Distinct Dorsal and Ventral Hippocampal CA3 Outputs Govern Contextual Fear Discrimination

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Independent quantitative trait loci influence ventral and dorsal hippocampal volume in recombinant inbred strains of mice

Anatomical and functional studies support segregation of the hippocampus into ventral and dorsal components along its septotemporal axis. However, it is unknown whether the development of these two components of the hippocampus is influenced by common or separate genetic factors. In this study, we used recombinant inbred strains of mice to determine whether the same or different quantitative trait loci (QTL) influence ventral and dorsal hippocampal volume. Using two sets of strains of recombinant inbred mice (BXD and AXB/BXA), we identified separate QTLs for ventral and dorsal hippocampal volume. In BXD mice, suggestive QTLs for ventral hippocampus were identified on chromosomes 2, 8 and 13, and a significant QTL for dorsal hippocampal volume was identified on chromosome 15. There was also a suggestive QTL for dorsal hippocampal volume on chromosome 13. In AXB/BXA mice, there were no significant or suggestive QTLs for ventral hippocampal volume, but a significant QTL for dorsal hippocampus was identified on chromosome 5. These findings suggest that the development of the ventral and dorsal components of the hippocampus is influenced by separate genetic loci.     

Functional structure of the intermediate and ventral hippocampo–prefrontal pathway in the prefrontal convergent system

The hippocampo–prefrontal pathway is a unique projection that connects distant ends of the cerebral cortex. The direct hippocampo–prefrontal projection arises from the ventral to intermediate third of the hippocampus, but not from the dorsal third. It forms a funnel-shaped structure that collects information from the large hippocampal area and projects it to the prefrontal cortex. The anatomical regional differentiation of the projection has not been described. The hippocampal region is differentiated into structural and behavioural roles. For example, it has been shown that the ventral, but not the dorsal, hippocampus reciprocally connects with the amygdala and influences emotional behaviours. These data imply that hippocampal variation along the dorso–ventral axis is contained within the hippocampo–prefrontal pathway. Here, we present electrophysiological studies that demonstrate regional differences in short- but not long-term plasticity in the intermediate/posterior-dorsal and ventral routes of the hippocampo–prefrontal pathway. Furthermore, behavioural studies revealed that each route appears to play a different role in working memory. These results suggest that hippocampal regional information is processed through different routes, with the integration of individual regulatory functions in the prefrontal convergent system.     

高原低氧条件下不同时间大鼠海马CA1区神经细胞粘附分子的表达

目的:观察高海拔低氧条件下不同时间大鼠海马CA1区神经细胞粘附分子的表达变化,探讨NCAM在机体对低氧应激反应中的作用。方法:将平原SD大鼠运至海拔(4100m)地区,在第2、5、9、15天取大鼠海马,常规免疫组化及RT-PCR检测高原环境下NCAM的表达变化。结果:NCAM在高海拔大鼠海马CA1区神经细胞NCAM的表达在第2、5、9天是明显低于正常(P0.05),在第15天达到正常(P0.05)。结论:高原低氧应激反应后NCAM基因表达先降低后升高,提示其在神经损伤修复过程中可能起重要作用。     

Serotonin receptor expression along the dorsal–ventral axis of mouse hippocampus

Using in situ hybridization, we describe, for the first time, the profiles of expression of serotonin receptors (Htr/5-HTR) along the dorsal–ventral axis of mouse hippocampus. cRNA probes for most Htrs, excluding Htr6, were used. All hippocampal subregions and the entorhinal cortex cells providing input into the hippocampus were examined. The study shows that some, but not all, Htrs are expressed in the cells of the hippocampal circuitry. At both the subfield and the cell type levels, a somewhat overlapping pattern is observed. Four serotonin receptors, Htr1a, Htr2a, Htr2c and Htr7, display an expression pattern that changes along the dorsal–ventral axis of the hippocampus. Given the proposed functional differentiation of the hippocampus along its long axis, with the dorsal pole more involved in cognitive functions and the ventral pole more involved in mood and anxiety, our results suggest that serotonin receptors enriched in the ventral pole probably contribute to mood- and anxiety-related behaviours.     

成年海马中神经发生及影响因素

动物成年后在其中枢神经系统内仍有神经发生。成年神经发生的主要区域是海马齿状回的颗粒下层和脑室下区的侧脑室外侧壁。目前认为成年后的海马神经发生参与记忆的形成,尤其对癫痫和神经退行性疾病的缓解和治疗具有重要意义。成年海马的神经发生受多种生理、病理因素的调控。我们就近年来成年海马神经发生的影响因素及其可能机制进行综述。     

A critique on the preparation and enzymatic characterization of synaptic and nonsynaptic mitochondria from hippocampus

1. In literature two interesting methods are described to obtain from whole pooled brains or areas three types of mitochondria, namely, those of perikaryal origin and those contained in synaptosomes. 2. However, for many types of studies, such "preparative" preparations are not useful; for example, in pharmacological studies only data from a single n number of animals may be of statistical usefulness and may be correctly analyzed by statistical tests. 3. Thus a method is described by which it was possible to characterize by enzyme activities three populations from single rat brain hippocampus. 4. During preparative "analytical" procedure, it was noted that the 10% Ficoll gradients previously used in the literature were unable to separate purified mitochondria-free mitochondria. This gradient should be 12% Ficoll for single areas. 5. In addition, when results are compared using the more appropriate omega 2t for calculations of gravity forces to be applied instead of the maximum or average g for different rotors, enzymatic characterization differed considerably among the various mitochondrial populations. 6. The above considerations are also true when different pestle clearances and/or pestle rotations speeds are used during omogenizations; also lysis conditions are essential. 7. Results showed that selected experimental conditions are to be used when subcellular fractions are to be analyzed biochemically.     

Anxiolytic-like effects of substance P administration into the dorsal, but not ventral, hippocampus and its influence on serotonin

Substance P (SP) is known to be involved in processes related to learning and memory, fear, anxiety and stress. SP and NK1 receptors are localized in the hippocampus, a brain structure involved in learning and memory as well as emotional processes. As there is evidence for differential functions of the ventral (VH) and dorsal (DH) hippocampus in a variety of behaviors, we here evaluated the effects of injections of SP into the VH and DH in rats submitted to the elevated plus-maze (EPM) and open field (OF) tests. The results obtained showed that infusions of 100 and 1000 ng of SP into the DH, but not VH, increased open arm activity in the EPM and in the central zone of the OF, indicative of anxiolytic-like action. These effects were observed in the absence of significant changes in general motor activity. In an additional experiment to examine whether these effects of SP are mediated by local serotoninergic mechanisms, extracellular concentrations of this monoamine were assessed by use of in vivo microdialysis. Infusions of SP into the DH did not influence the extracellular concentration of serotonin. These data indicate that neurokinins in the DH, but not VH, are involved in mechanisms associated with anxiety and that the mediation of SP in anxiety-related behaviors is independent of local serotonergic mechanisms.     

NAP (davunetide) protects primary hippocampus culture by modulating expression profile of antioxidant genes during limiting oxygen conditions

Abstract

Hypoxia is a well-known threat to neuronal cells and triggers the pathophysiological syndromes in extreme environments such as high altitudes and traumatic conditions such as stroke. Among several prophylactic molecules proven suitable for ameliorating free radical damage, NAP (an octapeptide with initial amino acids: asparagine/N, alanine/A, and proline/P) can be considered superlative, primarily due to its high permeability into brain through blood–brain barrier and observed activity at femtomolar concentrations. Several mechanisms of action of NAP have been hypothesized for its protective role during hypoxia, yet any distinct mechanism is unknown. Oxidative stress is advocated as the leading event in hypoxia; we, therefore, investigated the regulation of key antioxidant genes to understand the regulatory role of NAP in providing neuroprotection. Primary neuronal culture of rat was subjected to cellular hypoxia by limiting the oxygen concentration to 0.5% for 72 h and observing the prophylactic efficacies of 15fM NAP by conventional cell death assays using flow cytometry. We performed real-time quantitative polymerase chain reaction to comprehend the regulatory mechanism. Further, we validated the significantly regulated candidates by enzyme assays and immunoblotting. In the present study, we report that NAP regulates a major clad of cellular antioxidants and there is an involvement of more than one route of action in neuroprotection during hypoxia.     

Opioid peptides, particularly dynorphin, after amygdaloid-kindled seizures

The influence of amygdaloid kindling on brain and pituitary content of immunoreactive dynorphin (IR-DYN) and other opioid peptides was studied in rabbits. The kindling was very effective in increasing the hippocampal levels of IR-DYN, alpha-neoendorphin and Leu-enkephalin, but remained without any significant effect on the levels of IR-DYN and beta-endorphin in the majority of brain structures studied. The concentration of IR-DYN in the hippocampus remained at the control level throughout the development but was increased dramatically after completion of kindling. Biochemical alterations persisted for at least one month following the completion of kindling. The obtained results suggest that the hippocampal IR-DYN and related peptides may play some role in the maintenance of amygdaloid-kindled seizures.     

Incorporation of inwardly rectifying AMPA receptors at silent synapses during hippocampal long-term potentiation

Despite decades of study, the mechanisms by which synapses express the increase in strength during long-term potentiation (LTP) remain an area of intense interest. Here, we have studied how AMPA receptor subunit composition changes during the early phases of hippocampal LTP in CA1 pyramidal neurons. We studied LTP at silent synapses that initially lack AMPA receptors, but contain NMDA receptors. We show that strongly inwardly rectifying AMPA receptors are initially incorporated at silent synapses during LTP and are then subsequently replaced by non-rectifying AMPA receptors. These findings suggest that silent synapses initially incorporate GluA2-lacking, calcium-permeable AMPA receptors during LTP that are then replaced by GluA2-containing calcium-impermeable receptors. We also show that LTP consolidation at CA1 synapses requires a rise in intracellular calcium concentration during the early phase of expression, indicating that calcium influx through the GluA2-lacking AMPA receptors drives their replacement by GluA2-containing receptors during LTP consolidation. Taken together with previous studies in hippocampus and in other brain regions, these findings suggest that a common mechanism for the expression of activity-dependent glutamatergic synaptic plasticity involves the regulation of GluA2-subunit composition and highlights a critical role for silent synapses in this process.     

Hereditary hydrocephalus internus in a laboratory strain of golden hamsters ( Mesocricetus auratus)

Golden hamsters of one common laboratory strain had a high incidence of hydrocephalus internus. When a severity score of hydrocephalus was used, a major autosomal recessive locus could be identified. However, when a binary score (hydrocephalus, no hydrocephalus) was used, no such major locus could be detected and results of test matings were not consistent with Mendelian inheritance. Golden hamsters with severe forms of hydrocephalus had a dorsally compressed and ventrally intact hippocampus. Implications for the behavior and well-being of affected hamsters are unknown but researchers using this strain should be aware of the likely presence of hydrocephalus.     

Synchronization and Oscillatory Dynamics in Heterogeneous, Mutually Inhibited Neurons

We study some mechanisms responsible for synchronous oscillations and loss of synchrony at physiologically relevant frequencies (10–200 Hz) in a network of heterogeneous inhibitory neurons. We focus on the factors that determine the level of synchrony and frequency of the network response, as well as the effects of mild heterogeneity on network dynamics. With mild heterogeneity, synchrony is never perfect and is relatively fragile. In addition, the effects of inhibition are more complex in mildly heterogeneous networks than in homogeneous ones. In the former, synchrony is broken in two distinct ways, depending on the ratio of the synaptic decay time to the period of repetitive action potentials (_s/T), where T can be determined either from the network or from a single, self-inhibiting neuron. With _s/T > 2, corresponding to large applied current, small synaptic strength or large synaptic decay time, the effects of inhibition are largely tonic and heterogeneous neurons spike relatively independently. With _s/T < 1, synchrony breaks when faster cells begin to suppress their less excitable neighbors; cells that fire remain nearly synchronous. We show numerically that the behavior of mildly heterogeneous networks can be related to the behavior of single, self-inhibiting cells, which can be studied analytically.     

Septotemporal variations in hippocampal value and outcome processing

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慢性应激对大鼠海马锥体细胞形态结构的效应

为研究慢性应激相关精神障碍的发病机制,采用尼氏（Nissl）染色法、高尔基（Golgi）镀染法和透射电镜技术,探讨慢性应激对大鼠海马CA1、CA3区锥体细胞形态结构的效应.结果显示应激组大鼠海马CA1区锥体细胞形态结构较对照组无明显变化.应激组海马CA3区锥体细胞数（35.14±3.85）较对照组(38.74±3.54)显著减少（P＜0.05）;顶树突的总长度（155.67 μm±33.32 μm）较对照组（195.63 μm±34.61 μm）显著缩短（P＜0.05）;应激组大鼠海马CA3区锥体细胞出现超微结构的改变,包括细胞固缩、体积缩小、核膜皱缩、线粒体变性和粗面内质网模糊不清.这提示海马CA3区锥体细胞形态结构的改变,可能是慢性应激相关精神障碍的病理生理基础.     

Effect of nicotine on the level of extracellular amino acids in the hippocampus of rat

Using microdialysis, we compared intracerebral and subcutaneous administration of nicotine for the effect on the levels of extracellular amino acids in the hippocampus of anesthetized rats. Administration by microdialysis of 10 mM nicotine, resulting in a nicotine concentration of 0.134 μmol/g in the hippocampus, increased the extracellular levels of aspartic acid, glutamic acid, and serine by 26–60%. At 50 mM nicotine the increases in the levels of aspartic acid, glutamic acid, serine, glycine, and glutamine were between 76% and 141%. Subcutaneous administration of nicotine at a dose of 6 μmol/kg caused a 57% increase in the extracellular level of glutamic acid. After a dose of 12 μmol/kg that resulted in a nicotine level of 0.015 μmol/kg in the hippocampus, the extracellular level of glutamic acid was increased by 100%, and that of aspartic acid by 24%. Thus, higher cerebral nicotine levels were needed with intracerebral than with subcutaneous administration to obtain similar amino acid changes. Prior administration of mecamylamine or L-kynurenine prevented the subcutaneous nicotine-induced elevation of the extracellular levels of aspartic acid and glutamic acid. Our results indicate that receptor interactions modulate nicotine effects and that both nicotinic cholinergic and NMDA/glycine glutamatergic receptors participate in the action of nicotine in increasing extracellular amino acid levels.