Search Results (22)

α-Synuclein (α-Syn) is a key presynaptic protein, primarily known for its role in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, including dementia with Lewy bodies (DLB). Although much of the research has focused on the nigrostriatal dopamine (DA) pathway, there is growing recognition that the accumulation of misfolded α-Syn in the prefrontal cortex (PFC) is a critical driver of non-motor symptoms and cognitive deficits in PD and DLB. This review examines the dual role of α-Syn in the PFC circuitry, initially exploring its regulation of synaptic vesicle (SV) dynamics and recycling to maintain stable neurotransmission. We highlight its contribution to the modulation of glutamatergic (Glu) and GABAergic (γ-aminobutyric acid, GABA) synapses, which ensures the functional excitatory/inhibitory (E/I) balance of prefrontal circuits. Conversely, in PD and DLB, the transition of functional α-Syn monomers to pathological oligomers triggers a cascade of synaptic failures. We analyze how α-Syn aggregation causes pathology in dendritic spines, leads to a progressive reduction in the density of synaptic markers, and impairs cortical plasticity. Synthesizing evidence from neuroimaging studies, post-mortem human cortical samples, and animal models, this review emphasizes the PFC as a vulnerable brain region where α-Syn-mediated synaptic dysfunction translates into cognitive and emotional deficits. Deciphering these early synaptic alterations is essential for developing neuroprotective strategies that preserve cortical function in PD and DLB. Full article

The rapid expansion of digital technologies has created an unprecedented level of increased connectivity, yet the neurobiological mechanisms underlying these changes remain incompletely understood. This systematic review synthesizes the currently available evidence on neurobiological findings related to problematic internet use, problematic smartphone/social media use, and internet gaming disorder, with a focus on reward processing, attentional control, and emotional regulation. Across the included studies, recurrent findings suggested the involvement of fronto-striatal circuitry, salience- and reward-related regions, and executive-control networks. Alterations in large-scale brain networks, including the default mode, salience, and frontoparietal systems, were also reported, although the evidence base was heterogeneous and consisted largely of cross-sectional studies with modest sample sizes. Overall, the findings support a provisional neurobiological framework linking reward-related processing, inhibitory-control difficulties, and large-scale network alterations, but better-standardized studies are needed to draw conclusions. Full article

Prolonged grief disorder (PGD) affects approximately 10% of bereaved individuals and is now formally recognized in both the DSM-5-TR and ICD-11. Despite its prevalence, PGD often responds poorly to traditional therapeutic approaches. This manuscript outlines the protocol for an early-stage open-label feasibility trial investigating the use of psilocybin, a psychedelic compound, in treating PGD in adults, with a focus on young adults. The study will involve 20 participants diagnosed with PGD. Each participant will undergo a structured therapeutic process that includes a preparatory session, a single 25 mg dose of psilocybin, and post-session integration. Throughout the study, participants will be monitored via symptom assessments, including qualitative and quantitative data, with the main aims related to safety, feasibility and acceptability. Functional MRIs will be obtained pre- and post-dosing and collected during a standardized grief-elicitation methodology. Key outcome measures include changes in the severity of PGD and trauma symptoms, cognitive flexibility, openness to experience, meaning in life and subjective experiences during the psilocybin session. Neural activity will also be evaluated through fMRI to better understand the neurobiological effects of the treatment. This research represents one of the first clinical protocols specifically focused on the potential of psilocybin for treating PGD. The goal is to assess feasibility and safety while laying the groundwork for future randomized controlled trials. Full article

Traumatic brain injury (TBI) can lead to persistent adverse outcomes, including cognitive and emotional dysfunction, with recent estimates indicating that up to 50% of individuals with mild TBI experience long-term symptoms. Growing evidence suggests that biological sex influences TBI outcomes and recovery trajectories; however, the molecular underpinnings driving these sex-specific differences remain poorly understood. In this study, a preclinical TBI model was used to directly compare chronic glutamatergic alterations in adult male and female Sprague Dawley rats. To define frontocortical molecular signatures associated with sex-specific glutamatergic dysfunction, proteomic analyses were conducted. Proteomic data revealed dysregulation of key pathways, cellular processes, and molecular regulators involved in excitatory signaling and synaptic function in both sexes. Biomarker profiling identified a single common biomarker between males and females, along with multiple biomarkers unique to each sex. Furthermore, two key brain regions highly susceptible to TBI, the prefrontal cortex and hippocampal subregions, were examined for chronic alterations in key glutamatergic signaling proteins, including N-methyl-D-aspartate (NMDA) receptors and the excitatory synaptic marker postsynaptic density protein 95 (PSD95). Immunofluorescence analyses revealed both sex- and region-specific alterations in the expression of NMDA receptor subunits, as well as in PSD95. Notably, many of these changes were concentrated within the hippocampal subregions, suggesting long-term dysregulation of hippocampal glutamatergic circuitry following injury. Together, these findings indicate the emergence of chronic sex-specific pathophysiology in glutamate signaling after TBI and highlight the importance of incorporating sex as a biological variable in the development of precision medicine-based therapeutic strategies for TBI. Full article

Human behavior is shaped by a pervasive motive to align with others, manifesting across a wide range of tendencies—from motor synchrony and emotional contagion to convergence in beliefs and choices. Existing accounts explain how alignment arises through predictive coding and observation–execution mechanisms, but they do not address how it is regulated in a manner that considers when alignment is adaptive and with whom it should occur. We propose a goal-directed model of social alignment that integrates computational and neural levels of analysis, to enhance our understanding of alignment as a context-sensitive decision process rather than a reflexive social tendency. Computationally, alignment is formalized as a prediction-error minimization process over the gap between self and other, augmented by a meta-learning layer in which the learning rate is adaptively tuned according to the inferred value of aligning versus maintaining independence. Assessments of the traits and mental states of self and other serve as key inputs to this regulatory function. Neurally, higher-order representations of these inputs are carried by the mentalizing network (dmPFC, TPJ), which exerts top-down control through the executive control network (dlPFC, rIFG) to enhance or inhibit alignment tendencies generated by observation–execution (mirror) circuitry. By reframing alignment as a form of social decision-making under uncertainty, the model specifies both the computations and neural circuits that integrate contextual cues to arbitrate when and with whom to align. It yields testable predictions across developmental, comparative, cognitive, and neurophysiological domains, and provides a unified framework for understanding the adaptive functions of social alignment, such as strategic social learning, as well as its maladaptive outcomes, including groupthink and false information cascades. Full article

The maturation of brain regions involved in emotion regulation—particularly the amygdala and prefrontal cortex—from fetal life to age two is a dynamic process shaped by genetic and environmental factors. Early experiences, especially responsive caregiving, promote the growth of neural circuits supporting emotional expression and regulation. In contrast, early adversity such as neglect or chronic stress may disrupt these circuits and increase vulnerability to emotional difficulties. Elevated levels of placental CRH are linked to alterations in fetal brain development related to emotion. Neurodevelopmental processes like synaptic pruning and myelination, active during the first years, further shape emotional circuitry. These findings underscore the importance of early caregiving and timely interventions in fostering healthy emotional development. The present article proposes an integrative conceptual framework for early emotional and cognitive development, combining neurobiological models with contemporary theories in developmental psychology. Full article

Borderline personality disorder (BPD) is a complex and heterogeneous condition characterized by emotional instability, impulsivity, and impaired regulation of interpersonal relationships. This narrative review integrates findings from recent neuroimaging, neurochemical, and treatment studies to identify core neurobiological mechanisms and highlight translational potential. Evidence from 112 studies published up to 2025 is synthesized, encompassing structural MRI, resting-state and task-based functional MRI, EEG, PET, and emerging machine learning applications. Consistent disruptions are observed across the prefrontal–amygdala circuitry, the default mode network (DMN), and mentalization-related regions. BPD shows a dominant and stable pattern of hyperconnectivity in the precuneus. Transdiagnostic comparisons with PTSD and cocaine use disorder (CUD) suggest partial overlap in DMN dysregulation, though BPD-specific traits emerge in network topology. Machine learning models achieve a classification accuracy of 70–88% and may support the tracking of early treatment responses. Longitudinal fMRI studies indicate that psychodynamic therapy facilitates the progressive normalization of dorsal anterior cingulate cortex (dACC) activity and reductions in alexithymia. We discuss the role of phenotypic heterogeneity (internalizing versus externalizing profiles), the potential of neuromodulation guided by biomarkers, and the need for standardized imaging protocols. Limitations include small sample sizes, a lack of effective connectivity analyses, and minimal multicenter cohort representation. Future research should focus on constructing multimodal biomarker panels that integrate functional connectivity, epigenetics, and computational phenotyping. This review supports the use of a precision psychiatry approach for BPD by aligning neuroscience with scalable clinical tools. Full article

Endocannabinoids, acting primarily through CB1 receptors, are critical modulators of neuronal activity, influencing cognitive functions and emotional processing. CB1 receptors are highly expressed in the hippocampus, primarily on GABAergic interneurons, modulating the excitation/inhibition balance. Previous evidence suggests the functional heterogeneity of CB1 receptors along the dorsoventral axis of the hippocampus. However, it is not known whether CB1 receptors differentially modulate basic aspects of the local neuronal network along the hippocampus. This study investigated how CB1 receptor activation modulates excitability, paired-pulse inhibition (PPI), and short-term neuronal dynamics (STND) in the dorsal and ventral CA1 hippocampus under physiologically relevant conditions. Using extracellular recordings from hippocampal slices of male Wistar rats, we compared the effects of two CB1 receptor agonists, ACEA and WIN55,212-2, on network activity in the dorsal and ventral hippocampus. We found that both agonists significantly increased excitability and reduced PPI in the dorsal, but not the ventral, hippocampus. Similarly, CB1 receptor activation modulated STND more prominently in the dorsal hippocampus, reducing facilitation at low frequencies and reversing depression at high frequencies, whereas effects on the ventral region were minimal. These dorsoventral differences in the actions of cannabinoid receptor agonists occurred despite similar CB1 receptor expression levels in both regions, suggesting that functional differences arise from downstream mechanisms rather than receptor density. Pre-application of the GIRK channel blocker Tertiapin-Q occluded the effects of WIN55,212-2 on STND, indicating a significant role of GIRK channel-mediated signaling in CB1 receptor actions. These findings demonstrate that CB1 receptors modulate hippocampal circuitry in a region-specific manner, with the dorsal hippocampus being more sensitive to cannabinoid signaling, likely through differential engagement of intracellular signaling pathways such as GIRK channel activation. These results provide novel insights into how endocannabinoid signaling differentially regulates neuronal dynamics along the dorsoventral axis of the hippocampus. They also have important implications for understanding the role of cannabinoids in hippocampus-dependent behaviors. Full article

Subcortical innervation of the hippocampus by the raphe nucleus is essential for emotional and cognitive control. The two major afferents from raphe to hippocampus originate from serotonergic and glutamatergic neurons, of which the serotonergic control of hippocampal inhibitory network, theta activity, and synaptic plasticity have been extensively explored in the growing body of literature, whereas those of glutamatergic circuits have received little attention. Notably, both serotonergic and glutamatergic circuits between raphe and hippocampus are disrupted in Alzheimer’s disease (AD), which may contribute to initiation and progression of behavioral and psychological symptoms of dementia. Thus, deciphering the mechanism underlying abnormal raphe–hippocampal circuits in AD is crucial to prevent dementia-associated emotional and cognitive symptoms. In this review, we summarize the anatomical, neurochemical, and electrophysiological diversity of raphe nuclei as well as the architecture of raphe–hippocampal circuitry. We then elucidate subcortical control of hippocampal activity by raphe nuclei and their role in regulation of emotion and cognition. Additionally, we present an overview of disrupted raphe–hippocampal circuits in AD pathogenesis and analyze the available therapies that can potentially be used clinically to alleviate the neuropsychiatric symptoms and cognitive decline in AD course. Full article

Aggression is a fundamental behavior with essential roles in dominance assertion, resource acquisition, and self-defense across the animal kingdom. However, dysregulation of the aggression circuitry can have severe consequences in humans, leading to economic, emotional, and societal burdens. Previous inconsistencies in aggression research have been due to limitations in techniques for studying these neurons at a high spatial resolution, resulting in an incomplete understanding of the neural mechanisms underlying aggression. Recent advancements in optogenetics, pharmacogenetics, single-cell RNA sequencing, and in vivo electrophysiology have provided new insights into this complex circuitry. This review aims to explore the aggression-provoking stimuli and their detection in rodents, particularly through the olfactory systems. Additionally, we will examine the core regions associated with aggression, their interactions, and their connection with the prefrontal cortex. We will also discuss the significance of top-down cognitive control systems in regulating atypical expressions of aggressive behavior. While the focus will primarily be on rodent circuitry, we will briefly touch upon the modulation of aggression in humans through the prefrontal cortex and discuss emerging therapeutic interventions that may benefit individuals with aggression disorders. This comprehensive understanding of the neural substrates of aggression will pave the way for the development of novel therapeutic strategies and clinical interventions. This approach contrasts with the broader perspective on neural mechanisms of aggression across species, aiming for a more focused analysis of specific pathways and their implications for therapeutic interventions. Full article

Neurodevelopmental psychopathology seeks to understand higher-order emotion regulation circuitry to develop new therapies for adolescents with depression. Depressed (N = 34) and healthy youth (N = 19) completed neurofeedback (NF) training and exhibited increased bilateral amygdala and hippocampus activity in the region of interest (ROI) analyses by recalling positive autobiographical memories. We tested factors supportive of the engagement of emotion regulation’s neural areas during NF (i.e., parental support, medication, and gender effects upon anterior cingulate cortex (ACC) engagement). Whole-brain analyses yielded effects of NF vs. control condition and effects of diagnosis. Youth showed higher amygdala and hippocampus (AMYHIPPO) activity during the NF vs. control condition, particularly in the left hippocampus. ACC’s activity was also higher during NF vs. control. Higher average ACC activity was linked to better parental support, absent depression, female gender, and absent medication. Control youth showed higher average AMYHIPPO and ACC activity throughout the task and a faster decline in activity vs. depressed youths. Whole-brain level analyses showed higher activity in the frontotemporal network during the NF vs. control conditions, suggesting targeting their connectivity in future neurofeedback trials. Full article

The D2 dopamine receptor (D2R) signals through both G proteins and β-arrestins to regulate important physiological processes, such as movement, reward circuitry, emotion, and cognition. β-arrestins are believed to interact with G protein-coupled receptors (GPCRs) at the phosphorylated C-terminal tail or intracellular loops. GPCR kinases (GRKs) are the primary drivers of GPCR phosphorylation, and for many receptors, receptor phosphorylation is indispensable for β-arrestin recruitment. However, GRK-mediated receptor phosphorylation is not required for β-arrestin recruitment to the D2R, and the role of GRKs in D2R–β-arrestin interactions remains largely unexplored. In this study, we used GRK knockout cells engineered using CRISPR-Cas9 technology to determine the extent to which β-arrestin recruitment to the D2R is GRK-dependent. Genetic elimination of all GRK expression decreased, but did not eliminate, agonist-stimulated β-arrestin recruitment to the D2R or its subsequent internalization. However, these processes were rescued upon the re-introduction of various GRK isoforms in the cells with GRK2/3 also enhancing dopamine potency. Further, treatment with compound 101, a pharmacological inhibitor of GRK2/3 isoforms, decreased β-arrestin recruitment and receptor internalization, highlighting the importance of this GRK subfamily for D2R–β-arrestin interactions. These results were recapitulated using a phosphorylation-deficient D2R mutant, emphasizing that GRKs can enhance β-arrestin recruitment and activation independently of receptor phosphorylation. Full article

Binge-eating disorder (BED) is a highly prevalent disorder. Subthreshold BED conditions (sBED) are even more frequent in youth, but their significance regarding BED etiology and long-term prognosis is unclear. A better understanding of brain findings associated with BED and sBED, in the context of critical periods for neurodevelopment, is relevant to answer such questions. The present narrative review starts from the knowledge of the development of emotional self-regulation in youth, and the brain circuits supporting emotion-regulation and eating behaviour. Next, neuroimaging studies with sBED and BED samples will be reviewed, and their brain-circuitry overlap will be examined. Deficits in inhibition control systems are observed to precede, and hyperactivity of reward regions to characterize, sBED, with overlapping findings in BED. The imbalance between reward/inhibition systems, and the implication of interoception/homeostatic processing brain systems should be further examined. Recent knowledge of the potential impact that the high consumption of ultra-processed foods in paediatric samples may have on these sBED/BED-associated brain systems is then discussed. There is a need to identify, early on, those sBED individuals at risk of developing BED at neurodevelopmental stages when there is a great possibility of prevention. However, more neuroimaging studies with sBED/BED pediatric samples are needed. Full article

Adolescent depression is prevalent, debilitating, and associated with chronic lifetime mental health disorders. Understanding the neurobiology of depression is critical to developing novel treatments. We tested a neurofeedback protocol targeting emotional regulation and self-processing circuitry and examined brain activity associated with reduced symptom severity, as measured through self-report questionnaires, four hours after neurofeedback. Depressed (n = 34) and healthy (n = 19) adolescents participated in (i) a brief neurofeedback task that involves simultaneously viewing their own happy face, recalling a positive autobiographical memory, and increasing amygdala-hippocampal activity; (ii) a self- vs. other- face recognition task with happy, neutral, and sad facial expressions before and after the neurofeedback. In depressed youth, reduced depression after neurofeedback was associated with increased self-referential and visual areas’ activity during neurofeedback, specifically, increased activity in the cuneus, precuneus and parietal lobe. Reduced depression was also associated with increased activation of emotional regulation and cross-modal areas during a self-recognition task. These areas included the cerebellum, middle temporal gyrus, superior temporal gyrus, and supramarginal gyrus. However, decreased rumination was linked to decreased precuneus, angular and temporal gyri activity during neurofeedback. These results tentatively suggest that neurofeedback may induce short-term neurobiological changes in the self-referential and emotional regulation networks associated with reduced symptom severity among depressed adolescents. Full article

Affective and substance-use disorders are associated with overweight and obesity-related complications, which are often due to the overconsumption of palatable food. Both high-fat diets (HFDs) and psychostimulant drugs modulate the neuro-circuitry regulating emotional processing and metabolic functions. However, it is not known how they interact at the behavioural level, and whether they lead to overlapping changes in neurobiological endpoints. In this literature review, we describe the impact of HFDs on emotionality, cognition, and reward-related behaviour in rodents. We also outline the effects of HFD on brain metabolism and plasticity involving mitochondria. Moreover, the possible overlap of the neurobiological mechanisms produced by HFDs and psychostimulants is discussed. Our in-depth analysis of published results revealed that HFDs have a clear impact on behaviour and underlying brain processes, which are largely dependent on the developmental period. However, apart from the studies investigating maternal exposure to HFDs, most of the published results involve only male rodents. Future research should also examine the biological impact of HFDs in female rodents. Further knowledge about the molecular mechanisms linking stress and obesity is a crucial requirement of translational research and using rodent models can significantly advance the important search for risk-related biomarkers and the development of clinical intervention strategies. Full article