Maladaptive defensive behaviours in monoamine oxidase A-deficient mice

This is the publisher's version, also available electronically from http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=8369466&fileId=S1461145710001483Rich evidence indicates that monoamine oxidase (MAO) A, the major enzyme catalysing the degradation of monoamine neurotransmitters, plays a key role in emotional regulation. Although MAOA deficiency is associated with reactive aggression in humans and mice, the involvement of this enzyme in defensive behaviour remains controversial and poorly understood. To address this issue, we tested MAOA knockout (KO) mice in a spectrum of paradigms and settings associated with variable degrees of threat. The presentation of novel inanimate objects induced a significant reduction in exploratory approaches and increase in defensive behaviours, such as tail-rattling, biting and digging. These neophobic responses were context-dependent and particularly marked in the home cage. In the elevated plus- and T-mazes, MAOA KO mice and wild-type (WT) littermates displayed equivalent locomotor activity and time in closed and open arms; however, MAOA KO mice featured significant reductions in risk assessment, as well as unconditioned avoidance and escape. No differences between genotypes were observed in the defensive withdrawal and emergence test. Conversely, MAOA KO mice exhibited a dramatic reduction of defensive and fear-related behaviours in the presence of predator-related cues, such as predator urine or an anaesthetized rat, in comparison with those observed in their WT littermates. The behavioural abnormalities in MAOA KO mice were not paralleled by overt alterations in sensory and microvibrissal functions. Collectively, these results suggest that MAOA deficiency leads to a general inability to appropriately assess contextual risk and attune defensive and emotional responses to environmental cues

Monoamine Oxidase A is Required for Rapid Dendritic Remodeling in Response to Stress

Background: Acute stress triggers transient alterations in the synaptic release and metabolism of brain monoamine neurotransmitters. These rapid changes are essential to activate neuroplastic processes aimed at the appraisal of the stressor and enactment of commensurate defensive behaviors. Threat evaluation has been recently associated with the dendritic morphology of pyramidal cells in the orbitofrontal cortex (OFC) and basolateral amygdala (BLA); thus, we examined the rapid effects of restraint stress on anxiety-like behavior and dendritic morphology in the BLA and OFC of mice. Furthermore, we tested whether these processes may be affected by deficiency of monoamine oxidase A (MAO-A), the primary enzyme catalyzing monoamine metabolism. Methods: Following a short-term (1–4h) restraint schedule, MAO-A knockout (KO) and wild-type (WT) mice were sacrificed, and histological analyses of dendrites in pyramidal neurons of the BLA and OFC of the animals were performed. Anxiety-like behaviors were examined in a separate cohort of animals subjected to the same experimental conditions. Results: In WT mice, short-term restraint stress significantly enhanced anxiety-like responses, as well as a time-dependent proliferation of apical (but not basilar) dendrites of the OFC neurons; conversely, a retraction in BLA dendrites was observed. None of these behavioral and morphological changes were observed in MAO-A KO mice. Conclusions: These findings suggest that acute stress induces anxiety-like responses by affecting rapid dendritic remodeling in the pyramidal cells of OFC and BLA; furthermore, our data show that MAO-A and monoamine metabolism are required for these phenomena

Early postnatal inhibition of serotonin synthesis results in long-term reductions of perseverative behaviors, but not aggression, in MAO A-deficient mice

Monoamine oxidase (MAO) A, the major enzyme catalyzing the oxidative degradation of serotonin (5-hydroxytryptamine, 5-HT), plays a key role in emotional regulation. In humans and mice, MAO-A deficiency results in high 5-HT levels, antisocial, aggressive, and perseverative behaviors. We previously showed that the elevation in brain 5-HT levels in MAO-A knockout (KO) mice is particularly marked during the first two weeks of postnatal life. Building on this finding, we hypothesized that the reduction of 5-HT levels during these early stages may lead to enduring attenuations of the aggression and other behavioral aberrances observed in MAO-A KO mice. To test this possibility, MAO-A KO mice were treated with daily injections of a 5-HT synthesis blocker, the tryptophan hydroxylase inhibitor p-chloro-phenylalanine (pCPA, 300 mg/kg/day, IP), from postnatal day 1 through 7. As expected, this regimen significantly reduced 5-HT forebrain levels in MAO-A KO pups. These neurochemical changes persisted throughout adulthood, and resulted in significant reductions in marble-burying behavior, as well as increases in spontaneous alternations within a T-maze. Conversely, pCPA-treated MAO-A KO mice did not exhibit significant changes in anxiety-like behaviors in a novel open-field and elevated plus-maze; furthermore, this regimen did not modify their social deficits, aggressive behaviors and impairments in tactile sensitivity. Treatment with pCPA from postnatal day 8 through 14 elicited similar, yet milder, behavioral effects on marble-burying behavior. These results suggest that early developmental enhancements in 5-HT levels have long-term effects on the modulation of behavioral flexibility associated with MAO-A deficiency

The aggression and behavioral abnormalities associated with monoamine oxidase A deficiency are rescued by acute inhibition of serotonin reuptake

The termination of serotonin (5-hydroxytryptamine, 5-HT) neurotransmission is regulated by its uptake by the 5-HT transporter (5-HTT), as well as its degradation by monoamine oxidase (MAO)-A. MAO-A deficiency results in a wide set of behavioral alterations, including perseverative behaviors and social deficits. These anomalies are likely related to 5-HTergic homeostatic imbalances; however, the role of 5-HTT in these abnormalities remains unclear. To ascertain the role of 5-HTT in the behavioral anomalies associated to MAO-A deficiency, we tested the behavioral effects of its blocker fluoxetine on perseverative, social and aggressive behaviors in transgenic animals with hypomorphic or null-allele MAO-A mutations. Acute treatment with 5-HTT blocker fluoxetine (10 mg/kg, i.p.) reduced aggressive behavior in MAO-A knockout (KO) mice and social deficits in hypomorphic MAO-ANeo mice. Furthermore, this treatment also reduced perseverative responses (including marble burying and water mist-induced grooming) in both MAO-A mutant genotypes. Both MAO-A mutant lines displayed significant reductions in 5-HTT expression across the prefrontal cortex, amygdala and striatum, as quantified by immunohistochemical detection; however, the down-regulation of 5-HTT in MAO-ANeo mice was more pervasive and widespread than in their KO counterparts, possibly indicating a greater ability of the hypomorphic line to enact compensatory mechanisms with respect to 5-HT homeostasis. Collectively, these findings suggest that the behavioral deficits associated with low MAO-A activity may reflect developmental alterations of 5-HTT within 5-HTergic neurons. Furthermore, the translational implications of our results highlight 5-HT reuptake inhibition as an interesting approach for the control of aggressive outbursts in MAO-A deficient individuals

The VNTR 2 repeat in MAOA and delinquent behavior in adolescence and young adulthood: associations and MAOA promoter activity

Genetic studies of delinquent and criminal behavior are rare in spite of the wide recognition that individuals may differ in their propensity for delinquency and criminality. Using 2524 participants in Add Health in the United States, the present study demonstrates a link between the rare 2 repeat of the 30-bp VNTR in the MAOA gene and much higher levels of self-reported serious and violent delinquency. The evidence is based on a statistical association analysis and a functional analysis of MAOA promoter activity using two human brain-derived cell lines: neuroblastoma SH-SY5Y and human glioblastoma 1242-MG. The association analysis shows that men with a 2R report a level of serious delinquency and violent delinquency in adolescence and young adulthood that were about twice (CI: (0.21, 3.24), P = 0.025; and CI: (0.37, 2.5), P = 0.008 for serious and violent delinquency, respectively) as high as those for participants with the other variants. The results for women are similar, but weaker. In the functional analysis, the 2 repeat exhibits much lower levels of promoter activity than the 3 or 4 repeat

Monoamine oxidase A and A/B knockout mice display autistic-like features

This is the published version, also available electronically from http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=8876069&fileId=S1461145712000715Converging lines of evidence show that a sizable subset of autism-spectrum disorders (ASDs) is characterized by increased blood levels of serotonin (5-hydroxytryptamine, 5-HT), yet the mechanistic link between these two phenomena remains unclear. The enzymatic degradation of brain 5-HT is mainly mediated by monoamine oxidase (MAO)A and, in the absence of this enzyme, by its cognate isoenzyme MAOB. MAOA and A/B knockout (KO) mice display high 5-HT levels, particularly during early developmental stages. Here we show that both mutant lines exhibit numerous behavioural hallmarks of ASDs, such as social and communication impairments, perseverative and stereotypical responses, behavioural inflexibility, as well as subtle tactile and motor deficits. Furthermore, both MAOA and A/B KO mice displayed neuropathological alterations reminiscent of typical ASD features, including reduced thickness of the corpus callosum, increased dendritic arborization of pyramidal neurons in the prefrontal cortex and disrupted microarchitecture of the cerebellum. The severity of repetitive responses and neuropathological aberrances was generally greater in MAOA/B KO animals. These findings suggest that the neurochemical imbalances induced by MAOA deficiency (either by itself or in conjunction with lack of MAOB) may result in an array of abnormalities similar to those observed in ASDs. Thus, MAOA and A/B KO mice may afford valuable models to help elucidate the neurobiological bases of these disorders and related neurodevelopmental problem

NMDARs Mediate the Role of Monoamine Oxidase A in Pathological Aggression

This is the publisher's version, also available electronically from http://www.jneurosci.org/content/32/25/8574Converging evidence shows that monoamine oxidase A (MAO A), the key enzyme catalyzing serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) degradation, is a primary factor in the pathophysiology of antisocial and aggressive behavior. Accordingly, male MAO A-deficient humans and mice exhibit an extreme predisposition to aggressive outbursts in response to stress. As NMDARs regulate the emotional reactivity to social and environmental stimuli, we hypothesized their involvement in the modulation of aggression mediated by MAO A. In comparison with WT male mice, MAO A KO counterparts exhibited increases in 5-HT and NE levels across all brain regions, but no difference in glutamate concentrations and NMDAR binding. Notably, the prefrontal cortex (PFC) of MAO A KO mice exhibited higher expression of NR2A and NR2B, as well as lower levels of glycosylated NR1 subunits. In line with these changes, the current amplitude and decay time of NMDARs in PFC was significantly reduced. Furthermore, the currents of these receptors were hypersensitive to the action of the antagonists of the NMDAR complex (dizocilpine), as well as NR2A (PEAQX) and NR2B (Ro 25-6981) subunits. Notably, systemic administration of these agents selectively countered the enhanced aggression in MAO A KO mice, at doses that did not inherently affect motor activity. Our findings suggest that the role of MAO A in pathological aggression may be mediated by changes in NMDAR subunit composition in the PFC, and point to a critical function of this receptor in the molecular bases of antisocial personality

The Spitzer c2d Survey of Weak-line T Tauri Stars II: New Constraints on the Timescale for Planet Building

One of the central goals of the Spitzer Legacy Project ``From Molecular Cores to Planet-forming Disks'' (c2d) is to determine the frequency of remnant circumstellar disks around weak-line T Tauri stars (wTTs) and to study the properties and evolutionary status of these disks. Here we present a census of disks for a sample of over 230 spectroscopically identified wTTs located in the c2d IRAC (3.6, 4.5, 4.8, and 8.0 um) and MIPS (24 um) maps of the Ophiuchus, Lupus, and Perseus Molecular Clouds. We find that ~20% of the wTTs in a magnitude limited subsample have noticeable IR-excesses at IRAC wavelengths indicating the presence of a circumstellar disk. The disk frequencies we find in these 3 regions are ~3-6 times larger than that recently found for a sample of 83 relatively isolated wTTs located, for the most part, outside the highest extinction regions covered by the c2d IRAC and MIPS maps. The disk fractions we find are more consistent with those obtained in recent Spitzer studies of wTTs in young clusters such as IC 348 and Tr 37. From their location in the H-R diagram, we find that, in our sample, the wTTs with excesses are among the younger part of the age distribution. Still, up to ~50% of the apparently youngest stars in the sample show no evidence of IR excess, suggesting that the circumstellar disks of a sizable fraction of pre-main-sequence stars dissipate in a timescale of ~1 Myr. We also find that none of the stars in our sample apparently older than ~10 Myrs have detectable circumstellar disks at wavelengths < 24 um. Also, we find that the wTTs disks in our sample exhibit a wide range of properties (SED morphology, inner radius, L_DISK/L*, etc) which bridge the gaps observed between the cTTs and the debris disk regimes.Comment: 54 pages, 13 figures, Accepted by Ap

Sub-terahertz, microwaves and high energy emissions during the December 6, 2006 flare, at 18:40 UT

The presence of a solar burst spectral component with flux density increasing with frequency in the sub-terahertz range, spectrally separated from the well-known microwave spectral component, bring new possibilities to explore the flaring physical processes, both observational and theoretical. The solar event of 6 December 2006, starting at about 18:30 UT, exhibited a particularly well-defined double spectral structure, with the sub-THz spectral component detected at 212 and 405 GHz by SST and microwaves (1-18 GHz) observed by the Owens Valley Solar Array (OVSA). Emissions obtained by instruments in satellites are discussed with emphasis to ultra-violet (UV) obtained by the Transition Region And Coronal Explorer (TRACE), soft X-rays from the Geostationary Operational Environmental Satellites (GOES) and X- and gamma-rays from the Ramaty High Energy Solar Spectroscopic Imager (RHESSI). The sub-THz impulsive component had its closer temporal counterpart only in the higher energy X- and gamma-rays ranges. The spatial positions of the centers of emission at 212 GHz for the first flux enhancement were clearly displaced by more than one arc-minute from positions at the following phases. The observed sub-THz fluxes and burst source plasma parameters were found difficult to be reconciled to a purely thermal emission component. We discuss possible mechanisms to explain the double spectral components at microwaves and in the THz ranges.Comment: Accepted version for publication in Solar Physic