Anterior cingulate cortex is the most frequently activated cortex in human pain studies and is comprised of perigenual and midcingulate regions. Nociceptive information passes through the midline and intralaminar thalamic nuclei, however, links between the spinothalamic tract and spinoreticulothalamic system to the midline nuclei has never been made directly to cingulate cortex. A case of irritable bowel syndrome with severe visceral pain shows alleviation of symptoms with psychotherapy and reduced midcingulate and increased anterior insular activity. Two hypotheses guide these studies: Functions of perigenual areas 32, 25, 24a-c and midcingulate areas 32' and 24a'-d are driven by different midline thalamic inputs and these nuclei conduct parallel circuits for nociception and stress. Each animal will receive horseradish peroxidase either in the spinal cord or dorsocaudal medullary reticular nucleus, and three fluorescent dextran amine retrograde tracers in contralateral cingulate and/or insular areas followed by reactions for 4 antibodies.
Specific Aim #1 will evaluate the immunoarchitecture of the midline and dorsocaudal medullary nuclei with a neuron-specific antibody and antibodies for neurofilaments and calbindin. #2 will determine the projections of the midline nuclei to perigenual, midcingulate, and insular cortices with multiple fluorescent tracers that have the same uptake, transport, and signal properties. #3 will evaluate the topography of inputs to the midline nuclei with anterograde horseradish peroxidase following cervical spinal cord injections. #4 will assess the topography of inputs to the midline nuclei with horseradish peroxidase in the dorsocaudal medullary nucleus. #5 will evaluate overlap of dopamine-13 hydroxylase in each of the midline nuclei with inputs from spinothalamic and medullary nuclei to determine the overlap of nociceptive and stress circuits in the thalamus. These studies will provide the first evidence for differential projections of the midline thalamus to limbic cortex and the extent of spinothalamic, medullary, and locus coeruleus overlap in the medial thalamus and modulatation of sensory, affective, and motor domains of pain processing in anterior cingulate and insular cortices. The mechanisms of medial pain system processing will be identified and this will help interpret human imaging studies and assist in developing objective cdteria and therapies for treating the psychiatric consequences of chronic pain.
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