Haijiang Cai

Interests

Research

Neural circuits and animal behaviors. Research tools: Electrophysiology, Optogenetics, Chemogenetics, Calcium imaging, and Mouse BehaviorsResearch topics: Eating, Emotion, Circadian Rhythm Related diseases: Eating disorders, Obesity, Anxiety, Depression

Teaching

Neural circuits and animal behaviors, systems neuroscience

Courses

Scholarly Contributions

Journals/Publications

• Schnapp, W. I., Kim, J., Wang, Y., Timilsena, S., Fang, C., & Cai, H. (2024). Development of activity-based anorexia requires PKC-δ neurons in two central extended amygdala nuclei. Cell reports, 43(3), 113933.
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  Anorexia nervosa (AN) is a serious psychiatric disease, but the neural mechanisms underlying its development are unclear. A subpopulation of amygdala neurons, marked by expression of protein kinase C-delta (PKC-δ), has previously been shown to regulate diverse anorexigenic signals. Here, we demonstrate that these neurons regulate development of activity-based anorexia (ABA), a common animal model for AN. PKC-δ neurons are located in two nuclei of the central extended amygdala (EAc): the central nucleus (CeA) and oval region of the bed nucleus of the stria terminalis (ovBNST). Simultaneous ablation of CeA and ovBNST neurons prevents ABA, but ablating PKC-δ neurons in the CeA or ovBNST alone is not sufficient. Correspondingly, PKC-δ neurons in both nuclei show increased activity with ABA development. Our study shows how neurons in the amygdala regulate ABA by impacting both feeding and wheel activity behaviors and support a complex heterogeneous etiology of AN.
• Peterson, T., Mann, S., Sun, B. L., Peng, L., Cai, H., & Liang, R. (2023). Motionless volumetric structured light sheet microscopy. Biomedical optics express, 14(5), 2209-2224.
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  To meet the increasing need for low-cost, compact imaging technology with cellular resolution, we have developed a microLED-based structured light sheet microscope for three-dimensional and imaging of biological tissue in multiple modalities. All the illumination structure is generated directly at the microLED panel-which serves as the source-so light sheet scanning and modulation is completely digital, yielding a system that is simpler and less prone to error than previously reported methods. Volumetric images with optical sectioning are thus achieved in an inexpensive, compact form factor without any moving parts. We demonstrate the unique properties and general applicability of our technique by imaging of porcine and murine tissue from the gastrointestinal tract, kidney, and brain.
• Weninger, S. N., Herman, C., Meyer, R. K., Beauchemin, E. T., Kangath, A., Lane, A. I., Martinez, T. M., Hasneen, T., Jaramillo, S. A., Lindsey, J., Vedantam, G., Cai, H., Cope, E. K., Caporaso, J. G., & Duca, F. A. (2023). Oligofructose improves small intestinal lipid-sensing mechanisms via alterations to the small intestinal microbiota. Microbiome, 11(1), 169.
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  Upper small intestinal dietary lipids activate a gut-brain axis regulating energy homeostasis. The prebiotic, oligofructose (OFS) improves body weight and adiposity during metabolic dysregulation but the exact mechanisms remain unknown. This study examines whether alterations to the small intestinal microbiota following OFS treatment improve small intestinal lipid-sensing to regulate food intake in high fat (HF)-fed rats.
• Cai, H. (2022). Dissecting a disynaptic central amygdala - parasubthalamic nucleus neural circuit that mediates cholecystokinin-induced eating suppression. Molecular Metabolism.
• Sanchez, M. R., Wang, Y., Cho, T. S., Schnapp, W. I., Schmit, M. B., Fang, C., & Cai, H. (2022). Dissecting a disynaptic central amygdala-parasubthalamic nucleus neural circuit that mediates cholecystokinin-induced eating suppression. Molecular metabolism, 58, 101443.
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  Cholecystokinin (CCK) plays a critical role in regulating eating and metabolism. Previous studies have mapped a multi-synapse neural pathway from the vagus nerve to the central nucleus of the amygdala (CEA) that mediates the anorexigenic effect of CCK. However, the neural circuit downstream of the CEA is still unknown due to the complexity of the neurons in the CEA. Here we sought to determine this circuit using a novel approach.
• Burton, A., Obaid, S. N., Vázquez-Guardado, A., Schmit, M. B., Stuart, T., Cai, L., Chen, Z., Kandela, I., Haney, C. R., Waters, E. A., Cai, H., Rogers, J. A., Lu, L., & Gutruf, P. (2020). Wireless, battery-free subdermally implantable photometry systems for chronic recording of neural dynamics. Proceedings of the National Academy of Sciences of the United States of America, 117(6), 2835-2845.
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  Recording cell-specific neuronal activity while monitoring behaviors of freely moving subjects can provide some of the most significant insights into brain function. Current means for monitoring calcium dynamics in genetically targeted populations of neurons rely on delivery of light and recording of fluorescent signals through optical fibers that can reduce subject mobility, induce motion artifacts, and limit experimental paradigms to isolated subjects in open, two-dimensional (2D) spaces. Wireless alternatives eliminate constraints associated with optical fibers, but their use of head stages with batteries adds bulk and weight that can affect behaviors, with limited operational lifetimes. The systems introduced here avoid drawbacks of both types of technologies, by combining highly miniaturized electronics and energy harvesters with injectable photometric modules in a class of fully wireless, battery-free photometer that is fully implantable subdermally to allow for the interrogation of neural dynamics in freely behaving subjects, without limitations set by fiber optic tethers or operational lifetimes constrained by traditional power supplies. The unique capabilities of these systems, their compatibility with magnetic resonant imaging and computed tomography and the ability to manufacture them with techniques in widespread use for consumer electronics, suggest a potential for broad adoption in neuroscience research.
• Zhang-Molina, C., Schmit, M. B., & Cai, H. (2020). Neural Circuit Mechanism Underlying the Feeding Controlled by Insula-Central Amygdala Pathway. iScience, 23(4), 101033.
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  The Central nucleus of amygdala (CeA) contains distinct populations of neurons that play opposing roles in feeding. The circuit mechanism of how CeA neurons process information sent from their upstream inputs to regulate feeding is still unclear. Here we show that activation of the neural pathway projecting from insular cortex neurons to the CeA suppresses food intake. Surprisingly, we find that the inputs from insular cortex form excitatory connections with similar strength to all types of CeA neurons. To reconcile this puzzling result, and previous findings, we developed a conductance-based dynamical systems model for the CeA neuronal network. Computer simulations showed that both the intrinsic electrophysiological properties of individual CeA neurons and the overall synaptic organization of the CeA circuit play a functionally significant role in shaping CeA neural dynamics. We successfully identified a specific CeA circuit structure that reproduces the desired circuit output consistent with existing experimentally observed feeding behaviors.
• Zhou, C., Yan, X., Xiao, C., Wu, H., Tang, D., Luan, Y., Gu, W., & Cai, H. (2020). Internal States Influence the Representation and Modulation of Food Intake by Subthalamic Neurons.. Neuroscience bulletin, 36(11), 1355-1368. doi:10.1007/s12264-020-00533-3
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  Deep brain stimulation of the subthalamic nucleus (STN) is an effective therapy for motor deficits in Parkinson's disease (PD), but commonly causes weight gain in late-phase PD patients probably by increasing feeding motivation. It is unclear how STN neurons represent and modulate feeding behavior in different internal states. In the present study, we found that feeding caused a robust activation of STN neurons in mice (GCaMP6 signal increased by 48.4% ± 7.2%, n = 9, P = 0.0003), and the extent varied with the size, valence, and palatability of food, but not with the repetition of feeding. Interestingly, energy deprivation increased the spontaneous firing rate (8.5 ± 1.5 Hz, n = 17, versus 4.7 ± 0.7 Hz, n = 18, P = 0.03) and the depolarization-induced spikes in STN neurons, as well as enhanced the STN responses to feeding. Optogenetic experiments revealed that stimulation and inhibition of STN neurons respectively reduced (by 11% ± 6%, n = 6, P = 0.02) and enhanced (by 36% ± 15%, n = 7, P = 0.03) food intake only in the dark phase. In conclusion, our results support the hypothesis that STN neurons are activated by feeding behavior, depending on energy homeostatic status and the palatability of food, and modulation of these neurons is sufficient to regulate food intake.
• Tian, X., Tu, X., Della Croce, K., Yao, G., Cai, H., Brock, N., Pau, S., & Liang, R. (2019). Multi-wavelength quantitative polarization and phase microscope. Biomedical optics express, 10(4), 1638-1648.
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  We introduce a snapshot multi-wavelength quantitative polarization and phase microscope (MQPPM) for measuring spectral dependent quantitative polarization and phase information. The system uniquely integrates a polarized light microscope and a snap-shot quantitative phase microscope in a single system, utilizing a novel full-Stokes camera operating in the red, green, and blue (RGB) spectrum. The linear retardance and fast axis orientation of a birefringent sample can be measured simultaneously in the visible spectra. Both theoretical analysis and experiments have been performed to demonstrate the capability of the proposed microscope. Data from liquid crystal and different biological samples are presented. We believe that MQPPM will be a useful tool in measuring quantitative polarization and phase information of live cells.
• Wang, Y., Kim, J., Schmit, M. B., Cho, T. S., Fang, C., & Cai, H. (2019). A bed nucleus of stria terminalis microcircuit regulating inflammation-associated modulation of feeding. Nature communications, 10(1), 2769.
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  Loss of appetite or anorexia associated with inflammation impairs quality of life and increases morbidity in many diseases. However, the exact neural mechanism that mediates inflammation-associated anorexia is still poorly understood. Here we identified a population of neurons, marked by the expression of protein kinase C-delta, in the oval region of the bed nucleus of the stria terminalis (BNST), which are activated by various inflammatory signals. Silencing of these neurons attenuates the anorexia caused by these inflammatory signals. Our results demonstrate that these neurons mediate bidirectional control of general feeding behaviors. These neurons inhibit the lateral hypothalamus-projecting neurons in the ventrolateral part of BNST to regulate feeding, receive inputs from the canonical feeding regions of arcuate nucleus and parabrachial nucleus. Our data therefore define a BNST microcircuit that might coordinate canonical feeding centers to regulate food intake, which could offer therapeutic targets for feeding-related diseases such as anorexia and obesity.
• Zelikowsky, M., Yilmaz, M., Remedios, R., Meister, M., Kunwar, P. S., Cai, H., & Anderson, D. J. (2015). Ventromedial hypothalamic neurons control a defensive emotion state.. eLife, 4. doi:10.7554/elife.06633
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  Defensive behaviors reflect underlying emotion states, such as fear. The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself. We used optogenetic manipulations to probe the function of a specific hypothalamic cell type that mediates innate defensive responses. These neurons are sufficient to drive multiple defensive actions, and required for defensive behaviors in diverse contexts. The behavioral consequences of activating these neurons, moreover, exhibit properties characteristic of emotion states in general, including scalability, (negative) valence, generalization and persistence. Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center. These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers.
• Cai, H., Haubensak, W., Anthony, T. E., & Anderson, D. J. (2014). Central amygdala PKC-δ(+) neurons mediate the influence of multiple anorexigenic signals. Nature neuroscience, 17(9), 1240-8.
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  Feeding can be inhibited by multiple cues, including those associated with satiety, sickness or unpalatable food. How such anorexigenic signals inhibit feeding at the neural circuit level is not completely understood. Although some inhibitory circuits have been identified, it is not yet clear whether distinct anorexigenic influences are processed in a convergent or parallel manner. The amygdala central nucleus (CEA) has been implicated in feeding control, but its role is controversial. The lateral subdivision of CEA (CEl) contains a subpopulation of GABAergic neurons that are marked by protein kinase C-δ (PKC-δ). We found that CEl PKC-δ(+) neurons in mice were activated by diverse anorexigenic signals in vivo, were required for the inhibition of feeding by such signals and strongly suppressed food intake when activated. They received presynaptic inputs from anatomically distributed neurons activated by different anorexigenic agents. Our data suggest that CEl PKC-δ(+) neurons constitute an important node that mediates the influence of multiple anorexigenic signals.
• Haubensak, W., Kunwar, P. S., Cai, H., Ciocchi, S., Wall, N. R., Ponnusamy, R., Biag, J., Dong, H. W., Deisseroth, K., Callaway, E. M., Fanselow, M. S., Lüthi, A., & Anderson, D. J. (2010). Genetic dissection of an amygdala microcircuit that gates conditioned fear. Nature, 468(7321), 270-6.
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  The role of different amygdala nuclei (neuroanatomical subdivisions) in processing Pavlovian conditioned fear has been studied extensively, but the function of the heterogeneous neuronal subtypes within these nuclei remains poorly understood. Here we use molecular genetic approaches to map the functional connectivity of a subpopulation of GABA-containing neurons, located in the lateral subdivision of the central amygdala (CEl), which express protein kinase C-δ (PKC-δ). Channelrhodopsin-2-assisted circuit mapping in amygdala slices and cell-specific viral tracing indicate that PKC-δ(+) neurons inhibit output neurons in the medial central amygdala (CEm), and also make reciprocal inhibitory synapses with PKC-δ(-) neurons in CEl. Electrical silencing of PKC-δ(+) neurons in vivo suggests that they correspond to physiologically identified units that are inhibited by the conditioned stimulus, called CEl(off) units. This correspondence, together with behavioural data, defines an inhibitory microcircuit in CEl that gates CEm output to control the level of conditioned freezing.
• Xiao, C., Nashmi, R., Mckinney, S., Mcintosh, J. M., Lester, H. A., & Cai, H. (2009). Chronic nicotine selectively enhances alpha4beta2* nicotinic acetylcholine receptors in the nigrostriatal dopamine pathway.. The Journal of neuroscience : the official journal of the Society for Neuroscience, 29(40), 12428-39. doi:10.1523/jneurosci.2939-09.2009
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  These electrophysiological experiments, in slices and intact animals, study the effects of in vivo chronic exposure to nicotine on functional alpha4beta2* nAChRs in the nigrostriatal dopaminergic (DA) pathway. Recordings were made in wild-type and alpha4 nicotinic acetylcholine receptor (nAChR) subunit knock-out mice. Chronic nicotine enhanced methyllycaconitine citrate hydrate-resistant, dihydro-beta-erythroidine hydrobromide-sensitive nicotinic currents elicited by 3-1000 mum ACh in GABAergic neurons of the substantia nigra pars reticulata (SNr), but not in DA neurons of the substantia nigra pars compacta (SNc). This enhancement leads to higher firing rates of SNr GABAergic neurons and consequently to increased GABAergic inhibition of the SNc DA neurons. In the dorsal striatum, functional alpha4* nAChRs were not found on the neuronal somata; however, nicotine acts via alpha4beta2* nAChRs in the DA terminals to modulate glutamate release onto the medium spiny neurons. Chronic nicotine also increased the number and/or function of these alpha4beta2* nAChRs. These data suggest that in nigrostriatal DA pathway, chronic nicotine enhancement of alpha4beta2* nAChRs displays selectivity in cell type and in nAChR subtype as well as in cellular compartment. These selective events augment inhibition of SNc DA neurons by SNr GABAergic neurons and also temper the release of glutamate in the dorsal striatum. The effects may reduce the risk of excitotoxicity in SNc DA neurons and may also counteract the increased effectiveness of corticostriatal glutamatergic inputs during degeneration of the DA system. These processes may contribute to the inverse correlation between tobacco use and Parkinson's disease.
• Cai, H., Reim, K., Varoqueaux, F., Tapechum, S., Hill, K., Sørensen, J. B., Brose, N., & Chow, R. H. (2008). Complexin II plays a positive role in Ca2+-triggered exocytosis by facilitating vesicle priming. Proceedings of the National Academy of Sciences of the United States of America, 105(49), 19538-43.
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  SNARE-mediated exocytosis is a multistage process central to synaptic transmission and hormone release. Complexins (CPXs) are small proteins that bind very rapidly and with a high affinity to the SNARE core complex, where they have been proposed recently to inhibit exocytosis by clamping the complex and inhibiting membrane fusion. However, several other studies also suggest that CPXs are positive regulators of neurotransmitter release. Thus, whether CPXs are positive or negative regulators of exocytosis is not known, much less the stage in the vesicle life cycle at which they function. Here, we systematically dissect the vesicle stages leading up to exocytosis using a knockout-rescue strategy in a mammalian model system. We show that adrenal chromaffin cells from CPX II knockout mice exhibit markedly diminished releasable vesicle pools (comprising the readily and slowly releasable pools), while showing no change in the kinetics of fusion pore dilation or morphological vesicle docking. Overexpression of WT CPX II-but not of SNARE-binding-deficient mutants-restores the size of the the releasable pools in knockout cells, and in WT cells it markedly enlarges them. Our results show that CPXs regulate the size of the primed vesicle pools and have a positive role in Ca(2+)-triggered exocytosis.
• Kolski-andreaco, A., Currle, D. S., Chow, R. H., Chandy, K. G., & Cai, H. (2007). Mouse adrenal chromaffin cell isolation.. Journal of visualized experiments : JoVE, 129. doi:10.3791/129
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  Adrenal medullary chromaffin cell culture systems are extremely useful for the study of excitation-secretion coupling in an in vitro setting. This protocol illustrates the method used to dissect the adrenals and then isolate the medullary region by stripping away the adrenal cortex. The digestion of the medulla into single chromaffin cells is then demonstrated.
• Xiong, W., Ouyang, J., Michael, D. J., Chow, R. H., & Cai, H. (2006). Mechanisms of peptide hormone secretion.. Trends in endocrinology and metabolism: TEM, 17(10), 408-15. doi:10.1016/j.tem.2006.10.011
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  According to the classical view, peptide hormones are stored in large dense-core vesicles that release all of their cargo rapidly and completely when they fuse with and flatten into the plasma membrane. However, recent imaging studies suggest that this view is too simple. Even after vesicles fuse with the plasma membrane, cells might control the rate of dispersal of vesicle cargo - either by modulating the properties of the fusion pore that connects the vesicle lumen to the extracellular solution or by storing cargo in states that disperse slowly in the extracellular space. Understanding these mechanisms is important, owing to the increasing prevalence of diseases, such as type 2 diabetes mellitus, which arise from insufficient secretion of peptide hormones.
• Zhou, Z., Zhang, X., Zhang, F., Zhang, C., Xu, Z. D., Xu, Z., Xiao, H., Wang, L., Wang, L., Ning, F., Jin, S., Hokfelt, T., He, C., Guan, J., Cai, H., & Bao, L. (2003). Activation of delta opioid receptors induces receptor insertion and neuropeptide secretion.. Neuron, 37(1), 121-33. doi:10.1016/s0896-6273(02)01103-0
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  Here we describe a novel mechanism for plasma membrane insertion of the delta opioid receptor (DOR). In small dorsal root ganglion neurons, only low levels of DORs are present on the cell surface, in contrast to high levels of intracellular DORs mainly associated with vesicles containing calcitonin gene-related peptide (CGRP). Activation of surface DORs caused Ca(2+) release from IP(3)-sensitive stores and Ca(2+) entry, resulting in a slow and long-lasting exocytosis, DOR insertion, and CGRP release. In contrast, membrane depolarization or activation of vanilloid and P2Y(1) receptors induced a rapid DOR insertion. Thus, DOR activation induces a Ca(2+)-dependent insertion of DORs that is coupled to a release of excitatory neuropeptides, suggesting that treatment of inflammatory pain should include blockade of DORs.
• Zhang, X., Wang, H. F., Tong, Y., Lu, Y., Jin, S., Hokfelt, T., Grant, G., Cai, H., & Bao, L. (2002). Peripheral axotomy induces only very limited sprouting of coarse myelinated afferents into inner lamina II of rat spinal cord.. The European journal of neuroscience, 16(2), 175-85. doi:10.1046/j.1460-9568.2002.02080.x
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  Peripheral axotomy-induced sprouting of thick myelinated afferents (A-fibers) from laminae III-IV into laminae I-II of the spinal cord is a well-established hypothesis for the structural basis of neuropathic pain. However, we show here that the cholera toxin B subunit (CTB), a neuronal tracer used to demonstrate the sprouting of A-fibers in several earlier studies, also labels unmyelinated afferents (C-fibers) in lamina II and thin myelinated afferents in lamina I, when applied after peripheral nerve transection. The lamina II afferents also contained vasoactive intestinal polypeptide and galanin, two neuropeptides mainly expressed in small dorsal root ganglion (DRG) neurons and C-fibers. In an attempt to label large DRG neurons and A-fibers selectively, CTB was applied four days before axotomy (pre-injury-labelling), and sprouting was monitored after axotomy. We found that only a small number of A-fibers sprouted into inner lamina II, a region normally innervated by C-fibers, but not into outer lamina II or lamina I. Such sprouts made synaptic contact with dendrites in inner lamina II. Neuropeptide Y (NPY) was found in these sprouts in inner lamina II, an area very rich in Y1 receptor-positive processes. These results suggest that axotomy-induced sprouting from deeper to superficial layers is much less pronounced than previously assumed, in fact it is only marginal. This limited reorganization involves large NPY immunoreactive DRG neurons sprouting into the Y1 receptor-rich inner lamina II. Even if quantitatively small, it cannot be excluded that this represents a functional circuitry involved in neuropathic pain.

Presentations

• Cai, H. (2023, Apr). Eating and eating disorders: the role of amygdala neural circuits. Invited talk, University of Texas Southwestern Medical Center. Dallas: University of Texas Southwestern Medical Center.
• Cai, H. (2023, Jul). Central amygdala - parasubthalamic nucleus neural circuit for eating regulation. Invited talk, the 30th Annual Meeting of the Society for the Study of Ingestive Behavior (SSIB). Portland, OR: the Society for the Study of Ingestive Behavior (SSIB).
• Cai, H. (2023, Jun). Role of central extended amygdala in eating and eating disorders. Invited talk, the 2023 Annual Meeting of the Chinese-American Diabetes Association (CADA). San Diego: Chinese-American Diabetes Association (CADA).
• Cai, H. (2017, February). Neural circuits of feeding and anxiety. UA BIO5 Institute.
• Cai, H. (2017, March). Neural circuits of feeding and anxiety. UA Department of Nutritional Sciences Seminar.
• Cai, H. (2017, March). Neural circuits of feeding and anxiety. UA Department of Pharmacology Seminar.
• Cai, H. (2016, December). Neural circuits of feeding and anxiety. UA Physiological Sciences Forum. University of Arizona.
• Cai, H. (2016, Jan). Dissecting the neural circuits for feeding and emotion. UA Neuroscience GIDP Datablitz.
• Cai, H. (2016, September). “To eat or not to eat” – the central amygdala neural circuits for appetite control. UA College of Medicine Phoenix Department of Basic Medical Sciences Seminar Series.

Poster Presentations

• Cai, H., & Schmit, M. B. (2022). Central Amygdala PKCδ+ neurons respond to food approach in a CCK-modulated manner. . The 53rd Annual Meeting of Society for Neuroscience, San Diego, CA..
• Cai, H., & Schnapp, W. I. (2022). A subpopulation of central extended amygdala neurons regulates the development of activity-based anorexia (ABA). The 53rd Annual Meeting of Society for Neuroscience, San Diego, CA..
• Cai, H., & Schnapp, W. I. (2022). A subpopulation of extended central amygdala neurons regulates the development of activity-based anorexia (ABA). Neuronal Control of Appetite, Keystone Symposia. Banff, Alberta, Canada..