Associative long-term depression in the hippocampus in vitro

An association between the test and conditioning stimuli is critical for determining the nature of their interaction during learning and memory. Two experimental protocols which result in the induction of associative forms of long-term depression (LTD) at Schaffer collateral synapses onto CA1 pyramidal cells in vitro are reviewed in this article. The requirements for the induction of LTD with these protocols are discussed, as well as the relationship between these forms of associative LTD and so-called homosynaptic LTD. In particular, the biological basis of the experimentally demonstrated necessity for temporal and spatial conjunction between the test and conditioning stimuli is examined. © 1996 Wiley-Liss, Inc.     

Stress, depression and the hippocampus

Stress exposure is an important factor in the development of depressive disorders. Although the mechanisms of this relationship are largely unknown, several pieces of evidence point to an involvement of the hippocampal formation: 1. stressful stimuli cause remodeling of hipocampal pyramidal cells and inhibit neurogenesis in the dentate gyrus. Antidepressive drugs attenuate these effects, probably by increasing the expression of neurotrophic factors; 2. facilitation of serotonergic neurotransmission in the hippocampus attenuates behavioral consequences of stress and produce antidepressive-like effects in several animal models; 3. antagonism of glutamate, the main excitatory neurotransmitter of the hippocampus, also induce antidepressive-like effects; 4. increased hippocampal activity has been described in genetically selected rats that are more sensitive to depression models. Similar result was found in depressive patients that fail to respond to antidepressant drugs; 5. together with the amygdala, the hippocampus plays a key role on consolidation and evocation of aversive memories. The challenge for the future will be to integrate the results from these different fields (clinical, electrophysiological, pharmacological and molecular) in an unifying theory about the role of the hippocampus on mood regulation, depressive disorder and antidepressant effects.     

Minisatellite mapping in manic depression

Hypervariable regions of DNA exist at many discrete loci in the human genome. Variations in the length of specific classes of hypervariable DNA termed “minisatellite” sequences may be detected by hybridisation of radioactive probes composed of a common10–15 base pair repeat or “core” sequence which is shared by each of the minisatellite loci. Such a procedure was used to perform linkage analysis on a kindred in which a disease allele causing manic depression appeared to be segregating as an autosomal dominant. Results indicate no apparent linkage between a manic depression allele and at least 20 hypervariable genetic loci which acted as markers. However, because of the hypervariability of the minisatellite loci these results do not preclude similar analyses of other manic depressive pedigrees being productive because each such family will have distinct observable minisatellite alleles at loci specific to that family. The method could be usefully applied to the genetic analysis of other psychiatric disorders where heterogeneity is suspected and where a single autosomal major gene locus appears to be responsible for causing multiple cases within a single kindred.     

The role of the hippocampus in the pathophysiology of major depression

Converging lines of research suggest that the hippocampal complex (HC) may have a role in the pathophysiology of major depressive disorder (MDD). Although postmortem studies show little cellular death in the HC of depressed patients, animal studies suggest that elevated glucocorticoid levels associated with MDD may negatively affect neurogenesis, cause excitotoxic damage or be associated with reduced levels of key neurotrophins in the HC. Antidepressant medications may counter these effects, having been shown to increase HC neurogenesis and levels of brain-derived neurotrophic factor in animal studies. Neuropsychological studies have identified deficits in hippocampus-dependent recollection memory that may not abate with euthymia, and such memory impairment has been the most reliably documented cognitive abnormality in patients with MDD. Finally, data from imaging studies suggest both structural changes in the volume of the HC and functional alterations in frontotemporal and limbic circuits that may be critical for mood regulation. The extent to which such functional and structural changes determine clinical outcome in MDD remains unknown; a related, but also currently unanswered, question is whether the changes in HC function and structure observed in MDD are preventable or modifiable with effective treatment for the depressive illness.     

抑郁症模型鼠海马神经元细胞凋亡的初步研究

目的 研究抑郁症模型鼠海马神经元细胞的凋亡,探讨海马损害的病理生理机制。方法 选择旷场行为相近的成年SD雄性大鼠30只,随机分为实验组(15只)和对照组(15只),应用分养和长期不可预见的刺激制作成抑郁症模型。采用TUNEL染色法分析细胞凋亡,用免疫组化法检测凋亡的调控因子Bcl-xl。试验结果均采用SPSS 10.0软件处理。结果 与对照组比较,实验组大鼠海马内TUNEL染色阳性细胞增加,表达Bcl-xl蛋白的阳性细胞减少,两组有显著性差异。结论 抑郁症模型鼠海马神经元细胞凋亡增加。     

Cellular changes in the postmortem hippocampus in major depression.

BACKGROUND: Imaging studies report that hippocampal volume is decreased in major depressive disorder (MDD). A cellular basis for reduced hippocampal volume in MDD has not been identified. METHODS: Sections of right hippocampus were collected in 19 subjects with MDD and 21 normal control subjects. The density of pyramidal neurons, dentate granule cell neurons, glia, and the size of the neuronal somal area were measured in systematic, randomly placed three-dimensional optical disector counting boxes. RESULTS: In MDD, cryostat-cut hippocampal sections shrink in depth a significant 18% greater amount than in control subjects. The density of granule cells and glia in the dentate gyrus and pyramidal neurons and glia in all cornv ammonis (CA)/hippocampal subfields is significantly increased by 30%-35% in MDD. The average soma size of pyramidal neurons is significantly decreased in MDD. CONCLUSION: In MDD, the packing density of glia, pyramidal neurons, and granule cell neurons is significantly increased in all hippocampal subfields and the dentate gyrus, and pyramidal neuron soma size is significantly decreased as well. It is suggested that a significant reduction in neuropil in MDD may account for decreased hippocampal volume detected by neuroimaging. In addition, differential shrinkage of frozen sections of the hippocampus suggests differential water content in hippocampus in MDD.     

Leao''s spreading depression in the hippocampus explains transient global amnesia

Transient global amnesia has been explained by epileptic mechanisms or transient ischemic attacks affecting the hippocampus. None of these two mechanisms appear likely. The animal experimental phenomenon entitled spreading depression of cortical electrical activity (SD) or spreading depression of Leao has been implicated in migraine pathogenesis and may be relevant to transient global amnesia. In experimental animals, SD in the hippocampus causes a temporary functional ablation lasting minutes to hours with full functional recovery. Glutamate, which is present in large amounts in the hippocampus, may experimentally elicit spreading depression, and strong emotional events may possibly liberate glutamate and bring about this reaction in human patients.     

抑郁症大鼠海马体积异常的形态学探讨

目的观察抑郁症模型大鼠海马神经元形态结构改变及凋亡、自噬的变化,探讨抑郁症海马体积异常的机制。方法选用雄性成年SD大鼠,随机分为正常对照组和模型组,通过给予不可预见慢性温和应激建立抑郁症模型;采用尼氏染色观察海马神经元形态变化,流式细胞术检测海马神经元凋亡,Western blotting检测自噬相关蛋白LC-3和Beclin 1。结果与对照组比较,模型组海马体积萎缩,神经元数量减少,细胞凋亡率增高(P<0.05)。与对照组相比,模型组LC-3Ⅱ蛋白和LC-3Ⅱ/LC-3Ⅰ比值增高,Beclin 1相对表达增高(P<0.05)。结论抑郁症大鼠海马凋亡和自噬增强,可能是海马体积异常的原因之一。     

Seizure-like spreading depression in immature rabbit hippocampus in vitro

Cortical application of morphine (25, 100 and 400 micrograms) induced cortical spikes in a dose-related fashion and, at 400 micrograms, behavioral and electrographic seizures. These electrographic seizures were not opiate specific since this activity occurred undiminished in naltrexone-pretreated animals and was even potentiated in animals pretreated for 6 days with increasingly higher doses of systemic morphine. In contrast to the effects induced by morphine, the most consistent electrographic effect of cortically applied D-Ala2-methionine-enkephalin (DALA) and methadone was a depression of cortical EEG. These results support the hypothesis that the cortex and spinal cord together form the anatomical substrate of the documented nonspecific convulsive action of high systemically administered doses of morphine.     

A model of topological mapping of space in bat hippocampus

The mammalian hippocampus plays a key role in spatial learning and memory, but the exact nature of the hippocampal representation of space is still being explored. Recently, there has been a fair amount of success in modeling hippocampal spatial maps in rats, assuming a topological perspective on spatial information processing. In this article, we use the topological approach to study the formation of a 3D spatial map in bats, which produces several insights into neurophysiological mechanisms of the hippocampal spatial leaning. First, we demonstrate that, in order to produce accurate maps of the environment, place cell should be organized into functional groups, which can be interpreted as cell assemblies. Second, the model suggests that the readout neurons in these cell assemblies should function as integrators of synaptic inputs, rather than detectors of place cells' coactivity, which allows estimating the integration time window. Lastly, the model suggests that, in contrast with relatively slow moving rats, suppressing θ‐precession in bats improves the place cells capacity to encode spatial maps, which is consistent with the experimental observations. © 2016 Wiley Periodicals, Inc.     

Neurogenesis within the adult hippocampus under physiological conditions and in depression

Adult neurogenesis can only be observed in some specific brain regions. One of these areas is the dentate gyrus of the hippocampal formation. The progenitor cells located in the subgranular layer of the dentate gyrus proliferate, differentiate, and give rise to young neurons that can become integrated into existing neuronal circuits. Under physiological conditions, hippocampal neurogenesis is linked to hippocampal-dependent learning, whereas deficits in adult hippocampal neurogenesis have been shown to correlate with disturbances in spatial learning and memory. This review summarizes the phenomenon of adult hippocampal neurogenesis and the use of suitable markers for the investigation of adult hippocampal neurogenesis. In addition, we focused on the disturbances in neurogenesis that can be seen in depression. Interestingly, several antidepressants have been found to be capable of increasing the rate of hippocampal neurogenesis. Based on that, it can be speculated that factors, which directly or indirectly increase the rate of hippocampal neurogenesis, may be helpful in the treatment of depression.     

Overexpression of brain-derived neurotrophic factor in the hippocampus protects against post-stroke depression

Post-stroke depression is associated with reduced expression of brain-derived neurotrophic factor(BDNF). In this study, we evaluated whether BDNF overexpression affects depression-like behavior in a rat model of post-stroke depression. The middle cerebral artery was occluded to produce a model of focal cerebral ischemia. These rats were then subjected to isolation-housing combined with chronic unpredictable mild stress to generate a model of post-stroke depression. A BDNF gene lentiviral vector was injected into the hippocampus. At 7 days after injection, western blot assay and real-time quantitative PCR revealed that BDNF expression in the hippocampus was increased in depressive rats injected with BDNF lentivirus compared with depressive rats injected with control vector. Furthermore, sucrose solution consumption was higher, and horizontal and vertical movement scores were increased in the open field test in these rats as well. These findings suggest that BDNF overexpression in the hippocampus of post-stroke depressive rats alleviates depression-like behaviors.     

Flip side of synaptic plasticity: Long-term depression mechanisms in the hippocampus

There is growing interest in the phenomenon of long-term depression (LTD) of synaptic efficacy that, together with long-term potentiation (LTP), is a putative information storage mechanism in mammalian brain. In neural network models, multiple learning rules have been used for LTD induction. Similarly, in neurophysiological studies of hippocampal synaptic plasticity, a variety of activity patterns have been effective at inducing LTD, although experimental paradigms are still being optimized. In this review the authors summarize the major experimental paradigms and compare what is known about the mechanisms of LTD induction. Although all paradigms appear to initiate a cascade of events leading to an elevated level of Ca²⁺ postsynaptically, the extent to which these paradigms involve common expression mechanisms has not yet been tested. The authors discuss several critical experiments that would address this latter issue. Numerous questions about the properties and mechanisms of LTD(s) in the hippocampus remain to be answered, but it is clear that LTD has finally arrived, and will soon be attracting attention equal to its flip side, LTP. © 1994 Wiley-Liss, Inc.     

抑郁症与海马微管系统相关研究进展

本文从微管系统的相关概念及研究进展出发,叙述了海马微管系统与抑郁症发病的相关性,综述了抑郁症海马微管系统方面相关研究进展。     

Amygdala and hippocampus volumes in pediatric major depression.

BACKGROUND: The purpose of this study was to measure amygdala and hippocampus volumes in pediatric major depressive disorder (MDD) and to address the question of neuroanatomical continuity with adult-onset depression. METHODS: We studied 20 children and adolescents with MDD (17 female subjects) and 24 healthy comparison subjects (16 female subjects) using 1.5 Tesla magnetic resonance imaging. Group differences in left and right amygdala and hippocampus volumes were examined using repeated measures analyses of covariance, adjusting for age, gender, and whole brain volume. RESULTS: Depressed children had significant reductions of left and right amygdala volumes compared with healthy subjects. Hippocampus volumes did not differ between the groups. No significant correlations were found between amygdala volumes and depressive symptom severity, age at onset, or illness duration. CONCLUSIONS: Smaller amygdalas are present early in the course of pediatric depression and may predispose to the development of this disorder or perhaps more generally of childhood mood disorders. Future research should examine the longitudinal course and functional correlates of amygdala volume abnormalities in childhood-onset depression, including their possible moderation by gender.     

Revisiting the flip side: Long-term depression of synaptic efficacy in the hippocampus

Synaptic plasticity is widely regarded as a putative biological substrate for learning and memory processes. While both decreases and increases in synaptic strength are seen as playing a role in learning and memory, long-term depression (LTD) of synaptic efficacy has received far less attention than its counterpart long-term potentiation (LTP). Never-the-less, LTD at synapses can play an important role in increasing computational flexibility in neural networks. In addition, like learning and memory processes, the magnitude of LTD can be modulated by factors that include stress and sex hormones, neurotrophic support, learning environments, and age. Examining how these factors modulate hippocampal LTD can provide the means to better elucidate the molecular underpinnings of learning and memory processes. This is in turn will enhance our appreciation of how both increases and decreases in synaptic plasticity can play a role in different neurodevelopmental and neurodegenerative conditions.     

Stress and depression: possible links to neuron death in the hippocampus

Recent intriguing reports have shown an association between major depression and selective and persistent loss of hippocampal volume, prompting considerable speculation as to its underlying causes. In this paper we focus on the hypothesis that overt hippocampal neuron death could cause this loss and review current knowledge about how hippocampal neurons die during insults. We discuss (a) the trafficking of glutamate and calcium during insults; (b) oxygen radical generation and programmed cell death occurring during insults; (c) neuronal defenses against insults; (d) the role of energy availability in modulating the extent of neuron loss following such insults.
The subtypes of depression associated with hippocampal atrophy typically involve significant hypersecretion of glucocorticoids, the adrenal steroids secreted during stress. These steroids have a variety of adverse affects, direct and indirect, in the hippocampus. Thus glucocorticoids may play a contributing role toward neuron death. We further discuss how glucocorticoids cause or exacerbate cellular changes associated with hippocampal neuron loss in the context of the events listed above.     

Spatial olfactory learning facilitates long‐term depression in the hippocampus

Recently, it has emerged that visual spatial exploration facilitates synaptic plasticity at different synapses within the trisynaptic network. Particularly striking is the finding that visuospatial contexts facilitate hippocampal long‐term depression (LTD), raising the possibility that this form of plasticity may be important for memory formation. It is not known whether other sensory modalities elicit similar permissive effects on LTD. Here, we explored if spatial olfactory learning facilitates LTD in the hippocampus region of freely behaving rats. Patterned afferent stimulation of the Schaffer collaterals elicited short‐term depression (STD) (<1 h) of evoked responses in the Stratum radiatum of the CA1 region. Coupling of this protocol with novel exploration of a spatial constellation of olfactory cues facilitated short‐term depression into LTD that lasted for over 24 h. Facilitation of LTD did not occur when animals were re‐exposed 1 week later to the same odors in the same spatial constellation. Evaluation of learning behavior revealed that 1 week after the 1st odor exposure, the animals remembered the odors and their relative positions. These data support that the hippocampus can use nonvisuospatial resources, and specifically can use spatial olfactory information, to facilitate LTD and to generate spatial representations. The data also support that a tight relationship exists between the processing of spatial contextual information and the expression of LTD in the hippocampus. © 2013 Wiley Periodicals, Inc.