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Deficits in the neuroendocrine-immune network in the periphery associated with the onset and progression of mild cognitive impairment (MCI) and Alzheimer's disease (AD) have not been extensively studied. The present study correlatively examines the association between cell-mediated immune responses, stress hormones, amyloid precursor protein (APP) expression, peripheral blood mononuclear cells (PBMC), and intracellular signaling molecules in the pathophysiology of MCI and AD compared to adults. Serum APP, lymphocyte proliferation, total cholinesterase (TChE), butyrylcholinesterase (BChE) activities, cytokines (IL-2, IFN-γ, IL-6, and TNF-α), and intracellular signaling molecules (p-ERK, p-CREB, and p-Akt) were measured in the PBMCs of adult, old, MCI, and AD men and women initially and after 3 years in the same population. An age- and disease-associated decline in mini-mental state examination (MMSE) scores and lymphocyte proliferation of MCI and AD men and women were observed. An age- and disease-related increase in serum APP, cortisol levels, and TChE activity were observed in men and women. Enhanced production of Th1 cytokine, IL-2, pro-inflammatory cytokines, and suppressed intracellular transcription factors may promote the inflammatory environment in MCI and AD patients. The expression of CREB and Akt was lower in MCI and AD men, while the expression of p-ERK was higher, and p-CREB was lower in MCI and AD women after 3 years. These results suggest that changes in specific intracellular signaling pathways may influence alterations in cell-mediated immunity to promote disease progression in MCI and AD patients. [ABSTRACT FROM AUTHOR]

Nav1.8, a tetrodotoxin-resistant voltage-gated sodium channels (VGSCs) subtype encoded by SCN10A, which plays an important role in the production and transmission of peripheral neuropathic pain signals. Studies have shown that VGSCs may be key targets of MicroRNAs (miRNAs) in the regulation of neuropathic pain. In our study, bioinformatics analysis showed that the targeting relationship between miR-3584-5p and Nav1.8 was the most closely. The purpose of this study was to investigate the roles of miR-3584-5p and Nav1.8 in neuropathic pain. The effects of miR-3584-5p on chronic constriction injury (CCI)-induced neuropathic pain in rats was investigated by intrathecal injection of miR-3584-5p agomir (an agonist, 20 μM, 15 μL) or antagomir (an antagonist, 20 μM, 15 μL). The results showed that over-expression of miR-3584-5p aggravated neuronal injury by hematoxylin–eosin (H&E) staining and mechanical/thermal hypersensitivity in CCI rats. MiR-3584-5p indirectly inhibited the expression of Nav1.8 by up-regulating the expression of key proteins in the ERK5/CREB signaling pathway, and also inhibited the current density of the Nav1.8 channel, changed its channel dynamics characteristic, thereby accelerating the transmission of pain signals, and further aggravating pain. Similarly, in PC12 and SH-SY5Y cell cultures, miR-3584-5p increased the level of reactive oxygen species (ROS) and inhibited mitochondrial membrane potential (Δψm) in the mitochondrial pathway, decreased the ratio of apoptosis-related factor Bcl-2/Bax, and thus promoted neuronal apoptosis. In brief, over-expression of miR-3584-5p aggravates neuropathic pain by directly inhibiting the current density of Nav1.8 channel and altering its channel dynamics, or indirectly inhibiting Nav1.8 expression through ERK5/CREB pathway, and promoting apoptosis through mitochondrial pathway. [ABSTRACT FROM AUTHOR]

Cerebral ischemia is characterized by several pathological reaction evolving over time. Hyperactivation of glutamatergic neurons is the main factor leading to excitotoxicity which potentiates oxidative stress and triggers the mechanisms of neural apoptosis after cerebral ischemia. However, it is unclear whether glutamate in the ventral hippocampal Cornus Ammonis 1 (vCA1) acts a part in neurological deficits, pain perception, anxiety, and depression induced by ischemic stroke. We investigated the effects of chemogenetic inhibition or activation of vCA1 pyramidal neurons which are mainly glutamatergic neurons on sequelae induced by cerebral ischemia. Our results revealed that inhibition of vCA1 pyramidal neurons by chemogenetics alleviated neurological deficits, pain perception, anxiety, and depression caused by cerebral ischemia in mice, but activation of vCA1 pyramidal neurons had limited effects. Moreover, we found that stroke was accompanied by decreased levels of cAMP-response element-binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in vCA1, which are modulated by glutamate. In this study, overexpression of CREB protein in pyramidal neurons in vCA1 by AAV virus significantly upregulated the content of BDNF and ameliorated the dysfunction induced by ischemic stroke. Our results demonstrated activation of the CREB-BDNF pathway in vCA1 pyramidal neurons significantly improved neurological deficits, pain perception, anxiety, and depression induced by ischemic stroke. [ABSTRACT FROM AUTHOR]

Several studies have reported separate roles of adenosine receptors and circadian clockwork in major depressive disorder. While less evidence exists for regulation of the circadian clock by adenosine signaling, a small number of studies have linked the adenosinergic system, the molecular circadian clock, and mood regulation. In this article, we review relevant advances and propose that adenosine receptor signaling, including canonical and other alternative downstream cellular pathways, regulates circadian gene expression, which in turn may underlie the pathogenesis of mood disorders. Moreover, we summarize the convergent point of these signaling pathways and put forward a pattern by which Homer1a expression, regulated by both cAMP-response element binding protein (CREB) and circadian clock genes, may be the final common pathogenetic mechanism in depression. [ABSTRACT FROM AUTHOR]

Episodic memories acquired early in life are fragile and rapidly forgotten in both humans and nonhuman animals. However, early life experiences have been documented to profoundly affect brain function and physiology throughout life, suggesting that in certain circumstances, the developing brain is capable of producing long-term memory (LTM). In this study, we asked whether exposure to a novel environment, a process named "behavioral tagging," may promote the persistence of weak memories in male juvenile mice. Using a contextual fear conditioning (CFC) paradigm, we found that a weak training protocol, which typically induces a transient form of memory, results in LTM when paired with an exploration to a novel but not a familiar environment that occurs close in time to the training session. The promoting effect of the novel context exploration (NCE) on CFC-LTM formation is dependent on the activation of dopamine D1/D5 receptors and requires novel protein synthesis in the dorsal hippocampus. Moreover, NCE increases the size of overlapping CA1 neuronal ensembles engaged by CFC and NCE. These results provide direct support for the existence of a behavioral tagging process, in which exposure to novelty provides newly synthesized proteins to stabilize the contextual fear memory trace in juvenile mice. [ABSTRACT FROM AUTHOR]

Extracellular magnesium ion ([Mg2+]) is a well-known voltage-dependent blocker of NMDA receptors, which plays a critical role in the regulation of neuronal plasticity, learning, and memory. It is generally believed that NMDA receptor activation involves in Mg2+ being removed into extracellular compartment from the channel pore. On the other hand, Mg2+ is one of the most abundant intracellular cations, and involved in numerous cellular functions. However, we do not know if extracellular magnesium ions can influx into neurons to affect intracellular signaling pathways. In our current study, we found that extracellular [Mg2+] elevation enhanced CREB activation by NMDA receptor signaling in both mixed sex rat cultured neurons and brain slices. Moreover, we found that extracellular [Mg2+] led to CREB activation by NMDA application, albeit in a delayed manner, even in the absence of extracellular calcium, suggesting a potential independent role of magnesium in CREB activation. Consistent with this, we found that NMDA application leads to an NMDAR-dependent increase in intracellular-free [Mg2+] in cultured neurons in the absence of extracellular calcium. Chelating this magnesium influx or inhibiting P38 mitogen-activated protein kinase (p38 MAPK) blocked the delayed pCREB by NMDA. Finally, we found that NMDAR signaling in the absence of extracellular calcium activates p38 MAPK. Our studies thus indicate that magnesium influx, dependent on NMDA receptor opening, can transduce a signaling pathway to activate CREB in neurons. [ABSTRACT FROM AUTHOR]

Sialylated milk oligosaccharides (SMOs) have a multifunctional health benefit, yet the molecular details underlying their potential role in modulating intestinal maturation remains unknown. To test the hypothesis that sialyllactose (SL) may mediate intestinal maturation and function through controlling neuronal function, studies were carried out where the diet of postnatal piglets was supplemented with a mixture of 3′- and 6′-sialyllactose from postnatal day 3 to 38. Gene transcription pathways regulating enteric nervous system function, polysialic acid (polySia) synthesis, and cell proliferation were quantified. Our new findings show that SL intervention: (1) upregulated the level of gene and protein expression of the glial-derived neurotrophic factor (GDNF) in the ileum; (2) upregulated phosphorylation of the cAMP responsive element-binding protein (CREB), the downstream target of GDNF signaling pathway; (3) promoted cell proliferation based on an increase in the number and density of Ki-67 positive cells in the crypts; (4) increased the crypt width in the ileum by 10%, while gene markers for the functional cells were not affected; (5) upregulated mRNA expression level of ST8Sia IV, a key polysialyltransferase responsible for synthesis of polySia-NCAM; (6) reduced the incidence and severity of diarrhea. These results show that SL promotes intestinal maturation in neonatal piglets by upregulating GDNF, synthesis of polySia and CREB-interactive pathway. [ABSTRACT FROM AUTHOR]

Major depressive disorder is a chronic debilitating mental illness. Its pathophysiology at cellular and molecular levels is incompletely understood. Increasing evidence supports a pivotal role of the mitogen-activated protein kinase (MAPK), in particular the extracellular signal-regulated kinase (ERK) subclass of MAPKs, in the pathogenesis, symptomatology, and treatment of depression. In humans and various chronic animal models of depression, the ERK signaling was significantly downregulated in the prefrontal cortex and hippocampus, two core areas implicated in depression. Inhibiting the ERK pathway in these areas caused depression-like behavior. A variety of antidepressants produced their behavioral effects in part via normalizing the downregulated ERK activity. In addition to ERK, the brain-derived neurotrophic factor (BDNF), an immediate upstream regulator of ERK, the cAMP response element-binding protein (CREB), a transcription factor downstream to ERK, and the MAPK phosphatase (MKP) are equally vulnerable to depression. While BDNF and CREB were reduced in their activity in the prefrontal cortex and hippocampus of depressed animals, MKP activity was enhanced in parallel. Chronic antidepressant treatment readily reversed these neurochemical changes. Thus, ERK signaling in the depression-implicated brain regions was disrupted during the development of depression, which contributes to the long-lasting and transcription-dependent neuroadaptations critical for enduring depression-like behavior and the therapeutic effect of antidepressants. [ABSTRACT FROM AUTHOR]

Neonatal hypoxic–ischemic (HI) brain injury likely represents the major cause of long-term neurodevelopmental disabilities in surviving babies. Despite significant investigations, there is not yet any known reliable treatment to reduce brain damage in suffering infants. Our recent studies in an animal model of HI revealed the therapeutic potential of a histone deacetylase inhibitor (HDACi). The neuroprotective action was connected with the stimulation of neurogenesis in the dentate gyrus subgranular zone. In the current study, we investigated whether HDACi—sodium butyrate (SB)—would also lead to neurogenesis in the subventricular zone (SVZ). By using a neonatal rat model of hypoxia–ischemia, we found that SB treatment stimulated neurogenesis in the damaged ipsilateral side, based on increased DCX labeling, and restored the number of neuronal cells in the SVZ ipsilateral to lesioning. The neurogenic effect was associated with inhibition of inflammation, expressed by a transition of microglia to the anti-inflammatory phenotype (M2). In addition, the administration of SB increased the activation of the TrkB receptor and the phosphorylation of the transcription factor—CREB—in the ipsilateral hemisphere. In contrast, SB administration reduced the level of HI-induced p75NTR. Together, these results suggest that BDNF–TrkB signaling plays an important role in SB-induced neurogenesis after HI. These findings provide the basis for clinical approaches targeted at protecting the newborn brain damage, which may prove beneficial for treating neonatal hypoxia–ischemia. [ABSTRACT FROM AUTHOR]

Procyanidins, the oligomeric compounds formed from catechin and epicatechin molecules, are potentially effective targets as nutraceuticals or pharmaceuticals in the prevention and treatment of Alzheimer's disease (AD). Natural procyanidins can attenuate AD pathological features, extracellular amyloid deposits, and neurofibrillary tangles via reducing Aβ accumulation and tau pathology. The enhancement of cognition as well as modulation of synaptic plasticity by these compounds also participated in the alleviation of AD. Notably, procyanidins and some of their metabolites have been observed to upregulate SIRT1 (silent information regulator 1) which is essential for normal cognitive and synaptic plasticity, and stimulate CREB (cAMP response element binding) which acts as a molecular switch from short- to long-term memory. Based on the interplay of CREB-SIRT1 axis, it is therefore conceivable that the regulation of procyanidins by the means of CREB-SIRT1 could promote the cognitive function and is thus conducive for AD pathogenesis. This review focuses on the role of procyanidins, the main group of flavonoids, on AD and the potential mechanism involved CREB-SIRT1 axis. [ABSTRACT FROM AUTHOR]

We have recently demonstrated that δ-opioid receptor (DOR) activation attenuates α-synuclein expression/aggregation induced by MPP(+) and/or severe hypoxia. Since α-synuclein plays a critical role in the pathogenesis of Parkinson's disease, DOR activation may trigger an antiparkinson pathway(s) against α-synuclein-induced injury. However, the underlying mechanism is unknown yet. In HEK293T and PC12 cells, we investigated the effects of DOR activation on the oligomer formation induced by α-synuclein overexpression and mutation in normoxic and hypoxic conditions and explored the potential signaling pathways for DOR protection. We found that (1) increased expression of both wild-type and A53T-mutant α-synuclein led to the formation of α-synuclein oligomers and cytotoxic injury; (2) DOR activation largely attenuated the formation of toxic α-synuclein oligomers induced by α-synuclein overexpression/mutation and/or hypoxia; (3) DOR activation attenuated α-synuclein-induced cytotoxicity through TORC1/SIK1/CREB, but not the phospho-CREB pathway, while DOR activation reduced hypoxic cell injury through the phospho-CREB mechanism; and (4) the interaction of α-synuclein and the DJ-1 was involved in the mechanisms for DOR-mediated protection against α-synuclein oligomer formation. Our findings suggest that DOR attenuates the formation of toxic α-synuclein oligomers through the phos-CREB pathway under hypoxic conditions, and through TORC1/SIK1/CREB pathways in the conditions of α-synuclein overexpression and mutation. The DJ-1 gene was involved in the DOR protection against parkinsonian injury. [ABSTRACT FROM AUTHOR]

This study investigated changes in neuroinflammation and cognitive function in adult zebrafish exposed to acute hypoxia and protective effects of glucosamine (GlcN) against hypoxia-induced brain damage. The survival rate of zebrafish following exposure to hypoxia was improved by GlcN pretreatment. Moreover, hypoxia-induced upregulation of neuroglobin, NOS2α, glial fibrillary acidic protein, and S100β in zebrafish was suppressed by GlcN. Hypoxia stimulated cell proliferation in the telencephalic ventral domain and in cerebellum subregions. GlcN decreased the number of bromodeoxyuridine (BrdU)-positive cells in the telencephalon region, but not in cerebellum regions. Transient motor neuron defects, assessed by measuring the locomotor and exploratory activity of zebrafish exposed to hypoxia recovered quickly. GlcN did not affect hypoxia-induced motor activity changes. In passive avoidance tests, hypoxia impaired learning and memory ability, deficits that were rescued by GlcN. A learning stimulus increased the nuclear translocation of phosphorylated cAMP response element binding protein (p-CREB), an effect that was greatly inhibited by hypoxia. GlcN restored nuclear p-CREB after a learning trial in hypoxia-exposed zebrafish. The neurotransmitters, γ-aminobutyric acid and glutamate, were increased after hypoxia in the zebrafish brain, and GlcN further increased their levels. In contrast, acetylcholine levels were reduced by hypoxia and restored by GlcN. Acetylcholinesterase inhibitor physostigmine partially reversed the impaired learning and memory of hypoxic zebrafish. This study represents the first examination of the molecular mechanisms underlying hypoxia-induced memory and learning defects in a zebrafish model. Our results further suggest that GlcN-associated hexosamine metabolic pathway could be an important therapeutic target for hypoxic brain damage. [ABSTRACT FROM AUTHOR]

The molecular basis of memory loss in Alzheimer’s disease (AD), the main cause of senile dementia, is under investigation. In the present study, we have focused on the early hippocampal memory-related changes in APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. It is well known that molecules like cAMP response element binding (CREB) and binding protein (CBP) play a crucial role in memory consolidation. We analyzed CBP on its transcriptional activity and protein levels, finding a significant downregulation of both of them at 3-month-old mice. In addition, the downregulation of this molecule was associated with a decrease on acetylation levels of histone H3 in the hippocampus of APP/PS1 mice. Moreover, the p-CREB levels, which are important for memory acquisition at 3 months in APP/PS1 mice, were downregulated. Furthermore, we suggest that early neuroinflammation, especially due to the Tnfα gene increased expression, could also be responsible to this process of memory loss. Given all the previously mentioned results, we propose that an early suitable treatment to prevent the evolution of the disease should include a combination of drugs, including anti-inflammatories, which may decrease glial activation and Tnfα levels, and phosphodiesterase inhibitors that increase cAMP levels. [ABSTRACT FROM AUTHOR]

A body of evidence supports a relevant role of brain-derived neurotrophic factor (BDNF) in temporal lobe epilepsy (TLE). Magnetic resonance data reveal that the cerebral atrophy extends to regions that are functionally and anatomically connected with the hippocampus, especially the temporal cortex. We previously reported an increased expression of BDNF messenger for the exon VI in the hippocampus of temporal lobe epilepsy patients compared to an autopsy control group. Altered levels of this particular transcript were also associated with pre-surgical use of certain psychotropic. We extended here our analysis of transcripts I, II, IV, and VI to the temporal cortex since this cerebral region holds intrinsic communication with the hippocampus and is structurally affected in patients with TLE. We also assayed the cyclic adenosine monophosphate response element-binding (CREB) and glucocorticoid receptor (GR) genes as there is experimental evidence of changes in their expression associated with BDNF and epilepsy. TLE and pre-surgical pharmacological treatment were considered as the primary clinical independent variables. Transcripts BDNF I and BDNF VI increased in the temporal cortex of patients with pharmacoresistant TLE. The expression of CREB and GR expression follow the same direction. Pre-surgical use of selective serotonin reuptake inhibitors, carbamazepine (CBZ) and valproate (VPA), was associated with the differential expression of specific BDNF transcripts and CREB and GR genes. These changes could have functional implication in the plasticity mechanisms related to temporal lobe epilepsy. [ABSTRACT FROM AUTHOR]

Metabolic defects are common pathological phenomena following traumatic brain injury (TBI) which contribute to poor prognosis. Brain-derived neurotrophic factor (BDNF) is an important regulator of neuronal survival, development, function, and plasticity. This study was designed to investigate the potential effects of BDNF on TBI-induced metabolic defects and their underlying molecular mechanisms. BDNF was added into cultured neurons to a concentration of 25, 50, and 100 ng/ml, respectively, right after mechanical injury and metabolite levels were analyzed 4 h post injury. The mitochondrial phosphorylated cAMP response element-binding protein (pCREB) distribution and complex V synthesis, as well as their roles in metabolic defects, were evaluated. We found that exogenous BDNF improved metabolic defects, especially the uncoupling of oxidative phosphorylation. BDNF increased pCREB in mitochondrial inner membrane and matrix and promoted mitochondrial complex V synthesis. We also found that these results were negatively regulated by the mitochondrial permeability transition pore (MPTP) antagonist CsA and positively regulated by the MPTP agonist atractyloside. BDNF’s protectional effects on metabolic defects were abolished by CREB knockout. When administrated in a dominant interfering CREB mutant (A-CREB) model, mitochondrial pCREB accumulation could still be observed, but the synthesis of complex V and alleviation of metabolic defects were repressed. Our data demonstrate that exogenous BDNF mitigates neuronal metabolic defects following mechanical injury by promoting the pCREB accumulation in mitochondrial inner membrane and matrix, which is regulated by MPTP opening, thus facilitating the synthesis of mitochondrial complex V. [ABSTRACT FROM AUTHOR]

Earlier, protective role of curcumin in arsenic-induced dopamine (DA)–D2 receptor dysfunctions in corpus striatum has been demonstrated by us. In continuation to that, the present study is focused to decipher the molecular mechanisms associated with alterations in dopaminergic signaling on arsenic exposure in corpus striatum and assess the protective efficacy of curcumin. Exposure to arsenic (20 mg/kg, body weight p.o. for 28 days) in rats resulted to decrease the expression of presynaptic proteins-tyrosine hydroxylase and VMAT2 while no effect was observed on the expression of DAT in comparison to controls. A significant decrease in the expression of DA-D2 receptors associated with alterations in the expression of PKA, pDARPP32 (Thr 34), and PP1 α was clearly evident on arsenic exposure. Expression of BDNF and pGSK3β in corpus striatum was found decreased in arsenic-exposed rats. Simultaneous treatment with curcumin (100 mg/kg, body weight p.o. for 28 days) resulted to protect arsenic-induced alterations in the expression of DA-D2 receptors, PKA, pDARPP32, pCREB, and pPP1α. Neuroprotective efficacy of curcumin can possibly be attributed to its antioxidant potential which significantly protected arsenic-induced mitochondrial dysfunctions by modulating the ROS generation and apoptosis. Modulation in the expression of BDNF and pGSK3β in corpus striatum by curcumin exhibits the importance of neuronal survival pathway in arsenic-induced dopaminergic dysfunctions. Interestingly, curcumin was also found to protect arsenic-induced ultrastructural changes in corpus striatum. The results exhibit that curcumin modulates BDNF/DARPP32/CREB in arsenic-induced alterations in dopaminergic signaling in rat corpus striatum. [ABSTRACT FROM AUTHOR]

We previously demonstrated that sudden infant death syndrome (SIDS) infants have decreased orexin immunoreactivity within the hypothalamus and pons compared to non-SIDS infants. In this study, we examined multiple mechanisms that may promote loss of orexin expression including programmed cell death, impaired maturation/structural stability, neuroinflammation and impaired unfolding protein response (UPR). Immunofluorescent and immunohistochemical staining for a number of markers was performed in the tuberal hypothalamus and pons of infants (1-10 months) who died from SIDS ( n = 27) compared to age- and sex-matched non-SIDS infants ( n = 19). The markers included orexin A (OxA), dynorphin (Dyn), cleaved caspase 3 (CC3), cleaved caspase 9 (CC9), glial fibrillary acid protein (GFAP), tubulin beta chain 3 (TUBB3), myelin basic protein (MBP), interleukin 1β (IL-1β), terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL), c-fos and the UPR activation markers: phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (pPERK), and activating transcription factor 4 (ATF4). It was hypothesised that pPERK and ATF4 would be upregulated in Ox neurons in SIDS compared to non-SIDS . Within the hypothalamus, OxA and Dyn co-localised with a 20 % decrease in expression in SIDS infants ( P = 0.001). pPERK and ATF4 expression in OxA neurons were increased by 35 % ( P = 0.001) and 15 % ( P = 0.001) respectively, with linear relationships between the decreased OxA/Dyn expression and the percentages of co-localised pPERK/OxA and ATF4/OxA evident ( P = 0.01, P = 0.01). No differences in co-localisation with CC9, CC3, TUNEL or c-fos, nor expression of MBP, TUBB3, IL-1β and GFAP, were observed in the hypothalamus. In the pons, there were 40 % and 20 % increases in pPERK expression in the locus coeruleus ( P = 0.001) and dorsal raphe ( P = 0.022) respectively; ATF4 expression was not changed. The findings that decreased orexin levels in SIDS infants may be associated with an accumulation of pPERK suggest decreased orexin translation. As pPERK may inhibit multiple neuronal groups in the pons in SIDS infants, it could also indicate that a common pathway promotes loss of protein expression and impaired functionality of multiple brainstem neuronal groups. [ABSTRACT FROM AUTHOR]

Diminished adult neurogenesis is known to play a key role in the pathogenesis of diverse neurodegenerative disorders such as HIV-associated neurological disorders (HAND). Cocaine, often abused by HIV-infected patients, has been suggested to worsen HIV-associated CNS disease. Mounting evidence also indicates that HIV infection can lead not only to neuronal dysfunction or loss, but can also negatively impact neurogenesis, resulting in generation of fewer adult neural progenitor cells (NPCs) in the dentate gyrus of the hippocampus, brain area critical for memory and learning. The crucial role of platelet-derived growth factor-BB (PDGF-BB) in providing tropic support for the neurons as well as in promoting NPC proliferation has been demonstrated by us previously. However, whether PDGF-BB regulates neuronal differentiation especially in the context of HAND and drug abuse remains poorly understood. In this study, we demonstrate that pretreatment of rat hippocampal NPCs with PDGF-BB restored neuronal differentiation that had been impaired by HIV Tat and cocaine. To further study the intracellular mechanism(s) involved in this process, we examined the role of transient receptor potential canonical (TRPC) channels in mediating neuronal differentiation in the presence of PDGF-BB. TRPC channels are Ca-permeable, nonselective cationic channels that elicit a variety of physiological functions. Parallel but distinct ERK, Akt signaling pathways with downstream activation of CREB were found to be critical for neuronal differentiation. Pharmacological blocking of TRPC channels resulted in suppression of PDGF-mediated differentiation and PDGF-BB-induced activation of ERK and Akt, culminating also to inhibition of PDGF-induced activation of CREB. Taken together, these findings underpin the role of TRPC channel as a novel target regulating cell differentiation mediated by PDGF-BB. This finding could have implications for development of therapeutic interventions aimed at restoration of Tat and cocaine-mediated impairment of neurogenesis in drug abusing HAND patients. [ABSTRACT FROM AUTHOR]

Immunity and neuroinflammation play major roles in neuropathic pain. Spinal interleukin (IL)-17A, as a mediator connecting innate and adaptive immunity, has been shown to be an important cytokine in neuroinflammation and acute neuropathic pain. However, the effects and underlying mechanisms of spinal IL-17A in the maintenance of neuropathic pain remain unknown. This study was designed to investigate whether spinal IL-17A acted to maintain neuropathic pain and to elucidate the underlying mechanisms in IL-17A knockout or wild-type (WT) mice following L4 spinal nerve ligation (L4 SNL). WT mice were treated with anti-IL­17A neutralized monoclonal antibody (mAb) or recombinant IL-17A (rIL-17A). We showed that IL-17A levels were significantly increased 1, 3, 7, and 14 days after SNL in spinal cord. Double immunofluorescence staining showed that astrocytes were the major cellular source of spinal IL-17A. IL-17A knockout or anti-IL-17A mAb treatment significantly ameliorated hyperalgesia 7 days after SNL, which was associated with a significant reduction of p-CaMKII and p-CREB levels in spinal cord, whereas rIL-17A treatment conferred the opposite effects. Furthermore, we showed that blocking CaMKII with KN93 significantly reduced SNL- or rIL-17A-induced hyperalgesia and p-CREB expression. Our in vitro data showed that KN93 also significantly inhibited rIL-17A-induced CREB activation in primary cultured spinal neurons. Taken together, our study indicates that astrocytic IL-17A plays important roles in the maintenance of neuropathic pain through CaMKII/CREB signaling pathway in spinal cord, and thus targeting IL-17A may offer an attractive strategy for the treatment of chronic persistent neuropathic pain. [ABSTRACT FROM AUTHOR]

The dentate gyrus (DG) and CA1 regions of the hippocampus are intimately related physically and functionally, yet they react differently to insults. The purpose of this study was to determine the protective effects of regular treadmill exercise on late phase long-term potentiation (L-LTP) and its signaling cascade in the DG region of the hippocampus of rapid eye movement (REM) sleep-deprived rats. Adult Wistar rats ran on treadmills for 4 weeks then were acutely sleep deprived for 24 h using the modified multiple platform method. After sleep deprivation, the rats were anesthetized and L-LTP was induced in the DG region. Extracellular field potentials from the DG were recorded in vivo, and levels of L-LTP-related signaling proteins were assessed both before and after L-LTP expression using immunoblot analysis. Sleep deprivation reduced the basal levels of phosphorylated cAMP response element-binding protein (P-CREB) as well as other upstream modulators including calcium/calmodulin kinase IV (CaMKIV) and brain-derived neurotrophic factor (BDNF) in the DG of the hippocampus. Regular exercise prevented impairment of the basal levels of P-CREB and total CREB as well as those of CaMKIV in sleep-deprived animals. Furthermore, regular exercise prevented sleep deprivation-induced inhibition of L-LTP and post-L-LTP downregulation of P-CREB and BDNF levels in the DG. The current findings show that our exercise regimen prevents sleep deprivation-induced deficits in L-LTP as well as the basal and poststimulation levels of key signaling molecules. [ABSTRACT FROM AUTHOR]

Cognition in all mammals including human beings declines during aging. The cellular events responsible for this decay involve a reduction of neurogenesis in the dentate gyrus. Here, we show that treatment with a nature product from a traditional Chinese medicine, namely salidroside restores the capacity of the dentate gyrus to generate new neurons and intercepts learning and memory decays in mice during aging. We uncover that new neurons in aging mice have functional features of an adult granule neuron by forming excitatory synapses with their putative targeting neurons. Genetic inhibition of synaptic transmission from new neurons abolishes the therapeutic effects of salidroside in behavioral tests. We also identify that salidroside targets CREB transcription for the survival of new neurons in the dentate gyrus of old mice. Thus, salidroside is therapeutically effective against learning and memory decays via stimulation of CREB-dependent functional neurogenesis in aging. [ABSTRACT FROM AUTHOR]

Lactoferrin (Lf) is a sialic acid (Sia)-rich, iron-binding milk glycoprotein that has multifunctional health benefits. Its potential role in neurodevelopment and cognition remains unknown. To test the hypothesis that Lf may function to improve neurodevelopment and cognition, the diet of postnatal piglets was supplemented with Lf from days 3 to 38. Expression levels of selected genes and their cognate protein profiles were quantitatively determined. The importance of our new findings is that Lf (1) upregulated several canonical signaling pathways associated with neurodevelopment and cognition; (2) influenced ~10 genes involved in the brain-derived neurotrophin factor (BDNF) signaling pathway in the hippocampus and upregulated the expression of polysialic acid, a marker of neuroplasticity, cell migration and differentiation of progenitor cells, and the growth and targeting of axons; (3) upregulated transcriptional and translational levels of BDNF and increased phosphorylation of the cyclic adenosine monophosphate (cAMP) response element-binding protein, CREB, a downstream target of the BDNF signaling pathway, and a protein of crucial importance in neurodevelopment and cognition; and (4) enhanced the cognitive function and learning of piglets when tested in an eight-arm radial maze. The finding that Lf can improve neural development and cognition in postnatal piglets has not been previously described. [ABSTRACT FROM AUTHOR]

Bradykinin (BK) is a proinflammatory mediator and elevated in several brain injury and inflammatory diseases. The deleterious effects of BK on brain astrocytes may aggravate brain inflammation mediated through the upregulation of cytosolic phospholipase A (cPLA)/cyclooxygenase-2 (COX-2)-derived prostaglandin E (PGE) production. However, the signaling mechanisms underlying BK-induced cPLA expression in brain astrocytes remain unclear. Herein, we investigated the effects of activation of cPLA/COX-2 system on BK-induced cPLA upregulation in rat brain astrocytes (RBA-1). The data obtained with Western blotting, RT-PCR, and immunofluorescent staining analyses showed that BK-induced de novo cPLA expression was mediated through activation of cPLA/COX-2 system. Upregulation of native cPLA/COX-2 system by BK through activation of PKCδ, c-Src, MAPKs (ERK1/2 and JNK1/2) cascades led to PGE biosynthesis and release. Subsequently, the released PGE induced cPLA expression via the same signaling pathways (PKCδ, c-Src, ERK1/2, and JNK1/2) and then activated the cyclic AMP response element-binding protein (CREB) via B2 BK receptor-mediated cPLA/COX-2 system-derived PGE/EP-dependent manner. Finally, upregulation of cPLA by BK may promote more PGE production. These results demonstrated that in RBA-1, activation of CREB by PGE/EP-mediated PKCδ/c-Src/MAPK cascades is essential for BK-induced de novo cPLA protein. More importantly, upregulation of cPLA by BK through native cPLA/COX-2 system may be a positive feedback mechanism that enhances prolonged brain inflammatory responses. Understanding the mechanisms of cPLA/COX-2 system upregulated by BK on brain astrocytes may provide rational therapeutic interventions for brain injury and inflammatory diseases. [ABSTRACT FROM AUTHOR]

Activity-driven transcription is a key event associated with long-lasting forms of neuronal plasticity. Despite the efforts to investigate the regulatory mechanisms that control this complex process and the important advances in the knowledge of the function of many activity-induced genes in neurons, as well as the specific contribution of activity-regulated transcription factors, our understanding of how activity-driven transcription operates at the systems biology level is still very limited. This review focuses on the research of neuronal activity-driven transcription from an 'omics' perspective. We will discuss the different high-throughput approaches undertaken to characterize the gene programs downstream of specific activity-regulated transcription factors, including CREB, SRF, MeCP2, Fos, Npas4, and others, and the interplay between epigenetic and transcriptional mechanisms underlying neuronal plasticity changes. Although basic questions remain unanswered and important challenges still lie ahead, the refinement of genome-wide techniques for investigating the neuronal transcriptome and epigenome promises great advances. [ABSTRACT FROM AUTHOR]

Activating transcription factor 3 (ATF3) is a stress-induced transcription factor with diverse functions under disease states in multiple cell types. ATF3 has neuroprotective action against cerebral ischemia, which may involve caspase 3. However, the molecular mechanisms underlying ATF3 regulation of apoptosis are largely unknown. Here, we used gain- and loss-of-function and rescue approaches to demonstrate ATF3 attenuating hypoxic neuronal apoptosis. As well, the protective effect of ATF3 was mediated by downregulation of carboxyl-terminal modulator protein (CTMP), a pro-apoptotic factor that inhibits the anti-apoptotic Akt/PKB cascade. ATF3 (1) downregulated the mRNA and protein levels of CTMP; (2) its temporal expression pattern was reciprocal to that of CTMP; and (3) nuclear localization suggested that ATF3 may regulate CTMP transcription following hypoxic insult. Reporter assays demonstrated that ATF3 suppressed CTMP transcription, whereas ATF3 fusion with VP16, converting ATF3 to transcriptional activator, boosted CTMP transcription. By contrast, NF-κB increased CTMP transcription, and degradation-resistant IκBα decreased CTMP transcription. ChIP assays further confirmed that binding of ATF3 to the ATF/CREB site hindered NF-κB binding to the CTMP promoter, which repressed CTMP expression. Furthermore, CTMP siRNA treatment reduced hypoxic neuronal apoptosis by increasing p-Akt (Ser473) levels and leaving the upstream ATF3 level unchanged. We have identified an endogenous neuroprotective ATF3→CTMP signal cascade that may be a therapeutic target for reducing ischemic brain injury. [ABSTRACT FROM AUTHOR]

Maged1 is a member of the type II melanoma antigen (MAGE) family of proteins, which is highly conserved in the brain between mouse and human. Recently, Maged1 has been reported to be involved in depression and impaired sexual behavior. However, the role of Maged1 in learning and memory remains unknown. The aim of the present study was therefore to investigate whether Maged1 deficiency can impair learning and memory formation. By behavioral tests and electrophysiological recording, we observed that 5-6-month-old Maged1 knockout mice displayed the reduced basal synaptic transmission, pronounced hippocampal dysfunction, impaired spatial learning, and a deficit in long-term potentiation induction. Data from immunohistochemical and Western blot showed the reduced dendritic spine density and the number of synapses in the hippocampus of the Maged1 knockout mice, and Maged1 deficiency prevented the interaction of Maged1 with cAMP response element-binding protein (CREB). Furthermore, by chromatin immunoprecipitation and luciferase assay, we observed the downregulated activity of CREB and the suppressed CREB-dependent transcription after deficiency of Maged1, which lead to the decreased levels of brain-derived neurotrophic factor. Taken together, our results provide the evidence that Maged1 is involved in synaptic transmission and hippocampus-dependent learning and memory formation. [ABSTRACT FROM AUTHOR]

Throughout life, adult neurogenesis generates new neurons in the dentate gyrus of hippocampus that have a critical role in memory formation. Strategies able to stimulate this endogenous process have raised considerable interest because of their potential use to treat neurological disorders entailing cognitive impairment. We previously reported that mice exposed to extremely low-frequency electromagnetic fields (ELFEFs) showed increased hippocampal neurogenesis. Here, we demonstrate that the ELFEF-dependent enhancement of hippocampal neurogenesis improves spatial learning and memory. To gain insights on the molecular mechanisms underlying ELFEFs' effects, we extended our studies to an in vitro model of neural stem cells (NSCs) isolated from the hippocampi of newborn mice. We found that ELFEFs enhanced proliferation and neuronal differentiation of hippocampal NSCs by regulation of epigenetic mechanisms leading to pro-neuronal gene expression. Upon ELFEF stimulation of NSCs, we observed a significant enhancement of expression of the pro-proliferative gene hairy enhancer of split 1 and the neuronal determination genes NeuroD1 and Neurogenin1. These events were preceded by increased acetylation of H3K9 and binding of the phosphorylated transcription factor cAMP response element-binding protein (CREB) on the regulatory sequence of these genes. Such ELFEF-dependent epigenetic modifications were prevented by the Ca1-channel blocker nifedipine, and were associated with increased occupancy of CREB-binding protein (CBP) to the same loci within the analyzed promoters. Our results unravel the molecular mechanisms underlying the ELFEFs' ability to improve endogenous neurogenesis, pointing to histone acetylation-related chromatin remodeling as a critical determinant. These findings could pave the way to the development of novel therapeutic approaches in regenerative medicine. [ABSTRACT FROM AUTHOR]

In neurons, the convergence of multiple intracellular signaling cascades leading to cAMP-responsive element-binding protein (CREB) activation suggests that this transcription factor plays a critical role in integrating different inputs and mediating appropriate neuronal responses. The nature of this transcriptional response depends on both the type and strength of the stimulus and the cellular context. CREB-dependent gene expression has been involved in many different aspects of nervous system function, from embryonic development to neuronal survival, and synaptic, structural, and intrinsic plasticity. Here, we first review the different methodological approaches used to genetically manipulate CREB activity and levels in neurons in vivo in the adult brain, including recombinant viral vectors, mouse transgenesis, and gene-targeting techniques. We then discuss the impact of these approaches on our understanding of CREB's roles in neuronal plasticity and memory in rodents. Studies combining these genetic approaches with electrophysiology and behavior provide strong evidence that CREB is critically involved in the regulation of synaptic plasticity, intrinsic excitability, and long-term memory formation. These findings pave the way for the development of novel therapeutic strategies to treat memory disorders. [ABSTRACT FROM AUTHOR]

The inducible cAMP early repressor (ICER) is an endogenous repressor of cAMP-responsive element (CRE)-mediated gene transcription and belongs to the CRE-binding protein (CREB)/CRE modulator (CREM)/activating transcription factor 1 (ATF-1) gene family. ICER plays an important role in regulating the neuroendocrine system and the circadian rhythm. Other aspects of ICER function have recently attracted heightened attention. Being a natural inducible CREB antagonist, and more broadly, an inducible repressor of CRE-mediated gene transcription, ICER regulates long-lasting plastic changes that occur in the brain in response to incoming stimulation. This review will bring together data on ICER and its functions in the brain, with a special emphasis on recent findings highlighting the involvement of ICER in the regulation of long-term plasticity underlying learning and memory. [ABSTRACT FROM AUTHOR]

Photoreceptor cell death is the major hallmark of a group of human inherited retinal degenerations commonly referred to as retinitis pigmentosa (RP). Although the causative genetic mutations are often known, the mechanisms leading to photoreceptor degeneration remain poorly defined. Previous research work has focused on apoptosis, but recent evidence suggests that photoreceptor cell death may result primarily from non-apoptotic mechanisms independently of AP1 or p53 transcription factor activity, Bcl proteins, caspases, or cytochrome c release. This review briefly describes some animal models used for studies of retinal degeneration, with particular focus on the rd1 mouse. After outlining the major features of different cell death mechanisms in general, we then compare them with results obtained in retinal degeneration models, where photoreceptor cell death appears to be governed by, among other things, changes in cyclic nucleotide metabolism, downregulation of the transcription factor CREB, and excessive activation of calpain and PARP. Based on recent experimental evidence, we propose a putative non-apoptotic molecular pathway for photoreceptor cell death in the rd1 retina. The notion that inherited photoreceptor cell death is driven by non-apoptotic mechanisms may provide new ideas for future treatment of RP. [ABSTRACT FROM AUTHOR]

Addiction is a complex disorder because many factors contribute to the development and maintenance of addiction. One factor is learning. For example, drug-context associations that develop during drug use could facilitate drug craving upon re-exposure to contexts previously associated with drugs. Additionally, deficits in cognitive processes associated with withdrawal could precipitate relapse in attempts to ameliorate those deficits. Because addiction and learning involve common neural areas and cell signaling cascades, addiction-related changes in processes underlying plasticity may contribute to addiction. This article examines similarities between addiction and learning at the behavioral, neural, and cellular levels, with emphasis on the neural substrates underlying the effects of acute nicotine, chronic nicotine, and withdrawal from chronic nicotine on hippocampus-dependent contextual, learning. [ABSTRACT FROM AUTHOR]