Biology subjects

Niwa, M.

Publications and source records attributed to Niwa, M..

At least 19 recordsLinked to original sources

bioRxiv2026

Repeated Inertial Stimulation Reveals Divergent Plasticity in Peripheral and Central Vestibular Pathways

The vestibular system consists of peripheral end organs that provide the brain with temporally precise information about head position in space required for motor coordination and postural stability. Irregular vestibular afferents of the inner ear are particularly sensitive to rapid changes in acceleration, or jerk, which is necessary for making quick, corrective movements and postural adjustments. Vestibular short-latency evoked potentials (VsEPs) are waveforms that provide a measure of synchronous irregular afferent activity originating from peripheral (early peaks) and central (later peaks) vestibular pathways. These VsEPs are elicited by head jerk stimuli, commonly used preclinically. Previous studies have shown that early VsEP waves are dependent upon jerks of an adequate intensity, number, and duration. However, less is known about jerk characteristics necessary for generation of reliable VsEP signals centrally (later peaks). The present study examines the precise temporal dynamics of peripheral and central vestibular centers across a broad range of mechanical vestibular load in rats. We found differential changes in synchrony and timing driven by jerk repetition, intensity, and duration between early and late VsEP waves representing distinct anatomical components of the vestibular circuit. Our results suggest that central components are uniquely sensitive to jerk duration, intensity, and repetition, indicating a disconnect between peripheral and central neuronal recruitment, adaptive plasticity, and time-frequency dynamics. This work provides a foundation for using VsEP to assess jerk-induced physiological vestibular dysfunction and to understand how central relays differentially adapt to variations of mechanical vestibular stress compared with the precise, high-fidelity transmission observed in the periphery.

neuroscience↗

bioRxiv2026

Adolescent social isolation creates a latent vulnerability in maternal care with intergenerational social consequences, rescued by experienced mothers

Early-life adversity (ELA) can produce lasting alterations on brain and behavior, yet its effects on maternal caregiving and intergenerational social outcomes remain poorly understood. Using a mouse model of mild adolescent social isolation, we demonstrated that females exposed to isolation in late adolescence exhibited progressive deficits in pup-directed maternal behaviors, including nursing, licking, nest-building, and pup retrieval, while self-directed behaviors remain intact. Offspring reared by these dams displayed deficits in adult social behavior, including reduced sociability, impaired social novelty recognition, and diminished social odor discrimination, without affecting non-social memory, anxiety-like behavior, or locomotor activity. Chemogenetic activation of the medial cingulate cortex (mCg) to prelimbic cortex (PrL) pathway in offspring of stressed dams rescued social deficits, whereas inhibition of this pathway in control mice recapitulated the impairments. Notably, co-housing stressed dams with experienced parous females during the early postpartum period restored pup-directed maternal behaviors and normalized offspring social outcomes, demonstrating that social experience can buffer the intergenerational consequences of ELA. Circuit analyses identified the mCg[->]PrL projections as a predominantly excitatory pathway critical for social behavior. Electrophysiological recordings revealed hypofunction of this circuit in offspring of stressed dams, which was ameliorated by postpartum co-housing with parous females. Together, these findings define a neural circuit linking adolescent psychosocial adversity to impaired maternal caregiving and intergenerational social dysfunction, and highlight social support from experienced mothers as a potent modulator of maternal and offspring behavioral outcomes. Significance StatementAdverse social experiences before motherhood can compromise maternal caregiving and transmit social vulnerability across generations, yet the underlying mechanisms remain poorly understood. Using a mouse model of subtle adolescent social isolation, we demonstrate that even mild isolation selectively impairs postpartum caregiving behaviors while sparing other behavioral domains, resulting in social deficits in adult offspring. We identify the midcingulate-prelimbic cortex circuit as a critical neural substrate mediating these effects and show that social support from experienced mothers during the early postpartum period restores both maternal behavior and offspring social outcomes. Together, these findings define a neural and social mechanism for the intergenerational effects of adolescent psychosocial adversity.

animal behavior and cognition↗

bioRxiv2025

Mammalian Cells Integrate Endoplasmic Reticulum and Nuclear Envelope signals to time mitotic entry

Accurate cell division requires coordination between organelle organization and cell-cycle progression, but how architectural and functional cues from the endoplasmic reticulum (ER) and nuclear envelope (NE)--a continuous membrane network--interface with mitotic control remains unclear. Here, we demonstrate that mammalian cells integrate ER/NE structure and functions to regulate the onset and progression of mitosis. Perturbing ER function with diverse stressors causes a selective delay at the metaphase-anaphase transition, accompanied by defective spindle assembly, chromosome misalignment, and loss of coordinated ER-chromosome organization. Under these conditions, the checkpoint protein MAD1 fails to efficiently dissociate from the NE. ER stress also disrupts microtubule-organizing centers and the centriculum, an ER-derived compartment surrounding centrosomes. Restoring ER structure by expressing the shaping proteins CLIMP63(1-192) or REEP4 rescues spindle organization and mitotic progression. Conversely, transient metaphase arrest induced by partial APC/C inhibition remodels ER morphology independently of stress, and this remodeling is reversed by CLIMP63(1-192). These findings uncover a bidirectional link between ER structure function and the spindle assembly checkpoint, identifying the organelle architecture as an instructive signal that modulates mitotic timing in mammalian cell.

cell biology↗

bioRxiv2025

Decoding the Impact of Lipid Saturation on ER Signaling Networks, ERSU, UPR, and ERAD

The faithful inheritance of a functional endoplasmic reticulum (ER) in Saccharomyces cerevisiae is safeguarded by the ER Stress Surveillance (ERSU) checkpoint, which delays cytokinesis when ER homeostasis is perturbed. Under stress, ER transmission to the daughter cell is halted, while in parallel--but through independent pathways--the Unfolded Protein Response (UPR) restores ER function and ER-associated degradation (ERAD) eliminates misfolded proteins, ultimately allowing cell cycle re-entry. ER stress also transiently stimulates sphingolipid biosynthesis, with the intermediate phytosphingosine (PHS) acting as a key activator of ERSU. Yet, how broader lipid parameters--such as membrane composition, saturation, and fluidity--reshape ER quality control and, in particular, govern ER inheritance during division remains poorly understood. To address this, we employed a tightly controlled experimental system to selectively alter lipid saturation and phospholipid composition while monitoring ER inheritance within the framework of ER homeostasis maintained by UPR and ERAD. Strikingly, we found that perturbations in lipid balance exerted specific effects on ER inheritance that were distinct from their impact on UPR and ERAD. These findings reveal lipid homeostasis as a critical integrator of ER functional regulation, linking ERSU, UPR, and ERAD into a unified adaptive network that ensures robust ER transmission and cellular resilience under stress.

cell biology↗

bioRxiv2025

Cellular mechanism linking endoplasmic reticulum inheritance and cell cycle regulation of the nuclear genome

Endoplasmic reticulum (ER) stress triggers activation of the ER surveillance (ERSU) pathway-- a critical protective mechanism that transiently halts cortical ER inheritance to daughter cells and arrests cytokinesis by septin ring subunit Shs1 re-localization to the bud scar in response to ER stress. Once ER functional homeostasis is re-established, cells resume normal cell cycle progression; however, the molecular circuitry linking ER integrity to cell cycle regulation has remained largely unresolved. Here, we show that ER stress selectively disperse Bud2, a GAP for Bud1/Rsr1, severing its canonical role in cell polarity while integrating it into ER homeostasis signaling. Bud2 dispersion results in accelerated spindle pole body (SPB) duplication, spindle misorientation, defects in nuclear migration, and genome segregation errors under ER stress. Strikingly, a C-terminal truncation of Shs1 (shs1-{Delta}CTD) recapitulated the ER stress-induced dispersion of Bud2 phenotype even in the absence of ER stress, and delayed cell-cycle re-entry after ER homeostasis was regained--despite normal occurrence of typical ERSU hallmark events. Notably, Bud2 overexpression rescued the growth defects of shs1-{Delta}CTD mutants after ER homeostasis was re-established. Collectively, our findings reveal a new mechanistic axis whereby ER integrity coordinates organelle inheritance, cytoskeletal organization, and nuclear division via selective control of Bud2 and Shs1, establishing a direct regulatory bridge between ER status and mitotic fidelity.

cell biology↗

bioRxiv2024

Orchestration of SARS-CoV-2 Nsp4 and host-cell ESCRT proteins induces morphological changes of the endoplasmic reticulum

Upon entry into the host cell, the non-structural proteins 3, 4, and 6 (Nsp3, Nsp 4, and Nsp6) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) facilitate the formation of double- membrane vesicles (DMVs) through extensive rearrangement of the host cell endoplasmic reticulum (ER) to replicate the viral genome and translate viral proteins. To dissect the functional roles of each Nsp and the molecular mechanisms underlying the ER changes, we exploited both yeast S. cerevisiae and human cell experimental systems. Our results demonstrate that Nsp4 alone is sufficient to induce ER structural changes. Nsp4 expression led to robust activation of both the unfolded protein response (UPR) and the ER surveillance (ERSU) cell cycle checkpoint, resulting in cortical ER inheritance block and septin ring mislocalization. Interestingly, these ER morphological changes occurred independently of the canonical UPR and ERSU components but were mediated by the endosomal sorting complex for transport (ESCRT) proteins Vps4 and Vps24 in yeast. Similarly, ER structural changes occurred in human cells upon Nsp4 expression, providing a basis for a minimal experimental system for testing the involvement of human ESCRT proteins and ultimately advancing our understanding of DMV formation.

cell biology↗

bioRxiv2024

Hierarchical emergence of opponent coding in auditory belt cortex

We recorded from neurons in primary auditory cortex (A1) and middle-lateral belt area (ML) while rhesus macaques either discriminated amplitude-modulated noise (AM) from unmodulated noise or passively heard the same stimuli. We used several post-hoc pooling models to investigate the ability of auditory cortex to leverage population coding for AM detection. We find that pooled-response AM detection is better in the active condition than the passive condition, and better using rate-based coding than synchrony-based coding. Neurons can be segregated into two classes based on whether they increase (INC) or decrease (DEC) their firing rate in response to increasing modulation depth. In these samples, A1 had relatively fewer DEC neurons (26%) than ML (45%). When responses were pooled without segregating these classes, AM detection using rate-based coding was much better in A1 than in ML, but when pooling only INC neurons, AM detection in ML approached that found in A1. Pooling only DEC neurons resulted in impaired AM detection in both areas. To investigate the role of DEC neurons, we devised two pooling methods that opposed DEC and INC neurons - a direct subtractive method and a two-pool push-pull opponent method. Only the push-pull opponent method resulted in superior AM detection relative to indiscriminate pooling. In the active condition, the opponent method was superior to pooling only INC neurons during the late portion of the response in ML. These results suggest that the increasing prevalence of the DEC response type in ML can be leveraged by appropriate methods to improve AM detection.

neuroscience↗

bioRxiv2024

FcγR- and CD9-dependent synapse engulfing microglia in the thalamus drives cognitive impairment following cortical brain injury

Various states of microglia appear in neuroinflammation, but their impact on brain function and behavior is not fully understood. Here we report that synapse engulfing microglia in the thalamus are crucial for cognitive impairment after cortical brain injury. Region-specific manipulations of reactive microglia in the chronic phase of injuries showed that microglial changes in the thalamus, but not in the hippocampus, impaired recognition memory. Single-cell RNA-sequencing analysis revealed the enrichment of synapse engulfing microglia in the thalamus, which developed in a CD9-dependent manner and caused synaptic loss and recognition memory deficits. In the thalamus, the blood-brain barrier was disrupted, and extravasated {gamma}-immunoglobulins (IgG) co-localized with synapse engulfing microglia. Fc{gamma} receptor III blockade in the thalamus reduced synapse engulfing microglia, synapse loss, and recognition memory deficits. These findings demonstrate that the induction of synapse engulfing microglia in the thalamus by extravasated IgG/Fc{gamma}RIII and CD9 signals causes recognition memory deficits after cortical brain injury.

immunology↗

bioRxiv2024

Circulating extracellular microRNAs in the blood promote sociability in mice

Extracellular vesicles (EVs) are cell-derived small membrane vesicles and circulate throughout the body, but the impact of circulating EVs on brain function and behavior remains elusive. Here, we report that wild-type (WT) mouse blood, particularly EVs, increases sociability in socially impaired immunodeficient Rag1-/- mice, mimicking the effects of WT T cell transfer. These EVs localized to neurons and regulated PKC{varepsilon} expression, GABAA receptor synaptic localization, and inhibitory postsynaptic signaling in prefrontal cortex (PFC) pyramidal neurons. Injection of Rag1-/- EVs supplemented with miR-23a-3p and miR-103-3p enhanced synaptic function and sociability in Rag1-/- mice. T cells secreted miR-23a-3p via EVs, and Mir23a-/- T cells failed to increase sociability. Similar beneficial effects of WT blood EVs were observed in additional mouse models with sociability deficits, Cntnap2-/- and Shank3-/- mice. These findings uncover a previously unrecognized role of EV miRNAs in mediating immune modulation of synaptic function and social behavior, revealing a novel molecular pathway for immune-neuron communication.

neuroscience↗

bioRxiv2024

Wavelet transform of single-trial vestibular short-latency evoked potential reveals temporary reduction in signal detectability and temporal precision following noise exposure

The vestibular short-latency evoked potential (VsEP) reflects the activity of irregular vestibular afferents and their target neurons in the brain stem. Attenuation of trial-averaged VsEP waveforms is widely accepted as an indicator of vestibular dysfunction, however, more quantitative analyses of VsEP waveforms could reveal underlying neural properties of VsEP waveforms. Here, we present a time-frequency analysis of the VsEP with a wavelet transform on a single-trial basis, which allows us to examine trial-by-trial variability in the strength of VsEP waves as well as their temporal coherence across trials. Using this method, we examined changes in the VsEP following 110 dB SPL noise exposure in rats. We found detectability of head jerks based on the power of wavelet transform coefficients was significantly reduced 1 day after noise exposure but recovered nearly to pre-exposure level in 3 - 7 days and completely by 28 days after exposure. Temporal coherence of VsEP waves across trials was also significantly reduced on 1 day after exposure but recovered with a similar time course. Additionally, we found a significant reduction in the number of calretinin-positive calyces in the sacculi collected 28 days after noise exposure. Furthermore, the number of calretinin-positive calyces was significantly correlated with the degree of reduction in temporal coherence and/or signal detectability of the smallest-amplitude jerks. This new analysis of the VsEP provides more quantitative descriptions of noise-induced changes as well as new insights into potential mechanisms underlying noise-induced vestibular dysfunction. Significance StatementOur study presents a new method of VsEP quantification using wavelet transform on a single-trial basis. It also describes a novel approach to determine the stimulus threshold of the VsEP based on signal-detection theory and Rayleigh statistics. The present analysis could also be applied to analysis of auditory brain stem response (ABR). Thus, it has the potential to provide new insights into the physiological properties that underlie peripheral vestibular and auditory dysfunction.

neuroscience↗

bioRxiv2023

Noise-induced changes in rat head stability and orientation correlate with dysfunction of otolith irregular afferents

Exposure to intense noise damages both the cochlea and vestibular end organs. Our group previously reported attenuated vestibular short-latency evoked potentials (VsEP) and reduced numbers of calretinin-positive (CR+) calyces in the saccule following noise exposure. Here, we examined rats resting head orientation with respect to gravity as well as head stability following a 4-hour exposure to 120 dB SPL noise. We also assessed how behavioral changes are related to changes in VsEP waveforms and calretinin expression in the utricle and saccule to elucidate potential underlying mechanisms. We found significant reductions in the P2N2 and N2P3 amplitudes following noise exposure. The number of CR+ calyces in both saccule and utricle were also significantly reduced. The size of the reduction in N2P3 amplitude was significantly correlated to the number of CR+ calyces. Animals with a greater loss of CR+ calyces in the utricle following noise showed significant decreases in the average speed of y-axis rotational head motion, while those with a fewer loss of CR+ calyces showed significant increases. In addition, animals with larger noise-induced changes in VsEP and CR+ calyces held their heads motionless longer following noise exposure. We hypothesize that noise exposure is inherently destructive to an animals head stability and thereby manifests as an increase in average head speed in mildly to moderately affected animals. But when the damage was large enough, animals exhibited reduced duration and head motion speed as a behavioral adaptation. The noise exposure also significantly altered the pitch angle of head orientation in animals who had the largest reduction in CR+ calyces in the saccule, suggesting that saccular irregular afferents, including those that are CR+, are critical in control of head and body posture.

neuroscience↗

bioRxiv2023

Brefeldin A and M-COPA block the export of RTKs from the endoplasmic reticulum via simultaneous inactivation of ARF1, ARF4, and ARF5

Normal receptor tyrosine kinases (RTKs) need to reach the plasma membrane (PM) for ligand-induced activation, whereas its cancer-causing mutants can be activated before reaching the PM in organelles, such as the Golgi/trans-Golgi network (TGN). Inhibitors of protein export from the endoplasmic reticulum (ER), such as brefeldin A (BFA) and 2-methylcoprophilinamide (M-COPA), can suppress the activation of mutant RTKs in cancer cells, suggesting that RTK mutants cannot initiate signaling in the ER. BFA and M-COPA block the function of ADP-ribosylation factors (ARFs) that play a crucial role in ER-Golgi protein trafficking. However, which ARFs among AFR family proteins are inhibited by BFA or M-COPA, that is, which ARFs are involved in RTKs transport from the ER, remain unclear. In this study, we showed that M-COPA blocked the export of not only KIT but also PDGFRA/EGFR/MET RTKs from the ER. ER-retained RTKs could not fully transduce anti-apoptotic signals, thereby leading to cancer cell apoptosis. Moreover, single knockdown of ARF1, ARF3, ARF4, ARF5, or ARF6 could not block ER export of RTKs, indicating that BFA/M-COPA treatment cannot be mimicked by knockdown of only one ARF member. Interestingly, simultaneous transfection of ARF1, ARF4, and ARF5 siRNAs mirrored the effect of BFA/M-COPA treatment. Consistent with these results, in vitro pulldown assays showed that BFA/M-COPA blocked the function of ARF1, ARF4, and ARF5. Taken together, these results suggest that BFA/M-COPA targets at least ARF1, ARF4, and ARF5; in other words, RTKs require the simultaneous activation of ARF1, ARF4, and ARF5 for their ER export.

cell biology↗

bioRxiv2023

Adolescent stress impairs postpartum social behavior via anterior insula-prelimbic pathway

Adolescent stress can be a risk factor for abnormal social behavior in the postpartum period, which critically affects the safety of mothers and children. Nonetheless, the underlying mechanisms remain unclear. Using a newly established mouse model with optogenetics and in vivo calcium imaging, we found that adolescent psychosocial stress, combined with pregnancy and delivery, caused hypofunction of the glutamatergic pathway from the anterior insula to prelimbic cortex (AI-PrL pathway), which altered PrL neuronal activity, and in turn led to abnormal social behavior. Specifically, the AI-PrL pathway played a crucial role during recognizing the novelty of other mice by modulating "stable neurons" in PrL, which were constantly activated or inhibited by novel mice. We also observed that glucocorticoid receptor signaling in the AI-PrL pathway had a causal role in stress-induced postpartum changes. Our findings provide novel and functional insights into a cortico-cortical pathway underlying adolescent stress-induced postpartum social behavioral deficits.

neuroscience↗

bioRxiv2022

The nuclear GAPDH-HMGB cascade in cortical microglia regulates cognitive flexibility

We report a mechanism that underlies stress-induced cognitive inflexibility at the molecular level. In a mouse model under subacute stress in which deficits in rule shifting tasks were elicited, the nuclear glyceraldehyde dehydrogenase (N-GAPDH) cascade was activated specifically in microglia in the prelimbic cortex. The cognitive deficits were normalized with a pharmacological intervention with a compound (the RR compound) that selectively blocked the initiation of N-GAPDH cascade without affecting glycolytic activity. The normalization was also observed with a microglia-specific genetic intervention targeting the N-GAPDH cascade. Furthermore, hyperactivation of the prelimbic layer 5 excitatory neurons, which are known to be a neuronal substrate of cognitive inflexibility, was also normalized by the pharmacological and microglia-specific genetic interventions. The RR compound may offer a mechanism-driven, translational opportunity against stress-induced cognitive inflexibility. Taken together, we show a pivotal role of cortical microglia and microglia-neuron interaction in stress-induced cognitive inflexibility. We underscore the N-GAPDH cascade in microglia, which causally mediates stress-induced cognitive alteration.

molecular biology↗

bioRxiv2022

Iron regulates contrasting toxicity of uropathogenic Eschericia coli in macrophages and epithelial cells.

By far most urinary tract infections are caused by genetically diverse uropathogenic Escherichia coli (UPEC). Knowledge of the virulence mechanisms of UPEC is critical for drug development, but most studies focus on only a single strain of UPEC. In this study, we compared the virulence mechanisms of four antibiotic-resistant and highly pathogenic UPEC isolates in human blood monocyte-derived macrophages and a bladder epithelial cell (BEC) line: ST999, ST131, ST1981 and ST95. We found that while non-pathogenic E. coli strains are efficiently killed by macrophages in bactericidal single membrane vacuoles, the UPEC strains survive within double-membrane vacuoles. On side-by-side comparison, we found that whereas ST999 only carries Fe3+ importers, ST95 carries both Fe2+ and Fe3+ importers and the toxins haemolysin and colibactin. Moreover, we found that ST999 grows in the Fe3+ rich vacuoles of BECs and macrophages with concomitant increased expression of haem receptor chuA and the hydrogen peroxide sensor oxyR. In contrast, ST95 produces toxins in iron-depleted conditions similar to that of the urinary tract. Whereas ST95 also persist in the iron rich vacuoles of BECs, it produces colibactin in response to low Fe3+ contributing to macrophage death. Thus, iron regulates the contrasting toxicities of UPEC strains in macrophages and bladder epithelial cells due to low and high labile iron concentrations, respectively. Key findingsO_LIAntibiotics resistant uropathogenic E. coli strains ST999, ST131, ST1981, and ST95 survive within spacious double membrane vacuoles. Non-pathogenic E. coli strains XL1 blue and MG1655 are cleared in single membrane vacuoles in macrophages. C_LIO_LIST999 lacks Fe2+ importer and toxins, and grows in iron rich vacuoles of macrophages and bladder epithelial cells. C_LIO_LIST95 carries both Fe2+ and Fe3+ importers and grows in iron low conditions. C_LIO_LIST95 expresses toxins and induces cell death of infected macrophages, but not of bladder epithelial cells. C_LIO_LIBladder epithelial cells have a higher pool of labile iron than macrophages. Differential expression of virulence factors by ST999 and ST95 in bladder epithelial cells and macrophages is dependent on iron concentration. C_LI

immunology↗

bioRxiv2022

A Role for Nup153 in Nuclear Assembly Reveals Differential Requirements for Targeting of Nuclear Envelope Constituents

Assembly of the nucleus following mitosis requires rapid and coordinate recruitment of diverse constituents to the inner nuclear membrane. We have identified an unexpected role for the nucleoporin Nup153 in promoting the continued addition of a subset of nuclear envelope proteins during initial expansion of nascent nuclei. Specifically, disrupting the function of Nup153 interferes with ongoing addition of B-type lamins, lamin B receptor (LBR), and SUN1 early in telophase, after the nuclear envelope (NE) has initially enclosed chromatin. In contrast, effects on lamin A and SUN2 were minimal, pointing to differential requirements for the ongoing targeting of nuclear envelope proteins. Further, distinct mis-targeting phenotypes arose among the proteins that require Nup153 for NE targeting. Thus, disrupting the function of Nup153 in nuclear formation reveals several previously undescribed features important for establishing nuclear architecture: 1) a role for a nuclear basket constituent in ongoing recruitment of nuclear envelope components, 2) two functionally separable phases of nuclear envelope formation in mammalian cells, and 3) distinct requirements of individual nuclear envelope residents for continued targeting during the expansion phase of NE reformation.

cell biology↗

bioRxiv2021

The miR-124-AMPAR pathway connects polygenic risks with behavioral changes shared between schizophrenia and bipolar disorder

Schizophrenia (SZ) and bipolar disorder (BP) are highly heritable major psychiatric disorders that share a substantial portion of genetic risk as well as their clinical manifestations. This raises a fundamental question of whether, and how, common neurobiological pathways translate their shared polygenic risks into shared clinical manifestations. The present study shows the miR-124-AMPAR pathway as a key common neurobiological mediator that connects polygenic risks with behavioral changes shared between these two psychotic disorders. We discovered upregulation of miR-124 in biopsied neuronal cells and postmortem prefrontal cortex from both SZ and BP patients, implying its role not only as a biomarker, but also as a pathophysiological mediator. Intriguingly, the upregulation is associated with the polygenic risks shared between these two disorders. Seeking mechanistic dissection, we generated a mouse model that upregulates miR-124 in the medial prefrontal cortex, which includes brain regions homologous to sub-regions of the human prefrontal cortex. We demonstrated that upregulation of miR-124 increases GRIA2-lacking calcium permeable-AMPARs and perturbs AMPAR-mediated excitatory synaptic transmission, leading to deficits in the behavioral dimensions shared between SZ and BP.

neuroscience↗

bioRxiv2021

Early life stress-induced vulnerability to postpartum mental disturbance: prolonged dysregulation of the HPA axis and behavior

Stress during childhood and adolescence increases the risk for postpartum depression (PPD). Patients with depression who have experienced adverse life events tend to be treatment refractory. However, the mechanism by which stress during childhood and adolescence are involved in the pathophysiology of PPD remains unclear. We investigated the longitudinal effects of adolescent stress on the hypothalamic-pituitary-adrenal (HPA) axis and behaviors in the postpartum period through mouse and human studies. We observed that adolescent social isolation caused an aberrantly sustained elevation of glucocorticoids via dysregulation of the HPA axis, leading to long-lasting postpartum behavioral changes in female mice. The postpartum behavioral changes elicited by this adolescent stress were not ameliorated by the medicines currently used for PPD treatment. However, a post-delivery treatment with a glucocorticoid receptor antagonist effectively ameliorated the behavioral changes in mice. We also demonstrated a significant impact of stress during childhood and adolescence on the HPA axis dysregulation and PPD in women. We provide experimental evidence that suggests a mechanism-driven therapeutic strategy (repurposing a GR antagonist) for at least some cases of treatment refractory PPD.

molecular biology↗