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The brain map project aims to map out the neuron connections of the human brain. Even with all of the wirings mapped out, the global and physical understandings of the function and behavior are still challenging. Hopfield quantified the learning and memory process of symmetrically connected neural networks globally through equilibrium energy. The energy basins of attractions represent memories, and the memory retrieval dynamics is determined by the energy gradient. However, the realistic neural networks are asymmetrically connected, and oscillations cannot emerge from symmetric neural networks. Here, we developed a nonequilibrium landscape-flux theory for realistic asymmetrically connected neural networks. We uncovered the underlying potential landscape and the associated Lyapunov function for quantifying the global stability and function. We found the dynamics and oscillations in human brains responsible for cognitive processes and physiological rhythm regulations are determined not only by the landscape gradient but also by the flux. We found that the flux is closely related to the degrees of the asymmetric connections in neural networks and is the origin of the neural oscillations. The neural oscillation landscape shows a closed-ring attractor topology. The landscape gradient attracts the network down to the ring. The flux is responsible for coherent oscillations on the ring. We suggest the flux may provide the driving force for associations among memories. We applied our theory to rapid-eye movement sleep cycle. We identified the key regulation factors for function through global sensitivity analysis of landscape topography against wirings, which are in good agreements with experiments.neural circuits | free energy | entropy production | nonequilibrium thermodynamics A grand goal of biology is to understand the function of the human brain. The brain is a complex dynamical system (1-6). The individual neurons can develop action potentials and connect with each other through synapses to form the neural circuits. The neural circuits of the brain perpetually generate complex patterns of activity that have been shown to be related with special biological functions, such as learning, long-term associative memory, working memory, olfaction, decision making and thinking (7-9), etc. Many models have been proposed for understanding how neural circuits generate different patterns of activity. HodgkinHuxley model gives a quantitative description of a single neuronal behavior based on the voltage-clamp measurements of the voltage (4). However, various vital functions are carried out by the circuit rather than individual neurons. It is at present still challenging to explore the underlying global natures of the large neural networks built from individual neurons.Hopfield developed a model (5, 6) that makes it possible to explore the global natures of the large neural networks without losing the information of essential biological functions. For symmetric neural circuits, an energy landscape can be constructed that decreas...

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The present study was designed to investigate whether microRNAs (miRNAs) are involved in atrioventricular block (AVB) in the setting of myocardial ischemia (MI). A cardiac-specific miR-1 transgenic (Tg) mouse model was successfully established for the first time in this study using microinjection. miR-1 level was measured by real-time qRT-PCR. Whole-cell patch clamp was employed to record L-type calcium current (ICa,L) and inward rectifier K+ current (IK1). Expression of connexin 43 (Cx43) protein was determined by western blot analysis. Alternations of [Ca2+]i was detected by laser scanning confocal microscopy in ventricular myocytes. The incidence of AVB was higher in miR-1 Tg mice than that in wild-type (WT) mice. The normalized peak current amplitude of ICa,L was lower in ventricular myocytes from miR-1 Tg mice as compared with WT mice. Similarly, the current density of IK1 was decreased in miR-1 Tg mice than that in WT mice. Compared with WT mice, miR-1 Tg mice exhibited a significant decrease of the systolic [Ca2+]i in ventricular myocytes but a prominent increase of the resting [Ca2+]i. Moreover, Cx43 protein was downregulated in miR-1 Tg mice compared to that in WT mice. Administration of LNA-modified antimiR-1 reversed all the above changes. miR-1 overexpression may contribute to the increased susceptibility of the heart to AVB, which provides us novel insights into the molecular mechanisms underlying ischemic cardiac arrhythmias.

Edited by Tamas DalmayKeywords: miRNA Ischemic Heart disease IGF2 Angiogenesis SRF a b s t r a c t Angiogenesis, a key factor in ischemic heart disease, is rapidly initiated in response to hypoxic or ischemic conditions. MicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that regulate gene expression at post-transcriptional level. The recent discovery of the involvement of these RNAs in the control of angiogenesis renders them very attractive in the development of new approaches for restoring the angiogenic balance. In the present study, we explored that miR-483-5p, a microRNA embedded in the intron of insulin-like growth factor 2 (Igf2), acts as an endogenous angiogenesis-inhibiting factor. We identified that serum response factor (SRF) is one of miR-483-5p target genes. These findings indicated that the miR-483-5p-SRF pathway may offer a novel strategy for treatment with angiogenesis in ischemic heart disease patients.