Keywords: Research Typology, Knowledge Economy, Research System, Research Capabilities, Economic Development, Africa. JEL Classification: O30, O31, I21, O10

The management of scientific activities efficiently with the aim of development requires that their objectives, methods, roles and their links are clarified. In addition to the three usual research types -basic research, applied research and experimental development, the targeted societal research for decisionmaking is presented with its specificities. The relevant contrast appears to be less between basic research and experimental development, or between government-driven and society-driven research, than between market-driven research and public-service research. The open knowledge plays here a fundamental role in the evolution of the societies and in their development. The knowledge economy promotes useful research with a technological purpose, which makes very marginal the knowledge production and all what could allow the citizens as the societies to revitalise and redefine themselves, and to answer the present challenges. Eventually, we propose some tracks to strengthen research-developing capabilities in Africa.

Introduction

"If we are to take measures that will make a genuine difference to the lives of the 800 million people in Africa, to future generations and the environment upon which so many depend, we need sound and solid science," according to A. Steiner, UNEP Executive Director and United Nations under-general secretary (UNEP, 2006: xxiii). And [START_REF] Darnton | Google & the Future of Books[END_REF] stated that "our [US] republic was founded on faith in the central principle of the eighteenth-century Republic of Letters: the diffusion of light". But for instance at the African level, firstly at the "Science with Africa" conference organized by UNECA in March 2008 in Addis Ababa, the various themes (presentation of research findings, analysis of research conditions, research policies) were essentially all given equal importance: there lacked a clear analysis, and even an understanding, of what is research and what is not; of what sets it apart from other human activities. Barely any distinction was made between research, sciences and activities involving scientific knowledge. It is hard to manage these activities efficiently when their characteristics are not known. The preparatory documents for the CODIST I conference 1 give the same impression as well: the terms "science", "technology" and "innovation for development" are typically used together, as if they covered the same thing. This is akin to the opinion of [START_REF] Müller | Rendre technique un débat politique. Controverses autour des biotechnologies agricoles au sein de la FAO (Make technical a political debate. Controversy around agricultural biotechnologies within FAO)[END_REF] about the United Nations' Food and Agriculture Organisation (FAO): it thinks that corporate interests drive innovation, that innovation is positive, and that intellectual-property rights are required to stimulate innovation; progress is good because it progresses. What is remarkable about the vision of scientific progress is that the FAO conceives of progress as a "progression" that does not necessarily have a destination. The affirmation in the CODIST I concept note (UNECA, 2008) of a univocal link between experimental development and development is, we feel, equally open to criticism.

Likewise, a distinction must be made between research activities and studies and consulting activities. To ensure clarity of debate and efficiency of actions undertaken, one must define the outlines and activities of research, study and innovation: what are their objectives, methods and roles? How are they different and complementary? In what conditions are they conducted? Who are the stakeholders and participants?

More generally, research, science, innovation and development, and how they inter-relate, must be analysed by adopting a viewpoint that is critical in the scientific meaning of the word, i.e. by evaluating their positive and negative aspects and their contradictions as well.

To discuss these arguments, we focus above on the different types of research, from the basic to the societal research, positioning their relations with experimental development and innovation. We highlight the societal research for public decision in disseminated knowledge society. Then we discuss the meaning of knowledge economy in terms of innovation and open access to knowledge, and the link between scientific activities and development. After all, we propose some tracks to strengthen research-developing capabilities in Africa.

The different types of research

There are different types of research: Basic research, applied research, experimental development, societal research.

Basic research, applied research, experimental development

We will first try to discuss the end goals and processes of research. The contrast between basic research and applied research often structures debate, but we feel that this typology is simplistic and does not reflect current challenges. Although the boundaries of classification are by nature hazy and permeable, basic research, applied research and experimental development are the three types of conventionally recognised research, as defined by the Frascati manual (OECD, 2002).

The concept of basic research is by far the best defined. Its purpose is to understand and explain all phenomena and observable facts, or to identify and understand the mechanisms behind the phenomena as it is observed by the researcher, without any particular application or use in view. Its applications and findings are uncertain, its deadlines are unpredictable but always far in the future, and its profitability is random. Its findings belong to human heritage, and so cannot be patented (even though some have tried). Consequently, it receives mainly public funding.

Conversely, experimental development lead to the conception of pilot schemes and to the industrial and commercial implementation of research outputs, which can often be patented. It is essentially funded by the private sector, and its outputs belong mainly to investors.

The boundaries of applied research -which is neither basic nor experimental developmentare quite poorly defined in the daily research world. Sometimes, research is said to be applied simply because its area of application is precisely scoped, without this specifying how the research operates: for example, research will be described as being applied to transport or agriculture. In this case, it is called oriented basic research by OECD. Most often, applied research is defined as an extension of the discoveries of basic research: understanding new mechanisms through the latter can lead, in a totally unpredictable way, to new applications in terms of technologies or services, whose development is the purpose of applied research. Applied research then aims to acquire new knowledge in order to resolve practical and tangible problems or to develop applications, goods and services. Its findings are often considered patentable, and it is primarily conducted by the private sector.

The taxonomy of basic research / applied research is sometimes easy to apply. Reynolds (1998) defines basic research as the foundation of the knowledge base upon which decisionmakers rely whilst applied research tends to seek the cause and remedy for an immediate issue.

In biology, basic research will seek to understand a cell mechanism; applied research will possibly develop a drug based on the newly-discovered cell mechanism. In physics, basic research was done on the energy levels of elemental particles; then, with this new knowledge, applied research developed the laser. In the field of mathematics, basic research into algorithmics led to applied-research extensions in the area of encryption systems.

Basic research therefore seems to be the essential foundation for applied research as thus defined. The distinction may even appear artificial, given that one cannot exist without the other. In particular, they are linked by a spiral: discovery of a basic mechanism, which is used to develop a new practical application, which allows new advances in basic research, and therefore the discovery of new mechanisms… [START_REF] Denny | Research, capacity-building and empowerment for sustainable management of African wetland ecosystems[END_REF] reported that developing countries consider there is rather a need for studies on immediate every day problems than curiosity -driven research. It is more appropriate for industrialized and rich than poor countries. But lack of basic research leads to a poor knowledge and expertise capacity of the nation.

Targeted societal research for public decision-making

The concept of targeted research has emerged more recently: unifying basic research and applied research, it arises from social needs and is commissioned to resolve a concrete issue [START_REF] Barré | La science est morte, vive la science ! (Science is dead, long live science!)[END_REF][START_REF] Joumard | Recherche à visée sociétale, un enjeu pour nous tous (Societal research, an issue for all of us)[END_REF][START_REF] Pestre | L'évolution des champs de savoir, interdisciplinarité et noyaux durs (Evolution of knowledge fields, interdisciplinarity and core elements)[END_REF][START_REF] Jollivet | Canevas pour une réflexion sur une interdisciplinarité entre sciences de la nature et sciences sociales (Framework for a thought about interdisciplinarity between nature sciences and social sciences)[END_REF]. It is called mode-2 science [START_REF] Gibbons | The New Production of Knowledge: The Dynamics of Science and Research in Contemporary Societies[END_REF][START_REF] Nowotny | Re-thinking Science: Knowledge and the Public in an Age of Uncertainty[END_REF] or post-normal science [START_REF] Funtowicz | A New Scientific Methodology for Global Environmental Issues[END_REF][START_REF] Funtowicz | Science for the post normal age[END_REF]1997[START_REF] Luks | Post-normal science, Dematerialisierung und die Ökonomie -Über den (wirtschafts)wissenschaftlichen Umgang mit Umweltproblemen[END_REF][START_REF] Luks | Post-normal science and the rhetoric of inquiry: deconstructing normal science?[END_REF]Funtowicz et al., 1997).

The human sciences contain many examples of such research. To take examples from the field of transport: in psychology, understanding human behaviour in driving situations; in sociology, understanding users' modal choices; in geography, identifying laws that govern spatial phenomena such as urbanisation and transport flows. This research is defined as a response to concrete societal questions, implementing the principles of theoretical research but with constant interaction between field and theory that promotes an understanding of both.

The societal aspect of this research does not necessarily refer solely to the human and social sciences. Research on emissions of atmospheric pollutants by road transport has in the past 20 years highlighted essential parameters such as vehicle operating conditions (speed, gradient, ambient temperature, etc.) and the composition of vehicle fleets. In the field of rail safety, research has shown the importance of maintenance procedures and their optimisation, evaluated in terms of overall transport-system efficiency and not only of short-term profitability. In the environment field, work on the hierarchy of the physical and chemical causes of declining ecological quality of watercourses will allow better organisation of the measures needed for watercourse restoration and the health of local populations. In public health, at-risk groups or risk factors are identified for a given health event in order to choose action priorities according to very non-commercial criteria that are extremely important in citizens' minds (for example, the premature death of the elderly). In agronomic research, recent work has diagnosed the flaws of the dominant productivist system and shown it is possible to reconcile the profitability of agricultural production with environmental protection; but designing economical and autonomous systems is scarcely compatible with the short-term economic interests of a sector that lives on selling, and even importing, inputs and exporting goods.

This research therefore produces knowledge and explanations of a public, and even social, phenomenon. It often involves measuring and modelling a phenomenon in given spatial and temporal circumstances, and quantifying the role of an influential parameter in order to support the decision-making process (the concept of research for public decision-making is often used).

A second characteristic arising from this type of research is that its findings can immediately be commented upon by all, because the phenomenon under study is a public, social object and the concepts are very similar to mainstream concepts, especially if one bothers to translate the jargon. The fact that everyone can talk about it does not mean, however, that everyone talks about it properly. This is the strength and the difficulty inherent in this type of research. For instance, in the transport-environment sector, citizens highlight the role of congestion, but research highlights rather the role of increasing trip length, the congestion playing a positive role by decreasing the traffic demand.

Lastly, a third characteristic is that this research can be applied almost immediately (if one excludes power-related phenomena and multiple change-resistant factors) and can improve society's mode of organisation by minimising its environmental impact or the risk of accidents or deaths, to repeat the examples given above. The research is not typically applied in the market economy, and therefore does not receive the accelerating boost that profitability gives to a private-sector company. It must be the subject of a collective, political decision.

It is obvious that the basic / applied research typology no longer holds true: in these fields, the characteristics of research activity differ radically from those of basic research, although they are not part of the spiral which links applied research and basic research or in a continuum that adds economic value. This spiral, previously autonomous, is being challenged by the introduction of a major stakeholder: the society as a whole, with its representatives and lobbies. In the environmental field, researchers have highlighted multiple impacts of human activities on the environment, which has helped drive the emergence of social concern about environmental issues and then about the problem of the nature-society-economy schematic of sustainable development, which itself guides research activities, which, in turn, will doubtless yield new social concerns... In summary, the characteristics of this research, which we prefer to term societal rather than targeted, which is too vague term, could be:

-social utility: its applications are essentially in the field of the collective management of our society, and are not directly market-based. The current debates about sustainable development are one of its most accomplished expressions; -the non-patentability of its findings, even though the tools developed to obtain these findings can add value and/or be transferred into the market sphere; -the independence of research authors, which must be ensured by their status, and which alone can guarantee the defence of the collective interest through non-subjection to market interests; -the highlighting of strong relations between the phenomenon studied and parameters that are generally already known, and which are thus hierarchised and quantified; -its transversal, often multi or transdisciplinary character, not only drawing on disciplinary contributions but can set up new frameworks beyond them [START_REF] Funtowicz | Science for the post normal age[END_REF][START_REF] Gibbons | Mode 2 society and the emergence of context-sensitive science[END_REF], which cannot be reduced to the concepts of basic and applied research; -the natural insertion of its findings into public conversation, from the village square to society's big debates; -it is essentially publicly funded, because of its first three characteristics.

The relevant contrast therefore appears to be between commercial or market-driven research and public-service research not mediated by the market, rather than between a knowledge production system driven by government and academic community on one side and by the civil society on other side, understood to comprise individuals and groups. This last picture forgets the imbalance between the stakeholders with financial, social, cultural and expertise resources, and those without [START_REF] Saurugger | Les groupes d'intérêt entre démocratie associative et mécanismes de contrôle' (Lobbies between community democracy and control mecanisms)[END_REF].

In addition, societal research has the distinctive feature of often developing without, and sometimes against, scientific-research institutions, particularly in so-called alternative fields (organic agriculture, renewable energies, etc.). Some non-governmental organisations are now scientifically more competent than public institutions. In parallel, a rise can be seen in the scientific expertise ability of civil society; this emerging field forms science's third sector.

Societal research experiences the same funding and support problems as basic research. It generates little private profit through directly-patentable applications; its primary target is collective benefit, which may be against corporate logic. It should be steered by the research stakeholders themselves, in association with social demand. Peer review in accordance with appropriate criteria provides the necessary guarantees of research quality, but it includes a wider, more temporary and heterogeneous set of practitioners, collaborating on a problem defined in a specific and localised context [START_REF] Gibbons | Mode 2 society and the emergence of context-sensitive science[END_REF]. The short-termism of big corporations' steerage and the opaqueness of direct steerage by ministries and foundations can be a strong barrier to its development. Africa has to develop its own approach for scientific research based on the African culture and environment to respond to African priorities and solve their own problems and to address people's needs [START_REF] Stigter | Scientific research in Africa in the 21 st century, in need of a change of approach[END_REF].

Disseminated knowledge society

Society's research needs must also and especially include the production of public goods: open knowledge, plural and independent expertise, and non-profit innovation or innovation meeting non-solvent societal needs. However, the production of socially-useful knowledge and innovations is no longer the preserve of traditional public or private research institutions; it is also performed by the emerging third sector of knowledge and innovation, i.e. by multitudes of collectives (patients, farmers, consumers, peer-to-peer digital communities, etc.) which collectively take charge of producing scientific and technical knowledge and must be recognised as equally legitimate partners in public research. In this case, the term used is "disseminated knowledge society", which marks the entry into a finite world where science has a new role to play (precautionary principle, sustainable development). There is thus a need for innovation and research policies to promote clear social and environmental priorities and global concerns.

In this third sector, local communities in Africa also create knowledge and must therefore play a central role in creating local content. Local knowledge spans farming, wildlife and environmental management. The oral tradition is important in Africa as the main way of transmitting knowledge, which is memorised through different generations. Access to local knowledge is difficult for various reasons, especially the low level of development of institutions in most African countries (Raseroka, 2007: 13). As emphasised by the participants in CODI V (UNECA, 2007: 14), there is a need for wider availability and use of traditional and local knowledge, with universities, especially their libraries, being actively involved in the processing and dissemination of this knowledge.

Societal research is what creates the link between scientific knowledge and the multiple facets of society's organisation. It meets society's demand for better self-understanding, by of course incorporating the findings of basic research and of experimental development, and even by developing such research if necessary. Research findings have to be communicated in an understandable terms to government, general public and to local communities [START_REF] Denny | Research, capacity-building and empowerment for sustainable management of African wetland ecosystems[END_REF]. It is therefore essential in guiding the decisions of the individual, the citizen and the elected representative. It is an essential constituent of democratic transparency.

The knowledge economy

The knowledge economy is now presented as the new paradigm of science, economics and development. It is defined as the economy in which knowledge is perceived as an essential resource and a factor of production, but also the economy in which knowledge is the main driver of economic growth. It is characterised by four main pillars: innovation, investment in experimental development, human capital development, and incentives and legislation (Tapper, 2007: 10).

The knowledge economy closely combines two aspects that we will now discuss in turn: the growing importance of knowledge and its dissemination using new information and communication technologies (ICTs), and their partial privatisation.

Knowledge as an essential resource

According to A. [START_REF] Janneh | Opening address[END_REF], UNECA Executive Secretary, the current global society is driven by information and is characterised by knowledge-intensive industries and services, comparative advantage, and economic success being increasingly based on the effective utilisation of intangible assets such as knowledge, skills and innovative potential. Africa risks losing a high percentage of its human resource through a brain drain to countries where the knowledge industry is more developed. Although it is accepted that knowledge plays an essential role in success and that the brain drain is real, this statement has two flaws:

-It is far from certain that knowledge is playing a more important role than before. The industrial revolution in Europe and North America was based on the Enlightenment, rationalism from Descartes to Kant, and scientific creativity in the 19 th and 20 th centuries. -Referring only to industries and services in the dynamic of global society masks the essential role played by public services of all kinds, in particular by public education, university, public research, libraries and other public systems of information and culture, which actually absorb most of the exodus of African minds.

According to [START_REF] Amable | Introduction à l'économie de la connaissance (Introduction to the knowledge economy)[END_REF], the recent attention paid to the knowledge economy stems from the growing importance of research and education activities in the global economy. This rise in knowledge-intensiveness also concerns the associated ICTs. But it would take boundless technological optimism to conclude that the dissemination of these technologies can help South countries to catch up with those in the north. The dissemination of these techniques can only be considered as a complement to organisational, cultural and behavioural changes, and, in particular, to the improvement of individuals' skills. One of these elements, transplanted into a different context, is not in itself enough to trigger a virtuous dynamic.

The articulation or interconnection of the physical, technical, social, cultural and even psychological aspects highlights the need for a systemic approach. The idea is not for each person to be competent in everything, but, on the one hand, for each person, at least in the knowledgerich sphere, to have a wide and multi-disciplinary scientific culture, and, on the other hand, for a problem to be analysed with a range of approaches that cover the various aspects of the system.

This leads us to reflect on knowledge and how it is disseminated. Knowledge is a good that is hard to control, unrivalled and cumulative [START_REF] Vincente | Économie de la connaissance (Knowledge economy)[END_REF]. The first regime for incentivising knowledge creation is creating a market to restore private initiative. It aims to restrict access to knowledge by granting temporary exclusive rights to new knowledge. The second regime is public: open knowledge, with the circulation of codified knowledge, practical knowledge, and research instruments. The world of closed knowledge is a semi-permeable world that makes cooperation difficult. The idea of closed knowledge is closely associated with intellectual-property rights (copyright and patent rights). Policies that help to weaken open-science institutions may prove counter-productive in the long term.

It is obviously important to encourage the use of new ICTs in order to reduce the digital divide within African countries and between Africa and other regions, but especially because it is an extraordinary vehicle for exchange, culture, education and information, and therefore for accessing and disseminating knowledge. Nevertheless, it is advisable for each exchange platform to have a clear vision of its target audience. Researchers, businesspeople and the general public seek different information with various degrees of specialisation. These instruments should be initiated, and most of all administered, by Africans so that they reflect African concerns.

But it is just as important to conduct an intellectual-property policy in favour of open science, by excluding life and knowledge from the scope of patents, and by transitioning scientific journals into publications based on open access, creative commons, etc. Note that the shamans of 20 Indian tribes in Brazil, meeting in early December 2002 in São Luis, wrote very officially to the World Intellectual Property Organization with the backing of the Brazilian government to protest against the fact that their traditional knowledge -often related to the sacred domaincould be patented [START_REF] Barthélémy | Propriété intellectuelle : contre la loi de la jungle, les Indiens aiguïsent leurs armes juridiques (Intellectual property: Indians improve their legal tools)[END_REF].

However, according to A. Ouédraogo (UNECA, 2007: 5) of the International Labour Organisation (ILO), the knowledge economy is skills-and gender-biased and tends to generate income inequalities and unbalanced access to opportunities. Technoscience is indeed still maledominated, unlike the humanities and human sciences.

Knowledge privatisation and competition

On the basis of democratising information -which, in itself, is legitimate -a more questionable approach is often made official: that of systematic competition with the other economic powers [START_REF] Boudet | Économie de la connaissance et démocratie culturelle (Knowledge economy and culture democracy[END_REF]. The knowledge economy thus tends to format public opinion and institutions according to the dominant criteria of growth and instant profitability; this occurs to the detriment of the services which must nevertheless continue to be dispensed by science, art and culture in order to maintain an acceptable level of social cohesion both at school and in society [START_REF] Richez | Économie de la connaissance (Knowledge economy)[END_REF]. According to Alain Trautmann (2009), the leader of the "Sauvons la recherche" ("Save research") movement, which expresses the concerns of French researchers and plenty of their fellow citizens, this knowledge economy, by systematically linking research and innovation, is increasingly tending to constrict research activity. The knowledge economy promotes useful research with a technological purpose, which eliminates the human and social sciences. The training of the individual and the citizen, and the ability of societies to revitalise and redefine themselves, are thus severely unbalanced, benefiting growth with no prospect of the sustainable development of civilisation [START_REF] Boudet | Économie de la connaissance et démocratie culturelle (Knowledge economy and culture democracy[END_REF]. [START_REF] Amable | Introduction à l'économie de la connaissance (Introduction to the knowledge economy)[END_REF] thus warn against the normative aspect associated with the knowledge economy: a reform of institutions and organisational modes accompanying a new age of capitalism that is supposed to be characterised by intensified competition, by precarity and by the requirement of flexibility. Some of these elements are a myth; others are orienting societies towards a single model of capitalism under cover of technological determinism or of the need for modernity.

Knowledge is henceforth understood to be marketable only, a privatised factor or private growth; an object of trade: Instructive in this respect is the definition of the digital economy ("efinance, e-transactions, e-commerce, e-trade and e-content, e-legislation") in UNECA (2009: 3). The primary objective is the commercialisation of science, knowledge and life, followed by researchers being urged to be "competitive". The socio-cultural and institutional environment is thus becoming ever less conducive to basic or societal research and to knowledge that is hard to commercialise.

Trade, communication and business methods are now used to manage, and even produce, knowledge. This was epitomized by the holding of an "idea factory" at the UN "Science with Africa" conference in March 2008 in Addis Ababa: a sort of multi-session brainstorm, during which hundreds of participants launched thousands of ideas, from which a committee of unknown consultants extracted 20. This big bar-room discussion ignored the fact that the difficult thing is not to produce ideas or even to select the best ones, but to produce original and potentially productive ideas. It will subsequently be necessary to convince the community that they are good ideas, because the most original and doubtless most productive ideas are precisely the most vulnerable to all sorts of criticism and which meet with the most resistance. Original ideas are vulnerable because new: they are not yet well developed enough to be understood. It is therefore hard to defend them, because the arguments in their favour have not been fully constructed. This is why original ideas are often the most difficult to win approval for.

In addition, who has the power and is supposed to choose from among the ideas put forward, to decide which are admissible and which are not? This is a strategic activity for the African society in question. It requires highly-cultured people with very open minds. The legitimacy of the people tasked with this job is essential for the selected new ideas to gain social recognition and thus be embraced. In addition, [START_REF] Leach | Science and Citizens: Globalization and the Challenge of Engagement[END_REF] argue that many non-western views of knowledge, as seen in research in development studies, still do not fit with the prevailing view of 'expert knowledge' in the west and thus may not be considered legitimate. And even when scientists reach out for local knowledge, they may lack important skills needed for success.

This method, which occupied the participants for a good part of the conference, is in favour of banality and marketing, far from difficult intellectual production and its scientific rigour, which are essential for "improving capabilities".

There is a need to develop appropriate policy in Africa to develop and apply knowledge based services for marginal people [START_REF] Stigter | Scientific research in Africa in the 21 st century, in need of a change of approach[END_REF].

Research system and its connection with development

At the same conference, with the notable exception of several excellent papers -in particular by the president of the Academy of Sciences for the Developing World (TWAS), the representative of UNESCO, and a member of the European Research Foundation (ESF) -there was no analysis of the social and economic conditions of research, of scientific activity, or of the transfer of knowledge and know-how: analysis of scientific staff and of the conditions in which they work; of the fields they cover; of the conditions of success, etc. The human and social sciences were curiously absent, as if their development were only a matter of techniques and not, firstly, of human resource.

We feel it is essential to understand the conditions of scientific production and the environment that promotes it, for the three types of research presented above -basic research, experimental development, and societal research -while investigating in depth the relationships between research, knowledge and development. Development cannot be a blind process or one led in accordance with a simplistic ideology that matches the standards of the current developed countries. The exclusive focus on companies implies that a country's development derives quasiexclusively from the development of private-sector companies. This forgets the equally fundamental role of public services (water, electricity, transport, health, culture, education, etc.), without which solid development is not possible.

The contribution of all scientific activities to Africa's development should be studied. In particular, it would be advisable not to focus on specific aspects to the detriment of a holistic, balanced view. For example, questions must be asked about the role and boundaries of ICTs and of the geosciences in research, technological innovation, and lastly development. This analysis cannot be done only by the professionals and operators in these domains, who are both judges and judged.

Ultimately, a society cannot revitalise without analysing its actions (or inaction), its experiences, and the conditions of its past failures and successes. By this we mean a deep and rigorous analysis, and not a sub-ideology of marketing: here, human and social sciences research has a key role to play. In activities to do with information, science and technology, great importance should be given to the human and social sciences and not just to engineering sciences -and, indeed, to life sciences. Only human and social sciences can address questions such as: what are the decision-making processes? How is a transport system organised? What are the different economic systems in farming? What are the cultural barriers to innovation? Which cultural resources promote innovation and development? Which elements of traditional knowledge and know-how are liable to be factors of development? In development, what are the respective roles of the market, public services, and the informal sector? What role do international relations play in development? Which elements of governance accelerate or impede development?

Producing knowledge locally

The analysis of conditions of knowledge and know-how production obviously complements production itself. But political decision-makers need fast answers to their questions (projects, plans, policies, etc.). When national research has not been developed, as is the case in many South countries, there is no training through research or, consequently, emergence of local skills, including in research firms. Neither national research nor consultants in the South can therefore provide a general response to these questions.

The decision-makers will then use consultants or researchers from developed countries. Those unversed in local realities, and lacking the time or resources to become properly acquainted therewith, propose solutions that are formally good but with content based on their knowledge and culture, in a kind of copy-and-paste approach. Most often, these solutions are inadequate in substance because their execution is problematic owing to an unsuitable sociocultural environment. Through regulatory or advertising pressure, they can provide an acceptable short-term response, but it will not be sustainable.

The response to this is definitely investment in local research, and firstly by more highly valuing local researchers and giving them recognition.

The objective of research, however, must not be responding to the questions of political decision-makers. The link is more complex: research activity creates knowledge and know-how, promotes local skills, and thus increases the scientific skills of society, which enables local consultants to respond directly and properly to decision-makers' requests. An essential prerequisite for research is independence.

The research independence allows detachment from official data and from local knowledge and know-how, which, as far as possible, must be questioned before being validated. Independence is primarily necessary because research is not guided by a policy of narrow and short-term objectives. Electricity and the electric bulb were not discovered while improving the candle! The results of research are generally unexpected. This is true of basic research, but also to a great degree for societal research, which is far more productive than the simple question that drove it. Only experimental development is wholly guided by a precise objective, using existing knowledge.

But because small resources, it must be optimised and approach-sharing must be maximised. Collaborative research between researchers and universities is the most productive, and though it is promoted in policy messages, it is made very difficult by research conditions. Real backing should be given to researcher networks by eliminating obstacles in terms of regulation, management, finance and personal careers so that collaborative research is genuinely encouraged, particularly among South countries themselves. Researchers and sector professionals must therefore initiate and take part in specialist networks, which for a relatively small cost set up excellent ways of optimising research resources, notably through coordination, efficient exchange and training schemes, and the dissemination of knowledge and findings. This can be networks at every level, from regional to international. The pooling of knowledge, tools, methods and solutions is necessary, but must always be adapted to the context of the considered country or region.

Programme to strengthen research-developing capabilities in Africa

Africa needs the international community's support to strengthen its capability to develop its research. United Nations, convinced that Africa needs medium-and long-term scientific research for its development, can develop a support programme in synergy with the other ongoing programmes, to support the development of research in Africa. The United Nations University, UNESCO, the UNDP and other UN organisations can make an effective contribution to an integrated programme by leveraging their experience in these countries, in order to support the development of research in the various disciplines of interest by country and by region: intangible support for research (excluding facilities), facilitation of exchanges, joint projects, and the dissemination of skills and findings. The programme could revolve around the following:

A. Strengthen the self-confidence of African researchers -Improve institutional recognition of African researchers (pay, consideration), which would help keep brains in Africa; -Promote researchers' intellectual fulfilment by trusting their creative abilities, which would promote the emergence of African thinkers who would drive Africa upwards; -Promote African researchers' mobility, so that they can leave and then be able to come back; -Encourage African expatriates to take part in the development of research in their country of origin; -Host foreign students, especially from the North, in universities and research teams; -Set up research projects on a North-South cooperation basis; -Fund the hosting of North researchers for short assignments in African research teams; -Encourage the authoring in Africa of dissertations on topics of African interest, co-directed by parties from North and South; -Publish articles co-authored by researchers from North and South; -Summarise and publicise successful experiments conducted in Africa.

B. Build an African research community

In order to promote knowledge and know-how transfer between southern countries:

-Promote encounters with African researchers by holding conferences and seminars in Africa and by giving logistical support to participants; -Encourage the creation of bi-or multi-lateral, mono-or multi-disciplinary African research teams, by promoting the set-up of research cooperation projects; -Facilitate the physical mobility of researchers in Africa by lifting regulatory and logistical barriers, especially for transport; -Train researchers and students in research tools (software, hardware) and primarily in the specific methods of research: invest in people rather than equipment. This detailed proposal needs to be discussed and developed further. It could draw inspiration from the experience of the COST initiative 2 . Since 1971, this inter-governmental initiative has aimed to increase cooperation and interaction between researchers in nine scientific domains that cover most of the field. COST is organised by single cooperation "actions" on a given topic, with a limited number of researchers from at least five countries, for a period of three to four years. For example, COST funds participation in action-coordination meetings, inter-laboratory researcher exchanges lasting one to six months, training schools, seminars and, lastly, the dissemination of findings in the form of dedicated reports, conferences and websites. The initiative is open to non-European countries and particularly to Mediterranean-basin countries. Support from COST or another European source can certainly be envisaged for an African capability-strengthening programme.

The first stage could be to set up a pilot project of cooperation in a specific domain.

Conclusion

It is hard to manage the scientific activities efficiently with the aim of development when their characteristics are not known. One must define the outlines and activities of research and innovation: what are their objectives, methods and roles? How are they different and complementary? In what conditions are they conducted? Who are the stakeholders and participants?

We argue that in addition to the three types of conventionally recognised research -basic research, applied research and experimental development, we have to add the targeted societal research for decision-making, which introduces a major stakeholder, the society as a whole.

The discussion of these different research types indicates that the relevant contrast appears to be less between basic research and experimental development than between commercial or market-driven research and public-service research not mediated by the market. The open knowledge plays here a fundamental role in the evolution of the societies and in their development.

The concept or ideology of knowledge economy favours nevertheless instant profitability and constricts research activity, by promoting useful research with a technological purpose, which makes very marginal basic research, societal research, human and social sciences, and all what could allow the citizens as societies to revitalise and redefine themselves. The exclusive focus on companies implies that a country's development derives quasi-exclusively from the development of private-sector companies. This forgets the equally fundamental role of public services, without which solid development is not possible, nor even technological development.

The knowledge economy appears thus opposed to knowledge creation, although this new knowledge in exact or social sciences is absolutely needed by each of us and each society to answer the present challenges.

C.

  Cover the different forms of research -Provide equal support to the different forms of research: basic research, experimental development, societal research; -Draw on the knowledge and know-how transmission needs of the various tiers of African society in order to supply societal research; -Take a holistic, mid-to long-term approach to research; and -Promote multi-disciplinary research (engineering sciences, life sciences, human and social sciences). D. Strengthen research-management institutions -Improve the capabilities of research-management staff by training them in this specific activity, using workshops and seminars on research. E. Disseminate knowledge -Encourage and facilitate publication and dissemination of the findings of research done in Africa; -Support and encourage the development of online African science journals on an openaccess basis.

  Information, Science and Technology of UNECA, Addis Ababa, 28 April -1 May 2009. Available at: www.uneca.org/codist/codist1.asp 2 European Cooperation in Science and Technology, Available at: www.cost.esf.org


Kaspar E Vogt

Dr Marco Canepari
email: marco.canepari@ujf-grenoble.fr

On the Induction of Postsynaptic Granule Cell Purkinje Neuron LTP and LTD

In the last decade several experimental studies have demonstrated that particular patterns of synaptic activity can induce postsynaptic parallel fibre (PF) long-term potentiation (LTP). This form of plasticity can reverse postsynaptic PF long-term depression (PF-LTD), which has been traditionally considered the principal form of plasticity underlying cerebellar learning. Postsynaptic PF-LTP requires a transient increase of intracellular Ca 2+ concentration and, in contrast to PF-LTD, is induced without concomitant climbing fibre (CF) activation. Thus, it has been postulated that the polarity of long-term synaptic plasticity is determined by the amplitude of the Ca 2+ transient during the induction protocol, with PF-LTP induced by a smaller Ca 2+ signals without concomitant CF activation. However, this hypothesis is contradicted by recent studies. A quantitative analysis of Ca 2+ signals associated with induction of PF-LTP indicates that the bidirectional induction of long-term plasticity is regulated by more complex mechanisms. Here we review the state-of-the-art of research on postsynaptic PF-LTP and discuss the principal open questions on this topic.

Introduction

According to the classical theory, the activity-dependent weakening of erroneously activated cerebellar granule cell (CGN) to Purkinje neuron (PN) synapses is the most important form of synaptic plasticity in the cerebellum [START_REF] Marr | A theory of cerebellar cortex[END_REF][START_REF] Albus | A theory of cerebellar function[END_REF]. This view gained importance with the discovery that pairing parallel fiber (PF) and climbing fiber (CF) activity could induce long-term depression (LTD) of PF inputs [START_REF] Ito | Climbing fiber induced depression of both mossy fiber responsiveness and glutamate sensitivity of cerebellar Purkinje cells[END_REF][START_REF] Karachot | Stimulus parameters for induction of long-term depression in in vitro rat Purkinje cells[END_REF]. An important characteristic of the depression of PF excitatory postsynaptic potentials (EPSPs) is the postsynaptic site of induction and expression. PF-LTD requires elevation of free intracellular calcium concentration ( [Ca 2+ ] i ) [START_REF] Konnerth | Brief dendritic calcium signals initiate long-lasting synaptic depression in cerebellar Purkinje cells[END_REF] and activation of type-1 metabotropic glutamate receptors (mGluR1) [START_REF] Aiba | Deficient cerebellar longterm depression and impaired motor learning in mGluR1 mutant mice[END_REF][START_REF] Conquet | Motor deficit and impairment of synaptic plasticity in mice lacking mGluR1[END_REF][START_REF] Hartell | Induction of cerebellar long-term depression requires activation of glutamate metabotropic receptors[END_REF], leading to a decrease in AMPA receptor efficacy [START_REF] Hemart | Properties of glutamate receptors are modi. ed during long-term depression in rat cerebellar Purkinje cells[END_REF] and internalization [START_REF] Matsuda | Disruption of AMPA receptor GluR2 clusters following long-term depression induction in cerebellar Purkinje neurons[END_REF]. To reverse PF silencing, the necessity of a reset mechanism has been postulated [START_REF] Wong | A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP[END_REF][START_REF] Coesmans | Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control[END_REF][START_REF] Jörntell | Synaptic memories upside down: bidirectional plasticity at cerebellar parallel fiber-Purkinje cell synapses[END_REF].

In the last decade, the existence of postsynaptic forms of PF-LTP has been demonstrated [START_REF] Wong | A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP[END_REF][START_REF] Coesmans | Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control[END_REF]. This form of plasticity is a potential reset mechanism because it shares the same site of expression of PF-LTD. It was first shown that postsynaptic PF-LTP could be induced by repetitive (1 Hz) PF stimulation without concomitant CF activation. The induction mechanism required elevation of [Ca 2+ ] i , but smaller than that associated with the induction of CF-dependent PF-LTD [START_REF] Coesmans | Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control[END_REF]. This evidence suggested that the polarity of PF plasticity could be given by the size of the [Ca 2+ ] i transient which is higher for LTD [START_REF] Coesmans | Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control[END_REF][START_REF] Jörntell | Synaptic memories upside down: bidirectional plasticity at cerebellar parallel fiber-Purkinje cell synapses[END_REF]. The idea of different Ca 2+ thresholds responsible for plasticity mechanisms of different polarity was proposed in 1982 [START_REF] Bienenstock | Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex[END_REF] and termed BCM rule . According to the BCM rule, lower and higher Ca 2+ transients are associated with the induction of LTD and LTP respectively. Here, we will use the term inverse BCM rule [START_REF] Bienenstock | Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex[END_REF] to refer to a scenario where lower and higher Ca 2+ transients are associated with the induction of LTP and LTD respectively.

Recently, it has been shown that local [Ca 2+ ] i elevation associated with bursts of PF-EPSPs can be much larger than that associated with the CF-EPSP, but repetitive application of this protocol leads to postsynaptic PF-LTP [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF]. This finding, together with the evidence that LTP could not be induced solely by local Ca 2+ photo-release [START_REF] Tanaka | Ca2+ requirements for cerebellar long-term synaptic depression: role for a postsynaptic leaky integrator[END_REF] suggested that bidirectional induction of plasticity cannot be explained only in terms of [Ca 2+ ] i signal amplitude.

Here we review the most recent findings on PF-LTP induction mechanisms and discuss our current understanding.

Revisiting bidirectional induction of postsynaptic plasticity

PF-LTD is classically induced by pairing PF input (either single stimuli or bursts) with CF activity and CF activation has been substituted by postsynaptic depolarization [START_REF] Ito | Cerebellar Long-Term Depression: Characterization, Signal Transduction, and Functional Roles[END_REF][START_REF] Hartell | Parallel fiber plasticity[END_REF]. PF-LTD is also induced by strong PF stimulation without pairing with CF activity [START_REF] Hartell | Strong activation of parallel fibers produces localized calcium transients and a form of LTD that spreads to distant synapses[END_REF]. Although some molecular pathways leading to synaptic depression may be similar in different induction protocols, the expected time course and the spatial localization of triggering signals remain essentially diverse. The same argument applies to PF-LTP. Thus far, LTP was induced by three stimulation protocols, namely the one-pulse induced PF-LTP , the burst induced PF-LTP and single-train induced PF-LTP (see Fig. 1).

The first induction protocol to be characterized was the one-pulse induced PF-LTP (Fig. 1a), a repetition of a single pulse of PF stimulation at 1 Hz for 5 minutes [START_REF] Wong | A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP[END_REF][START_REF] Coesmans | Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control[END_REF]. Pairing a PF-EPSP with a CF-EPSP, with the CF-EPSP following the PF-EPSP, reversed LTP into LTD [START_REF] Coesmans | Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control[END_REF].

Both plasticity forms required transient [Ca 2+ ] i elevation and 20 mM injection of the high affinity buffer BAPTA could lead to LTP induction with a CF pairing [START_REF] Coesmans | Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control[END_REF]. To interpret this result, it has been suggested that PF plasticity follows an inverse BCM rule compared to hippocampal synapses [START_REF] Jörntell | Synaptic memories upside down: bidirectional plasticity at cerebellar parallel fiber-Purkinje cell synapses[END_REF]. According to this view, LTP would be induced by a smaller [Ca 2+ ] i signal compared to LTD and the additional Ca 2+ would be provided by the CF depolarisation. Further support for this hypothesis came from a previous report showing that CF-EPSP was associated with a supra-linear Ca 2+ signal and that for minimal PF activation this signal was mGluR1-dependent and limited to dendritic spines [START_REF] Wang | Coincidence detection in single dendritic spines mediated by calcium release[END_REF]. The inverse BCM rule hypothesis, however, did not take into account two factors that were reported in that study. First, the protocol used for pairing consisted of a burst of PF-EPSPs (typically 5-10 pulses at 100 Hz) and not in a single pulse. Second, by increasing the number of stimulated PF, a more prominent mGluR1independent supra-linear Ca 2+ signal was observed in a larger portion of the dendrite. It was later reported that the size of this supra-linear Ca 2+ signal depended on the delay between the PF burst and the CF-EPSP, but this delay was different from that associated with mGluR1dependent short-term synaptic depression [START_REF] Brenowitz | Associative short-term synaptic plasticity mediated by endocannabinoids[END_REF] and PF-LTD [START_REF] Safo | Endocannabinoids control the induction of cerebellar LTD[END_REF]. Indeed, it has been shown that mGluR1-independent supra-linear Ca 2+ summation is due to the local and transient saturation of the endogenous Ca 2+ buffer and can elevate [Ca 2+ ] i to micromolar concentrations, much higher compared to [Ca 2+ ] i elevation associated with a CF-EPSP [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF]. Repetition of a burst of 7 PF-EPSPs at 1 Hz for one minute induced postsynaptic PF-LTP (burst induced PF-LTP, Fig 1b).

The evidence that a [Ca 2+ ] i signal larger than a CF-mediated [Ca 2+ ] i signal induces LTP (and not LTD) led to a revision of the simple inverse BCM rule proposed before [START_REF] Coesmans | Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control[END_REF][START_REF] Jörntell | Synaptic memories upside down: bidirectional plasticity at cerebellar parallel fiber-Purkinje cell synapses[END_REF].

The general validity of the inversed BCM rule was also explored in a study where plasticity induction was tested by local Ca 2+ photo-release. It was found that at high concentrations at spiny peri-dendritic regions could induce LTD, but no LTP was observed for smaller Ca 2+ signals [START_REF] Tanaka | Ca2+ requirements for cerebellar long-term synaptic depression: role for a postsynaptic leaky integrator[END_REF].

Both the one-pulse induced and the burst induced PF-LTP require repetitive application of the stimulating protocol. More recently, it was found that postsynaptic LTP can be also induced in vivo by a single train of 15 stimuli at 100 Hz (single-train induced PF-LTP, Fig. 1c) [START_REF] Wang | Long-term potentiation of the responses to parallel fiber stimulation in mouse cerebellar cortex in vivo[END_REF].

The interpretation of these experimental observations points to more complicated scenarios underlying the induction of postsynaptic PF-LTP, but also of PF-LTD. In the case of postsynaptic PF-LTD, the induction can occur with moderate PF stimulation and pairing with a CF-EPSP, or using a stronger PF stimulation intensity [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF][START_REF] Hartell | Strong activation of parallel fibers produces localized calcium transients and a form of LTD that spreads to distant synapses[END_REF] without concomitant CF stimulation. The burst of PF-EPSPs that induces PF-LTD is associated with a [Ca 2+ ] i signal > 2 µM [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF] and the evidence that Ca 2+ photo-release can induce this form of plasticity [START_REF] Tanaka | Ca2+ requirements for cerebellar long-term synaptic depression: role for a postsynaptic leaky integrator[END_REF] suggests that a large Ca 2+ signal is sufficient to induce PF-LTD. In contrast, both postsynaptic PF-LTP and PF-LTD induced by weaker PF stimulation seem to require additional signalling associated with PF synaptic transmission. This signalling, that may involve well-defined spatio-temporal patterns of Ca 2+ signals as well as Ca 2+ -independent biochemical pathways, may also be different for different protocols of plasticity induction. For instance, activation of mGluR1 was shown to be necessary for single-train induced PF-LTP [START_REF] Wang | Coincidence detection in single dendritic spines mediated by calcium release[END_REF] but not for burst induced PF-LTP [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF].

The electrophysiological induction protocol is the first step of one or more sequences of events leading to a change in the efficacy or in the number of synaptic receptors. In this dynamic process, a measurable fundamental molecule is Ca 2+ . Thus the first aspect that will be carefully analysed is the spatial distribution and the time-course of Ca 2+ signals associated with PF-and CF-EPSPs during different induction protocols. Ca 2+ signals are fundamental variables in the biochemical cascades activated by the induction mechanisms, where other proteins are involved. For many different molecules, although a role in synaptic plasticity has been demonstrated, the direct association with a particular pathway was limited by the available pharmacological or genetic tools. Some controversial issues arising from molecular analysis are discussed below. Finally, upstream to the molecular pathways, induction protocols are produced by artificial electrical stimulation at a given site. Several studies have shown that induction protocols in brain slices can produce different results according to the position of the stimulating electrode and to the orientation of the slice. These discrepancies may be due to the architecture of the presynaptic fibres as well as to the localization of synaptic contacts and the use of spatially well defined stimulation may help to isolate specific signalling pathways. In addition, this information can shed light on the functional organization of the cerebellar circuitry. Thus, this is the third aspect addressed in this review.

Potential Ca 2+ signals involved in postsynaptic PF-LTP induction

Although the size of [Ca 2+ ] i transients cannot be directly correlated with the polarity of longterm synaptic plasticity, the spatial distribution and the time-course of Ca 2+ signals can be a determinant for bidirectional induction of plasticity. Indeed, the contribution of Ca 2+ in a particular pathway may in general depend on its co-localization with a particular Ca 2+ -binding protein (localization of Ca 2+ signal) as well as on the kinetics of the Ca 2+ -protein interaction.

The contribution of Ca 2+ entry via AMPA receptors is negligible in mature PNs [START_REF] Kuruma | Dynamics of Ca 2+ and Na + in the dendrites of mouse cerebellar Purkinje cells evoked by parallel fibre stimulation[END_REF] and there is no evidence of dendritic Ca 2+ entry via NMDA receptors although there is recent evidence that these receptors are still expressed in PNs in mature mice [START_REF] Renzi | Climbing-fibre activation of NMDA receptors in Purkinje cells of adult mice[END_REF]. Thus, following excitatory postsynaptic activity, [Ca 2+ ] i elevation is due to Ca 2+ entry via voltage-gated Ca 2+ channels (VGCCs) activated by dendritic depolarisation, or by secondary pathways triggered by mGluR1 activation in the case of PF activity (Fig. 2a). Activation of VGCCs following dendritic depolarisation triggers local dendritic Ca 2+ spikes [START_REF] Llinas | Electrophysiological properties of in vitro Purkinje cell dendrites in mammalian cerebellar slices[END_REF][START_REF] Rancz | Dendritic calcium spikes are tunable triggers of cannabinoid release and short-term synaptic plasticity in cerebellar Purkinje neurons[END_REF]. A single dendritic Ca 2+ spike can be elicited either by a CF-EPSP, in the bulk of the dendritic arbour, or by one or more PF-EPSPs locally [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF]. The fast [Ca 2+ ] i elevation associated with a calcium spike has a peak of ~100-200 nM and a duration of few milliseconds as measured using low-affinity dyes [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF][START_REF] Schmidt | Mutational analysis of dendritic Ca2+ kinetics in rodent Purkinje cells: role of parvalbumin and calbindin D28k[END_REF] and depicted in Fig. 2b. When several calcium spikes occur during a high-frequency burst, the transient saturation of the endogenous calcium buffer can elevate [Ca 2+ ] i to higher concentrations (see Fig. 2c), depending on the number and the architecture of the PFs activated. This phenomenon can be observed only in association with PF-EPSP bursts, or with a CF-EPSP following a PF-EPSP burst [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF]. The time-course of the [Ca 2+ ] i elevation following a PF-EPSP burst depends on the timing of calcium spikes. The different spatial distribution of calcium spikes elicited either by CF or PF stimulation can play an important role in the bidirectional induction of plasticity and this hypothesis should be further investigated.

Activation of mGluR1 is associated with PF-EPSPs. Currently, there is evidence for two Ca 2+ signals mediated by mGluR1 activation [START_REF] Canepari | Kinetic, pharmacological and activity-dependent separation of two Ca2+ signalling pathways mediated by type 1 metabotropic glutamate receptors in rat Purkinje neurones[END_REF]. The faster signal is Ca 2+ release from stores via InsP 3 receptors. Evidence from several laboratories indicates that Ca 2+ release from stores can be localised in dendritic spines [START_REF] Canepari | Kinetic, pharmacological and activity-dependent separation of two Ca2+ signalling pathways mediated by type 1 metabotropic glutamate receptors in rat Purkinje neurones[END_REF][START_REF] Finch | Local calcium signalling by inositol-1,4,5-trisphosphate in Purkinje cell dendrites[END_REF][START_REF] Takechi | A new class of synaptic response involving calcium release in dendritic spines[END_REF]. In rats, this signal has well-defined kinetics, as depicted in Fig. 2d, and it peaks ~100 ms after mGluR1 activation [START_REF] Canepari | Kinetic, pharmacological and activity-dependent separation of two Ca2+ signalling pathways mediated by type 1 metabotropic glutamate receptors in rat Purkinje neurones[END_REF]. It is primed by Ca 2+ influx [START_REF] Canepari | Kinetic, pharmacological and activity-dependent separation of two Ca2+ signalling pathways mediated by type 1 metabotropic glutamate receptors in rat Purkinje neurones[END_REF] and facilitated by a concomitant CF-EPSP [START_REF] Sarkisov | Order-dependent coincidence detection in cerebellar Purkinje neurons at the inositol trisphosphate receptor[END_REF]. A slower signal is Ca 2+ influx via nonselective cation conductance [START_REF] Caneparim | Ca2+ ion permeability and single-channel properties of the metabotropic slow EPSC of rat Purkinje neurons[END_REF]. A recent study suggested that this conductance is the TRPC3 channel, widely expressed in PNs [START_REF] Hartmann | TRPC3 channels are required for synaptic transmission and motor coordination[END_REF]. This signal is slower and smaller in size compared to Ca 2+ release from stores [START_REF] Canepari | Kinetic, pharmacological and activity-dependent separation of two Ca2+ signalling pathways mediated by type 1 metabotropic glutamate receptors in rat Purkinje neurones[END_REF] as depicted in Fig. 2e. Fig. 2f shows the four [Ca 2+ ] i transients reported in Fig. 2b-e normalised andsuperimposed.

The time course of different [Ca 2+ ] i transients can play a role in synaptic plasticity by selective activation of proteins with different kinetics. Both Ca 2+ influx associated with Ca 2+ spikes and Ca 2+ release from stores can in principle occur in dendritic spines, in the bulk of the dendrite or in both and a different spatial distribution can result in the activation of different molecular pathways. Finally, the interplay of [Ca 2+ ] i transients with well-defined kinetics can play a crucial role in the timing of signals associated with different patterns of stimulation that induce long-term synaptic plasticity.

In conclusion, it must be pointed out that in induction mechanisms produced by repetitive stimulation not only the [Ca 2+ ] i transient associated with one individual stimulation, but also its evolution during the repetition as well as the change in the basal [Ca 2+ ] i must be taken into account.

Molecular pathways associated with repetitive stimulations

It is well established that changes in the phosphorylation state of AMPA receptor subunits regulate the efficacy of AMPA receptors to glutamate binding as well as their insertion/internalization balance (for a review see [START_REF] Roche | Glutamate receptor phosphorylation and synaptic plasticity[END_REF]). Thus, research on molecular cascades leading to different forms of postsynaptic cerebellar plasticity focused on pathways that could produce changes in kinase/phosphatase activation. Several types of kinase inhibitors affect LTD (see for a review [START_REF] Ito | Cerebellar Long-Term Depression: Characterization, Signal Transduction, and Functional Roles[END_REF]). However, the same kinase/phosphatase may act at different stages of a molecular cascade or within different concomitant pathways. This multiple action of a single enzyme complicates the analysis and generates discrepancies in the interpretation of results. A typical example is the old controversy on the role of protein kinase C (PKC). At postsynaptic PNs, PKC can phosphorylate the ser880 site of GluR2 leading to its internalization [START_REF] Chung | Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins[END_REF], but also interacts with mitogen-activated protein kinase involved in LTD [START_REF] Tanaka | A positive feedback signal transduction loop determines timing of cerebellar long-term depression[END_REF]. Presynaptically, PKC regulates the granule cell synthesis of nitric oxide (NO) [START_REF] Okada | Protein kinase C modulates calcium sensitivity of nitric oxide synthase in cerebellar slices[END_REF] which is involved both in LTP [START_REF] Wong | A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP[END_REF] and in LTD [START_REF] Daniel | Long-term depression requires nitric oxide and guanosine 39,59 cyclic monophosphate production in rat cerebellar Purkinje cells[END_REF] induction. Thus, unspecific block of PKC prevents CF-dependent LTD in cultures [START_REF] Linden | Participation of postsynaptic PKC in cerebellar long-term depression in culture[END_REF], but this form of plasticity is surprisingly still intact in mice which are deficient of PKC-, exclusively expressed in PNs [START_REF] Abellovich | Modified hippocampal long-term potentiation in PKC-mutant mice[END_REF].

In a recent investigation, it was reported that inhibition of several types of phosphatases prevents postsynaptic LTP, suggesting that bidirectional plasticity may be finally controlled by the balance of kinase/phosphatase activation [START_REF] Belmeguenai | A role for protein phosphatases 1, 2A, and 2B in cerebellar long-term potentiation[END_REF]. Interestingly, in another report, LTP was prevented by the block N-ethylmaleimide-sensitive factor, suggesting that the binding of this molecule to GluR2 and not GluR2 dephosphorylation may be responsible for LTP [START_REF] Kakegawa | A mechanism underlying AMPA receptor trafficking during cerebellar long-term potentiation[END_REF].

In summary, it is important to remark that mechanisms underlying different induction protocols are likely to be associated with different molecular pathways, but the interpretation of results from pharmacological and genetic explorations is often limited by the fact that the same molecule may be involved in more steps of a putative molecular pathway underlying synaptic plasticity. In addition, the situation is further complicated by the involvement of the same molecule in pathways occurring in parallel during the application of a particular induction protocol.

Geometric constraints of postsynaptic LTP and LTD induction

In brain slices, EPSPs (and related induction protocols) are evoked by a stimulating electrode positioned at a particular site of the slice cut with a particular orientation. Whereas initial studies on cerebellar plasticity did not take into account this factor, more recently it was found that an important aspect of postsynaptic PF-LTP (or PF-LTD) induction is its critical dependence on the spatial organisation of the synapses with respect to dendritic geometry which reflects the architecture of the afferents. PF synapses, formed along the parallel axons of the molecular layer, are ~90% of the contacts between granule cells and PNs, whereas the remaining 10%, called ascending fibers (AFs), are formed in the ascending tracts of the granule cell axons [START_REF] Gundappa-Sulur | Ascending granule cell axon: an important component of cerebellar cortical circuitry[END_REF]. In experiments performed in coronal slices of the rat, where activation of PF and of AF synapses can be separated (Fig. 3a), both one-pulse induced parallel PF-LTP and PF-LTD have been shown to be inducible only by PF stimulation and not by AF stimulation [START_REF] Sims | Differences in transmission properties and susceptibility to long-term depression reveal functional specialization of ascending axon and parallel fiber synapses to Purkinje cells[END_REF][START_REF] Sims | Differential susceptibility to synaptic plasticity reveals a functional specialization of ascending axon and parallel fiber synapses to cerebellar Purkinje cells[END_REF]. The postsynaptic PF-LTD induced by pairing the one-pulse protocol with CF stimulation is mGluR1-dependent and a critical correlation was found between glutamate spillover and PF-LTD induction [START_REF] Marcaggi | Endocannabinoid signaling depends on the spatial pattern of synapse activation[END_REF]. Thus, in another study, it was suggested that the difference between PF and AF susceptibility reported before [START_REF] Sims | Differential susceptibility to synaptic plasticity reveals a functional specialization of ascending axon and parallel fiber synapses to cerebellar Purkinje cells[END_REF] was actually due to the spatial arrangement of the afferents [START_REF] Marcaggi | Short-and long-term depression of rat cerebellar parallel fibre synaptic transmission mediated by synaptic crosstalk[END_REF]. According to this view, PF stimulation results in the activation of afferents contacting postsynaptic Purkinje neurons at adjacent dendritic spines and in the local glutamate accumulation necessary for spillover and chemical crosstalk among adjacent spines.

Because the one-pulse induced LTD was shown to be different for the PF and the AF pathways, the same type of analysis in coronal slices was performed for the burst-induced PF-LTP [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF]. In contrast to what reported for one-pulse induced plasticity, LTP was found both at the PF and at the AF pathways. This induction protocol did not require mGluR1-mediated Ca 2+ signals [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF] associated with glutamate spillover [START_REF] Marcaggi | Endocannabinoid signaling depends on the spatial pattern of synapse activation[END_REF], but required Ca 2+ influx associated with Ca 2+ spikes that could be elicited both by the activation of the PF and the AF pathways [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF].

To explore more in details the differences in synaptic plasticity, regardless of whether synaptic contacts originate from PF or AF pathways, we summarize in Fig. 3a which hypothetical geometric scenarios of CGC-PN synapses can occur under different constraints. In the first case, depicted in Fig. 3b, adjacent CGC axons are stimulated. This configuration can occur by stimulating in the vicinity of the PN dendrite in sagittal slices or in the molecular layer in coronal slices. Thus, CGC-PN synapses can target adjacent spines allowing for glutamate accumulation, transient uptake saturation and glutamate spillover onto adjacent spines [START_REF] Marcaggi | Endocannabinoid signaling depends on the spatial pattern of synapse activation[END_REF][START_REF] Marcaggi | Short-and long-term depression of rat cerebellar parallel fibre synaptic transmission mediated by synaptic crosstalk[END_REF]. In the second case, depicted in Fig. 3c, axons that activate spines belonging to the same dendritic branch (but not adjacent) are excited. This configuration may be what happens when AF are stimulated in coronal slices, by position the stimulating electrode in the granule cell layer below the PN. Under this condition, synaptic activation may be insufficient for chemical crosstalk but may still allow localised depolarisation and excitation. Finally, sparse spines belonging to different dendritic branches may be activated (see Fig. 3d). This configuration can hypothetically occur by using more stimulating electrodes.

The evidence that different forms of LTP (and LTD) are remarkably dependent on the physical arrangement of the afferents implies an important functional role of the spatial organization of the CGC-PN synapses. The possibility of synaptic crosstalk, either by activation of adjacent synapses via glutamate spillover, or by the local summation of depolarisation leading to dendritic calcium spikes, may underlie the translation of the spatial organisation into a functional organisation of PF afferents.

Summary and future directions

It is proven that both postsynaptic PF-LTP and postsynaptic PF-LTD require [Ca 2+ ] i elevation, but the hypothesis that the polarity of postsynaptic PF long-term synaptic plasticity is determined by Ca 2+ signals of different amplitude appears unlikely. More realistically, [Ca 2+ ] i elevation following PF and/or CF activation may occur at different spatial and temporal scales triggering local biochemical pathways and activating sensors with different kinetics. In addition, Ca 2+ -dependent pathways may interact with Ca 2+ -independent pathways as suggested by the evidence that Ca 2+ photo-release does not mimic the induction of long-term synaptic plasticity observed by synaptic stimulation [START_REF] Tanaka | Ca2+ requirements for cerebellar long-term synaptic depression: role for a postsynaptic leaky integrator[END_REF]. In these experiments, PF-LTP was not observed even when [Ca 2+ ] i was within the range normally associated with LTP. This leaves two options: either the Ca 2+ signal did not properly mimic the physiological signal or the synaptically evoked Ca 2+ increase is accompanied by an as-of-yet undetermined signal. The first option might be explored by optimizing the spatio-temporal characteristics of the photo-released Ca 2+ . For the second option, some of the candidates of necessary signals that are not present by Ca 2+ photo-release are presynaptic release of NO or postsynaptic binding of glutamate to the AMPA receptors and subsequent membrane depolarization.

The mechanisms and conditions necessary for the induction of postsynaptic PF-LTP are a cornerstone in the relationship between cerebellar activity and memory formation. Our current understanding on this topic is a mosaic of information with several apparent discrepancies. Part of these discrepancies arise from the fact that postsynaptic PF-LTP has been characterised under different experimental conditions, i.e. different induction stimulation protocols (see Fig. 1) but also different species and different stages of development. For instance, whereas in vitro studies in rats [START_REF] Wong | A new form of cerebellar long-term potentiation is postsynaptic and depends on nitric oxide but not cAMP[END_REF][START_REF] Coesmans | Bidirectional parallel fiber plasticity in the cerebellum under climbing fiber control[END_REF] and mice [START_REF] Canepari | Dendritic Spike Saturation of Endogenous Calcium Buffer and Induction of Postsynaptic Cerebellar LTP[END_REF] have been carried out in 3-5 weeks old animals, in vivo LTP has been characterised in adult mice [START_REF] Wang | Long-term potentiation of the responses to parallel fiber stimulation in mouse cerebellar cortex in vivo[END_REF]. Interestingly, one-pulse induced PF-LTP, as well as PF-LTD induced by CF pairing, have been observed also in a non-mammalian nervous system [START_REF] Han | Synaptic plasticity and calcium signaling in Purkinje cells of the central cerebellar lobes of mormyrid fish[END_REF]. Other discrepancies originate from the incomplete interpretation of non-quantitative data on Ca 2+ signalling, missing information on the spatio-temporal distribution of [Ca 2+ ] i transients associated with the different induction protocols. Advanced optical techniques are available, allowing Ca 2+ measurements at the level of single spines [START_REF] Denk | Imaging calcium dynamics in dendritic spines[END_REF][START_REF] Sabatini | Ca(2+) signaling in dendritic spines[END_REF]. In particular, using two-photon microscopy, it is possible to measure [Ca 2+ ] i transients from individual spines using low affinity dyes [START_REF] Wang | Coincidence detection in single dendritic spines mediated by calcium release[END_REF] that produce minimal perturbation of the physiological [Ca 2+ ] i dynamics. The use of two-photon voltage measurements, recently available [START_REF] Fisher | Two-photon excitation of potentiometric probes enables optical recording of action potentials from mammalian nerve terminals in situ[END_REF], may provide additional information on the spatial distribution of local excitation that appears essential for long-term plasticity induction.

A final aspect that may produce controversial results is the spatial arrangement of CGC-PN synapses, which mirrors the highly ordered functional architecture of the cerebellar circuitries.

The use of stimulating electrodes can bias the conditions for postsynaptic PF-LTP induction by artificially selecting pathways of stimulation and these pathways may be very different in different experimental conditions. This aspect must be taken into account especially when performing experiments on sagittal cerebellar slices, which are ideal for imaging studies, but preclude the possibility to control the arrangements of the stimulated presynaptic afferents. entry through TRPC3 triggered by mGluR1 activation (signal e). (b) [Ca 2+ ] i signal associated with one calcium spike: peak ~100-200 nM, duration ~10 ms; estimate from [START_REF] Bienenstock | Theory for the development of neuron selectivity: orientation specificity and binocular interaction in visual cortex[END_REF]. (c) [Ca 2+ ] i signal

Fig. 1 .

 1 Fig.1. Protocols that induce postsynaptic PF-LTP. (a) One-pulse induced parallel PF-LTP: one

Fig. 2 .

 2 Fig.2. Schematic of four [Ca 2+ ] i signals associated with excitatory synaptic transmission. (a)

Acknowledgements

This work was supported by the University of Basel and by the SNSF grant 3100A0_122000 (M.C.). We thank prof. Josef Kapfhammer for valuable comments on the manuscript.


Sangnam Nam

Michael E Davies

Michael Elad

Rémi Gribonval

Cosparse Analysis Modeling

In the past decade there has been a great interest in a synthesis-based model for signals, based on sparse and redundant representations. This work considers an alternative analysis-based model, where an analysis operator multiplies the signal, leading to a cosparse outcome. We consider this analysis model, in the context of a generic missing data problem. Our work proposes a uniqueness result for the solution of this problem, based on properties of the analysis operator and the measurement matrix. A new greedy algorithm for solving the missing data problem is proposed along with theoretical study of the success of the algorithm and experimental results.

I. INTRODUCTION

Given a set of incomplete linear observation y = Mx0 ∈ R m of a signal x0 ∈ R d , m < d, the assumption that x0 admits a sparse representation z0 in some synthesis dictionary D is known to be of significant help in recovering the original signal x0. Indeed, it is now well understood that under incoherence assumptions on the matrix MD, one can recover vectors x0 with sufficiently sparse representations by solving the optimization problem:

xS := Dẑ; ẑ := arg min z z τ subject to y = MDz (1) for 0 ≤ τ ≤ 1.
An alternative to (1) which has also been used successfully in practice is to consider the analysis τ -optimization [START_REF] Elad | Analysis versus synthesis in signal priors[END_REF], [START_REF] Portilla | Image restoration through l0 analysis-based sparse optimization in tight frames[END_REF], [START_REF] Selesnick | Signal restoration with overcomplete wavelet transforms: Comparison of analysis and synthesis priors[END_REF]:

xA := arg min x Ωx τ subject to y = Mx, (2)
where Ω : R d → R p is an analysis operator. Typically the dimensions are m < d ≤ p, n.

The fact that z0 contains few zeros, i.e., is sparse may be thought of as the principal reason why one can recover the socalled sparse signals via [START_REF] Blumensath | Sampling theorems for signals from the union of finite-dimensional linear subspaces[END_REF]. We show that while the optimization (2) has similar look to (1), a different model, which we name the cosparse analysis model, is more closely linked to (2) than the sparse synthesis model. In particular, contrary to the sparse model, we are more interested in the signals x0 whose analysis representation Ωx0 contains many zeros. We call such signals cosparse and the quantity := p -Ωx0 0 the cosparsity.

II. UNIQUENESS

Based on the existing work [START_REF] Blumensath | Sampling theorems for signals from the union of finite-dimensional linear subspaces[END_REF], [START_REF] Lu | Sampling signals from a union of subspaces[END_REF], we establish [START_REF] Nam | The cosparse analysis model and algorithms[END_REF] the uniqueness of cosparse signals in the context of linear inverse problems above. The result we have derived has simple forms for two particular classes of analysis operators: Ω that is in general position, which means that the rows of Ω has no non-trivial linear dependencies, and the popular 2D TV analysis operators Ω that consists of all the vertical and horizontal one-step differences in a 2D image. For these two types of Ω, we have:

The authors acknowledge the support by the European Community's FP7-FET program, SMALL project, under grant agreement no. 225913. 2) Let Ω be the 2D TV analysis operator. Then, the problem y = Mx has at most one -cosparse solution if m + ≥ 2d.

III. ALGORITHM, THEORY, AND EXPERIMENTAL RESULT

With the uniqueness property established, we propose a new greedy algorithm which aims to recover cosparse signals based on incomplete linear observations. This algorithm, named the Greedy Analysis Pursuit (GAP), may be considered as the counterpart of the Orthogonal Matching Pursuit (OMP) in the sparse model. However, the GAP tries to detect the elements outside the locations of the zeros of analysis representations, this way carving its way towards the index set of zeros in the end.

We then provide a theoretical condition that guarantees the success of both the GAP and the analysis 1-minimization in cosparse signal recovery. Finally, we run some synthetic experiments to demonstrate the effectiveness of the proposed algorithm. Interestingly, we observe that GAP performs better than the analysis 1-minimization in the given tasks. In particular, Fig. 1 shows SNR vs the number of radial observation lines in the Shepp Logan phantom recovery problem.

Fig. 1 .

 1 Fig. 1. SNR vs Number of radial observation lines in the Shepp Logan phantom recovery. The line for GAP is clipped because the SNR was over 150 from 12 radial lines.