Date of Award
Doctor of Philosophy (PhD)
The biological basis of human intelligence is largely a mystery, but likely required evolutionary adaptations to achieve the information processing capacity needed to expand the complexity of cognition among species. The link between evolutionary expansion of signaling complexity in the brain and cognition has largely focused on neuronal mechanisms, in part because information processing has historically been attributed to these cells. However, astrocytes are emerging as a second type of brain cell that is capable of processing information due to their capacity to release glutamate and, thereby, regulate neural circuits. Hence, a modern question is whether astrocytes contributed to the signaling complexity required for sophisticated forms of cognition. The glutamate release mechanism system xc- (Sxc) is the ideal mechanism to investigate this question because it is evolutionarily novel to vertebrate species and it is expressed by astrocytes. The central hypothesis tested herein is that Sxc increased the complexity of glutamate signaling and is required for behavior requiring complex cognition. To test, a genetically modified rat with Sxc activity eliminated was generated (MSxc rats). Phenotyping revealed that loss of Sxc activity produced changes in behavior that reflect diminished cognition or top-down processing including impaired reversal learning, set-shifting, and attentional allocation. Remarkably, loss of Sxc did not impact central regulation of metabolism, Pavlovian conditioning, instrumental conditioning, locomotor activity, and novel-object recognition. Additionally, Sxc is integral to the regulation of neural networks. In the nucleus accumbens, we found that a loss of Sxc altered synaptic strength in a circuit specific manner. Further, we found that Sxc-mediated glutamate release is regulated by presynaptic (the neuropeptide PACAP), postsynaptic (endocannabinoid) and hormonal (glucocorticoids) signaling mechanisms. Further interrogation of Sxc regulation by PACAP revealed that this neuropeptide acts on both neurons and astrocytes to facilitate bidirectional neuron-astrocyte signaling between Sxc and extrasynaptic NMDA receptors. The in vivo relevance of this mechanism is established by our findings that PACAP microinjected into the nucleus accumbens attenuates cocaine-primed reinstatement, and the regulation of this behavior requires both Sxc and NMDA receptors. These findings support the possibility that future therapeutics could restore cognition by targeting astrocytes.