Project Summary
Hypoglycemia is a serious complication of diabetes resulting from insulin treatment which can
lead to cognitive deficits, brain damage, loss of consciousness and death. A primary response
to hypoglycemia is an increase in cerebral blood flow (CBF), which augments the supply of
glucose to the brain. A hypoglycemia-induced increase in adenosine in the brain is thought to
mediate CBF increases. However, astrocytes, which release vasodilating agents and regulate
vascular tone, might also contribute to hypoglycemia-induced vessel dilation and CBF
increases. This novel hypothesis, that astrocytes contribute to hypoglycemia-induced CBF
increases, is supported by our preliminary experiments. We will test this hypothesis by
simultaneously monitoring astrocyte Ca2+ signaling and blood vessel diameter in the
somatosensory cortex of awake mice with two-photon microscopy as blood glucose is lowered
by insulin administration. The hypothesis will be tested in the following aims.
Aim 1. Test the hypothesis that astrocytes mediate hypoglycemia-induced vessel
dilation. The relation between blood glucose, astrocyte Ca2+ signaling, and vessel diameter will
be determined as blood glucose is lowered by insulin administration in control mice and in IP3R2
KO mice, where astrocyte Ca2+ signaling is reduced. As suggested by our preliminary results,
we anticipate that vessel dilation will be reduced in IP3R2 KO animals, demonstrating that
astrocytes contribute to hypoglycemia-induced vessel dilation.
Aim 2. Test the hypothesis that adenosine evokes Ca2+ increases in astrocytes and the
release of vasodilating prostaglandins (PGs) and epoxyeicosatrienoic acids (EETs)
during hypoglycemia. Adenosine mediates hypoglycemia-induced CBF increases. We will test
the hypothesis that adenosine dilation of vessels acts in part by stimulating astrocytes and
evoking astrocyte Ca2+ increases. PGs and EETs are released from astrocytes and dilate
cerebral vessels. We will test whether one or both of these astrocyte vasodilators contribute to
hypoglycemia-induced vessel dilation.
Aim 3. Determine whether neurovascular coupling is altered during hypoglycemia.
Increases in neuronal activity evoke local increases in CBF. This response, termed functional
hyperemia, supplies active neurons with needed glucose and oxygen. We will test whether
vessel dilation evoked by whisker stimulation is altered during hypoglycemia.