Changwan Chen

All Publications

• Sequential Activation of Lateral Hypothalamic Neuronal Populations during Feeding and Their Assembly by Gamma Oscillations. The Journal of neuroscience : the official journal of the Society for Neuroscience Altafi, M., Chen, C., Korotkova, T., Ponomarenko, A. 2024; 44 (43)

  Abstract

  Neural circuits supporting innate behaviors, such as feeding, exploration, and social interaction, intermingle in the lateral hypothalamus (LH). Although previous studies have shown that individual LH neurons change their firing relative to the baseline during one or more behaviors, the firing rate dynamics of LH populations within behavioral episodes and the coordination of behavior-related LH populations remain largely unknown. Here, using unsupervised graph-based clustering of LH neurons firing rate dynamics in freely behaving male mice, we identified distinct populations of cells whose activity corresponds to feeding, specific times during feeding bouts, or other innate behaviors-social interaction and novel object exploration. Feeding-related cells fired together with a higher probability during slow and fast gamma oscillations (30-60 and 60-90 Hz) than during nonrhythmic epochs. In contrast, the cofiring of neurons signaling other behaviors than feeding was overall similar between slow gamma and nonrhythmic epochs but increased during fast gamma oscillations. These results reveal a neural organization of ethological hierarchies in the LH and point to behavior-specific motivational systems, the dysfunction of which may contribute to mental disorders.

  View details for DOI 10.1523/JNEUROSCI.0518-24.2024

  View details for PubMedID 39256049

  View details for PubMedCentralID PMC11502232

• The dynamic state of a prefrontal-hypothalamic-midbrain circuit commands behavioral transitions. Nature neuroscience Chen, C., Altafi, M., Corbu, M. A., Trenk, A., van den Munkhof, H., Weineck, K., Bender, F., Carus-Cadavieco, M., Bakhareva, A., Korotkova, T., Ponomarenko, A. 2024; 27 (5): 952-963

  Abstract

  Innate behaviors meet multiple needs adaptively and in a serial order, suggesting the existence of a hitherto elusive brain dynamics that brings together representations of upcoming behaviors during their selection. Here we show that during behavioral transitions, possible upcoming behaviors are encoded by specific signatures of neuronal populations in the lateral hypothalamus (LH) that are active near beta oscillation peaks. Optogenetic recruitment of intrahypothalamic inhibition at this phase eliminates behavioral transitions. We show that transitions are elicited by beta-rhythmic inputs from the prefrontal cortex that spontaneously synchronize with LH 'transition cells' encoding multiple behaviors. Downstream of the LH, dopamine neurons increase firing during beta oscillations and also encode behavioral transitions. Thus, a hypothalamic transition state signals alternative future behaviors, encodes the one most likely to be selected and enables rapid coordination with cognitive and reward-processing circuitries, commanding adaptive social contact and eating behaviors.

  View details for DOI 10.1038/s41593-024-01598-3

  View details for PubMedID 38499854

  View details for PubMedCentralID PMC11089001

• Circuit mechanism for suppression of frontal cortical ignition during NREM sleep. Cell Li, B., Ma, C., Huang, Y. A., Ding, X., Silverman, D., Chen, C., Darmohray, D., Lu, L., Liu, S., Montaldo, G., Urban, A., Dan, Y. 2023; 186 (26): 5739-5750.e17

  Abstract

  Conscious perception is greatly diminished during sleep, but the underlying circuit mechanism is poorly understood. We show that cortical ignition-a brain process shown to be associated with conscious awareness in humans and non-human primates-is strongly suppressed during non-rapid-eye-movement (NREM) sleep in mice due to reduced cholinergic modulation and rapid inhibition of cortical responses. Brain-wide functional ultrasound imaging and cell-type-specific calcium imaging combined with optogenetics showed that activity propagation from visual to frontal cortex is markedly reduced during NREM sleep due to strong inhibition of frontal pyramidal neurons. Chemogenetic activation and inactivation of basal forebrain cholinergic neurons powerfully increased and decreased visual-to-frontal activity propagation, respectively. Furthermore, although multiple subtypes of dendrite-targeting GABAergic interneurons in the frontal cortex are more active during wakefulness, soma-targeting parvalbumin-expressing interneurons are more active during sleep. Chemogenetic manipulation of parvalbumin interneurons showed that sleep/wake-dependent cortical ignition is strongly modulated by perisomatic inhibition of pyramidal neurons.

  View details for DOI 10.1016/j.cell.2023.11.012

  View details for PubMedID 38070510

• Place fields of single spikes in hippocampus involve Kcnq3 channel-dependent entrainment of complex spike bursts. Nature communications Gao, X., Bender, F., Soh, H., Chen, C., Altafi, M., Schütze, S., Heidenreich, M., Gorbati, M., Corbu, M. A., Carus-Cadavieco, M., Korotkova, T., Tzingounis, A. V., Jentsch, T. J., Ponomarenko, A. 2021; 12 (1): 4801

  Abstract

  Hippocampal pyramidal cells encode an animal's location by single action potentials and complex spike bursts. These elementary signals are believed to play distinct roles in memory consolidation. The timing of single spikes and bursts is determined by intrinsic excitability and theta oscillations (5-10 Hz). Yet contributions of these dynamics to place fields remain elusive due to the lack of methods for specific modification of burst discharge. In mice lacking Kcnq3-containing M-type K+ channels, we find that pyramidal cell bursts are less coordinated by the theta rhythm than in controls during spatial navigation, but not alert immobility. Less modulated bursts are followed by an intact post-burst pause of single spike firing, resulting in a temporal discoordination of network oscillatory and intrinsic excitability. Place fields of single spikes in one- and two-dimensional environments are smaller in the mutant. Optogenetic manipulations of upstream signals reveal that neither medial septal GABA-ergic nor cholinergic inputs alone, but rather their joint activity, is required for entrainment of bursts. Our results suggest that altered representations by bursts and single spikes may contribute to deficits underlying cognitive disabilities associated with KCNQ3-mutations in humans.

  View details for DOI 10.1038/s41467-021-24805-2

  View details for PubMedID 34376649

  View details for PubMedCentralID PMC8355348

• Prefrontal - subthalamic pathway supports action selection in a spatial working memory task. Scientific reports Heikenfeld, C., Mederos, S., Chen, C., Korotkova, T., Schnitzler, A., Ponomarenko, A. 2020; 10 (1): 10497

  Abstract

  Subthalamic nucleus (STN) is the main source of feed-forward excitation in the basal ganglia and a main target of therapeutic deep brain stimulation in movement disorders. Alleviation of motor symptoms during STN stimulation can be accompanied by deterioration of abilities to quickly choose between conflicting alternatives. Cortical afferents to the subthalamic region (ST), comprising STN and zona incerta (ZI), include projections from the medial prefrontal cortex (mPFC), yet little is known about prefrontal-subthalamic coordination and its relevance for decision-making. Here we combined electrophysiological recordings with optogenetic manipulations of projections from mPFC to ST in mice as they performed a spatial working memory task (T-maze) or explored an elevated plus maze (anxiety test). We found that gamma oscillations (30-70 Hz) are coordinated between mPFC and ST at theta (5-10 Hz) and, less efficiently, at sub-theta (2-5 Hz) frequencies. An optogenetic detuning of the theta/gamma cross-frequency coupling between the regions into sub-theta range impaired performance in the T-maze, yet did not affect anxiety-related behaviors in the elevated plus maze. Both detuning and inhibition of the mPFC-ST pathway led to repeated incorrect choices in the T-maze. These effects were not associated with changes of anxiety and motor activity measures. Our findings suggest that action selection in a cognitively demanding task crucially involves theta rhythmic coordination of gamma oscillatory signaling in the prefrontal-subthalamic pathway.

  View details for DOI 10.1038/s41598-020-67185-1

  View details for PubMedID 32591609

  View details for PubMedCentralID PMC7320162

• The anterior insular cortex unilaterally controls feeding in response to aversive visceral stimuli in mice. Nature communications Wu, Y., Chen, C., Chen, M., Qian, K., Lv, X., Wang, H., Jiang, L., Yu, L., Zhuo, M., Qiu, S. 2020; 11 (1): 640

  Abstract

  Reduced food intake is common to many pathological conditions, such as infection and toxin exposure. However, cortical circuits that mediate feeding responses to these threats are less investigated. The anterior insular cortex (aIC) is a core region that integrates interoceptive states and emotional awareness and consequently guides behavioral responses. Here, we demonstrate that the right-side aIC CamKII+ (aICCamKII) neurons in mice are activated by aversive visceral signals. Hyperactivation of the right-side aICCamKII neurons attenuates food consumption, while inhibition of these neurons increases feeding and reverses aversive stimuli-induced anorexia and weight loss. Similar manipulation at the left-side aIC does not cause significant behavioral changes. Furthermore, virus tracing reveals that aICCamKII neurons project directly to the vGluT2+ neurons in the lateral hypothalamus (LH), and the right-side aICCamKII-to-LH pathway mediates feeding suppression. Our studies uncover a circuit from the cortex to the hypothalamus that senses aversive visceral signals and controls feeding behavior.

  View details for DOI 10.1038/s41467-020-14281-5

  View details for PubMedID 32005806

  View details for PubMedCentralID PMC6994462

• Postsynaptic RIM1 modulates synaptic function by facilitating membrane delivery of recycling NMDARs in hippocampal neurons. Nature communications Wang, J., Lv, X., Wu, Y., Xu, T., Jiao, M., Yang, R., Li, X., Chen, M., Yan, Y., Chen, C., Dong, W., Yang, W., Zhuo, M., Chen, T., Luo, J., Qiu, S. 2018; 9 (1): 2267

  Abstract

  NMDA receptors (NMDARs) are crucial for excitatory synaptic transmission and synaptic plasticity. The number and subunit composition of synaptic NMDARs are tightly controlled by neuronal activity and sensory experience, but the molecular mechanism mediating NMDAR trafficking remains poorly understood. Here, we report that RIM1, with a well-established role in presynaptic vesicle release, also localizes postsynaptically in the mouse hippocampus. Postsynaptic RIM1 in hippocampal CA1 region is required for basal NMDAR-, but not AMPA receptor (AMPAR)-, mediated synaptic responses, and contributes to synaptic plasticity and hippocampus-dependent memory. Moreover, RIM1 levels in hippocampal neurons influence both the constitutive and regulated NMDAR trafficking, without affecting constitutive AMPAR trafficking. We further demonstrate that RIM1 binds to Rab11 via its N terminus, and knockdown of RIM1 impairs membrane insertion of Rab11-positive recycling endosomes containing NMDARs. Together, these results identify a RIM1-dependent mechanism critical for modulating synaptic function by facilitating membrane delivery of recycling NMDARs.

  View details for DOI 10.1038/s41467-018-04672-0

  View details for PubMedID 29891949

  View details for PubMedCentralID PMC5995852

• Endocytosis of GluN2B-containing NMDA receptors mediates NMDA-induced excitotoxicity. Molecular pain Wu, Y., Chen, C., Yang, Q., Jiao, M., Qiu, S. 2017; 13: 1744806917701921

  Abstract

  N-methyl-D-aspartate (NMDA) receptor overactivation is involved in neuronal damage after stroke. However, the mechanism underlying NMDA receptor-mediated excitotoxicity remains unclear. In this study, we confirmed that excessive activation of NMDARs led to cell apoptosis in PC12 cells and in primary cultured cortical neurons, which was mediated predominantly by the GluN2B-containing, but not the GluN2A-containing NMDARs. In addition, Clathrin-dependent endocytosis participated in NMDA-induced excitotoxicity. Furthermore, we identified that GluN2B-containing NMDARs underwent endocytosis during excessive NMDA treatment. Peptides specifically disrupting the interaction between GluN2B and AP-2 complex not only blocked endocytosis of GluN2B induced by NMDA treatment but also abolished NMDA-induced excitotoxicity. These results demonstrate that Clathrin-dependent endocytosis of GluN2B-containing NMDARs is critical to NMDA-induced excitotoxicity in PC12 cells and in primary cultured cortical neurons, and therefore provide a novel target for blocking NMDAR-mediated excitotoxicity.

  View details for DOI 10.1177/1744806917701921

  View details for PubMedID 28326942

  View details for PubMedCentralID PMC5391130