Amygdala PACAP as a mediator of the emotional components of pain

Chronic pain alters sensory responses and carries a strong emotional component. Persistent pain can heighten pain experiences, resulting in hyperalgesia and allodynia. Further, patients suffering from chronic pain are more prone to experience a range of affective disorders including depression, sleep dysregulation, panic disorders, anxiety abnormalities and stress-related disorders including post-traumatic stress disorder (PTSD). Hence while pain serves a protective function to prevent additional physiological harm by driving behavioral and cognitive responses, chronic or persistent pain can lead to maladaptive nociceptive responses and exacerbate psychopathologies. Among brain regions, the amygdala is centrally situated to integrate the many descending and ascending signals to modulate the sensory and emotional components of pain. The amygdala is well studied for its role in fear and stress-related behavioral processes. The central nucleus of the amygdala (CeA), and in particular the lateral capsular subdivision of the CeA (CeLC), receives prominent ascending pain neurotransmission via the spino- parabrachioamygdaloid tract. In this pathway, peripheral nociceptive signals carried via primary sensory Aδ- and C-fibers terminate in the dorsal horn where second order neurons send projections via the spino-parabrachial pathway to the lateral parabrachial nucleus (LPBn). Thus, the LPBn collects cutaneous (mechanical and thermal), deep (muscular and articular) and visceral nociceptive signals and relays the information in a highly organized manner principally to the CeLC for nociceptive processing. In pain, the CeA and the LPBn-CeLC projections have been shown to undergo plasticity in the forms of enhanced synaptic transmission and alterations in neurotransmitter and receptor expression. Accordingly, the neurocircuit intersections in the CeA can modulate the sensory and emotional responses to pain. Yet despite these associations, the mediators and mechanisms underlying the emotional consequences of pain are poorly understood. Pituitary adenylate cyclase activating polypeptide (PACAP) is a neural and endocrine pleiotropic peptide important in the development and homeostatic regulation of many physiological systems. Recently, the expression of PACAP and its cognate PAC1 receptor has been shown to be upregulated in specific limbic regions by chronic stress. PACAP infusions into several limbic regions is anxiogenic, and altered blood PACAP levels and PAC1 receptor polymorphism have been associated with PTSD and other stress-related disorders. Here, we establish that CeLC PACAP originates from the LPBn as part of the spino-parabrachoamygdaloid pathway. Chronic pain enhanced PACAP expression along LPBn-CeLC projections, indicating it may be a component of pain- related plasticity. CeA PACAP signaling was sufficient to induce nociceptive hypersensitivity and anxiety-like behaviors. In a chronic neuropathic pain model, CeA PACAP signaling was found to contribute to heightened anxiety-like behaviors and nociceptive responses. Further, we characterized one prominent intracellular signaling mechanism through which CeA PACAP signaling influences these behaviors. In these experiments we provide evidence that CeA PACAP signaling plays an important role in the emotional components of pain and that alterations in CeA PACAP signaling are part of pain-related plasticity. This work establishes novel molecular mechanisms that underlie the emotional component of pain and may contribute to the development of chronic pain and associated affective disorders

SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration

High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1β release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1β release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer's disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer's disease, providing mechanistic insight into the biology of neuroinflammation

Neuronal diversity of the amygdala and the bed nucleus of the stria terminalis

The amygdala complex is a diverse group of more than 13 nuclei, segregated in five major groups: the basolateral (BLA), central (CeA), medial (MeA), cortical (CoA), and basomedial (BMA) amygdala nuclei. These nuclei can be distinguished depending on their cytoarchitectonic properties, connectivity, genetic, and molecular identity, and most importantly, on their functional role in animal behavior. The extended amygdala includes the CeA and the bed nucleus of the stria terminalis (BNST). Both CeA and the BNST share similar cellular organization, including common neuron types, reciprocal connectivity, and many overlapping downstream targets. In this section, we describe the advances of our knowledge on neuronal diversity in the amygdala complex and the BNST, based on recent functional studies, performed at genetic, molecular, physiological, and anatomical levels in rodent models, especially rats and mice. Molecular and connection property can be used separately, or in combinations, to define neuronal populations, leading to a multiplexed neuronal diversity-supporting different functional roles. © 2020 Elsevier B.V

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Oxytocin reduces background anxiety in a fear-potentiated startle paradigm: Peripheral vs central administration. Neuropsychopharmacology 36

Oxytocin reportedly decreases anxious feelings in humans and may therefore have therapeutic value for anxiety disorders, such as post-traumatic stress disorder (PTSD). As PTSD patients have exaggerated startle responses, a fear-potentiated startle paradigm in rats may have face validity as an animal model to examine the efficacy of oxytocin in treating these symptoms. Oxytocin (0, 0.01, 0.1, or 1.0 mg, subcutaneously) was given either 30 min before fear conditioning, immediately after fear conditioning, or 30 min before fear-potentiated startle testing to assess its effects on acquisition, consolidation, and expression of conditioned fear, respectively. Startle both in the presence and absence of the fear-conditioned light was significantly diminished by oxytocin when administered at acquisition, consolidation, or expression. There was no specific effect of oxytocin on light fear-potentiated startle. In an additional experiment, oxytocin had no effects on acoustic startle without previous fear conditioning. Further, in a context-conditioned test, previous light-shock fear conditioning did not increase acoustic startle during testing when the fear-conditioned light was not presented. The data suggest that oxytocin did not diminish cue-specific conditioned nor contextually conditioned fear, but reduced background anxiety. This suggests that oxytocin has unique effects of decreasing background anxiety without affecting learning and memory of a specific traumatic event. Oxytocin may have antianxiety properties that are particularly germane to the hypervigilance and exaggerated startle typically seen in PTSD patients