[NR2B-pERK1/2-pElk-1 signaling contributes to the avoidance learning and memory of rats].

AIM: To investigate whether NR2B-pERK1/2-pElk-1 signaling contributes to the Y-maze learning and memory of rat brain. METHODS: 45 adult male SD rats were divided into 4 groups: (1) Ifenprodil peritoneal injection group (Ifenprodil ip, n = 14); (2) DMSO peritoneal injection group(DMSO ip, n = 15); (3) Ifenprodil cerebral ventricle injection group (Ifenprodil ic, n = 8); (4) DMSO cerebral ventricle injection group(DMSO ic, n = 8). Y-maze training and test were used as an learning and memory enhancing stimulus. Immunohistochemical and Western blotting methods were used for detecting pERK1/2 and pElk-1 expression intensity of different brain regions. RESULTS: Compared with the DMSO ip group, the ifenprodil ip group showed no change on the Y-maze learning score (P > 0.05), but its Y-maze memory score tested 24 after learning decreased (P < 0.05). Ifenprodil peritoneal injection made brain pERK1/2 and pElk-1 expression decreased generally. In hippocampus, marginal division of striatum(MrD), amygdala,these changes were more significant (P < 0.05). Compared with the DMSO ic group, the reconsolidation of Y-maze memory tested 6 hours after ifenprodil injection was impaired in ifenprodil ic group (P < 0.05). The OD value of pERK1/2 and pElk-1 positive bands in ifenprodil ic group attenuated generally. The pElk-1 positive bands of caudate putamen and MrD almost disappeared in ifenprodil ic group. CONCLUSION: NR2B is essential for the formation of long-term memory, reconsolidation of Y-maze memory. The deactivation of NR2B by ifenprodil will impair these courses. Meanwhile, the deactivation of NR2B attenuates pERK1/2 and pElk-1 expression of learning and memory related regions after Y-maze learning and memory reconsolidation test. In MrD and caudate putamen, the pElk-1 expression are completely blocked by ifenprodil after memory reconsolidation test.

Expression of c-fos and c-jun proteins in the marginal division of the rat striatum during learning and memory training.

BACKGROUND: A new brain region, the marginal division (MrD), was discovered at the caudal margin of the neostriatum. The MrD was shown to be involved in learning and memory in the rat. The aim of this study was to investigate the expression of the immediate-early genes c-fos and c-jun in the MrD of the striatum during learning and memory processes in the rat, immunocytochemical and Western blot methods were used to examine Y-maze trained rats. METHODS: The rats were divided into three groups, namely the training, pseudotraining, and control groups. After Y-maze training, the expression of the immediate-early genes c-fos and c-jun in the MrD of the rats was investigated using immunocytochemical and Western blot methods. RESULTS: After one hour of Y-maze training, the expression of c-jun and c-fos proteins was significantly enhanced in the MrD; the c-jun protein, in particular, was more intensely expressed in this region than in other parts of the striatum. The expression of these two proteins in the training group was significantly higher than in the pseudotraining and control groups. In addition, positive expression was also found in the hippocampus, cingulum cortex, thalamus, and in other areas. Western blot disclosed two immunoreactive bands for the anti-c-fos antibody (47 kD and 54 kD) and two immunoreactive bands for the anti-c-jun antibody (39 kD and 54 kD). CONCLUSIONS: These results indicate that the immediate-early genes c-fos and c-jun participate in signal transduction during the learning and memory processes associated with Y-maze training in rats.

[Clinical analysis of the relationship between injury of the marginal division and cognitive impairment].

OBJECTIVE: To investigate the relationship between injury in the marginal division (MrD) of the striatum and the cognitive impairment. METHODS: Twenty patients with injury in the MrD of the striatum were examined routinely by magnetic resonance imaging (MRI). Cognitive tests of each patient were performed and the results evaluated against their MRI findings. A comparative study of the MRI features and the degree of cognitive impairment was also performed between these patients and 10 patients with Alzheimer's disease (AD). RESULTS: Ischemic injury was the main cause of MrD injuries, manifested by abnormal signals (long T1 and T2 signals) in the MrD. The findings in the 10 AD patients were characterized by atrophy of the temporal lobe, hippocampus and the cortex. The average mini-mental-status examination (MMSE) score of the 20 patients was 19.7, with impaired memory and computation abilities as the main manifestations of cognitive impairments. The average MMSE score in the AD group was 11, and the cognitive impairments included all aspects of the cognitive function. No significant difference of the cognitive impairment was noted between the patients with only injury in the MrD and those with also the injury in other areas of the striatum. CONCLUSION: The MrD is probably a new area related to the memory function of the brain, and the injury of MrD may cause cognitive impairment.

Hippocampal long-term potentiation attenuated by lesions in the marginal division of neostriatum.

The marginal division (MrD) is a spindled-neurons consisted zone at the caudal border of the neostriatum in the mammalian brain and has been verified as contributing to associative learning and declarative memory in the rat and human with behavior and functional magnetic resonance imaging methods. It was proved to have functional connections with the limbic system. Whether the MrD has influence on the hippocampal long-term potentiation (LTP) was investigated in this study. LTP was induced from the dentate gyrus (DG) in the hippocampus by high-frequency stimulation (HFS) to the perforant path (PP). The amplitude of the population spike (PS) and the slope of the excitatory postsynaptic potential (EPSP) increased significantly to form LTP in the DG of the hippocampus after HFS of PP in normal and saline-injected control groups of rats. Lesions introduced in the MrD reduced significantly both the amplitude of PS and the slope of the EPSP following HFS of the PP. The results indicated that lesions in the MrD could attenuate LTP formation in the hippocampus. Our data suggest that the MrD might very possibly have excitatory functional influence on the hippocampus and therefore might influence the function of the hippocampus.

Interactions among memory-related centers in the brain.

The structures associated with learning and memory have been widely studied for over 100 years. The idea of the famous neuropsychologist K.S. Lashley, that learning and memory are stored diffusely in the brain, dominated neuroscience in the early half of Twentieth Century. Since Scoville reported in 1957 a persistent impairment of recent memory caused by bilateral medial temporal lobe resection in a patient, the concept that different brain structures play different roles in learning and memory has been established, but the structures were thought to work separately. The connections and functional influences between hippocampus and prefrontal cortex, thalamus and hippocampus, prefrontal cortex and thalamus, amygdala and hippocampus, basal nucleus of Meynert and medial temporal lobe system, and amygdala and thalamus were successively reported. The marginal division (MrD) is a pan-shaped structure consisting of spindle-shaped neurons at the caudal margin of the neostriatum in the mammalian brain. The MrD has been shown to contribute to associative learning and declarative memory by behavioral study in rats and by functional magnetic resonance image study in humans. Lesions in the MrD influenced the learning and memory function of the basal nucleus of Meynert and attenuated hippocampal long-term potentiation. The MrD is likely, based on its position, advanced development in higher mammalian brains, abundant and swift blood supply, and complex connections, to be an important subcortical memory center in the brain. The above-mentioned studies demonstrated that memory-related centers could influence each other and play different roles. Therefore, we propose that there are very possibly hierachical memory centers in the brain.

New component of the limbic system: Marginal division of the neostriatum that links the limbic system to the basal nucleus of Meynert.

The limbic system refers to a group of connected neural regions that are associated with motivation, learning, and memory. The marginal division (MrD) is a zone located at the caudal border of the neostriatum in mammalian brains that has been shown to be involved in learning and memory. In a previous study, c-fos expression showed functional connections between the MrD, basal nucleus of Meynert (NBM) and limbic system (Shu et al., 1988a, 1999). In the present study, to explore the relationship between these regions, the expression of limbic system-associated membrane protein (LAMP) was investigated using molecular and immunohistochemical methods. Synaptic and functional connections between the MrD and the NBM were studied also using tract tracing, electron microscopic and behavioral methods. LAMP is thought to be a marker of the limbic system and expression of LAMP protein and mRNA was observed in both the MrD and the limbic system. From such results, it is concluded that the MrD is a new component of the limbic system. Fibers from the MrD were observed projecting and synapsing on cholinergic neurons of the NBM. As reduction of learning and memory was induced by lesioning the projection from the MrD to the NBM, it would seem that the MrD modulates the learning and memory function of the NBM. In conclusion, the results of these studies suggest that the MrD is a new component of the limbic system, and there are functional and structural connections between the MrD, NBM and limbic system. The MrD seems to act as a link between the limbic system and the NBM, and plays a role in learning and memory.

[Role of the marginal division of human neostriatum in working memory capacity for numbers received through hearing: a functional magnetic resonance imaging study].

OBJECTIVE: With the help with functional magnetic resonance imaging (fMRI) technique, we aim to clarify whether the marginal division of the striatum (MrD) is involved in the working memory function of human brain for remembering numbers received through hearing. METHODS: Thirteen healthy volunteers were instructed to undertake both a working memory task, in which the subjects were asked to remember as many numbers read to them as possible, and a non-working memory control task, in which the subjects were not asked to remember the numbers. FMRI of the brain was performed in the 2 groups while the tests were being carried out separately, and the activity of the brain regions was compared between these 2 tasks. RESULTS: Eleven volunteers passed the working memory task for digit remembering. Highly active areas were observed in the prefrontal cortex and the MrD with predominance by the left side during performance of the working memory task, while other regions of the neostriatum were not excited. The prefrontal cortex and the MrD were not obviously activated during the performance in the control test. CONCLUSION: The results suggest that the MrD, along with the prefrontal cortex in the human brain, is involved in working memory function in remembering numbers assigned through hearing. The MrD is probably a subcortical memory center, which is linked to other memory-related brain areas.

[Expression of gamma-amino butyric acid and its receptor in the marginal division of rat striatum].

OBJECTIVE: To investigate the expression of the inhibitory amino acid gamma-aminobutyric acid (GABA) and its receptor GABAR (B1) mRNA in the marginal division of rat striatum. METHODS: The expression of GABA and its receptor GABAR (B1) mRNA was studied by way of immunocytochemistry and molecular in situ hybridization method. RESULTS: Dense GABA-positive immunoreactive fibers and a few positive cells were found in the marginal division of the rat striatum, along with glutamic acid decarboxylase (GAD)-positive fibers and cell bodies. GABA- and GAD-positive cells and fibers were also seen in the cerebral cortex and hippocampus. Numerous cells positive of the expression of GABAR (B1) receptors mRNA were observed in the marginal division whereas only a few positive cells were found in the caudate putamen. GABAR (B1) receptor mRNA expression was also observed in some cells in the cerebral cortex and hippocampus. CONCLUSION: The expression of GABA and its receptor in the marginal division of rat striatum indicates a regulatory mechanism of the marginal division of the striatum by GABA, suggesting that GABA can affect the learning and memory function of the marginal division through inhibiting the neurotransmitter release in the presynaptic terminal or modulating the other neurotransmitters.

[Functional connection between the marginal division and hippocampus in rats].

OBJECTIVE: To investigate the functional connection between the marginal division of the striatum and hippocampus, a brain region that play a vital role in learning and memory. METHODS: Morphological localization of functional activity of the nervous system was employed. Kainic acid (0.01%) was stereotaxically injected into the hippocampus as a chemical stimulus, and immunohistochemistry method was used to show the expression of c-Fos in rat brain. RESULTS: c-Fos was intensely expressed in the hippocampus, amygdaloid nucleus, the bed nucleus of the stria terminals and cerebral cortex; in the striatum, a stretch in the marginal division where c-Fos-positive nuclei congregated was observed, while c-Fos expression was scarcely detectable in the caudate putamen and globus pallidus. CONCLUSION: Functional connection exists between the marginal division and hippocampus in rats.

[Research progress in the structure and functions of the marginal division in the striatum].

In the year 1987, we discovered a new area in the striatum that was subsequently designated as the marginal division according to the location where it situates. More than 10 years of systemic study has yielded substantial knowledge of the unique structure of this new region, and it has come to light that the marginal division is predominantly associated with learning and memory functions, as have been recognized by researchers either nation-wide or world-wide. Further study of the marginal division may have potential significance in efforts to promote human intelligence and in contriving means for prevention of Alzheimer's disease.

[Effects of hypoxia on AChE and NADPH-d levels in the marginal division and learning and memory functions of rats].

OBJECTIVE: To observe the pathological changes and changes in acetylcholinesterase (AChE) and reduced nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) levels in the marginal division (MrD) following hypoxia, and explore the relation of hypoxia to damages of learning and memory functions. METHODS: Hypoxia models were established in 40 SD rats by treatment with the mixture of 8% oxygen and 92% nitrogen 5 times daily for 5 consecutive days, and the sham-hypoxia group was constituted by 10 rats receiving normal oxygen supply in the same manner as above. Another 10 untreated rats were used as normal control. The rats completing the hypoxia induction procedures were subjected to Y-maze test before their brain sections, along with those of the rats in the other 2 groups, were prepared for HE staining and immunohistochemical staining. RESULTS: AChE immunohistochemical results of the normal control group revealed numerous AChE-positive fibers and some positive cells in the striatum where the MrD was more lightly stained than the other regions. In the rats with hypoxia, however, the MrD was more intensely stained in comparison with the control, but the stain in other regions of the striatum did not manifest any significant differences between the groups. The MrD of normal rats possessed more NADPH-d-positive cells, all spindle-shaped, than the other regions of the striatum, and hypoxia did not result in morphological changes of the cells but significant reduction of their quantity occurred. CONCLUSION: Hypoxia may cause reduction of the learning and memory functions of rats and gives rise to alterations of AChE and NADPH-d staining patterns in the MrD. The MrD is more vulnerable to hypoxia as evidenced by more obvious changes in AChE and NADPH-d staining in the MrD than in the other regions of the striatum, which may be associated with the impairment of the learning and memory functions by hypoxia.

[Distribution of substance P and its receptor in the marginal division of rat striatum and its association with the function of learning and memory].

OBJECTIVE: To investigate the distribution of the substance P (SP) and its receptor in the marginal division (MrD) of rat striatum and to understand the relationship between SP and the learning and memory function of rats. METHODS: Using immunohistochemistry and in situ hybridization techniques, the distribution of SP and its receptor in the MrD was studied, and the relationship between the SP and learning and memory of the MrD was observed by means of SP receptor gene knockout in combination with Y-maze test. RESULTS: Numerous SP immunopositive fibers and large quantities of SP receptor protein and NK1 mRNA were identified in the MrD of rat striatum. After knockout of the SP receptor gene in the MrD, the ability of learning and memory of the rats was obviously decreased. CONCLUSION: SP and its receptor in the MrD may play important roles in the learning and memory function of rat, possibly through the regulation of the neurotransmitters as 5-HT by SP via NK1 receptor.

[Effects of kainic acid that damages the marginal division of rat striatum on hippocampal long-term potentiation].

OBJECTIVE: To investigate the relationship between the marginal division (MrD) of the striatum and other brain regions associated with learning and memory. METHODS: Long-term potentiation (LTP) was induced by high-frequency stimulation of the perforant path-dentate gyrus, and changes in hippocampal LTP after destruction of the marginal division with kainic acid were observed. RESULTS: High-frequency stimulation of the perforant path produced significant increases in the peak amplitudes of the population spike (PS) in normal rats and those receiving saline treatment. In rats with damaged MrD, the increase in PS and the excitatory postsynaptic potential were less obvious compared with normal or saline-treated rats, indicating that the LTP of the hippocampus was attenuated by damage of the MrD. CONCLUSION: Damage of the MrD impacts the LTP formation in the hippocampus.

[Expression of immediate-early genes c-fos and c-jun in the marginal division of striatum during learning and memory].

OBJECTIVE: To study the expression of immediate-early genes c-fos and c-jun in the marginal division (MrD) of rat striatum during learning and memory. METHODS: After Y-maze training in rats, the expression of immediate-early genes c-fos and c-jun in the MrD was investigated immunocytochemically. RESULTS: After 1 h of Y- maze training, the expression of c-Fos and c-Jun proteins was significantly enhanced in the MrD, where c-Jun protein in particular was more intensely expressed than in other parts of the striatum. The training group showed significantly higher expressions of the 2 proteins than pseudotraining group (P<0.01). In addition, positive expression was also observed in the hippocampus, cingulum cortex and other parts of the brain. CONCLUSION: Immediate-early genes c-fos and c-jun in the MrD participate in the signal transduction during learning and memory processes in the courses of Y-maze training of the rats.

[Hemorrhage in the medial areas of bilateral putamens causing deficiency of memory and calculation: report of one case].

Bilateral cerebral hemorrhages in the medial areas of bilateral putamens that impair the memory and calculation abilities are rare clinical entities. In the case presently reported, the patient suffered initial cerebral hemorrhage 3 years ago in the medial area of putamen on the right side with light left paralysis but the learning and memory functions were intact. A recent cerebral hemorrhage on the left side leaving mild paralysis of the right upper limb, however, had caused considerable loss of his recent memory and calculation ability. As the 2 cerebral hemorrhages were found to cause damage to the marginal devision, the symptoms developed in this special case had provided clinical evidence for the postulation that the marginal division is associated with memory and calculation function.

Differential display analysis of gene expression in the hippocampus, marginal division and other related brain areas: a preliminary study.

OBJECTIVE: To investigate the difference in the expression profiles in the hippocampus, marginal division and other related brain areas for identification of genes specific to the hippocampus and marginal division. METHODS: Fetal hippocampus, marginal division, caudate putamen and amygdala were obtained and mRNA differential display technique was employed to study the gene expression in the 4 brain areas. RESULTS: Two differentially expressed fragments were isolated from each of the hippocampus and marginal division, and cloning and sequence analysis of one of the fragment 277 bp in length from the hippocampus showed total homology with the sequence of human clone AC0049. CONCLUSION: The 4 brain areas have different gene expression profiles.

Immunocytochemical study of the marginal division in human striatum.

OBJECTIVE: To demonstrate the existence of the marginal division in human stritum. METHODS: The cytoar-chitecture and distribution of the neurotransmitters in human fetal striatum were studied using Nissl staining and immuno-cytochemistry. RESULTS: In the sections with Nissl staining, a distinct fusiform cell zone was observed between the putamen and the globus pallidus of the human striatum. The long axes of these neurons in this region stretched dorsoventrally in parallel with the border between the putamen and the globus pallidus. Numerous L-ENK-, NT-, SOM-and SP-positive fibers and a few L-ENK-and NT-positive cells were found in the marginal division. CONCLUSION: For the first time we demonstrate that human also have the marginal division in the striatum which is similar to that of the mammals as the rats, cats and monkeys