Methods of simulating the behavior of granule cells in hippocampus based on informon theory

Postulated pathways between neurones in hippocampus are briefly described, as are experiments demonstrating potentiation. It is suggested that variable synapses between the perforant path and granule cells may be acting like informons, and that inhibitory synapses from basket cells to granule cells may be performing the associated function of reinforcement.Methods for simulating the behaviour of a granule/basket cell pair, based on these two hypotheses, are described; it is explained how such a system can be used to predict the behaviour of a population of cells if all granule cells and all basket cells are similarly excited. The limitations of the present simulation are pointed out; suggestions are made for the inclusion of further details in future work.     

Cdk5 regulates accurate maturation of newborn granule cells in the adult hippocampus

Newborn granule cells become functionally integrated into the synaptic circuitry of the adult dentate gyrus after a morphological and electrophysiological maturation process. The molecular mechanisms by which immature neurons and the neurites extending from them find their appropriate position and target area remain largely unknown. Here we show that single-cell–specific knockdown of cyclin-dependent kinase 5 (cdk5) activity in newborn cells using a retrovirus-based strategy leads to aberrant growth of dendritic processes, which is associated with an altered migration pattern of newborn cells. Even though spine formation and maturation are reduced in cdk5-deficient cells, aberrant dendrites form ectopic synapses onto hilar neurons. These observations identify cdk5 to be critically involved in the maturation and dendrite extension of newborn neurons in the course of adult neurogenesis. The data presented here also suggest a mechanistic dissociation between accurate dendritic targeting and subsequent synapse formation.     

The speed of sound through trabecular bone predicted by Biot theory

Cancellous bone is a highly porous material filled with fluid. The mechanical properties of cancellous bone determine whether the bone is normal or osteoporotic. Wave propagation can be used to measure the elastic constants of cancellous bone. Recently, poroelasticity theory has been used to predict the elastic constants of cancellous bone from the wave velocities. In this study, it is shown that the fast wave, predicted by the Biot theory, corresponds to the wave penetrating the trabeculae, while the slow wave is determined by the interaction between the trabeculae and the fluid. The trabecular shape does not affect the wave velocity significantly when using the variable, which is determined by the microstructure, and the slow wave velocity decreases after the porosity reaches 80%.     

Protein symmetry and the co-operative ligand-binding behaviour predicted by allosteric Koshland models

It is shown that the nearest-neighbour interaction two-conformation allosteric models of Koshland, Nemethy & Filmer (1966) predict binding curves with a centre of symmetry when the protein is also symmetrical and induced-fit is assumed. When nonexclusive binding to both conformations is assumed, the models predict that the family of homotropic binding curves obtained by varying the heterotropic ligand has a centre of symmetry. It is argued that the symmetry or asymmetry of binding curves is the main experimentally verifiable prediction of allosteric models insofar as they are models of interaction between protein subunits.Symmetry in a binding curve greatly simplifies the analysis of cooperative behaviour. The co-operative features possible with a symmetric binding curve for a four-site protein are analysed. The sign of co-operativity may either be uniform or change twice as saturation increases; the conditions for the various possibilities are given. For example, in terms of the intrinsic binding constants per site A^∥₁, A2, etc. the necessary and sufficient condition for positive macroscopic co-operativity over the whole symmetric binding curve is A^∥₁≤ A2, A ^∥₁ ≤ A3 which should be contrasted with the obvious A^∥₁ ≤ Al, AZ ≤A^∥₃ (positive microscopic co-operativity) which is only a sufficient but not a necessary condition. A symmetric curve may have one or three, but no more, extrema of the “Hill coefficient” h. For three extrema a change of sign of microscopic (but not necessarily macroscopic) co-operativity is necessary but not sufficient. In the case where there are off-centre maxima of h, then h < 2 everywhere on the curve.The Koshland models predict qualitative and quantitative restrictions on the forms of binding curves additional to that of symmetry. In tetrameric induced fit models, negative co-operativity in the mid-region of the curve and positive co-operativity in the outside regions is possible, but not the opposite, and three extrema of h are possible with uniform positive but not with uniform negative co-operativity.Thus by recognising the importance of symmetry it has been possible to describe and categorise all the co-operativity behaviour possible with the most plausible Koshland tetrameric models. Several experimental examples of probable non-exclusive binding to proteins and enzymes are discussed, and it is shown how the symmetry point of view illuminates their interpretation.     

Antibodies that recognize astrotactin block granule neuron binding to astroglia

To provide a rapid, specific assay for receptor systems involved in the binding of cerebellar granule neurons to astroglia, granule cells, purified from early postnatal mice, or from E15-E16 chicks, were radiolabeled with [35S]methionine and plasma membranes were prepared. The kinetics of binding of radiolabeled material to primary mouse or chick glia or to the mouse G26-24 astrocytoma cell line was measured in the presence or absence of antibodies against astrotactin, neural cell adhesion molecules, cadherins, or integrins. Addition of Fab fragments of astrotactin antibodies reduced the amount of granule cell membrane binding to astroglia by 70%. In contrast, Fab fragments of antibodies against the neural adhesion molecules N-CAM, L1, and N-cadherin and against integrin did not reduce the level of granule cell membrane binding to astroglia. Combinations of antibodies against N-CAM, L1, N-cadherin, and integrin also did not impair neuron binding to glia.     

Cell orientation by a microgrooved substrate can be predicted by automatic control theory

Cells have the ability to measure and respond to extracellular signals like chemical molecules and topographical surface features by changing their orientation. Here, we examined the orientation of cultured human melanocytes exposed to grooved topographies. To predict the cells' orientation response, we describe the cell behavior with an automatic controller model. The predicted dependence of the cell response to height and spatial frequency of the grooves is obtained by considering the symmetry of the system (cell + substrate). One basic result is that the automatic controller responds to the square of the product of groove height and spatial frequency or to the aspect ratio for symmetric grooves. This theoretical prediction was verified by the experiments, in which melanocytes were exposed to microfabricated poly(dimethylsiloxane) substrates having parallel rectangular grooves of heights (h) between 25 and 200 nm and spatial frequencies (L) between 100 and 500 mm(-1). In addition, the model of the cellular automatic controller is extended to include the case of different guiding signals acting simultaneously.     

Mechanical disassembly of single virus particles reveals kinetic intermediates predicted by theory

New experimental approaches are required to detect the elusive transient intermediates predicted by simulations of virus assembly or disassembly. Here, an atomic force microscope (AFM) was used to mechanically induce partial disassembly of single icosahedral T=1 capsids and virions of the minute virus of mice. The kinetic intermediates formed were imaged by AFM. The results revealed that induced disassembly of single minute-virus-of-mice particles is frequently initiated by loss of one of the 20 equivalent capsomers (trimers of capsid protein subunits) leading to a stable, nearly complete particle that does not readily lose further capsomers. With lower frequency, a fairly stable, three-fourths-complete capsid lacking one pentamer of capsomers and a free, stable pentamer were obtained. The intermediates most frequently identified (capsids missing one capsomer, capsids missing one pentamer of capsomers, and free pentamers of capsomers) had been predicted in theoretical studies of reversible capsid assembly based on thermodynamic-kinetic models, molecular dynamics, or oligomerization energies. We conclude that mechanical manipulation and imaging of simple virus particles by AFM can be used to experimentally identify kinetic intermediates predicted by simulations of assembly or disassembly.     

Spatial information enhanced by non-spatial information in hippocampal granule cells

The hippocampus organizes sequential memory composed of non-spatial information (such as objects and odors) and spatial information (places). The dentate gyrus (DG) in the hippocampus receives two types of information from the lateral and medial entorhinal cortices. Non-spatial and spatial information is delivered respectively to distal and medial dendrites (MDs) of granule cells (GCs) within the molecular layer in the DG. To investigate the role of the association of those two inputs, we measured the response characteristics of distal and MDs of a GC in a rat hippocampal slice and developed a multi-compartment GC model with dynamic synapses; this model reproduces the response characteristics of the dendrites. Upon applying random inputs or input sequences generated by a Markov process to the computational model, it was found that a high-frequency random pulse input to distal dendrites (DDs) and, separately, regular burst inputs to MDs were effective for inducing GC activation. Furthermore, when the random and theta burst inputs were simultaneously applied to the respective dendrites, the pattern discrimination for theta burst input to MDs that caused slight GC activation was enhanced in the presence of random input to DDs. These results suggest that the temporal pattern discrimination of spatial information is originally involved in a synaptic characteristic in GCs and is enhanced by non-spatial information input to DDs. Consequently, the co-activation of two separate inputs may play a crucial role in the information processing on dendrites of GCs by usefully combing each temporal sequence.     

Induction of apoptosis in cerebellar granule cells by 2,4-dichlorophenoxyacetic acid

2,4-Dichlorophenoxyacetic acid (2,4-D) and derivatives are herbicides widely used in Argentina and other parts of the world. Exposure to 2,4-D, its ester and salt formulations, have been associated with a range of adverse health effects in humans and different animal species, from embryotoxicity and teratogenicity to neurotoxicity. In this work, we demonstrate that after 24 hs of treatment with 1 and 2 mM 2,4-D there is an induction of apoptosis in cerebellar granule cells (CGC) in culture. However, with 2 mM 2,4-D one population of CGC developed features of apoptosis while another appeared to die by necrosis. This process is associated with an increase in caspase-3 activity after 12 hs of treatment with the herbicide, which is preceded by cytochrome c release from the mitochondria. Treatment of CGC with 2,4-D appears to induce apoptosis by a direct effect on mitochondria producing cytochrome c release and consequently activation of caspase-3, being mitochondrial damage sufficient for triggering the events that may cause apoptosis.     

Morphological alterations in newly born dentate gyrus granule cells that emerge after status epilepticus contribute to make them less excitable

Computer simulations of external current stimulations of dentate gyrus granule cells of rats with Status Epilepticus induced by pilocarpine and control rats were used to evaluate whether morphological differences alone between these cells have an impact on their electrophysiological behavior. The cell models were constructed using morphological information from tridimensional reconstructions with Neurolucida software. To evaluate the effect of morphology differences alone, ion channel conductances, densities and distributions over the dendritic trees of dentate gyrus granule cells were the same for all models. External simulated currents were injected in randomly chosen dendrites belonging to one of three different areas of dentate gyrus granule cell molecular layer: inner molecular layer, medial molecular layer and outer molecular layer. Somatic membrane potentials were recorded to determine firing frequencies and inter-spike intervals. The results show that morphologically altered granule cells from pilocarpine-induced epileptic rats are less excitable than control cells, especially when they are stimulated in the inner molecular layer, which is the target area for mossy fibers that sprout after pilocarpine-induced cell degeneration. This suggests that morphological alterations may act as a protective mechanism to allow dentate gyrus granule cells to cope with the increase of stimulation caused by mossy fiber sprouting.     

The application of statistical decision theory to animal behaviour

Statistical decision theory is discussed as a general framework for analysing how animals should learn. Attention is focused on optimal foraging behaviour in stochastic environments. We emphasise the distinction between the mathematical procedure that can be used to find optimal solutions and the mechanism an animal might use to implement such solutions. The mechanisms might be specific to a restricted class of problems and produce suboptimal behaviour when faced with problems outside this class. We illustrate this point by an example based on what is known in the literature on animal learning as the partial reinforcement effect.     

Experimental evidence that sentinel behaviour is affected by risk

Sentinels are a conspicuous feature of some cooperative societies and are often assumed to provide benefits in terms of increased predator detection. Similar to other cooperative behaviours, variation in investment in sentinel behaviour should reflect variation in the benefits of such behaviour. However, evidence for this is inconclusive: to date experiments have manipulated the cost of sentinel behaviour, and considerations of changes in the benefits of sentinel activity on investment patterns are lacking. Here, we experimentally manipulated the benefits of sentinel behaviour in the cooperatively breeding pied babbler (Turdoides bicolor) to assess whether this had any impact on sentinel activity. We simulated the presence of an unseen predator using playbacks of heterospecific alarm calls, and the presence of an actual predator using a model snake. In both cases, the increase in perceived predation risk caused an increase in sentinel activity, demonstrating that investment in sentinel activity increases when the benefits are greater.     

Genetic disruption of mineralocorticoid receptor leads to impaired neurogenesis and granule cell degeneration in the hippocampus of adult mice

To dissect the effects of corticosteroids mediated by the mineralocorticoid (MR) and the glucocorticoid receptor (GR) in the central nervous system, we compared MR^–/– mice, whose salt loss syndrome was corrected by exogenous NaCl administration, with GR^–/– mice having a brain-specific disruption of the GR gene generated by the Cre/loxP-recombination system. Neuropathological analyses revealed a decreased density of granule cells in the hippocampus of adult MR^–/– mice but not in mice with disruption of GR. Furthermore, adult MR^–/– mice exhibited a significant reduction of granule cell neurogenesis to 65% of control levels, possibly mediated by GR due to elevated corticosterone plasma levels. Neurogenesis was unaltered in adult mice with disruption of GR. Thus, we could attribute long-term trophic effects of adrenal steroids on dentate granule cells to MR. These MR-related alterations may participate in the pathogenesis of hippocampal changes observed in ageing, chronic stress and affective disorders.     

Effect of change in concentration upon lens turbidity as predicted by the random fluctuation theory.

Theoretical calculations were performed to predict how the light scattering intensity would change with changes in concentration in the gel state. The theory of light scattering was applied to a random distribution of hard spheres. The spherical particles with constant diameter were embedded in a medium having a different refractive index. The light-scattering intensities obtained as a function of concentration showed that in dilute solutions the scattered light intensity increases with concentration. However, in concentrated solution greater than 0.1 or 0.2 volume fraction, the light-scattering intensity decreases with increase in concentration.     

Dendritic integration in hippocampal dentate granule cells

Hippocampal granule cells are important relay stations that transfer information from the entorhinal cortex into the hippocampus proper. This process is critically determined by the integrative properties of granule cell dendrites. However, their small diameter has so far hampered efforts to examine their properties directly. Using a combination of dual somatodendritic patch-clamp recordings and multiphoton glutamate uncaging, we now show that the integrative properties of granule cell dendrites differ substantially from other principal neurons. Due to a very strong dendritic voltage attenuation, the impact of individual synapses on granule cell output is low. At the same time, integration is linearized by voltage-dependent boosting mechanisms, only weakly affected by input synchrony, and independent of input location. These experiments establish that dentate granule cell dendritic properties are optimized for linear integration and strong attenuation of synaptic input from the entorhinal cortex, which may contribute to the sparse activity of granule cells in vivo.