Functional imaging of focal brain activation in conscious rats: Impact of [¹⁴C]glucose metabolite spreading and release

Abstract

Labeled glucose and its analogs are widely used in imaging and metabolic studies of brain function, astrocyte-neuron interactions, and neurotransmission. Metabolite shuttling among astrocytes and neurons is essential for cell-cell transfer of neurotransmitter precursors and supply and elimination of energy metabolites, but dispersion and release of labeled compounds from activated tissue would reduce signal registration in metabolic labeling studies, causing underestimation of focal functional activation. Processes and pathways involved in metabolite trafficking and release were therefore assessed in the auditory pathway of conscious rats. Unilateral monotonic stimulation increased glucose utilization (CMR(glc)) in tonotopic bands in the activated inferior colliculus by 35-85% compared with contralateral tissue when assayed with [(14)C]deoxyglucose (DG), whereas only 20-30% increases were registered with [1- or 6-(14)C]glucose. Tonotopic bands were not evident with [1-(14)C]glucose unless assayed during halothane anesthesia or pretreatment with probenecid but were detectable with [6-(14)C]glucose. Extracellular lactate levels transiently doubled during acoustic stimulation, so metabolite spreading was assessed by microinfusion of [(14)C]tracers into the inferior colliculus. The volume of tissue labeled by [1-(14)C]glucose exceeded that by [(14)C]DG by 3.2- and 1.4-fold during rest and acoustic activation, respectively. During activation, the tissue volume labeled by U-(14)C-labeled glutamine and lactate rose, whereas that by glucose fell 50% and that by DG was unchanged. Dispersion of [1-(14)C]glucose and its metabolites during rest was also reduced 50% by preinfusion of gap junction blockers. To summarize, during brain activation focal CMR(glc) is underestimated with labeled glucose because of decarboxylation reactions, spreading within tissue and via the astrocyte syncytium, and release from activated tissue. These findings help explain the fall in CMR(O2)/CMR(glc) during brain activation and suggest that lactate and other nonoxidized metabolites of glucose are quickly shuttled away from sites of functional activation.

Cortical metabolic rates as measured by 2-deoxyglucose-uptake are increased after waking and decreased after sleep in mice

“…The stability of 2-DG in the brain tissue, however, is less than previously assumed [30], since it has been shown that 10 min after the injection 2-DG is lost from the brain at a significant rate [11,12]. In any case, the direct comparison of metabolic rates assessed by the 2-DG and 14 C-glucose consumption revealed close correspondence between the two methods for many brain regions [9,10], and 2-DG appears to be a more sensitive marker of regional functional activation after sensory stimulation compared to 14 Cglucose [7][8][9]. Furthermore, the use of 2-DG enabled us to compare our results with previous reports [26,30,35].…”

Gap Junction Dysfunction in the Prefrontal Cortex Induces Depressive-Like Behaviors in Rats

“…Given the role of gap junctions in the buffering of ions, long-range signaling, and exchange of small molecules in astroglial networks (Theis et al, 2005;Scemes and Giaume, 2006;Wallraff et al, 2006;Cruz et al, 2007), astroglial GJCs may play an important role in allowing information processing and integration from a large number of neurons, in providing metabolites to remote sites during high neuronal demand, and in buffering ion or neurotransmitter concentrations . In particular, owing to the proximity of astrocyte gap junctions and neuronal synapses, the concept of the tripartite synapse was initiated (Araque et al, 1999;Perea et al, 2009) and astrocytic networks, thanks to their permeability to Ca 2 + and the potential gliotransmitters such as glutamate, could coordinate the activity of local groups of synapses .…”

Connexin 43-Mediated Astroglial Metabolic Networks Contribute to the Regulation of the Sleep-Wake Cycle

“…Since each astrocyte can contact over 100,000 synapses (Bushong et al, 2002) and enwrap 4 to 8 neuronal somata (Halassa et al, 2007), the demand on one astrocyte for energy metabolite supply might be overwhelming. Thus, by increasing the effective volume of the intracellular compartment (De Pina-Benabou et al, 2001) and allowing glucose/lactate trafficking towards areas of high neuronal activity (Ball et al, 2007; Cruz et al, 2007; Rouach et al, 2008; Gandhi et al, 2009), gap junctional communication between astrocytes could provide better metabolic support to neurons than could be achieved by individual uncoupled astrocytes.…”