Active Coping Behavior Research Articles

Hypocretin modulation of behavioral coping strategies for social stress.

Best known for promoting wakefulness and arousal, the neuropeptide hypocretin (Hcrt) also plays an important role in mediating stress responses, including social stress. However, central and systemic manipulation of the Hcrt system has produced diverse behavioral outcomes in animal models. In this review, we first focus on studies where similar manipulations of the Hcrt system led to divergent coping behaviors. We hypothesize that Hcrt differentially facilitates active and passive coping behaviors in response to social stress by acting in different brain regions and on different cell types. We then focus on region and cell type-specific effects of Hcrt in the ventral pallidum, lateral habenula, ventral tegmental area, nucleus accumbens, amygdala, and bed nucleus of the stria terminalis. Overall, the evidence suggests that rather than enhancing or inhibiting behavioral responses to social stress, Hcrt may signal the heightened arousal associated with stressful contexts. The resulting behavioral effects depend on which circuits Hcrt release occurs in and which receptor types are activated. Further study is needed to determine how and why circuit specific activation of Hcrt neurons occurs.

Pre-operative environmental enrichment does not yield a prophylactic effect against traumatic brain injury-induced neurobehavioral deficits

The robustness of environmental enrichment (EE) in ameliorating neurobehavioral and cognitive deficits after experimental traumatic brain injury (TBI) is unequivocal. What is equivocal is whether EE can function as a prophylactic to afford resiliency and neuroprotection against TBI. We hypothesized that pre-operative EE would yield a protective effect against TBI-induced motor, cognitive, and coping deficits, and that further improvements would be conferred when EE is provided before and after TBI. To test the hypotheses, adult male rats received either 4 weeks of EE or standard (STD) housing prior to undergoing a controlled cortical impact of moderate severity (2.8 mm deformation at 4 m/s) or sham injury while under anesthesia. After injury, the rats were randomly assigned to post-operative EE or STD housing. Motor ability, spatial learning, and memory retention were assessed by beam-walk and water maze tests, respectively. Active and passive behavioral coping strategies were evaluated with the shock probe defensive burying (SPDB) test. c-Fos and cortical lesion volume were also quantified. The post-TBI enrichment groups (EE + TBI + EE and STD + TBI + EE) did not differ (p > 0.05) and performed better than the post-TBI STD-housed groups (EE + TBI + STD and STD + TBI + STD) on motor and cognition (p < 0.05). The post-TBI STD groups did not differ, regardless of whether in EE or STD living conditions before injury (p > 0.05). Moreover, both post-TBI enrichment groups performed better in the SPDB test relative to the STD + TBI + STD group (p < 0.05). c-Fos + cells were upregulated in the ipsilateral CA1 in both pre-injury EE groups relative to the pre-injury STD groups (p < 0.05). No statistical differences were observed in cortical lesion volume among the groups. Overall, these data do not support the hypothesis as no neuroprotective effect was observed with 4 weeks of pre-operative EE and no additional benefit was achieved in the TBI group receiving both pre-and-post EE relative to the TBI group receiving only post-EE. However, the data do reinforce the consistency of post-TBI EE in producing robust neurobehavioral benefits, which further supports this paradigm as a relevant preclinical model of neurorehabilitation.

Exploring the role of orexins in the modulation of social reward

Abstract Rationale positive social interactions are essential for mental health, by offering emotional support, reducing stress levels, and promoting resilience against drugs of abuse effects. However, not all individuals perceive social interaction as rewarding. Objectives the goal of this study was to investigate whether the modulation of the orexin system can shift passive coping and non-social behavior (vulnerable) to active coping and social behavior (resilient). This knowledge is primordial for stress- and addiction-related disorders, and for other psychiatric disorders involving impairment in social interaction. Methods male C57/BL6N mice categorized into social and non-social groups, received injections of SB334867, a selective orexin 1 receptor (OX1R) antagonist, before the conditioning sessions with a male conspecific of the same weight and age. Results our results from the conditioned place preference test (CPP) show that SB334867 has no effect on social preference in non-social mice, but it reduces their stress levels and depression-like behavior. These effects appear to be due to a higher OX1R expression in the basolateral amygdala (BLA), a stress-related brain area, of non-social mice compared to their social counterparts. Conclusions these data suggest that the orexin system may be a target to alleviate stress and depression-like behavior in non-social individuals rather than to promote social reward.

Differential Functions of Oxytocin Receptor-Expressing Neurons in the Ventromedial Hypothalamus in Social Stress Responses: Induction of Adaptive and Maladaptive Coping Behaviors

The flexibility to adjust actions and attitudes in response to varying social situations is a fundamental aspect of adaptive social behavior. Adaptive social behaviors influence an individual's vulnerability to social stress. While oxytocin has been proposed to facilitate active coping behaviors during social stress, the exact mechanisms remain unknown. By using a social defeat stress paradigm in male mice, we identified the distribution of oxytocin receptor (OXTR)-expressing neurons in the ventrolateral part of the ventromedial hypothalamus (vlVMH) that are activated during stress by detection of c-Fos protein expression. We then investigated the role of vlVMH OXTR-expressing neurons in social defeat stress responses by chemogenetic methods or deletion of local OXTRs. The social defeat posture was measured for quantification of adaptive social behavior during repeated social stress. Social defeat stress activated OXTR-expressing neurons rather than estrogen type 1-expressing neurons in the rostral vlVMH. OXTR-expressing neurons in the vlVMH were glutamatergic. Chemogenetic activation of vlVMH OXTR-expressing neurons facilitated exhibition of the social defeat posture during exposure to social stress, while local OXTR deletion suppressed it. In contrast, over-activation of vlVMH-OXTR neurons induced generalized social avoidance after exposure to chronic social defeat stress. Neural circuits for the social defeat posture centered on OXTR-expressing neurons were identified by viral tracers and c-Fos mapping. VlVMH OXTR-expressing neurons are a functionally unique population of neurons that promote an active coping behavior during social stress, but their excessive and repetitive activation under chronic social stress impairs subsequent social behavior.

The BigMove Intervention for People With Physical and Mental Health Conditions: A First Evaluation of Self-Perceived Health, Quality of Life, Coping and Mental and Social Functioning.

The BigMove intervention aims to improve the functioning and quality of life of people with physical and mental health conditions via an integrated care approach. This pilot study evaluates the impact of the intervention on self-perceived health (SPH), quality of life (QoL), active coping behaviour, and mental and social functioning. Data were analysed from N = 457 participants who had been referred to the intervention by their general practitioner (mean age 48.98 years; 76% female). Three patient-reported and one clinician-rated measures were used: SPH, QoL (MANSA), active coping behaviour (UPCC-ACT), mental and social functioning (HoNOS). Pre- and post-intervention measurements (from 2011 to 2018) were compared using paired-samples t-tests. Due to missing data, analyses were conducted with 205-257 participants per completed outcome. Associations with age and sex were assessed using repeated-measures ANOVA. Clinically relevant change was evaluated with the Edwards-Nunnally index and standard error of measurement (SEM) scores. Post-intervention, there were statistically significant improvements for all outcomes (p < 0.0001) with moderate to large effect sizes (d = 0.41 to 1.02). The observed changes in outcomes can be considered as clinically relevant improvements. This pilot study provides preliminary evidence that the intervention has positive effects on SPH, QoL, active coping behaviour, and mental and social functioning.

Glutamatergic supramammillary nucleus neurons respond to threatening stressors and promote active coping

Threat-response neural circuits are conserved across species and play roles in normal behavior and psychiatric diseases. Maladaptive changes in these neural circuits contribute to stress, mood, and anxiety disorders. Active coping in response to stressors is a psychosocial factor associated with resilience against stress-induced mood and anxiety disorders. The neural circuitry underlying active coping is poorly understood, but the functioning of these circuits could be key for overcoming anxiety and related disorders. The supramammillary nucleus (SuM) has been suggested to be engaged by threat. SuM has many projections and a poorly understood diversity of neural populations. In studies using mice, we identified a unique population of glutamatergic SuM neurons (SuMVGLUT2+::POA) based on projection to the preoptic area of the hypothalamus (POA) and found SuMVGLUT2+::POA neurons have extensive arborizations. SuMVGLUT2+::POA neurons project to brain areas that mediate features of the stress and threat responses including the paraventricular nucleus thalamus (PVT), periaqueductal gray (PAG), and habenula (Hb). Thus, SuMVGLUT2+::POA neurons are positioned as a hub, connecting to areas implicated in regulating stress responses. Here we report SuMVGLUT2+::POA neurons are recruited by diverse threatening stressors, and recruitment correlated with active coping behaviors. We found that selective photoactivation of the SuMVGLUT2+::POA population drove aversion but not anxiety like behaviors. Activation of SuMVGLUT2+::POA neurons in the absence of acute stressors evoked active coping like behaviors and drove instrumental behavior. Also, activation of SuMVGLUT2+::POA neurons was sufficient to convert passive coping strategies to active behaviors during acute stress. In contrast, we found activation of GABAergic (VGAT+) SuM neurons (SuMVGAT+) neurons did not alter drive aversion or active coping, but termination of photostimulation was followed by increased mobility in the forced swim test. These findings establish a new node in stress response circuitry that has projections to many brain areas and evokes flexible active coping behaviors.

Glutamatergic supramammillary nucleus neurons respond to threatening stressors and promote active coping.

Threat-response neural circuits are conserved across species and play roles in normal behavior and psychiatric diseases. Maladaptive changes in these neural circuits contribute to stress, mood, and anxiety disorders. Active coping in response to stressors is a psychosocial factor associated with resilience against stress-induced mood and anxiety disorders. The neural circuitry underlying active coping is poorly understood, but the functioning of these circuits could be key for overcoming anxiety and related disorders. The supramammillary nucleus (SuM) has been suggested to be engaged by threat. SuM has many projections and a poorly understood diversity of neural populations. In studies using mice, we identified a unique population of glutamatergic SuM neurons (SuMVGLUT2+::POA) based on projection to the preoptic area of the hypothalamus (POA) and found SuMVGLUT2+::POA neurons have extensive arborizations. SuMVGLUT2+::POA neurons project to brain areas that mediate features of the stress and threat responses including the paraventricular nucleus thalamus (PVT), periaqueductal gray (PAG), and habenula (Hb). Thus, SuMVGLUT2+::POA neurons are positioned as a hub, connecting to areas implicated in regulating stress responses. Here we report SuMVGLUT2+::POA neurons are recruited by diverse threatening stressors, and recruitment correlated with active coping behaviors. We found that selective photoactivation of the SuMVGLUT2+::POA population drove aversion but not anxiety like behaviors. Activation of SuMVGLUT2+::POA neurons in the absence of acute stressors evoked active coping like behaviors and drove instrumental behavior. Also, activation of SuMVGLUT2+::POA neurons was sufficient to convert passive coping strategies to active behaviors during acute stress. In contrast, we found activation of GABAergic (VGAT+) SuM neurons (SuMVGAT+) neurons did not alter drive aversion or active coping, but termination of photostimulation was followed by increased mobility in the forced swim test. These findings establish a new node in stress response circuitry that has projections to many brain areas and evokes flexible active coping behaviors.

Chronic caffeine decreases anxiety-like behavior in the marble burying task in adolescent rats.

Exposure to chronic caffeine during adolescence has been shown to produce decreased anxiety-like behaviors in rats as well as decreased immobility in the forced swim test (FST) suggesting an antidepressant-like effect. The effects of chronic caffeine on anxiety, however, have been found to be test-dependent and sexually dimorphic. In addition, decreased immobility in the FST has been argued to reflect a shift toward active coping behavior as opposed to an antidepressant-like effect. In order to further characterize the effects of adolescent caffeine exposure, the present experiment assessed the effects of caffeine on marble burying behavior in a two-zone marble burying task. There was no difference in the amount of time rats spent in the two zones failing to support a shift in coping strategy. Caffeine-exposed rats spent less time engaged in marble burying activity and buried slightly fewer marbles, suggesting an anxiolytic effect of caffeine. In addition, caffeine treated rats spent less time engaged in nondirected burying and slightly more time actively engaging with the marbles; however, these effects appeared to be sexually dimorphic as they were driven by larger changes in the females. Overall, these results support an anxiolytic effect of adolescent caffeine, with female behavior appearing to be more affected by caffeine than males.

A preliminary, quantitative study on the use of traditional and complementary medicine by cancer patients seen at the Senkatana oncology clinic, Maseru, Lesotho

BackgroundThe use of traditional and complementary medicine (TCM) by cancer patients remains common in several countries especially in the Sub-Saharan Africa. However, the reasons for use are complex and change with time and geographic location, they may vary from therapy to therapy, and they are different from one individual to another. The use of TCM has been associated with active coping behaviour and a way through which patients take control of their own health. However, cancer patients do not disclose their use of TCM to the attending healthcare professionals and therefore the effects of these medicines on the patients may not be ascertained.AimTo investigate the use of traditional and complementary medicines among patients diagnosed with cancer.MethodsA cross-sectional, quantitative study was conducted at Senkatana Oncology clinic in May to June 2023. Cancer patients underwent standardized, quantitative interviews using structured questionnaires about their use of TCM. Descriptive statistics were used to analyse the data. Logistic regression analysis was also used to identify factors associated with satisfaction with the performance of TCM.ResultsAll interviewed patients (n = 50, 100%) reported to be using TCM. Patients consisted of 24 females (48%) and 26 males (52%) in the age range 14 to 82 years old. The majority of the study population was in the age group 35–44 years old. The most prevalent cancer among participating males was prostate cancer and among females was cervical cancer. Biological products use was the most prominent with the highest average percentage usage (14.7%). The majority of patients (66%, n = 33) indicated that they just wanted to try everything that could help. Patients (n = 47, 94%) further reported that they had been using complementary medicine during the same period as they were using conventional treatment so that both may work to help each other. Neither gender nor age predicted satisfaction with the performance of traditional and complementary medicine.ConclusionsIt is concluded that all interviewed cancer patients use TCM. Patients indicated that one of the reasons for using TCM was that they wanted to try everything that could help in their cancer care. Patients further reported that they did not inform their oncologist of their concurrent use of TCM because they had been advised not to use other medicines besides what they are given at the clinic.

Validation of the Korean Version of the Health Care Climate Questionnaire among Cancer Survivors

Healthcare professionals should support autonomy in their patients in order for them to maintain the motivation to cope actively with their conditions. The Health Care Climate Questionnaire (HCCQ) is useful for assessing patients’ perceptions of the autonomy support provided to them. We aimed to validate the psychometric properties of the Korean version of the HCCQ (HCCQ-K) among Korean cancer survivors. This study evaluated the factor structure, concurrent validity, and internal consistency. Data from 367 cancer survivors were analyzed using confirmatory factor analysis (CFA), Pearson’s correlations, and Cronbach’s α values. The CFA validated that the single-factor structure of the HCCQ-K had an excellent fit that was consistent with that of the original English version. Concurrent validity was confirmed by moderate correlations between the HCCQ-K and both psychological well-being and self-management. Reliability was verified by satisfactory internal consistency, with a Cronbach’s α value of 0.91 and strong item-total and inter-item correlations. The HCCQ-K is therefore a valid and reliable tool for assessing autonomy support provided by healthcare professionals to Korean cancer survivors. The HCCQ-K may help healthcare professionals understand their patients’ needs for autonomy support and develop strategies to motivate active coping behaviors.

Beliefs about depression relate to active and avoidant coping in high-symptom adolescents

BackgroundPerceptions of personal attributes as less malleable are associated with more severe depression symptoms and less active coping in youth. Perceptions of depression itself as relatively fixed have been linked to more severe depression symptoms; however, it is not known how beliefs about depression relate to active and avoidant coping behaviors in particular. MethodsWe gathered information about beliefs about depression and activation and avoidance behaviors among 104 adolescents with high depression symptoms. The primary depression belief examined was prognostic pessimism, or the belief that depression is relatively permanent. We calculated correlations between this belief and activation and avoidance/rumination behaviors. ResultsPrognostic pessimism was negatively correlated with behavioral activation scores (r = −0.31; p = .001), and was positively correlated with behavioral avoidance/rumination scores (r = 0.30; p = .002). LimitationsThis data was cross-sectional, and relied on self-report measures of depression beliefs and behaviors. ConclusionsAdolescents who believe that depression is relatively permanent might feel less motivated to engage in effortful activation behaviors, instead favoring avoidance. These results may help elucidate the ways in which malleability beliefs relate to mental health outcomes among adolescents, and highlight prognostic pessimism as a potential treatment target for reducing depressogenic behaviors.

Impact and Role of Hypothalamic Corticotropin Releasing Hormone Neurons in Withdrawal from Chronic Alcohol Consumption in Female and Male Mice.

Worldwide, alcohol use and abuse are a leading risk of mortality, causing 5.3% of all deaths (World Health Organization, 2022). The endocrine stress system, initiated by the peripheral release of corticotropin releasing hormone (CRH) from primarily glutamatergic neurons in the paraventricular nucleus of the hypothalamus (PVN), is profoundly linked with alcohol use, abuse, and relapse (Blaine and Sinha, 2017). These PVN CRH-releasing (PVNCRH) neurons are essential for peripheral and central stress responses (Rasiah et al., 2023), but little is known about how alcohol affects these neurons. Here, we show that two-bottle choice alcohol consumption blunts the endocrine-mediated corticosterone response to stress during acute withdrawal in female mice. Conversely, using slice electrophysiology, we demonstrate that acute withdrawal engenders a hyperexcitable phenotype of PVNCRH neurons in females that is accompanied by increased glutamatergic transmission in both male and female mice. GABAergic synaptic transmission was unaffected by alcohol history. We then tested whether chemogenetic inhibition of PVNCRH neurons would restore stress response in female mice with a history of alcohol drinking in the looming disk test, which mimics an approaching predator threat. Accordingly, inhibition of PVNCRH neurons reduced active escape in hM4Di alcohol history mice only. This study indicates that stress-responsive PVNCRH neurons in females are particularly affected by a history of alcohol consumption. Interestingly, women have indicated an increase in heavy alcohol use to cope with stress (Rodriguez et al., 2020), perhaps pointing to a potential underlying mechanism in alcohol-mediated changes to PVNCRH neurons that alter stress response.SIGNIFICANCE STATEMENT Paraventricular nucleus of the hypothalamus neurons that release corticotropin releasing hormone (PVNCRH) are vital for stress response. These neurons have been understudied in relation to alcohol and withdrawal despite profound relations between stress, alcohol use disorders (AUD), and relapse. In this study, we use a variety of techniques to show that acute withdrawal from a history of alcohol impacts peripheral stress response, PVNCRH neurons, and behavior. Specifically, PVNCRH are in a hyperactive state during withdrawal, which drives an increase in active stress coping behaviors in female mice only. Understanding how alcohol use and withdrawal affects stress responding PVNCRH neurons may contribute to finding new potential targets for the treatment of alcohol use disorder.

Factors Influencing Posttraumatic Growth Among Primary Caregivers of Patients with Oncologic Emergencies in Taiwan Intensive Care Units: A Cross-Sectional Study of Patient–Caregiver Dyads

(1) To assess the levels of fear of cancer recurrence (FCR), social support, coping styles, and posttraumatic growth; (2) to identify factors associated with posttraumatic growth; and (3) to compare patient and primary caregiver characteristics by level of posttraumatic growth (no-to-little posttraumatic growth vs. moderate-to-high posttraumatic growth) in the primary caregivers of patients with an oncologic emergency. A cross-sectional study design was adopted. Data were collected by convenience sampling of cancer patient-caregiver dyads who experienced an oncologic emergency within the last 6 months at a medical center in northern Taiwan. The patients, who had completed cancer treatment, were in an intensive care unit. They were assessed for disease severity, physical performance, and demographic and clinical characteristics. Primary caregivers were assessed for FCR, social support, coping styles, and posttraumatic growth using a set of questionnaires. We found that 80.8% of primary caregivers reported moderate-to-high posttraumatic growth and 19.2% reported no-to-little posttraumatic growth. Greater posttraumatic growth in primary caregivers was associated with experiencing more patient oncologic emergencies, younger caregiver age, a higher caregiver FCR score, and caregivers' use of active coping behaviors. Caregivers were less likely to report posttraumatic growth if they experienced fewer patient oncologic emergencies, were older, reported lower FCR, and used active coping strategies less frequently. Developing scenario-based simulations to facilitate caregiving for an oncologic emergency and providing psychological counseling to encourage active coping can help primary caregivers recover emotionally from an oncologic emergency and facilitate growth.

Corticosteroid Treatment During Sepsis Alters Hippocampal Function in Male and Female Survivors

BackgroundMillions of sepsis survivors annually face neuropsychiatric sequelae of their illness. Corticosteroids are frequently administered for sepsis, and their use improves neuropsychiatric outcomes, but the mechanisms are unknown. In light of prior work that has shown persistent inflammation in sepsis survivors, we hypothesized that short-term corticosteroid treatment during illness would reverse the long-term impact of sepsis on inflammatory gene expression in the hippocampus and rescue associated changes to affective behaviors. MethodsMale and female mice underwent cecal ligation and puncture or a sham surgery to induce acute infection and were treated for 5 days with corticosterone or vehicle. Starting 2 weeks after the surgery, we performed functional phenotyping in the survivor mice followed by hippocampal RNA sequencing to identify underlying mechanisms. ResultsLong-term cecal ligation and puncture survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal axis activity, and persistent systemic and neuroinflammation. Corticosterone treatment during illness did not reverse anxiety-like behavior or inflammation in survivors. Instead, corticosterone treatment impaired object memory and increased active coping behavior in females. History of corticosterone treatment influenced the expression of >10% of detectable transcripts in the dorsal and ventral hippocampus, including a coordinated downregulation of activity-dependent genes. ConclusionsCorticosterone treatment during sepsis impaired memory formation in survivors and caused a lasting decrease in hippocampal neural activity, which could underlie its effect on memory. Future studies should focus on how this lasting effect of corticosteroid treatment on hippocampal activity and memory translates into improved neuropsychiatric outcomes in human sepsis survivors.

Coping, rumination, and electronic word-of-mouth: Segmenting consumer responses to service failure via fuzzy clustering

This study deploys a novel clustering algorithm to identify distinct segments of consumers based on the strategies they use to ‘cope’ with service failure. Drawing from different anger prototypes and felt intensity therein, it identifies how consumer segments employ a diverse range of rumination behaviours following service failure, with this used to predict manifestations of eWOM thereafter. Individuals with experience of service failure within the Iranian hotel industry context were surveyed, with findings identifying four discrete consumer segments underpinned by varied combinations of active, expressive, and denial-based post-failure coping behaviours. Each distinct segment activated different rumination behaviours. Further, logit models demonstrate that three eWOM archetypes are driven by different predictors, suggesting that consumers’ online behaviours following service failure are heterogeneous and shaped by the coping strategy employed.

Context-induced renewal of passive but not active coping behaviours in the shock-probe defensive burying task.

Renewal is the return of extinguished responding after removal from the extinction context. Renewal has been extensively studied using classical aversive conditioning procedures that measure a passive freezing response to an aversive conditioned stimulus. However, coping responses to aversive stimuli are complex and can be reflected in passive and active behaviours. Using the shock-probe defensive burying task, we investigated whether different coping responses are susceptible to renewal. During conditioning, male, Long-Evans rats were placed into a specific context (Context A) where an electrified shock-probe delivered a 3 mA shock upon contact. During extinction, the shock-probe was unarmed in either the same (Context A) or a different context (Context B). Renewal of conditioned responses was assessed in the conditioning context (ABA) or in a novel context (ABC or AAB). Renewal of passive coping responses, indicated by an increased latency and a decreased duration of shock-probe contacts, was observed in all groups. However, renewal of passive coping, measured by increased time spent on the side of the chamber opposite the shock-probe, was only found in the ABA group. Renewal of active coping responses linked to defensive burying was not observed in any group. The present findings highlight the presence of multiple psychological processes underlying even basic forms of aversive conditioning and demonstrate the importance of assessing a broader set of behaviours to tease apart these different underlying mechanisms. The current findings suggest that passive coping responses may be more reliable indicators for assessing renewal than active coping behaviours associated with defensive burying.

A non-hallucinogenic LSD analog with therapeutic potential for mood disorders

Hallucinations limit widespread therapeutic use of psychedelics as rapidly acting antidepressants. Here we profiled the non-hallucinogenic lysergic acid diethylamide (LSD) analog 2-bromo-LSD (2-Br-LSD) at more than 33 aminergic G protein-coupled receptors (GPCRs). 2-Br-LSD shows partial agonism at several aminergic GPCRs, including 5-HT2A, and does not induce the head-twitch response (HTR) in mice, supporting its classification as a non-hallucinogenic 5-HT2A partial agonist. Unlike LSD, 2-Br-LSD lacks 5-HT2B agonism, an effect linked to cardiac valvulopathy. Additionally, 2-Br-LSD produces weak 5-HT2A β-arrestin recruitment and internalization invitro and does not induce tolerance invivo after repeated administration. 2-Br-LSD induces dendritogenesis and spinogenesis in cultured rat cortical neurons and increases active coping behavior in mice, an effect blocked by the 5-HT2A-selective antagonist volinanserin (M100907). 2-Br-LSD also reverses the behavioral effects of chronic stress. Overall, 2-Br-LSD has an improved pharmacological profile compared with LSD and may have profound therapeutic value for mood disorders and other indications.

Dorsal raphe serotonergic neurons preferentially reactivate dorsal dentate gyrus cell ensembles associated with positive experience

Major depressive disorder (MDD) is among the most common mental illnesses. Serotonergic (5-HT) neurons are central to the pathophysiology and treatment of MDD. Repeatedly recalling positive episodes is effective for MDD. Stimulating 5-HT neurons of the dorsal raphe nucleus (DRN) or neuronal ensembles in the dorsal dentate gyrus (dDG) associated with positive memories reverses the stress-induced behavioral abnormalities. Despite this phenotypic similarity, their causal relationship is unclear. This study revealed that the DRN 5-HT neurons activate dDG neurons; surprisingly, this activation was specifically observed in positive memory ensembles rather than neutral or negative ensembles. Furthermore, we revealed that dopaminergic signaling induced by activation of DRN 5-HT neurons projecting to the ventral tegmental area mediates an increase in active coping behavior and positive dDG ensemble reactivation. Our study identifies a role of DRN 5-HT neurons as specific reactivators of positive memories and provides insights into how serotonin elicits antidepressive effects.

Different synaptic mechanisms of intermittent and continuous theta-burst stimulations in a severe foot-shock induced and treatment-resistant depression in a rat model

Treatment-resistant depression (TRD) is a condition wherein patients with depression fail to respond to antidepressant trials. A new form of repetitive transcranial magnetic stimulation (rTMS), called theta-burst stimulation (TBS), which includes intermittent theta-burst stimulation (iTBS) and continuous theta-burst stimulation (cTBS), is non-inferior to rTMS in TRD treatment. However, the mechanism of iTBS and cTBS underlying the treatment of TRD in the prefrontal cortex (PFC) remains unclear. Hence, we applied foot-shock stress as a traumatic event to develop a TRD rat model and investigated the different mechanisms of iTBS and cTBS. The iTBS and cTBS treatment were effective in depressive-like behavior and active coping behavior. The iTBS treatments improved impaired long-term potentiation and long-term depression (LTD), whereas the cTBS treatment only improved aberrant LTD. Moreover, the decrease in mature brain-derived neurotrophic factor (BDNF)-related protein levels were reversed by iTBS treatment. The decrease in proBDNF-related protein expression was improved by iTBS and cTBS treatment. Both iTBS and cTBS improved the decreased α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and downregulation of mammalian target of the rapamycin (mTOR) signaling pathway. The iTBS produces both excitatory and inhibitory synaptic effects, and the cTBS only produces inhibitory synaptic effects in the PFC.

GluN2D expression is regulated by restraint stress and supports active stress coping bouts

Stress coping strategies represent critical responses to environmental challenges, and active coping has been linked to stress resilience in humans. Understanding the neuroadaptations that support these strategies may provide insights into adaptive and maladaptive stress responses. NMDA receptors (NMDARs) play key roles in neuroadaptation, and NMDARs have been specifically implicated in stress responsiveness. Constitutive knockout mice have been used to implicate the GluN2D NMDAR subunit in regulation of stress-sensitive and affective behavior, but the brain regions in which GluN2D expression changes drive these effects remain unknown. Here we report that following an acute restraint stressor, GluN2D subunit expression is specifically decreased in the bed nucleus of the stria terminalis (BNST), a key region involved in stress processing, in male but not female mice, with no differences found in the thalamus or ventral hippocampus in either sex. Rodents engage in active struggling events during restraint stress that may represent active coping strategies to stress. Thus, we assessed active coping bouts during acute and chronic restraint stress sessions in GluN2D knockout mice. During the first restraint session, GluN2D knockout mice exhibited a pronounced decrease in struggling bouts during restraint stress relative to wild-type littermates, consistent with a role of GluN2D in active coping responses to stress. Repeated, daily restraint sessions revealed a sex-specific role of GluN2D expression on certain aspects of active coping behaviors, with male GluN2D KO mice exhibiting a decrease in total coping bouts measured across five sessions. However, BNST-specific knockdown of GluN2D in male mice did not alter active coping bouts, suggesting either a multi-synaptic role of GluN2D and/or a developmental role of GluN2D in this behavior. Altogether, these data are consistent with a growing literature suggesting that exploration of GluN2D control of stress circuit actions may lead to a novel therapeutic target to consider for stress-related mood disorders.