Basic Research Studies > Stress
and Noradrenergic function
Stress and Noradrenergic function
Brain
noradrenergic neurons, peptides and stress (NIH/NIDA)
A: Brightfield
photomicrograph showing an injection of biotinylated
dextran amine (BDA) into the paraventricular nucleus
of the hypothalamus in rat brain. 3V: third ventricle
AHC: anterior hypothalamic area f: fornix LH: lateral
hypothalamus. Straight black arrows indicate neurons
exhibiting peroxidase labeling for BDA at the injection
site
B: Darkfield photomicrograph
showing BDA transport in locus coerelues (LC) area
following an injection into the PVN of the hypothalamus.
Immunoperoxidase labeled fibers can be seen in
the LC area (arrowheads). LC: locus coeruleus scp:
superior cerebellar peduncle IV: fourth ventricle
MeV: mesencephalic nucleus of the trigeminal nerve.
Arrows dorsal (D) and lateral (L) indicate orientation
of tissue section. Scale bars = 300mm.
Image courtesy of Elisabeth
Van Bockstaele.
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Goal: To test the hypothesis that the stress-related neurohormone,
corticotropin releasing factor (CRF), serves as a neurotransmitter
to activate neurons in the locus coeruleus during stress.
The studies include neuroanatomical experiments aimed at
elucidating the synaptic interactions of CRH containing axon
terminal with noradrenergic cells of the locus coeruleus.
Convergent findings suggest that the stress-related neurohormone, corticotropin-releasing
factor (CRF) serves as a neuromodulator in the locus coeruleus (LC),
a noradrenergic nucleus, to regulate the activity of this forebrain-projecting
system during stress. CRF-induced LC activation may be important for
cognitive aspects of the stress response, such as increased arousal and
alterations in attention, and therefore may be adaptive. However, a history
of stress alters the sensitivity of the LC-noradrenergic system to CRF
and this may underlie certain symptoms of stress-related psychiatric
disorders (e.g., hyperarousal, difficulty concentrating).
To advance our understanding of the cellular mechanisms by which CRF
alters LC activity, we are investigating:
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The mechanisms underlying stress-induced plasticity and the consequences
of CRF-LC interactions that may impact on cognition. We are using an
antiserum directed against the CRF-R1 receptor that has recently become
available to characterize and quantify the localization of CRF-R1 on
neurochemically identified cellular processes within the LC.
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Internalization and trafficking of the CRF-R1 receptor at the ultrastructural
level in rats that have been administered CRF in the LC, or that have
been acutely exposed to stressors. Changes in LC activity are correlated
to indices of CRF-R1 cellular translocation.
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The cellular mechanisms underlying postsynaptic changes in LC sensitivity
to CRF that are observed in rats with a history of stress, using a
variety of approaches including reverse transcriptase-polymerase chain
reaction (RT-PCR) to measure changes in CRF-receptor mRNA in the LC;
Western blot analysis to measure protein levels in the LC of CRF receptors,
as well as levels of components of the signaling cascade linked to
CRF-R1 activation, and ultrastructural analysis of receptor internalization
and recycling.
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The consequences of CRF modulation of the LC-noradrenergic system
on forebrain activity and behavior controlled by attention to sensory
stimuli. This entails quantifying the effect of CRF in the LC on the
activity of neuronal ensembles in a functionally connected network
(the whiskerpad-barrelfield cortex) during sensory stimulation (whiskerpad
stimulation). The effect of CRF in the LC on behavior controlled by
whiskerpad stimulation is also being determined.
The goal of these studies is to advance our understanding of the cellular
mechanisms underlying the acute effects of stress on the LC-norepinephrine
system, mechanisms underlying stress-induced plasticity of this system
and the role of this system in cognitive responses to stress.
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