Functional characterization of an amygdala to accumbens nociceptive circuit

超过1亿的美国人患有慢性疼痛，经历持续的伤害性感觉和消极

Over 100 million Americans suffer from chronic pain, experiencing persistent nociceptive sensory and negative affective symptoms. Currently available pain treatments are inadequate at safely and effectively relieving both the sensory and affective features of chronic pain, partly because of their lack of specificity to modulate distinct neural cell-types and processes. While diagnostic imaging tools have correlated the affective unpleasantness of chronic pain with dysfunction across broad brain regions-such as the basolateral amygdala (BLA) and nucleus accumbens (NAc)-they lack specificity to identify individual functional cell types that might underlie this maladaptive plasticity. A key first step towards identifying and targeting affective nociceptive neural circuits is to visualize the dynamics of nociceptive transmissions between affective-motivational brain regions during the transition from acute to chronic pain. The research goal of the proposed project is to functionally characterize a nociceptive BLA to NAc circuit that contributes to negative affective-motivational behavior in acute and chronic nociceptive states. Dysfunction of the BLA has been implicated in chronic pain and neuropsychiatric disorders through the process of assigning valence to internal and external sensory information. The BLA contains a functional subpopulation of negative valence neurons essential for the emotionally aversive aspect of nociception (BLA"0 ci). Inhibition of BLAnoci neurons reduces affective-motivational responses to noxious stimuli in acute and chronic nociceptive states. BLA neurons send long-range axons to many downstream targets, including the NAc, a striatal structure important for driving appetitive and aversive behaviors. Preliminary data suggests that BLAnoci neurons project to the "limbic" NAc Shell subregion (NAcSh). Furthermore, there is a group of neurons highly responsive to noxious stimuli within the NAcSh (the "inner-horn"; NAcSh1H) that a bundle of BLAnoci axons strongly innervate. However, it is unknown if BLAnoci neurons transmit affective nociceptive information to the NAcSh1H nor if NAcSh1H neurons are essential for driving nociception-related negative affective-motivational behaviors. Aim 1 will functionally characterize the BLA"0 ci to NAcSh1H circuit in acute and chronic nociceptive states using in vivo calcium imaging and optogenetic activation of BLAnoci axon terminals in awake behaving subjects. Aim 2 will image and manipulate NAcSh1H neuron activity in acute and chronic nociceptive states using calcium imaging and optogenetic manipulation of NAcSh1H neural activity. Completion of these proposed aims will result in the characterization of a potentially key affective circuit between the BLA and NAcSh1H encoding acute and chronic nociceptive information. The outcome of this proposal will help the field of affective pain neuroscience better understand neural circuit function in healthy and pathological states. Furthermore, this research may inform future translational investigations into treatments for the negative affective symptoms of chronic pain. Completion of this fellowship will achieve the training goals of expanding the technical expertise of Ms. Wojick in systems neuroscience and facilitate her career goal of becoming a leading expert in affective pain research.