Antidepressant actions of lateral habenula deep brain stimulation differentially correlate with CaMKII/GSK3/AMPK signaling locally and in the infralimbic cortex

High frequency deep brain stimulation (DBS) of the lateral habenula (LHb) reduces symptoms of depression in severely treatment-resistant individuals. Despite the observed therapeutic effects, the molecular underpinnings of DBS are poorly understood. This study investigated the efficacy of high frequency LHb DBS (130Hz; 200��A; 90��s) in an animal model of tricyclic antidepressant resistance. Further, we reported DBS mediated changes in Ca(2+)/calmodulin-dependent protein kinase (CaMKII��/��), glycogen synthase kinase 3 (GSK3��/��) and AMP-activated protein kinase (AMPK) both locally and in the infralimbic cortex (IL). Protein expressions were then correlated to immobility time during the forced swim test (FST). Antidepressant actions were quantified via FST. Treatment groups comprised of animals treated with adrenocorticotropic hormone alone (ACTH; 100��g/day, 14days, n=7), ACTH with active DBS (n=7), sham DBS (n=8), surgery only (n=8) or control (n=8). Active DBS significantly reduced immobility in ACTH-treated animals (p<0.05). For this group, western blot results demonstrated phosphorylation status of LHb CaMKII��/�� and GSK3��/�� significantly correlated to immobility time in the FST. Concurrently, we observed phosphorylation status of CaMKII��/��, GSK3��/��, and AMPK in the IL to be negatively correlated with antidepressant actions of DBS. These findings suggest that activity dependent phosphorylation of CaMKII��/��, and GSK3��/�� in the LHb together with the downregulation of CaMKII��/��, GSK3��/��, and AMPK in the IL, contribute to the antidepressant actions of DBS.

Mood regulatory actions of nucleus accumbens deep brain stimulation

The mood regulatory mechanisms of deep brain stimulation (DBS)therapy are yet to be fully understood. DBS is shown to have antidepressant actions in severe, treatment-resistant depression (TRD).Interestingly, DBS of mesoaccumbens neurologic targets, includingthe nucleus accumbens (NAc), have also been shown to induce mania in vulnerable individuals. The nucleus accumbens (NAc) is a critical node in the mesocorticolimbic system and plays a major role in mediating antidepressant behavioral responses in the forced swim test (FST), a preclinical screen for antidepressant efficacy. This study investigates the antidepressant effects of NAc DBS in an established animal model of TRD. Wistar rats were divided into 4 groups: TRD-DBS (n = 9), TRD-Sham (n = 8), TRD (n = 10), and Control (n = 10). Bilateral stimulating electrodes were implanted into the NAc of TRD-Sham and TRD-DBS animals. Antidepressant-resistance and depression behaviors were induced through adrenocorticotropic-hormone (ACTH-(1&ndash;24); 100 lg/day; 2nd and 3rd weeks) administration and concurrent social isolation (all 3 weeks) respectively. DBS was administered throughout the 2nd week of ACTH treatment via a back mounted rodent DBS system. 24-hour locomotor activity counts were obtained using infrareddetectors and weekly sucrose preference tests were performedthroughout the 3 week protocol. Open field and FST were completedat the end of the 3 weeks. Brains were then removed and stored at 80&deg;C. NAc tissue levels of brain-derived and glialderived neurotrophic factors (BDNF and GDNF, respectively) were quantified using western blot. Results demonstrate significant increases in locomotor activity for TRD-DBS animals (DBS-Vs-Sham: p = 0.0248). Lowered immobility was observed during FST for TRD-DBS animals (DBS-Vs-Sham: p = 0.0188). ACTHinduced BDNF expression increased in the outer region substructure NAc-shell (p = 0.0487) and decreased in the inner region substructure NAc-core (p = 0.0275) compared to controls. These datasupport antidepressant actions of NAc DBS in TRD. Local changes in neurotrophic factors may contribute to these mechanisms. Importantly, observed increases in locomotor activity over the 3 weeks highlight the potential for mesoaccumbens DBS to impact behaviors such as locomotor activity which may contribute to risk for induction of mania. Preliminary analysis of concurrent effects of daily dopamine reuptake inhibitor GBR12909 (16 mg/kg) administration coupled with NAc DBS demonstrates dopamine-mediated augmentation of these mania-like behaviors.

The real effects of banking supervision:evidence from enforcement actions

We present a novel way to examine macro-financial linkages by focusing on the real effects of bank supervisors��� enforcement actions. Exploiting plausibly exogenous variation in supervisory monitoring intensity, we show that enforcement actions in single-market banks trigger temporarily large adverse effects for the macroeconomy by reducing personal income growth, the number of establishments, and increasing unemployment. These effects are related to contractions in bank lending and liquidity creation, and are more pronounced when we consider enforcement actions on both single-market and multi-market banks, and in counties with fewer banks and greater external financial dependence.

Analyse g��ostatistique des aires prot��g��es de la Communaut�� m��tropolitaine de Montr��al : d��fis et priorit��s d'actions pour un am��nagement durable du territoire

Avec son plan m��tropolitain d���am��nagement et de d��veloppement, la communaut�� m��tropolitaine de Montr��al met de l���avant plusieurs orientations visant la sph��re environnementale. Parmi les objectifs formul��s, on retrouve la mise en valeur des atouts naturels de la r��gion et la protection de 17 % du territoire, ce qui n���est pas ��tonnant sachant les nombreux avantages reli��s �� la pr��sence des milieux naturels sur un territoire urbanis��. Les aires prot��g��es sont en effet essentielles au maintien de la biodiversit�� et des services ��cosyst��miques associ��s au bien-��tre humain. Toutefois, les analyses g��ostatistiques r��alis��es indiquent que peu de municipalit��s de la r��gion respectent les orientations mises de l���avant par la communaut�� et que la plupart des bassins versants n���ont pas un niveau ad��quat de protection. Les statistiques pr��sent��es par la communaut�� m��tropolitaine de Montr��al (9,6 % d���aires prot��g��es) sont certes acceptables �� premi��re vue si l���on consid��re l�����tat de la situation au Qu��bec (9,33 %) et dans la zone sud de la province (4,8 %), mais une ��tude plus approfondie d��montre que la majeure partie des territoires prot��g��s sont en milieu aquatique (77 %) et la pr��sence d���importantes zones de carences en aires prot��g��es au nord-est et au sud-ouest. En ce qui concerne les aspects sociaux et ��conomiques, la localisation actuelle des aires prot��g��es cr��e des iniquit��s en mati��re d���acc��s �� la nature (33 % des municipalit��s ont une portion de leur territoire �� plus de 5 km de tout espace prot��g��), et les municipalit��s qui font des efforts en termes de conservation ne sont pas n��cessairement celles qui en retirent les b��n��fices sur le plan de la richesse fonci��re. Compte tenu de la complexit�� inh��rente �� la mise en oeuvre des objectifs du plan m��tropolitain dans le contexte r��gional, diverses pistes de solutions peuvent ��tre envisag��es pour le d��veloppement du r��seau d���aires prot��g��es. De meilleures politiques d���am��nagement du territoire et un cadre l��gislatif ad��quat semblent indispensables afin de mettre un frein �� la destruction des milieux naturels, d���encourager la connexion entre les noyaux de biodiversit�� et d���inciter la restauration des milieux perturb��s. Des r��gles qui tiennent compte des particularit��s r��gionales doivent aussi ��tre mises en place afin de promouvoir le partage des co��ts et b��n��fices de la conservation. Il faudra faire valoir les b��n��fices des aires prot��g��es aupr��s du public, car la simple protection des territoires ne sera pas suffisante �� la saine gestion des ��cosyst��mes et l���implication des acteurs concern��s sera absolument n��cessaire sachant les multiples menaces qui guettent les milieux naturels.

The influence of actions on auditory perception: cognitive and neural mechanisms

It is well known that self-generated stimuli are processed differently from externally generated stimuli. For example, many people have noticed since childhood that it is very difficult to make a self-tickling. In the auditory domain, self-generated sounds elicit smaller brain responses as compared to externally generated sounds, known as the sensory attenuation (SA) effect. SA is manifested in reduced amplitudes of evoked responses as measured through MEEG, decreased firing rates of neurons and a lower level of perceived loudness for self-generated sounds. The predominant explanation for SA is based on the idea that self-generated stimuli are predicted (e.g., the forward model account). It is the nature of their predictability that is crucial for SA. On the contrary, the sensory gating account emphasizes a general suppressive effect of actions on sensory processing, regardless of the predictability of the stimuli. Both accounts have received empirical support, which suggests that both mechanisms may exist. In chapter 2, three behavioural studies concerning the influence of motor activation on auditory perception were presented. Study 1 compared the effect of SA and attention in an auditory detection task and showed that SA was present even when substantial attention was paid to unpredictable stimuli. Study 2 compared the loudness perception of tones generated by others between Chinese and British participants. Compared to externally generated tones, a decrease in perceived loudness for others generated tones was found among Chinese but not among the British. In study 3, partial evidence was found that even when reading words that are related to action, auditory detection performance was impaired. In chapter 3, the classic SA effect of M100 suppression was replicated with MEG in study 4. With time-frequency analysis, a potential neural information processing sequence was found in auditory cortex. Prior to the onset of self-generated tones, there was an increase of oscillatory power in the alpha band. After the stimulus onset, reduced gamma power and alpha/beta phase locking were found. The three temporally segregated oscillatory events correlated with each other and with SA effect, which may be the underlying neural implementation of SA. In chapter 4, a TMS-MEG study was presented investigating the role of the cerebellum in adapting to delayed presentation of self-generated tones (study 5). It demonstrated that in sham stimulation condition, the brain can adapt to the delay (about 100 ms) within 300 trials of learning by showing a significant increase of SA effect in the suppression of M100, but not M200 component. Whereas after stimulating the cerebellum with a suppressive TMS protocol, the adaptation in M100 suppression disappeared and the pattern of M200 suppression reversed to M200 enhancement. These data support the idea that the suppressive effect of actions on auditory processing is a consequence of both motor driven sensory predictions and general sensory gating. The results also demonstrate the importance of neural oscillations in implementing SA effect and the critical role of the cerebellum in learning sensory predictions under sensory perturbation.

Investigating Angiotensin II in cardiac remodelling and the counter-regulatory actions of Angiotensin-(1-9)

Cardiovascular diseases (CVDs) including, hypertension, coronary heart disease and heart failure are the leading cause of death worldwide. Hypertension, a chronic increase in blood pressure above 140/90 mmHg, is the single main contributor to deaths due to heart disease and stroke. In the heart, hypertension results in adaptive cardiac remodelling, including LV hypertrophy to normalize wall stress and maintain cardiac contractile function. However, chronic increases in BP results in the development of hypertensive heart disease (HHD). HHD describes the maladaptive changes during cardiac remodelling which result in reduced systolic and diastolic function and eventually heart failure. This includes ventricular dilation due to eccentric hypertrophy, cardiac fibrosis which stiffens the ventricular wall and microvascular rarefaction resulting in a decrease in coronary blood flow albeit an increase in energy demand. Chronic activation of the renin-angiotensin-system (RAS) with its effector peptide angiotensin (Ang)II plays a key role in the development of hypertension and the maladaptive changes in HHD. Ang II acts via the angiotensin type 1 receptor (AT1R) to mediate most of its pathological actions during HHD, including stimulation of cardiomyocyte hypertrophy, activation of cardiac fibroblasts and increased collagen deposition. The counter-regulatory axis of the RAS which is centred on the ACE2/Ang-(1-7)/Mas axis has been demonstrated to counteract the pathological actions of Ang II in the heart and vasculature. Ang-(1-7) via the Mas receptor prevents Ang II-induced cardiac hypertrophy and fibrosis and improves cardiac contractile function in animal models of HHD. In contrast, less is known about Ang-(1-9) although evidence has demonstrated that Ang-(1-9) also antagonises Ang II and is anti-hypertrophic and anti-fibrotic in animal models of acute cardiac remodelling. However, so far it is not well documented whether Ang-(1-9) can reverse established cardiac dysfunction and remodelling and whether it is beneficial when administered chronically. Therefore, the main aim of this thesis was to assess the effects of chronic Ang-(1-9) administration on cardiac structure and function in a model of Ang II-induced cardiac remodelling. Furthermore, this thesis aimed to investigate novel pathways contributing to the pathological remodelling in response to Ang II. First, a mouse model of chronic Ang II infusion was established and characterised by comparing the structural and functional effects of the infusion of a low and high dose of Ang II after 6 weeks. Echocardiographic measurements demonstrated that low dose Ang II infusion resulted in a gradual decline in cardiac function while a high dose of Ang II induced acute cardiac contractile dysfunction. Both doses equally induced the development of cardiac hypertrophy and cardiac fibrosis characterised by an increase in the deposition of collagen I and collagen III. Moreover, increases in gene expression of fibrotic and hypertrophic markers could be detected following high dose Ang II infusion over 6 weeks. Following this characterisation, the high dose infusion model was used to assess the effects of Ang-(1-9) on cardiac structural and functional remodelling in established disease. Initially, it was evaluated whether Ang-(1-9) can reverse Ang II-induced cardiac disease by administering Ang-(1-9) for 2-4 weeks following an initial 2 week infusion of a high dose of Ang II to induce cardiac contractile dysfunction. The infusion of Ang-(1-9) for 2 weeks was associated with a significant improvement of LV fractional shortening compared to Ang II infusion. However, after 4 weeks fractional shortening declined to Ang II levels. Despite the transient improvement in cardiac contractile function, Ang-(1-9) did not modulate blood pressure, LV hypertrophy or cardiac fibrosis. To further investigate the direct cardiac effects of Ang-(1-9), cardiac contractile performance in response to Ang-(1-9) was evaluated in the isolated Langendorff-perfused rat heart. Perfusion of Ang-(1-9) in the paced and spontaneously beating rat heart mediated a positive inotropic effect characterised by an increase in LV developed pressure, cardiac contractility and relaxation. This was in contrast to Ang II and Ang-(1-7). Furthermore, the positive inotropic effect to Ang-(1-9) was blocked by the AT1R antagonist losartan and the protein kinase A inhibitor H89. Next, endothelial-to-mesenchymal transition (EndMT) as a novel pathway that may contribute to Ang II-induced cardiac remodelling was assessed in Ang II-infused mice in vivo and in human coronary artery endothelial cells (HCAEC) in vitro. Infusion of Ang II to mice for 2-6 weeks resulted in a significant decrease in myocardial capillary density and this was associated with the occurrence of dual labelling of endothelial cells for endothelial and mesenchymal markers. In vitro stimulation of HCAEC with TGF�� and Ang II revealed that Ang II exacerbated TGF-induced gene expression of mesenchymal markers. This was not correlated with any changes in SMAD2 or ERK1/2 phosphorylation with co-stimulation of TGF�� and Ang II. However, superoxide production was significantly increased in HCAEC stimulated with Ang II but not TGF��. Finally, the role of Ang II in microvesicle (MV)-mediated cardiomyocyte hypertrophy was investigated. MVs purified from neonatal rat cardiac fibroblasts were found to contain detectable Ang II and this was increased by stimulation of fibroblasts with Ang II. Treatment of cardiomyocytes with MVs derived from Ang II-stimulated fibroblasts induced cardiomyocyte hypertrophy which could be blocked by the AT1R antagonist losartan and an inhibitor of MV synthesis and release brefeldin A. Furthermore, Ang II was found to be present in MVs isolated from serum and plasma of Ang II-infused mice and SHRSP and WKY rats. Overall, the findings of this thesis demonstrate for the first time that the actions of Ang-(1-9) in cardiac pathology are dependent on its time of administration and that Ang-(1-9) can reverse Ang II-induced cardiac contractile dysfunction by acting as a positive inotrope. Furthermore, this thesis demonstrates evidence for an involvement of EndMT and MV signalling as novel pathways contributing to Ang II-induced cardiac fibrosis and hypertrophy, respectively. These findings provide incentive to further investigate the therapeutic potential of Ang-(1-9) in the treatment of cardiac contractile dysfunction in heart disease, establish the importance of novel pathways in Ang II-mediated cardiac remodelling and evaluate the significance of the presence of Ang II in plasma-derived MVs.

Bridging natural and social sciences: a framework for identify strategies and actions for the conservation of biodiversity.

The Atlantic Forest is one of the most diverse areas in the world and considered a hotspot. Several actions are needed for its preservation, among them the implementation of the Biodiversity Corridors. The Atlantic Forest has three biodiversity corridors and the Rio de Janeiro State, which harbors huge species diversity, is in the Serra do Mar Corridor. We developed socioeconomic, political and environmental indicators to present conservation strategies supported by a wide database. These indicators complemented the previous surveys of priority areas which emphasized biotic elements, and their integration allowed the elaboration of strategies for the conservation and management, regionally directed, to support actions to be implemented by the Government. The analysis was done considering three subjects: Anthropic Pressure, Physical and Biotic State, and Present Ability of Response. Data analysis followed a synthesis-aggregation schedule and the resulting database was taken to a workshop, where specialists proposed strategies and actions for the conservation. These strategies were discussed considering vegetation remnant distribution, biological relevance, environmental vulnerability, kind of anthropic pressure in the region and potential for success of the actions proposed, based on the ability of response. Rio de Janeiro State is very diverse in biotic, physical, political, socioeconomic and cultural aspects which demand specific actions for each region. So, depending on the present situation of the natural and anthropic environments and on the present and future sources of degradation, regionally directed actions are applicable. This specificity in conservation actions will enable that the State remnants will be more successfully protected.

The role of microcomputer-based laboratory display in supporting the construction of new understanding in kinematics

Teachers' failure to utilise MBL activities more widely may be due to not recognising their capacity to transform the nature of laboratory activities to be more consistent with contemporary constructivist theories of learning. This research aimed to increase understanding of how MBL activities specifically designed to be consistent with a constructivist theory of learning support or constrain student construction of understanding. The first author conducted the research with his Year 11 physics class of 29 students. Dyads completed nine tasks relating to kinematics using a Predict-Observe-Explain format. Data sources included video and audio recordings of students and teacher during four 70-minute sessions, students' display graphs and written notes, semi-structured student interviews, and the teacher's journal. The study identifies the actors and describes the patterns of interactions in the MBL. Analysis of students' discourse and actions identified many instances where students' initial understanding of kinematics were mediated in multiple ways. Students invented numerous techniques for manipulating data in the service of their emerging understanding. The findings are presented as eight assertions. Recommendations are made for developing pedagogical strategies incorporating MBL activities which will likely catalyse student construction of understanding.

A Multiplicative Homomorphic Sealed-Bid Auction-Based on Goldwasser-Micali Encryption

Instead of the costly encryption algorithms traditionally employed in auction schemes, efficient Goldwasser-Micali encryption is used to design a new sealed-bid auction. Multiplicative homomorphism instead of the traditional additive homomorphism is exploited to achieve security and high efficiency in the auction. The new scheme is the currently known most efficient non-interactive sealed-bid auction with bid privacy.

The impact of unique characteristics of projects and project-based organisations on knowledge transfer

Knowledge has been recognised as an important organisational asset that increases in value when shared; the opposite to other organisational assets which decrease in value during their exploitation. Effective knowledge transfer in organisations helps to achieve and maintain competitive advantage and ultimately organisational success. So far, the research on knowledge transfer has focused on traditional (functional) organisations. Only recently has attention been directed towards knowledge transfer in projects. Existing research on project learning has recognised the need for knowledge transfer within and across projects in project-based organisations (PBOs). Most projects can provide valuable new knowledge from unexpected actions, approaches or problems experienced during the project phases. The aim of this paper is to demonstrate the impact of unique projects characteristics on knowledge transfer in PBO. This is accomplished through review of the literature and a series of interviews with senior project practitioners. The interviews complement the findings from the literature. Knowledge transfer in projects occurs by social communication and transfer of lessons learned where project management offices (PMOs) and project managers play significant roles in enhancing knowledge transfer and communication within the PBO and across projects. They act as connectors between projects and the PBO ���hub���. Moreover, some project management processes naturally facilitate knowledge transfer across projects. On the other hand, PBOs face communication challenges due to unique and temporary characteristics of projects. The distance between projects and the lack or weakness of formal links across projects, create communication problems that impede knowledge transfer across projects. The main contribution of this paper is to demonstrate that both social communication and explicit informational channels play important role in inter-project knowledge transfer. Interviews also revealed the important role organisational culture play in knowledge transfer in PBOs.

Meaning in movement : a gestural design game

This paper describes a design game that we called 'Meaning in Movement'. The purpose was to explore notions of professional dental practice with dental practioners in terms of gestures, actions and movements. The game represents a first step towards involving gestures, actions and movements in a design dialog with practioners for the purpose of designing future interactive systems which are more appropriate to the type of skilful actions and richly structured environments of dentists and dental assistants.

Review article : ecological approach in studying the relation of perception-action : review of the theoretical and empirical data

In daily activities people are using a number of available means for the achievement of balance, such as the use of hands and the co-ordination of balance. One of the approaches that explains this relationship between perception and action is the ecological theory that is based on the work of a) Bernstein (1967), who imposed the problem of ���the degrees of freedom���, b) Gibson (1979), who referred to the theory of perception and the way which the information is received from the environment in order for a certain movement to be achieved, c) Newell (1986), who proposed that movement can derive from the interaction of the constraints that imposed from the environment and the organism and d) Kugler, Kelso and Turvey (1982), who showed the way which ���the degrees of freedom��� are connected and interact. According to the above mentioned theories, the development of movement co-ordination can result from the different constraints that imposed into the organism-environment system. The close relation between the environmental and organismic constraints, as well as their interaction is responsible for the movement system that will be activated. These constraints apart from shaping the co-ordination of specific movements can be a rate limiting factor, to a certain degree, in the acquisition and mastering of a new skill. This frame of work can be an essential tool for the study of catching an object (e.g., a ball). The importance of this study becomes obvious due to the fact that movements that involved in catching an object are representative of every day actions and characteristic of the interaction between perception and action.

Movements in gesture interfaces

There is a mismatch between the kinds of movements used in gesture interfaces and our existing theoretical understandings of gesture. We need to re-examine the assumptions of gesture research and develop theory more suited to gesture interface design. In addition to improved theory, we need to develop ways for participants in the process of design to adapt, extend and develop theory for their own design contexts. Gesture interface designers should approach theory as a contingent resource for design actions that is responsive to the needs of the design process.

Modeling key compromise impersonation attacks on group key exchange protocols

A key exchange protocol allows a set of parties to agree upon a secret session key over a public network. Two-party key exchange (2PKE) protocols have been rigorously analyzed under various models considering different adversarial actions. However, the analysis of group key exchange (GKE) protocols has not been as extensive as that of 2PKE protocols. Particularly, the security attribute of key compromise impersonation (KCI) resilience has so far been ignored for the case of GKE protocols. We first model the security of GKE protocols addressing KCI attacks by both outsider and insider adversaries. We then show that a few existing protocols are not secure even against outsider KCI attacks. The attacks on these protocols demonstrate the necessity of considering KCI resilience for GKE protocols. Finally, we give a new proof of security for an existing GKE protocol under the revised model assuming random oracles.