The long-term objective of this project is to determine the neural mechanisms of integrative function in local synaptic circuits of the deep spinal dorsal horn (Rexed's laminae III-V). The ultimate goal is a better understanding of basic mechanisms underlying normal somesthesis and spread of hyperexcitability in neurological models of hyperalgesia.
The specific aims build upon our previous work which shows that laminae III-V neurons express firing behavior related to cutaneous mechanosensory afferent input and efferent synaptic organization and can exhibit persistent hyperexcitability following brief direct activation. Experiments will test the general hypotheses that i) neurons in laminae III-V are organized into circuits according to intrisnsic electrophysiological properties of the pre- and postsynaptic cells and ii) induction of hyperexcitability in laminae III-V neurons alters integrative function, increasing responsiveness to natural sensory stimulation and local synaptic input. The following project aims are proposed: Determine the spike-frequency adaptation properties and signaling characteristics of synaptically-linked interneurons in laminae III-V of the dorsal horn. Determine the nature of synaptic connections between interneurons in laminae III-V, whether excitatory or inhibitory, or both. Determine whether the persistent membrane depolarization and firing augmentation evoked in laminae III-V interneurons is accompanied by increases in responsiveness to natural sensory stimulation increases and local synaptic inputs.
These aims will be accomplished using isolated preparation of rodent thoracolumbar spinal cord that facilitate access to small interneurons with intact sensory input. Synaptic connections between neurons will be investigated directly using dual whole-cell recording methodology and pharmacological antagonists of synaptic function. Immunocytochemistry and laser scanning confocal microscopy will be used to anatomically localize synaptic markers in physiologically identified neurons. The results will advance knowledge of spinal mechanisms of somethesis and contribute to understanding of painful sensory sequelae of spinal cord and peripheral injury, including secondary hyperalgesia and allodynia.
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