MSK1 is required for the beneficial synaptic and cognitive effects of enriched experience across the lifespan.

Positive experiences, such as social interaction, cognitive training and physical exercise, have been shown to ameliorate some of the harms to cognition associated with ageing. Animal models of positive interventions, commonly known as environmental enrichment, strongly influence neuronal morphology and synaptic function and enhance cognitive performance. While the profound structural and functional benefits of enrichment have been appreciated for decades, little is known as to how the environment influences neurons to respond and adapt to these positive sensory experiences. We show that adult and aged male wild-type mice that underwent a 10-week environmental enrichment protocol demonstrated improved performance in a variety of behavioural tasks, including those testing spatial working and spatial reference memory, and an enhancement in hippocampal LTP. Aged animals in particular benefitted from enrichment, performing spatial memory tasks at levels similar to healthy adult mice. Many of these benefits, including in gene expression, were absent in mice with a mutation in an enzyme, MSK1, which is activated by BDNF, a growth factor implicated in rodent and human cognition. We conclude that enrichment is beneficial across the lifespan and that MSK1 is required for the full extent of these experience-induced improvements of cognitive abilities, synaptic plasticity and gene expression.

Emerging roles of brain metabolism in cognitive impairment and neuropsychiatric disorders.

Here we discuss the role of diverse environmental manipulations affecting cognition with special regard to psychiatric conditions. We present evidence supporting a direct causal correlation between the valence of the environmental stimulation and some psychopathological traits and how the environment influences brain structure and function with special regard to oxidative stress and mitochondrial activity. Increasing experimental evidence supports a role for mitochondrial dysfunctions in neuropsychiatric disorders. Brain mitochondria are considered crucial mediators of allostasis, that is the capability to adapt to stress via a complex interaction between the autonomic, metabolic, and immune systems to maintain cellular homeostasis. In this process, mitochondria act as highly dynamic integrators by sensing and transducing stressors into adaptation mechanisms via metabolic stress mediators, such as glucocorticoids and catecholamines. Alterations in cellular homeostasis induced by chronic stress are thought to predispose to disease by triggering the so-called "mitochondrial allostatic load". This process is characterized by functional and structural changes of the mitochondria, ultimately leading to oxidative stress, inflammation, mitochondrial DNA damage and apoptosis. In this review we discuss the role of diverse environmental manipulations to affect cognition with special regard to psychiatric conditions. How the environment influences brain structure and function, and the interactions between rearing conditions, oxidative stress and mitochondrial activity are fundamental questions that are still poorly understood. As will be discussed, increasing experimental evidence supports a role for mitochondrial dysfunctions in neuropsychiatric disorders. Brain mitochondria are considered crucial mediators of allostasis, that is the capability to adapt to stress via a complex interaction between the autonomic, metabolic, and immune systems to maintain cellular homeostasis. In this process, mitochondria act as highly dynamic integrators by sensing and transducing stressors into adaptation mechanisms via metabolic stress mediators, such as glucocorticoids and catecholamines. Alterations in cellular homeostasis induced by chronic stress are thought to predispose to disease by triggering the so-called "mitochondrial allostatic load". This process is characterized by functional and structural changes of the mitochondria, ultimately leading to oxidative stress, inflammation, mitochondrial DNA damage and apoptosis. The brain requires considerable mitochondrial reserve not only to sustain basal neuronal needs but also to provide increasing energy demands during stress. Consistently with these high energetic requirements, it is reasonable to hypothesise that the brain is particularly vulnerable to mitochondrial defects. Thus, even subtle metabolic alterations might have a substantial impact on cognitive functions. Over the last decade, several experimental evidence supported the hypothesis that a suboptimal mitochondrial function, which could be of genetic origin or acquired following adverse life events, is a key vulnerability factor for stress-related psychopathologies. Chronic psychological stress is a major promoter of anxiety as well as of oxidative damage, as shown in several studies. Recent evidence from mouse models harbouring mutations in mitochondrial genes demonstrated the role of mitochondria in modulating the response to acute psychological stress. However, it has yet to be determined whether mitochondrial dysfunctions are the cause or the consequence of anxiety. In this review, we discuss how adverse psychosocial environments can impact mitochondrial bioenergetics at the molecular level and we gather evidence from several studies linking energy metabolism and stress resilience/vulnerability. Moreover, we review recent findings supporting that metabolic dysfunction can underlie deficits in complex social behaviours. As will be discussed, aberrations in mitochondrial functionality have been found in the nucleus accumbens of highly anxious mice and mediate low social competitiveness. In addition, alterations in sociability can be reversed by enhancing mitochondrial functions. Recent evidence also demonstrated that a specific mutation in mitochondrial DNA, previously linked to autism spectrum disorder, produces autistic endophenotypes in mice by altering respiration chain and reactive oxygen species (ROS) production. Finally, we discuss a "Negative Enrichment" model that can explain some of the psychopathological conditions relevant to humans. Evidence of a direct causal correlation of valence of environmental stimulation and psychopathological traits will be presented, and possible molecular mechanisms that focus on oxidative stress. Collectively, the findings described here have been achieved with a wide set of behavioural and cognitive tasks with translational validity. Thus, they will be useful for future work aimed to elucidate the fine metabolic alterations in psychopathologies and devise novel approaches targeting mitochondria to alleviate these conditions.

CREB serine 133 is necessary for spatial cognitive flexibility and long-term potentiation.

The transcription factor cAMP response element-binding protein (CREB) is widely regarded as orchestrating the genomic response that underpins a range of physiological functions in the central nervous system, including learning and memory. Of the means by which CREB can be regulated, emphasis has been placed on the phosphorylation of a key serine residue, S133, in the CREB protein, which is required for CREB-mediated transcriptional activation in response to a variety of activity-dependent stimuli. Understanding the role of CREB S133 has been complicated by molecular genetic techniques relying on over-expression of either dominant negative or activating transgenes that may distort the physiological role of endogenous CREB. A more elegant recent approach targeting S133 in the endogenous CREB gene has yielded a mouse with constitutive replacement of this residue with alanine (S133A), but has generated results (no behavioural phenotype and no effect on gene transcription) at odds with contemporary views as to the role of CREB S133, and which may reflect compensatory changes associated with the constitutive mutation. To avoid this potential complication, we generated a post-natal and forebrain-specific CREB S133A mutant in which the expression of the mutation was under the control of CaMKIIα promoter. Using male and female mice we show that CREB S133 is necessary for spatial cognitive flexibility, the regulation of basal synaptic transmission, and for the expression of long-term potentiation (LTP) in hippocampal area CA1. These data point to the importance of CREB S133 in neuronal function, synaptic plasticity and cognition in the mammalian brain.

Mitogen and Stress-activated Protein Kinase 1 Negatively Regulates Hippocampal Neurogenesis.

Neurogenesis in the subgranular zone (SGZ) of the adult hippocampus can be stimulated by a variety of means, including via exposure of experimental animals to an enriched environment that provides additional sensory, social, and motor stimulation. Tangible health and cognitive benefits accrue in enriched animals, including the amelioration of signs modelling psychiatric, neurological and neurodegenerative conditions that affect humans, which may in part be due to enhanced production of neurons. A key factor in the neuronal response to enrichment is the release of brain-derived neurotrophic factor (BDNF) and the activation of the Mitogen-Activated Protein Kinase (MAPK) cascade, which can lead to the stimulation of neurogenesis. Mitogen- and Stress-Activated protein Kinase 1 (MSK1) is a nuclear enzyme downstream of BDNF and MAPK that regulates transcription. MSK1 has previously been implicated in both basal and stimulated neurogenesis on the basis of studies with mice lacking MSK1 protein. In the present study, using mice in which only the kinase activity of MSK1 is lacking, we show that the rate of cellular proliferation in the SGZ (Ki-67 staining) is unaffected by the MSK1 kinase-dead (KD) mutation, and no different from controls levels after five weeks of enrichment. However, compared to wild-type mice, the number of doublecortin (DCX)-positive cells was greater in both standard-housed and enriched MSK1 KD mice. These observations suggest that, while MSK1 does not influence the basal rate of proliferation of neuronal precursors, MSK1 negatively regulates the number of cells destined to become neurons, potentially as a homeostatic control on the number of new neurons integrating into the dentate gyrus.

Experience Recruits MSK1 to Expand the Dynamic Range of Synapses and Enhance Cognition.

Experience powerfully influences neuronal function and cognitive performance, but the cellular and molecular events underlying the experience-dependent enhancement of mental ability have remained elusive. In particular, the mechanisms that couple the external environment to the genomic changes underpinning this improvement are unknown. To address this, we have used male mice harboring an inactivating mutation of mitogen- and stress-activated protein kinase 1 (MSK1), a brain-derived neurotrophic factor (BDNF)-activated enzyme downstream of the mitogen-activated protein kinase (MAPK) pathway. We show that MSK1 is required for the full extent of experience-induced improvement of spatial memory, for the expansion of the dynamic range of synapses, exemplified by the enhancement of hippocampal long-term potentiation (LTP) and long-term depression (LTD), and for the regulation of the majority of genes influenced by enrichment. In addition, and unexpectedly, we show that experience is associated with an MSK1-dependent downregulation of key MAPK and plasticity-related genes, notably of EGR1/Zif268 and Arc/Arg3.1, suggesting the establishment of a novel genomic landscape adapted to experience. By coupling experience to homeostatic changes in gene expression MSK1, represents a prime mechanism through which the external environment has an enduring influence on gene expression, synaptic function, and cognition.SIGNIFICANCE STATEMENT Our everyday experiences strongly influence the structure and function of the brain. Positive experiences encourage the growth and development of the brain and support enhanced learning and memory and resistance to mood disorders such as anxiety. While this has been known for many years, how this occurs is not clear. Here, we show that many of the positive aspects of experience depend on an enzyme called mitogen- and stress-activated protein kinase 1 (MSK1). Using male mice with a mutation in MSK1, we show that MSK1 is necessary for the majority of gene expression changes associated with experience, extending the range over which the communication between neurons occurs, and for both the persistence of memory and the ability to learn new task rules.

A proteomic signature for CNS adaptations to the valence of environmental stimulation.

Environmental Enrichment leads to a significant improvement in long-term performance across a range of cognitive functions in mammals and it has been shown to produce an increased synaptic density and neurogenesis. Nevertheless it is still an open question as to whether some key aspects of spatial learning & memory and procedural learning might be embodied by different molecular pathways to those of social cognition. Associated with synaptic changes and potentially underlying conditions, the Ras-ERK pathway has been proposed to be the primary mediator of in vivo adaptations to environmental enrichment, acting via the downstream Ras-ERK signalling kinase MSK1 and the transcription factor CREB. Herein, we show that valence of environmental stimulation increased social competition and that this is associated with a specific proteomic signature in the frontal lobe but notably not in the hippocampus. Specifically, we show that altering the valence of environmental stimuli affected the level of social competition, with mice from negatively enriched environments winning significantly more encounters-even though mice from positive were bigger and should display dominance. This behavioural phenotype was accompanied by changes in the proteome of the fronto-ventral pole of the brain, with a differential increase in the relative abundance of proteins involved in the mitochondrial metabolic processes of the TCA cycle and respiratory processes. Investigation of this proteomic signature may pave the way for the elucidation of novel pathways underpinning the behavioural changes caused by negative enrichment and further out understanding of conditions whose core feature is increased social competition.

Enhancing cognition through pharmacological and environmental interventions: Examples from preclinical models of neurodevelopmental disorders.

In this review we discuss the role of environmental and pharmacological treatments to enhance cognition with special regards to neurodevelopmental related disorders and aging. How the environment influences brain structure and function, and the interactions between rearing conditions and gene expression, are fundamental questions that are still poorly understood. We propose a model that can explain some of the discrepancies in findings for effects of environmental enrichment on outcome measures. Evidence of a direct causal correlation of nootropics and treatments that enhanced cognition also will be presented, and possible molecular mechanisms that include neurotrophin signaling and downstream pathways underlying these processes are discussed. Finally we review recent findings achieved with a wide set of behavioral and cognitive tasks that have translational validity to humans, and should be useful for future work on devising appropriate therapies. As will be discussed, the collective findings suggest that a combinational therapeutic approach of environmental enrichment and nootropics could be particularly successful for improving learning and memory in both developmental disorders and normal aging.

The Kinase Function of MSK1 Regulates BDNF Signaling to CREB and Basal Synaptic Transmission, But Is Not Required for Hippocampal Long-Term Potentiation or Spatial Memory.

The later stages of long-term potentiation (LTP) in vitro and spatial memory in vivo are believed to depend upon gene transcription. Accordingly, considerable attempts have been made to identify both the mechanisms by which transcription is regulated and indeed the gene products themselves. Previous studies have shown that deletion of one regulator of transcription, the mitogen- and stress-activated kinase 1 (MSK1), causes an impairment of spatial memory. Given the ability of MSK1 to regulate gene expression via the phosphorylation of cAMP response element binding protein (CREB) at serine 133 (S133), MSK1 is a plausible candidate as a prime regulator of transcription underpinning synaptic plasticity and learning and memory. Indeed, prior work has revealed the necessity for MSK1 in homeostatic and experience-dependent synaptic plasticity. However, using a knock-in kinase-dead mouse mutant of MSK1, the current study demonstrates that, while the kinase function of MSK1 is important in regulating the phosphorylation of CREB at S133 and basal synaptic transmission in hippocampal area CA1, it is not required for metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD), two forms of LTP or several forms of spatial learning in the watermaze. These data indicate that other functions of MSK1, such as a structural role for the whole enzyme, may explain previous observations of a role for MSK1 in learning and memory.

Altered fronto-striatal functions in the Gdi1-null mouse model of X-linked Intellectual Disability.

RAB-GDP dissociation inhibitor 1 (GDI1) loss-of-function mutations are responsible for a form of non-specific X-linked Intellectual Disability (XLID) where the only clinical feature is cognitive impairment. GDI1 patients are impaired in specific aspects of executive functions and conditioned response, which are controlled by fronto-striatal circuitries. Previous molecular and behavioral characterization of the Gdi1-null mouse revealed alterations in the total number/distribution of hippocampal and cortical synaptic vesicles as well as hippocampal short-term synaptic plasticity, and memory deficits. In this study, we employed cognitive protocols with high translational validity to human condition that target the functionality of cortico-striatal circuitry such as attention and stimulus selection ability with progressive degree of complexity. We previously showed that Gdi1-null mice are impaired in some hippocampus-dependent forms of associative learning assessed by aversive procedures. Here, using appetitive-conditioning procedures we further investigated associative learning deficits sustained by the fronto-striatal system. We report that Gdi1-null mice are impaired in attention and associative learning processes, which are a key part of the cognitive impairment observed in XLID patients.

Loss of Either Rac1 or Rac3 GTPase Differentially Affects the Behavior of Mutant Mice and the Development of Functional GABAergic Networks.

Rac GTPases regulate the development of cortical/hippocampal GABAergic interneurons by affecting the early development and migration of GABAergic precursors. We have addressed the function of Rac1 and Rac3 proteins during the late maturation of hippocampal interneurons. We observed specific phenotypic differences between conditional Rac1 and full Rac3 knockout mice. Rac1 deletion caused greater generalized hyperactivity and cognitive impairment compared with Rac3 deletion. This phenotype matched with a more evident functional impairment of the inhibitory circuits in Rac1 mutants, showing higher excitability and reduced spontaneous inhibitory currents in the CA hippocampal pyramidal neurons. Morphological analysis confirmed a differential modification of the inhibitory circuits: deletion of either Rac caused a similar reduction of parvalbumin-positive inhibitory terminals in the pyramidal layer. Intriguingly, cannabinoid receptor-1-positive terminals were strongly increased only in the CA1 of Rac1-depleted mice. This increase may underlie the stronger electrophysiological defects in this mutant. Accordingly, incubation with an antagonist for cannabinoid receptors partially rescued the reduction of spontaneous inhibitory currents in the pyramidal cells of Rac1 mutants. Our results show that Rac1 and Rac3 have independent roles in the formation of GABAergic circuits, as highlighted by the differential effects of their deletion on the late maturation of specific populations of interneurons.

Acquisition of conditioned responding in a multiple schedule depends on the reinforcement's temporal contingency with each stimulus.

Forty mice acquired conditioned responses to stimuli presented in a multiple schedule with variable inter-trial intervals (ITIs). In some trials, reinforcement was preceded by a variable conditioned stimulus (CS), while other trials were reinforced following distinctive fixed-duration CS. A third stimulus was presented but never paired with reinforcement. Subjects in five groups experienced ITIs of different durations. Acquisition of responding to each stimulus depended only on the cycle-to-trial ratio (C/T), and thus on the temporal contingency of each stimulus. Acquisition was unaffected by whether CSs were of fixed or variable duration.

RAB GTPases and RAB-interacting proteins and their role in the control of cognitive functions.

A RAS-related class of small monomeric G proteins, the RAB GTPases, is emerging as of key biological importance in compartment specific directional control of vesicles formation, transport and fusion. Thanks to human genetic observation and to the consequent dedicated biochemical work, substantial progress has been made on the understanding of the role played by RAB GTPases and their effector proteins on neuronal development and the shaping of cognitive functions. This review is highlighting these initial elements to broaden the current scope of research on developmental cognitive deficits and take the point of view of RAB GTPases control on membrane transport in neurons and astrocytes.

Comparison of the mGlu(5) receptor positive allosteric modulator ADX47273 and the mGlu(2/3) receptor agonist LY354740 in tests for antipsychotic-like activity.

Recently, it has been proposed that activation of either metabotropic glutamate receptors e.g. mGlu(5) by positive allosteric modulators or stimulation of mGluR(2/3) receptors by agonists may offer new strategy in schizophrenia treatment. The aim of the present study was to compare the effect of mGlu(5) receptor positive allosteric modulator, ADX47273 (S-(4-Fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone), mGluR(2/3) agonist, LY354740 ((1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate) and selected neuroleptics in animal models for positive schizophrenia symptoms. ADX47273 (3 and 10mg/kgi.p.), the typical antipsychotic haloperidol (0.1 and 0.2mg/kgi.p.), the atypical antipsychotics aripiprazole (1.25-5mg/kgi.p.) and olanzapine (2.5 and 5mg/kgi.p.) all reduced amphetamine-induced hyperlocomotion in Sprague-Dawley rats, unlike the mGlu(2/3) receptor agonist LY354740 (1-10mg/kgi.p.). Interestingly, haloperidol (0.1 and 0.2mg/kgi.p.), aripiprazole (1.25-5mg/kgi.p.) and olanzapine (1.25-5mg/kgi.p.), but not ADX47273 (1-10mg/kgi.p.), all reduced spontaneous locomotion and rearings at doses effective against amphetamine-induced hyperlocomotion. This indicates that the effect of ADX47273 in combination with amphetamine may be specific, and also suggests a lack of sedative side effects. Moreover, ADX47273 (30mg/kgi.p.), haloperidol (0.1 and 0.2mg/kgi.p.) and aripiprazole (5 and 10mg/kgi.p.) reversed apomorphine (0.5mg/kgs.c.)-induced deficits of prepulse inhibition, whereas neither LY354740 (1-10mg/kgi.p.) nor olanzapine (1.25-5mg/kgi.p.) produced this effect. Lack of effect of olanzapine was unexpected and at present no convincing explanation can be provided. In conclusion, in selected rodent models for positive schizophrenia symptoms, ADX47273 showed better efficacy than LY354740.

Effects of a metabotropic glutamate receptor group II agonist LY354740 in animal models of positive schizophrenia symptoms and cognition.

It has been proposed that activation of metabotropic glutamate receptor subtype 2/3 (mGluR2/3) may induce both antipsychotic and anxiolytic effects. The aim of this study was to evaluate further the effect of the mGluR2/3 agonist, LY354740 [(+)-2-aminobicyclo(3.1.0)hexane-2,6-dicarboxylate monohydrate] in animal models relevant to both psychotic and cognitive impairment in schizophrenia. The elevated plus maze was used to select the doses for further experiments, LY354740 induced anxiolytic-like effects at doses of 3 and 10 mg/kg but not 1 mg/kg. At a dose of 10 mg/kg. LY354740 attenuated phencyclidine (PCP)-induced locomotor activity. Administered alone, it had no effect on horizontal activity, but at doses of 3 and 10 mg/kg, slightly decreased vertical activity (rearings). LY354740 (1-10 mg/kg intraperitoneally) affected neither prepulse inhibition in normal rats nor reversed the disruption of prepulse inhibition produced by PCP (2 mg/kg subcutaneously). Moreover, LY354740 (3-10 mg/kg) did not modify PCP-induced working memory deficits assessed in a spontaneous alternation task and had no effect on PCP-evoked amnesia in the passive avoidance test. LY354740 alone (3 and 10 mg/kg) induced working memory deficits, but had no effect on acquisition of passive avoidance. In conclusion, LY354740 was effective in models for anxiety and positive symptoms of schizophrenia but not in models for sensorimotor gating and cognitive impairment.

Therapeutically relevant plasma concentrations of memantine produce significant L-N-methyl-D-aspartate receptor occupation and do not impair learning in rats.

Subchronic treatment with memantine using osmotic pumps in male rats was used to verify whether plasma levels significantly blocking L-N-methyl-D-aspartate (NMDA) receptors (and shown previously to be neuroprotective) may impair learning. Treatment with 6.27, 12.5 and 18.8 mg/rat/day provided plasma levels of 1.03+/-0.08, 5.07+/-0.68 and 11.68+/-0.90 micromol/l. Only the lowest plasma level is therapeutically relevant and has previously been shown to be neuroprotective. Significant deficits in a passive avoidance task were only observed at the highest dose. Working memory, tested as spontaneous alternation in the cross maze, was impaired by the middle and highest doses, and these doses also induced hyperlocomotion. Microdialysis experiments with in-vivo recovery (27.4%) showed that infusion of memantine at 6.27 mg/rat/day (ca. 23 mg/kg/day) produced a concentration of 990+/-105 nmol/l in extracellular fluid. In-vivo NMDA receptor occupancy experiments demonstrated significant, dose-dependent receptor occupancy of 32.7 and 65.7% by memantine at the doses producing 1 and 5 micromol/l plasma levels, respectively. Moreover, acute administration (2.5 mg/kg intraperitoneally) of memantine to mature female rats produced approximately two-fold higher plasma levels than in young male rats. In conclusion, a dose of memantine which produces a plasma level (1 micromol/l) within the therapeutic range, reported previously to be neuroprotective, leads to intracellular brain levels similar to the affinity of memantine for NMDA receptors (receptor binding, patch clamp). This has been also extended by the experiments showing that at this plasma concentration, memantine occupies ca. 30% NMDA receptors in the brain and produces no cognitive impairment.

Investigation on tolerance development to subchronic blockade of mGluR5 in models of learning, anxiety, and levodopa-induced dyskinesia in rats.

In the present study, we evaluated the effects of subchronic blockade of mGluR5 by 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) on learning, anxiety and levodopa-induced dyskinesia in rats. In addition, we excluded the possibility that subchronic treatment produced pharmacokinetic changes using brain microdialysis. MTEP (5 mg/kg) impaired spatial learning in a radial maze task and contextual fear conditioning (CFC) when administered acutely, and the same effect was observed following a 4-day pre-treatment regime. Similarly, MTEP (5 mg/kg) exerted anxiolytic-like effects in CFC when given before the test whether administered after acute or sub-chronic treatment. Similarly, in levodopa-induced dyskinesia, sub-chronic (7 subsequent days) treatment with MTEP (5 mg/kg) resulted in a significant reduction in abnormal involuntary movements (AIMs), comparable to single acute administration. The data indicate that tolerance does not develop to the anxiolytic and antidyskinetic effects of mGluR5 antagonist MTEP at least at the used treatment mode and tested doses. However, at least at the doses tested, also no tolerance to the memory impairing effect of MTEP was observed. Depending on the indication and model, the amnesic effects of MTEP should be taken into account as a potential limitation, also after repetitive treatment.

Intra-female aggression in the mouse (Mus musculus domesticus) is linked to the estrous cycle regularity but not to ovulation.

Intraspecific communication between mice takes place mainly via urinary chemosignals or "pheromones". Pheromones can influence aggressive and reproductive behavior as well as the neuroendocrine condition of the recipient female mice via their olfactory system. In this study, reproductively cyclic mice in the estrus phase were used to test intraspecific agonistic aggressive behavior. Data were obtained also on the count of the eggs shed in the oviducts. The results showed that (i) individually housed female mice are more aggressive toward an intruder female mouse than grouped mice, (ii) mice in which the vomeronasal organ was removed show aggressive behavior intermediate between individually housed and grouped mice, and (iii) a within group analysis did not show a positive correlation between aggression and presence of shed eggs in the oviducts.

Comparison of the mGluR1 antagonist A-841720 in rat models of pain and cognition.

In the current study we compared the potency of the selective metabotropic glutamate receptor (mGluR1) antagonist A-841720 (7-Azepan-1-yl-4-dimethylamino-7H-9-thia-1,5,7-triaza-fluoren-8-one) in rodent models of pain with its effects in models of learning and memory, to obtain information regarding the therapeutic window of this compound. A-841720 significantly reduced formalin-induced behaviours and complete Freund's adjuvant (CFA)-induced tactile allodynia, starting at doses of 1 and 10 mg/kg, respectively. At the dose of 3 mg/kg, however, A-841720 significantly reduced the percentage of spontaneous alternations in a radial-maze task. In contextual-fear conditioning, A-841720, given at the dose of 10 mg/kg before acquisition, significantly reduced freezing behaviour tested 24 h later. In the same task, repeated treatment for 5 days did not reduce the impairing effect of the challenge dose, indicating a lack of tolerance development. In a passive-avoidance task, A-841720 at 10 mg/kg administered before acquisition, significantly reduced the latency to enter the dark box on the retention test. Given that complete Freund's adjuvant is a better measure of analgesia, these results indicate that the selective mGluR1 antagonist A-841720 has analgesic potential in a dose range at which it also produces memory impairments. This diminishes its therapeutic potential for the treatment of chronic pain.

Mouse major urinary proteins trigger ovulation via the vomeronasal organ.

The major urinary proteins are a species-specific complex of proteins excreted by male mice that influence the reproductive behavior and the neuroendocrine condition of female mice through the olfactory system. The aim of this work is to determine their influence on ovulation. The major urinary proteins isolated from the urine of adult male mice were voided of bound odorants, dissolved at a physiological concentration in urine of prepubertal mice, and put on the nostril of reproductively cycling female mice housed in groups, the first day of estrus at 1100. The eggs shed in the oviducts were counted under dissection the morning of the second day of estrus. The results showed that 1) a single stimulus of the major urinary proteins increased ovulation nearly as much as the whole urine of male mice, 2) the effect was not elicited by male rat urine which contains different proteins, 3) a peptide with four residues of the amino-terminal sequence of the major urinary proteins stimulated ovulation, and 4) mice that had been isolated or had the vomeronasal organ (VNO) removed did not respond to the major urinary proteins and had a high spontaneous ovulation. The results suggest that the major urinary proteins activate the neuroendocrine system through the VNO and trigger ovulation.