Some time cells fired at the same absolute or relative time to the delay onset, but most developed qualitatively different firing patterns under distinct delay periods. This pattern of responses to changing the delay period is reminiscent of the prominent observation of “partial remapping” of place cells when salient spatial cues are altered (e.g., Muller and Kubie, 1987, Breese et al., 1989, Markus et al., 1995, Sharp et al., 1995, Shapiro et al., see more 1997 and Skaggs and McNaughton, 1998). Thus, when salient spatial parameters or task demands are altered in rats traversing open fields, some hippocampal place cells maintain their firing patterns, but others cease firing, begin firing, or fire with qualitatively

different patterns related to the animal’s location even within the same recording session. As animals performed this task, they occupied different locations in each sequential trial period, and they could move during each trial period. These variations in behavior allowed us to determine that, in addition to time and the object that began click here each sequence, both behavioral variation and place contributed to the differences in firing patterns between and within trial periods. In particular, during the delay when there were no differences between overt stimuli and behavior, the activity of most cells was strongly and equivalently influenced by a combination of time and place. As typically

observed in studies on place cells, the activity of time cells was also influenced by behavioral variations reflected in head direction and speed (reviewed in Eichenbaum, 2004). In addition, notably, previous studies have shown that hippocampal neurons encode ongoing behavioral context as well as spatial location, head direction, and speed (e.g., Wood et al., 2000). The present results extend this broad range of contextual variables that affect single-neuron activity to the flow of time in bridging of temporal gaps within sequences of events. Five main findings indicate that hippocampal representation of time during sequential events is quite similar to its representation of space as animals

explore an open field: (1) A large proportion of hippocampal neurons are engaged during performance of through a sequence memory task, just as a large fraction of hippocampal neurons are place cells when rats are engaged in spatial exploration (Thompson and Best, 1989 and Muller, 1996). These findings suggest that place cells and time cells may reflect fundamental mechanisms by which hippocampal neuronal networks parse any spatiotemporal context into quantal units of where and when important events occur. Speculating further, while place cells and time cells are appropriately named for the variables they represent in spatially and temporally defined behavioral paradigms, they may be processing information that is fundamentally neither spatial nor temporal.

As Tet proteins are responsible for the conversion of 5mC to 5hmC and regulation of the DNA methylation status in various tissues, PD0332991 cost which may have an effect on chromatin structure and gene expression (Guo et al., 2011b, Branco et al., 2012 and Cohen et al., 2011), we hypothesized that downregulation in expression of learning- and memory-related genes in Tet1KO brains may be

due to a direct role of Tet1 in the regulation of methylation of these genetic loci. As Npas4 has been shown to function as a critical upstream regulator of a genetic program that includes other activity-regulated neuronal plasticity genes, such as c-Fos, we decided to concentrate upon the analysis of the methylation status of the Npas4 in the brain of the Tet1+/+ and Tet1KO mice. We therefore performed sodium bisulfite sequencing of the Npas4 promoter-exon1 junction area, which contains 14 CpGs in the promoter region and 26 CpGs in exon 1. Sodium bisulfite sequencing of DNA from the control brains showed that the Npas4 promoter-exon 1 junction is methylated in both cortex (∼3.5% of CpGs methylated) and hippocampus (∼8% of CpGs methylated). We found that the same DNA region was hypermethylated in the Tet1KO mouse cortex (∼20%), compared to controls, and it was even more highly methylated in Tet1KO hippocampus (∼45%) ( Figure 4D). Thus, the loss of Tet1 appears to increase CpG methylation in the promoter-exon

1 region of Npas4 in selleck screening library the Tet1KO mouse hippocampus and cortex, which may result in its decreased expression. Consistently, applying Gluc-MSqPCR method, we found reduced 5hmC coupled with increased 5mC levels at the promoter Olopatadine region of Npas4 ( Figure S4A) in Tet1KO mice. There is little data

on the molecular mechanisms specifically regulating memory extinction (Lattal et al., 2003, Myers and Davis, 2007 and Radulovic and Tronson, 2010). One of the genes that have been demonstrated to be important for extinction is c-Fos ( Herry and Mons, 2004 and Tronson et al., 2009). As expression of a set of neuronal activity-regulated genes was strongly altered in the brains of Tet1KO mice, we hypothesized that such dysregulation may be responsible for memory extinction and synaptic plasticity impairment in Tet1KO animals. Since c-Fos and its critical upstream regulator Npas4 were among a few genes consistently downregulated in both cortex and hippocampus in naive Tet1KO mice, we decided to test their expression after memory extinction training. Six pairs of 4-month-old male Tet1+/+ and Tet1KO littermate mice were subjected to Pavlovian contextual fear conditioning followed by massed memory extinction training as described earlier. The groups of three control and Tet1KO mice were sacrificed 20 min after the training, and mRNA was extracted from hippocampal and cortical tissues to perform gene expression analysis.

, 2010 and Pan et al., 2010). A later role for Notch signaling in the inner ear sensory epithelia is in its more traditional role: lateral inhibition. When hair cells begin to develop from the sensory epithelium, they signal via Dll1/Jag2/Notch1 interactions to suppress hair cell differentiation in the adjacent cells and instead direct them to develop as support cells (Haddon et al., 1998). The Notch signal induces expression of Hes5, a downstream effector in the Notch pathway (Kageyama and Ohtsuka, 1999),

and the Hes5 likely represses Atoh1, the bHLH class transcription factor necessary for hair cell development. In this way the alternating rows of hair cells and support cells are set up during development. Notch is also necessary for appropriate development of the retina. Maintained expression of Notch causes the progenitor cells to develop as Müller glia (Vetter and Moore, 2001), like the support cells in the ear, TGF-beta inhibitor and loss Notch effectors, Hes5, Hes1, and Hesr2 leads to a

reduction in Müller glial production (Hojo et al., 2000). Inhibition of the Notch pathway in the developing retina causes premature neural differentiation of the progenitor cells and the loss of Müller glia (Nelson et al., 2007). Although Notch is perhaps the best-studied signaling system in the sensory click here epithelia, several members of the FGF family of receptor tyrosine kinase ligands also are of critical importance. In the auditory epithelium of the inner ear, FGF20 and Fgfr1 are critical for the early stages of cochlear development, including the initiation of Atoh1 expression (Hayashi et al., 2008b and Pirvola

et al., 2002). Later in cochlear development, FGF8 and Fgfr3 are necessary for the proper differentiation of one type of supporting cell, the pillar cells (Colvin et al., 1996, Domínguez-Frutos et al., 2009, Hayashi et al., 2007, Jacques et al., 2007 and Puligilla et al., 2007). In the retina and olfactory system, FGF8 is also important for the early specification of the sensory domains, and several other FGFs and FGF receptors are expressed in these organs. Other signaling molecules, Carnitine dehydrogenase including members of the Wnt, BMP, EGF, and IGF families, have been shown to be involved in the normal development in these systems, and although the details may be different, there are many conserved features. Of the specialized sensory epithelia, the olfactory epithelium shows the most robust regeneration in response to injury (Graziadei and Monti Graziadei, 1985). All cell types, including the sensory receptor neurons, can be regenerated in all species that have been examined. Severing the axons at the lamina cribosa in rats and mice causes extensive apoptosis in the olfactory receptor neurons within a few days (Cowan and Roskams, 2002). The epithelium at this point contains only the sustentacular cells and the globose and horizontal basal cells.

This is plausible because both heterotrimeric G proteins and adenylyl cyclases have been detected on endosomes and there is evidence that endosomes may contribute to a noncanonical mechanism of prolonged 7TMR signaling (Calebiro et al., 2009; Vilardaga et al., 2012). However, it has not been directly determined whether or not internalized 7TMRs can indeed elicit a “conventional” mode of acute G protein-linked signaling from the endosome membrane. This Review attempts to summarize Selleck Compound Library the present understanding of mechanisms

and functional consequences of endocytic membrane trafficking of neuromodulatory 7TMRs, focusing on catecholamine and opioid neuropeptide receptors as important and relatively well characterized examples. There has been significant recent progress in understanding molecular sorting operations that determine the membrane trafficking itinerary of these 7TMRs after

entry Adriamycin price to the endocytic pathway. Much remains unknown about the mechanistic basis of 7TMR sorting, particularly ubiquitylation-independent trafficking to lysosomes and the role of cytoskeletal dynamics in sequence-directed recycling, and little is known about the operation of any specific 7TMR sorting mechanism in neurons. One particularly interesting area for future study concerns the organization of specific 7TMR trafficking mechanisms with respect to the highly differentiated and polarized architecture of neurons. There is already evidence for enhanced endocytosis

of opioid receptors in dendrites after systemic administration of opioid drugs Thymidine kinase (Haberstock-Debic et al., 2003) and for reduced functional desensitization of various 7TMRs including opioid receptors in presynaptic relative to postsynaptic compartments (Wetherington and Lambert, 2002; Pennock et al., 2012). However, much remains to be learned about how 7TMR regulatory machineries are compartmentalized in neurons, and if there are differences in the regulated endocytic trafficking of receptors produced by local compared to global receptor activation. Related to this is the question of which membrane domain(s) are the source of physiologically salient 7TMR signaling. The traditional view is that G protein-linked signaling is restricted to the plasma membrane and based on rapid diffusion of downstream mediators. However, it is increasingly clear that even classical “diffusible” mediators such as cAMP are spatially restricted through local synthesis and destruction (Willoughby et al., 2006), and neuromodulators such as opioid neuropeptides exhibit a limited range of action in neural tissue (Banghart and Sabatini, 2012). Accordingly, the precise subcellular location of 7TMR activation is likely to be an important parameter in neuromodulation, particularly for projection neurons and neurons with extensive dendritic arbors.

The

data suggest PMA and DAG enhance GTP exchange activity by recruiting RGEF-1b to internal membranes that contain transiently or persistently colocalized LET-60. C1 domains are composed of ∼50 amino acids and contain two His and six Cys residues that are conserved (Figure 7B). Collectively, the Cys and His side chains ligate two zinc ions, thereby creating a rigid structure that supports a binding pocket. Three β strands and two hydrophobic loops (A and B) (Figure 7B) generate surfaces that bind DAG/PMA and facilitate partial immersion of C1 domains into a lipid bilayer. A conserved Pro in loop A is critical for high-affinity PMA binding (Hurley and Misra, 2000). Consequently, Pro503 in RGEF-1b was mutated to Gly. The mutation extinguished basal GTP exchange (Figure 7C, lanes 1 and 3) MG-132 manufacturer and sharply suppressed GTP loading activity at a concentration of PCI32765 PMA (50 nM) that maximally activated WT RGEF-1b (Figure 7C, lanes 2 and 4; Figure 7D lane 1, upper and lower panels). However, incubation of cells with high concentrations of PMA (200–400 nM) elicited similar, maximal catalytic activities for RGEF-1bP503G and RGEF-1b (Figure 7D). The results indicate that the mutant exchanger folds normally, but Pro503 is essential for high-affinity PMA binding by the C1 domain. RGEF-1bP503G failed to activate LET-60 when bombesin triggered DAG synthesis (Figure 7C, lane 8). Bombesin peptide concentration (200 nM) was

20-fold higher than necessary to saturate bombesin receptors and optimally activate PLCβ (Feng et al., 2007). Thus, Pro503 is indispensable for coupling increased DAG content to RGEF-1b activation. Maximal, bombesin-induced production of DAG did not compensate for the diminished C1 domain function of RGEF-1bP503G. RGEF-1bP503G was

not stably recruited to membranes by 50 nM PMA or 200 nM bombesin (Figure 7Af and 7Ah). Evidently, transient association of RGEF-1bP503G with membrane-bound, nonmetabolized PMA was sufficient to modestly activate LET-60 (Figure 7C, lane 4). Reduced binding affinity of RGEF-1bP503G from for transiently synthesized, rapidly metabolized DAG prevented exchanger activation by endogenous second messenger (Figure 7C, lane 8). Thus, high-affinity DAG binding activity of the C1 domain is essential for intracellular targeting and maximal catalytic activity of RGEF-1b. In vivo consequences of RasGRP C1 domain dysfunction are unknown. Therefore, animals expressing rgef-1::RGEF-1b or rgef-1::RGEF-1bP503G transgenes (rgef-1−/− background) were incubated with odorants detected by AWC or AWA neurons. RGEF-1b restored chemotaxis to both odorants ( Figure 7E). In contrast, panneuronal expression of RGEF-1bP503G did not alter low CI values observed in RGEF-1b-deficient C. elegans ( Figure 7E). Thus, C1 domain-mediated targeting to membranes is a key determinant of a RasGRP function (chemotaxis) in vivo. MPK-1 phosphorylation was assayed to determine if the RGEF-1bP503G mutation affected signaling in AWC neurons.

Specifically, the compensation mechanism in monarchs and locusts seems to be optimized for the difference in DRA architecture between both species, which dictates the region

of the sky observed by the DRA. We further propose that elevation compensation involves use of the circadian clock to track solar elevation changes over the course of the day. The use of a clock could explain how polarized and unpolarized light stimuli are properly integrated at the level of a single neuron, even though the stimuli are processed in separate pathways. For migrating monarchs to maintain a constant flight bearing over the day, they need a mechanism LY294002 price to compensate for the constantly changing sun position. We hypothesize that

this mechanism involves two distinct interaction sites between the circadian clock and MI-773 chemical structure the sun compass system. The first interaction ensures that all skylight information received by the sun compass system is consistent (elevation compensation), and the second interaction ensures that the animal flies in the correct direction, despite changing solar azimuth positions over the course of the day (azimuth compensation). Azimuthal compensation probably occurs on the output side of the sun compass, after integrating information from both eyes. Flight simulator experiments have shown that the antennae of the monarch are the location of the clock needed for azimuth compensation (Merlin et al., 2009) and defining a neural circuit from the antennae to the sun compass system is under investigation (Reppert et al., 2010). Elevation compensation, on the other hand, involves a clock interaction near the sensory periphery of the sun compass system, as this process is already apparent in the recorded TuLAL1 and TL neurons, which provide input to the sun compass. Thus, brain clock-derived, CRYPTOCHROME1-positive Vasopressin Receptor fibers in the monarch accessory

medulla may mediate this interaction, because of their close proximity to photoreceptor input from the DRA (Sauman et al., 2005). These two forms of compensation, though interrelated, are distinct, because migrating monarchs can use the solar azimuth alone, independent of E-vector tuning and solar elevation, for appropriately time-compensated directional flight ( Stalleicken et al., 2005). Further studies in the monarch will focus on the precise anatomical and functional interface of each of these two identified forms of clock-compass interactions. In a broader context, the complex integration of different skylight cues in insects is an example of how ambiguous aspects of the sensory environment are integrated into a coherent neuronal representation of the outside world. The fundamental problem of disambiguation occurs across all sensory modalities and across all species, including humans.

, 2012).

It is, therefore, conceivable that in cases in which AD was diagnosed clinically there might have been a component of vascular pathology. New imaging and CSF biomarkers for the in vivo diagnosis of AD may provide additional insights into whether vascular factors are pathogenically linked to AD (Chui et al., 2012, Haight et al., 2013 and Purnell et al., 2009). Mounting evidence that Aβ has powerful vascular effects Selleckchem PLX-4720 also suggests a link between AD and vascular disease. Aβ1−40 constrict isolated cerebral and systemic blood vessels (Niwa et al., 2001, Paris et al., 2003 and Thomas et al., 1996), whereas application of Aβ1−40 to the exposed cerebral cortex of mice reduces CBF and impairs the increase in CBF induced by endothelium-dependent vasodilators and functional hyperemia (Niwa et al., 2000a and Niwa et al., 2000b). Similarly, functional hyperemia, endothelium-dependent responses and autoregulation are profoundly impaired in young mice overexpressing mutated forms of APP, in which brain Aβ is elevated, but there are no plaques, behavioral alterations, or reductions in resting glucose utilization (Niwa et al., 2000b, Niwa BMS-354825 mouse et al., 2002 and Tong et al., 2012). These data suggest that the cerebrovascular effects of Aβ are not attributable to CAA or amyloid plaques, and are not a consequence of neuronal energy

hypometabolism. APP-overexpressing mice have increased brain damage following occlusion of the middle cerebral artery (Koistinaho et al., 2002 and Zhang et al., 1997), an effect in part related to poor collateral circulation due to vascular dysregulation (Zhang et al., 1997). The vascular alterations induced by Aβ are abrogated by overexpression of the ROS scavenging enzyme superoxide dismutase or deficiency of the NADPH oxidase subunit NOX2 (Iadecola et al., 1999, Park et al., 2005 and Park also et al., 2008), implicating ROS produced by the

enzyme NADPH oxidase in the vascular dysfunction. The mechanisms of NADPH oxidase activation involve the Aβ-binding scavenger receptor CD36 (Park et al., 2011). Aged APP mice deficient in CD36 are protected from cerebrovascular alterations and behavioral deficits, effects associated with reduced CAA compared to controls, but no reduction of amyloid plaques (Park et al., 2013b). Thus, CD36, which is located in vascular and perivascular cells, may contribute to the accumulation of Aβ in cerebral blood vessels. Hypoperfusion and hypoxia caused by vascular insufficiency may also facilitate Aβ production by activating the APP cleavage enzyme β-secretase (Kitaguchi et al., 2009, Sun et al., 2006, Tesco et al., 2007 and Wen et al., 2004a). Cerebral ischemia promotes amyloid plaque formation (Garcia-Alloza et al., 2011, Kitaguchi et al., 2009 and Okamoto et al., 2012), and tau phosphorylation (Koike et al., 2010, Wen et al., 2007 and Wen et al., 2004b).

Because the GluR6 and KA2 ATD heterodimer is formed with very high affinity, it is unlikely that this assembly undergoes large conformational changes in an intact receptor. Because the dimer is stabilized by contacts find more mediated by both the R1 and R2 domains, it is also unlikely that the individual subunits in a dimer could undergo substantial

changes in domain closure in response to small ligands. By contrast, although we can set only a lower limit of 3–5 μM on the Kd for formation of the tetrameric ATD dimer of dimers assembly, it is very likely that the tetramer is a dynamic assembly in which the two arms formed by ATD dimers can move relative to each other. It is thus tempting to speculate that if the ATD interacts with other proteins in the synaptic cleft, this could affect receptor clustering and mobility and in addition regulate ion channel activity via conformational changes propagated to the ligand binding domain. The AMPA receptor ATD has been reported to bind to N-cadehrins (Saglietti et al., 2007) and neuronal pentraxins thereby contributing to excitatory synapotogenesis (O’Brien et al., 1999, PARP inhibitor Ripley et al., 2011, Sia et al., 2007 and Xu et al., 2003). Likewise, the GluN1 ATD and the extracellular domain of EphB mediate

EphrinB and NMDA receptor interaction (Dalva et al., 2000 and Takasu et al., 2002). More recently, the Delta2 receptor ATD has been shown to form trans-synaptic interactions via cerebelin-1 Florfenicol precursor

protein and neurexin ( Matsuda et al., 2010 and Uemura et al., 2010). The exact nature and stoichiometry of these interactions is not known but will be influenced by the different stabilities of the high-affinity dimer and low-affinity dimer of dimers interfaces in individual iGluR subtypes. The GluR6 and KA2 ATDs were expressed in adherent and suspension cultures of wild-type HEK293T cells for SEC-UV/RI/MALS and AUC studies and purified as described previously (Kumar and Mayer, 2010 and Kumar et al., 2009). For crystallization the proteins were expressed in N-acetyl glucosaminyltransferase I-deficient GnTI− HEK293 cells and digested with Endo H (Reeves et al., 2002). Complete descriptions are given in Supplemental Experimental Procedures. X-ray diffraction data sets were collected using synchrotron radiation at the Advanced Photon Source (GM/CA CAT; beamline 23-ID-B) and were indexed, integrated, and scaled using HKL2000 (Otwinowski and Minor, 1997). The GluR6Δ1 homodimer and GluR6Δ1/KA2 heterodimer structures were solved by molecular replacement using the program PHASER (McCoy et al., 2007) and search probes composed of monomers of rat GluR6 (PDB ID: 3H6H) and KA2 (PDB ID: 3OM0) ATDs. The structures were iteratively built and refined with riding hydrogens using Coot (Emsley and Cowtan, 2004) and Phenix (Adams et al.

Members of this family are produced as inactive precursors that are maturated in the trans-golgi into large latent Adriamycin complexes that are released to the ECM. After a conformational change (controlled by integrins, ROS, pH, and others), active TGFβs are exposed to their receptor binding sites. These signal largely through an

Smad2/3-dependent mechanism leading to the recruitment of Smad4 and the induction of gene expression ( Kaminska et al., 2013). TGFβ and TGFβ receptor expression has been found in every cell type of the CNS. It has effects on neuronal survival, microglia migration, and phagocytosis and has angiogenic potential on cerebral endothelial cells ( Beck and Schachtrup, 2012). Its most documented effects, however, are carried out in astrocytes by promoting its migration, inhibiting its proliferation, and increasing the production of ECM components ( Kaminska et al., 2013). Considered tissue-resident macrophages much like Kupffer cells for the liver or histiocytes in connective tissues, microglia are the only cells in the CNS that are of hematopoietic origin (Soulet and Rivest, 2008b). Fate-mapping analysis has demonstrated that hematopoietic precursors from the yolk sac populate the CNS before the eighth embryonic day in mice (Ginhoux et al., 2010). Once present, microglia are capable of self-renewal and do

not require replenishment for circulating monocytic precursors (Ajami Ergoloid et al., 2007). They are thus distinct from the monocyte lineage of cells and other tissue-specific macrophages such as Kuppfer cells Stem Cells inhibitor in the liver, for which the maintenance is dependent upon the recruitment of bone marrow-derived cells (BMDCs) from the circulation (Klein et al., 2007). In the CNS, initial reports suggested that the recruitment of BMDCs was an active event in normal physiology (Simard and Rivest, 2004). After an intense debate on the subject (Soulet and Rivest, 2008a), a consensus appears to have been reached following new experimental evidence that BMDC recruitment is a marginal effect in normal physiology (Lampron

et al., 2012) but important in pathological conditions affecting the integrity of the CNS such as stroke (Schilling et al., 2009), multiple sclerosis (Floris et al., 2004), amyotrophic lateral sclerosis (Vaknin et al., 2011), and others. This recruitment can be beneficial or harmful, depending on the condition studied (Shechter and Schwartz, 2013). In their native state, microglia are highly ramified cells with a small cellular body. Its extended processes allow microglia to rapidly sense the presence of tissue damages or signs of infections through PRRs. Microglia are highly plastic cells, they respond rapidly to the danger signals released by injured cells and secrete appropriate cytokines both to clear debris and to attract other microglial cells (Soulet and Rivest, 2008b).

Stressed BALB mice showed significantly longer latency periods to feeding (Figure S2F), with no significant differences in weight Thiazovivin manufacturer loss induced by food deprivation (Figure S2G) or feeding activities (Figure S2H). Furthermore, the increased latency to feed induced by CUMS was reversed with continuous IMI treatment (Figure S2F). Anxiety behavior was also examined using the elevated zero

maze test. The amount of time spent in the open section and frequency of rearing were not affected by CUMS (data not shown). Social interaction time also provides an index of anxiety and depression-like behavior. More anxious and depressed rodents spend less time in social interactions (File and Seth, 2003 and Berton et al., 2006). C646 Stressed BALB mice spent significantly less time engaged in social interactions and had fewer interactions than the nonstressed controls. This effect was also reversed with continuous IMI treatment (Figures S2I and S2J).

Taken together, these results indicate an increase in depression- and anxiety-related behaviors in stressed BALB mice. In contrast with the BALB mice, B6 mice subjected to CUMS did not show any behavioral changes in the sucrose preference test (Figures S3A and S3B) or forced swim test (Figures S3C and S3D), but they did demonstrate a reduced latency to feed in the novelty-suppressed feeding test (Figure S3E) and increased interaction times in the social interaction test

(Figure S3G), suggesting a decrease in anxiety-related behaviors in stressed B6 mice. In addition to behavioral characterization, we also examined the plasma corticosterone (CORT) levels of mice to investigate how CUMS influences neuroendocrine function. We found increased plasma CORT levels 60 min after the initiation of a stressor in both BALB and B6 mice on day 3 of the CUMS session (Figures S4A and S4B). In contrast, on day 38 of the CUMS session, B6 mice showed a reduction in plasma CORT levels 60 min check after the initiation of the stressor (Figure S4B). This effect was not observed in BALB mice (Figure S4A). Thus, BALB mice responded to CUMS with an increase in depression-like phenotypes, whereas the B6 mice responded to the same stress conditions with a decrease in anxiety-related behaviors. These behavioral and neuroendocrine data indicate that BALB and B6 mice develop “passive” and “active” responses to stress, suggesting that these strains of mice are susceptible and adaptive strains to CUMS, respectively. Neurotrophic factors play important roles in the regulation of synaptic and structural plasticity in the brain and may be involved in depression (Nestler et al., 2002 and Duman and Monteggia, 2006).