IMPROBED: Multiple Problem-Solving Brain via Evolved Developmental Programs

Artificial neural networks (ANNs) were originally inspired by the brain; however, very few models use evolution and development, both of which are fundamental to the construction of the brain. We describe a simple neural model, called IMPROBED, in which two neural programs construct an artificial brain that can simultaneously solve multiple computational problems. One program represents the neuron soma and the other the dendrite. The soma program decides whether neurons move, change, die, or replicate. The dendrite program decides whether dendrites extend, change, die, or replicate. Since developmental programs build networks that change over time, it is necessary to define new problem classes that are suitable to evaluate such approaches. We show that the pair of evolved programs can build a single network from which multiple conventional ANNs can be extracted, each of which can solve a different computational problem. Our approach is quite general and it could be applied to a much wider variety of problems.

Development of the L-type CaV / BK Complex Simulator (I): electrophysiological interaction

Complexes formed by voltage-activated calcium channels (CaV) and high-conductance potassium channels activated by Ca2+ (BK) have been studied in smooth muscle, secretory cells and in synaptic terminals, where they regulate muscle contraction, secretory activity, and neurotransmission. However, the complex formed by L- type CaV channels and BK in the soma has been poorly treated. Based on immunostaining studies showing the coexistence of these channels in the neuron soma, their possible interaction was theoretically studied. Two simulators based on the Hodgkin and Huxley formalism were developed to perform virtual experiments on current and voltage clamp. The mathematical models were implemented in Visual Basic® 6.0 and were solved numerically. The results indicate that the BK channels were activated with internal Ca2+ at mM concentrations. The BK channels follow the kinetics of L-type CaVs. The interaction of L-type CaV – BK complex in the soma produced a decrease in neuronal excitability.

EphrinB2-EphB2 signaling for dendrite protection after neuronal ischemia in vivo and oxygen-glucose deprivation in vitro

In order to rescue neuronal function, neuroprotection should be required not only for the neuron soma but also the dendrites. Here, we propose the hypothesis that ephrin-B2-EphB2 signaling may be involved in dendritic degeneration after ischemic injury. A mouse model of focal cerebral ischemia with middle cerebral artery occlusion (MCAO) method was used for EphB2 signaling test in vivo. Primary cortical neuron culture and oxygen-glucose deprivation were used to assess EphB2 signaling in vitro. siRNA and soluble ephrin-B2 ectodomain were used to block ephrin-B2-Ephb2 signaling. In the mouse model of focal cerebral ischemia and in neurons subjected to oxygen-glucose deprivation, clustering of ephrin-B2 with its receptor EphB2 was detected. Phosphorylation of EphB2 suggested activation of this signaling pathway. RNA silencing of EphB2 prevented neuronal death and preserved dendritic length. To assess therapeutic potential, we compared the soluble EphB2 ectodomain with the NMDA antagonist MK801 in neurons after oxygen-glucose deprivation. Both agents equally reduced lactate dehydrogenase release as a general marker of neurotoxicity. However, only soluble EphB2 ectodomain protected the dendrites. These findings provide a proof of concept that ephrin-B2-EphB2 signaling may represent a novel therapeutic target to protect both the neuron soma as well as dendrites against ischemic injury.

Different dendritic domains of the GnRH neuron underlie the pulse and surge modes of GnRH secretion in female mice

The gonadotropin-releasing hormone (GnRH) neurons exhibit pulse and surge modes of activity to control fertility. They also exhibit an unusual bipolar morphology comprised of a classical soma-proximal dendritic zone and an elongated secretory process that can operate as both a dendrite and an axon, termed a ‘dendron’. We show using expansion microscopy that the highest density of synaptic inputs to a GnRH neuron exists at its distal dendron. In vivo, selective chemogenetic inhibition of the GnRH neuron distal dendron abolishes the luteinizing hormone (LH) surge and markedly dampens LH pulses. In contrast, inhibitory chemogenetic and optogenetic strategies targeting the GnRH neuron soma-proximal dendritic zone abolish the LH surge but have no effect upon LH pulsatility. These observations indicate that electrical activity at the soma-proximal dendrites of the GnRH neuron is only essential for the LH surge while the distal dendron represents an autonomous zone where synaptic integration drives pulsatile GnRH secretion.

NMDA Receptor Subunits Change after Synaptic Plasticity Induction and Learning and Memory Acquisition

NMDA ionotropic glutamate receptors (NMDARs) are crucial in activity-dependent synaptic changes and in learning and memory. NMDARs are composed of two GluN1 essential subunits and two regulatory subunits which define their pharmacological and physiological profile. In CNS structures involved in cognitive functions as the hippocampus and prefrontal cortex, GluN2A and GluN2B are major regulatory subunits; their expression is dynamic and tightly regulated, but little is known about specific changes after plasticity induction or memory acquisition. Data strongly suggest that following appropriate stimulation, there is a rapid increase in surface GluN2A-NMDAR at the postsynapses, attributed to lateral receptor mobilization from adjacent locations. Whenever synaptic plasticity is induced or memory is consolidated, more GluN2A-NMDARs are assembled likely using GluN2A from a local translation and GluN1 from local ER. Later on, NMDARs are mobilized from other pools, and there are de novo syntheses at the neuron soma. Changes in GluN1 or NMDAR levels induced by synaptic plasticity and by spatial memory formation seem to occur in different waves of NMDAR transport/expression/degradation, with a net increase at the postsynaptic side and a rise in expression at both the spine and neuronal soma. This review aims to put together that information and the proposed hypotheses.