| Summary: | <p> The process by which new learning generates a long-term memory is termed consolidation. Long-term memories are not established instantaneously with learning, but are built through a number of time-dependent processes. Stress and emotional arousal are known to modulate memory consolidation through the action of hormones and neurotransmitters such as noradrenaline. Although most studies done thus far on memory mechanisms have focused on the role of neurons, it is becoming increasingly clear that the glial cells astrocytes play active roles in cognitive processes including learning and memory. Our laboratory has shown that, in rats, the astrocytic breakdown of glycogen into lactate, and lactate transport into neurons, are required in the hippocampus for long-term potentiation (LTP) and for the consolidation of inhibitory avoidance, a type of fear-based contextual memory. These results demonstrated that astrocytic-neuronal metabolic coupling mediated by lactate is an essential mechanism of long-term synaptic plasticity and long-term memory consolidation. My work in this thesis expanded on these findings and asked three questions. First, is lactate-mediated metabolic coupling a general mechanism of plasticity occurring in different brain regions? Second, is there a role for this metabolic coupling in the modulation of memory consolidation mediated by stress? Third, what is the function of lactate transported into neurons? </p><p> Indeed, the coordinated function of multiple brain regions is critical for consolidation. The hippocampus is an essential brain structure for long-term memory formation, with important contributions from the amygdala for modulation of the emotional valence of a memory, and over time, an increasingly important role of cortical structures for memory storage. </p><p> In Chapter I, I demonstrate that breakdown of astrocytic glycogen into lactate also plays a role in long-term memory formation in the basolateral amygdala and anterior cingulate cortex. In Chapter II, I describe how astrocytes mediate the effect of the neuromodulator noradrenaline on memory formation in the hippocampus. Specifically, β<sub>2</sub>-adrenergic receptors expressed in astrocytes but not neurons are required for memory consolidation. β<sub> 2</sub>-adrenergic receptors mediate lactate release from astrocytes and memory impairment due to knockdown of β<sub>2</sub>-adrenergic receptors in astrocytes can be rescued by administration of lactate. Thus, these astrocytic adrenergic receptors critically support memory by engaging astrocyte-neuron metabolic coupling via lactate. </p><p> In Chapter III, I show that the function of this lactate is to critically provide energetic support for neuronal changes required for memory consolidation. </p><p> Altogether my results suggest that astrocytic mechanisms play an essential role in memory consolidation in different brain regions and that stress-mediated noradrenergic regulation critically engages astrocytic adrenergic receptors. They also show that these metabolic coupling mechanisms are important because they provide energy for neuronal molecular changes supporting memory formation.</p>
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