PVN-mPFC OT projections modulate pup-directed pup care or attacking in virgin mandarin voles.

Many species of animals exhibit caregiving or aggression toward conspecific offspring. The neural mechanisms underlying the infanticide and pup care remain poorly understood. Here, using monogamous mandarin voles (Microtus mandarinus), we found that more oxytocin (OT) neurons in the paraventricular nucleus (PVN) were activated during pup caring than infanticide. Optogenetic activation of OT neurons in the PVN facilitated pup caring in male and female mandarin voles. In infanticide voles, optogenetic activation of PVN OT cells or PVN-medial prefrontal cortex (mPFC) OT projection fibers prolonged latency to approach and attack pups, whereas inhibition of these OT neurons or projections facilitated approach and infanticide. Optogenetic activation of PVN OT neuron projections to the mPFC in males shortened the latency to approach and retrieve pups and facilitated the initiation of pup care, but produced no effects on pup-care females. In addition, OT release in the mPFC increased upon approaching and retrieving pups, and decreased upon attacking pups. Intraperitoneal injection of OT promoted pup care and inhibited infanticide behavior. It is suggested that the OT system, especially PVN OT neurons projecting to mPFC, modulates pup-directed behaviors and OT can be used to treat abnormal behavioral responses associated with some psychological diseases such as depression and psychosis.

A fine line between attack and care.

Oxytocin neuron projections from two brain regions involved in parental care regulate both parental care and infanticidal behaviors in virgin mandarin voles.

Synaptophysin and GSK-3beta activity in the prefrontal cortex may underlie the effects of REM sleep deprivation and lithium on behavioral functions and memory performance in male rats.

Rapid-eye movement (REM) stage of sleep serves a critical role in processing cognitive and behavioral functions. Evidence shows that REM sleep deprivation (REM SD) strongly affects the mood state and cognitive abilities. However, there are many inconsistent reports. Although the exact molecular mechanisms underlying REM SD effects have not well been discovered, however, molecular factors including those affected synaptic plasticity and mood state may be involved. There are two important molecular factors that have not been well studied: synaptophysin and glycogen synthase kinase-3 beta (GSK-3beta). The present study aimed to investigate the role of synaptophysin and GSK-3beta in the modulation of memory and behavioral changes induced by REM SD and lithium (as a potent GSK-3beta inhibitor and mood stabilizer). Multiple platform apparatus was used to induce REM SD for 48 h. Lithium was injected at the dose of 50 mg/kg, intraperitoneal (i.p.). Locomotor activity, anxiety-like behavior, pain threshold, novel object recognition memory, and synaptophysin and GSK-3beta level in the prefrontal cortex were evaluated. Results showed REM SD increased locomotor activity, decreased pain threshold, impaired novel object recognition memory, decreased synaptophysin and increased GSK-3beta levels. Lithium reversed these effects. Anxiety-like behavior was unaffected. For the first time, the present study showed that GSK-3beta and synaptophysin may be involved in the modulation of behavior and cognition induced by REM SD and lithium. In conclusion, we suggested that GSK-3beta upregulation and synaptophysin downregulation may underlie the deleterious effects of REM SD, while lithium may counteract REM SD effects via restoring the level of both.

How the arts heal: a review of the neural mechanisms behind the therapeutic effects of creative arts on mental and physical health.

Background: The creative arts have long been known for their therapeutic potential. These modalities, which include dance, painting, and music, among others, appear to be effective in enhancing emotional expression and alleviating adverse physiological and psychological effects. Engagement in creative arts can be pursued as a personal hobby, in a classroom setting, or through a formal therapeutic intervention with a qualified therapist. Engagement can be active (i.e., creating) or passive (i.e., viewing, listening). Regardless of the modality and manner of engagement, the mechanisms explaining the therapeutic efficacy of creative arts remain poorly understood. Objective: This study aims to systematically review research investigating the neurological mechanisms activated during active or passive engagement in creative arts, with a specific emphasis on the roles of the medial prefrontal cortex (mPFC) and the amygdala in emotional regulation (ER) and creative behaviors. The review seeks to provide preliminary evidence for the possible existence of common neural mechanisms underlying both phenomena, which could inform the development of targeted therapeutic interventions leveraging creative arts for ER. Methods: A systematic review was conducted following the Cochrane Collaboration guideline and PRISMA standards to identify studies examining the neurological mechanisms underlying creative activities. Results: A total of six out of 85 records meet the inclusion criteria, with all being basic research studies. Preliminary findings suggest that active and passive engagement with creative arts consistently activate neural circuits implicated in adaptive emotional regulation, including the mPFC and amygdala. These activations mirror the neural pathways engaged in effective ER strategies, suggesting the possible existence of shared mechanisms between creative expression and emotional processing. Conclusion: The evidence underscores the potential of creative arts as a complementary therapeutic strategy alongside conventional care and other evidence-based mind-body modalities. By elucidating the shared neural mechanisms between creative arts engagement and ER, this review contributes to the theoretical and practical understanding of the role of creative arts in mental health. Future research is recommended to further explore these neural correlations and their implications for therapeutic practice.

The dorsomedial prefrontal cortex promotes self-control by inhibiting the egocentric perspective.

The dorsomedial prefrontal cortex (dmPFC) plays a crucial role in social cognitive functions, including perspective-taking. Although perspective-taking has been linked to self-control, the mechanism by which the dmPFC might facilitate self-control remains unclear. Using the multimodal neuroimaging dataset from the Human Connectome Project (Study 1, N =978 adults), we established a reliable association between the dmPFC and self-control, as measured by discounting rate-the tendency to prefer smaller, immediate rewards over larger, delayed ones. Experiments (Study 2, N = 36 adults) involving high-definition transcranial direct current stimulation showed that anodal stimulation of the dmPFC reduces the discounting of delayed rewards and decreases the congruency effect in egocentric but not allocentric perspective in the visual perspective-taking tasks. These findings suggest that the dmPFC promotes self-control by inhibiting the egocentric perspective, offering new insights into the neural underpinnings of self-control and perspective-taking, and opening new avenues for interventions targeting disorders characterized by impaired self-regulation.

Exercise alleviates CUS-induced depressive-like behaviors by modulating paracellular and transcellular permeability of the blood-brain barrier in the prefrontal cortex.

BACKGROUND: Increased blood-brain barrier (BBB) permeability is implicated in the pathophysiology of major depressive disorder (MDD). While aerobic exercise has shown promise in mitigating MDD symptoms by potentially preserving BBB integrity, the detailed mechanisms remain unclear. This study explores these mechanisms to assess aerobic exercise's therapeutic potential for MDD. METHODS: Male C57BL/6 J mice were used in this study to investigate the effects of aerobic exercise on CUS-induced BBB permeability and depressive-like behaviors. Chronic unpredictable stress (CUS)-induced MDD mouse models were divided into three groups: Control, CUS, and CUS+Exercise. We monitored body weight, blood S100ß levels, and cytokines via ELISA. Claudin-5 and Caveolin-1 (CAV-1) expressions in the medial prefrontal cortex were evaluated using Western blotting and immunofluorescence. BBB permeability was assessed using biocytin-TMR and Alb-Alexa 594 tracers. Transmission electron microscopy was used to observe ultrastructural changes in the BBB directly. Depression-related behaviors were tested through several behavioral assays. RESULTS: CUS significantly increased CAV-1 expression and Alb-Alexa 594 leakage, suggesting enhanced transcellular BBB permeability. Despite unchanged Claudin-5 levels, its tight junction ultrastructure was altered, leading to increased biocytin-TMR leakage. Aerobic exercise ameliorated these disruptions, reduced inflammatory cytokines, and improved behavioral outcomes in CUS mice. CONCLUSION: Disruptions in both paracellular and transcellular BBB pathways are pivotal in depression development. Aerobic exercise offers potential therapeutic benefits for MDD linked with BBB dysfunction by mitigating stress-induced structural and functional changes.

Differing effectiveness of transcranial random noise stimulation and transcranial direct current stimulation for enhancing working memory in healthy individuals: a randomized controlled trial.

BACKGROUND: Transcranial direct current stimulation (tDCS) applied to the left dorsolateral prefrontal cortex (DLPFC) is a promising technique for enhancing working memory (WM) performance in healthy and psychiatric populations. However, limited information is available about the effectiveness of transcranial random noise stimulation (tRNS) applied to the left DLPFC on WM. This study investigated the effectiveness of tRNS on WM compared with that of tDCS, which has established functional evidence. METHODS: This randomized, double-blind, sham-controlled trial enrolled 120 healthy right-handed adults who were randomly allocated to four stimulation groups: tRNS + direct current (DC) offset, tRNS, tDCS, or sham. Each stimulus was placed over the left DLPFC and had a current intensity of 2 mA applied for 20 min during the dual n-back task. The dual n-back task was repeated thrice: pre-stimulation, during stimulation, and post-stimulation. The d-prime scores, and response times were calculated as the main outcome measures. A linear mixed model was created to identify the main effects and interactions between the groups and times, with the group and time as fixed effects, and baseline performance and the subject as a covariate and random effect, respectively. The relationships between the benefit of each stimulus and baseline WM performance were also examined. RESULTS: For the d-prime score during stimulation, the tRNS group significantly performed better than the sham group at online assessment (ß = 0.310, p = 0.001). In the relationships between the benefit of each stimulus and baseline WM performance, the tRNS group had significantly larger negative line slopes than the sham group for the d-prime score (ß = -0.233, p = 0.038). CONCLUSIONS: tRNS applied to the left DLPFC significantly improved WM performance and generated greater benefits for healthy individuals with lower WM performance. These findings highlight the potential utility of tRNS for enhancing WM performance in individuals with lower WM performance and contribute evidence for clinical application to patients with cognitive decline. TRIAL REGISTRATION: This study was registered in the University Hospital Medical Information Network Clinical Trial Registry in Japan (UMIN000047365) on April 1, 2022; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000054021 .

Reinforced pain catastrophizing during menstrual phase among women with primary dysmenorrhea is mediated by cerebral blood flow in the medial prefrontal cortex.

Pain catastrophizing is a prominent psychological factor that is strongly correlated with pain. Although the complex properties of pain catastrophizing vary across different pain phases, the contribution of chronic pain to its progression from a general trait to a higher state remains unclear. This study aimed to examine the neural mechanisms and degree to which pain catastrophizing is reinforced in the context of primary dysmenorrhea (PDM), one of the most prevalent gynaecological complaints experienced by women of reproductive age. Altogether, 29 women with moderate-to-severe PDM were included in this study. Arterial spin labelling was used to quantify the cerebral blood flow (CBF) in each participant in both the pain-free and painful phases. The pain catastrophizing scale (PCS) was completed in two phases, and the Short-Form McGill Pain Questionnaire was completed in the painful phase. Compared with pain catastrophizing in the pain-free phase (PCSpf), pain catastrophizing in the painful phase (PCSp) is higher and positively correlated with the composite factor of menstrual pain. CBF analysis indicated that the PCSp is positively associated with CBF in the frontal cortex, hippocampus and amygdala. The reinforcement of pain catastrophizing correlates with CBF in the prefrontal cortex. Specifically, the medial prefrontal cortex, which correlates with pain state, plays a crucial role in mediating the reinforcing effect of pain in the PCSp. These results promote the mechanical comprehension of pain catastrophizing management in individuals with chronic pain.

Mind Language Disturbances and PET-Signs of Depression vs Alzheimer's Disease: Are There Any Common Patterns Identified?

BACKGROUND: There is a broad appreciation that a diagnosis of depression (D) in the elderly is a strong risk factor for incident dementia, particularly Alzheimer's disease (AD). Indeed, the two disorders might constitute a dyad, although their causal relationship is uncertain, given the likely bidirectional and compounding effects of social withdrawal and loss of previous activities, and the manifestation of language disturbances, cognitive dysfunction, and social disruption that are typical of both conditions. We argue that language declines in D and AD share common patterns and biological underpinnings, and that D/AD patients might benefit from intensive language remediation training aiming to improve the functioning of neural networks that are linked to similar cognitive impairments. METHODS: A literature search in PubMed database included topics of language disturbances, cognitive impairments, and molecular brain imaging by positron emission tomography (PET) to identify common patterns in D and AD regarding language decline and its neurobiological underpinnings. RESULTS: Language disturbances show a particular commonality in the two disorders, manifesting in simplified language and particular speech markers (e.g., lexical and semantic repetitions, arguably due to ruminations in D and memory deficits in AD). PET can reveal abnormal protein deposits that are practically diagnostic of AD, but cerebrometabolic deficits to PET with the glucose tracer FDG show a certain commonality in D and AD. Typical findings of hypometabolism in the frontal lobes doubtless underlie the executive function deficits, where frontal hypometabolism in prodromal D increases with AD progression. This may reflect overlapping changes in noradrenaline and other neurotransmitter (e.g. serotonin) changes. Cerebrometabolic deficits associated with language dysfunction may inform targeted language remediation treatments in the D/AD progression. CONCLUSIONS: Language remediation techniques targeting specific language disturbances might present an important complimentary treatment strategy along with an adjusted pharmacotherapy approach and standard psychosocial rehabilitation interventions. We see a need for investigations of language remediation informed by the overlapping pathologies and language disturbances in D and AD.

Brain activity associated with emotion regulation predicts individual differences in working memory ability.

Previous behavioral research has found that working memory is associated with emotion regulation efficacy. However, there has been mixed evidence as to whether the neural mechanisms between emotion regulation and working memory overlap. The present study tested the prediction that individual differences on the working memory subtest of the Weschler Adult Intelligence Scale (WAIS-IV) could be predicted from the pattern of brain activity produced during emotion regulation in regions typically associated with working memory, such as the dorsal lateral prefrontal cortex (dlPFC). A total of 101 participants completed an emotion regulation fMRI task in which they either viewed or reappraised negative images. Participants also completed working memory test outside the scanner. A whole brain covariate analysis contrasting the reappraise negative and view negative BOLD response found that activity in the right dlPFC positively related to working memory ability. Moreover, a multivoxel pattern analysis approach using tenfold cross-validated support vector regression in regions-of-interest associated with working memory, including bilateral dlPFC, demonstrated that we could predict individual differences in working memory ability from the pattern of activity associated with emotion regulation. These findings support the idea that emotion regulation shares underlying cognitive processes and neural mechanisms with working memory, particularly in the dlPFC.

Orexin mechanisms in the prelimbic cortex modulate the expression of contextual conditioned fear.

RATIONALE: Despite the existing anatomical and physiological evidence pointing to the involvement of orexinergic projections from the lateral hypothalamus (LH) in regulating fear-related responses, little is known regarding the contribution of the orexin system in the prelimbic cortex (PL) on contextual fear. OBJECTIVES: We investigated the role of orexin-A (OrxA) and orexin type 1 receptors (Orx1R) in the PL during the expression of contextual conditioned fear in mice. METHODS: Neural tract tracing of the LH-PL pathway and Orx1R immunoreactivity in the PL of C57BL/6 male mice were performed. In a pharmacological approach, the animals were treated with either the Orx1R selective antagonist SB 334,867 (3, 30, and 300 nM/0.1 µL) or OrxA (28, 70, and 140 pmol/0.1 µL) in the PL before the test session of contextual fear conditioning. RESULTS: Neural tract tracing deposits in the LH showed some perikarya, mainly axons and terminal buttons in the PL, suggesting LH-PL reciprocate pathways. Furthermore, we showed a profuse network comprised of Orx1R-labeled thin varicose fibers widely distributed in the same field of LH-PL pathways projection. The selective blockade of Orx1R with SB 334,867 at 30 and 300 nM in the PL caused a decrease in freezing response, whereas the treatment with OrxA at 140 pmol promoted an increase in freezing response. CONCLUSION: In summary, these data confirmed an anatomical link between LH and PL, established the presence of Orx1R in the PL, and a modulatory role of the orexin system in such structure, possibly mainly via Orx1R, during contextual fear conditioning.

Nucleus reuniens: Modulating emotional overgeneralization in peri-adolescents with anxiety.

BACKGROUND: Anxiety affects 4.4-million children in the USA with an onset between childhood and adolescence, a period marked by neural changes that impact emotions and memory. Negative overgeneralization - or responding similarly to innocuous events that share features with past aversive experiences - is common in anxiety but remains mechanistically underspecified. The nucleus reuniens (RE) has been considered a crucial candidate in the modulation of memory specificity. Our study investigated its activation and functional connectivity with the medial prefrontal cortex (mPFC) and hippocampus (HPC) as neurobiological mechanisms of negative overgeneralization in anxious youth. METHODS: As part of a secondary data analysis, we examined data from 34 participants between 9 and 14 years of age (mean age ± SD, 11.4 ± 2.0 years; 16 females) with varying degrees of anxiety severity. During the Study session participants rated images as negative, neutral, and positive. After 12 h, participants returned for a Test session, where they performed a memory recognition test with repeated (targets) and similar (lures) images. Labeling negative relative to neutral lures as "old" (false alarms) was our operational definition of negative overgeneralization. RESULTS: Negative relative to neutral false alarmed stimuli displayed elevated RE activation (at Study and Test) and increased functional connectivity with the Cornu Ammonis (CA) 1 (at Test). Elevated anxiety severity was associated with reductions in the RE-mPFC functional coupling for neutral relative to negative stimuli. Exploratory analyses revealed similar patterns in activation and functional connectivity with positive stimuli. CONCLUSIONS: Our findings demonstrate the importance of the RE in negative overgeneralization and anxiety.

Efficacy and Safety of Transcranial Direct Current Stimulation as an Add-On Trial Treatment for Acute Bipolar Depression Patients With Suicidal Ideation.

AIMS: Bipolar depression poses an overwhelming suicide risk. We aimed to examine the efficacy and safety of transcranial direct current stimulation (tDCS) combined with quetiapine in bipolar patients as a suicidal intervention. METHODS: In a single-center, double-blind, treatment-naive bipolar depression patients with suicidal ideation were randomly assigned to quetiapine in combination with either active (n = 16) or sham (n = 15) tDCS over the left dorsolateral prefrontal cortex for three consecutive weeks. The 30-min, 2-mA tDCS was conducted twice a day on the weekday of the first week and then once a day on the weekdays of the two following weeks. Primary efficacy outcome measure was the change in the Beck Scale for Suicidal Ideation (BSSI). Secondary outcomes included changes on the 17-item Hamilton Depression Rating Scale (HDRS-17) and Montgomery-Asberg Depression Rating Scale (MADRS). Outcome was evaluated on Day 3 and weekend. Safety outcome was based on the reported adverse reactions. RESULTS: Active tDCS was superior to sham tDCS on the BSSI at Day 3 and tended to sustain every weekend during the treatment process, compared to baseline. However, no difference between active and sham in HDRS-17 and MADRS was found. Response and remission rate also supported the antisuicide effect of tDCS, with higher response and remission rate in BSSI, but no antidepressant effect, compared to sham, over time. Regarding safety, active tDCS was well tolerated and all the adverse reactions reported were mild and limited to transient scalp discomfort. CONCLUSION: The tDCS was effective as an antisuicide treatment for acute bipolar depression patients with suicidal ideation, with minimal side effects reported.

Analgesic effect of dance movement therapy: An fNIRS study.

OBJECTIVE: This study aims to explores the physiological and psychological mechanisms of exercise-induced hypoalgesia (EIH) by combining the behavioral results with neuroimaging data on changes oxy-hemoglobin (HbO) in prefrontal cortex (PFC). METHODS: A total of 97 healthy participants were recruited and randomly divided into three groups: a single dance movement therapy (DMT) group, a double DMT group, and control group. Evaluation indicators included the pressure pain threshold (PPT) test, the color-word stroop task (CWST) for wearing functional near-infrared spectroscopy (fNIRS), and the self-assessment manikin (SAM). The testing time is before intervention, after intervention, and one hour of sit rest after intervention. RESULTS: 1) Repeated measures ANOVA revealed that, there is a time * group effect on the PPT values of the three groups of participants at three time points. After 30 min of acute dance intervention, an increase in the PPT values of 10 test points occurred in the entire body of the participants in the experimental group with a significant difference than the control group. 2) In terms of fNIRS signals, bilateral DLPFC and left VLPFC channels were significantly activated in the experimental group. 3) DMT significantly awakened participants and brought about pleasant emotions, but cognitive improvement was insignificant. 4) Mediation effect analysis found that the change in HbO concentration in DLPFC may be a mediator in predicting the degree of improvement in pressure pain threshold through dance intervention (total effect ß = 0.7140). CONCLUSION: In healthy adults, DMT can produce a diffuse EIH effect on improving pressure pain threshold, emotional experience but only showing an improvement trend in cognitive performance. Dance intervention significantly activates the left ventrolateral and bilateral dorsolateral prefrontal cortex. This study explores the central nervous system mechanism of EIH from a physiological and psychological perspective.

Dopamine loss alters glutamate synapses and transporters in the medial prefrontal cortex and anxiety-related behaviour in a male MPTP rodent model of Parkinson's disease.

Anxiety is a prominent non-motor symptom of Parkinson's disease (PD). Changes in the B-spectrum recordings in PD patients of the prefrontal cortex correlate with increased anxiety. Using a rodent model of PD, we reported alterations in glutamate synapses in the striatum and substantia nigra following dopamine (DA) loss. We hypothesize that DA loss will result in increased anxiety-related behaviours and that this will be associated with alterations in glutamate synapses and transporters within the medial prefrontal cortex (mPFC). Following 4 weeks of progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, there was an increase in anxiety-related behaviours and a 78% decrease in plasma corticosterone levels versus the vehicle (VEH)-treated mice. This was associated with a 30% decrease in the density of dendritic spines in Layers Il/Ill, and a 53% decrease in the density of glutamate immuno-gold labelling within vesicular glutamate transporter 1 (Vglut1)-labelled nerve terminals and spines, with no change within vesicular glutamate transporter 2 (Vglut2) positive terminals/spines in the MPTP versus VEH groups. Our prior work determined that a decrease in striatal glutamate terminal density was associated with an increase in extracellular glutamate levels. There was an increase in protein expression of Vglut1 (40%), Vglut2 (37%) and glutamate aspartate transporter (GLAST) (225%), and a decrease in glutamate transporter 1 (GLT-1) (50%) and excitatory amino acid carrier 1 (EAAC1) (51%), in the MPTP versus VEH groups within the mPFC. These data suggest that the decrease in dendritic spines within the mPFC following nigrostriatal DA loss may be due to increased extracellular glutamate levels (decrease in glutamate transporters), leading to an increase in anxiety-related behaviours.

Postnatal Allergic Inhalation Induces Glial Inflammation in the Olfactory Bulb and Leads to Autism-Like Traits in Mice.

Autism spectrum disorder (ASD) is one of the most prevalent neurodevelopmental disorders. To explore its pathophysiology, we investigated the association between neonatal allergic exposure and behavioral changes. Adult female C57BL/6J mice were immunized with adjuvant (aluminum hydroxide) or ovalbumin emulsified with adjuvant. After immunization, the mice were mated, and offspring were born at full term. The postnatal dams and infants were then simultaneously exposed to an allergen (ovalbumin) or vehicle via inhalation. After weaning, behavioral testing and histopathological analyses were conducted on male offspring. Compared with the vehicle-exposed offspring, the ovalbumin-exposed offspring had decreased sociability and increased repetitive behavior, thus representing an ASD-like phenotype in mice. Moreover, histopathological analyses revealed that the ovalbumin-exposed mice had increased astroglial, microglial, and eosinophilic infiltration in the olfactory bulb, as well as increased eosinophils in the nasal mucosa. The ovalbumin-exposed mice also had decreased dendritic spine density and a lower proportion of mature spines, suggesting the impairment of stimulus-induced synaptogenesis. In conclusion, postnatal allergic exposure induced an ASD-like phenotype, as well as allergic rhinitis, which was followed by glial inflammation in the olfactory bulb parenchyma.

Human hippocampus and dorsomedial prefrontal cortex infer and update latent causes during social interaction.

Latent-cause inference is the process of identifying features of the environment that have caused an outcome. This problem is especially important in social settings where individuals may not make equal contributions to the outcomes they achieve together. Here, we designed a novel task in which participants inferred which of two characters was more likely to have been responsible for outcomes achieved by working together. Using computational modeling, univariate and multivariate analysis of human fMRI, and continuous theta-burst stimulation, we identified two brain regions that solved the task. Notably, as each outcome occurred, it was possible to decode the inference of its cause (the responsible character) from hippocampal activity. Activity in dorsomedial prefrontal cortex (dmPFC) updated estimates of association between cause-responsible character-and the outcome. Disruption of dmPFC activity impaired participants' ability to update their estimate as a function of inferred responsibility but spared their ability to infer responsibility.

Inulin may prevent the high-fat diet induced-obesity via suppressing endocannabinoid system in the prefrontal cortex in Wistar rats.

High-fat diets contribute to various metabolic disorders. Inulin supplementation has been shown to reduce appetite, lower food intake, and promote weight loss. Although there is evidence that the endocannabinoid system has metabolic effects in the prefrontal cortex, studies investigating the effects of inulin on the endocannabinoid system are limited. This study investigated the impact of inulin on obesity through the endocannabinoid system in the prefrontal cortex. Twenty-four male Wistar rats were fed one of four diets over 12 weeks. Findings indicated that a high-fat diet led to obesity, whereas inulin reduced food intake and supported weight loss. Consequently, inulin supplementation both prevented obesity and significantly decreased the expressions of Adrb3 and Adcy1, and anandamide and 2-arachidonylglycerol levels in the prefrontal cortex. Additionally, inulin lowered leptin in circulation and stimulated Trpv1. Thus, inulin may mitigate obesity development, possibly by modulating gene expressions linked to obesity in the prefrontal cortex via endocannabinoids.

α-Synuclein aggregation decreases cortico-amygdala connectivity and impairs social behavior in mice.

Abnormal accumulation of insoluble α-synuclein (α-Syn) inclusions in neurons, neurites, and glial cells is the defining neuropathology of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy. Accumulation of α-Syn inclusions in the amygdala has been well-documented in post-mortem studies of PD and DLB brains, as well as preclinical animal models of these conditions. Though α-Syn pathology is closely associated with neurodegeneration, there is a poor correlation between neuronal loss in the amygdala and the clinical features of PD and DLB. Moreover, functional interaction between the cerebral cortex and the amygdala is critical to regulating emotion, motivation, and social behaviors. The cortico-amygdala functional interaction is likely to be disrupted by the development of α-Syn pathology in the brain. Thus, we hypothesize that neuronal α-Syn inclusions disrupt cortical modulation of the amygdala circuits and are sufficient to drive social behavioral deficits. In the present work, we designed a series of longitudinal studies to rigorously measure the time courses of neurodegeneration, functional impairment of cortico-amygdala connectivity, and development of amygdala-dependent social behavioral deficits to test this hypothesis. We injected α-Syn preformed fibrils (PFFs) into the dorsal striatum to induce α-Syn aggregation in the amygdala and the medial prefrontal cortex (mPFC) of C57BL6 mice of both sexes, followed by a detailed analysis of temporal development of α-Syn pathology, synaptic deficits, and neuronal loss in the amygdala, as well as behavioral deficits at 3-12 months post injections. Development of α-Syn inclusions caused losses of cortical axon terminals and cell death in the basolateral amygdala (BLA) at 6- and 12-months post injections, respectively. At a relatively early stage of 3 months post injections, the connection strength of the mPFC-BLA synapse was decreased in PFFs-injection mice compared to controls. Meanwhile, the PFFs-injected mice showed impaired social interaction behavior, which was rescued by chemogenetic stimulation of mPFC-BLA connections. Altogether, we presented a series of evidence to delineate circuit events in the amygdala associated with the accumulation of α-Syn inclusions in the mouse brain, highlighting that functional impairment of the amygdala is sufficient to cause social behavior deficits. The present work further suggests that early circuit modulation could be an effective approach to alleviate symptoms associated with α-Syn pathology, necessitating studies of functional consequences of α-Syn aggregation.

Cannabidiol partially rescues behavioral, neuroinflammatory and endocannabinoid dysfunctions stemming from maternal obesity in the adult offspring.

Maternal obesity is known to increase the risk of psychiatric disorders, such as anxiety, depression, schizophrenia and autism spectrum disorder in the offspring. While preventive measures are well-documented, practical approaches for addressing the damages once they are already established are limited. We have recently demonstrated the interplay between maternal obesity and treatment with cannabidiol (CBD) on neuroinflammation and peripheral metabolic disturbances during adolescence, however, it is known that both factors tend to vary throughout life. Therefore, here we investigated the potential of CBD to mitigate these alterations in the adult offspring of obese dams. Female Wistar rats were fed a cafeteria diet for 12 weeks prior to mating, and during gestation and lactation. Offspring received CBD (50 mg/kg) for 3 weeks from the 70th day of life. Behavioral tests assessed anxiety-like manifestations and social behavior, while neuroinflammatory and endocannabinoid markers were evaluated in the hypothalamus, prefrontal cortex (PFC) and hippocampus, as well as the biochemical profile in the plasma. CBD treatment attenuated maternal obesity-induced anxiety-like and social behavioral alterations, restoring exacerbated astrocytic and microglial markers in the hypothalamus, PFC and hippocampus of the offspring, as well as endocannabinoid levels in the PFC, with notable sex differences. Additionally, CBD attenuated plasma glucose and lipopolysaccharides (LPS) concentrations in females. These findings underscore the persistent influence of maternal obesity on the offspring's health, encompassing metabolic irregularities and behavioral impairments, as well as the role of the endocannabinoid system in mediating these outcomes across the lifespan.