Synaptic Plasticity and the Warburg Effect

Functional brain imaging studies show that in certain brain regions glucose utilization exceeds oxygen consumption, indicating the predominance of aerobic glycolysis. In this issue, Goyal et al. (2014) report that this metabolic profile is associated with an enrichment in the expression of genes involved in synaptic plasticity and remodeling processes

Deciphering Neuron-Glia Compartmentalization in Cortical Energy Metabolism

Energy demand is an important constraint on neural signaling. Several methods have been proposed to assess the energy budget of the brain based on a bottom-up approach in which the energy demand of individual biophysical processes are first estimated independently and then summed up to compute the brain's total energy budget. Here, we address this question using a novel approach that makes use of published datasets that reported average cerebral glucose and oxygen utilization in humans and rodents during different activation states. Our approach allows us (1) to decipher neuron-glia compartmentalization in energy metabolism and (2) to compute a precise state-dependent energy budget for the brain. Under the assumption that the fraction of energy used for signaling is proportional to the cycling of neurotransmitters, we find that in the activated state, most of the energy (∼80%) is oxidatively produced and consumed by neurons to support neuron-to-neuron signaling. Glial cells, while only contributing for a small fraction to energy production (∼6%), actually take up a significant fraction of glucose (50% or more) from the blood and provide neurons with glucose-derived energy substrates. Our results suggest that glycolysis occurs for a significant part in astrocytes whereas most of the oxygen is utilized in neurons. As a consequence, a transfer of glucose-derived metabolites from glial cells to neurons has to take place. Furthermore, we find that the amplitude of this transfer is correlated to (1) the activity level of the brain; the larger the activity, the more metabolites are shuttled from glia to neurons and (2) the oxidative activity in astrocytes; with higher glial pyruvate metabolism, less metabolites are shuttled from glia to neurons. While some of the details of a bottom-up biophysical approach have to be simplified, our method allows for a straightforward assessment of the brain's energy budget from macroscopic measurements with minimal underlying assumptions

Fine Gating Properties of Channels Responsible for Persistent Sodium Current Generation in Entorhinal Cortex Neurons

The gating properties of channels responsible for the generation of persistent Na+ current (INaP) in entorhinal cortex layer II principal neurons were investigated by performing cell-attached, patch-clamp experiments in acutely isolated cells. Voltage-gated Na+-channel activity was routinely elicited by applying 500-ms depolarizing test pulses positive to −60 mV from a holding potential of −100 mV. The channel activity underlying INaP consisted of prolonged and frequently delayed bursts during which repetitive openings were separated by short closings. The mean duration of openings within bursts was strongly voltage dependent, and increased by e times per every ∼12 mV of depolarization. On the other hand, intraburst closed times showed no major voltage dependence. The mean duration of burst events was also relatively voltage insensitive. The analysis of burst-duration frequency distribution returned two major, relatively voltage-independent time constants of ∼28 and ∼190 ms. The probability of burst openings to occur also appeared largely voltage independent. Because of the above “persistent” Na+-channel properties, the voltage dependence of the conductance underlying whole-cell INaP turned out to be largely the consequence of the pronounced voltage dependence of intraburst open times. On the other hand, some kinetic properties of the macroscopic INaP, and in particular the fast and intermediate INaP-decay components observed during step depolarizations, were found to largely reflect mean burst duration of the underlying channel openings. A further INaP decay process, namely slow inactivation, was paralleled instead by a progressive increase of interburst closed times during the application of long-lasting (i.e., 20 s) depolarizing pulses. In addition, long-lasting depolarizations also promoted a channel gating modality characterized by shorter burst durations than normally seen using 500-ms test pulses, with a predominant burst-duration time constant of ∼5–6 ms. The above data, therefore, provide a detailed picture of the single-channel bases of INaP voltage-dependent and kinetic properties in entorhinal cortex layer II neurons

Biophysical Properties and Slow Voltage-Dependent Inactivation of a Sustained Sodium Current in Entorhinal Cortex Layer-II Principal Neurons: A Whole-Cell and Single-Channel Study

The functional and biophysical properties of a sustained, or “persistent,” Na+ current (INaP) responsible for the generation of subthreshold oscillatory activity in entorhinal cortex layer-II principal neurons (the “stellate cells”) were investigated with whole-cell, patch-clamp experiments. Both acutely dissociated cells and slices derived from adult rat entorhinal cortex were used. INaP , activated by either slow voltage ramps or long-lasting depolarizing pulses, was prominent in both isolated and, especially, in situ neurons. The analysis of the gating properties of the transient Na+ current (INaT) in the same neurons revealed that the resulting time-independent “window” current (INaTW) had both amplitude and voltage dependence not compatible with those of the observed INaP , thus implying the existence of an alternative mechanism of persistent Na+-current generation. The tetrodotoxin-sensitive Na+ currents evoked by slow voltage ramps decreased in amplitude with decreasing ramp slopes, thus suggesting that a time-dependent inactivation was taking place during ramp depolarizations. When ramps were preceded by increasingly positive, long-lasting voltage prepulses, INaP was progressively, and eventually completely, inactivated. The V1/2 of INaP steady state inactivation was approximately −49 mV. The time dependence of the development of the inactivation was also studied by varying the duration of the inactivating prepulse: time constants ranging from ∼6.8 to ∼2.6 s, depending on the voltage level, were revealed. Moreover, the activation and inactivation properties of INaP were such as to generate, within a relatively broad membrane-voltage range, a really persistent window current (INaPW). Significantly, INaPW was maximal at about the same voltage level at which subthreshold oscillations are expressed by the stellate cells. Indeed, at −50 mV, the INaPW was shown to contribute to >80% of the persistent Na+ current that sustains the subthreshold oscillations, whereas only the remaining part can be attributed to a classical Hodgkin-Huxley INaTW. Finally, the single-channel bases of INaP slow inactivation and INaPW generation were investigated in cell-attached experiments. Both phenomena were found to be underlain by repetitive, relatively prolonged late channel openings that appeared to undergo inactivation in a nearly irreversible manner at high depolarization levels (−10 mV), but not at more negative potentials (−40 mV)

The role of astroglia in neuroprotection

Astrocytes are the main neural cell type responsible for the maintenance of brain homeostasis. They form highly organized anatomical domains that are interconnected into extensive networks. These features, along with the expression of a wide array of receptors, transporters, and ion channels, ideally position them to sense and dynamically modulate neuronal activity. Astrocytes cooperate with neurons on several levels, including neurotransmitter trafficking and recycling, ion homeostasis, energy metabolism, and defense against oxidative stress. The critical dependence of neurons upon their constant support confers astrocytes with intrinsic neuroprotective properties which are discussed here. Conversely, pathogenic stimuli may disturb astrocytic function, thus compromising neuronal functionality and viability. Using neuroinflammation, Alzheimer's disease, and hepatic encephalopathy as examples, we discuss how astrocytic defense mechanisms may be overwhelmed in pathological conditions, contributing to disease progression

Cellular Bases of Brain Energy Metabolism and Their Relevance to Functional Brain Imaging: Evidence for a Prominent Role of Astrocytes

Survey of Brain Energy Metabolism at the Organ and Regional Level

Alzheimer's disease: the amyloid hypothesis and the Inverse Warburg effect.

Epidemiological and biochemical studies show that the sporadic forms of Alzheimer's disease (AD) are characterized by the following hallmarks: (a) An exponential increase with age; (b) Selective neuronal vulnerability; (c) Inverse cancer comorbidity. The present article appeals to these hallmarks to evaluate and contrast two competing models of AD: the amyloid hypothesis (a neuron-centric mechanism) and the Inverse Warburg hypothesis (a neuron-astrocytic mechanism). We show that these three hallmarks of AD conflict with the amyloid hypothesis, but are consistent with the Inverse Warburg hypothesis, a bioenergetic model which postulates that AD is the result of a cascade of three events-mitochondrial dysregulation, metabolic reprogramming (the Inverse Warburg effect), and natural selection. We also provide an explanation for the failures of the clinical trials based on amyloid immunization, and we propose a new class of therapeutic strategies consistent with the neuroenergetic selection model

A Historical Review of Diachrony and Semantic Dimensions of Trace in Neurosciences and Lacanian Psychoanalysis.

Experience leaves a trace in the nervous system through plasticity. However, the exact meaning of the mnesic trace is poorly defined in current literature. This article provides a historical review of the term trace in neuroscience and psychoanalysis literature, to highlight two relevant aspects: the diachronic and the semantic dimensions. There has been a general interest in diachrony, or a form of evolution of the trace, but its indissociable semantic dimension remains partially disregarded. Although frequently implied, the diachronic and semantic dimensions of the trace are rarely clearly articulated. We situate this discussion into the classical opposition of syntax, or rules of inscription of the trace in the nervous system, and semantics, or the content of the trace, which takes into consideration the attempt of the human being to build coherence. A general observation is that the study of the term trace follows trends of the thought of the given epoch. This historical analysis also reveals the decay of the idea that the trace is reliable to the experience. From the articulation between neurosciences and psychoanalysis in a historical perspective, this review shows that the trend is to consider trace as a production of the subject, resulting in a permanent rewriting in an attempt to give meaning to the experience. This trend is becoming increasingly evident in light of recent research in neurosciences and psychoanalysis

How do you frame ill-defined problems? A study on creative logics in action

Problem framing is pivotal to fostering knowledge and innovation, especially in the modern environment where problems are often ill defined. However, the managerial literature has thus far mainly addressed problem framing from an outcome perspective, overlooking the processes that lead to the outcomes. A common view is that the complexity, ambiguity and uncertainty of ill-defined problems call for a creative process. Therefore, through ethnographically observing six design thinking workshops, this study adopts a qualitative approach to explore the problem framing creative process. Specifically, we unpack three thinking modalities involved in the creative process (i.e. creative logics) of problem framing: analogical reasoning, associative thinking and abductive reasoning. We suggest that individuals enact these through seven creative operations. In addition, we link these creative operations to two types of problem framing outcomes: referenced frames and crafted frames. From a practitioner perspective, this study casts new light on the importance of problem framing for creativity and innovation, highlighting the ways in which individuals operationalize the creative logics to frame ill-defined problems as original problems worth solving

Modulation of the glutamate-evoked release of arachidonic acid from mouse cortical neurons: involvement of a pH-sensitive membrane phospholipase A2

Excitatory synaptic transmission is associated with changes in both extracellular and intracellular pH. Using mouse cortical neurons in primary cultures, we studied the sensitivity of glutamate-evoked release of 3H-arachidonic acid (3H-AA) to changes in extracellular pH (pHo) and related intracellular pH (pHi). As pHo was shifted from 7.2 to 7.8, the glutamate-evoked release of 3H-AA was enhanced by approximately threefold. The effect of alkaline pHo on the glutamate response was rapid, becoming significant within 2 min. 3H-AA release, evoked by both NMDA and kainate, was also enhanced by pHo alkalinization. NMDA- and kainate-induced increase in free intracellular Ca2+ was unaffected by changing pHo from 7.2 to 7.8, indicating that the receptor-induced Ca2+ influx is not responsible for the pHo sensitivity of the glutamate-evoked release of 3H-AA. Alkalinization of pHi obtained by incubating neurons in the presence of HCO3- or NH4 enhanced the glutamate-evoked release of 3H-AA, while pHi acidification obtained by blockade of Na+/H+ and Cl-/HCO3- exchangers decreased the glutamate response. Membrane-bound phospholipase A2 (mPLA2) activity was stimulated by Ca2+ in a pH-dependent manner, increasing its activity as pH was shifted from 7.2 to 7.8. This pH profile corresponds to the pH profile of the glutamate-, NMDA- and kainate-evoked release of 3H-AA. Taken together, these results indicate that the glutamate-evoked release of 3H-AA may be mediated by the pH-sensitive mPLA2. Since excitatory neurotransmission mediated by glutamate results in both pHo and pHi changes and since AA enhances glutamatergic neurotransmission at both pre- and postsynaptic levels, the data reported here reveals a possible molecular mechanism whereby glutamate can modulate its own signalling efficacy in a pH-dependent manner by regulating the release of AA