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Lorsung, R., Cramer, N., Alipio, J.B., Ji, Y., Han, S., Masri, R., Keller, A. Sex differences in central amygdala glutamate responses to calcitonin gene-related peptide. (2024) Journal of Neuroscience. DOI: 10.1523/JNEUROSCI.1898-24.2024

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Women are disproportionately affected by chronic pain compared to men. While societal and environmental factors contribute to this disparity, sex-based biological differences in the processing of pain are also believed to play significant roles. The central lateral nucleus of the amygdala (CeLC) is a key region for the emotional-affective dimension of pain, and a prime target for exploring sex differences in pain processing since a recent study demonstrated sex differences in CGRP actions in this region. Inputs to CeLC from the parabrachial nucleus (PB) play a causal role in aversive processing, and release both glutamate and calcitonin gene-related peptide (CGRP). CGRP is thought to play a crucial role in chronic pain by potentiating glutamatergic signaling in CeLC.However, it is not known if this CGRP-mediated synaptic plasticity occurs similarly in males and females. Here, we tested the hypothesis that female CeLC neurons experience greater potentiation of glutamatergic signaling than males following CGRP exposure. Using trains of optical stimuli to evoke transient CGRP release from PB terminals in CeLC, we find that subsequent glutamatergic responses are preferentially potentiated in CeLC neurons from female mice. This potentiation was CGRP-dependent and involved a postsynaptic mechanism. This sex difference in CGRP sensitivity may explain sex differences in affective pain processing. The central lateral nucleus of the amygdala (CeLC) receives a dense projection from parabrachial nucleus (PB) neurons that corelease calcitonin gene-related peptide (CGRP) and glutamate following aversive stimuli. This PB→CeLC projection plays a causal role in chronic pain. We show that endogenous CGRP release potentiates glutamate signaling in female, but not male, CeLC neurons. In the context of previous work in male CeLC, this suggests that that females are more sensitive to even transient CGRP release events. Understanding how this sex difference in CGRP sensitivity arises could enhance strategies for treating chronic pain in both women and men.

Jhang, J., Park, S., Liu, S., O'Keefe, D.D., Han, S. A top-down slow breathing circuit that alleviates negative affect in mice. (2024) Nature Neuroscience. DOI: 10.1038/s41593-024-01799-w

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Kim, D.I., Kang, S.J., Jhang, J., Jo, Y.S., Park, S., Ye, M., Pyeon, G.H., Im, G.H., Kim, S.G., Han, S. Encoding opposing valences through frequency-dependent transmitter switching in single peptidergic neurons. (2024) bioRxiv. DOI: 10.1101/2024.11.09.622790

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Kim, D.I., Park, S., Park, S., Ye, M., Chen, J.Y., Kang, S.J., Jhang, J., Hunker, A.C., Zweifel, L.S., Caron, K.M., Vaughan, J.M., Saghatelian, A., Palmiter, R.D., Han, S. Presynaptic sensor and silencer of peptidergic transmission reveal neuropeptides as primary transmitters in pontine fear circuit. (2024) Cell. DOI: 10.1016/j.cell.2024.06.035

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Kang, S.J., Kim, J.H., Kim, D.I., Roberts, B.Z., Han, S. A pontomesencephalic PACAPergic pathway underlying panic-like behavioral and somatic symptoms in mice. (2024) Nature Neuroscience. DOI: 10.1038/s41593-023-01504-3

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Ren, X., Liu, S., Virlogeux, A., Kang, S.J., Brusch, J., Liu, Y., Dymecki, S.M., Han, S., Goulding, M., Acton, D. Identification of an essential spinoparabrachial pathway for mechanical itch. (2023) Neuron. DOI: 10.1016/j.neuron.2023.03.013

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Jhang, J., Liu, S., O'Keefe, D.D., Han, S. A top-down slow breathing circuit that alleviates negative affect. (2023) bioRxiv. DOI: 10.1101/2023.02.25.529925

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Kim, D.I., Park, S., Ye, M., Chen, J.Y., Jhang, J., Hunker, A.C., Zweifel, L.S., Palmiter, R.D., Han, S. Novel genetically encoded tools for imaging or silencing neuropeptide release from presynaptic terminals . (2023) bioRxiv. DOI: 10.1101/2023.01.19.524797

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Kang, S.J., Liu, S., Ye, M., Kim, D.I., Pao, G.M., Copits, B.A., Roberts, B.Z., Lee, K.F., Bruchas, M.R., Han, S. A central alarm system that gates multi-sensory innate threat cues to the amygdala. (2022) Cell Reports. 40(7):111222. DOI: 10.1016/j.celrep.2022.111222

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Liu, S., Han, S. Simultaneous recording of breathing and neural activity in awake behaving mice. (2022) STAR Protoc. 3(2):101412. DOI: 10.1016/j.xpro.2022.101412

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Liu, S., Ye, M., Pao, G.M., Song, S.M., Jhang, J., Jiang, H., Kim, J.H., Kang, S.J., Kim, D.I., Han, S. Divergent brainstem opioidergic pathways that coordinate breathing with pain and emotions. (2021) Neuron. DOI: 10.1016/j.neuron.2021.11.029

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Liu, S., Kim, D.I., Oh, T.G., Pao, G.M., Kim, J.H., Palmiter, R.D., Banghart, M.R., Lee, K.F., Evans, R.M., Han, S. Neural basis of opioid-induced respiratory depression and its rescue. (2021) Proceedings of the National Academy of Sciences of the United States of America. 118(23). DOI: 10.1073/pnas.2022134118

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Campos, C.A., Bowen, A.J., Han, S., Wisse, B.E., Palmiter, R.D., Schwartz, M.W. Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. (2017) Nature Neuroscience. 20(7):934-942. DOI: 10.1038/nn.4574

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Rubinstein, M.*, Han, S.*, Tai, C., Westenbroek, R.E., Hunker, A., Scheuer, T., Catterall, W.A. Dissecting the phenotypes of Dravet syndrome by gene deletion. (2015) Brain : A Journal of Neurology. 138(Pt 8):2219-33. DOI: 10.1093/brain/awv142

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Neurological and psychiatric syndromes often have multiple disease traits, yet it is unknown how such multi-faceted deficits arise from single mutations. Haploinsufficiency of the voltage-gated sodium channel Nav1.1 causes Dravet syndrome, an intractable childhood-onset epilepsy with hyperactivity, cognitive deficit, autistic-like behaviours, and premature death. Deletion of Nav1.1 channels selectively impairs excitability of GABAergic interneurons. We studied mice having selective deletion of Nav1.1 in parvalbumin- or somatostatin-expressing interneurons. In brain slices, these deletions cause increased threshold for action potential generation, impaired action potential firing in trains, and reduced amplification of postsynaptic potentials in those interneurons. Selective deletion of Nav1.1 in parvalbumin- or somatostatin-expressing interneurons increases susceptibility to thermally-induced seizures, which are strikingly prolonged when Nav1.1 is deleted in both interneuron types. Mice with global haploinsufficiency of Nav1.1 display autistic-like behaviours, hyperactivity and cognitive impairment. Haploinsufficiency of Nav1.1 in parvalbumin-expressing interneurons causes autistic-like behaviours, but not hyperactivity, whereas haploinsufficiency in somatostatin-expressing interneurons causes hyperactivity without autistic-like behaviours. Heterozygous deletion in both interneuron types is required to impair long-term spatial memory in context-dependent fear conditioning, without affecting short-term spatial learning or memory. Thus, the multi-faceted phenotypes of Dravet syndrome can be genetically dissected, revealing synergy in causing epilepsy, premature death and deficits in long-term spatial memory, but interneuron-specific effects on hyperactivity and autistic-like behaviours. These results show that multiple disease traits can arise from similar functional deficits in specific interneuron types.

Han, S., Soleiman, M.T., Soden, M.E., Zweifel, L.S., Palmiter, R.D. Elucidating an Affective Pain Circuit that Creates a Threat Memory. (2015) Cell. 162(2):363-374. DOI: 10.1016/j.cell.2015.05.057

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Carter, M.E., Han, S., Palmiter, R.D. Parabrachial calcitonin gene-related peptide neurons mediate conditioned taste aversion. (2015) Journal of Neuroscience. 35(11):4582-6. DOI: 10.1523/JNEUROSCI.3729-14.2015

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Han, S., Tai, C., Jones, C.J., Scheuer, T., Catterall, W.A. Enhancement of inhibitory neurotransmission by GABAA receptors having α2,3-subunits ameliorates behavioral deficits in a mouse model of autism. (2014) Neuron. 81(6):1282-1289. DOI: 10.1016/j.neuron.2014.01.016

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Han, S., Tai, C., Westenbroek, R.E., Yu, F.H., Cheah, C.S., Potter, G.B., Rubenstein, J.L., Scheuer, T., de la Iglesia, H.O., Catterall, W.A. Autistic-like behaviour in Scn1a+/- mice and rescue by enhanced GABA-mediated neurotransmission. (2012) Nature. 489(7416):385-90. DOI: 10.1038/nature11356

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Han, S., Yu, F.H., Schwartz, M.D., Linton, J.D., Bosma, M.M., Hurley, J.B., Catterall, W.A., de la Iglesia, H.O. Na(V)1.1 channels are critical for intercellular communication in the suprachiasmatic nucleus and for normal circadian rhythms. (2012) Proceedings of the National Academy of Sciences of the United States of America. 109(6):E368-77. DOI: 10.1073/pnas.1115729109

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Eckel-Mahan, K.L., Phan, T., Han, S., Wang, H., Chan, G.C., Scheiner, Z.S., Storm, D.R. Circadian oscillation of hippocampal MAPK activity and cAmp: implications for memory persistence. (2008) Nature Neuroscience. 11(9):1074-82.

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Han, S., Kim, T.D., Ha, D.C., Kim, K.T. Rhythmic expression of adenylyl cyclase VI contributes to the differential regulation of serotonin N-acetyltransferase by bradykinin in rat pineal glands. (2005) Journal of Biological Chemistry. 280(46):38228-34. DOI: 10.1074/jbc.M508130200

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Sung Han, PhD

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