Biology subjects

Hikida, T.

Publications and source records attributed to Hikida, T..

14 recordsLinked to original sources

bioRxiv2026

The slow-acting G-protein Gz defines the duration of circadian rest time

Duration of nightly rest is a trait that varies between individuals, influenced by a complex interplay between multiple genetic and environmental factors. The central circadian clock that orchestrates daily rhythm in behavior/sleep resides in the suprachiasmatic nucleus (SCN). Yet, how the SCN encodes the "length" of the circadian rest phase ({rho}) remains an open question. Here we demonstrate that the unique G-protein-subtype Gz contributes to this process by sculpting the waveform of the circadian cAMP-PKA activity rhythm within the SCN. Genetic deletion and subsequent rescue of Gz expression reversibly altered the {rho} duration, shifting it from [~]10 h in Gz+/+ mice to [~]7.5 h in Gz-/-; mice, accompanied by proportional changes in peak cAMP-PKA activity duration and transcriptome remodeling in the SCN. Notably, intra-SCN cAMP activation led to behavioral rest, with Gz specifically shaping this response without affecting 24-h rhythmicity. These findings suggest that the SCN is not merely a rhythm-generator, but actively allocates the {rho}-rest period via Gz signaling.

neuroscience↗

bioRxiv2026

Inside insight: decoding how insight emerges from competing world models

When and how does insight emerge? We conceptualize insight as a sudden realization arising from restructuring a world model: an internal interpretation linking actions to outcomes. Yet these latent dynamics remain difficult to access, even with behavior and verbal report. Here we developed inside insight dynamics (IID), a machine-learning framework that estimates latent world-model dynamics from behavioral data. Using IID, we analyzed mouse behavior in indirect- and direct-rule tasks, each requiring a shift from an initial world model to a rule-consistent representation. IID inferred the "when" of insight-like shifts by estimating the timing of transitions between competing world models, and examined the "how" by comparing alternative learning processes underlying them. This analysis revealed distinct mechanisms of world-model learning: the indirect- and direct-rule tasks were better explained by gated learning and parallel learning, respectively. Thus, IID opens a route to quantifying latent insight dynamics from observable behavior alone.

neuroscience↗

bioRxiv2025

Intermingled representation of oral cavity in mouse trigeminal ganglion

Somatotopy serves as a fundamental principle underlying sensory information processing, traditionally emphasized in the study of the cerebral cortex. However, little effort has been directed towards unraveling the spatial organization characterizing the earlier stages of sensory pathways. In this study, we developed a novel methodology to visualize individual neurons within the trigeminal ganglion--a crucial cluster of cell bodies of sensory neurons innervating the face. Our investigations revealed a reliable sensory response to stimulation of the lower teeth or lip within this ganglion. The responsive neurons were confined to a specific portion of the trigeminal ganglion, consistent with innervation of the lower oral cavity by the mandibular nerve. Contrary to our expectations, we did not observe a discernible map delineating specific regions of the oral cavity. Instead, the spatial representation of the teeth and lips exhibited unexpected intermingling. These findings challenge conventional understandings rooted in cortical maps and suggest that such conceptual frameworks may not be applicable to earlier stages of sensory pathways for the oral cavity. Our study sheds light on the complex spatial organization of sensory processing in the trigeminal system, highlighting the need for further research to elucidate the underlying mechanisms and implications for sensory perception and clinical interventions. Impact statementIn vivo calcium imaging revealed that neurons responding to tooth stimulation are sparsely distributed in the trigeminal ganglion, intermixed with neurons responding to lip stimulation.

neuroscience↗

bioRxiv2025

Flexible value coding in the mesolimbic dopamine system depending on internal water and sodium balance

Homeostatic imbalances elicit strong cravings, such as thirst and salt appetite, to restore equilibrium. Although midbrain dopaminergic neurons are known to encode the value of foods, their nutritional state-dependency remains unknown. Here, we show that the activity of the dopaminergic mesolimbic pathway flexibly expresses the positive and negative values of water and salt depending on the internal state in mice. Mice showed behavioral preference and aversion to water and salt depending on their internal water and sodium balance. Fiber photometry recordings revealed that dopamine neurons in the ventral tegmental area and dopamine release in the nucleus accumbens flexibly showed bidirectional excitatory and inhibitory responses to water and salt intake in a state-dependent manner. Furthermore, these dopaminergic and behavioral responses could be simulated by a homeostatic reinforcement learning model. Our results demonstrate the nutritional state-dependency of value coding in mesolimbic dopamine systems, providing new insights into neural circuits underlying homeostatic regulation of appetitive and avoidance behaviors.

neuroscience↗

bioRxiv2025

Noradrenergic efferent subsystems that gate traumatic social learning

Individuals experience varying magnitudes of stress in their daily lives. Although stress responses facilitate adaptive processes to cope with changing environments, severe stress can lead to traumatic learning and anxiety disorders. However, the neuronal mechanisms underlying the influence of stress severity on these processes remain unclear. Here, we show that traumatic social stress engages anatomically distinct locus coeruleus noradrenergic (LCNA) subpopulations that exhibit dynamic responses scaled to aversive salience. Using whole-brain activity and axonal projection mappings, we identified projectome subtypes of LCNA neurons, which are differentially recruited by single versus consecutive aversive social experiences. While hippocampus-projecting LCNA neurons responded to general social contacts, thalamus-projecting LCNA neurons tracked the aversive salience of social stimuli. Functional manipulations revealed a bidirectional role of thalamus-projecting LCNA neurons in social avoidance learning. These findings reveal the functional architecture of LCNA subsystems that regulate traumatic social learning via dynamic scaling to aversive salience.

neuroscience↗

bioRxiv2024

Heterogeneous Appetite Patterns in Depression: Computational Modeling of Nutritional Interoception, Reward Processing, and Decision-Making

Accurate interoceptive processing in decision-making is essential to maintain homeostasis and overall health. Disruptions in this process have been associated with various psychiatric conditions, including depression. Recent studies have focused on nutrient homeostatic dysregulation in depression for effective subtype classification and treatment. Neurophysiological studies have associated changes in appetite in depression with altered activation of the mesolimbic dopamine system and interoceptive regions, such as the insular cortex, suggesting that disruptions in reward processing and interoception drive changes in nutrient homeostasis and appetite. This study aimed to explore the potential of computational psychiatry in addressing these issues. Using a homeostatic reinforcement learning model formalizing the link between internal states and behavioral control, we investigated the mechanisms by which altered interoception affects homeostatic behavior and reward system activity via simulation experiments. Simulations of altered interoception demonstrated behaviors similar to those of depression subtypes, such as appetite dysregulation. Specifically, reduced interoception led to decreased reward system activity and increased punishment, mirroring the neuroimaging study findings of decreased appetite in depression. Conversely, increased interoception was associated with heightened reward activity and impaired goal-directed behavior, reflecting an increased appetite. Furthermore, effects of interoception manipulation were compared with traditional reinforcement learning parameters (e.g., inverse temperature {beta} and delay discount{gamma} ), which represent cognitive-behavioral features of depression. The results suggest that disruptions in these parameters contribute to depressive symptoms by affecting the underlying homeostatic regulation. Overall, this study findings emphasize the importance of integrating interoception and homeostasis into decision-making frameworks to enhance subtype classification and facilitate the development of effective therapeutic strategies.

systems biology↗

bioRxiv2024

Sex-dependant differences in the ability of nicotine to modulate discrimination learning and cognitive flexibility in mice.

1Nicotine, an addictive compound found in tobacco, functions as an agonist of nicotinic acetylcholine receptors (nAChRs) in the brain. Interestingly, nicotine has been reported to act as a cognitive enhancer in both human subjects and experimental animals. However, its effects in animal studies have not always been consistent, and sex differences have been identified in the effects of nicotine on several behaviors. Specifically, the role that sex plays in modulating the effects of nicotine on discrimination learning and cognitive flexibility in rodents is still unclear. Here, we evaluated sex-dependent differences in the effect of daily nicotine administration at various doses (0.125, 0.25, and 0.5 mg/kg) on visual discrimination (VD) learning and reversal (VDR) learning in mice. In male mice, nicotine significantly improved performance in VDR, but not VD, task, while, in female mice, nicotine significantly worsened performance in the VD, but not VDR, task. Next, to investigate the cellular mechanisms that underlie the sex differences in the effects of nicotine on cognition, transcriptomic analyses were performed on prefrontal cortex tissue samples from male and female mice that had undergone VD and VDR tasks. Pathway enrichment analysis and Protein-protein interaction (P-PI) analysis using gene sets with altered gene expression found three types of effects of nicotine: those common to both sexes, those in males only, and those in females only. Decreased expression of postsynaptic-related genes in males and increased expression of innate immunity-related genes in females were identified as possible molecular mechanisms related to sex differences in the effects of nicotine on cognition in discrimination learning and cognitive flexibility.

animal behavior and cognition↗

bioRxiv2024

Importin α4 deficiency induces psychiatric disorder-related behavioral deficits and neuroinflammation in mice.

Importin 4, which is encoded by the Kpna4 gene, is a well characterized nuclear-cytoplasmic transport factor known to mediate transport of transcription factors including NF-{kappa}B. Here, we report that Kpna4 knock-out (KO) mice exhibit psychiatric disorder-related behavioral abnormalities such as anxiety-related behaviors, deceased social interaction and sensorimotor gating deficits. Contrary to a previous study predicting attenuated NF-{kappa}B activity as a result of Kpna4 deficiency, we observed a significant increase in expression levels of NF-{kappa}B genes and pro-inflammatory cytokines such as TNF, Il1{beta} or Il-6 in the Prefrontal Cortex or Basolateral Amygdala of the KO mice. Moreover, examination of inflammatory responses in primary cells revealed that Kpna4 deficient cells have an increased inflammatory response, which was rescued by addition of not only full-length, but also a nuclear transport deficient truncation mutant of importin 4, suggesting contribution of its non-transport functions. Furthermore, RNAseq of sorted adult Microglia and Astrocytes and subsequent transcription factor analysis suggested increases in Polycomb repressor complex 2 (PRC2) activity in Kpna4 KO cells. Taken together, importin 4 deficiency induces psychiatric disorder-related behavioral deficits in mice, along with an increased inflammatory response and possible alteration of PRC2 activity in glial cells.

neuroscience↗

bioRxiv2023

Leveraging Machine Learning to Uncover the Hidden Links between Trusting Behavior and Biological Markers

Understanding the decision-making mechanisms underlying trust is essential, particularly for patients with mental disorders who experience difficulties in developing trust. We aimed to explore biomarkers associated with trust-based decision-making by quantitative analysis. However, quantification of decision-making properties is difficult because it cannot be directly observed. Here, we developed a machine learning method based on Bayesian hierarchical model to quantitatively decode the decision-making properties from behavioral data of a trust game. By applying the method to data of patients with MDD and healthy controls, we estimated model parameters regulating trusting decision-making. The estimated model was able to predict behaviors of each participant. Although there is no difference of the estimated parameters between MDD and healthy controls, several biomarkers were associated with the decision-making properties in trusting behavior. Our findings provide valuable insights into the trusting decision-making, offering a basis for developing targeted interventions to improve their social functioning and overall well-being.

bioinformatics↗

bioRxiv2023

Dual roles for nucleus accumbens core dopamine D1-expressing neurons projecting to the substantia nigra pars reticulata in limbic and motor control

The nucleus accumbens (NAc) is a critical component of a limbic basal ganglia circuit that is thought to play an important role in decision-making and the processing of rewarding stimuli. As part of this circuit, dopamine D1 receptor-expressing medium spiny neurons (D1-MSNs) of the NAc core are known to send a major projection to the substantia nigra pars reticulata (SNr). However, the functional role of this SNr-projecting NAc D1-MSNs (NAcD1-MSN-SNr) pathway is still largely uncharacterized. Moreover, as the SNr is thought to belong to both limbic and motor information processing basal ganglia loops, it is possible that the NAcD1-MSN-SNr pathway may be able to influence both limbic and motor functions. In this study we investigated the effect of optogenetic activation of the NAcD1-MSN-SNr pathway on reward-learning and locomotor behavior. Stimulation of the axon terminals of NAc core D1-MSNs in the SNr induced a preference for a laser-paired location, self-stimulation via a laser-paired lever, and augmented instrumental responding for a liquid reward-paired lever. Additionally, stimulation was observed to increase locomotor behavior when delivered bilaterally and induced contralateral turning behavior when delivered unilaterally. These findings indicate that the NAcD1-MSN-SNr pathway is able to control both reward learning and motor behaviors.

neuroscience↗

bioRxiv2021

Distinct Roles of Dopamine D1 and D2 Receptor-expressing Neurons in the Nucleus Accumbens for a Strategy Dependent Decision Making

To optimize decision making, animals need to execute not only a strategy to choose a good option but sometimes also one to avoid a bad option. A psychological study indicates that positive and negative information is processed in a different manner in the brain. The nucleus accumbens (NAc) contains two different types of neurons, dopamine D1 and D2 receptor-expressing neurons which are implicated in reward-based decision making and aversive learning. However, little is known about the neural mechanisms by which D1 or D2 receptor-expressing neurons in the NAc contribute to the execution of the strategy to choose a good option or one to avoid a bad option under decision making. Here, we have developed two novel visual discrimination tasks for mice to assess the strategy to choose a good option and one to avoid a bad option. By chemogenetically suppressing the subpopulation of the NAc neurons, we have shown that dopamine D2 receptor-expressing neurons in the NAc selectively contribute to the strategy to avoid a bad option under reward-based decision making. Furthermore, our optogenetic and calcium imaging experiments indicate that dopamine D2 receptor-expressing neurons are activated by error choices and the activation following an error plays an important role in optimizing the strategy in the next trial. Our findings suggest that the activation of D2 receptor-expressing neurons by error choices through learning enables animals to execute the appropriate strategy.

neuroscience↗

bioRxiv2021

Computational mechanisms of osmoregulation: a reinforcement learning model for sodium appetite

Homeostatic control with oral nutrient intake is a vital complex system involving the orderly interactions between the external and internal senses, behavioral control, and reward learning. Sodium appetite is a representative system and has been intensively investigated in animal models of homeostatic systems and oral nutrient intake. However, the system-level mechanisms for regulating sodium intake behavior and homeostatic control remain unclear. In the current study, we attempted to provide a mechanistic understanding of sodium appetite behavior by using a computational model, the homeostatic reinforcement learning model, in which homeostatic behaviors are interpreted as reinforcement learning processes. Through simulation experiments, we confirmed that our homeostatic reinforcement learning model successfully reproduced homeostatic behaviors by regulating sodium appetite. These behaviors include the approach and avoidance behaviors to sodium according to the internal states of individuals. In addition, based on the assumption that the sense of taste is a predictor of changes in the internal state, the homeostatic reinforcement learning model successfully reproduced the previous paradoxical observations of the intragastric infusion test, which cannot be explained by the classical drive reduction theory. Moreover, we extended the homeostatic reinforcement learning model to multi-modal data, and successfully reproduced the behavioral tests in which water and sodium appetite were mediated by each other. Finally, through an experimental simulation of chemical manipulation in a specific neural population in the brain stem, we proposed a testable hypothesis for the function of neural circuits involving sodium appetite behavior. The study results support the idea that osmoregulation via sodium appetitive behavior can be understood as a reinforcement learning process and provide a mechanistic explanation for the underlying neural mechanisms of sodium appetite and homeostatic behavior. Author SummaryThe taste of high-concentration saltwater is rewarding during sodium depletion, while it is aversive in a sodium sufficient state. This "sodium appetite" is a clear manifestation of homeostasis maintenance and proper action selection in animals, reflecting the internal environment. To reveal the computational mechanism of this property, we applied a machine learning model, in which homeostatic stability is a reward and the goal is to maximize the sum of the reward, and simulated animal behavioral experiments. The results suggest that the mechanism of sodium-appetite behavior is based on the machine learning model. Specifically, by replicating the results of neural circuit manipulation, which controls sodium appetite, an algorithm in which the function of a neural population affects sodium appetite behaviors was proposed. Our results provide a fundamental computational model for a mechanism by a function of a neural cell type to regulate animal behavior. More generally, this study can be fundamental to understanding the computational process of decision making reflecting the internal environment.

neuroscience↗

bioRxiv2018

The cortico-striatal circuit regulates sensorimotor gating via Disc1/Huntingtin-mediated Bdnf transport

Sensorimotor information processing that underlies normal cognitive and behavioral traits is dysregulated across a subset of neurological and psychiatric disorders. The cross-disease deficit in sensorimotor gating poses a unique opportunity to integrate hierarchical findings at molecular, cellular, through circuitry levels to obtain an in-depth mechanistic understanding of this process that contributes to brain physiology and pathophysiology beyond categorical segmentation of brain disorders. Based on circuitry recording with wild-type mice, we demonstrated that the cortico-striatal projection mediates sensorimotor gating responses during prepulse inhibition (PPI) task. We also found that these circuitry responses were disrupted in Disc1 locus-impairment (LI) mice, a model representing neuropsychiatric conditions. Thus, we hypothesized that Disc1-mediated molecular and cellular machinery along the cortico-striatal circuit may regulate sensorimotor gating. Anatomical and biochemical analyses of Disc1-LI mice revealed attenuated Bdnf transport along the cortico-striatal circuit. Pharmacologically augmenting Bdnf transport by chronic lithium administration, in part via Ser-421 phosphorylation of Huntingtin (Htt) and its integration into the motor machinery, restored the striatal Bdnf levels and PPI deficits in Disc1-LI mice, suggesting that the Bdnf transport attenuation mechanistically underlies the circuitry and behavioral deficits. These results also shed light on a novel mechanism and utility of lithium that is currently used as a major mood stabilizer in clinical settings. Collectively, the present study illustrates integrative biological mechanisms for sensorimotor gating, underscoring the cross-disease nature of this behavioral dimension and translational utility of the findings under the era of precision medicine in brain disorders.

neuroscience↗

bioRxiv2018

Opposing roles of dopamine receptor D1- and D2-expressing neurons in the anteromedial olfactory tubercle in acquisition of place preference in mice

Olfaction induces adaptive motivated behaviors. Odors associated with food induce attractive behavior, whereas those associated with dangers induce aversive behavior. We previously reported that learned odor-induced attractive and aversive behaviors accompany activation of the olfactory tubercle (OT) in a domainand cell type-specific manner. Odor cues associated with a sugar reward induced attractive behavior and c-fos expression in the dopamine receptor D1-expressing neurons (D1 neurons) in the anteromedial OT. In contrast, odor cues associated with electrical shock induced aversive behavior and c-fos expression in the D2 neurons in the anteromedial OT, as well as the D1 neurons in the lateral OT. Here, we investigated whether the D1 and D2 neurons in the anteromedial OT play distinct roles in attractive or aversive behaviors, using optogenetic stimulation and real-time place preference (RTPP) tests. Mice expressing ChETA (ChR2/E123T)-EYFP in the D1 neurons in the anteromedial OT spent a longer time in the photo-stimulation side of the place preference chamber than the control mice expressing EYFP. On the other hand, upon optogenetic stimulation of the D2 neurons in the anteromedial OT, the mice spent a shorter time in the photo-stimulation side than the control mice. Local neural activation in the anteromedial OT during the RTPP tests was confirmed by c-fos mRNA expression. These results suggest that the D1 and D2 neurons in the anteromedial OT play distinct roles in attractive and aversive behaviors, respectively.

neuroscience↗