Phasic Firing in Vasopressin Cells: Understanding Its Functional Significance through Computational Models

Vasopressin neurons, responding to input generated by osmotic pressure, use an intrinsic mechanism to shift from slow irregular firing to a distinct phasic pattern, consisting of long bursts and silences lasting tens of seconds. With increased input, bursts lengthen, eventually shifting to continuous firing. The phasic activity remains asynchronous across the cells and is not reflected in the population output signal. Here we have used a computational vasopressin neuron model to investigate the functional significance of the phasic firing pattern. We generated a concise model of the synaptic input driven spike firing mechanism that gives a close quantitative match to vasopressin neuron spike activity recorded in vivo, tested against endogenous activity and experimental interventions. The integrate-and-fire based model provides a simple physiological explanation of the phasic firing mechanism involving an activity-dependent slow depolarising afterpotential (DAP) generated by a calcium-inactivated potassium leak current. This is modulated by the slower, opposing, action of activity-dependent dendritic dynorphin release, which inactivates the DAP, the opposing effects generating successive periods of bursting and silence. Model cells are not spontaneously active, but fire when perturbed by random perturbations mimicking synaptic input. We constructed one population of such phasic neurons, and another population of similar cells but which lacked the ability to fire phasically. We then studied how these two populations differed in the way that they encoded changes in afferent inputs. By comparison with the non-phasic population, the phasic population responds linearly to increases in tonic synaptic input. Non-phasic cells respond to transient elevations in synaptic input in a way that strongly depends on background activity levels, phasic cells in a way that is independent of background levels, and show a similar strong linearization of the response. These findings show large differences in information coding between the populations, and apparent functional advantages of asynchronous phasic firing

Modulation of kainic acid neurotoxicity in rats

1. Systemically administered kainic acid causes a dose dependent increase in the amount of peripheral benzodiazepine receptor in the rat hippocampus, as assessed by [3H]PK11195 binding. 2. This increase in binding is due to an increase in Bmax and not K0. The increase in PK11195 binding indicates that reactive gliosis has occurred and, by inference, neuronal loss. 3. The kainic acid induced elevation in binding is blocked by the non-NMDA antagonist GYKI 52466 and the NMDA antagonists MK801 and CPP. 4. The adenosine A1 receptor agonist R-phenylisopropyladenosine (R-PIA) is able to attenuate the kainic acid induced neuronal loss in a dose dependent and time dependent manner. 5. The R-PIA response is blocked by 8-cyclopentyl,-l ,3- dipropylxanthine (DPCPX) in a dose dependent manner, although DPCPX is unable to potentiate kainate induced neurotoxicity. 6. 8-p-sulfophenyltheophylline (8-SPT), is unable to cross the blood-brain barrier, and is unable to block the R-PIA induced neuroprotection indicating that the R-PIA effect is centrally mediated. 7. Kynurenine, but not kynurenic acid or tryptophan is able to attenuate kainic acid induced neurotoxicity in a dose dependent manner. 8. Kainic acid and potassium chloride (KCl) are able to release [3H] glutamate from hippocampal slices in a dose dependent manner. 9. The kainic acid induced elevation induces a period of heightened release after the first, but not second or third stimulations, and this is not seen after either KCl or kainic acid/KCl stimulations. 10. The adenosine A1 agonist 2-chloroadenosine (5muM) is unable to block the kainic acid induced release of [3H] glutamate. 11. DPCPX (5nM) is able to induce a significant decrease in KCl stimulated release of [3H] glutamate but not the kainic acid induced release. 12. In conclusion, kainic acid is causing neurotoxicity in a dose dependent manner that is mediated through both non-NMDA and NMD A receptors, and can be attenuated by R-PIA, and ascorbate

A hermeneutic of integral human development: bridging the gap between magisterial theory and Catholic agency Praxis

The thesis evolved out of an experience of working for, or being involved with, Catholic agencies devoted to implementing humanitarian and long-term development programmes over three decades (‘Roman Catholic Faith-based Organisations’, RCFBOs). In the encyclical Populorum Progressio (1967), Pope Paul VI called for an ‘authentic development’ which would result in a shift for the poor from living in inhuman conditions to more human ones within their culture. Paul’s contribution to the debate about development was to insist that development was not just about the economy but had to be holistic and include the whole of life - social, political, cultural as well as religious. Since then, subsequent popes have built on Paul’s foundations such that a concept of Integral Human Development (IHD) is now firmly placed within the corpus of Catholic Social Teaching (CST), the ‘official’ Church teaching on issues affecting life and society. Some Catholic agencies have taken the concept of IHD and incorporated it into their work and praxis in the field. The thesis aims to delineate a fuller hermeneutic, or theological understanding, of IHD for both RCFBOs and the institutional Church. IHD lacks explicit definition by the magisterium (teaching authority) of the Church, and does not take into account the praxis of the agencies mandated by bishops’ conferences, and indeed the Holy See, to implement IHD programmes in the field. To delineate a fuller hermeneutic of IHD, I researched the teaching on one of the central tenets of the Catholic faith, diakonia, serving or ministering to the poor, in Scripture, Tradition and CST. Over four chapters (three to six), I construct a hermeneutic of IHD, and examine it in the light of RCFBO praxis. I found that the occasional mutual antagonism of Church and agencies was caused largely by ignorance of Church teaching on the part of RCFBOs (as well as among some priests and bishops) and by the lack of knowledge of, and exposure to, RCFBO praxis on the part of the institutional Church. I propose dialogue. I show in Chapter Seven how the reflections of the teaching are found in two pieces of research I undertook; one concerned an early IHD programme run by Caritas Australia in rural Cambodia, and the other drew on interviews with focus groups of participants in a training programme led by the Catholic agency, Faith and Praxis, in Cameroon. In the case of the cohorts in Cambodia, the ‘reflections of the teaching’ included: the seeking out in the micro-society of villages the poorest people which included the disabled, those who were leading dysfunctional lives of addiction and domestic violence, and people living with HIV; an increase in the learning of skills to provide opportunities to earn a decent income, and in the building up of self-esteem and self-confidence. Acquiring these life skills even broke through the barrier of patriarchy with women being elected into leadership positions in the self-help groups. This transformation of lifestyle earned the people the admiration of their fellow villagers as well as local authorities so that they could then access services such as clinics and schools for themselves and their families; active participation of the so-called ‘beneficiaries’ in the programme to induce a feeling of ownership, and to build up their confidence in themselves and their abilities, while ensuring that empathy is increased among them to guarantee that those previously shunned by the village, such as those with HIV, are included in the programme; the transformation of the staff of community-based organisations (CBOs) to be more empathetic to the poorest they sought out, to phase out their involvement in programmes only when they are sure of their sustainability, while, being local, available for advice in the long-term; and IHD also influenced Caritas Australia which continued to operate within a subsidiarity-induced partnership approach to development, so that power was given to the local entity, ACR Cambodia, and the CBOs which worked in the local areas. All of them were Khmer Buddhists, as were the programme participants. In the case of Faith and Praxis, I show that the methodologies used in the programme, many of which are faith-based, led to the transformation of the participants who were mostly members of religious congregations. Some rediscovered their original charism and proceeded to live with the poor in the rural villages. On the basis of this research, both primary and secondary, I concluded (a) that IHD resulted in good developmental outcomes for the poorest because, at its best, it cohered with the culture and values of the programme participants, and its way of working has engendered greater self-esteem and confidence among the poor; (b) that faith resources could be used as assets in development, empowering the poor, enabling them to discern the causes of their poverty and assisting them to find their own solutions to their own problems; (c) that the greater dialogue I have proposed between RCFBOs and the institutional Church on the basis of my hermeneutic of IHD could overcome any tensions over the Catholicity of the agencies or the lack of prophetic stances by some Church leaders. My hope remains that this study, which has brought together a theology which underpins IHD and the praxis of Catholic agencies, along with suggestions to ameliorate both, will, in the spirit of the Second Vatican Council and the papacy of Pope Francis, be regarded as a Catholic approach to a development which is professional, authentic, and holistic as well as being pro-poorest, pro-dignity and pro-planet to RCFBOs, the Church and the world