Coxsackievirus Adenovirus Receptor Loss Impairs Adult Neurogenesis, Synapse Content, and Hippocampus Plasticity.

UNLABELLED: Although we are beginning to understand the late stage of neurodegenerative diseases, the molecular defects associated with the initiation of impaired cognition are poorly characterized. Here, we demonstrate that in the adult brain, the coxsackievirus and adenovirus receptor (CAR) is located on neuron projections, at the presynapse in mature neurons, and on the soma of immature neurons in the hippocampus. In a proinflammatory or diseased environment, CAR is lost from immature neurons in the hippocampus. Strikingly, in hippocampi of patients at early stages of late-onset Alzheimer's disease (AD), CAR levels are significantly reduced. Similarly, in triple-transgenic AD mice, CAR levels in hippocampi are low and further reduced after systemic inflammation. Genetic deletion of CAR from the mouse brain triggers deficits in adult neurogenesis and synapse homeostasis that lead to impaired hippocampal plasticity and cognitive deficits. We propose that post-translational CAR loss of function contributes to cognitive defects in healthy and diseased-primed brains. SIGNIFICANCE STATEMENT: This study addressed the role of the coxsackievirus and adenovirus receptor (CAR), a single-pass cell adhesion molecule, in the adult brain. Our results demonstrate that CAR is expressed by mature neurons throughout the brain. In addition, we propose divergent roles for CAR in immature neurons, during neurogenesis, and at the mature synapse. Notably, CAR loss of function also affects hippocampal plasticity.

Dithiocarb (N,N-diethyldithiocarbamate, DEDTC) decreases levels of biogenic monoamines in the adult mouse brain.

AIMS: Dithiocarb (diethyldithiocarbamate, DEDTC) belongs to the group of dithiocarbamates and is the main metabolite of disulphiram, a drug of choice for the treatment of alcohol dependence. Its therapeutic potential relays on its ability to create an unpleasant aversive reaction following the ingestion of alcohol, and this effect is usually accompanied by neurobehavioural symptoms. Most of these can be attributed to the impaired metabolism of brain biogenic amines. METHODS: To gain new insights into the dithiocarbamates and their effects on neurotransmitter systems, an in vivo experimental model based on daily injections of DEDTC in adult mice for 7 days was established. To this end, the concentrations of the three major brain monoamines, dopamine (DA), noradrenaline (NA) and serotonin (5-HT) were measured in whole brain extracts with high-performance liquid chromatography (HPLC). The levels of D2 dopamine receptor (D2R) were evaluated by Western blot and by immunohistochemical techniques the cell pattern of tyrosine hydroxylase (TH), dopa beta hydroxylase (DBH) and choline acetyltransferase ChAT) were analysed. RESULTS: A significant reduction in DA and 5-HT levels was observed, whereas NA was not affected. Moreover, decreases in D2R levels, as well as in enzymes such as TH, DBH and ChAT, were found. CONCLUSIONS: Our data suggest that DEDTC provokes alterations in biogenic amines and in different substrates of neurotransmitter systems, which could explain some of the neurobehavioural effects observed in patients treated with disulphiram.

PI3 k/akt inhibition induces apoptosis through p38 activation in neurons.

Accumulating evidence suggests that the PI3K/AKT pathway is a pro-survival signalling system in neurons. Therefore, the inhibition of this pathway may be implicated in the degeneration of neurons in Parkinson's disease (PD), Alzheimer's disease (AD), and other neurological disorders. Here we study the participation of the mitogen-activated protein kinase (MAPK) pathway on apoptosis induced by PI3K/AKT inhibition in cultured cerebellar granule cells (CGCs). LY294002, a specific PI3K/AKT inhibitor, selectively activated the p38 MAPK kinase pathway and enhanced c-Jun phosphorylation, but did not activate JNK. The pharmacological inhibitors SB203580 (p38 inhibitor) and SP600125 (a JNK inhibitor) protected primary cultures of rat CGCs from LY294002-induced apoptosis. Furthermore, both compounds decreased the phosphorylation of c-Jun and lowered mRNA levels of the pro-apoptotic gene dp5, a direct target of c-Jun. Taken together, our data demonstrate that PI3K/AKT inhibition induces neuronal apoptosis, a process that is mediated by the activation of p38 MAPK/c-Jun/dp5.

Microarray analysis of rat hippocampus exposed to excitotoxicity: reversal Na(+)/Ca(2+) exchanger NCX3 is overexpressed in glial cells.

Multiple factors are involved in the glutamate-induced excitotoxicity phenomenon, such as overload of ionotropic and metabotropic receptors, excess Ca(2+) influx, nitric oxide synthase activation, oxidative damage due to increase in free radicals, and release of endogenous polyamine, among others. In order to attempt a more integrated approach to address this issue, we established, by microarray analysis, the hippocampus gene expression profiles under glutamate-induced excitotoxicity conditions. Increased gene expression is mainly related to excitotoxicity (CaMKII, glypican 2, GFAP, NCX3, IL-2, and Gmeb2) or with cell damage response (dynactin and Ecel1). Several genes that augmented their expression are related to glutamatergic system modulation, in particular with NMDA receptor modulation and calcium homeostasis (IL-2, CaMKII, acrosin, Gmeb2, hAChE, Slc83a, and SP1 factor). Conversely, among genes that diminished their expression, we found the Syngap 1, which is downregulated by CaMKII, and the MHC II, which is downregulated by glutamate. Changes observed in gene expression induced by monosodium glutamate (MSG) neonatal treatment in the hippocampus are consistent with the activation of the mechanisms that modulate NMDA receptor function as well as with the implementation of plastic response to cell damage and intracellular calcium homeostasis. Regarding this aspect, we report here that NCX3/Slc8a3, a Na(+)/Ca(2+) membrane exchanger, is highly expressed in astrocytes, both in vitro and in vivo, in response to glutamate-induced excitotoxicity. Hence, the results of this analysis present a broad view of the expression profile elicited by MSG neonatal treatment, and lead us to suggest the possible molecular pathways of action and reaction involved under this experimental model of excitotoxicity.

GSK3ß inhibition is involved in the neuroprotective effects of cyclin-dependent kinase inhibitors in neurons.

In the present study, we evaluated the effects of roscovitine (Rosco) and flavopiridol (Flavo), both of which are classified as cyclin-dependent kinase (CDK) inhibitors, on apoptosis induced by the inhibition of PI3K/AKT pathway in cerebellar granule neurons (CGNs). Our results demonstrate that both CDK inhibitors prevented apoptosis induced by LY294002 (LY), as also occurs with SB415286 (SB4), a selective GSK3ß inhibitor. Our findings also indicate that these CDK inhibitors inhibit GSK3ß, representing a potential pharmacological mechanism involved in their neuroprotective properties. Thus, the increased activity of GSK3ß induced by LY294002 and detected by dephosphorylation at Ser9 was prevented by both compounds. Likewise, GSK3ß activity was measured by a radioactivity assay, revealing that CDK inhibitors and SB415286 prevented the increase in GSK3ß activity induced by PI3K inhibition. In addition, we analysed c-Jun, which is also a mediator of PI3K inhibition-induced apoptosis. However, neither of the CDK inhibitors nor SB415286 prevented the increase in c-Jun phosphorylation induced by PI3K inhibition. Therefore, our data identify GSK3ß as a crucial mediator of CGN apoptosis induced by PI3K inhibition and indicate that the antiapoptotic effects of CDKs are mediated by the inhibition of this pharmacological target.

Sirtuin activators: designing molecules to extend life span.

Resveratrol (RESV) exerts important pharmacological effects on human health: in addition to its beneficial effects on type 2 diabetes and cardiovascular diseases, it also modulates neuronal energy homeostasis and shows antiaging properties. Although it clearly has free radical scavenger properties, the mechanisms involved in these beneficial effects are not fully understood. In this regard, one area of major interest concerns the effects of RESV on the activity of sirtuin 1 (SIRT1), an NAD(+)-dependent histone deacetylase that has been implicated in aging. Indeed, the role of SIRT1 is currently the subject of intense research due to the antiaging properties of RESV, which increases life span in various organisms ranging from yeast to rodents. In addition, when RESV is administered in experimental animal models of neurological disorders, it has similar beneficial effects to caloric restriction. SIRT1 activation could thus constitute a potential strategic target in neurodegenerative diseases and in disorders involving disturbances in glucose homeostasis, as well as in dyslipidaemias or cardiovascular diseases. Therefore, small SIRT1 activators such as SRT501, SRT2104, and SRT2379, which are currently undergoing clinical trials, could be potential drugs for the treatment of type 2 diabetes, obesity, and metabolic syndrome, among other disorders. This review summarises current knowledge about the biological functions of SIRT1 in aging and aging-associated diseases and discusses its potential as a pharmacological target.

Gene expression profile in JNK3 null mice: a novel specific activation of the PI3K/AKT pathway.

JNK3 is mainly expressed in the CNS and it plays a crucial role in neuronal death in several neurodegenerative diseases. By contrast, the isoforms JNK1 and JNK2 seem to be involved in brain development. The lack of Jnk3 confers neuroprotection, although mechanisms responsible are unknown. The present study analyzes the gene expression profile in hippocampus from mice lacking Jnk3 in comparison to wild-type mice. The microarray analysis showed that 22 genes are differentially expressed (z-score>2 in two independent arrays) in Jnk3 null mice. Among these, we focused on pi3kcb, as it is directly related to the prosurvival phosphoinositide-3-kinase (PI3K)/AKT pathway. Results from Jnk3 null mice showed an increase in pik3cb transcript and protein, together with an increase in PI3K activity and phosphorylation of AKT. By contrast, these changes were not observed in Jnk1 null mice, which do not present neuroresistance to certain neurodegenerative insults. Therefore, our results indicate that the activation of PI3K/AKT pathway in hippocampus because of the increase in pik3cb transcription and that this mechanism is specifically related to the lack of Jnk3.

Content and traffic of taurine in hippocampal reactive astrocytes.

Taurine is one of the most abundant free amino acids in the mammalian central nervous system, where it is crucial to proper development. Moreover, taurine acts as a neuroprotectant in various diseases; in epilepsy, for example, it has the capacity to reduce or abolish seizures. In the present study, taurine levels has been determine in mice treated with Kainic Acid (KA) and results showed an increase of this amino acid in hippocampus but not in whole brain after 3 and 7 days of KA treatment. This increase occurs when gliosis was observed. Moreover, taurine transporter (TAUT) was found in astrocytes 3 and 7 days after KA treatment, together with an increase in cysteine sulfinic acid decarboxylase (csd) mRNA, that codifies for the rate-limiting enzyme of taurine synthesis, in the hippocampus at the same times after KA treatment. Glial cultures enriched in astrocytes were developed to demonstrate that these cells are responsible for changes in taurine levels after an injury to the brain. The cultures were treated with proinflammatory cytokines to reproduce gliosis. In this experimental model, an increase in the immunoreactivity of GFAP was observed, together with an increase in CSD and taurine levels. Moreover, an alteration in the taurine uptake-release kinetics was detected in glial cells treated with cytokine. All data obtained indicate that astrocytes could play a key role in taurine level changes induced by neuronal damage. More studies are, therefore, needed to clarify the role taurine has in relation to neuronal death and repair.

Recovery of axonal myelination sheath and axonal caliber in the mouse corpus callosum following damage induced by N,N-diethyldithiocarbamate.

Disulfiram is an aldehyde dehydrogenase inhibitor used for the treatment of alcohol dependence and of cocaine addiction. It has been demonstrated that subchronic administration of disulfiram or N,N-diethyldithiocarbamate (DEDTC), the main derivative of disulfiram, to rats can produce central-peripheral distal axonopathy. However, few data regarding the axonal effects of these compounds in the central nervous system exist. Our previous studies have revealed DEDTC-induced axonal damage in the mouse brain during the course of postnatal development, together with alterations in axonal pathfinding and in the myelination process, with partial recovery during the post-treatment period. In order to gather new data about how this axonal damage and recovery occurs in the central nervous system, we performed an ultrastructural analysis of the axons located in the corpus callosum from mice treated with DEDTC during postnatal development. The axonal caliber throughout the axonal area, the maximum axonal diameter, the maximum fiber diameter, and the axonal circularity, at different postnatal stages [from postnatal day (P)9 to P30], were analyzed. In addition, parameters related to the myelinization process (number of myelinated axons, sheath thickness, and the ratio of myelinated axons to total axons) were evaluated. A reduction in the average value of axonal caliber during treatment and a delay in the axonal myelination process were detected. Whereas early recovery of individual axons occurred after treatment (P22), complete recovery of myelinated axons occurred at late postnatal stages (P42). Therefore, chronic treatment with dithiocarbamates requires periods of rest to encourage the recovery of myelinated axons.

Antiapoptotic effects of roscovitine on camptothecin-induced DNA damage in neuroblastoma cells.

In the present study dopaminergic neuroblastoma B65 cells were exposed to Camptothecin (CPT) (0.5-10 µM), either alone or in the presence of roscovitine (ROSC). The results show that CPT induces apoptosis through the activation of ataxia telangiectasia mutated (ATM)-induced cell-cycle alteration in neuroblastoma B65 cells. The apoptotic process is mediated through the activation of cystein proteases, namely calpain/caspases. However, whereas a pan-caspase inhibitor, zVADfmk, inhibited CPT-mediated apoptosis, a calpain inhibitor, calpeptin, did not prevent cell death. Interestingly, CPT also induces CDK5 activation and ROSC (25 µM) blocked CDK5, ATM activation and apoptosis (as measured by caspase-3 activation). By contrast, selective inhibition of ATM, by KU55933, and non-selective inhibition, by caffeine, did not prevent CPT-mediated apoptosis. Thus, we conclude that CDK5 is activated in response to DNA damage and that CDK5 inhibition prevents ATM and p53ser15 activation. However, pharmacological inhibition of ATM using KU55933 and caffeine suggests that ATM inhibition by ROSC is not the only mechanism that might explain the anti-apoptotic effects of this drug in this apoptosis model. Our findings have a potential clinical implication, suggesting that combinatory drugs in the treatment of cancer activation should be administered with caution.

Resveratrol inhibits proliferation and promotes apoptosis of neuroblastoma cells: role of sirtuin 1.

Resveratrol prolongs lifespan and prevent cancer formation; however, the mechanisms are not understood. Here we evaluated the cell-cycle inhibition and apoptosis of resveratrol in B65 neuroblastoma cells, and we also studied the effects of resveratrol on the mammalian silent information regulator 2 (SIRT1). Results show that resveratrol reduces cell viability and causes apoptosis at 24 h of treatment. Resveratrol partially blocked cell proliferation, and significantly increased the fraction of cells arrested in the S phase. The role of SIRT1 in cell-cycle effects mediated by resveratrol was studied through changes in the expression of SIRT1 using western blot. Exposure to resveratrol decreased SIRT1 content, concomitant with an increase in the acetylated form of sirtuin substrates p53 and NFκ-ß. Treatment of B65 neuroblastoma cells with resveratrol also reduced the content of the phosphorylated form of AKT. Exposure to the SIRT1 inhibitors nicotinamide and sirtinol altered neither cell viability nor the fraction of apoptotic cells. Furthermore, when cells were exposed simultaneously to resveratrol and nicotinamide or sirtinol, no changes were observed in the fraction of apoptotic cells. Our results show that a decrease in SIRT1 content, caused by exposure to resveratrol, does not appear to be involved in cell-cycle arrest or activation of apoptosis.

Activation of ataxia telangiectasia muted under experimental models and human Parkinson's disease.

In the present study we demonstrated that neurotoxin MPP(+)-induced DNA damage is followed by ataxia telangiectasia muted (ATM) activation either in cerebellar granule cells (CGC) or in B65 cell line. In CGC, the selective ATM inhibitor KU-55933 showed neuroprotective effects against MPP(+)-induced neuronal cell loss and apoptosis, lending support to the key role of ATM in experimental models of Parkinson's disease. Likewise, we showed that knockdown of ATM levels in neuroblastoma B65 cells using an ATM-specific siRNA attenuates the phosphorylation of retinoblastoma protein without affecting other cell-cycle proteins involved in the G(0)/G(1) cell-cycle phase. Moreover, we demonstrated DNA damage, in human brain samples of PD patients. These findings support a model in which MPP(+) leads to ATM activation with a subsequent DNA damage response and activation of pRb. Therefore, this study demonstrates a new link between DNA damage by MPP(+) and cell-cycle re-entry through retinoblastoma protein phosphorylation.

Corticosteroid-binding-globulin (CBG)-deficient mice show high pY216-GSK3ß and phosphorylated-Tau levels in the hippocampus.

Corticosteroid-binding globulin (CBG) is the specific carrier of circulating glucocorticoids, but evidence suggests that it also plays an active role in modulating tissue glucocorticoid activity. CBG polymorphisms affecting its expression or affinity for glucocorticoids are associated with chronic pain, chronic fatigue, headaches, depression, hypotension, and obesity with an altered hypothalamic pituitary adrenal axis. CBG has been localized in hippocampus of humans and rodents, a brain area where glucocorticoids have an important regulatory role. However, the specific CBG function in the hippocampus is yet to be established. The aim of this study was to investigate the effect of the absence of CBG on hippocampal glucocorticoid levels and determine whether pathways regulated by glucocorticoids would be altered. We used cbg-/- mice, which display low total-corticosterone and high free-corticosterone blood levels at the nadir of corticosterone secretion (morning) and at rest to evaluate the hippocampus for total- and free-corticosterone levels; 11ß-hydroxysteroid dehydrogenase expression and activity; the expression of key proteins involved in glucocorticoid activity and insulin signaling; microtubule-associated protein tau phosphorylation, and neuronal and synaptic function markers. Our results revealed that at the nadir of corticosterone secretion in the resting state the cbg-/- mouse hippocampus exhibited slightly elevated levels of free-corticosterone, diminished FK506 binding protein 5 expression, increased corticosterone downstream effectors and altered MAPK and PI3K pathway with increased pY216-GSK3ß and phosphorylated tau. Taken together, these results indicate that CBG deficiency triggers metabolic imbalance which could lead to damage and long-term neurological pathologies.

ATM is involved in cell-cycle control through the regulation of retinoblastoma protein phosphorylation.

Ataxia telangiectasia mutated protein (ATM) is a member of the phosphatidylinositol-3 kinase (PI3K) family, which has a role in the cellular response to DNA double-strand breaks (DSBs). In the present study, we evaluated the role of ATM in cell-cycle control in dopaminergic rat neuroblastoma B65 cells. For this purpose, ATM activity was either inhibited pharmacologically with the specific inhibitor KU-55933, or the ATM gene was partially silenced by transfection with small interfering RNA (siRNA). Our data indicate that although ATM inhibition did not affect the cell cycle, both treatments specifically decreased the levels of cyclin A and retinoblastoma protein (pRb), phosphorylated at Ser780. Furthermore, ATM inhibition decreased the active form of p53, which is phosphorylated at Ser15, and also decreased Bax and p21 expression. Using H(2)O(2) as a positive control of DSBs, caused a rapid pRb phosphorylation, this was prevented by KU-55933 and siRNA treatment. Collectively, our data demonstrate how a new molecular network on ATM regulates the cell cycle through the control of pRb phosphorylation. These findings support a new target of ATM.

Differences in activation of ERK1/2 and p38 kinase in Jnk3 null mice following KA treatment.

The MAPK family is formed by extracellular signal-regulated kinases p38 kinase and stress-activated protein kinases (SAPK/JNK). There are three genes that encode for three JNK proteins. JNK3 is mainly expressed in the central nervous system and has been related to various processes in that tissue. Specifically, JNK3 plays a crucial role in neuronal death in several neurodegenerative diseases. The activation of this kinase has been described in epilepsy, Alzheimer's disease, Parkinson's disease and Huntington's disease. Different studies have shown that the lack of the Jnk3 gene confers neuroprotection. However, the specific mechanism involved in such neuroprotection has not yet been elucidated. Therefore, in the present study, we analyzed the neuroprotection in mice lacking Jnk3 against neuronal death induced by kainic acid. Moreover, we analyzed the activation of different MAPKs. The results revealed that neuronal death was attenuated and different activation/inactivation of p38 and extracellular signal-regulated kinases 1/2 was reported with respect to control. Therefore, the data indicate that the lack of the JNK3 protein modulates other MAPKs and these changes could also have a pivotal role in neuroprotection.

Tau hyperphosphorylation and axonal damage induced by N,N-diethyldithiocarbamate (DEDTC) treatment along late postnatal development is followed by a rescue during adulthood.

Axonal degeneration has been described as the pathological hallmark of peripheral neuropathies induced by DEDTC. In addition, axonal damage has also been observed in the brain of mice treated daily with DEDTC along postnatal development, though with this experimental model there was observed to be axonal recovery after treatment, during the adulthood. To focus on this axonal dynamic activity, damage-recovery, a key axonal protein, the microtubule associated protein tau, was analyzed in this DEDTC model. Tau is a phosphoprotein and its dynamic site-specific phosphorylation is essential for its proper function; in fact, high levels are correlated with cell dysfunction. Furthermore, the levels of tau phosphorylation are associated with dynamic microtubules during periods of high plasticity. Thus, phosphorylated tau at two sites of phosphorylation, Ser(199) and Ser(396), were evaluated during the second week of postnatal development and throughout adulthood. The results obtained by Western blot made it evident that the levels of p-tau Ser(199) and p-tau Ser(396) were higher in treated mice than in controls. Interestingly, by immunohistochemistry there was shown to be an increase in p-tau-immunolabeling in neuronal soma together with axonal tract alterations in treated animals with respect to controls, and the analyses of GSK3 beta and cdk5 revealed an increase in its activity in DEDTC-treated animals. Nevertheless, in the adult a general decline in p-tau was observed together with a rescue of axonal tract. All these data support the idea that the axonal damage induced by DEDTC treatment along postnatal development is followed by an axonal rescue during adulthood.

Effects of MPP+ on the molecular pathways involved in cell cycle control in B65 neuroblastoma cells.

The toxicity caused by cell exposure to 1-methyl-4-phenylpyridinium ion (MPP(+)) is a useful model in the study of Parkinson's disease (PD). However, the exact molecular mechanisms triggered by MPP(+) in cell death are currently unclear. In the present research, we show that exposure to MPP(+) induce the cell death of neuroblastoma-derived dopaminergic B65 cells, which is not reversed by the widely known caspase inhibitor Z-VAD fmk or by calpain inhibition. Likewise, when B65 cells were treated with MPP(+), the DNA damage pathway that involves p53 was activated, and cells were arrested in the G(2)/M phase of the cell cycle. Interestingly, MPP(+) has two effects on the expression of cell cycle-related proteins. It increases the content of cyclins A, E, cdk2 and the phosphorylated form of pRb (serine 780). However, MPP(+) 5mM decreased the expression of cyclin D1, B1 and cdk4. The decrease in the expression of cyclin B1 may be related to the arrest of cells observed in the G(2)/M phase of cell cycle. The increase in S phase cell cycle proteins and retinoblastoma protein phosphorylation was an unexpected result. As the antioxidant trolox attenuated the process of cell loss and changes in the cell cycle, as measured by flow cytometry, we concluded that oxidative stress was involved in the effects of MPP(+) in this cell line. In summary, the present work characterizes the molecular changes involved in damage caused by MPP(+) in B65 cells, and highlights the effects of MPP(+) on molecules involved in the control of cell cycle progression.

Neuroprotective Effects of the Absence of JNK1 or JNK3 Isoforms on Kainic Acid-Induced Temporal Lobe Epilepsy-Like Symptoms.

The activation of c-Jun-N-terminal kinases (JNK) pathway has been largely associated with the pathogenesis and the neuronal death that occur in neurodegenerative diseases. Altogether, this justifies why JNKs have become a focus of screens for new therapeutic strategies. The aim of the present study was to identify the role of the different JNK isoforms (JNK1, JNK2, and JNK3) in apoptosis and inflammation after induction of brain damage. To address this aim, we induced excitotoxicity in wild-type and JNK knockout mice (jnk1 -/- , jnk2 -/- , and jnk3 -/- ) via an intraperitoneal injection of kainic acid, an agonist of glutamic-kainate-receptors, that induce status epilepticus.Each group of animals was divided into two treatments: a single intraperitoneal dose of saline solution, used as a control, and a single intraperitoneal dose (30 mg/kg) of kainic acid. Our results reported a significant decrease in neuronal degeneration in the hippocampus of jnk1 -/- and jnk3 -/- mice after kainic acid treatment, together with reduced or unaltered expression of several apoptotic genes compared to WT treated mice. In addition, both jnk1 -/- and jnk3 -/- mice exhibited a reduction in glial reactivity, as shown by the lower expression of inflammatory genes and a reduction of JNK phosphorylation. In addition, in jnk3 -/- mice, the c-Jun phosphorylation was also diminished.Collectively, these findings provide compelling evidence that the absence of JNK1 or JNK3 isoforms confers neuroprotection against neuronal damage induced by KA and evidence, for the first time, the implication of JNK1 in excitotoxicity. Accordingly, JNK1 and/or JNK3 are promising targets for the prevention of cell death and inflammation during epileptogenesis.

What is CAR doing in the middle of the adult neurogenic road?

The molecular and cellular basis of adult neurogenesis has attracted considerable attention for fundamental and clinical applications because neural stem cells and newborn neurons may, one day, be harnessed to replace neurons and allow cognitive improvement in the diseased brain. In rodents, neural progenitors are located in the dentate gyrus and the sub/periventricular zone. In the dentate gyrus the generation of newborn neurons is associated with plasticity, including regulation of memory. The role of subventricular zone neural precursors that migrate to the olfactory bulb is less characterized. Identifying factors that impact neural stem cell proliferation, migration and differentiation is therefore sine qua non before we can harness their potential. Here, we expand upon our recent results showing that CAR, the coxsackievirus and adenovirus receptor, is among the developing list of key players when it comes to the complex process of integrating newborn neurons into existing circuits in the mature brain.

Modular organization of the brainstem noradrenaline system coordinates opposing learning states.

Noradrenaline modulates global brain states and diverse behaviors through what is traditionally believed to be a homogeneous cell population in the brainstem locus coeruleus (LC). However, it is unclear how LC coordinates disparate behavioral functions. We report a modular LC organization in rats, endowed with distinct neural projection patterns and coding properties for flexible specification of opposing behavioral learning states. LC projection mapping revealed functionally distinct cell modules with specific anatomical connectivity. An amygdala-projecting ensemble promoted aversive learning, while an independent medial prefrontal cortex-projecting ensemble extinguished aversive responses to enable flexible behavior. LC neurons displayed context-dependent inter-relationships, with moderate, discrete activation of distinct cell populations by fear or safety cues and robust, global recruitment of most cells by strong aversive stimuli. These results demonstrate a modular organization in LC in which combinatorial activation modes are coordinated with projection- and behavior-specific cell populations, enabling adaptive tuning of emotional responding and behavioral flexibility.