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Stress and Noradrenergic Function

Rita Valentino, PhD

Rita Valentino, PhD
Children's Hospital of Philadelphia
Principal Investigator

Elisabeth J. Van Bockstaele, PhD

Elisabeth J. Van Bockstaele, PhD
Co-Investigator

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Brain Noradrenergic Neurons, Peptides and Stress (NIH/NIDA)

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:

  1. 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.
  2. 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.
  3. 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.
  4. 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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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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