German Parents and Educators of Two to Four-Year-Old Children as Informants for the Strengths and Difficulties Questionnaire (SDQ).

Screeners are used in early intervention and early childhood education and care programs to identify children's potential need for further evaluation and diagnostics. The Strengths and Difficulties Questionnaire (SDQ) is a brief behavioral screening instrument that can be completed by both parents and educators to assess the social and emotional traits of children. However, multiple informants' reports vary. In this study, the extent to which parents' (n = 241) and educators' (n = 157) differ and agree in their assessments of children aged 3.5 years on average, was examined. T-tests were used to examine differences between informants and correlations within a multitrait-multimethod matrix (MTMM) in their agreement. Results showed moderate to high levels of rater agreement ranging from r = .35 and r = .53 on the five subscales of the SDQ. We found that hyperactivity, peer relationship problems, and prosocial behavior vary due to meaningful reasons, e.g., the home vs. pre-school setting, and the informant's relationship towards the child. Hyperactivity seems to be relatively consistent across settings. Methodological variations might explain differences in emotional symptoms and conduct problems. Considering ratings from multiple informants outlines a more comprehensive view of children's behavior and should be preferred over single-informant research designs.

The effects of virtual reality and stress ball distraction on procedure-related emotional appearance, pain, fear, and anxiety during phlebotomy in children: A randomized controlled study.

BACKGROUND: Virtual reality (VR) and stress balls can be used during phlebotomy in school-age children. OBJECTIVES: This randomized controlled study was conducted to evaluate the effect of distraction methods using VR and stress balls on the emotional behavior, pain, fear, and anxiety associated with phlebotomy in children aged 7-12. METHODS: A parallel trial with a three-arm design approach was adopted for this randomized controlled trial, guided by the CONSORT checklist. The study sample (n = 150) was divided into VR, stress ball, and control group using stratified randomization. The mean scores obtained from the Children's Emotional Manifestation Scale, Wong-Baker FACES Pain Rating Scale, Child Anxiety Scale-State, and Child Fear Scale were compared between the groups. Linear regression analysis and correlation analysis were performed. RESULTS: Significant differences were found in phlebotomy-related pain, fear, and anxiety. While there was no difference in emotional behavior before the phlebotomy, a significant difference was found after the phlebotomy. Being in the virtual reality group explained 30.8 % of the difference between the before and after phlebotomy-related-emotional behavior scores. A strong, positive, and significant relationship was found between emotional behavior scores after phlebotomy and phlebotomy-related fear, pain, and anxiety scores (p < .01). CONCLUSION: Virtual reality and stress ball distraction were found to be effective in reducing pain, fear, and anxiety during phlebotomy. Virtual reality distraction is effective in reducing negative emotional behaviors. APPLICATION TO PRACTICE: The VR distraction can be used in the pediatric population in pain, fear, anxiety, and emotional behavior management during phlebotomy. CLINICALTRIALS: gov Identifier: NCT05818761.

Comparative study on emotional behavior and parental job stress of only-child and non-only-child preschool children.

BACKGROUND: Studies have revealed that Children's psychological, behavioral, and emotional problems are easily influenced by the family environment. In recent years, the family structure in China has undergone significant changes, with more families having two or three children. AIM: To explore the relationship between emotional behavior and parental job stress in only preschool and non-only preschool children. METHODS: Children aged 3-6 in kindergartens in four main urban areas of Shijiazhuang were selected by stratified sampling for a questionnaire and divided into only and non-only child groups. Their emotional behaviors and parental pressure were compared. Only and non-only children were paired in a 1:1 ratio by class and age (difference less than or equal to 6 months), and the matched data were compared. The relationship between children's emotional behavior and parents' job stress before and after matching was analyzed. RESULTS: Before matching, the mother's occupation, children's personality characteristics, and children's rearing patterns differed between the groups (P < 0.05). After matching 550 pairs, differences in the children's parenting styles remained. There were significant differences in children's gender and parents' attitudes toward children between the two groups. The Strengths and Difficulties Questionnaire (SDQ) scores of children in the only child group and the Parenting Stress Index-Short Form (PSI-SF) scores of parents were significantly lower than those in the non-only child group (P < 0.05). Pearson's correlation analysis showed that after matching, there was a positive correlation between children's parenting style and parents' attitudes toward their children (r = 0.096, P < 0.01), and the PSI-SF score was positively correlated with children's gender, parents' attitudes toward their children, and SDQ scores (r = 0.077, 0.193, 0.172, 0.222). CONCLUSION: Preschool children's emotional behavior and parental pressure were significantly higher in multi-child families. Parental pressure in differently structured families was associated with many factors, and preschool children's emotional behavior was positively correlated with parental pressure.

Neuromodulator regulation and emotions: insights from the crosstalk of cell signaling.

The unraveling of the regulatory mechanisms that govern neuronal excitability is a major challenge for neuroscientists worldwide. Neurotransmitters play a critical role in maintaining the balance between excitatory and inhibitory activity in the brain. The balance controls cognitive functions and emotional responses. Glutamate and γ-aminobutyric acid (GABA) are the primary excitatory and inhibitory neurotransmitters of the brain, respectively. Disruptions in the balance between excitatory and inhibitory transmission are implicated in several psychiatric disorders, including anxiety disorders, depression, and schizophrenia. Neuromodulators such as dopamine and acetylcholine control cognition and emotion by regulating the excitatory/inhibitory balance initiated by glutamate and GABA. Dopamine is closely associated with reward-related behaviors, while acetylcholine plays a role in aversive and attentional behaviors. Although the physiological roles of neuromodulators have been extensively studied neuroanatomically and electrophysiologically, few researchers have explored the interplay between neuronal excitability and cell signaling and the resulting impact on emotion regulation. This review provides an in-depth understanding of "cell signaling crosstalk" in the context of neuronal excitability and emotion regulation. It also anticipates that the next generation of neurochemical analyses, facilitated by integrated phosphorylation studies, will shed more light on this topic.

Daytime aspartame intake results in larger influences on body weight, serum corticosterone level, serum/cerebral cytokines levels and depressive-like behaviors in mice than nighttime intake.

Aspartame (APM) is one of the most widely used artificial sweeteners worldwide. Studies have revealed that consuming APM may negatively affect the body, causing oxidative stress damage to multiple organs and leading to various neurophysiological symptoms. However, it's still unclear if consuming APM and one's daily biological rhythm have an interactive effect on health. In this study, healthy adult C57BL/6 mice were randomly divided into four groups: Control group (CON), oral gavage sham group (OGS), daytime APM intragastric group (DAI) and nighttime APM intragastric group (NAI). DAI and NAI groups were given 80 mg/kg body weight daily for 4 weeks. We found that DAI and NAI groups had significantly increased mean body weight, higher serum corticosterone levels, up-regulated pro-inflammatory responses in serum and brain, and exacerbated depressive-like behaviors than the CON and the two APM intake groups. Moreover, all these changes induced by APM intake were more significant in the DAI group than in the NAI group. The present study, for the first time, revealed that the intake of APM and daily biological rhythm have an interactive effect on health. This suggests that more attention should be paid to the timing of APM intake in human beings, and this study also provides an intriguing clue to the circadian rhythms of experimental animals that researchers should consider more when conducting animal experiments.

Intestinal gluconeogenesis: A translator of nutritional information needed for glycemic and emotional balance.

At the interface between the outside world and the self, the intestine is the first organ receiving nutritional information. One intestinal function, gluconeogenesis, is activated by various nutrients, particularly diets enriched in fiber or protein, and thus results in glucose production in the portal vein in the post-absorptive period. The detection of portal glucose induces a nervous signal controlling the activity of the central nuclei involved in the regulation of metabolism and emotional behavior. Induction of intestinal gluconeogenesis is necessary for the beneficial effects of fiber or protein-enriched diets on metabolism and emotional behavior. Through its ability to translate nutritional information from the diet to the brain's regulatory centers, intestinal gluconeogenesis plays an essential role in maintaining physiological balance.

Resveratrol Reduces Neuroinflammation and Hippocampal Microglia Activation and Protects Against Impairment of Memory and Anxiety-Like Behavior in Experimental Cerebral Palsy.

Cerebral palsy (CP) is a neurodevelopmental disorder characterized by motor and postural impairments. However, early brain injury can promote deleterious effects on the hippocampus, impairing memory. This study aims to investigate the effects of resveratrol treatment on memory, anxiety-like behavior, and neuroinflammation markers in rats with CP. Male Wistar rats were subjected to perinatal anoxia (P0-P1) and sensory-motor restriction (P2-P28). They were treated with resveratrol (10 mg/kg, 0.1 ml/100 g) or saline from P3-P21, being divided into four experimental groups: CS (n = 15), CR (n = 15), CPS (n = 15), and CPR (n = 15). They were evaluated in the tests of novel object recognition (NORT), T-Maze, Light-Dark Box (LDB), and Elevated Plus Maze (EPM). Compared to the CS group, the CPS group has demonstrated a reduced discrimination index on the NORT (p < 0.0001) and alternation on the T-Maze (p < 0.01). In addition, the CPS group showed an increase in permanence time on the dark side in LDB (p < 0.0001) and on the close arms of the EPM (p < 0.001). The CPR group demonstrated an increase in the object discrimination index (p < 0.001), on the alternation (p < 0.001), on the permanence time on the light side (p < 0.0001), and on the open arms (p < 0.001). The CPR group showed a reduction in gene expression of IL-6 (p = 0.0175) and TNF-α (p = 0.0007) and an increase in Creb-1 levels (p = 0.0020). The CPS group showed an increase in the activated microglia and a reduction in cell proliferation in the hippocampus, while CPR animals showed a reduction of activated microglia and an increase in cell proliferation. These results demonstrate promising effects of resveratrol in cerebral palsy behavior impairment through reduced neuroinflammation in the hippocampus.

Family function and emotional behavior problems in Chinese children and adolescents: A moderated mediation model.

BACKGROUND: Studies have shown that family function is associated with emotional behavior problems. However, the underlying relationship mechanisms between family function and emotional behavior problems in children and adolescents is not fully understood. Therefore, the purpose of this study is to explore the mediating effect of resilience and the moderating effect of sleep quality using a moderated mediation model. METHODS: 6363 children and adolescents in grades four to nine were surveyed in some areas of Anhui Province, China. Family function, resilience, sleep quality, and emotional behavior problems were measured through a self-administered questionnaire. All data analysis was by performed by SPSS 23.0. RESULTS: The results showed that family function was negatively associated with emotional behavior problems (r = -0.307, p < 0.01). Resilience partially mediated the relationship between family function and emotional behavior problems (indirect effect = -0.108, accounted for 38.4 %). Sleep quality moderated the relationship between family function and resilience (ß = -0.039, P < 0.001). CONCLUSION: Resilience and sleep quality respectively played a mediating and moderating effect in the relationship between family function and emotional behavior problems. These findings suggest that we should pay attention to the family function of children and adolescents in time, improve their resilience and sleep quality, so as to effectively reduce the occurrence of emotional behavior problems.

Impact of sociodemographic disadvantage on neurobehavioral outcomes in children with newly diagnosed seizures and their unaffected siblings over 36 months.

OBJECTIVE: This study was undertaken to determine the short-term and longer term impact of sociodemographic disadvantage on the emotional-behavioral status of youths with new onset epilepsy and their unaffected siblings at the time of diagnosis and the subsequent 3 years. METHODS: Three hundred twelve youths with newly diagnosed epilepsies and 223 unaffected siblings, aged 6-16 years, were independently assessed regarding their emotional and behavioral status by their parents and teachers at baseline, and at 18 at 36 months later; youths with seizures also completed self-report measures of depression, anxiety, and hostility at those three time points. A sociodemographic disadvantage score was computed for each family (children with newly diagnosed seizures and their siblings), and families were separated into four categories from most disadvantaged to least disadvantaged. RESULTS: In both children and siblings, the least disadvantaged group exhibited the lowest level of neurobehavioral problems, whereas the most disadvantaged group showed a higher level of neurobehavioral problems across all the same behavior metrics. Findings remained stable and significant across all informants (parent, teacher, child) and across all time periods (throughout the 3-year period). Furthermore, both corrected and uncorrected linear regression analyses indicated that disadvantage was a more constant and stable predictor of behavioral and emotional problems over time compared to clinical seizure characteristics and abnormalities in magnetic resonance imaging and electroencephalographic testing. SIGNIFICANCE: Sociodemographic disadvantage bears a strong relationship to youths with emotional and behavioral problems both at the time of diagnosis as well as prospectively. The relationship is robust and reflected in reports from multiple informants (parent, teacher, child self-report), evident in siblings as well, and possibly more explanatory than traditional clinical seizure variables. Future studies will be needed to determine whether this disadvantage factor is modifiable with early intervention.

miRNA-132/212 Deficiency Disrupts Selective Corticosterone Modulation of Dorsal vs. Ventral Hippocampal Metaplasticity.

Cortisol is a potent human steroid hormone that plays key roles in the central nervous system, influencing processes such as brain neuronal synaptic plasticity and regulating the expression of emotional and behavioral responses. The relevance of cortisol stands out in the disease, as its dysregulation is associated with debilitating conditions such as Alzheimer's Disease, chronic stress, anxiety and depression. Among other brain regions, cortisol importantly influences the function of the hippocampus, a structure central for memory and emotional information processing. The mechanisms fine-tuning the different synaptic responses of the hippocampus to steroid hormone signaling remain, however, poorly understood. Using ex vivo electrophysiology and wild type (WT) and miR-132/miR-212 microRNAs knockout (miRNA-132/212-/-) mice, we examined the effects of corticosterone (the rodent's equivalent to cortisol in humans) on the synaptic properties of the dorsal and ventral hippocampus. In WT mice, corticosterone predominantly inhibited metaplasticity in the dorsal WT hippocampi, whereas it significantly dysregulated both synaptic transmission and metaplasticity at dorsal and ventral regions of miR-132/212-/- hippocampi. Western blotting further revealed significantly augmented levels of endogenous CREB and a significant CREB reduction in response to corticosterone only in miR-132/212-/- hippocampi. Sirt1 levels were also endogenously enhanced in the miR-132/212-/- hippocampi but unaltered by corticosterone, whereas the levels of phospo-MSK1 were only reduced by corticosterone in WT, not in miR-132/212-/- hippocampi. In behavioral studies using the elevated plus maze, miRNA-132/212-/- mice further showed reduced anxiety-like behavior. These observations propose miRNA-132/212 as potential region-selective regulators of the effects of steroid hormones on hippocampal functions, thus likely fine-tuning hippocampus-dependent memory and emotional processing.

Behavioral State-Dependent Modulation of Prefrontal Cortex Activity by Respiration.

Respiration-rhythmic oscillations in the local field potential emerge in the mPFC, a cortical region with a key role in the regulation of cognitive and emotional behavior. Respiration-driven rhythms coordinate local activity by entraining fast γ oscillations as well as single-unit discharges. To what extent respiration entrainment differently engages the mPFC network in a behavioral state-dependent manner, however, is not known. Here, we compared the respiration entrainment of mouse PFC local field potential and spiking activity (23 male and 2 female mice) across distinct behavioral states: during awake immobility in the home cage (HC), during passive coping in response to inescapable stress under tail suspension (TS), and during reward consumption (Rew). Respiration-driven rhythms emerged during all three states. However, prefrontal γ oscillations were more strongly entrained by respiration during HC than TS or Rew. Moreover, neuronal spikes of putative pyramidal cells and putative interneurons showed significant respiration phase-coupling throughout behaviors with characteristic phase preferences depending on the behavioral state. Finally, while phase-coupling dominated in deep layers in HC and Rew conditions, TS resulted in the recruitment of superficial layer neurons to respiration. These results jointly suggest that respiration dynamically entrains prefrontal neuronal activity depending on the behavioral state.SIGNIFICANCE STATEMENT The mPFC, through its extensive connections (e.g., to the amygdala, the striatum, serotoninergic and dopaminergic nuclei), flexibly regulates cognitive behaviors. Impairment of prefrontal functions can lead to disease states, such as depression, addiction, or anxiety disorders. Deciphering the complex regulation of PFC activity during defined behavioral states is thus an essential challenge. Here, we investigated the role of a prefrontal slow oscillation that has recently attracted rising interest, the respiration rhythm, in modulating prefrontal neurons during distinct behavioral states. We show that prefrontal neuronal activity is differently entrained by the respiration rhythm in a cell type- and behavior-dependent manner. These results provide first insight into the complex modulation of prefrontal activity patterns by rhythmic breathing.

(R)-ketamine attenuates neurodevelopmental disease-related phenotypes in a mouse model of maternal immune activation.

Infections during pregnancy are associated with an increased risk of neuropsychiatric disorders with developmental etiologies, such as schizophrenia and autism spectrum disorders (ASD). Studies have shown that the animal model of maternal immune activation (MIA) reproduces a wide range of phenotypes relevant to the study of neurodevelopmental disorders. Emerging evidence shows that (R)-ketamine attenuates behavioral, cellular, and molecular changes observed in animal models of neuropsychiatric disorders. Here, we investigate whether (R)-ketamine administration during adolescence attenuates some of the phenotypes related to neurodevelopmental disorders in an animal model of MIA. For MIA, pregnant Swiss mice received intraperitoneally (i.p.) lipopolysaccharide (LPS; 100 µg/kg/day) or saline on gestational days 15 and 16. The two MIA-based groups of male offspring received (R)-ketamine (20 mg/kg/day; i.p.) or saline from postnatal day (PND) 36 to 50. At PND 62, the animals were examined for anxiety-like behavior and locomotor activity in the open-field test (OFT), as well as in the social interaction test (SIT). At PND 63, the prefrontal cortex (PFC) was collected for analysis of oxidative balance and gene expression of the cytokines IL-1ß, IL-6, and TGF-ß1. We show that (R)-ketamine abolishes anxiety-related behavior and social interaction deficits induced by MIA. Additionally, (R)-ketamine attenuated the increase in lipid peroxidation and the cytokines in the PFC of the offspring exposed to MIA. The present work suggests that (R)-ketamine administration may have a long-lasting attenuation in deficits in emotional behavior induced by MIA, and that these effects may be attributed to its antioxidant and anti-inflammatory activity in the PFC.

Coparenting change after couple therapy using self-reports and observational data.

Parent couples are involved in a coparenting bond and in a romantic relationship. Research on couple therapy has mainly explored the impact of couple therapy on romantic relationships; however, little is known about how couple therapy affects the coparenting relationship. Self-reports of positive and negative coparenting and observed emotional behavior in coparenting-related conversation tasks were assessed pre- and posttherapy (6 months intervals) in 64 mixed-sex parental couples. Results showed that mothers and fathers reported more positive coparenting after therapy. There were no significant changes in the reported negative coparenting and in the emotional behavior. Exploratory analyses indicated gender differences in emotional expression. The findings suggest that fathers might have been more active in the coparenting conversation after therapy.

Oxytocin treatments or activation of the paraventricular nucleus-the shell of nucleus accumbens pathway reduce adverse effects of chronic social defeat stress on emotional and social behaviors in Mandarin voles.

Chronic social stress can cause psychological disease. Although oxytocin (OT) has been showed to modulate effects of chronic social defeat stress (CSDS) on emotional and social behaviors, however, how OT circuits mediate effects of CSDS on emotional and social abnormalities remains unclear. Here, we found that repeated intraperitoneal OT administration in the process of CSDS buffered adverse effects of CSDS on emotional and social behaviors in mandarin voles (Microtus mandarinus) of both sexes except no effect on depression-like behavior of males. Repeated OT treatments during CSDS prevented decrease of oxytocin receptors in nucleus accumbens (NAc) in females, but produced no effects on males. Furthermore, using designer receptors exclusively activated by designer drugs (DREADDs)-based chemogenetic tools, we determined that the activation of the paraventricular nucleus (PVN)-the shell of NAc (NAcs) projections before social defeat during CSDS process significantly prevented the increase of the anxiety-like behaviors and social avoidance induced by CSDS in both sexes, and reversed the depressive-like behaviors induced by CSDS only in females. Besides, optogenetic activation of PVN-NAcs projections after CSDS reduced anxiety-like behaviors and increased levels of sociality. Collectively, we suggest that PVN-NAcs projections modulate emotional and social behaviors during or after the process of CSDS sex-specifically, although AAV viruses did not specifically infect OT neurons. These findings offer potential targets for preventing or treating emotional and social disorders induced by chronic stress.

Inherited pain hypersensitivity and increased anxiety-like behaviors are associated with genetic epilepsy in Wistar Audiogenic Rats: Short- and long-term effects of acute and chronic seizures on nociception and anxiety.

Anxiety and pain hypersensitivity are neurobehavioral comorbidities commonly reported by patients with epilepsies, and preclinical models are suitable to investigate the neurobiology of behavioral and neuropathological alterations associated with these epilepsy-related comorbidities. This work aimed to characterize endogenous alterations in nociceptive threshold and anxiety-like behaviors in the Wistar Audiogenic Rat (WAR) model of genetic epilepsy. We also assessed the effects of acute and chronic seizures on anxiety and nociception. WARs from acute and chronic seizure protocols were divided into two groups to assess short- and long-term changes in anxiety (1 day or 15 days after seizures, respectively). To assess anxiety-like behaviors, the laboratory animals were submitted to the open field, light-dark box, and elevated plus maze tests. The von Frey, acetone, and hot plate tests were used to measure the endogenous nociception in seizure-free WARs, and postictal antinociception was recorded at 10, 30, 60, 120, 180 min, and 24 h after seizures. Seizure-free WARs presented increased anxiety-like behaviors and pain hypersensitivity, displaying mechanical and thermal allodynia (to heat and cold stimuli) in comparison to nonepileptic Wistar rats. Potent postictal antinociception that persisted for 120 to 180 min was detected after acute and chronic seizures. Additionally, acute and chronic seizures have magnified the expression of anxiety-like behaviors when assessed at 1 day and 15 days after seizures. Behavioral analysis indicated more severe and persistent anxiogenic-like alterations in WARs submitted to acute seizures. Therefore, WARs presented pain hypersensitivity and increased anxiety-like behaviors endogenously associated with genetic epilepsy. Acute and chronic seizures induced postictal antinociception in response to mechanical and thermal stimuli and increased anxiety-like behaviors when assessed 1 day and 15 days later. These findings support the presence of neurobehavioral alterations in subjects with epilepsy and shed light on the use of genetic models to characterize neuropathological and behavioral alterations associated with epilepsy.

Activation of endogenous retrovirus triggers microglial immuno-inflammation and contributes to negative emotional behaviors in mice with chronic stress.

BACKGROUND: The "missing" link of complex and multifaceted interplay among endogenous retroviruses (ERVs) transcription, chronic immuno-inflammation, and the development of psychiatric disorders is still far from being completely clarified. The present study was aimed to investigate the mechanism of protective role of inhibiting ERVs on reversing microglial immuno-inflammation in basolateral amygdala (BLA) in chronic stress-induced negative emotional behaviors in mice. METHODS: Male C57BL/6 mice were exposed to chronic unpredictable mild stress (CUMS) for 6 w. Negative emotional behaviors were comprehensively investigated to identify the susceptible mice. Microglial morphology, ERVs transcription, intrinsic nucleic acids sensing response, and immuno-inflammation in BLA were assessed. RESULTS: Mice with chronic stress were presented as obviously depressive- and anxiety-like behaviors, and accompanied with significant microglial morphological activation, murine ERVs genes MuERV-L, MusD, and IAP transcription, cGAS-IFI16-STING pathway activation, NF-κB signaling pathway priming, as well as NLRP3 inflammasome activation in BLA. Antiretroviral therapy, pharmacological inhibition of reverse transcriptases, as well as knocking-down the ERVs transcriptional regulation gene p53 significantly inhibited microglial ERVs transcription and immuno-inflammation in BLA, as well as improved the chronic stress-induced negative emotional behaviors. CONCLUSIONS: Our results provided an innovative therapeutic approach that targeting ERVs-associated microglial immuno-inflammation may be beneficial to the patients with psychotic disorders.

Transgenerational transmission of aspartame-induced anxiety and changes in glutamate-GABA signaling and gene expression in the amygdala.

We report the effects of aspartame on anxiety-like behavior, neurotransmitter signaling and gene expression in the amygdala, a brain region associated with the regulation of anxiety and fear responses. C57BL/6 mice consumed drinking water containing 0.015% or 0.03% aspartame, a dose equivalent of 8 to 15% of the FDA recommended maximum human daily intake, or plain drinking water. Robust anxiety-like behavior (evaluated using open field test and elevated zero maze) was observed in male and female mice consuming the aspartame-containing water. Diazepam, an allosteric modulator of the GABA-A receptor, alleviated the anxiety-like behavior. RNA sequencing of the amygdala followed by KEGG biological pathway analysis of differentially expressed genes showed glutamatergic and GABAergic synapse pathways as significantly enriched. Quantitative PCR showed upregulation of mRNA for the glutamate NMDA receptor subunit 2D (Grin2d) and metabotropic receptor 4 (Grm4) and downregulation of the GABA-A receptor associated protein (Gabarap) mRNA. Thus, taken together, our diazepam and gene expression data show that aspartame consumption shifted the excitation-inhibition equilibrium in the amygdala toward excitation. Even more strikingly, the anxiety-like behavior, its response to diazepam, and changes in amygdala gene expression were transmitted to male and female offspring in two generations descending from the aspartame-exposed males. Extrapolation of the findings to humans suggests that aspartame consumption at doses below the FDA recommended maximum daily intake may produce neurobehavioral changes in aspartame-consuming individuals and their descendants. Thus, human population at risk of aspartame's potential mental health effects may be larger than current expectations, which only include aspartame-consuming individuals.

The modulation of emotional and social behaviors by oxytocin signaling in limbic network.

Neuropeptides can exert volume modulation in neuronal networks, which account for a well-calibrated and fine-tuned regulation that depends on the sensory and behavioral contexts. For example, oxytocin (OT) and oxytocin receptor (OTR) trigger a signaling pattern encompassing intracellular cascades, synaptic plasticity, gene expression, and network regulation, that together function to increase the signal-to-noise ratio for sensory-dependent stress/threat and social responses. Activation of OTRs in emotional circuits within the limbic forebrain is necessary to acquire stress/threat responses. When emotional memories are retrieved, OTR-expressing cells act as gatekeepers of the threat response choice/discrimination. OT signaling has also been implicated in modulating social-exposure elicited responses in the neural circuits within the limbic forebrain. In this review, we describe the cellular and molecular mechanisms that underlie the neuromodulation by OT, and how OT signaling in specific neural circuits and cell populations mediate stress/threat and social behaviors. OT and downstream signaling cascades are heavily implicated in neuropsychiatric disorders characterized by emotional and social dysregulation. Thus, a mechanistic understanding of downstream cellular effects of OT in relevant cell types and neural circuits can help design effective intervention techniques for a variety of neuropsychiatric disorders.

High-frequency rTMS modulates emotional behaviors and structural plasticity in layers II/III and V of the mPFC.

Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique, and it has been increasingly used as a nonpharmacological intervention for the treatment of various neurological and neuropsychiatric diseases, including depression. In humans, rTMS over the prefrontal cortex is used to induce modulation of the neural circuitry that regulates emotions, cognition, and depressive symptoms. However, the underlying mechanisms are still unknown. In this study, we investigated the effects of a short (5-day) treatment with high-frequency (HF) rTMS (15 Hz) on emotional behavior and prefrontal cortex morphological plasticity in mice. Mice that had undergone HF-rTMS showed an anti-depressant-like activity as evidenced by decreased immobility time in both the Tail Suspension Test and the Forced Swim Test along with increased spine density in both layer II/III and layer V apical and basal dendrites. Furthermore, dendritic complexity assessed by Sholl analysis revealed increased arborization in the apical portions of both layers, but no modifications in the basal dendrites branching. Overall, these results indicate that the antidepressant-like activity of HF-rTMS is paralleled by structural remodeling in the medial prefrontal cortex.