A Role for Astrocytes in Nociception, Nucleus Accumbens Physiology, and REM Sleep Regulation.
Astrocytes are non-neuronal cells in the nervous system that elevate their intracellular
calcium in response to stimuli. Astrocytes express receptors for neurotransmitters and
ensheath pre- and post-synaptic neuronal processes. Abundant evidence suggests
astrocytes not only detect activity of the synapse, but also release chemicals, termed
gliotransmitters, that influence synaptic s... read moretrength and plasticity. Due to their ability
to influence synaptic physiology, astrocytes have gained recognition as modulators of
behavior. A very interesting feature of astrocytes is that they are not uniform across
the brain. Astrocytes in the spinal cord, for example, have distinct protein expression
profiles from those in the nucleus accumbens and the cortex. Moreover, astrocytes have
different targets depending on the receptors expressed by surrounding neurons, which are
also heterogeneous across brain regions. In this thesis, three distinct roles for
astrocytes will be explored: the role of astrocyte gliotransmission in modulating
baseline mechanical nociception and nucleus accumbens physiology as well as how
astrocyte IP3/Ca2+ signaling regulates REM sleep. Astrocytes release ATP, which is
degraded to adenosine that tonically activates adenosine 1 receptors in the hippocampus.
Here, adenosine 1 receptors are the dominant adenosine receptor type and through the
activation of these receptors, astrocytes increase post-synaptic glutamate receptor
function. However in studies conducted in this thesis, decreased A1 receptor activation
was not correlated with decreased glutamate receptor function. In the nucleus accumbens,
expression levels of adenosine 2 receptors are predominant. This may explain why the
gliotransmitter, adenosine does not play the same role in the nucleus accumbens as it
does in the hippocampus. In the spinal cord, in addition to adenosine receptors, ATP
receptors are prominently expressed. Astrocytes in the dorsal horn of the spinal cord
become reactive after peripheral nerve injury. It is thought that purinergic signaling
in the spinal cord mediates persistent nociception. In a mouse model of attenuated
gliotransmission, known to have reduced adenosine tone in the cortex and hippocampus,
baseline mechanical nociception thresholds are reduced, suggesting gliotransmission has
an anti-nociceptive effect. Finally, in the context of sleep, when gliotransmission is
attenuated, NREM slow wave activity in the brain is reduced. Interestingly, this
phenotype was not recapitulated when astrocyte IP3-mediated Ca2+ signaling, thought to
be the primary mechanism of calcium signaling, leading to gliotransmission, was
attenuated. However, REM sleep was enhanced in these mice. These finding suggest that
astrocytes regulate different aspects of sleep through non-overlapping signaling
cascades. Overall, this thesis highlights the different functions of astrocytes across
regions of the central nervous system.
Thesis (Ph.D.)--Tufts University, 2015.
Submitted to the Dept. of Neuroscience.
Advisor: Philip Haydon.
Committee: Maribel Rios, Kathleen Dunlap, Michele Jacob, and Radhika Basheer.
Keyword: Neurosciences.read less