Postpartum loneliness predicts future depressive symptoms: a nationwide Japanese longitudinal study.

PURPOSE: The COVID-19 pandemic has intensified feelings of loneliness, especially among postpartum women. This nationwide Japanese longitudinal study assessed the impact of such feelings on depressive symptoms and mother-to-infant bonding difficulties (MIBD), two pivotal determinants of maternal and infant well-being. METHODS: Starting with a baseline survey conducted between July and August 2021, we tracked 1254 postpartum Japanese women who initially reported minimal depressive symptoms (i.e., Edinburgh Postnatal Depression Scale < 9) and MIBD (i.e., Mother-to-Infant Bonding Scale < 5), over a follow-up period of approximately 6 months. Baseline loneliness was evaluated with the UCLA Loneliness Scale Short-Form (UCLA-LS3-SF3). RESULTS: Forty-nine percent of the sample reported the presence of baseline feelings of loneliness. After propensity score matching on sociodemographics and various pregnancy, childbirth, and COVID-19-related aspects, baseline loneliness was associated with increased risks of later depressive symptoms but not MIBD. Using restricted cubic spline logistic regression and considering loneliness as a continuous variable, we found a positive increasing quadratic relationship with depressive symptoms. As loneliness increased, so did the risk of later depressive symptoms. However, there was no significant association between loneliness and MIBD. These results were confirmed through a sensitivity analysis using inverse probability weighting to address attrition bias. CONCLUSION: Feelings of postpartum loneliness are associated with future risks of depressive symptoms. The data suggests that addressing loneliness in postpartum women early is crucial to safeguarding their well-being and that of their infants.

Toward a computational understanding of how reminiscing about positive autobiographical memories influences decision-making under risk.

Recent computational psychiatric research has dissected decision-making under risk into different underlying cognitive computational constructs and identified disease-specific changes in these constructs. Studies are underway to investigate what kind of behavioral or psychological interventions can restore these cognitive, computational constructs. In our previous study, we showed that reminiscing about positive autobiographical memories reduced risk aversion and affected probability weighting in the opposite direction from that observed in psychiatric disorders. However, in that study, we compared positive versus neutral memory retrieval by using a within-subjects crossover posttest design. Therefore, the change of decision-making from baseline is unclear. Furthermore, we used a hypothetical decision-making task and did not include monetary incentives. We attempt to address these limitations and investigated how reminiscing about positive autobiographical memories influences decision-making under risk using a between-subjects pretest posttest comparison design with performance-contingent monetary incentives. In thirty-eight healthy, young adults, we found that reminiscing about positive memories reinforced the commonly observed inverted S-shaped nonlinear probability weighting (f = 0.345, medium to large in effect size). In contrast, reminiscing about positive memories did not affect risk aversion in general. Given that the change in probability weighting after reminiscing about positive memories is in the opposite direction from that observed in psychiatric disorders, our results indicate that positive autobiographical memory retrieval might be a useful behavioral intervention strategy for amending the altered decision-making under risk in psychiatric diseases.

The effect of positive autobiographical memory retrieval on decision-making under risk: A computational model-based analysis.

Psychiatric disorders such as depressive and anxiety disorders are associated with altered decision-making under risk. Recent advances in neuroeconomics and computational psychiatry have further discomposed risk-based decision-making into distinct cognitive computational constructs and showed that there may be disorder-specific alterations in these constructs. As a result, it has been suggested these cognitive computational constructs may serve as useful behavioral biomarkers for these disorders. However, to date, little is known about what psychological or behavioral interventions can help to reverse and manage the altered cognitive computational constructs underlying risk-based decision-making. In the present study, we set out to investigate whether recalling positive autobiographical memories may affect risk-based decision-making in healthy volunteers using a description-based task. Specifically, based on theories of behavioral economics, we dissected risk preference into two cognitive computational constructs, utility sensitivity and probability weighting. We found that compared to recalling neutral memories, retrieving positive autobiographical memories increased utility sensitivity (Cohen's d = 0.447), indicating reduced risk aversion. Meanwhile, we also tested the influence of memory retrieval on probability weighting, the effect, however, was unreliable and requires further in-depth investigation. Of clinical relevance, the change in risk aversion after recalling positive memories was in the opposite direction compared to those reported in psychiatric disorders. These results argue for the potential therapeutic effect of positive autobiographical memory retrieval for the amendment of altered risk-based decision-making in psychiatric disorders.

Computational markers of experience- but not description-based decision-making are associated with future depressive symptoms in young adults.

BACKGROUND: Early prediction of high depressive symptoms is crucial for selective intervention and the minimization of functional impairment. Recent cross-sectional studies indicated decision-making deficits in depression, which may be an important contributor to the disorder. Our goal was to test whether description- and experience-based decision making, two major neuroeconomic paradigms of decision-making under uncertainty, predict future depressive symptoms in young adults. METHODS: One hundred young adults performed two decision-making tasks, one description-based, in which subjects chose between two gambling options given explicitly stated rewards and their probabilities, and the other experience-based, in which subjects were shown rewards but had to learn the probability of those rewards (or cue-outcome contingencies) via trial-and-error experience. We evaluated subjects' depressive symptoms with BDI-II at baseline (T1) and half a year later (T2). RESULTS: Comparing subjects with low versus high levels of depressive symptoms at T2 showed that the latter performed worse on the experience- but not description-based task at T1. Computational modeling of the decision-making process suggested that subjects with high levels of depressive symptoms had a more concave utility function, indicating enhanced risk aversion. Furthermore, a more concave utility function at T1 increased the odds of high depressive symptoms at T2, even after controlling depressive symptoms at T1, perceived stress at T2, and several covariates (OR = 0.251, 95% CI [0.085, 0.741]). CONCLUSIONS: This is the first study to demonstrate a prospective link between experience-based decision-making and depressive symptoms. Our results suggest that enhanced risk aversion in experience-based decision-making may be an important contributor to the development of depressive symptoms.

Nonlinear Probability Weighting in Depression and Anxiety: Insights From Healthy Young Adults.

Both depressive and anxiety disorders have been associated with excessive risk avoidant behaviors, which are considered an important contributor to the maintenance and recurrence of these disorders. However, given the high comorbidity between the two disorders, their independent association with risk preference remains unclear. Furthermore, due to the involvement of multiple cognitive computational factors in the decision-making tasks employed so far, the precise underlying mechanisms of risk preference are unknown. In the present study, we set out to investigate the common versus unique cognitive computational mechanisms of risk preference in depression and anxiety using a reward-based decision-making task and computational modeling based on economic theories. Specifically, in model-based analysis, we decomposed risk preference into utility sensitivity (a power function) and probability weighting (the one-parameter Prelec weighting function). Multiple linear regression incorporating depression (BDI-II) and anxiety (STAI state anxiety) simultaneously indicated that only depression was associated with one such risk preference parameter, probability weighting. As the symptoms of depression increased, subjects' tendency to overweight small probabilities and underweight large probabilities decreased. Neither depression nor anxiety was associated with utility sensitivity. These associations remained even after controlling covariates or excluding anxiety-relevant items from the depression scale. To our knowledge, this is the first study to assess risk preference due to a concave utility function and nonlinear probability weighting separately for depression and anxiety using computational modeling. Our results provide a mechanistic account of risk avoidance and may improve our understanding of decision-making deficits in depression and anxiety.

Regular Vigorous-Intensity Physical Activity and Walking Are Associated with Divergent but not Convergent Thinking in Japanese Young Adults.

The beneficial effects of regular physical activity (PA) on cognitive functions have received much attention. Recent research suggests that regular PA may also enhance creative thinking, an indispensable cognitive factor for invention and innovation. However, at what intensity regular PA brings the most benefits to creative thinking remains uninvestigated. Furthermore, whether the levels of regular PA affect the acute PA effects on creative thinking is also unclear. In the present study, using a previous dataset that investigated the effects of an acute bout of aerobic exercise on creative thinking in healthy Japanese young adults (22.98 ± 1.95 years old) in the year 2020, we tested the association between different intensities of regular PA (i.e., vigorous, moderate, and walking) and creative thinking with the cross-sectional baseline data using multiple linear regression. We also investigated whether regular PA levels were associated with the acute aerobic exercise intervention effects on creative thinking. The results showed that cross-sectionally, the regular PAs were differentially associated with divergent but not convergent thinking. Specifically, whereas the amount of vigorous-intensity PA was positively associated with fluency and flexibility, the amount of walking was positively associated with novelty on the alternate uses test (AUT) measuring divergent thinking. Importantly, the explained variances of fluency, flexibility, and novelty were 20.3% (p = 0.040), 18.8% (p = 0.055), and 20.1% (p = 0.043), respectively. None of the regular PAs predicted convergent thinking (i.e., an insight problem-solving task), nor were they associated with the acute aerobic exercise intervention effects on divergent and convergent thinking. These findings suggest that engaging in regular vigorous-intensity PA and walking may be useful strategies to enhance different aspects of divergent thinking in daily life.

Sex difference in the weighting of expected uncertainty under chronic stress.

The neurobiological literature implicates chronic stress induced decision-making deficits as a major contributor to depression and anxiety. Given that females are twice as likely to suffer from these disorders, we hypothesized the existence of sex difference in the effects of chronic stress on decision-making. Here employing a decision-making paradigm that relies on reinforcement learning of probabilistic predictive relationships, we show female volunteers with a high level of perceived stress in the past month are more likely to make suboptimal choices than males. Computational characterizations of this sex difference suggest that while under high stress, females and males differ in their weighting but not learning of the expected uncertainty in the predictive relationships. These findings provide a mechanistic account of the sex difference in decision-making under chronic stress and may have important implications for the epidemiology of sex difference in depression and anxiety.

Affinity Improvement of a Cancer-Targeted Antibody through Alanine-Induced Adjustment of Antigen-Antibody Interface.

To investigate favorable single amino acid substitutions that improve antigen-antibody interactions, alanine (Ala) mutagenesis scanning of the interfacial residues of a cancer-targeted antibody, B5209B, was performed based on X-ray crystallography analysis. Two substitutions were shown to significantly enhance the binding affinity for the antigen, by up to 30-fold. One substitution improved the affinity by a gain of binding enthalpy, whereas the other substitution improved the affinity by a gain of binding entropy. Molecular dynamics simulations showed that the enthalpic improvement could be attributed to the stabilization of distant salt bridges located at the periphery of the antigen-antibody interface. The entropic improvement was due to the release of water molecules that were stably trapped in the antigen-antibody interface of the wild-type antibody. Importantly, these effects of the Ala substitutions were caused by subtle adjustments of the binding interface. These results will be helpful to design high-affinity antibodies with avoiding entropy-enthalpy compensation.

GABAergic inhibition reduces the impact of synaptic excitation on somatic excitation.

The effect of excitatory synaptic input on the excitation of the cell body is believed to vary depending on where and when the synaptic activation occurs in dendritic trees and the spatiotemporal modulation by inhibitory synaptic input. However, few studies have examined how individual synaptic inputs influence the excitability of the cell body in spontaneously active neuronal networks mainly because of the lack of an appropriate method. We developed a calcium imaging technique that monitors synaptic inputs to hundreds of spines from a single neuron with millisecond resolution in combination with whole-cell patch-clamp recordings of somatic excitation. In rat hippocampal CA3 pyramidal neurons ex vivo, a fraction of the excitatory synaptic inputs were not detectable in the cell body against background noise. These synaptic inputs partially restored their somatic impact when a GABAA receptor blocker was intracellularly perfused. Thus, GABAergic inhibition reduces the influence of some excitatory synaptic inputs on the somatic excitability. Numerical simulation using a single neuron model demonstrates that the timing and locus of a dendritic GABAergic input are critical to exert this effect. Moreover, logistic regression analyses suggest that the GABAergic inputs sectionalize spine activity; that is, only some subsets of synchronous synaptic activity seemed to be preferably passed to the cell body. Thus, dendrites actively sift inputs from specific presynaptic cell assemblies.

A Case of Adenomyoepithelioma of the Breast Showing Strong Uptake of 18 F-Fluorodeoxyglucose on a Positron Emission Tomography.

An adenomyoepithelioma of the breast is a rare tumor characterized by biphasic proliferation of both epithelial and myoepithelial cells. This tumor is generally considered as a benign neoplasm, and there are few reports describing the imaging features of this tumor through 18 F-fluorodeoxyglucose positron emission tomography (FDG-PET). Here, we report a case of an adenomyoepithelioma that showed strong uptake of FDG on PET similar to that observed with a malignant tumor. A 73-year-old woman presented to our hospital with a 3.5-cm, mobile, and elastic hard tumor in the upper area of the left breast. Although the findings of mammography, ultrasonography, and contrast-enhanced magnetic resonance imaging suggested that the tumor was malignant, it was diagnosed as an adenomyoepithelioma by core needle biopsy. An invasive ductal carcinoma, 0.5-cm in size, was detected in the medial upper area of the ipsilateral breast during an examination. Although FDG-PET demonstrated no lymph node or distant metastases from the invasive ductal carcinoma, strong uptake of FDG was detected in the adenomyoepithelioma. Breast conserving surgery and sentinel lymph node biopsy for the invasive ductal carcinoma together with resection of the adenomyoepithelioma was performed. A diagnosis of adenomyoepithelioma was confirmed through histologic examination of the resected specimen. This case indicates that some adenomyoepitheliomas may show a strong uptake of FDG on PET, which resembles a malignant tumor.

Prdm16 is crucial for progression of the multipolar phase during neural differentiation of the developing neocortex.

The precise control of neuronal migration and morphological changes during differentiation is essential for neocortical development. We hypothesized that the transition of progenitors through progressive stages of differentiation involves dynamic changes in levels of mitochondrial reactive oxygen species (mtROS), depending on cell requirements. We found that progenitors had higher levels of mtROS, but that these levels were significantly decreased with differentiation. The Prdm16 gene was identified as a candidate modulator of mtROS using microarray analysis, and was specifically expressed by progenitors in the ventricular zone. However, Prdm16 expression declined during the transition into NeuroD1-positive multipolar cells. Subsequently, repression of Prdm16 expression by NeuroD1 on the periphery of ventricular zone was crucial for appropriate progression of the multipolar phase and was required for normal cellular development. Furthermore, time-lapse imaging experiments revealed abnormal migration and morphological changes in Prdm16-overexpressing and -knockdown cells. Reporter assays and mtROS determinations demonstrated that PGC1α is a major downstream effector of Prdm16 and NeuroD1, and is required for regulation of the multipolar phase and characteristic modes of migration. Taken together, these data suggest that Prdm16 plays an important role in dynamic cellular redox changes in developing neocortex during neural differentiation.

Ubiquitination of Lysine 867 of the Human SETDB1 Protein Upregulates Its Histone H3 Lysine 9 (H3K9) Methyltransferase Activity.

Posttranslational modifications (PTMs) of proteins play a crucial role in regulating protein-protein interactions, enzyme activity, subcellular localization, and stability of the protein. SET domain, bifurcated 1 (SETDB1) is a histone methyltransferase that regulates the methylation of histone H3 on lysine 9 (H3K9), gene silencing, and transcriptional repression. The C-terminal region of SETDB1 is a key site for PTMs, and is essential for its enzyme activity in mammalian and insect cells. In this study, we aimed to evaluate more precisely the effect of PTMs on the H3K9 methyltransferase activity of SETDB1. Using mass spectrometry analysis, we show that the C-terminal region of human SETDB1 purified from insect cells is ubiquitinated. We also demonstrate that the ubiquitination of lysine 867 of the human SETDB1 is necessary for full H3K9 methyltransferase activity in mammalian cells. Finally, we show that SETDB1 ubiquitination regulates the expression of its target gene, serpin peptidase inhibitor, clade E, member 1 (SERPINE1) by methylating H3K9. These results suggest that the ubiquitination of SETDB1 at lysine 867 controls the expression of its target gene by activating its H3K9 methyltransferase activity.

Similarity in Neuronal Firing Regimes across Mammalian Species.

UNLABELLED: The architectonic subdivisions of the brain are believed to be functional modules, each processing parts of global functions. Previously, we showed that neurons in different regions operate in different firing regimes in monkeys. It is possible that firing regimes reflect differences in underlying information processing, and consequently the firing regimes in homologous regions across animal species might be similar. We analyzed neuronal spike trains recorded from behaving mice, rats, cats, and monkeys. The firing regularity differed systematically, with differences across regions in one species being greater than the differences in similar areas across species. Neuronal firing was consistently most regular in motor areas, nearly random in visual and prefrontal/medial prefrontal cortical areas, and bursting in the hippocampus in all animals examined. This suggests that firing regularity (or irregularity) plays a key role in neural computation in each functional subdivision, depending on the types of information being carried. SIGNIFICANCE STATEMENT: By analyzing neuronal spike trains recorded from mice, rats, cats, and monkeys, we found that different brain regions have intrinsically different firing regimes that are more similar in homologous areas across species than across areas in one species. Because different regions in the brain are specialized for different functions, the present finding suggests that the different activity regimes of neurons are important for supporting different functions, so that appropriate neuronal codes can be used for different modalities.

Analysis of the subcellular localization of the human histone methyltransferase SETDB1.

SET domain, bifurcated 1 (SETDB1) is a histone methyltransferase that methylates lysine 9 on histone H3. Although it is important to know the localization of proteins to elucidate their physiological function, little is known of the subcellular localization of human SETDB1. In the present study, to investigate the subcellular localization of hSETDB1, we established a human cell line constitutively expressing enhanced green fluorescent protein fused to hSETDB1. We then generated a monoclonal antibody against the hSETDB1 protein. Expression of both exogenous and endogenous hSETDB1 was observed mainly in the cytoplasm of various human cell lines. Combined treatment with the nuclear export inhibitor leptomycin B and the proteasome inhibitor MG132 led to the accumulation of hSETDB1 in the nucleus. These findings suggest that hSETDB1, localized in the nucleus, might undergo degradation by the proteasome and be exported to the cytosol, resulting in its detection mainly in the cytosol.

MicroRNA-153 Regulates the Acquisition of Gliogenic Competence by Neural Stem Cells.

Mammalian neural stem/progenitor cells (NSPCs) sequentially generate neurons and glia during CNS development. Here we identified miRNA-153 (miR-153) as a modulator of the temporal regulation of NSPC differentiation. Overexpression (OE) of miR-153 delayed the onset of astrogliogenesis and maintained NSPCs in an undifferentiated state in vitro and in the developing cortex. The transcription factors nuclear factor I (NFI) A and B, essential regulators of the initiation of gliogenesis, were found to be targets of miR-153. Inhibition of miR-153 in early neurogenic NSPCs induced precocious gliogenesis, whereas NFIA/B overexpression rescued the anti-gliogenic phenotypes induced by miR-153 OE. Our results indicate that miR-mediated fine control of NFIA/B expression is important in the molecular networks that regulate the acquisition of gliogenic competence by NSPCs in the developing CNS.

Chemical corrector treatment ameliorates increased seizure susceptibility in a mouse model of familial epilepsy.

Epilepsy is one of the most common and intractable brain disorders. Mutations in the human gene LGI1, encoding a neuronal secreted protein, cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). However, the pathogenic mechanisms of LGI1 mutations remain unclear. We classified 22 reported LGI1 missense mutations as either secretion defective or secretion competent, and we generated and analyzed two mouse models of ADLTE encoding mutant proteins representative of the two groups. The secretion-defective LGI1(E383A) protein was recognized by the ER quality-control machinery and prematurely degraded, whereas the secretable LGI1(S473L) protein abnormally dimerized and was selectively defective in binding to one of its receptors, ADAM22. Both mutations caused a loss of function, compromising intracellular trafficking or ligand activity of LGI1 and converging on reduced synaptic LGI1-ADAM22 interaction. A chemical corrector, 4-phenylbutyrate (4PBA), restored LGI1(E383A) folding and binding to ADAM22 and ameliorated the increased seizure susceptibility of the LGI1(E383A) model mice. This study establishes LGI1-related epilepsy as a conformational disease and suggests new therapeutic options for human epilepsy.

Structural features of interfacial tyrosine residue in ROBO1 fibronectin domain-antibody complex: Crystallographic, thermodynamic, and molecular dynamic analyses.

ROBO1, fibronectin Type-III domain (Fn)-containing protein, is a novel immunotherapeutic target for hepatocellular carcinoma in humans. The crystal structure of the antigen-binding fragment (Fab) of B2212A, the monoclonal antibody against the third Fn domain (Fn3) of ROBO1, was determined in pursuit of antibody drug for hepatocellular carcinoma. This effort was conducted in the presence or absence of the antigen, with the chemical features being investigated by determining the affinity of the antibody using molecular dynamics (MD) and thermodynamics. The structural comparison of B2212A Fab between the complex and the free form revealed that the interfacial Tyr(L) 50 (superscripts L, H, and F stand for the residues in the light chain, heavy chain, and Fn3, respectively) played important roles in Fn3 recognition. That is, the aromatic ring of Tyr(L) 50 pivoted toward Phe(F) 68, forming a CH/π interaction and a new hydrogen bond with the carbonyl O atom of Phe(F) 68. MD simulations predicted that the Tyr(L) 50-Phe(F) 68 interaction almost entirely dominated Fab-Fn3 binding, and Ala-substitution of Tyr(L) 50 led to a reduced binding of the resultant complex. On the contrary, isothermal titration calorimetry experiments underscored that Ala-substitution of Tyr(L) 50 caused an increase of the binding enthalpy between B2212A and Fn3, but importantly, it induced an increase of the binding entropy, resulting in a suppression of loss in the Gibbs free energy in total. These results suggest that mutation analysis considering the binding entropy as well as the binding enthalpy will aid in the development of novel antibody drugs for hepatocellular carcinoma.