PhD in Neuroscience

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Curriculum vitae

Phd thesis

Role of Astrocyte Energy Metabolism in Memory Stability

The Astrocyte-Neuron Lactate Shuttle (ANLS) model establishes that in response to glutamate-mediated neuronal activity, astrocytes take up glucose and process it through aerobic glycolysis resulting in lactate formation. Lactate can also be formed through the breakdown of glycogen by increased extracellular K+ levels associated with increased neuronal activity or by the activation of noradrenaline and β2 adrenergic receptors. Consequently, such lactate is released via monocarboxylate transporters (MCT) 1 and 4 from astrocytes and taken up by neurons via MCT2 to fuel their tricarboxylic cycle. This mechanism is involved in learning paradigms and processes such as memory formation and consolidation, long-term potentiation, and synaptic stabilization.

The role of glycogen-derived lactate in plasticity and memory processing was demonstrated by the inhibition of glycogen phosphorylase within 1,4-dideoxy-1,4-amino-D-arabinitol (DAB), which resulted in amnesia when injected prior to training or at specific times after training. This conclusion is strongly reinforced by the discovery of defects in short-term memory and learning impairment when using glycogen synthase knockout mice. In addition, previous studies show an amnesia rescue after intrahippocampal administration of L-lactate. New evidence suggests that astrocytes have intrinsic neurochemical plasticity that alters the availability and provision of metabolic substrates long after experience.

From the ultrastructural point of view, evidence indicated that the use of L-lactate to restore memory formation corresponds to the increase in the number of dendritic spines in the hippocampus, as it happens in a learning rodent. Spinesprovide an anatomical substrate for memory storage and synaptic transmission. It has been demonstrated that long-term memory formation leads to an increase in spine volume, postsynaptic density surface area, and astrocytic glycogen granules.

Objectives

Quantification of glycogen content
First, we aim to quantify the glycogen content in the whole brain and specific areas such as the hippocampus and prefrontal cortex at different stages of the memory consolidation process.

Memory inhibition and rescue with L-lactate
Second, we will block long-term memory by inhibiting the glycogenolysis pathway to synthesize lactate and test whether acute injection of L-lactate is enough to rescue and stabilize memory after 3 and 7 days. 

Role of glycogen in long-term memory
We will explore the mechanisms through which glycogen levels are maintained in the long term in astrocytes surrounding facilitated synapses after learning. This will allow us to elucidate the role of glycogen in the maintenance of long-term memory.

Morphological analysis with electron microscopy
Finally, using serial electron microscopy, we intend to identify the morphological changes in the hippocampus after long-term memory inhibition and its subsequent rescue with lactate at different time points.

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