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The effects of melatonin on spatial memory deficits in Alzheimer’s disease (AD) have been thoroughly investigated. Our previous study demonstrated that melatonin rescues hippocampus-dependent spatial memory deficits by arresting hippocampal pathological progression in an animal model of AD, which occurs via the inhibition of GSK3β and an increase in c-Fos. Based on the interaction between the amygdala and hippocampus, it is important to determine whether melatonin also improves amygdala-dependent emotional memory to understand the mechanism of melatonin amelioration of memory deficits in AD. The basolateral amygdala (BLA) is essential for the processing of emotions, including cued fear conditioning and anxiety. In the present study, we intraperitoneally injected Tg2576 mice with melatonin for 4 months and measured amygdala-dependent emotional memory using cued fear conditioning and a step-down passive avoidance test; the expression of c-Fos, Arc, phosphorylated CREB (pCREB) and other related genes were subsequently measured using Real-time polymerase chain reaction (RT-PCR) and Western blot in BLA. Our findings suggest that melatonin ameliorates amygdala-dependent emotional memory in AD via up-regulation of the pCREB/c-Fos pathway. [ABSTRACT FROM AUTHOR]

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been implicated in stress adaptation with potential relevance in mood disorder management. PACAP deficient (KO) mice on CD1 background were shown to have depression-like phenotype. Here we aimed at investigating effects of chronic variable mild stress (CVMS) in non-injected, vehicle and imipramine-treated KO mice vs. wildtype (WT) counterparts. We hypothesized reduced FosB neuronal activity in stress-related centers, altered activity and peptide/neurotransmitter content of corticotropin-releasing factor (CRF) cells of the oval (ovBST) bed nucleus of stria terminalis (BST), urocortin 1 (Ucn1) neurons of centrally projecting Edinger-Westphal nucleus (cpEW) and serotonin (5HT) cells of dorsal raphe (DR) in PACAP deficiency. CVMS caused decreased body weight and increased adrenal size, corticosterone (CORT) titers and depression-like behavior in WT mice, in contrast to KO animals. CVMS increased FosB in the central (CeA) and medial amygdala, dorsomedial (dmBST), ventral (vBST), ovBST, CA1 area, dentate gyrus (DG), ventral lateral septum, parvo- (pPVN) and magnocellular paraventricular nucleus, lateral periaqueductal gray, cpEW and DR. Lack of PACAP blunted the CVMS-induced FosB rise in the CeA, ovBST, dmBST, vBST, CA1 area, pPVN and DR. The CVMS-induced FosB expression in ovBST-CRF and cpEW-Ucn1 neurons was abolished in KO mice. Although CVMS did not induce FosB in 5HT-DR neurons, PACAP KO mice had increased 5HT cell counts and 5HT content. We conclude that PACAP deficiency affects neuronal reactivity in a brain area-specific manner in stress centers, as well as in ovBST-CRF, cpEW-Ucn1 and 5HT-DR neurons leading to reduced CVMS response and altered depression level. [ABSTRACT FROM AUTHOR]

Summary Exocrine gland-secreting peptide 1 (ESP1) released into male tear fluids is a male pheromone that stimulates sexually receptive behavior in female mice via the vomeronasal sensory system. ESP1 also induces c-Fos expression in male brain regions distinct from those in females. However, behavior in males following ESP1 exposure has not been examined. In the present study, we show that ESP1, in conjunction with unfamiliar male urine, enhances male aggression via the specific vomeronasal receptor V2Rp5. In addition, male mice that secrete ESP1 but lack V2Rp5 exhibit a lower level of aggressiveness than do mice that express V2Rp5. These results suggest that ESP1 not only acts as a male pheromone in both sexes but also serves as an auto-stimulatory factor that enhances male aggressiveness by self-exposure. Finally, re-activation of ESP1-induced c-Fos-positive neurons by using the designer receptor exclusively activated by designer drug (DREADD) approach resulted in enhancement of sexual and aggressive behaviors in female and male mice, respectively, indicating that sexually dimorphic activation in the brain is a neural basis for the sex-specific behavioral responses to ESP1. [ABSTRACT FROM AUTHOR]

Paternal behavior is not innate but arises through social experience. After mating and becoming fathers, male mice change their behavior toward pups from infanticide to paternal care. However, the precise brain areas and circuit mechanisms connecting these social behaviors are largely unknown. Here we demonstrated that the c-Fos expression pattern in the four nuclei of the preoptic-bed nuclei of stria terminalis ( BST) region could robustly discriminate five kinds of previous social behavior of male mice (parenting, infanticide, mating, inter-male aggression, solitary control). Specifically, neuronal activation in the central part of the medial preoptic area ( cMPOA) and rhomboid nucleus of the BST ( BSTrh) retroactively detected paternal and infanticidal motivation with more than 95% accuracy. Moreover, cMPOA lesions switched behavior in fathers from paternal to infanticidal, while BSTrh lesions inhibited infanticide in virgin males. The projections from cMPOA to BSTrh were largely GABAergic. Optogenetic or pharmacogenetic activation of cMPOA attenuated infanticide in virgin males. Taken together, this study identifies the preoptic- BST nuclei underlying social motivations in male mice and reveals unexpected complexity in the circuit connecting these nuclei. [ABSTRACT FROM AUTHOR]

Vesicular glutamate transporters (VGLUTs) control the storage and release of glutamate, which plays a critical role in pain processing. The VGLUT2 isoform has been found to be densely distributed in the nociceptive pathways in supraspinal regions, and VGLUT2-deficient mice exhibit an attenuation of neuropathic pain; these results suggest a possible involvement of VGLUT2 in neuropathic pain. To further examine this, we investigated the temporal changes in VGLUT2 expression in different brain regions as well as changes in glutamate release from thalamic synaptosomes in spared nerve injury (SNI) mice. We also investigated the effects of a VGLUT inhibitor, Chicago Sky Blue 6B (CSB6B), on pain behavior, c-Fos expression, and depolarization-evoked glutamate release in SNI mice. Our results showed a significant elevation of VGLUT2 expression up to postoperative day 1 in the thalamus, periaqueductal gray, and amygdala, followed by a return to control levels. Consistent with the changes in VGLUT2 expression, SNI enhanced depolarization-induced glutamate release from thalamic synaptosomes, while CSB6B treatment produced a concentration-dependent inhibition of glutamate release. Moreover, intracerebroventricular administration of CSB6B, at a dose that did not affect motor function, attenuated mechanical allodynia and c-Fos up-regulation in pain-related brain areas during the early stages of neuropathic pain development. These results demonstrate that changes in the expression of supraspinal VGLUT2 may be a new mechanism relevant to the induction of neuropathic pain after nerve injury that acts through an aggravation of glutamate imbalance. [ABSTRACT FROM AUTHOR]

To address the role of mixed anxiety/mood disorder on appetitive associative learning, we verify whether previous chronic light deprivation changes ethanol-induced conditioned place preference and its respective expression of c-Fos and pCREB, markers of neuronal activity and plasticity. The experimental group was maintained in light deprivation for 24 h for a period of 4 wk. Subsequently, it was adapted to a standard light-dark cycle for 1 wk. As a control, some mice were maintained in standard cycle for a period of 4 wk (Naive group). Then, all animals were submitted to behavioral tests to assess emotionality: elevated plus maze; open field; and forced swim. After that, they were submitted to ethanol-induced conditioned place preference. Ninety minutes after the place preference test, they were perfused, and their brains processed for c-Fos and pCREB immunohistochemistry. Light deprivation induced anxiety-like trait (elevated plus maze), despair (forced swim), and hyperlocomotion (open field), common features seen in other animal models of depression. Ethanol-induced conditioned place preference was accompanied by increases on c-Fos and pCREB in the hippocampus, prefrontal cortex and striatum. Interestingly, mice previously submitted to light deprivation did not develop either acquisition and/or expression of ethanol-induced conditioned place preference or increases in c-Fos and pCREB. Therefore, chronic light deprivation mimics several behavioral aspects of other animal models of depression. Furthermore, it could be useful to study the neurochemical mechanisms involved in the dual diagnosis. However, given its likely deleterious effects on appetitive associative memory, it should be used with caution to investigate the cognitive aspects related to the dual diagnosis. [ABSTRACT FROM AUTHOR]

Dysregulation of hypothalamic-pituitary-adrenal ( HPA) axis activation is associated with changes in addiction-related behaviors. In this study, we tested whether sex differences in the acute effects of methamphetamine ( MA) exposure involve differential activation of the HPA axis. Male and female mice were injected with MA (1 mg/kg) or saline for comparison of plasma corticosterone and analysis of the immediate early gene c-Fos in brain. There was a prolonged elevation in corticosterone levels in female compared to male mice. C-Fos was elevated in both sexes following MA in HPA axis-associated regions, including the hypothalamic paraventricular nucleus ( PVN), central amygdala, cingulate, and CA3 hippocampal region. MA increased the number of c-Fos and c-Fos/glucocorticoid receptor ( GR) dual-labeled cells to a greater extent in males than females in the cingulate and CA3 regions. MA also increased the number of c-fos/vasopressin dual-labeled cells in the PVN as well as the number and percentage of c-Fos/ GR dual-labeled cells in the PVN and central amygdala, although no sex differences in dual labeling were found in these regions. Thus, sex differences in MA-induced plasma corticosterone levels and activation of distinct brain regions and proteins involved in HPA axis regulation may contribute to sex differences in acute effects of MA on the brain. [ABSTRACT FROM AUTHOR]

The neurotransmitter serotonin plays an important role in the regulation of the circadian clock. To gain further insight into the mechanisms by which serotonin regulates rhythmicity, the authors investigated photic and nonphotic effects on the circadian clock in Pet-1 knockout mice. In these mice, the serotonergic system suffers a developmental loss of 70% of serotonin neurons, with the remaining neurons being deficient in serotonergic function as well. Pet-1 knockout mice show significantly decreased phase delays of the circadian clock in response to light pulses in the early night; however, this difference was not reflected in a difference in the expression of Fos protein in the suprachiasmatic nucleus. There were no genotypic differences detected in the phase-shifting response to injection of the 5-HT1A/7 (serotonin 1A and 7) agonist 8-OH-DPAT ((±)-8-hydroxy-2-(dipropylamino)tetralin hydrobromide); however, there were small but significant differences in the phase-shifting responses to cages between genotypes and sexes. Several different patterns of wheel-running activity were observed in knockout mice that differed from those in wild-type mice, suggesting that normal serotonergic function is necessary for the proper consolidation of nocturnal activity. Overall, these data are consistent with other pharmacological and genetic studies demonstrating a significant role for serotonin in circadian clock function. [ABSTRACT FROM AUTHOR]

Highlights: [•] GluA1 knockout mice display enhanced novelty-induced locomotion. [•] GluA1 knockout mice also show enhanced novelty-induced hippocampal c-Fos expression. [•] mGluR2/3 agonist reduced GluA1 knockout hyperlocomotion in males. [•] mGluR2/3 agonist reduced novelty-induced c-Fos in male GluA1 knockout hippocampus. [ABSTRACT FROM AUTHOR]

Highlights: [•] Parvalbumin, COX-2 or c-Fos neurons decreased in hippocampus and cerebellum. [•] Calbindin D28k or calretinin neurons decreased in hippocampus and cerebellum. [•] The decreased immunoreactivities were observed in 4- and 8-week old NPC−/− mice. [ABSTRACT FROM AUTHOR]

Early-life stress has long-lasting effects on neuroendocrine and behaviour in adulthood. Maternal separation ( MS) is used as a model of early-life stress and daily repeated MS ( RMS) for 3 h during the first two postnatal weeks is widely used in rodent studies. However, it is not fully understood whether early-life animals desensitise/habituate to repeated stress. In the present study, we investigated the effects of daily RMS for 3 h and acute/single time MS ( SMS) for 3 h on the plasma corticosterone level and c- Fos expression in the brain in mice at different postnatal ages. Mice were subjected to: (i) RMS from postnatal day ( PND) 1 to 14 ( RMS14); (ii) RMS from PND14 to 21 ( RMS21); (iii) SMS on PND14 ( SMS14); and (iv) SMS on PND21 ( SMS21). Plasma corticosterone and c- Fos expression were examined on the final day in each experiment. The basal corticosterone levels in RMS14 and RMS21 were equal to those in respective age-matched controls. After the final separation, the levels were significantly increased and were comparable with those after SMS14 and SMS21, respectively. Histological analysis indicated that c- Fos expression significantly increased in many brain regions, including the paraventricular nucleus, prefrontal cortex, hippocampus, and basolateral and medial amygdale in both SMS14 and SMS21 mice. However, c- Fos expression in RMS14 mice significantly increased in many regions, whereas such increases were hardly seen in RMS21 mice. These results indicate that repeated early-life stress neither increases basal corticosterone, nor decreases the magnitude of the corticosterone response during the first three postnatal weeks, although desensitisation of c- Fos expression induced by repeated stress is changed during postnatal development. [ABSTRACT FROM AUTHOR]

Abstract: Histone deacetylase (HDAC) enzymes play important roles in physiological and pathological processes by catalyzing the deacetylation of lysine residues in histone and non-histone proteins. Inhibition of HDACs has emerged as an attractive therapeutic strategy for various diseases including cancer and inflammatory diseases. We recently found that MS-275, a class I-specific HDAC inhibitor, exhibits an anabolic effect on bone through promoting expression of alkaline phosphatase in osteoblasts. MS-275 has also been suggested to inhibit inflammatory bone destruction, but the underlying mechanisms are still poorly understood. In this study, we investigated the effects and mechanism of action of MS-275 on osteoclast differentiation and activation. We found that MS-275 inhibits osteoclast differentiation in coculture of osteoblasts and bone marrow cells without affecting expression of receptor activator of NF-κB ligand (RANKL), a key cytokine for osteoclast differentiation, in osteoblasts. MS-275 inhibited RANKL-mediated osteoclast differentiation from its precursors by suppressing RANKL-induced expression of c-Fos, a crucial transcription factor for osteoclastogenesis. The inhibitory effect of MS-275 on osteoclast differentiation was blunted by ectopic overexpression of c-Fos. In addition to osteoclast differentiation, MS-275 decreased bone resorbing activity of mature osteoclasts. Consistent with the in vitro effects, MS-275 decreased osteoclast number and bone destruction in IL-1-induced mouse calvarial bone destruction model. Taken together, our results demonstrate that MS-275 suppresses bone destruction by inhibiting osteoclast differentiation and activation, suggesting a potential therapeutic value of MS-275 for bone disorders associated with increased bone resorption. [Copyright &y& Elsevier]

Summary: Estrogen may be involved in psychosis by an interaction with central dopaminergic activity. Aromatase knockout mice are unable to produce estrogen and have been shown to display altered behavioural responses and effects of the dopamine releaser, amphetamine. This study investigates the effect of gonadal status on amphetamine-induced c-fos expression in the brains of female aromatase knockout and wildtype mice. Six groups of mice were treated intraperitoneally with saline or 5mg/kg amphetamine. Fos immunoreactivity was assessed in the cingulate cortex, caudate putamen and nucleus accumbens. Aromatase knockout mice showed markedly reduced amphetamine-induced Fos immunoreactivity compared to wildtype mice. However, the amphetamine response was restored in aromatase-knockout mice after ovariectomy, which reduced this effect in wildtype controls. Estrogen supplementation reversed the effect of ovariectomy in wildtype mice but had no additional significant effect in aromatase-knockout mice. These results indicate that mechanisms involved in amphetamine-induced c-fos expression are altered in aromatase knockout mice and that the primary hormone involved in this effect is not estrogen, but may be another factor released from the ovaries, such as an androgen. These results provide new insight into the effect of gonadal hormones on amphetamine induced c-fos expression in this mouse model of estrogen deficiency. These results could be important for our understanding of the role of sex steroid hormones in psychosis. [Copyright &y& Elsevier]

Mice lacking c-fos develop osteopetrosis due to a block in osteoclast differentiation. Carboxy-terminal phosphorylation of Fos on serine 374 by ERK1/2 and serine 362 by RSK1/2 regulates Fos stability and transactivation potential in vitro. To assess the physiological relevance of Fos phosphorylation in vivo, serine 362 and/or serine 374 was replaced by alanine (Fos362A, Fos374A and FosAA) or by phospho-mimetic aspartic acid (FosDD). Homozygous mutants were healthy and skeletogenesis was largely unaffected. Fos C-terminal phosphorylation, predominantly on serine 374, was found important for osteoclast differentiation in vitro and affected lipopolysaccharide (LPS)-induced cytokine response in vitro and in vivo. Importantly, skin papilloma development was delayed in FosAA, Fos362A and Rsk2-deficient mice, accelerated in FosDD mice and unaffected in Fos374A mutants. Furthermore, the related Fos protein and putative RSK2 target Fra1 failed to substitute for Fos in papilloma development. This indicates that phosphorylation of serines 362 and 374 exerts context-dependent roles in modulating Fos activity in vivo. Inhibition of Fos C-terminal phosphorylation on serine 362 by targeting RSK2 might be of therapeutic relevance for skin tumours. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor receptor-associated factor 6 (TRAF6) plays a critical role in establishing both innate and acquired immune responses by mediating signals from the TNF superfamily, the TLR/IL-1R family, and the T-cell receptor. Here, we report a previously unidentified function of TRAF6 in IL-2 signaling. CD3/CD28 stimulation-induced proliferation and Il2 mRNA expression in Traf6CD4 T cells were dramatically enhanced. This enhancement is likely due to hyperactive IL-2 signaling, in which activation of the Jak1-Erk pathway was enhanced and the subsequent Fos gene expression was up-regulated. To elucidate the molecular mechanisms of the enhanced activation of Jak1, IL-2 signaling was reconstituted in mouse embryonic fibroblast (MEF) cells to investigate the interaction between TRAF6 and the TRAF6-binding site that overlaps with the Jak1-binding site present in the IL-2R β-chain. The Jak1-Erk pathway was activated upon IL-2 stimulation in Traf6MEF cells, while a β-chain mutation that inactivates TRAF6 binding but retains Jak1 binding abrogated the TRAF6-dependent reduction in IL-2 signaling. These results indicate that the binding of TRAF6 to the TRAF6-binding site of the β-chain negatively regulates IL-2-induced Jak1 activation, which is likely to be involved in the proper regulation of T-cell activation and development. [ABSTRACT FROM AUTHOR]

Abstract: Voluntary wheel running activates dentate gyrus granule neurons and increases adult hippocampal neurogenesis. Average daily running distance typically increases over a period of 3 weeks in rodents. Whether neurogenesis and cell activation are greater at the peak of running as compared to the initial escalation period is not known. Therefore, adult C57BL/6J male mice received 5 days of BrdU injections, at the same age, to label dividing cells during the onset of wheel access or after 21 days during peak levels of running or in sedentary conditions. Mice were sampled either 24h or 25 days after the last BrdU injection to measure cell proliferation and survival, respectively. Immunohistochemistry was performed on brain sections to identify the numbers of proliferating BrdU-labeled cells, and new neurons (BrdU/NeuN co-labeled) in the dentate gyrus. Ki67 was used as an additional mitotic marker. The induction of c-Fos was used to identify neurons activated from running. Mice ran approximately half as far during the first 5 days as compared to after 21 days. Running increased Ki67 cells at the onset but after 21 days levels were similar to sedentary. Numbers of BrdU cells were similar in all groups 24h after the final injection. However, after 25 days, running approximately doubled the survival of new neurons born either at the onset or peak of running. These changes co-varied with c-Fos expression. We conclude that sustained running maintains a stable rate of neurogenesis above sedentary via activity-dependent increases in differentiation and survival, not proliferation, of progenitor cells in the C57BL/6J model. [Copyright &y& Elsevier]

Background: The c-fos proto-oncogene is an archetype for rapid and integrative transcriptional activation. Innumerable studies have focused on the canonical promoter, located upstream from the transcriptional start site. However, several regulatory sequences have been found in the first intron. Methodology/Principal Findings: Here we describe an extremely conserved region in c-fos first intron that contains a putative TATA box, and functional TRE and CRE sites. This fragment drives reporter gene activation in fibroblasts, which is enhanced by increasing intracellular calcium and cAMP and by cotransfection of CREB or c-Fos/c-Jun expression vectors. We produced transgenic mice expressing a lacZ reporter controlled by the intronic promoter. Lac Z expression of this promoter is restricted to the developing central nervous system (CNS) and the mesenchyme of developing mammary buds in embryos 12.5 days post-conception, and to brain tissue in adults. RT-QPCR analysis of tissue mRNA, including the anlage of the mammary gland and the CNS, confirms the existence of a novel, nested mRNA initiated in the first intron. Conclusions/Significance: Our results provide evidence for a novel, developmentally regulated promoter in the first intron of the c-fos gene. [ABSTRACT FROM AUTHOR]

Cholecystokinin (CCK) and leptin are two important satiety factors that are considered to act in synergy to reduce meal size. Peripheral injection of CCK activates neurones in several hypothalamic nuclei, including the supraoptic (SON) and paraventricular (PVN) nuclei and neurones in the brainstem of fed rats. We investigated whether peripheral leptin would modulate the effects of CCK on neuronal activity in the hypothalamus and brainstem of fasted rats by investigating Fos expression in the PVN, SON, arcuate nucleus, ventromedial hypothalamus (VMH), dorsomedial hypothalamus (DMH), area postrema (AP) and the nucleus tractus solitarii (NTS). Male rats, fasted for 24 h, received either one i.p. injection of vehicle, leptin or CCK-8 alone, or received one injection of vehicle or leptin before an i.p. injection of CCK-8. We found that CCK increased Fos expression in the PVN and SON as well as in the NTS and AP, but had no effect on Fos expression in the arcuate nucleus, VMH or DMH compared to vehicle. Leptin injected alone significantly increased Fos expression in the arcuate nucleus but had no effect on Fos expression in the VMH, DMH, SON, PVN, AP or NTS compared to vehicle. Fos expression was significantly increased in the AP in rats injected with both leptin and CCK compared to rats injected with vehicle and CCK. Unexpectedly, there was significantly less Fos expression in the PVN and SON of fasted rats injected with leptin and CCK than in rats injected with vehicle and CCK, suggesting that leptin attenuated CCK-induced Fos expression in the SON and PVN. However, Fos expression in the NTS was similar in fasted rats injected with vehicle and CCK or with leptin and CCK. Taken together, these results suggest that leptin dampens the effects of CCK on Fos expression in the SON and PVN, independently from NTS pathways, and this may reflect a direct action on magnocellular neurones. [ABSTRACT FROM AUTHOR]

Abstract: Expression of immediate early genes, such as c-fos, has been extensively used as a marker of neural activity. However, their expression in the brain has so far been examined by using invasive procedures. In this study, we tried to image c-fos expression in the mouse barrel cortex noninvasively by detecting bioluminescence produced by the reporter luciferase. To detect asymmetry in c-fos expression in the bilateral barrel cortices, we used ten Fos-Luc mice and removed long whiskers on one side. After 1h of exploration in a novel cage, luciferin was intraperitoneally administrated under gas anesthesia and bioluminescence was measured with a cooled CCD camera. We observed moderate but clear emission over the head that was significantly stronger on the side of removal. After regrowth of the whiskers, the same mice had the vibrissae clipped on the other side. Bioluminescence was again dominant on the side of removal. In three of the mice, c-fos expression was examined immunohistochemically. The distribution of bioluminescence generally agreed with that of the c-fos positive cells though the bioluminescence tended to distribute wider, by around 0.5mm, probably due to scattering of light through the tissues. The results show that expression of c-fos in the mouse barrel cortex can be imaged repeatedly and noninvasively in the living animal. [Copyright &y& Elsevier]

Abstract: There are sex differences in the neurochemistry of brainstem nuclei that participate in the control of breathing as well as sex differences in respiratory responses to hypoxia. Central chemoreception refers to the detection within the brain of minute changes in carbon dioxide (CO2) levels and the subsequent modulation of breathing. Putative central chemoreceptor sites are widespread and include cells located near the ventral surface of the brainstem in the retrotrapezoid nucleus (RTN), in the medullary midline raphe nuclei, and, more dorsally in the medulla, in the nucleus of the solitary tract and in the locus caeruleus at the pontomedullary junction as well as in the fastigial nucleus of the cerebellum. In this study, we ask if the cells that respond to CO2 differ between the sexes. We used a transgenic mouse with a c-fos promoter driven tau-lacZ reporter construct (FTL) to map the locations of cells in the mouse brainstem and cerebellum that responded to exposure of mice of both sexes to 5% CO2 or room air (control). X-gal (5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside) histochemical staining to detect the beta-galactosidase enzyme produced staining in the brains of mice of both sexes in all of the previously identified putative chemoreceptor sites, with the exception of the fastigial nucleus. Notably, the male RTN region contained significantly more x-gal-labeled cells than the female RTN region. In addition to new observations regarding potential sex differences in the retrotrapezoid region, we found the FTL mouse to be a useful tool for identifying cells that respond to the exposure of the whole animal to relatively low concentrations of CO2. [Copyright &y& Elsevier]

Abstract: DYT1 dystonia is caused by a trinucleotide deletion of GAG (ΔGAG) in DYT1, which codes for torsinA. A previous epidemiologic study suggested an association of DYT1 ΔGAG mutation with early-onset recurrent major depression. However, another study reported no significant association with depression, but instead showed an association with anxiety and dystonia. In this study, we analyzed these related behaviors in Dyt1 ΔGAG heterozygous knock-in mice. The knock-in mice showed a subtle anxiety-like behavior but did not show depression-like behaviors. The mutant mice also displayed normal sensorimotor gating function in a prepulse inhibition test. While normal hippocampus-dependent contextual fear memory and hippocampal CA1 long-term potentiation (LTP) were observed, the knock-in mice exhibited an enhancement in the formation of cued fear memories. Anatomical analysis indicated that the number of c-fos positive cells was significantly increased while the size of the central nucleus of the amygdala (CE) was significantly reduced in the knock-in mice. These results suggest that the Dyt1 ΔGAG mutation increased the activity of the CE and enhanced the acquisition of the cued fear memory. [Copyright &y& Elsevier]

Abstract: The aims of the present study were to establish if nalfurafine, a kappa opioid agonist, inhibits compulsive scratching in mice elicited by the s.c. administration (behind the neck) of 5′-guanidinonaltrindole (GNTI), a kappa opioid antagonist; to assess if nalfurafine prevents c-fos expression provoked by GNTI or compound 48/80, two chemically diverse pruritogens; and to distinguish on the basis of neuroanatomy, those neurons in the brainstem activated by either GNTI-induced itch or formalin-induced pain (both compounds given s.c. to the right cheek). Pretreatment of mice with nalfurafine (0.001–0.03 mg/kg s.c.) attenuated GNTI (0.3 mg/kg)-evoked scratching dose-dependently. A standard antiscratch dose of nalfurafine (0.02 mg/kg) had no marked effect on the spontaneous locomotion of mice. Tolerance did not develop to the antiscratch activity of nalfurafine. Both GNTI and compound 48/80 provoked c-fos expression on the lateral side of the superficial layer of the dorsal horn of the cervical spinal cord and pretreating mice with nalfurafine inhibited c-fos expression induced by both pruritogens. In contrast to formalin, GNTI did not induce c-fos expression in the trigeminal nucleus suggesting that pain and itch sensations are projected differently along the sensory trigeminal pathway. Our data indicate that the kappa opioid system is involved, at least in part, in the pathogenesis of itch; and that nalfurafine attenuates excessive scratching and prevents scratch-induced neuronal activity at the spinal level. On the basis of our results, nalfurafine holds promise as a potentially useful antipruritic in human conditions involving itch. [Copyright &y& Elsevier]

Abstract: Repeated exposure to drugs of abuse induces a variety of persistent changes in the brain and the dopamine D1 receptor plays a major role in the process. To understand intracellular mechanisms contributing to cocaine-induced neuroadaptations, we previously examined the role of the immediate early gene Fos using a mouse in which Fos is disrupted primarily in D1 receptor-expressing neurons in the brain. We found that both dendritic remodeling of medium spiny neurons and behavioral sensitization induced by repeated exposure to cocaine are attenuated in the mutant mice. Moreover, the expression of genes encoding several transcription factors, neurotransmitter receptors and intracellular signaling molecules following repeated cocaine administration is altered in the mutant mice compared to that in wild-type mice. In the present study, we have investigated the role of Fos in regulating neuronal excitability at a cellular level and found that medium spiny nucleus accumbens neurons in the mutant mice exhibit increased excitability and attenuated inhibitory responses to stimulation of D1 receptors compared to those in wild-type mice. Our findings suggest that Fos functions in D1 receptor-bearing neurons to regulate neuronal activity which may contribute to the persistence of drug-induced changes. [Copyright &y& Elsevier]

Abstract: A previous study showed that two mouse models of behavioral depression, immune system activation and depletion of brain monoamines, are accompanied by marked reductions in stimulated neural activity in brain regions involved in motivated behavior. The present study tested whether this effect is common to other depression models by examining the effects of repeated forced swimming, chronic subordination stress or acute intraventricular galanin injection – three additional models – on baseline or stimulated c-fos expression in several brain regions known to be involved in motor or motivational processes (secondary motor, M2, anterior piriform cortex, APIR, posterior cingulate gyrus, CG, nucleus accumbens, NAC). Each of the depression models was found to reduce the fos response stimulated by exposure to a novel cage or a swim stress in all four of these brain areas but not to affect the response of a stress-sensitive region (paraventricular hypothalamus, PVH) that was included for control purposes. Baseline fos expression in these structures was either unaffected or affected in an opposite direction to the stimulated response. Pretreatment with either desmethylimipramine (DMI) or tranylcypromine (tranyl) attenuated these changes. It is concluded that the pattern of a reduced neural function of CNS motor/motivational regions with an increased function of stress areas is common to 5 models of behavioral depression in the mouse and is a potential experimental analog of the neural activity changes occurring in the clinical condition. [Copyright &y& Elsevier]

The standard mode of action for oestradiol is via activation of nuclear oestrogen receptors (ERs), which initiate DNA transcription leading to protein formation. In the present study, we examined the rapid and potentially ER-independent action of oestradiol using Fos as a marker of neural activity. We assessed Fos immunoreactivity (ir) in brains of mice with functional versus nonfunctional ERs. Fos-ir was compared in brains of control mice that did and did not receive oestradiol treatment prior to sacrifice, and cell numbers in the preoptic area (POA), ventromedial nucleus of the hypothalamus (VMH), area 2 of cingulate cortex (CG2), granular layer of accessory olfactory bulb (Gr-AOB), olivary pretectal nucleus (OPT) and pyramidal layer of field CA3 of hippocampus (Py-CA3) were increased 90 min after oestradiol treatment. By contrast, in brains of double oestrogen receptor αβ knockout (ERαβKO) female mice, no change in Fos-ir was noted after oestradiol treatment in the POA, VMH, Gr-AOB or Py-CA3, suggesting that these responses to oestradiol depend on ERα and/or ERβ. However, Fos-ir was induced by oestradiol in the OPT and CG2 in ERαβKO mice. These regions do not contain ERα-ir in control brains. In ERαβKO brains as well, ERα-ir was absent, suggesting that the mutant ERα (E1) present in ERαKO brain is also absent in these regions. We speculate that oestradiol has rapid effects in the OPT and CG2 via a novel mechanism that does not require either classic oestrogen receptor. [ABSTRACT FROM AUTHOR]

Recently, it has been proposed that a variety of environmental disruptors (EDs) disturb the neonatal development of the brain in mammals because of their lipophilic characteristics. Therefore, the synergism of these lipophilic compounds is important when evaluating the risk from EDs. In mouse cerebellar granule cells (CGCs), the activity-dependent expression of the brain-derived neurotrophic factor (BDNF) gene is activated through an influx of calcium ions (Ca2+) into CGCs caused by membrane depolarization, which is involved in the activity-dependent development of not only the cerebellum but also other regions of the brain after birth. In our previous study, we reported that permethrin and some other pyrethroid insecticides, which are suspected of being EDs, repressed the induction of c-fos and BDNF mRNA expression, accompanying a reduction of Ca2+ influx at doses non-toxic to CGCs. In the present study, we investigated whether other lipophilic compounds influenced the Ca2+ signal-induced expression of both genes as permethrin did and, if so, whether these effects were synergistic or additional. Pretreatment with p,p′-DDT, diethylstilbestrol (DES) or bisphenol A dose-dependently repressed the induction of both genes as well as the increase in the uptake of Ca2+ by CGCs. Simultaneous exposure of CGCs with permethrin, p,p′-DDT and DES, in addition, revealed an additional repression on the induction of the genes and the Ca2+ uptake. These results suggest that toxic effects of EDs might, at least additionally, occur in the brain even if the concentration of each compound is lower than the effective dose for humans. [Copyright &y& Elsevier]

A mouse strain has been developed that expresses low levels of the NRI subunit of the NMDA receptor. These mice are a model of chronic developmental NMDA receptor hypofunction and may therefore have relevance to the hypothesized NMDA receptor hypofunction in schizophrenia. Many schizophrenia patients show exaggerated behavioral and neuronal responses to amphetamine compared to healthy subjects. Studies were designed to determine if the NRI -deficient mice would exhibit enhanced sensitivity to amphetamine. Effects of amphetamine on behavioral activation and Fos induction were compared between the NRI-deficient mice and wild-type controls. The NRI hypomorphic mice and controls exhibited similar locomotor activation after administration of amphetamine at 2 mg/kg. The mutant mice showed slightly reduced peak locomotor activity and slightly increased stereotypy after 4 mg/kg amphetamine. There were no differences in Fos induction in response to amphetamine in the caudate putamen, nucleus accumbens, medial or central amygdala nuclei, or bed nucleus of the stria terminalis. However, amphetamine-induced Fos was substantially attenuated in the medial frontal (infralimbic) and cingulate cortices, basolateral amygdala, and in the lateral septum of the mutant mice. The results suggest a neuroanatomically selective activation deficit to amphetamine challenge in the NR I -deficient mice. [ABSTRACT FROM AUTHOR]

The article discusses several studies which investigate how brain of mammals stores and retrieves context-dependent memory. It says that studies have used transgenic mice to express the transcriptional activator tTA under the control of the promoter of the direct gene Fos. It states that the two groups of researchers two methodological genetic approaches as combined with a memory-learning paradigm called contextual fear conditioning.