Frontiers in neuroenergetics最新文献

During psychosocial stress, the brain demands extra energy from the body to satisfy its increased needs. For that purpose it uses a mechanism referred to as "cerebral insulin suppression" (CIS). Specifically, activation of the stress system suppresses insulin secretion from pancreatic beta-cells, and in this way energy-particularly glucose-is allocated to the brain rather than the periphery. It is unknown, however, how the brain of obese humans organizes its supply and demand during psychosocial stress. To answer this question, we examined 20 obese and 20 normal weight men in two sessions (Trier Social Stress Test and non-stress control condition followed by either a rich buffet or a meager salad). Blood samples were continuously taken and subjects rated their vigilance and mood by standard questionnaires. First, we found a low reactive stress system in obesity. While obese subjects showed a marked hormonal response to the psychosocial challenge, the cortisol response to the subsequent meal was absent. Whereas the brains of normal weight subjects demanded for extra energy from the body by using CIS, CIS was not detectable in obese subjects. Our findings suggest that the absence of CIS in obese subjects is due to the absence of their meal-related cortisol peak. Second, normal weight men were high reactive during psychosocial stress in changing their vigilance, thereby increasing their cerebral energy need, whereas obese men were low reactive in this respect. Third, normal weight subjects preferred carbohydrates after stress to supply their brain, while obese men preferred fat and protein instead. We conclude that the brain of obese people organizes its need, supply, and demand in a low reactive manner.

Glycogen is a complex glucose polymer found in a variety of tissues, including brain, where it is localized primarily in astrocytes. The small quantity found in brain compared to e.g., liver has led to the understanding that brain glycogen is merely used during hypoglycemia or ischemia. In this review evidence is brought forward highlighting what has been an emerging understanding in brain energy metabolism: that glycogen is more than just a convenient way to store energy for use in emergencies-it is a highly dynamic molecule with versatile implications in brain function, i.e., synaptic activity and memory formation. In line with the great spatiotemporal complexity of the brain and thereof derived focus on the basis for ensuring the availability of the right amount of energy at the right time and place, we here encourage a closer look into the molecular and subcellular mechanisms underlying glycogen metabolism. Based on (1) the compartmentation of the interconnected second messenger pathways controlling glycogen metabolism (calcium and cAMP), (2) alterations in the subcellular location of glycogen-associated enzymes and proteins induced by the metabolic status and (3) a sequential component in the intermolecular mechanisms of glycogen metabolism, we suggest that glycogen metabolism in astrocytes is compartmentalized at the subcellular level. As a consequence, the meaning and importance of conventional terms used to describe glycogen metabolism (e.g., turnover) is challenged. Overall, this review represents an overview of contemporary knowledge about brain glycogen and its metabolism and function. However, it also has a sharp focus on what we do not know, which is perhaps even more important for the future quest of uncovering the roles of glycogen in brain physiology and pathology.

Existing current based models that capture spike activity, though useful in studying information processing capabilities of neurons, fail to throw light on their internal functioning. It is imperative to develop a model that captures the spike train of a neuron as a function of its intracellular parameters for non-invasive diagnosis of diseased neurons. This is the first ever article to present such an integrated model that quantifies the inter-dependency between spike activity and intracellular energetics. The generated spike trains from our integrated model will throw greater light on the intracellular energetics than existing current models. Now, an abnormality in the spike of a diseased neuron can be linked and hence effectively analyzed at the energetics level. The spectral analysis of the generated spike trains in a time-frequency domain will help identify abnormalities in the internals of a neuron. As a case study, the parameters of our model are tuned for Alzheimer's disease and its resultant spike trains are studied and presented. This massive initiative ultimately aims to encompass the entire molecular signaling pathways of the neuronal bioenergetics linking it to the voltage spike initiation and propagation; due to the lack of experimental data quantifying the inter dependencies among the parameters, the model at this stage adopts a particular level of functionality and is shown as an approach to study and perform disease modeling at the spike train and the mitochondrial bioenergetics level.

Flickering light dilates retinal arterioles and increases retinal blood flow, a response termed functional hyperemia. This response is diminished in diabetic patients even before the appearance of overt clinical retinopathy. The loss of functional hyperemia could deprive retinal neurons of oxygen and nutrients, possibly exacerbating the development of diabetic retinopathy. We have tested whether inhibiting inducible nitric oxide synthase (iNOS) reverses the loss of functional hyperemia in diabetic rat retinas in vivo. Changes in retinal arteriole diameter were measured following diffuse flickering light stimulation in control rats, streptozotocin-induced type 1 diabetic rats and diabetic rats treated with aminoguanidine (AG; an iNOS inhibitor), either acutely via IV injection or chronically in drinking water. Flickering light-evoked large arteriole dilations (10.8 ± 1.1%) in control rats. This response was diminished by 61% in diabetic animals (4.2 ± 0.3%). Both acute and chronic treatment with AG restored flicker-induced arteriole dilations in diabetic rats (8.8 ± 0.9 and 9.5 ± 1.3%, respectively). The amplitude of the corneal electroretinogram b-wave was similar in control and diabetic animals. These findings demonstrate that inhibiting iNOS with AG is effective in preventing the loss of, and restoring, normal functional hyperemia in the diabetic rat retina. Previous work has demonstrated the efficacy of iNOS inhibitors in slowing the progression of diabetic retinopathy. This effect could be due, in part, to a restoration of functional hyperemia.

The interactive vasculo-neuro-glial system controlling energy supply in the brain is absent in vitro where energy provision is determined by experimental conditions. Despite the fact that neuronal activity is extremely energy demanding, little has been reported on the state of energy metabolism in submerged brain slices. Without this information, the arbitrarily chosen oxygenation and metabolic provisions make questionable the efficient oxidative metabolism in slices. We show that in mouse hippocampal slices (postnatal day 19-44), evoked neuronal discharges, spontaneous network activity (initiated by 4-aminopyridine), and synaptic stimulation-induced NAD(P)H autofluorescence depend strongly on the oxygen availability. Only the rate of perfusion as high as ~15 ml/min (95% O(2)) provided appropriate oxygenation of a slice. Lower oxygenation resulted in the decrease of both local field potentials and spontaneous network activity as well as in significant modulation of short-term synaptic plasticity. The reduced oxygen supply considerably inhibited the oxidation phase of NAD(P)H signaling indicating that the changes in neuronal activity were paralleled by the decrease in aerobic energy metabolism. Interestingly, the dependence of neuronal activity on oxygen tension was clearly shifted toward considerably larger pO(2) values in slices when compared to in vivo conditions. With sufficient pO(2) provided by a high perfusion rate, partial substitution of glucose in ACSF for β-hydroxybutyrate, pyruvate, or lactate enhanced both oxidative metabolism and synaptic function. This suggests that the high pO(2) in brain slices is compulsory for maintaining oxidative metabolism, and glucose alone is not sufficient in fulfilling energy requirements during neuronal activity. Altogether, our results demonstrate that energy metabolism determines the functional state of neuronal network, highlighting the need for the adequate metabolic support to be insured in the in vitro experiments.

Accumulating evidence suggests that different energy metabolites play a role not only in neuronal but also in glial signaling. Recently, astroglial Ca(2+) transients evoked by the major citric acid cycle metabolite succinate (SUC) and gamma-hydroxybutyrate (GHB) that enters the citric acid cycle via SUC have been described in the brain reward area, the nucleus accumbens (NAc). Cells responding to SUC by Ca(2+) transient constitute a subset of ATP-responsive astrocytes that are activated in a neuron-independent way. In this study we show that GHB-evoked Ca(2+) transients were also found to constitute a subset of ATP-responsive astrocytes in the NAc. Repetitive Ca(2+) dynamics evoked by GHB suggested that Ca(2+) was released from internal stores. Similarly to SUC, the GHB response was also characterized by an effective concentration of 50 μM. We observed that the number of ATP-responsive cells decreased with increasing concentration of either SUC or GHB. Moreover, the concentration dependence of the number of ATP-responsive cells were highly identical as a function of both [SUC] and [GHB], suggesting a mutual receptor for SUC and GHB, therefore implying the existence of a distinct GHB-recognizing astroglial SUC receptor in the brain. The SUC-evoked Ca(2+) signal remained in mice lacking GABA(B) receptor type 1 subunit in the presence and absence of the N-Methyl-d-Aspartate (NMDA) receptor antagonist (2R)-amino-5-phosphonovaleric acid (APV), indicating action mechanisms independent of the GABA(B) or NMDA receptor subtypes. By molecular docking calculations we found that residues R99, H103, R252, and R281 of the binding crevice of the kidney SUC-responsive membrane receptor SUCNR1 (GPCR91) also predict interaction with GHB, further implying similar GHB and SUC action mechanisms. We conclude that the astroglial action of SUC and GHB may represent a link between brain energy states and Ca(2+) signaling in astrocytic networks.