The role of the prefrontal cortex in modulating aggression in humans and rodents.

Accumulating evidence suggests that the prefrontal cortex (PFC) plays an important role in aggression. However, the findings regarding the key neural mechanisms and molecular pathways underlying the modulation of aggression by the PFC are relatively scattered, with many inconsistencies and areas that would benefit from exploration. Here, we highlight the relationship between the PFC and aggression in humans and rodents and describe the anatomy and function of the human PFC, along with homologous regions in rodents. At the molecular level, we detail how the major neuromodulators of the PFC impact aggression. At the circuit level, this review provides an overview of known and potential subcortical projections that regulate aggression in rodents. Finally, at the disease level, we review the correlation between PFC alterations and heightened aggression in specific human psychiatric disorders. Our review provides a framework for PFC modulation of aggression, resolves several intriguing paradoxes from previous studies, and illuminates new avenues for further study.

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.

The effects of moderate alcohol and THC co-use during male and female rat adolescence on AKT-GSK3ß signaling in adulthood.

Alcohol and cannabis are often taken in combination, and extensive co-use has been linked to enduring changes in cognitive and metabolic functioning. The underlying mechanisms for these effects are unclear, but we recently demonstrated that co-administration of ethanol and delta-9-tetrahydrocannbinol (THC) to adolescent rats caused lasting adaptations in GABA and glycogen synthase kinase 3ß (GSK3ß) signaling in the medial prefrontal cortex (mPFC). As a ubiquitous protein kinase, GSK3ß is downstream to the protein kinase B (also known as AKT) pathway that is activated by insulin receptor signaling in a main control center for metabolism and energy homeostasis, the mediobasal hypothalamus (MBH). Our goal here was to investigate if volitional co-use of low to moderate levels of ethanol and THC would impact the total and phosphorylated levels (p) of AKT and GSK3ß in the mPFC and MBH. Peri-adolescent Long Evans rats [postnatal day (P) 30-47] consumed 10 % ethanol, cookies laced with THC (3-10 mg/kg/day), both drugs, or vehicle controls. On P114, we modeled re-exposure to a behaviorally relevant dose of THC by challenging rats (i.p.) with 5 mg/kg THC (or vehicle) and sacrificed them 30 min later. Western blot analysis revealed that THC challenge increased pAKT and pGSK3ß compared to control similarly across all treatment groups, sexes, and brain regions; no effects on total levels of AKT or GSK3ß were found. Previously reported behavioral results from these rats showed no differences in working memory assessed in adulthood. Although future studies will be necessary to determine the role of exposure dose on drug-induced adaptations in AKT and GSK3ß signaling, the current findings suggest that moderate volitional co-use of alcohol and THC may not produce long-term deficits that persist into adulthood.

Sex-dependent perturbations in risky choice behavior and prefrontal tyrosine hydroxylase levels induced by repetitive mild traumatic brain injury.

Head trauma often impairs cognitive processes mediated within the prefrontal cortex (PFC), leading to impaired decision making and risk-taking behavior. Mild traumatic brain injury (mTBI) accounts for approximately 80 % of reported head injury cases. Most neurological symptoms of a single mTBI are transient; however, growing evidence suggests that repeated mTBI (rmTBI) results in more severe impairments that worsen with each subsequent injury. Although mTBI-induced disruption of risk/reward decision making has been characterized, the potential for rmTBI to exacerbate these effects and the neural mechanisms involved are unknown. Catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), modulate PFC-mediated functions. Imbalances in catecholamine function have been associated with TBI and may underlie aberrant decision making. We used a closed head-controlled cortical impact (CH-CCI) model in rats to evaluate the effects of rmTBI on performance of a probabilistic discounting task of risk/reward decision making behavior and expression levels of catecholamine regulatory proteins within the PFC. RmTBI produced transient increases in risky choice preference in both male and female rats, with these effects persisting longer in females. Additionally, rmTBI increased expression of the catecholamine synthetic enzyme, tyrosine hydroxylase (TH), within the orbitofrontal (OFC) region of the PFC in females only. These results suggest females are more susceptible to rmTBI-induced disruption of risk/reward decision making behavior and dysregulation of catecholamine synthesis within the OFC. Together, using the CH-CCI model of rodent rmTBI to evaluate the effects of multiple insults on risk-taking behavior and PFC catecholamine regulation begins to differentiate how mTBI occurrences affect neuropathological outcomes across different sexes.

Characterization of GABAergic marker expression in prefrontal cortex in dexamethasone induced depression/anxiety model.

Background: The pivotal responsibility of GABAergic interneurons is inhibitory neurotransmission; in this way, their significance lies in regulating the maintenance of excitation/inhibition (E/I) balance in cortical circuits. An abundance of glucocorticoids (GCs) exposure results in a disorder of GABAergic interneurons in the prefrontal cortex (PFC); the relationship between this status and an enhanced vulnerability to neuropsychiatric ailments, like depression and anxiety, has been identified, but this connection is still poorly understood because systematic and comprehensive research is lacking. Here, we aim to investigate the impact of dexamethasone (DEX, a GC receptor agonist) on GABAergic interneurons in the PFC of eight-week-old adult male mice. Methods: A double-blind study was conducted where thirty-two mice were treated subcutaneously either saline or DEX (0.2 mg/10 ml per kg of body weight) dissolved in saline daily for 21 days. Weight measurements were taken at five-day intervals to assess the emotional changes in mice as well as the response to DEX treatment. Following the 21-day regimen of DEX injections, mice underwent examinations for depression/anxiety-like behaviours and GABAergic marker expression in PFC. Results: In a depression/anxiety model generated by chronic DEX treatment, we found that our DEX procedure did trigger depression/anxiety-like behaviors in mice. Furthermore, DEX treatment reduced the expression levels of a GABA-synthesizing enzyme (GAD67), Reelin, calcium-binding proteins (parvalbumin and calretinin) and neuropeptides co-expressed in GABAergic neurons (somatostatin, neuropeptide Y and vasoactive intestinal peptide) in the PFC were reduced after 21 days of DEX treatment; these reductions were accompanied by decreases in brain size and cerebral cortex thickness. Conclusion: Our results indicate that a reduction in the number of GABAergic interneurons may result in deficiencies in cortical inhibitory neurotransmission, potentially causing an E/I imbalance in the PFC; this insight suggests a potential breakthrough strategy for the treatment of depression and anxiety.

Maternal separation alters peripheral immune responses associated with IFN-γ and OT in mice.

The co-evolution of social behavior and the immune system plays a critical role in individuals' adaptation to their environment. However, also need for further research on the key molecules that co-regulate social behavior and immunity. This study focused on neonatal mice that were separated from their mothers for 4 hours per day between the 6th and 16th day after birth. The results showed that these mice had lower plasma levels of IFN-γ and oxytocin, but higher levels of plasma glucocorticoids (GC), then impacting their social abilities. Additionally, maternal separation led to decreased levels of BDNF, IGF2, and CREB mRNAs in the hippocampus, while levels in the prefrontal cortex (PFC) remained unaffected. Maternal separation also resulted in increased levels of oxytocin and CRH mRNA in the hypothalamus, as well as an increase in CD45+ lymphocyte subsets in the meninges and choroid plexus (CP), with CD8+ lymphocytes in meninges and CD4+ lymphocytes in CP showing an increase. In IFN-γ-/- mice, a decrease in social preference was observed alongside lower plasma oxytocin levels. Moreover, IFN-γ-/- mice exhibited reduced numbers of oxytocin neurons in the paraventricular nucleus of the paraventricular nucleus of hypothalamus (PVN), decreased BDNF levels in the PFC and hippocampus, and alterations in CD45+ lymphocytes in CP and meninges, with an increase in CD8+ lymphocytes in meninges and CD4+ lymphocytes in CP. These findings highlight the immunological impact of social stress on IFN-γ regulation, suggesting that the immunomodulatory molecule IFN-γ may influence social behavior by affecting synaptic efficiency in brain regions such as the hippocampus and PFC, which are linked to oxytocin in the PVN.

Shared oscillatory mechanisms of alpha-band activity in prefrontal regions in eyes open and closed state using a portable EEG acquisition device.

Alpha oscillations are associated with various psychiatric disorders, with many studies focusing on the prefrontal cortex, where transcranial alternating current stimulation (TACS) is applied in the alpha frequency band. This approach often involves selecting individualized alpha frequencies to resonate with their endogenous alpha oscillations. While strong alpha oscillations (8-13 Hz) are typically induced when the eyes are closed, they can also occur during the resting state with eyes open. However, it remains unclear whether these alpha oscillations share a common neural generation mechanism. Exploring which of these alpha oscillations is more suitable as a stable alpha peak frequency is a question of significant interest. Therefore, to systematically study this issue, we specifically collected resting-state electroencephalographic (EEG) data from the prefrontal region of 40 individuals, under both eyes-open and closed- eye conditions, with multiple follow-ups extending up to nine months. Through spectral analysis on each person's entire dataset and averaging the results, we observed a significant positive correlation between the alpha-band power in the eyes-open and the eyes-closed states, in terms of both absolute power and relative power. Further analysis revealed that this correlation was primarily contributed by the periodic activity within the alpha band. Upon modelling the oscillatory components, we discovered distinct differences in the oscillatory characteristics-such as number of the alpha sub-oscillations between the eyes-open state and the eyes-closed state. Our study is the first to systematically explored the relationship between alpha oscillations in the prefrontal cortex in the eyes-open and eyes-closed states, identifying both shared part of the neural generation mechanism and some distinct neural mechanisms that are unique to each state.

Atypical prefrontal neural activity during an emotional interference control task in adolescents with autism spectrum disorder: A functional near-infrared spectroscopy study.

Autism spectrum disorder (ASD) is typically characterized by impairments in social interaction and communication, which may be associated with a failure to naturally orient to social stimuli, particularly in recognizing and responding to facial emotions. As most previous studies have used nonsocial stimuli to investigate inhibitory control in children and adults with ASD, little is known about the behavioral and neural activation patterns of emotional inhibitory control in adolescent with ASD. Functional neuroimaging studies have underscored the key role of the prefrontal cortex (PFC) in inhibitory control and emotional face processing. Thus, this study aimed to examine whether adolescent with ASD exhibited altered PFC processing during an emotional Flanker task by using non-invasive functional near-infrared spectroscopy (fNIRS). Twenty-one adolescents with high-functioning ASD and 26 typically developing (TD) adolescents aged 13-16 years were recruited. All participants underwent an emotional Flanker task, which required to decide whether the centrally positioned facial emotion is consistent with the laterally positioned facial emotion. TD adolescents exhibited larger RT and mean O2Hb level in the incongruent condition than the congruent condition, evoking cortical activations primarily in right PFC regions in response to the emotional Flanker effect. In contrast, ASD adolescents failed to exhibit the processing advantage for congruent versus incongruent emotional face in terms of RT, but showed cortical activations primarily in left PFC regions in response to the emotional Flanker effect. These findings suggest that adolescents with ASD rely on different neural strategies to mobilize PFC neural resources to address the difficulties they experience when inhibiting the emotional face.

Effects of lateral ventricle injection of 5,7-dihydroxytryptamine on neurons in the medial prefrontal cortex of rats: An electrophysiology study.

The medial prefrontal cortex (mPFC) is closely associated with various psychopathologies in humans, and its dysfunction is invariably accompanied by abnormalities in the serotonin (5-hydroxytryptamine, 5-HT) system of the brain. In this study, in-vivo extracellular recording techniques were used to investigate changes in the excitability of pyramidal neurons and interneurons in the rat mPFC following injection of 5,7-dihydroxytryptamine (5,7-DHT) into the bilateral lateral ventricles to damage the serotoninergic neurons. The levels of 5-HT in the mPFC and dorsal raphe nucleus of rats were determined by high-performance liquid chromatography. The results showed that the levels of 5-HT were significantly reduced in the mPFC and dorsal raphe nucleus two weeks after injection of 5,7-DHT into the bilateral lateral ventricles, relative to the normal group. The discharge frequency of pyramidal neurons in the mPFC was markedly increased compared to the normal group, with a significant rise in burst discharge, while the average discharge frequency of interneurons was significantly reduced and tended towards irregular activity. The results of the study indicated that the brain's 5-HT neurotransmitter system not only directly affects the activity of mPFC pyramidal neurons but also modulates the electrical activity of interneurons, thereby regulating the local microcircuitry within the mPFC and participating in its function.

Prefrontal cortex activation and working memory performance in individuals with non-clinical depression: Insights from fNIRS.

Previous research has extensively explored cognitive and neural deficits in clinically diagnosed depression, but the early stages of depression, where symptoms do not meet clinical thresholds, are less explored. This study investigated neurocognitive markers in individuals with non-clinical depression. The study assessed working memory (WM) performance and hemodynamic responses of prefrontal cortex (PFC) in 30 individuals with non-clinical depression and 41 healthy controls using two-back tasks with four stimulus types: numbers, letters, shapes, and emotional facial expressions. Hemodynamic responses were measured via oxyhemoglobin (HbO) using functional near-infrared spectroscopy. Results showed that individuals with non-clinical depression have significantly lower WM performance compare to healthy controls, particularly for shape- and emotional facial expression-based tasks. No differences were observed for the number- and letter- based tasks. Additionally, individual with non-clinical depression exhibited elevated HbO levels, indicating increased PFC activation. Specifically, significant HbO differences observed in the bilateral ventrolateral PFC during shape-based tasks, and in the left medial, bilateral orbital, and bilateral ventrolateral PFCs during emotional facial expression-based tasks. In conclusion, individuals with non-clinical depression may experience WM deficits and PFC dysregulation, even without a clinical diagnosis. This study highlights the role of stimulus type in understanding WM performance and PFC activation in depression.

The claustrum and synchronized brain states.

Cortical activity is constantly fluctuating between distinct spatiotemporal activity patterns denoted by changes in brain state. States of cortical desynchronization arise during motor generation, increased attention, and high cognitive load. Synchronized brain states comprise spatially widespread, coordinated low-frequency neural activity during rest and sleep when disengaged from the external environment or 'offline'. The claustrum is a small subcortical structure with dense reciprocal connections with the cortex suggesting modulation by, or participation in, brain state regulation. Here, we highlight recent work suggesting that neural activity in the claustrum supports cognitive processes associated with synchronized brain states characterized by increased low-frequency network activity. As an example, we outline how claustrum activity could support episodic memory consolidation during sleep.

Investigating the impact of mental rehearsal on prefrontal and motor cortical haemodynamic responses in surgeons using optical neuroimaging.

Introduction: Inadequate exposure to real-life operating can impede timely acquisition of technical competence among surgical residents, and is a major challenge faced in the current training climate. Mental rehearsal (MR)-the cognitive rehearsal of a motor task without overt physical movement-has been shown to accelerate surgical skills learning. However, the neuroplastic effect of MR of a complex bimanual surgical task is unknown. The aim of this study is to use functional near-infrared spectroscopy (fNIRS) to assess the impact of MR on prefrontal and motor cortical activation during a laparoscopic knot tying task. Methods: Twelve surgical residents performed a laparoscopic knot tying task before and after either mental rehearsal (MR, intervention group) or textbook reading (TR, control group). In both groups, fNIRS was used to measure changes in oxygenated hemoglobin concentration (HbO2) in the prefrontal (24 channels) and motor cortices (22 channels). Technical performance was measured using leak volume, objective performance score and task progression score. Results: MR led to a decrease in HbO2 (reduced activation) in the bilateral prefrontal cortex (PFC), and an increase in HbO2 (increased activation) in the left middle frontal gyrus, left precentral gyrus, and left postcentral gyrus. No discernible changes in activation were observed after TR in either the PFC or motor cortex. Moreover, smaller ΔHbO2 responses in the right PFC and greater ΔHbO2 responses in the left motor cortex were observed in the MR group compared with the TR group. Leak volume was significantly less following MR (p = 0.019), but not after TR (p = 0.347). Mean objective performance score was significantly higher following MR compared with TR (p = 0.043). Conclusion: Mental rehearsal may enhance surgical skill acquisition and technical proficiency by reducing utilization of attentional resources in the prefrontal cortex and improving neural efficiency in motor areas during a laparoscopic surgical task.

Stress-induced c-fos expression in the medial prefrontal cortex differentially affects the main residing cell phenotypes.

Stress poses a challenge to the body's equilibrium and triggers a series of responses that enable organisms to adapt to stressful stimuli. The medial prefrontal cortex (mPFC), particularly in acute stress conditions, undergoes significant physiological changes to cope with the demands associated with cellular activation. The proto-oncogene c-fos and its protein product c-Fos have long been utilized to investigate the effects of external factors on the central nervous system (CNS). While c-Fos expression has traditionally been attributed to neurons, emerging evidence suggests its potential expression in glial cells. In this study, our main objective was to explore the expression of c-Fos in glial cells and examine how acute stress influences these activity patterns. We conducted our experiments on male Wistar rats, subjecting them to acute stress and sacrificing them 2 h after the stressor initiation. Using double-labelling fluorescent immunohistochemistry targeting c-Fos, along with markers such as GFAP, Iba-1, Olig2, NG2, and NeuN, we analyzed 35 µm brain slices obtained from the mPFC. Our findings compellingly demonstrate that c-Fos expression extends beyond neurons and is present in astrocytes, oligodendrocytes, microglia, and NG2 cells-the diverse population of glial cells. Moreover, we observed distinct regulation of c-Fos expression in response to stress across different subregions of the mPFC. These results emphasize the importance of considering glial cells and their perspective in studies investigating brain activity, highlighting c-Fos as a response marker in glial cells. By shedding light on the differential regulation of c-Fos expression in response to stress, our study contributes to the understanding of glial cell involvement in stress-related processes. This underscores the significance of including glial cells in investigations of brain activity and expands our knowledge of c-Fos as a potential marker for glial cell responses.

Diminished negative emotion regulation through affect labeling and reappraisal: insights from functional near infrared spectroscopy on lateral prefrontal cortex activation.

BACKGROUND: Reappraisal, an emotion regulation strategy, includes reinterpretation and affect labeling involving verbalizing emotions. In general, reappraisal is supported by lateral prefrontal cortical regions, which are also known to underlie cognitive regulation. Other research has shown that affect labeling combined with reappraisal of negative emotions increases lateral prefrontal cortex activity more than reappraisal alone does, suggesting that affect labeling facilitates emotional regulation. However, the influence of affect labeling on the efficacy of reappraisal in reducing subjective negative emotions has not been determined. METHODS: In the experiment, 35 participants (mean age = 28.2 years (SD = 9.63); 12 women and 23 men) viewed vignettes that aroused negative emotion. Then, they rated subjective negative emotions as baseline values. Following the baseline rating, the task branched into four conditions, combining affect labeling and emotion regulation factors. In the affect-labeling factor, participants selected emotional labels consistent with their own emotions or not. Regarding the emotion regulation factor, participants engaged in reappraisal to regulate their negative emotions. Throughout the experiment, the intensity of negative emotions was measured three times, mirroring the baseline measurement. Oxyhemoglobin (OxyHb) signal values in prefrontal cortex regions during tasks were measured by functional near-infrared spectroscopy. RESULTS: Differences between the subjective negative emotion ratings at baseline and after reappraisal indicated that reappraisal significantly reduced negative emotion with and without affect labeling (t (1173.05) = 29.97, p < 0.001), and the combination of affect labeling and reappraisal was less effective in regulating negative emotions at the subjective level than reappraisal without affect labeling (t (1172.03) = 3.15, p < 0.01). Additionally, there was an increase in OxyHb signal in the bilateral dorsolateral prefrontal and right ventral prefrontal cortices while participants performed reappraisal with affect labeling. CONCLUSION: Our findings suggest that affect labeling, when performed prior to cognitive reappraisal, may influence the process of negative emotion regulation in complex ways. The interaction between affect labeling and reappraisal appears to modulate prefrontal cortex activity, potentially reflecting changes in cognitive processing during emotion regulation attempts. These results highlight the need for further investigation into the intricate relationship between different emotion regulation strategies.

An overview of the pathophysiology of agitation in Alzheimer's dementia with a focus on neurotransmitters and circuits.

Alzheimer's dementia (AD) is a progressive, neurodegenerative disease often accompanied by neuropsychiatric symptoms that profoundly impact both patients and caregivers. Agitation is among the most prevalent and distressing of these symptoms and often requires treatment. Appropriate therapeutic interventions depend on understanding the biological basis of agitation and how it may be affected by treatment. This narrative review discusses a proposed pathophysiology of agitation in Alzheimer's dementia based on convergent evidence across research approaches. Available data indicate that agitation in Alzheimer's dementia is associated with an imbalance of activity between key prefrontal and subcortical brain regions. The monoamine neurotransmitter systems serve as key modulators of activity within these brain regions and circuits and are rendered abnormal in AD. Patients with AD who exhibited agitation symptoms during life have alterations in neurotransmitter nuclei and related systems when the brain is examined at autopsy. The authors present a model of agitation in Alzheimer's dementia in which noradrenergic hyperactivity along with serotonergic deficits and dysregulated striatal dopamine release contribute to agitated and aggressive behaviors.

Meta-learning of human motor adaptation via the dorsal premotor cortex.

Meta-learning enables us to learn how to learn the same or similar tasks more efficiently. Decision-making literature theorizes that a prefrontal network, including the orbitofrontal and anterior cingulate cortices, underlies meta-learning of decision making by reinforcement learning. Recently, computationally similar meta-learning has been theorized and empirically demonstrated in motor adaptation. However, it remains unclear whether meta-learning of motor adaptation also relies on a prefrontal network. Considering hierarchical information flow from the prefrontal to motor cortices, this study explores whether meta-learning is processed in the dorsolateral prefrontal cortex (DLPFC) or in the dorsal premotor cortex (PMd), which is situated upstream of the primary motor cortex, but downstream of the DLPFC. Transcranial magnetic stimulation (TMS) was delivered to either PMd or DLPFC during a motor meta-learning task, in which human participants were trained to regulate the rate and retention of motor adaptation to maximize rewards. While motor adaptation itself was intact, TMS to PMd, but not DLPFC, attenuated meta-learning, impairing the ability to regulate motor adaptation to maximize rewards. Further analyses revealed that TMS to PMd attenuated meta-learning of memory retention. These results suggest that meta-learning of motor adaptation relies more on the premotor area than on a prefrontal network. Thus, while PMd is traditionally viewed as crucial for planning motor actions, this study suggests that PMd is also crucial for meta-learning of motor adaptation, processing goal-directed planning of how long motor memory should be retained to fit the long-term goal of motor adaptation.

GPR158 in pyramidal neurons mediates social novelty behavior via modulating synaptic transmission in male mice.

Impairment in social communication skills is a hallmark feature of autism spectrum disorder (ASD). The role of G-protein-coupled receptor 158 (GPR158) in ASD remains largely unexplored. In this study, we observed that both constitutive and cell-/tissue-specific knockouts of Gpr158 in pyramidal neurons or the medial prefrontal cortex (mPFC) result in impaired novelty preference, while sociability remains unaffected in male mice. Notably, the loss of GPR158 leads to a significant decline in excitatory synaptic transmission, characterized by a reduction in glutamate vesicles, as well as the expression and phosphorylation of GluN2B in the mPFC. We successfully rescue the phenotype of social novelty deficits either by reintroducing GPR158 in the mPFC of Gpr158 deficient mice or by chemogenetic activation of pyramidal neurons where Gpr158 is specifically ablated. Our findings indicate that GPR158 in pyramidal neurons plays a specific role in modulating social novelty and may represent a potential target for treating social disorders.

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.

Efficacy of sequential primary motor and prefrontal cortices intermittent Theta burst stimulation in persistent somatoform PAIN disorder (TAP-PAIN): A randomized sham-controlled pilot trial.

Aim: There is a need to elucidate intermittent Theta burst stimulation (iTBS) as a novel treatment in persistent somatoform pain disorder (PSPD). Methods: Twenty patients were randomly allocated to active iTBS (n = 11) and sham iTBS (n = 9) and received 10 iTBS sessions, 2 sessions per day, sequentially to primary motor and dorsolateral prefrontal cortices for 5 days in a week. Each iTBS session comprised of 2 sec. per train of 10 bursts (3 pulses per burst at 50 Hz; total 30 pulses) and were given with a gap of 5 Hz, total of 20 trains, and 600 pulses. Visual Analogue Scale, Brief Pain Inventory and Global Pain Scale (GPS), Montgomery and Asberg Depression Rating Scale, Hamilton Anxiety Rating Scale - Anxiety, World Health Organization Quality-of-Life Scale-brief, and Pittsburgh Sleep Quality Index were applied at baseline, after last session, and at 2 weeks after last TBS session. Intention to treat analysis was conducted. Results: Both groups were comparable for baseline psychopathology scores including clinical variables like age (t = 0.865; P = 0.398), duration of illness (t = 1.600; P = 0.127), and motor threshold (t = 0.304; P = 0.765). On repeated measures ANOVA, a significant within-group time effect for VAS, BPI-Severity, BPI-Interference, BDI - II, MADRS, HAM-A, and WHOQOL- BREF was found for active and sham TBS groups, respectively. GPS scores had significant within-group (active) * time interaction (F = 11.651; P = .001; ηp2 = 0.538) and between-group * time interaction (F = 3.407; P = 0.044; ηp2 = 0.159). However, between-group * time effect interaction was lost after covariance (F = 1.726; P = 0.196; ηp2 = 0.110). Conclusion: No major adverse effects were reported. Our pilot trial concludes that safe therapeutic efficacy of iTBS in PSPD is inconclusive. Lower total number of sessions along with small sample size may limit the study findings.

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.