Maladaptive defensive behaviours in monoamine oxidase A-deficient mice

Rich 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

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

Regulation of the transcription factor EB-PGC1α axis by beclin-1 controls mitochondrial quality and cardiomyocyte death under stress

In cardiac ischemia-reperfusion injury, reactive oxygen species (ROS) generation and upregulation of the hypoxia-inducible protein BNIP3 result in mitochondrial permeabilization, but impairment in autophagic removal of damaged mitochondria provokes programmed cardiomyocyte death. BNIP3 expression and ROS generation result in upregulation of beclin-1, a protein associated with transcriptional suppression of autophagy-lysosome proteins and reduced activation of transcription factor EB (TFEB), a master regulator of the autophagy-lysosome machinery. Partial beclin-1 knockdown transcriptionally stimulates lysosome biogenesis and autophagy via mTOR inhibition and activation of TFEB, enhancing removal of depolarized mitochondria. TFEB activation concomitantly stimulates mitochondrial biogenesis via PGC1α induction to restore normally polarized mitochondria and attenuate BNIP3- and hypoxia-reoxygenation-induced cell death. Conversely, overexpression of beclin-1 activates mTOR to inhibit TFEB, resulting in declines in lysosome numbers and suppression of PGC1α transcription. Importantly, knockdown of endogenous TFEB or PGC1α results in a complete or partial loss, respectively, of the cytoprotective effects of partial beclin-1 knockdown, indicating a critical role for both mitochondrial autophagy and biogenesis in ensuring cellular viability. These studies uncover a transcriptional feedback loop for beclin-1-mediated regulation of TFEB activation and implicate a central role for TFEB in coordinating mitochondrial autophagy with biogenesis to restore normally polarized mitochondria and prevent ischemia-reperfusion-induced cardiomyocyte death

Pharmacological insights into the role of P2X4 receptors in behavioural regulation: lessons from ivermectin

This is the publisher's version, also available electronically from http://journals.cambridge.org/action/displayAbstract?fromPage=online&aid=8920271&fileId=S1461145712000909Purinergic ionotropic P2X receptors are a family of cation-permeable channels that bind extracellular adenosine 5′-triphosphate. In particular, convergent lines of evidence have recently highlighted P2X4 receptors as a potentially critical target in the regulation of multiple nervous and behavioural functions, including pain, neuroendocrine regulation and hippocampal plasticity. Nevertheless, the role of the P2X4 receptor in behavioural organization remains poorly investigated. To study the effects of P2X4 activation, we tested the acute effects of its potent positive allosteric modulator ivermectin (IVM, 2.5–10 mg/kg i.p.) on a broad set of paradigms capturing complementary aspects of perceptual, emotional and cognitive regulation in mice. In a novel open field, IVM did not induce significant changes in locomotor activity, but increased the time spent in the peripheral zone. In contrast, IVM produced anxiolytic-like effects in the elevated plus maze and marble burying tasks, as well as depression-like behaviours in the tail-suspension and forced swim tests. The agent induced no significant behavioural changes in the conditioned place preference test and in the novel object recognition task. Finally, the drug induced a dose-dependent decrease in sensorimotor gating, as assessed by pre-pulse inhibition (PPI) of the acoustic startle reflex. In P2X4 knockout mice, the effects of IVM in the open field and elevated plus maze were similar to those observed in wild type mice; conversely, the drug significantly increased startle amplitude and failed to reduce PPI. Taken together, these results suggest that P2X4 receptors may play a role in the regulation of sensorimotor gatin

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

Socio-economic and environmental trade-offs in Amazonian protected areas and Indigenous territories revealed by assessing competing land uses

Protected area (PA) assessments rarely evaluate socio-economic and environmental impacts relative to competing land uses, limiting understanding of socio-environmental trade-offs from efforts to protect 30% of the globe by 2030. Here we assess deforestation and poverty outcomes (fiscal income, income inequality, sanitation and literacy) between 2000 and 2010 of strict PAs (SPAs), sustainable-use PAs (SUPAs) and Indigenous territories (ITs) compared with different land uses (agriculture and mining concessions) across ~5,500 census tracts in the Brazilian Legal Amazon. ITs reduced deforestation relative to all alternative land uses (48–83%) but had smaller socio-economic benefits compared with other protection types and land uses (18–36% depending on outcome), indicating that Indigenous communities experience socio-economic trade-offs. By contrast, SUPAs, and potentially SPAs, did not reduce deforestation relative to small-scale agriculture (landholdings <10 ha) but did so relative to larger agricultural landholdings (70–82%). Critically, these reductions in deforestation frequently occurred without negative socio-economic outcomes. By contrast, ITs and SUPAs protected against deforestation from mining, but at the cost of smaller improvements in income and inequality. Our results suggest that although PAs in the Brazilian Legal Amazon substantially reduced deforestation without compromising local socio-economic development, efforts to secure Indigenous rights need additional interventions to ensure these communities are not further disadvantaged

Environmental Costs of Government-Sponsored Agrarian Settlements in Brazilian Amazonia

Brazil has presided over the most comprehensive agrarian reform frontier colonization program on Earth, in which ~1.2 million settlers have been translocated by successive governments since the 1970's, mostly into forested hinterlands of Brazilian Amazonia. These settlements encompass 5.3% of this ~5 million km2 region, but have contributed with 13.5% of all land conversion into agropastoral land uses. The Brazilian Federal Agrarian Agency (INCRA) has repeatedly claimed that deforestation in these areas largely predates the sanctioned arrival of new settlers. Here, we quantify rates of natural vegetation conversion across 1911 agrarian settlements allocated to 568 Amazonian counties and compare fire incidence and deforestation rates before and after the official occupation of settlements by migrant farmers. The timing and spatial distribution of deforestation and fires in our analysis provides irrefutable chronological and spatially explicit evidence of agropastoral conversion both inside and immediately outside agrarian settlements over the last decade. Deforestation rates are strongly related to local human population density and road access to regional markets. Agrarian settlements consistently accelerated rates of deforestation and fires, compared to neighboring areas outside settlements, but within the same counties. Relocated smallholders allocated to forest areas undoubtedly operate as pivotal agents of deforestation, and most of the forest clearance occurs in the aftermath of government-induced migration

Transparency and sustainability in global commodity supply chains

Over the last few decades rapid advances in processes to collect, monitor, disclose, and disseminate information have contributed towards the development of entirely new modes of sustainability governance for global commodity supply chains. However, there has been very little critical appraisal of the contribution made by different transparency initiatives to sustainability and the ways in which they can (and cannot) influence new governance arrangements. Here we seek to strengthen the theoretical underpinning of research and action on supply chain transparency by addressing four questions: (1) What is meant by supply chain transparency? (2) What is the relevance of supply chain transparency to supply chain sustainability governance? (3) What is the current status of supply chain transparency, and what are the strengths and weaknesses of existing initiatives? and (4) What propositions can be advanced for how transparency can have a positive transformative effect on the governance interventions that seek to strengthen sustainability outcomes? We use examples from agricultural supply chains and the zero-deforestation agenda as a focus of our analysis but draw insights that are relevant to the transparency and sustainability of supply chains in general. We propose a typology to distinguish among types of supply chain information that are needed to support improvements in sustainability governance, and illustrate a number of major shortfalls and systematic biases in existing information systems. We also propose a set of ten propositions that, taken together, serve to expose some of the potential pitfalls and undesirable outcomes that may result from (inevitably) limited or poorly designed transparency systems, whilst offering guidance on some of the ways in which greater transparency can make a more effective, lasting and positive contribution to sustainability

Criteria for effective zero-deforestation commitments

Zero-deforestation commitments are a type of voluntary sustainability initiative that companies adopt to signal their intention to reduce or eliminate deforestation associated with commodities that they produce, trade, and/or sell. Because each company defines its own zero-deforestation commitment goals and implementation mechanisms, commitment content varies widely. This creates challenges for the assessment of commitment implementation or effectiveness. Here, we develop criteria to assess the potential effectiveness of zero-deforestation commitments at reducing deforestation within a company supply chain, regionally, and globally. We apply these criteria to evaluate 52 zero-deforestation commitments made by companies identified by Forest 500 as having high deforestation risk. While our assessment indicates that existing commitments converge with several criteria for effectiveness, they fall short in a few key ways. First, they cover just a small share of the global market for deforestation-risk commodities, which means that their global impact is likely to be small. Second, biome-wide implementation is only achieved in the Brazilian Amazon. Outside this region, implementation occurs mainly through certification programs, which are not adopted by all producers and lack third-party near-real time deforestation monitoring. Additionally, around half of all commitments include zero-net deforestation targets and future implementation deadlines, both of which are design elements that may reduce effectiveness. Zero-net targets allow promises of future reforestation to compensate for current forest loss, while future implementation deadlines allow for preemptive clearing. To increase the likelihood that commitments will lead to reduced deforestation across all scales, more companies should adopt zero-gross deforestation targets with immediate implementation deadlines and clear sanction-based implementation mechanisms in biomes with high risk of forest to commodity conversion.ISSN:0959-3780ISSN:1872-949

Spatial and temporal dimensions of landscape fragmentation across the Brazilian Amazon

The Brazilian Amazon in the past decades has been suffering severe landscape alteration, mainly due to anthropogenic activities, such as road building and land clearing for agriculture. Using a high-resolution time series of land cover maps (classified as mature forest, non-forest, secondary forest) spanning from 1984 through 2011, and four uncorrelated fragmentation metrics (edge density, clumpiness index, area-weighted mean patch size and shape index), we examined the temporal and spatial dynamics of forest fragmentation in three study areas across the Brazilian Amazon (Manaus, Santarém and Machadinho d’Oeste), inside and outside conservation units. Moreover, we compared the impacts on the landscape of: (1) different land uses (e.g. cattle ranching, crop production), (2) occupation processes (spontaneous vs. planned settlements) and (3) implementation of conservation units. By 2010/2011, municipalities located along the Arc of Deforestation had more than 55% of the remaining mature forest strictly confined to conservation units. Further, the planned settlement showed a higher rate of forest loss, a more persistent increase in deforested areas and a higher relative incidence of deforestation inside conservation units. Distinct agricultural activities did not lead to significantly different landscape structures; the accessibility of the municipality showed greater influence in the degree of degradation of the landscapes. Even with a high proportion of the landscapes covered by conservation units, which showed a strong inhibitory effect on forest fragmentation, we show that dynamic agriculturally driven economic activities, in municipalities with extensive road development, led to more regularly shaped, heavily fragmented landscapes, with higher densities of forest edge