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Glutamatergic signals in the dorsal raphe nucleus (DRN) regulate maternal aggression and care in mice. We examined whether glutamatergic input from the medial prefrontal cortex (mPFC) to the DRN might regulate maternal aggression and care in mice. In the maternal aggression test, each dam was exposed to an identical intruder male twice for 5 min, 60 min apart. During the latter trial (opt trial), the terminals of glutamatergic neurons from the mPFC to the DRN were manipulated using optogenetic techniques. Compared to the former trial (pre-opt trial), the inhibition of glutamatergic input in the opt trial decreased bite frequency and prevented the shortening of biting latency. In contrast, the activation of glutamatergic input at 5 Hz increased the biting frequency. Meanwhile, the activation of glutamatergic input at 1, 10, and 20 Hz prevented the shortening of biting latency without affecting biting frequency. In the maternal care test, activation of glutamatergic input at 5 Hz did not affect maternal care. Our results suggest that glutamatergic neurons from the mPFC to the DRN differently regulate maternal aggression, depending on temporal patterns of their activation, and that the glutamatergic signals that enhance maternal aggression are not involved in the regulation of maternal care. • Inhibition of the mPFC glutamatergic input into the DRN suppresses biting behavior. • Optogenetic activation of the glutamatergic inputs at 5 Hz enhances biting behavior. • The mPFC glutamatergic input into the DRN does not affect maternal care. [ABSTRACT FROM AUTHOR]

Abstract Lactating female mice nurture their pups and attack intruders in their territory. When an intruder invades a dam's territory, she needs to switch her behavior from care to aggression to protect her pups and territory. Although the neuronal mechanisms underlying each distinct behavior have been studied, it is unclear how these behaviors are displayed alternatively. The dorsal raphe nucleus (DRN) regulates both nurturing and aggressive behaviors. In the present study, we examined whether the DRN is involved in regulating alternative display of maternal care and aggression. We first examined neuronal activity in the medial prefrontal cortex (mPFC) and lateral habenula (LHb), which send glutamatergic input to the DRN, in dams by injecting Fluorogold, a retrograde tracer, into the DRN. The number of c-Fos- and Fluorogold-positive neurons in the mPFC and LHb increased in the dams that displayed biting behavior in response to an intruder, but remained unchanged in the dams that displayed nurturing behavior. Injections of N-methyl- d -aspartic acid (NMDA) receptor antagonists or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate receptor antagonists into the DRN inhibited biting behavior but not nurturing behavior. In contrast, injections of NMDA or AMPA into the DRN inhibited nurturing behavior. These results suggest that glutamatergic signals in the DRN, which may originate from the mPFC and/or LHb, regulate the preferential display of biting behavior over nurturing behavior in dams. [ABSTRACT FROM AUTHOR]

Animals consume energy for reproduction, as well as survival. Excess or insufficient energy investment into reproduction, respectively, threatens the survival of parents or leads to the failure of reproduction. Management of energy consumption in reproduction is important, not only for the success of the process, but also for the survival of the parents. Reproductive behaviors, such as mating and parental behavior, are indispensable for achieving each event of reproduction including gametogamy, parturition, and lactation. Therefore, reproductive behavior is one of the important factors in managing energy consumption for reproduction. Orexigenic and anorexigenic molecules in the hypothalamus have been implicated in the regulation of reproductive functions. An orexigenic neuropeptide, neuropeptide Y (NPY), has been also implicated in the regulation of both reproduction and energy state of animals. In this review, we will first summarize the neuronal mechanism for regulating reproductive functions by orexigenic and anorexigenic molecules in the hypothalamus. Second, we will focus on the NPY neuronal pathways regulating reproductive behavior in the intra- and extra-hypothalamic brain areas. We will highlight the NPY neuronal pathway from the arcuate nucleus to the dorsal raphe nucleus as a novel extra-hypothalamic pathway for energy state-dependent regulation of reproductive behavior. Finally, we will propose a biological significance of the extra-hypothalamic NPY neuronal pathway, which plays an important role in the associative control of feeding and reproductive behaviors. [ABSTRACT FROM AUTHOR]

Drinking behavior is regulated by endogenous factors such as the hydration condition of animals and exogenous factors such as the taste of ingested fluids. These factors have been suggested to interact with each other via serotonergic (5-HT) signaling to regulate drinking behavior. In the present study, we examined how dehydration affects the intake of bitter water, which suppresses drinking behavior, via 5-HT signaling. Water deprivation increased water intake for 1 h, depending on the duration of water deprivation. The intake of 1 mM quinine, which is a bitter tastant, was lower than that of water in mice deprived of water for 24 h but not 48 h. We next examined the involvement of the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN), which contain a large population of 5-HT neurons, in changing tolerance for quinine intake after water deprivation. The intake of quinine following water deprivation for 24 h, but not 48 h, increased the number of tryptophan hydroxylase-positive neurons expressing c-Fos in the DRN, but not in the MRN. Moreover, administration of paroxetine, a selective serotonin reuptake inhibitor, decreased the intake of quinine solution, but not water, in mice deprived of water for 48 h, indicating that paroxetine treatment restored the aversion to quinine. These results suggest that unresponsiveness of 5-HT neurons in the DRN may be involved in the dehydration-induced increase in tolerance for bitter water. [ABSTRACT FROM AUTHOR]

Maternal care is indispensable for the survival of mammalian offspring. Although virgin female mice avoid pups, they actively display maternal behavior after parturition. To determine which brain regions are involved in the qualitative differences observed in the responses of virgin and lactating females to pups, we compared the expression of c-Fos, which is a marker of neuronal activation, in brain regions involved in regulating maternal behavior. Pup presentation increased the number of c-Fos-positive cells in both the ventrotegmental area (VTA) and nucleus accumbens to a greater extent in lactating females than in virgin females. The bed nucleus of striaterminalis (BNST), which innervates VTA neurons to regulate both aversive and rewarding responses, showed increased number of c-Fos-positive cells following pup presentation in virgin females, butnotin lactating females. On the other hand, the number of c-Fos-positive cells in the medial preoptic area (MPOA) increased in both virgin and lactating females. The number of c-Fos-positive cells in lactating females not presented with pups was high and similar to that in virgin females presented with pups. Moreover, c-Fos-positive GABAergicneurons projecting from the MPOA to the BNST was confirmed using a retrograde tracer Fluorogold in lactating females. Our results indicate that constitutive GABAergic modulation projecting from the MPOA may suppress the activity of BNST neurons and prevent avoidance responses to pups in lactating females. [ABSTRACT FROM AUTHOR]

Summary Lactation is indispensable for the survival of mammalian pups. However, any excess of energy expenditure for lactation over energy intake threatens the mother's survival. Here, we report that an orexigenic molecule, neuropeptide Y (NPY), mediates nutritional state-dependent regulation of maternal behavior. After 9 h of fasting, dams showed a dramatic decrease in the expression of maternal behavior. Intracerebroventricular or direct dorsal raphe nucleus (DRN) injection of NPY inhibited the expression of maternal behavior in non-fasted dams. In contrast, injection of the NPY Y1 receptor antagonist BIBP-3226 into the DRN, in which the expression of the Y1 receptor was confirmed in serotonergic (5-HT) and GABAergic interneurons, recovered the expression of maternal behavior in fasted dams. When the pups were presented, the increase in the number of c-Fos-positive GABAergic, but not serotonergic, neurons was smaller in fasted than in non-fasted dams. These results suggest that NPY may inhibit pup-induced activation of GABAergic neurons via the Y1 receptor. Injection of a 5-HT 1A agonist, GABA A receptor antagonist, or GABA B receptor antagonist into the DRN induced incomplete maternal behavior in non-fasted dams. In contrast, each of a 5-HT 2A receptor agonist or a GABA B receptor agonist, but not a GABA A receptor agonist, recovered separate components of maternal behavior in fasted dams. These results suggest that NPY inhibits both 5-HT neuronal activity and its modulation via the GABA receptor in the DRN, resulting in the suppression of maternal behavior under food-restricted conditions. [ABSTRACT FROM AUTHOR]

Abstract: Aims: In the present study, we found that saccharin, an artificial calorie-free sweetener, promotes neurite extension in the cultured neuronal cells. The purposes of this study are to characterize the effect of saccharine on neurite extension and to determine how saccharin enhances neurite extension. Main methods: The analyses were performed using mouse neuroblastoma N1E-115 cells and rat pheochromocytoma PC12 cells. Neurite extension was evaluated by counting the cells bearing neurites and measuring the length of neurites. Formation, severing and transportation of the microtubules were evaluated by immunostaining and western blotting analysis. Key findings: Deprivation of glucose increased the number of N1E-115 cells bearing long processes. And the effect was inhibited by addition of glucose. Saccharin increased the number of these cells bearing long processes in a dose-dependent manner and total neurite length and longest neurite length in each cell. Saccharin also had a similar effect on NGF-treated PC12 cells. Saccharin increased the amount of the microtubules reconstructed after treatment with nocodazole, a disruptor of microtubules. The effect of saccharin on microtubule reconstruction was not influenced by dihydrocytochalasin B, an inhibitor of actin polymerization, indicating that saccharin enhances microtubule formation without requiring actin dynamics. In the cells treated with vinblastine, an inhibitor of microtubule polymerization, after microtubule reorganization, filamentous microtubules were observed more distantly from the centrosome in saccharin-treated cells, indicating that saccharin enhances microtubule severing and/or transportation. Significance: These results suggest that saccharin enhances neurite extension by promoting microtubule organization. [Copyright &y& Elsevier]

Abstract: Olfaction plays an important role in animal communication. We hypothesized that males recognize the attractive volatile odors attributed to female reproductive ability. We measured the period during which a male mouse spent sniffing volatile odors from a sham-operated female mouse or an ovariectomized mouse without visual or tactile contact. Intact male mice spent more time sniffing volatile odors from proestrous, estrous or metestrous females than from ovariectomized females. There was no difference in castrated male mice. To investigate the involvement of sexual hormone in this behavior, castrated male mice were treated with 17 α-estradiol (E), dihydrotestosterone (DHT), or both. E-treatment did not affect sniffing behavior. Regardless of the estrous stages, DHT-treated castrated males spent less time sniffing the volatile odors from sham-operated than from ovariectomized female mice. Both E- and DHT-treated castrated males spent less time sniffing the volatile odors from proestrous or estrous females than from ovariectomized females. These results suggest that neither androgen nor estrogen is sufficient for reproducing male attraction to volatile female mouse odors, and that androgen signaling has a competitive effect against the attraction. [Copyright &y& Elsevier]

• Juvenile mice, over the age of 14-days, can induce biting behavior in dams. • Consumption of food pellets does not affect the induction of biting behavior. • The frequency of biting behavior depends on the strain of the dams and intruders. • Body hair around the proximal tail contains the aggression-inducible chemical cues. Maternal care and aggression are representative of maternal behavior among lactating female mice. Even neonates and juveniles, who are not biological offspring, can induce maternal care and aggression in dams. Here, we investigated the factors that induce maternal aggression through exposure to juvenile mice. We first addressed the role of intruder age on the induction of maternal aggression in dams. BALB/c dams displayed attacking behavior towards 14-day-old C57BL/6J male intruders. Consumption of food pellets during the weaning period was unlikely to affect the induction of attacking behavior, as the intruders reared by breastfeeding, without food pellets, induced intensive attacking behavior in dams. Next, we compared the intruder-mediated induction of attacking behavior through different mouse strains. Specifically, BALB/c intruders induced a lower level of attacking behavior in BALB/c or ICR dams, compared to the other strains tested. However, BALB/c intruders induced intense attacking behavior in C57BL/6N dams, indicating that the occurrence of attacking behavior is dependent on the strains of dams as well as intruders. A cross-fostering experiment highlighted that the rearing by an original mother was required for C57BL/6J juveniles to induce attacking behavior. In contrast, BALB/c intruders may emit an inhibitory factor that limits attacking behavior. We finally explored which parts of the body emit these aggression-inducible signals. Removal of body hair around the proximal tail of the intruders significantly decreased the attacking behavior of dams, demonstrating that chemical cues, namely pheromones, attached to the body hair around the proximal tail may be essential for inducing attacking behavior in dams. [ABSTRACT FROM AUTHOR]

Aims Bilateral lesions of the mesencephalic trigeminal sensory nucleus (Me5), which receives histaminergic neurons from the tuberomammillary nucleus (TMN), alter nocturnal feeding and related behaviors in mice, concomitant with a decrease in orexin mRNA level in the perifornical area (PFA) during the dark phase. Therefore, we investigated the neuronal input to the TMN from the Me5, as well as the effects of TMN lesions on the circadian profiles of feeding and related behaviors. Main methods We examined the presence of neurons projecting from the Me5 to the TMN by direct injection of a retrograde tracer, Fluorogold, into the TMN E2 sub-region (TMN-E2). We also assessed feeding, drinking, and locomotion for 24 h using an automated feeding behavior measurement apparatus, and analyzed the hypothalamic orexin mRNA levels in both TMN-lesion and sham-operated mice. Key findings The presence of neuronal projections from the Me5 to the TMN-E2 was confirmed. A decrease in food and water intake and locomotion during the latter half of the dark phase was delayed in TMN-lesion but not sham-operation mice. Further, orexin mRNA expression levels were higher in both the PFA and lateral hypothalamus area (LHA) in TMN-E2-lesion mice relative to control mice, during the early half of the dark phase compared with the light phase. Significance Our results suggest that histaminergic neurons in the TMN-E2 receive signals from the Me5 that modulate a switch from dark to light phase feeding and related behaviors, which in turn may be regulated by orexin neurons in the PFA and/or LHA. [ABSTRACT FROM AUTHOR]

Aims Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DAergic) neurons in the substantia nigra pars compacta (SNpc). In PD, thinking and retrieval deficits often arise from cognitive impairments. However, the mechanism of cognitive disorders in PD remains unknown. Therefore, we investigated cognitive function in PD model mice produced by intraperitoneal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which specifically destroys the DAergic neurons in the SNpc. Main methods We evaluated the cognitive function of MPTP-treated mice (PD mice) using the contextual fear conditioning test. In the test, each experiment consists of three phases: training, re-exposure, and testing. Mice were trained with a foot shock (a weak unconditioned stimulus: 1 mA/2 s duration, once, or an intense unconditioned stimulus: 2 mA/2 s duration, twice), and 24 h later, mice were re-exposed to the training context for 3 min to determine reconsolidation or 30 min to determine extinction. The percentage of time spent freezing was measured during the test session as indexes of memory consolidation, reconsolidation, and extinction. Key findings Reconsolidation of PD mice occurred normally but memory extinction was facilitated in PD mice compared to control mice. Moreover, memory retention in PD mice was attenuated earlier than in controls following repeated conditioned stimuli every day. Significance PD mice with selective loss of DAergic neurons in the SNpc showed attenuated memory retention, probably via facilitated extinction learning. [ABSTRACT FROM AUTHOR]

Abstract: Aims: The mesencephalic trigeminal sensory nucleus (Me5), which receives signals originating from oral proprioceptors and projects its fibers to the hypothalamus, regulates mastication and modulates satiation. Because the Me5 neurons display circadian rhythms in circadian mPer1 gene expression and bilateral Me5 lesions change feeding and exploratory behavior profiles, we speculated that Me5 may influence the daily timing of feeding. Therefore, we explored the effects of bilateral caudal Me5 lesions on the circadian profiles of feeding and its related behaviors. Main methods: We measured the activities of feeding, drinking, and locomotion for 24h using an automated feeding behavior measurement apparatus and analyzed the mRNA expression levels of hypothalamic orexigenic and anorexigenic signaling molecules in both Me5-lesioned and sham-operated mice. Key findings: Food and water intake and locomotor activity decreased significantly in Me5-lesioned mice during the dark phase without affecting these total indexes when measured over the entire day. Analysis of the mRNA expression levels of hypothalamic orexigenic and anorexigenic signaling molecules showed that prepro-orexin (orexin) mRNA in the perifornical area was significantly decreased during the dark phase only in Me5-lesioned mice. Significance: Bilateral caudal Me5 lesions alter the nocturnal properties of food and water intake and locomotor activity in mice and decrease the mRNA expression level of orexin in the perifornical area during the dark phase. These results suggest that Me5 activity may influence the nocturnal properties of feeding and its related behaviors by adjusting the activity of orexin neurons in the perifornical area. [Copyright &y& Elsevier]

Integrin-linked kinase (ILK) is a focal adhesion serine/ threonine protein kinase with an important role in integrin and growth factor signaling pathways. Recently, we demonstrated that ILK is expressed in N1E-115 neuroblastoma cells and controls integrin-dependent neurite outgrowth in serum-starved cells grown on laminin (Ishii, T., Satoh, E., and Nishimura, M. (2001) J. Biol. Chem. 276, 42994-43003). Here we report that ILK controls tau phosphorylation via regulation of glycogen synthase kinase-3β (GSK-3β) activity in N1E-115 cells. Stable transfection of a kinase-deficient ILK mutant (DN-ILK) resulted in aberrant tau phosphorylation in N1E-115 cells at sites recognized by the Tau-1 antibody that are identical to some of the phosphorylation sites in paired helical filaments, PHF-tau, in brains of patients with Alzheimer's disease. The tau phosphorylation levels in the DN-ILK-expressing cells are constant under normal and differentiating conditions. On the other hand, aberrant tau phosphorylation was not observed in the parental control cells. ILK inactivation resulted in an increase in the active form but a decrease in the inactive form of GSK-3β, which is a candidate kinase involved in PHF-tau formation. Moreover, inhibition of GSK-3β with lithium prevented aberrant tau phosphorylation in the DN-ILK-expressing cells. These results suggest that ILK inactivation results in aberrant tau phosphorylation via sustained activation of GSK-3β in N1E-115 Cells. ILK directly phosphorylates GSK-3β and inhibits its activity. Therefore, endogenous ILK protects against GSK-3β-induced aberrant tau phosphorylation via inhibition of GSK-3β activity in N1E-115 cells. [ABSTRACT FROM AUTHOR]

Highlights: [•] Cattle were immunized with M3-NcGRA7. [•] M3-NcGRA7 induced antigen-specific antibody and IFN-γ production from the PBMC. [•] M3-NcGRA7 vaccination reduced parasite load in the brain. [•] M3-NcGRA7 (50μg antigen) vaccination induced protective immune responses in cattle. [Copyright &y& Elsevier]

Abstract: Previously, we have found that post-weaning mice fed exclusively milk display low-frequency exploratory behavior compared to mice fed a food pellet diet (). Because cognitive functions play a key role in animal exploration, in the present study we examined the effect of an exclusively milk formula diet on spatial learning and memory in a water maze and also on induction of long-term potentiation (LTP) and long-term depression (LTD) at the Schaffer collateral-CA1 synapse in the hippocampus. Exclusively milk-fed mice exhibited slower learning and memory deficits in hidden water maze tests as compared with pellet-fed mice. Moreover, milk-fed mice showed a significant inhibition of LTD but a normal induction of LTP. Despite these functional deficits, adult neurogenesis in the dentate gyrus of the hippocampus, which has been proposed to have a causal relationship to spatial memory, was stimulated in milk-fed mice. These result suggest that an exclusively milk formula diet after weaning leads to a stimulation of hippocampal neurogenesis but causes deficits in the induction of LTD in the CA1 hippocampal region and impairment of spatial learning and memory. [Copyright &y& Elsevier]

Abstract: The mesencephalic trigeminal sensory nucleus (Me5), which receives signals originating from oral proprioceptors, becomes active at weaning and contributes to the acquisition of active exploratory behavior [Ishii, T., Furuoka, H., Kitamura, N., Muroi, Y., and Nishimura, M. (2006) Brain Res. 1111, 153–161]. Because cognitive functions play a key role in animal exploration, in the present study we assessed the role of Me5 in spatial learning and memory in the water maze. Mice with bilateral Me5 lesions exhibited severe deficits in both a reversal learning and a reversal probe test compared with sham-operated mice. In spite of these reversal tests, Me5 lesions had no effect on a hidden platform test. These results suggest that Me5-lesioned mice show a perseveration of the previously learned spatial strategy rather than an inability to learn a new strategy, resulting in reduced spatial memory resetting. Moreover, adult neurogenesis in the dentate gyrus of the hippocampus, which has been proposed to have a causal relationship to spatial memory, was stimulated in Me5-lesioned mice. Thus, a stimulation of hippocampal neurogenesis observed after Me5 lesions may lead to a rigidity and perseverance of the previously learned strategy because of inferential overuse of past memories in a novel situation. These results suggest that Me5 contributes to spatial memory resetting by controlling the rate of hippocampal neurogenesis through an ascending neuronal pathway to the hippocampus. [Copyright &y& Elsevier]

Abstract: Post-weaning mice fed exclusively milk display low-frequency exploratory behavior [Ishii, T., Itou, T., and Nishimura, M. (2005) Life Sci. 78, 174–179] compared to mice fed a food pellet diet. This low-frequency exploratory behavior switched to high-frequency exploration after a switch from exclusively milk formula to a food pellet diet. Acquisition of the high-frequency exploratory behavior was irreversible. Recently, we demonstrated that the mesencephalic trigeminal nucleus (Me5) is involved in the control of feeding and exploratory behavior in mice without modulating the emotional state [Ishii, T., Furuoka, H., Itou, T., Kitamura, N., and Nishimura, M. (2005) Brain Res. 1048, 80–86]. We therefore investigated whether the Me5 is involved in acquisition of high-frequency exploratory behavior induced by the switch in diet from an exclusively milk formula to food pellets. Mouse feeding and exploratory behaviors were analyzed using a food search compulsion apparatus, which was designed to distinguish between the two behaviors under standard living conditions. Immunohistochemical analysis of immediate early genes indicated that the Me5, which receives signals from oral proprioceptors, is transiently activated after the diet change. The change from low-frequency to high-frequency exploratory behavior was prevented in milk-fed mice by bilateral lesion of the Me5. These results suggest that the Me5 is activated by signals associated with mastication-induced proprioception and contributes to the acquisition of active exploratory behavior. [Copyright &y& Elsevier]