Towards a Mathematical Theory of Cortical Micro-circuits

The theoretical setting of hierarchical Bayesian inference is gaining acceptance as a framework for understanding cortical computation. In this paper, we describe how Bayesian belief propagation in a spatio-temporal hierarchical model, called Hierarchical Temporal Memory (HTM), can lead to a mathematical model for cortical circuits. An HTM node is abstracted using a coincidence detector and a mixture of Markov chains. Bayesian belief propagation equations for such an HTM node define a set of functional constraints for a neuronal implementation. Anatomical data provide a contrasting set of organizational constraints. The combination of these two constraints suggests a theoretically derived interpretation for many anatomical and physiological features and predicts several others. We describe the pattern recognition capabilities of HTM networks and demonstrate the application of the derived circuits for modeling the subjective contour effect. We also discuss how the theory and the circuit can be extended to explain cortical features that are not explained by the current model and describe testable predictions that can be derived from the model.     

Chaperone-Like Manner of Human Neuronal Tau Towards Lactate Dehydrogenase

In our experiments, inactivation of lactate dehydrogenase (LDH, EC1.1.1.27) in the presence of human microtubule-associated tau is observably suppressed during thermal and guanidine hydrochloride (GdnHCl) denaturation. Kinetic studies show tau can prevent LDH from self-aggregation monitored by light scattering during thermal denaturation. On the other hand, neuronal tau promotes reactivation of LDH and suppresses self-aggregation of non-native LDH when GdnHCl solution is diluted. Furthermore, the reactivation yield of LDH decreases significantly with delayed addition of tau. All experiments were completed in the reducing buffer with 1 mM DTT to avoid between tau and LDH forming the covalent bonds during unfolding and refolding. Thus, Tau prevents proteins from misfolding and aggregating into insoluble, nonfunctional inclusions and assists them to refold to reach the stable native state by binding to the exposed hydrophobic patches on proteins instead of by forming or breaking covalent bonds. Additionally, tau remarkably enhances reactivation of GDH (glutamic dehydrogenase, EC 1.4.1.3), another carbohydrate metabolic enzyme, also showing a chaperone-like manner. It suggests that neuronal tau non-specifically functions a chaperone-like protein towards the enzymes of carbohydrate metabolism.     

Towards On-line Adaptation of Neuro-prostheses with Neuronal Evaluation Signals

Many experiments have successfully demonstrated that prosthetic devices for restoring lost body functions can in principle be controlled by brain signals. However, stable long-term application of these devices, required for paralyzed patients, may suffer substantially from on-going signal changes for example adapting neural activities or movements of the electrodes recording brain activity. These changes currently require tedious re-learning procedures which are conducted and supervised under laboratory conditions, hampering the everyday use of such devices. As an efficient alternative to current methods we here propose an on-line adaptation scheme that exploits a hypothetical secondary signal source from brain regions reflecting the user’s affective evaluation of the current neuro- prosthetic’s performance. For demonstrating the feasibility of our idea, we simulate a typical prosthetic setup controlling a virtual robotic arm. Hereby we use the additional, hypothetical evaluation signal to adapt the decoding of the intended arm movement which is subjected to large non-stationarities. Even with weak signals and high noise levels typically encountered in recording brain activities, our simulations show that prosthetic devices can be adapted successfully during everyday usage, requiring no special training procedures. Furthermore, the adaptation is shown to be stable against large changes in neural encoding and/or in the recording itself.     

Towards Neuronal Organoids: A Method for Long-Term Culturing of High-Density Hippocampal Neurons

One of the goals in neuroscience is to obtain tractable laboratory cultures that closely recapitulate in vivo systems while still providing ease of use in the lab. Because neurons can exist in the body over a lifetime, long-term culture systems are necessary so as to closely mimic the physiological conditions under laboratory culture conditions. Ideally, such a neuronal organoid culture would contain multiple cell types, be highly differentiated, and have a high density of interconnected cells. However, before these types of cultures can be created, certain problems associated with long-term neuronal culturing must be addressed. We sought to develop a new protocol which may further prolong the duration and integrity of E18 rat hippocampal cultures. We have developed a protocol that allows for culturing of E18 hippocampal neurons at high densities for more than 120 days. These cultured hippocampal neurons are (i) well differentiated with high numbers of synapses, (ii) anchored securely to their substrate, (iii) have high levels of functional connectivity, and (iv) form dense multi-layered cellular networks. We propose that our culture methodology is likely to be effective for multiple neuronal subtypes–particularly those that can be grown in Neurobasal/B27 media. This methodology presents new avenues for long-term functional studies in neurons.     

Towards a Quantitative Theory of Epidermal Calcium Profile Formation in Unwounded Skin

We propose and mathematically examine a theory of calcium profile formation in unwounded mammalian epidermis based on: changes in keratinocyte proliferation, fluid and calcium exchange with the extracellular fluid during these cells’ passage through the epidermal sublayers, and the barrier functions of both the stratum corneum and tight junctions localised in the stratum granulosum. Using this theory, we develop a mathematical model that predicts epidermal sublayer transit times, partitioning of the epidermal calcium gradient between intracellular and extracellular domains, and the permeability of the tight junction barrier to calcium ions. Comparison of our model’s predictions of epidermal transit times with experimental data indicates that keratinocytes lose at least 87% of their volume during their disintegration to become corneocytes. Intracellular calcium is suggested as the main contributor to the epidermal calcium gradient, with its distribution actively regulated by a phenotypic switch in calcium exchange between keratinocytes and extracellular fluid present at the boundary between the stratum spinosum and the stratum granulosum. Formation of the extracellular calcium distribution, which rises in concentration through the stratum granulosum towards the skin surface, is attributed to a tight junction barrier in this sublayer possessing permeability to calcium ions that is less than 15 nm s⁻¹ in human epidermis and less than 37 nm s⁻¹ in murine epidermis. Future experimental work may refine the presented theory and reduce the mathematical uncertainty present in the model predictions.     

Neuronal Control of Mucus Secretion by Leeches: Toward a General Theory for Serotonin

The large Retzius cells are serotonin-containing neurons whoseimpulse activity controls the secretion of mucus from the skinof leeches. Serotonin elicits the secretion of mucus withoutany apparent synaptic transfers in either the central or peripheralnervous systems. Such a secretogogue function may be more generalas serotonin controls the secretion of mucus from the gastrointestinaltract of mammals and from the ciliated gills of bivalved molluscs.Furthermore, the qualitative and quantitative distribution ofserotonin in molluscs, annelids, arthropods, and vertebratescorresponds approximately with mucosecretory structures. Serotoninappears also to control other secretory functions in some ofthese animals. It is proposed therefore that serotonin mightoften function in controlling secretion.     

Violence Against Women in Cambodia: Towards a Culturally Responsive Theory of Change

Almost one in four women in Cambodia is a victim of physical, emotional or sexual violence. This article brings together two seldom connected fields: Theory of Change (ToC) and cultural responsiveness in international development. It applies these approaches to a priority in global health, which is to prevent violence against women (VAW) and, drawing on my research on the epigenesis of VAW in Cambodia, develops an argument on the need for interventions to work with tradition and culture rather than only highlight it in problematic terms. The research draws on an ethnographic study carried out in Cambodia with 102 perpetrators and survivors of emotional, physical and sexual VAW and 228 key informants from the Buddhist and healing sectors. The eight ‘cultural attractors’ identified in the author’s prior research highlight the cultural barriers to acceptance of the current Theory of Change. ToC for VAW prevention in Cambodia seems to assume that local culture promotes VAW and that men and women must be educated to eradicate the traditional gender norms. There is a need for interventions to work with tradition and culture rather than only highlight it in problematic terms. The cultural epigenesis of VAW in Cambodia is an insight which can be used to build culturally responsive interventions and strengthen the primary prevention of VAW.     

Coping with Drought: Towards a Multilevel Understanding Based on Conservation of Resources Theory

There is substantial research on psychological consequences of disasters. However, most disaster studies to date have focused on acute disasters, ignoring slow-onset chronic hazards, such as extreme climate conditions and pollution. Using a multilevel theoretical framework based on the Conservation of Resources theory (S. E. Hobfoll, The Ecology of Stress, Hemisphere, New York, 1988; Stress, Culture, and Community: The Psychology and Philosophy of Stress, Plenum, New York, 1998) and the “ecological analogy” (see e.g., S. E. Hobfoll and R. S Lilly, Journal of Community Psychology, 21:128–148, 1993; E. J. Trickett, Extreme Stress and Communities: Impact and Intervention, Kluwer, Boston, 1995), this critical review of the current literature is aimed at increasing our understanding of personal and community impacts of drought as a classic example of a natural, slow-onset disaster affecting large numbers of people worldwide. A gap in the current literature was identified concerning appraisal and coping at the individual level. These include psychological coping strategies and the role of resources other than economic resources in explaining vulnerability to negative consequences of drought, such as personal resources (e.g., knowledge, skills, self-sufficiency, mastery, control) and social resources (e.g., social support). Important differences were identified with fast-onset disasters. Most importantly, dealing with drought is generally an integrated part of life for people in drought prone areas. Therefore, individuals may not recognize that their problems are part of a community wide stressor, and raising community awareness during severe and long droughts that deplete community resources needs special attention. Implications for studying drought and effective intervention strategies are given.     

Cross-Correlation Functions for a Neuronal Model

Cross-correlation functions, R_XY(t,τ), are obtained for a neuron model which is characterized by constant threshold θ, by resetting to resting level after an output, and by membrane potential U(t) which results from linear summation of excitatory postsynaptic potentials h(t). The results show that: (1) Near time lag τ = 0, R_XY(t,τ) = f_U [θ-h(τ), t + τ] {h′(τ) + E_U [u′(t + τ)]} for positive values of this quantity, where f_U(u,t) is the probability density function of U(t) and E_U [u′(t + τ)] is the mean value function of U′(t + τ). (2) Minima may appear in R_XY(t,τ) for a neuron subjected only to excitation. (3) For large τ, R_XY(t,τ) is given approximately by the convolution of the input autocorrelation function with the functional of point (1). (4) R_XY(t,τ) is a biased estimator of the shape of h(t), generally over-estimating both its time to peak and its rise time.     

Towards a synthetic chloroplast

Background

The evolution of eukaryotic cells is widely agreed to have proceeded through a series of endosymbiotic events between larger cells and proteobacteria or cyanobacteria, leading to the formation of mitochondria or chloroplasts, respectively. Engineered endosymbiotic relationships between different species of cells are a valuable tool for synthetic biology, where engineered pathways based on two species could take advantage of the unique abilities of each mutualistic partner.

Results

We explored the possibility of using the photosynthetic bacterium Synechococcus elongatus PCC 7942 as a platform for studying evolutionary dynamics and for designing two-species synthetic biological systems. We observed that the cyanobacteria were relatively harmless to eukaryotic host cells compared to Escherichia coli when injected into the embryos of zebrafish, Danio rerio, or taken up by mammalian macrophages. In addition, when engineered with invasin from Yersinia pestis and listeriolysin O from Listeria monocytogenes, S. elongatus was able to invade cultured mammalian cells and divide inside macrophages.

Conclusion

Our results show that it is possible to engineer photosynthetic bacteria to invade the cytoplasm of mammalian cells for further engineering and applications in synthetic biology. Engineered invasive but non-pathogenic or immunogenic photosynthetic bacteria have great potential as synthetic biological devices.