Sayaka Inoue

All Publications

• A functional cellular framework for sex and estrous cycle-dependent gene expression and behavior. Cell Knoedler, J. R., Inoue, S., Bayless, D. W., Yang, T., Tantry, A., Davis, C., Leung, N. Y., Parthasarathy, S., Wang, G., Alvarado, M., Rizvi, A. H., Fenno, L. E., Ramakrishnan, C., Deisseroth, K., Shah, N. M. 1800

  Abstract

  Sex hormones exert a profound influence on gendered behaviors. How individual sex hormone-responsive neuronal populations regulate diverse sex-typical behaviors is unclear. We performed orthogonal, genetically targeted sequencing of four estrogen receptor 1-expressing (Esr1+) populations and identified 1,415 genes expressed differentially between sexes or estrous states. Unique subsets of these genes were distributed across all 137 transcriptomically defined Esr1+ cell types, including estrous stage-specific ones, that comprise the four populations. We used differentially expressed genes labeling single Esr1+ cell types as entry points to functionally characterize two such cell types, BNSTprTac1/Esr1 and VMHvlCckar/Esr1. We observed that these two cell types, but not the other Esr1+ cell types in these populations, are essential for sex recognition in males and mating in females, respectively. Furthermore, VMHvlCckar/Esr1 cell type projections are distinct from those of other VMHvlEsr1 cell types. Together, projection and functional specialization of dimorphic cell types enables sex hormone-responsive populations to regulate diverse social behaviors.

  View details for DOI 10.1016/j.cell.2021.12.031

  View details for PubMedID 35065713

• Neural basis for estrous cycle-dependent control of female behaviors. Neuroscience research Inoue, S. 2021

  Abstract

  Females display changes in distinct behaviors along the estrous cycle. Levels of circulating ovarian sex steroid hormones peak around ovulation, which occur around estrus phase of the cycle. This increase of sex hormones is thought to be important for changes in behaviors, however, neural circuit mechanisms of periodic behavioral changes in females are not understood well. Different lines of research indicate sex hormonal effects on several forms of neuronal plasticity. This review provides an overview of behavioral and plastic changes that occur in an estrous cycle-dependent manner and explores the current research linking these changes to understand neural circuit mechanisms that control female behaviors.

  View details for DOI 10.1016/j.neures.2021.07.001

  View details for PubMedID 34331974

• Periodic Remodeling in a Neural Circuit Governs Timing of Female Sexual Behavior. Cell Inoue, S., Yang, R., Tantry, A., Davis, C., Yang, T., Knoedler, J. R., Wei, Y., Adams, E. L., Thombare, S., Golf, S. R., Neve, R. L., Tessier-Lavigne, M., Ding, J. B., Shah, N. M. 2019

  Abstract

  Behaviors are inextricably linked to internal state. We have identified a neural mechanism that links female sexual behavior with the estrus, the ovulatory phase of the estrous cycle. We find that progesterone-receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) are active and required during this behavior. Activating these neurons, however, does not elicit sexual behavior in non-estrus females. We show that projections of PR+ VMH neurons to the anteroventral periventricular (AVPV) nucleus change across the 5-day mouse estrous cycle, with 3-fold more termini and functional connections during estrus. This cyclic increase in connectivity is found in adult females, but not males, and regulated by estrogen signaling in PR+ VMH neurons. We further show that these connections are essential for sexual behavior in receptive females. Thus, estrogen-regulated structural plasticity of behaviorally salient connections in the adult female brain links sexual behavior to the estrus phase of the estrous cycle.

  View details for DOI 10.1016/j.cell.2019.10.025

  View details for PubMedID 31735496

• CDKL5 controls postsynaptic localization of GluN2B-containing NMDA receptors in the hippocampus and regulates seizure susceptibility NEUROBIOLOGY OF DISEASE Okuda, K., Kobayashi, S., Fukaya, M., Watanabe, A., Murakami, T., Hagiwara, M., Sato, T., Ueno, H., Ogonuki, N., Komano-Inoue, S., Manabe, H., Yamaguchi, M., Ogura, A., Asahara, H., Sakagami, H., Mizuguchi, M., Manabe, T., Tanaka, T. 2017; 106: 158-170

  Abstract

  Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders accompanied by intractable epilepsies, i.e. West syndrome or atypical Rett syndrome. Here we report generation of the Cdkl5 knockout mouse and show that CDKL5 controls postsynaptic localization of GluN2B-containing N-methyl-d-aspartate (NMDA) receptors in the hippocampus and regulates seizure susceptibility. Cdkl5 -/Y mice showed normal sensitivity to kainic acid; however, they displayed significant hyperexcitability to NMDA. In concordance with this result, electrophysiological analysis in the hippocampal CA1 region disclosed an increased ratio of NMDA/α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated excitatory postsynaptic currents (EPSCs) and a significantly larger decay time constant of NMDA receptor-mediated EPSCs (NMDA-EPSCs) as well as a stronger inhibition of the NMDA-EPSCs by the GluN2B-selective antagonist ifenprodil in Cdkl5 -/Y mice. Subcellular fractionation of the hippocampus from Cdkl5 -/Y mice revealed a significant increase of GluN2B and SAP102 in the PSD (postsynaptic density)-1T fraction, without changes in the S1 (post-nuclear) fraction or mRNA transcripts, indicating an intracellular distribution shift of these proteins to the PSD. Immunoelectron microscopic analysis of the hippocampal CA1 region further confirmed postsynaptic overaccumulation of GluN2B and SAP102 in Cdkl5 -/Y mice. Furthermore, ifenprodil abrogated the NMDA-induced hyperexcitability in Cdkl5 -/Y mice, suggesting that upregulation of GluN2B accounts for the enhanced seizure susceptibility. These data indicate that CDKL5 plays an important role in controlling postsynaptic localization of the GluN2B-SAP102 complex in the hippocampus and thereby regulates seizure susceptibility, and that aberrant NMDA receptor-mediated synaptic transmission underlies the pathological mechanisms of the CDKL5 loss-of-function.

  View details for DOI 10.1016/j.nbd.2017.07.002

  View details for Web of Science ID 000408290800014

  View details for PubMedID 28688852

• Social Control of Hypothalamus-Mediated Male Aggression. Neuron Yang, T. n., Yang, C. F., Chizari, M. D., Maheswaranathan, N. n., Burke, K. J., Borius, M. n., Inoue, S. n., Chiang, M. C., Bender, K. J., Ganguli, S. n., Shah, N. M. 2017; 95 (4): 955–70.e4

  Abstract

  How environmental and physiological signals interact to influence neural circuits underlying developmentally programmed social interactions such as male territorial aggression is poorly understood. We have tested the influence of sensory cues, social context, and sex hormones on progesterone receptor (PR)-expressing neurons in the ventromedial hypothalamus (VMH) that are critical for male territorial aggression. We find that these neurons can drive aggressive displays in solitary males independent of pheromonal input, gonadal hormones, opponents, or social context. By contrast, these neurons cannot elicit aggression in socially housed males that intrude in another male's territory unless their pheromone-sensing is disabled. This modulation of aggression cannot be accounted for by linear integration of environmental and physiological signals. Together, our studies suggest that fundamentally non-linear computations enable social context to exert a dominant influence on developmentally hard-wired hypothalamus-mediated male territorial aggression.

  View details for PubMedID 28757304

  View details for PubMedCentralID PMC5648542

• Rapid induction of granule cell elimination in the olfactory bulb by noxious stimulation in mice NEUROSCIENCE LETTERS Komano-Inoue, S., Murata, K., Mori, K., Yamaguchi, M. 2015; 598: 6-11

  Abstract

  Elimination of granule cells (GCs) in the olfactory bulb (OB) is not a continuous event but is rather promoted during short time windows associated with the animal's behavior. We previously showed that apoptotic GC elimination is enhanced during food eating and subsequent rest or sleep, and that top-down inputs from the olfactory cortex (OC) to the OB during the postprandial period are the crucial signal promoting GC elimination. However, whether enhanced GC elimination occurs during behaviors other than postprandial behavior is not clear. Here, we investigated whether exposure to noxious stimulation promotes apoptotic GC elimination in mice. Mice were delivered a brief electrical foot shock, during and immediately after which they showed startle and fear responses. Surprisingly, the number of apoptotic GCs increased 2-fold within 10 min after the start of foot shock delivery. This enhancement of GC apoptosis was significantly suppressed by injection of the GABAA receptor agonist muscimol in the OC, despite these muscimol-injected mice showing similar behavioral responses by foot shock as control mice. These results indicate that GC elimination is promoted in foot shock-delivered mice within a short time period of startle and fear responses. They also indicate that OC activity plays a central role in the enhanced GC elimination during this period, as is also the case in GC elimination during the postprandial period.

  View details for DOI 10.1016/j.neulet.2015.05.002

  View details for Web of Science ID 000356549800002

  View details for PubMedID 25943284

• Top-down inputs from the olfactory cortex in the postprandial period promote elimination of granule cells in the olfactory bulb EUROPEAN JOURNAL OF NEUROSCIENCE Komano-Inoue, S., Manabe, H., Ota, M., Kusumoto-Yoshida, I., Yokoyama, T. K., Mori, K., Yamaguchi, M. 2014; 40 (5): 2724-2733

  Abstract

  Elimination of granule cells (GCs) in the olfactory bulb (OB) is not a continual event but is promoted during a short time window in the postprandial period, typically with postprandial sleep. However, the neuronal mechanisms for the enhanced GC elimination during the postprandial period are not understood. Here, we addressed the question of whether top-down inputs of centrifugal axons from the olfactory cortex (OC) during the postprandial period are involved in the enhanced GC elimination in the OB. Electrical stimulation of centrifugal axons from the OC of anesthetized mice increased GC apoptosis. Furthermore, pharmacological suppression of top-down inputs from the OC to the OB during the postprandial period of freely behaving mice by γ-aminobutyric acid (GABA)A receptor agonist injection in the OC significantly decreased GC apoptosis. Remarkable apoptotic GC elimination in the sensory-deprived OB was also suppressed by pharmacological blockade of top-down inputs. These results indicate that top-down inputs from the OC to the OB during the postprandial period are the crucial signal promoting GC elimination, and suggest that the life and death decision of GCs in the OB is determined by the interplay between bottom-up sensory inputs from the external world and top-down inputs from the OC.

  View details for DOI 10.1111/ejn.12679

  View details for Web of Science ID 000341981500002

  View details for PubMedID 25041475