Impressive progress has been made in defining and understanding supraspinal pathways with projections to spinal sympathetic preganglionic neurons (SPNs). In contrast, there has been little progress in characterizing another fundamental set of central nervous system pathways involved in the direct regulation of the sympathetic outflow, and therefore in the control of cardiovascular function. Almost nothing is known about putative neurotransmitters released by, or the locations of the cells of origin which give rise to, intraspinal circuits with monosynaptic connections to sympathetic preganglionic neurons. The present application focuses efforts in this direction and is particularly concerned with the identification of inhibitory pathways that are likely to be critical for the normal regulation of cardiovascular function and which may be compromised in at least one example of chronic, sympathetic hyperactivity. Using (1) pre- and postembedding immunoperoxidase, immunofluorescence, and immunogold immunocytochemical procedures; and (2) trans-synaptic and transneuronal labeling methods, the following light and electron microscopic projects have been proposed.
Specific Aim 1 would test the hypothesis that glycine is an inhibitory neurotransmitter contained in terminals contacting sympathetic preganglionic neurons. The projects would determine: (1) the intracellular, somadendritic localization of glycine receptor-like immunoreactivity (GlyR-LIR, 93 kd subunit) within retrogradely labeled SPNs in four autonomic nuclei in thoracic spinal cord (Ilp, Ilf, IC, and CA); (2) whether terminal boutons opposite postsynaptic GlyR-LIR exhibit a homogeneous morphology; and (3) if boutons containing gamma-aminobutyric acid-like immunoreactivity (GABA-LIR) are opposite postsynaptic GlyR-LIR within SPNs.
Specific Aim 2 would test the hypothesis that spinal' interneurons in laminae V and VII of thoracic spinal cord give rise to principal or collateral axon projections to SPNs. The studies would determine: (1) the segmental and intersegmental (propriospinal) distributions of spinal interneurons projecting to SPNs that have been retrogradely labeled with one of two transneuronally transported tracer substances: wheat germ agglutinin (WGA) or the atoxic binding fragment of tetanus toxin, Fragment C (TTC); and (2) whether the laminar and segmental distributions of WGA- or TTC-labeled spinal interneurons shift or remain constant when populations of SPNs with different postsynaptic targets are retrogradely labeled.
Specific Aim 3 would test the hypothesis that transneuronally WGA- or TTC-labeled spinal-SPN pathways originating in laminae V and VII of thoracic spinal cord synthesize and release the inhibitory neurotransmitters glycine or GABA, and/or the excitatory neurotransmitter/ neuromodulator substance P(SP): do WGA- or TTC-labeled interneurons contain GABA-, glycine-, or SP-LIR? Specific Aim 4 would test the hypothesis that cardiovascular hyperactivity manifest in tetanus is a consequence of intoxication of inhibitory synapses contacting SPNs. The experiments would establish whether trans-synaptically TTC-labeled terminal boutons on SPNs in Ilf, Ilp, IC and CA: (1) contain GABA-LIR; and/or (2) are opposite postsynaptic GlyR-LIR. All experiments would be performed in rats.
|Shao, Yufang; Akmentin, Wendy; Toledo-Aral, Juan Jose et al. (2002) Pincher, a pinocytic chaperone for nerve growth factor/TrkA signaling endosomes. J Cell Biol 157:679-91|
|Ligorio, M A; Akmentin, W; Gallery, F et al. (2000) Ultrastructural localization of the binding fragment of tetanus toxin in putative gamma-aminobutyric acidergic terminals in the intermediolateral cell column: a potential basis for sympathetic dysfunction in generalized tetanus. J Comp Neurol 419:471-84|
|Cabot, J B (1996) Some principles of the spinal organization of the sympathetic preganglionic outflow. Prog Brain Res 107:29-42|
|Cabot, J B; Bushnell, A; Alessi, V et al. (1995) Postsynaptic gephyrin immunoreactivity exhibits a nearly one-to-one correspondence with gamma-aminobutyric acid-like immunogold-labeled synaptic inputs to sympathetic preganglionic neurons. J Comp Neurol 356:418-32|
|Cabot, J B; Alessi, V; Carroll, J et al. (1994) Spinal cord lamina V and lamina VII interneuronal projections to sympathetic preganglionic neurons. J Comp Neurol 347:515-30|
|Cabot, J B; Alessi, V; Bushnell, A (1992) Glycine-like immunoreactive input to sympathetic preganglionic neurons. Brain Res 571:1-18|
|Cabot, J B; Mennone, A; Bogan, N et al. (1991) Retrograde, trans-synaptic and transneuronal transport of fragment C of tetanus toxin by sympathetic preganglionic neurons. Neuroscience 40:805-23|
|Bogan, N; Cabot, J B (1991) Light and electron microscopic analyses of intraspinal axon collaterals of sympathetic preganglionic neurons. Brain Res 541:241-51|
|Cabot, J B; Carroll, J; Bogan, N (1991) Localization of cardiac parasympathetic preganglionic neurons in the medulla oblongata of pigeon, Columba livia: a study using fragment C of tetanus toxin. Brain Res 544:162-8|
|Bogan, N; Mennone, A; Cabot, J B (1989) Light microscopic and ultrastructural localization of GABA-like immunoreactive input to retrogradely labeled sympathetic preganglionic neurons. Brain Res 505:257-70|
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