Following the 2-h infusion period, the glucose metabolic index (Rg) of individual tissues was measured using a fixed-dose bolus of 2-deoxy-[¹⁴C]glucose. Under the steady-state conditions of the experiment, HGP was assumed to be equal to Rd, and both variables were found to be significantly correlated to the fasting glucose concentration (r=0.534,P<0.05,n=19). On the other hand, MCR was found to be inversely correlated to the fasting plasma glucose concentration (r=0.670,P<0.01,n=19). When the animals were divided into three groups as described above, HGP in group C animals was significantly elevated compared with group A (20.8±2.6 vs 12.7±0.6 mg · kg^–1 · min^–1;P<0.05), and MCR showed a tendency to be lower in group C than group A, although the difference was not statistically significant. HGP and MCR were not significantly different between groups A and B. Measurement of the glucose metabolic index in individual tissues showed that group C animals had significantly higher Rg values in muscles and adipse tissues compared with those in group A (P<0.05). In addition, Rg in group B white gastrocnemius and soleus were significantly higher than in group A despite similar rates of HGP and levels of glycaemia. These findings suggest that an early increase in skeletal muscle glucose uptake and hyperinsulinaemia can be demonstrated in group BPsammomysobesus before significant hyperglycaemia.     

Glutamatergic inputs to midbrain dopaminergic neurons in primates

Anterograde tract-tracing and immunohistochemical methods were used to study projections from the pedunculopontine tegmental nucleus (PPN) to midbrain dopaminergic neurons in the squirrel monkey (Saimiri sciureus). The PPN harbored numerous cholinergic and glutamatergic neurons, as well as neurons that displayed both cholinergic and glutamatergic markers. Injections of anterograde tracer into the PPN led to intense fiber labeling in the substantia nigra pars compacta (SNc) and the ventral tegmental area (VTA). This pedunculonigral projection was partly bilateral. At the electron microscopic level, about 40–60% of the anterogradely labeled terminal boutons were glutamate-positive and formed asymmetric synapses with the dopaminergic neurons of the SNc–VTA complex. These data provide direct evidence for a pedunculonigral glutamatergic projection. This projection may play a crucial role in the control of the firing pattern of SNc–VTA dopaminergic neurons and could be involved in glutamate-mediated excitotoxicity that is believed to lead to SNc cell death in Parkinson's disease.     

Transient increase of synapsin-I immunoreactivity in the mossy fiber layer of the hippocampus after transient forebrain ischemia in the mongolian gerbil

Synapsin-I is a vesicular phosphoprotein, which regulates neurotransmitter release, neurite development, and maturation of synaptic contacts during normal development and following various brain lesions in adulthood. In the present study, we have examined by immunohistochemistry possible modifications in the expression of synapsin-I in the hippocampus of Mongolian gerbils after transient forebrain ischemia. The animals were subjected to 5 min of transient forebrain ischemia through bilateral common carotid occlusion, and were examined at different time-points post-ischemia. Transient forebrain ischemia produces cell death of the majority of CA1 pyramidal neurons of the hippocampus and polymorphic hilar neurons of the dentate gyrus. This is followed by reactive changes, including synaptic reorganization and modifications in the expression of synaptic proteins, which provide the molecular bases of synaptic plasticity. Transient decrease of synapsin-I immunoreactivity was observed in the inner zone of the molecular layer of the dentate gyrus, thus suggesting denervation and posterior reinervation in this area. In addition, a strong increase in synapsin-I immunoreactivity was observed in the hilus of the dentate gyrus and in the mossy fiber layer of the hippocampus at 2, 4 and 7 days after ischemia. Parallel increases in synaptophysin immunoreactivity were not observed, thus suggesting a selective induction of synapsin-I after ischemia. The present results indicate that synapsin-I participates in the reactive response of granule cells to transient forebrain ischemia in the hippocampus of the gerbil, and suggest a role for this protein in the plastic adaptations of the hippocampus following injury.     

Direct comparison of projections from the central amygdaloid region and nucleus accumbens shell

Certain neurochemical and connectional characteristics common to extended amygdala and the nucleus accumbens shell suggest that the two represent a single functional-anatomical continuum. If this is so, it follows that the outputs of the two structures should be substantially similar. To address this, projections from the caudomedial shell and central nucleus of the amygdala, a key extended amygdala structure, were demonstrated in Sprague-Dawley rats with different anterograde axonal tracers processed separately to exhibit distinguishable brown and blue-black precipitates. The caudomedial shell projection is strong in the ventral pallidum and along the medial forebrain bundle through the lateral preopticohypothalamic continuum into the ventral tegmental area, distal to which it thins abruptly. The central nucleus projects strongly to the bed nucleus of the stria terminalis and the sublenticular extended amygdala, but substantially to the lateral hypothalamus only at levels behind the rostral part of the entopeduncular nucleus. Innervation of the ventral tegmental area by the central amygdala is minimal, but the lateral one-third of the substantia nigra, pars compacta and an adjacent lateral part of the retrorubral field receive substantial central amygdala input. Central amygdaloid projections are robust in caudal brainstem sites, such as the reticular formation, parabrachial nucleus, nucleus of the solitary tract and dorsal vagal complex, all of which receive little input from the accumbens. The substantial differences in the output systems of the caudomedial shell of accumbens and central amygdala suggest that the two represent distinct functional-anatomical systems.     

Effect of dopamine denervation and dopamine agonist administration on serine phosphorylation of striatal NMDA receptor subunits

Sensitization of striatal N-methyl-d-aspartate (NMDA) receptors has been implicated in the pathogenesis of the response alterations associated with dopaminomimetic treatment of parkinsonian animals and patients. To determine whether serine phosphorylation of NMDA receptor subunits by activation of Ca2+/calmodulin-dependent protein-kinase II (CaMKII) contributes to this process, we examined the effects of unilateral nigrostriatal ablation with 6-hydroxydopamine and subsequent treatment with levodopa, SKF 38393 (D1-preferring dopamine agonist), or quinpirole (D2-preferring agonist) on motor responses and phosphorylation states. Three weeks of twice-daily levodopa administration to rats shortened the duration of their rotational response to levodopa or SKF 38393 challenge, but prolonged the duration of quinpirole-induced rotation. At the same time, levodopa treatment elevated serine phosphorylation of striatal NR2A (p<0.02), but not that of NR2B subunits, without associated changes in subunit protein levels. Chronic treatment with SKF 38393 increased NR2A (p<0.0001) but decreased NR2B (p<0.004) serine phosphorylation. In contrast, chronic quinpirole treatment had no effect on NR2A but increased NR2B phosphorylation (p<0.0001). The acute intrastriatal injection of the CaMKII inhibitor KN93 (1.0 micrograms) not only normalized the levodopa-induced motor response alterations but also attenuated the D1 and D2 receptor-mediated serine phosphorylation of NR2A and NR2B subunits, respectively (p<0.02). These results suggest that a CaMKII-mediated rise in serine phosphorylation of NMDA receptor subunits induced by intermittent stimulation of D1 or D2 dopaminergic receptors contributes to the apparent enhancement in striatal NMDA receptor sensitivity and thus to the dopaminergic response plasticity in levodopa-treated parkinsonian rats.     

可乐定对脑缺血大鼠单胺类神经递质和内皮素的影响

目的：探讨可乐定能否缓解脑缺血大鼠单胺类神经递质和内皮素水平的紊乱。方法：大鼠ｉｐ苯巴比妥３０ｍｇ／ｋｇ麻醉,结扎双侧锁骨下动脉及颈总动脉致全脑缺血,采用荧光法及放免法测定单胺类神经递质和内皮素水平。结果：大鼠缺血３０ｍｉｎ再灌６０ｍｉｎ,与假手术组相比,缺血组脑中去甲肾上腺素（ＮＥ）,５－羟色胺（５－ＨＴ）水平明显减少４２％及２４％,但ＤＡ水平明显上升３３％,同时,脑与血浆中内皮素水平分别升高９