The abilities of neuronal populations to encode rapidly varying stimuli and respond quickly to abrupt input changes are crucial for basic neuronal computations, such as coincidence detection, grouping by synchrony, and spike-timing-dependent plasticity, as well as for the processing speed of neuronal networks. Theoretical analyses have linked these abilities to the fast-onset dynamics of action potentials (APs). Using a combination of whole-cell recordings from rat neocortical neurons and computer simulations, we provide the first experimental evidence for this conjecture and prove its validity for the case of distal AP initiation in the axon initial segment (AIS), typical for cortical neurons. Neocortical neurons with fast-onset APs in the soma can phase-lock their population firing to signal frequencies up to ~300 – 400 Hz and respond within 1–2 ms to subtle changes of input current. The ability to encode high frequencies and response speed were dramatically reduced when AP onset was slowed by experimental manipulations or was intrinsically slow due to immature AP generation mechanisms. Multicompartment conductance-based models reproducing the initiation of spikes in the AIS could encode high frequencies only if AP onset was fast at the initiation site (e.g., attributable to cooperative gating of a fraction of sodium channels) but not when fast onset of somatic AP was produced solely by backpropagation. We conclude that fast-onset dynamics is a genuine property of cortical AP generators. It enables fast computations in cortical circuits that are rich in recurrent connections both within each region and across the hierarchy of areas.

In the frame of Multicenter observational study ECVD-RF (Epidemiology of Cardiovascular Diseases and their Risk Factors in Regions of Russian Federation) by the unique protocol the investigation of representative selections of adult population at the age of 25-64 y.o. of 11 regions RF (n=18305, including males, n=6919 and females n=11386): Volgograd, Vologda, Voronezh, Ivanovo, Kemerovo, Orenburg, Samara, Tomsk, Tyumen, Saint-Petersburg and Northern Osetia-Alania. The prevalence of the following risk factors (RF) of cardiovascular diseases is evaluated: high blood pressure — 33,8%, obesity — 29,7%, high total cholesterol — 57,6%, high glucose level or diabetes — 4,6%, smoking (tobacco consumption) — 25,7%, insufficient (low) level of physical activity — 38,8%, excessive salt consumption — 49,9% and insufficient vegetables and fruits consumption — 41,9%. Gender differences and an increase with the age of the parameters mentioned are described.The absence of a epidemiologic monitoring system at the Federal level leads to an impossibility of clear conclusions on the RF dynamics in Russian population. While comparing the ECVD-RF study with previous epidemiological studies we can just cautiously suppose the existence in 21st age of negative dynamics of one RF (obesity, dyslipidemia) and positive dynamics of the others (smoking).

Hebbian-type learning rules, which underlie learning and refinement of neuronal connectivity, postulate input specificity of synaptic changes. However, theoretical analyses have long appreciated that additional mechanisms, not restricted to activated synapses, are needed to counteract positive feedback imposed by Hebbian-type rules on synaptic weight changes and to achieve stable operation of learning systems. The biological basis of such mechanisms has remained elusive. Here we show that, in layer 2/3 pyramidal neurons from slices of visual cortex of rats, synaptic changes induced at individual synapses by spike timing-dependent plasticity do not strictly follow the input specificity rule. Spike timing-dependent plasticity is accompanied by changes in unpaired synapses: heterosynaptic plasticity. The direction of heterosynaptic changes is weight-dependent, with balanced potentiation and depression, so that the total synaptic input to a cell remains preserved despite potentiation or depression of individual synapses. Importantly, this form of heterosynaptic plasticity is induced at unpaired synapses by the same pattern of postsynaptic activity that induces homosynaptic changes at paired synapses. In computer simulations, we show that experimentally observed heterosynaptic plasticity can indeed serve the theoretically predicted role of robustly preventing runaway dynamics of synaptic weights and activity. Moreover, it endows model neurons and networks with essential computational features: enhancement of synaptic competition, facilitation of the development of specific intrinsic connectivity, and the ability for relearning. We conclude that heterosynaptic plasticity is an inherent property of plastic synapses, crucial for normal operation of learning systems.

Extensive convergent evidence collectively suggests that mitochondrial dysfunction is central to the pathogenesis of Parkinson’s disease (PD). Recently, changes in the dynamic properties of mitochondria have been increasingly implicated as a key proximate mechanism underlying neurodegeneration. However, studies have been limited by the lack of a model in which mitochondria can be imaged directly and dynamically in dopaminergic neurons of the intact vertebrate CNS. We generated transgenic zebrafish in which mitochondria of dopaminergic neurons are labeled with a fluorescent reporter, and optimized methods allowing direct intravital imaging of CNS dopaminergic axons and measurement of mitochondrial transport in vivo. The proportion of mitochondria undergoing axonal transport in dopaminergic neurons decreased overall during development between 2 days post-fertilization (dpf) and 5dpf, at which point the major period of growth and synaptogenesis of the relevant axonal projections is complete. Exposure to 0.5 – 1.0mM MPP+ between 4 – 5 dpf did not compromise zebrafish viability or cause detectable changes in the number or morphology of dopaminergic neurons, motor function or monoaminergic neurochemistry. However, 0.5mM MPP+ caused a 300% increase in retrograde mitochondrial transport and a 30% decrease in anterograde transport. In contrast, exposure to higher concentrations of MPP+ caused an overall reduction in mitochondrial transport. This is the first time mitochondrial transport has been observed directly in CNS dopaminergic neurons of a living vertebrate and quantified in a PD model in vivo. Our findings are compatible with a model in which damage at presynaptic dopaminergic terminals causes an early compensatory increase in retrograde transport of compromised mitochondria for degradation in the cell body. These data are important because manipulation of early pathogenic mechanisms might be a valid therapeutic approach to PD. The novel transgenic lines and methods we developed will be useful for future studies on mitochondrial dynamics in health and disease.