Impact of High-Fat Diet and Early Stress on Depressive-Like Behavior and Hippocampal Plasticity in Adult Male Rats

During development, the brain goes through fundamental processes, including organization of neural networks and plasticity. Environmental interventions may change initial brain programming, leading to long-lasting effects and altering the susceptibility to psychopathologies, including depression disorder. It is known that depression is a psychiatric disorder with a high prevalence worldwide, including high rates among adolescents. In this study, we evaluated whether social isolation in the prepubertal period and chronic use of high-fat diet (HFD) may induce depressive-like behavior in male adult rats. We also investigated hippocampal plasticity markers and neurotransmitter systems. We found both social isolation and HFD induced a depressive-like behavior in the forced swimming task. Moreover, chronic HFD reduced synaptic markers in hippocampus, demonstrated by reductions in βIII-tubulin (neuronal marker), PSD-95, SNAP-25, and neurotrophin-3. The HFD group also presented decreased glutamatergic and GABAergic receptors subunits. On the other hand, stress affected hippocampal brain-derived neurotrophic factor (BDNF) signaling pathways, and increased expression of subunit of the NMDA receptor (NR2A). Both factors (stress and diet) decreased GR in the hippocampus without affecting plasma corticosterone at basal levels. Interactions between early stress and HFD access were observed only in the BNDF receptor (tropomyosin receptor kinase B; TrkB) and synaptophysin. In summary, these findings showed that a brief social isolation and chronic HFD, during a sensitive developmental period, cause depressive-like behavior in adulthood. The mechanisms underlying these behavioral effects may involve changes in the levels of synaptic proteins in hippocampus: HFD consumption appears to affect synaptic markers, while social isolation affected BDNF signaling more significantly.     

Fucoidan exerts antidepressant-like effects in mice via regulating the stability of surface AMPARs

The inflammatory hypothesis is one of the most important mechanisms of depression. Fucoidan is a bioactive sulfated polysaccharide abundant in brown seaweeds with anti-inflammatory activity. However, the antidepressant effects of fucoidan on chronic stress-induced depressive-like behaviors have not been well elucidated. Here, we used two different depressive-like mouse models, lipopolysaccharide (LPS) and chronic restraint stress (CRS) models, to explore the detailed molecular mechanism underlying its antidepressant-like effects in C57BL/6J mice by combining multiple behavioral, molecular and immunofluorescence experiments. Adenovirus-mediated overexpression of caspase-1 and pharmacological inhibitors were also used to clarify the antidepressant mechanisms of fucoidan. We found that acute administration of fucoidan did not produce antidepressant effects in the tail suspension test (TST) and forced swim test (FST). Interestingly, chronic fucoidan administration not only dose-dependently reduced stress-induced depressive-like behaviors in the TST, FST, sucrose preference test (SPT), and novelty-suppressed feeding test (NSFT), but also alleviated the downregulation of brain-derived neurotrophic factor (BDNF)-dependent synaptic plasticity via inhibiting caspase-1-mediated inflammation in the hippocampus of mice. Moreover, fucoidan significantly ameliorated behavioral and synaptic plasticity abnormalities in the overexpression of caspase-1 in the hippocampus of mice. Furthermore, blocking BDNF abolished the antidepressant-like effects of fucoidan in mice. Therefore, our findings clearly indicate that fucoidan provides a potential supplementary noninvasive treatment for depression by inhibition of hippocampal inflammation.     

Microarray analysis of cultured rat hippocampal neurons treated with brain derived neurotrophic factor

Brain derived neurotrophic factor (BDNF) has been shown to exert multiple actions on neurons. It plays a role in neuronal growth and maintenance and use-dependent plasticity, such as long-term potentiation and learning. This neurotrophin is believed to regulate neuronal plasticity by modifying neuronal excitability and morphology. There is experimental evidence for both an acute and a long-term effect of BDNF on synaptic transmission and structure but the molecular mechanisms underlying these events have not been completely clarified. In order to study the BDNF-induced molecular changes, the set of genes modulated in cultured hippocampal neurons by BDNF treatment was investigated after subchronic treatment with the neurotrophin. Microarray analysis performed with these cells, revealed increased expression of mRNA encoding the neuropeptides neuropeptide Y and somatostatin, and of the secreted peptide VGF (non acronymic), all of which participate in neurotransmission. In addition, the expression of genes apolipoprotein E (ApoE), delta-6 fatty acid desaturase (Fads2) and matrix metalloproteinase 14 (Mmp14), which play a role in neuronal remodelling, was also enhanced. More studies are needed to investigate and confirm the role of these genes in synaptic plasticity, but the results reported in this paper show that microarray analysis of hippocampal cultures can be used to expand our current knowledge of the molecular events triggered by BDNF in the hippocampus.     

Brain-derived neurotrophic factor induces cell surface expression of short-form tenascin R complex in hippocampal postsynapses

Brain-derived neurotrophic factor (BDNF) is involved in hippocampal functions such as learning and memory and it plays a crucial role in regulating synaptic plasticity. To investigate potential mechanisms by which BDNF participates in neuronal communication through postsynaptic membrane proteins, we generated monoclonal antibodies against the synaptoneurosomal particulate fraction of mouse brain. One of the monoclonal antibodies, termed mAb#27, was found to be useful for analyzing BDNF-induced externalization of synaptoneurosomal membrane proteins of the hippocampus. In dissociated neuronal cultures, BDNF stimulation increased mAb#27 immunoprecipitates of biotin-labeled proteins with apparent masses, 55kDa, 80kDa, 100kDa, 130kDa, 140kDa and 160kDa. The mAb#27 recognition molecules were located in specific hippocampal regions of the brain and at postsynaptic sites in cultured cells. Proteomic studies of the mAb#27 immunocomplex identified newly derived short forms of tenascin R (TNR) as the mAb#27 recognition molecule. Contactin 1, prostaglandin regulatory-like protein and GABA A receptor subunit beta3 were identified as TNR-associated proteins. These proteins were recruited to mAb#27 when BDNF was applied to cells in culture. Each molecules identified in the present study contributes to the postsynaptic plasticity or the active cycle of cellular vesicle membranes. The formation of the TNR complex may serve as an underlying basis for synaptic plasticity in the hippocampus. Our results demonstrate that BDNF plays a role in external molecular dynamics and is likely to regulate synaptic functions such as the enhancement of neuronal excitability through GABAergic neurons.     

应激抑郁发生中糖皮质激素对BDNF信号通路的影响

脑源性神经营养因子(brain derived neurotrophic factor,BDNF)是一个关键性的神经营养因子,它既影响突触的形成和重构,又可以通过突触前和突触后机制改变突触传递的效能,从而对神经结构和功能可塑性发挥调节作用。BDNF主要通过结合TrkB受体激活细胞内信号系统来发挥它积极的生物学效应。研究表明,中枢神经系统BDNF表达或功能的变化与抑郁症的发生相关,而应激引起糖皮质激素(glucocorticoid,GC)的增加也是导致抑郁发生的重要原因之一。值得注意的是,GCs的增加会影响BDNF,一方面GCs降低BDNF的表达,另一方面GCs受体GR与BNDF受体TrkB相互作用。过多的GCs干扰了BDNF信号,使BDNF功能受到影响,导致抑郁患者脑内,尤其是海马结构的损害。就抑郁发生中糖皮质激素对BDNF功能影响的研究进展作一介绍。     

Functional interactions between steroid hormones and neurotrophin BDNF

Brain-derived neurotrophic factor (BDNF), a critical neurotrophin, regulates many neuronal aspects including cell differentiation, cell survival, neurotransmission, and synaptic plasticity in the central nervous system (CNS). Though BDNF has two types of receptors, high affinity tropomyosin-related kinase (Trk)B and low affinity p75 receptors, BDNF positively exerts its biological effects on neurons via activation of TrkB and of resultant intracellular signaling cascades including mitogen-activated protein kinase/extracellular signal-regulated protein kinase, phospholipase Cγ, and phosphoinositide 3-kinase pathways. Notably, it is possible that alteration in the expression and/or function of BDNF in the CNS is involved in the pathophysiology of various brain diseases such as stroke, Parkinson's disease, Alzheimer's disease, and mental disorders. On the other hand, glucocorticoids, stress-induced steroid hormones, also putatively contribute to the pathophysiology of depression. Interestingly, in addition to the reduction in BDNF levels due to increased glucocorticoid exposure, current reports demonstrate possible interactions between glucocorticoids and BDNF-mediated neuronal functions. Other steroid hormones, such as estrogen, are involved in not only sexual differentiation in the brain, but also numerous neuronal events including cell survival and synaptic plasticity. Furthermore, it is well known that estrogen plays a role in the pathophysiology of Parkinson's disease, Alzheimer's disease, and mental illness, while serving to regulate BDNF expression and/or function. Here, we present a broad overview of the current knowledge concerning the association between BDNF expression/function and steroid hormones (glucocorticoids and estrogen).     

Bipolar disorder: involvement of signaling cascades and AMPA receptor trafficking at synapses

There is increasing evidence that severe mood disorders are associated with impairment of structural plasticity and cellular resilience. Cumulative data demonstrate that mood stabilizers regulate intracellular signaling cascades, including protein kinase C (PKC), PKA, mitogen-activated protein (MAP) kinase, glycogen synthase kinase 3-beta (GSK3-beta) and intracellular calcium, which are signaling pathways that regulate synaptic plasticity. In this context, it is noteworthy that a growing body of data indicates that the glutamatergic system, has a major role in neuronal plasticity and cellular resilience, might be involved in the pathophysiology and treatment of mood disorders. AMPA glutamate-receptor trafficking is important in synaptic plasticity and might play crucial roles in maintaining critical neuronal circuits associated with mood. Two clinically effective, structurally dissimilar, antimanic agents, lithium and valproate (VPA), down-regulate synaptic expression of AMPA receptor subunit GluR1 in hippocampus in chronically treated rats. This reduction in synaptic GluR1 by lithium and VPA is due to attenuated phosphorylation of GluR1 at a specific PKA site (residue 845 of GluR1), which is crucial for AMPA receptor insertion. By contrast,imipramine, which can provoke mania, increases synaptic expression of GluR1 in the hippocampus in vivo. Furthermore, there is ample evidence from preclinical and clinical research that the glutamatergic system is involved in the pathophysiology of mood disorders and that many of the somatic treatments used for mood disorders including antidepressants, mood stabilizers, atypical antipsychotic drugs and electroconvulsive therapy have both direct and indirect effects on the glutamatergic system. Given these findings, further research with medications that specifically affect the glutamatergic system is warranted. Recent studies in our lab have shown that riluzole, a FDA approved medicine that regulates the glutamatergic system, shows antidepressant efficacy in unipolar and bipolar depression. These studies indicate that regulation of glutamate-mediated synaptic plasticity might play a role in the treatment of mood disorders, and raise new avenues for novel therapies for this devastating illness.     

Targeting the Hippocampal Mossy Fiber Synapse for the Treatment of Psychiatric Disorders

It is widely known that new neurons are continuously generated in the dentate gyrus of the hippocampus in the adult mammalian brain. This neurogenesis has been implicated in depression and antidepressant treatments. Recent evidence also suggests that the dentate gyrus is involved in the neuropathology and pathophysiology of schizophrenia and other related psychiatric disorders. Especially, abnormal neuronal development in the dentate gyrus may be a plausible risk factor for the diseases. The synapse made by the mossy fiber, the output fiber of the dentate gyrus, plays a critical role in regulating neuronal activity in its target CA3 area. The mossy fiber synapse is characterized by remarkable activity-dependent short-term synaptic plasticity that is established during the postnatal development and is supposed to be central to the functional role of the mossy fiber. Any defects, including developmental abnormalities, in the dentate gyrus and drugs acting on the dentate gyrus can modulate the mossy fiber-CA3 synaptic transmission, which may eventually affect hippocampal functions. In this paper, I review recent evidence for involvement of the dentate gyrus and mossy fiber synapse in psychiatric disorders and discuss potential importance of drugs targeting the mossy fiber synapse either directly or indirectly in the therapeutic treatments of psychiatric disorders.     

An animal model of a behavioral intervention for depression

Although conditioned inhibition of fear (or learned safety) is a learning process critical for preventing chronic stress, a predisposing factor for depression and other psychopathologies, little is known about its functional purposes or molecular mechanisms. To obtain better insight into learned safety, we investigated its behavioral and molecular characteristics and found that it acts as a behavioral antidepressant in two animal models. Learned safety promotes the survival of newborn cells in the dentate gyrus of the hippocampus, while its antidepressant effect is abolished in mice with ablated hippocampal neurogenesis. Learned safety also increases the expression of BDNF in the hippocampus and leads to downregulation of genes involved in the dopaminergic and neuropeptidergic but not the serotonergic system in the basolateral amygdala. These data suggest that learned safety is an animal model of a behavioral antidepressant that shares some neuronal hallmarks of pharmacological antidepressants but is mediated by different molecular pathways.     

Modulation of synaptic plasticity by stress hormone associates with plastic alteration of synaptic NMDA receptor in the adult hippocampus

Stress exerts a profound impact on learning and memory, in part, through the actions of adrenal corticosterone (CORT) on synaptic plasticity, a cellular model of learning and memory. Increasing findings suggest that CORT exerts its impact on synaptic plasticity by altering the functional properties of glutamate receptors, which include changes in the motility and function of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of glutamate receptor (AMPAR) that are responsible for the expression of synaptic plasticity. Here we provide evidence that CORT could also regulate synaptic plasticity by modulating the function of synaptic N-methyl-D-aspartate receptors (NMDARs), which mediate the induction of synaptic plasticity. We found that stress level CORT applied to adult rat hippocampal slices potentiated evoked NMDAR-mediated synaptic responses within 30 min. Surprisingly, following this fast-onset change, we observed a slow-onset (>1 hour after termination of CORT exposure) increase in synaptic expression of GluN2A-containing NMDARs. To investigate the consequences of the distinct fast- and slow-onset modulation of NMDARs for synaptic plasticity, we examined the formation of long-term potentiation (LTP) and long-term depression (LTD) within relevant time windows. Paralleling the increased NMDAR function, both LTP and LTD were facilitated during CORT treatment. However, 1-2 hours after CORT treatment when synaptic expression of GluN2A-containing NMDARs is increased, bidirectional plasticity was no longer facilitated. Our findings reveal the remarkable plasticity of NMDARs in the adult hippocampus in response to CORT. CORT-mediated slow-onset increase in GluN2A in hippocampal synapses could be a homeostatic mechanism to normalize synaptic plasticity following fast-onset stress-induced facilitation.     

Interplay between brain BDNF and glutamatergic systems: A brief state of the evidence and association with the pathogenesis of depression

The excitatory neurotransmitter glutamate system and the brain-derived neurotrophic factor (BDNF) system are principally involved in phenomena of cellular and synaptic plasticity. These systems are interacting, and disclosing mechanisms of such interactions is critically important for understanding the machinery of neuroplasticity and its modulation in normal and pathological situations. The short state of evidence in this review addresses experimentally confirmed connections of these mechanisms and their potential relation to the pathogenesis of depression. The connections between the two systems are numerous and bidirectional, providing for mutual regulation of the glutamatergic and BDNF systems. The available data suggest that it is complex and well-coordinating nature of these connections that secures optimal synaptic and cellular plasticity in the normal brain. Both systems are associated with the pathogenesis of depression, and the disturbance of tight and well-balanced associations between them results in unfavorable changes in neuronal plasticity underlying depressive disorders and other mood diseases.     

Proposed glucocorticoid-mediated zinc signaling in the hippocampus

Corticosteroid hormones are secreted from the adrenal glands in hourly pulses and signal the hippocampus for the development and function. In contrast, the stress-induced rise in corticosteroid concentrations has a profound effect on emotional arousal, motivational processes and cognitive performance. This rise is required as the stress response to maintain homeostasis in the living body or restore it. However, abnormal rise in corticosteroid concentrations is a disadvantage to the hippocampus. Corticosteroid-glutamatergic interactions during information processing are proposed as a potential model to explain many of the diverse actions of corticosteroids in synaptic plasticity such as long-term potentiation and cognition. Because zincergic neurons are a subtype of glutamatergic neurons and release Zn(2+) and glutamate into the synaptic cleft, it is possible that homeostasis of synaptic Zn(2+), in addition to homeostasis of glutamate, is modified by glucocorticoids, followed by the changes in cognitive function and stress response. Zn(2+) signal participates in cognitive and emotional behavior in cooperation with signaling of glucocorticoids and glutamate, while can disadvantageously act on the hippocampus under sever stress circumstances. This paper analyzes the actions of glucocorticoid-mediated Zn(2+) signal in the hippocampus under stressful circumstances and its significance in both hippocampal function and dysfunction.     

Resilin and chitinous cuticle form a composite structure for energy storage in jumping by froghopper insects

Background

Erythropoietin (EPO) improves cognition of human subjects in the clinical setting by as yet unknown mechanisms. We developed a mouse model of robust cognitive improvement by EPO to obtain the first clues of how EPO influences cognition, and how it may act on hippocampal neurons to modulate plasticity.

Results

We show here that a 3-week treatment of young mice with EPO enhances long-term potentiation (LTP), a cellular correlate of learning processes in the CA1 region of the hippocampus. This treatment concomitantly alters short-term synaptic plasticity and synaptic transmission, shifting the balance of excitatory and inhibitory activity. These effects are accompanied by an improvement of hippocampus dependent memory, persisting for 3 weeks after termination of EPO injections, and are independent of changes in hematocrit. Networks of EPO-treated primary hippocampal neurons develop lower overall spiking activity but enhanced bursting in discrete neuronal assemblies. At the level of developing single neurons, EPO treatment reduces the typical increase in excitatory synaptic transmission without changing the number of synaptic boutons, consistent with prolonged functional silencing of synapses.

Conclusion

We conclude that EPO improves hippocampus dependent memory by modulating plasticity, synaptic connectivity and activity of memory-related neuronal networks. These mechanisms of action of EPO have to be further exploited for treating neuropsychiatric diseases.     

La dépression et le traitement antidépresseur: de la neurotoxicité à la neurogenèse

Major depressive disorder is characterized by structural and neurochemical changes in limbic structures, including the hippocampus that regulates mood and cognitive functions. Hippocampal atrophy is observed in patients with depression: structural changes in the hippocampus associated with depression include dendritic atrophy, decreased adult neurogenesis and reduced volume. Impairment of neuroplasticity in the hippocampus, amygdala and cortex is hypothesized to be the mechanism by which cognitive function, episodic verbal memory and emotions are altered in depression. Chronic stress exposure and depression leads to hippocampal atrophy and cell loss as well as to decreased expression of neurotrophic growth factors. All types of antidepressant drugs reverse or block the effects of stress. Chronic antidepressant administration upregulates neurogenesis and neuroplasticity in the adult hippocampus and these cellular responses are required for the effects of antidepressants in animal models of depression.     

Mechanisms of heterosynaptic metaplasticity

Synaptic plasticity is fundamental to the neural processes underlying learning and memory. Interestingly, synaptic plasticity itself can be dynamically regulated by prior activity, in a process termed ‘metaplasticity’, which can be expressed both homosynaptically and heterosynaptically. Here, we focus on heterosynaptic metaplasticity, particularly long-range interactions between synapses spread across dendritic compartments, and review evidence for intracellular versus intercellular signalling pathways leading to this effect. Of particular interest is our previously reported finding that priming stimulation in stratum oriens of area CA1 in the hippocampal slice heterosynaptically inhibits subsequent long-term potentiation and facilitates long-term depression in stratum radiatum. As we have excluded the most likely intracellular signalling pathways that might mediate this long-range heterosynaptic effect, we consider the hypothesis that intercellular communication may be critically involved. This hypothesis is supported by the finding that extracellular ATP hydrolysis, and activation of adenosine A2 receptors are required to induce the metaplastic state. Moreover, delivery of the priming stimulation in stratum oriens elicited astrocytic calcium responses in stratum radiatum. Both the astrocytic responses and the metaplasticity were blocked by gap junction inhibitors. Taken together, these findings support a novel intercellular communication system, possibly involving astrocytes, being required for this type of heterosynaptic metaplasticity.     

iTRAQ-Based Quantitative Proteomics Suggests Synaptic Mitochondrial Dysfunction in the Hippocampus of Rats Susceptible to Chronic Mild Stress

Mounting studies show that hippocampal synaptic transmission and plasticity are abnormal in depression. It has been suggested that impairment of synaptic mitochondrial functions potentially occurs in the hippocampus. Thus, the synaptic mitochondria may be a crucial therapeutic target in the course of depression. Here, we investigated the potential dysregulation of synaptic mitochondrial proteins in the hippocampus of a chronic mild stress (CMS) rat model. Proteomic changes of hippocampal synaptosomes containing synaptic mitochondria were quantitatively examined using the isobaric tag for relative and absolute quantitation labeling combined with tandem mass spectrometry. 45 Proteins were identified to be differentially expressed, of which 21 were found to be putative synaptic mitochondrial proteins based on gene ontology component and SynaptomeDB analyses. Detailed investigations of protein functions and disease relevance support the importance of hippocampal synaptic mitochondria as a key substrate contributing to impairment in synaptic plasticity of stress-related disorders. Interestingly, eight synaptic mitochondrial proteins were specifically associated to the susceptible group, and might represent part of molecular basis of depression. Further analysis indicated that the synaptic mitochondrial oxidative phosphorylation (OXPHOS) system was heavily affected by CMS in the susceptible rats. The present results provide novel insights into the disease mechanism underlying the abnormal OXPHOS that is responsible for energy-demanding synaptic plasticity, and thereby increase our understanding of the role of hippocampal synaptic mitochondrial dysfunction in depression.