Medial prefrontal neuroplasticity during extended-release naltrexone treatment of opioid use disorder - a longitudinal structural magnetic resonance imaging study.

Opioid use disorder (OUD) has been linked to macroscopic structural alterations in the brain. The monthly injectable, extended-release formulation of µ-opioid antagonist naltrexone (XR-NTX) is highly effective in reducing opioid craving and preventing opioid relapse. Here, we investigated the neuroanatomical effects of XR-NTX by examining changes in cortical thickness during treatment for OUD. Forty-seven OUD patients underwent structural magnetic resonance imaging and subjectively rated their opioid craving ≤1 day before (pre-treatment) and 11 ± 3 days after (on-treatment) the first XR-NTX injection. A sample of fifty-six non-OUD individuals completed a single imaging session and served as the comparison group. A publicly available [¹¹C]carfentanil positron emission tomography dataset was used to assess the relationship between changes in cortical thickness and µ-opioid receptor (MOR) binding potential across brain regions. We found that the thickness of the medial prefrontal and anterior cingulate cortices (mPFC/aCC; regions with high MOR binding potential) was comparable between the non-OUD individuals and the OUD patients at pre-treatment. However, among the OUD patients, mPFC/aCC thickness significantly decreased from pre-treatment to on-treatment. A greater reduction in mPFC/aCC thickness was associated with a greater reduction in opioid craving. Taken together, our study suggests XR-NTX-induced cortical thickness reduction in the mPFC/aCC regions in OUD patients. The reduction in thickness does not appear to indicate a restoration to the non-OUD level but rather reflects XR-NTX's distinct therapeutic impact on an MOR-rich brain structure. Our findings highlight the neuroplastic effects of XR-NTX that may inform the development of novel OUD interventions.

Antidepressant Effects of Ginsenoside Rc on L-Alpha-Aminoadipic Acid-Induced Astrocytic Ablation and Neuroinflammation in Mice.

Depression is a prevalent and debilitating mental disorder that affects millions worldwide. Current treatments, such as antidepressants targeting the serotonergic system, have limitations, including delayed onset of action and high rates of treatment resistance, necessitating novel therapeutic strategies. Ginsenoside Rc (G-Rc) has shown potential anti-inflammatory and neuroprotective effects, but its antidepressant properties remain unexplored. This study investigated the antidepressant effects of G-Rc in an L-alpha-aminoadipic acid (L-AAA)-induced mouse model of depression, which mimics the astrocytic pathology and neuroinflammation observed in major depressive disorder. Mice were administered G-Rc, vehicle, or imipramine orally after L-AAA injection into the prefrontal cortex. G-Rc significantly reduced the immobility time in forced swimming and tail suspension tests compared to vehicle treatment, with more pronounced effects than imipramine. It also attenuated the expression of pro-inflammatory cytokines (TNF-α, IL-6, TGF-ß, lipocalin-2) and alleviated astrocytic degeneration, as indicated by increased GFAP and decreased IBA-1 levels. Additionally, G-Rc modulated apoptosis-related proteins, decreasing caspase-3 and increasing Bcl-2 levels compared to the L-AAA-treated group. These findings suggest that G-Rc exerts antidepressant effects by regulating neuroinflammation, astrocyte-microglia crosstalk, and apoptotic pathways in the prefrontal cortex, highlighting its potential as a novel therapeutic agent for depression.

Transdiagnostic depression severity and its relationship to global and prefrontal-amygdala structural properties in people with major depression and post-traumatic stress disorder.

While some studies have used a transdiagnostic approach to relate depression to metabolic or functional brain alterations, the structural substrate of depression across clinical diagnostic categories is underexplored. In a cross-sectional study of 52 patients with major depressive disorder and 51 with post-traumatic stress disorder, drug-naïve, and spanning mild to severe depression severity, we examined transdiagnostic depressive correlates with regional gray matter volume and the topological properties of gray matter-based networks. Locally, transdiagnostic depression severity correlated positively with gray matter volume in the right middle frontal gyrus and negatively with nodal topological properties of gray matter-based networks in the right amygdala. Globally, transdiagnostic depression severity correlated positively with normalized characteristic path length, a measure implying brain integration ability. Compared with 62 healthy control participants, both major depressive disorder and post-traumatic stress disorder patients showed altered nodal properties in regions of the fronto-limbic-striatal circuit, and global topological organization in major depressive disorder in particular was characterized by decreased integration and segregation. These findings provide evidence for a gray matter-based structural substrate underpinning depression, with the prefrontal-amygdala circuit a potential predictive marker for depressive symptoms across clinical diagnostic categories.

Atlas-based structural analysis of prefrontal cortex atrophy in major depressive disorder: Correlations with severity and episode frequency.

BACKGROUND: Current models of major depressive disorder (MDD) primarily focus on the structural and functional changes in key prefrontal areas responsible for emotional regulation. Among these regions some sections such as the dorsal prefrontal area, has received limited attention regarding its structural abnormalities in MDD. This study aims to evaluate volumetric abnormalities in brain regions associated with markers of depression severity and episode frequency. METHODS: The study included 33 MDD patients and 33 healthy subjects. Using an atlas-based method, we measured the volumes of several key brain regions based on MRI data. The regions of interest included prefrontal and posterior sections of the middle frontal gyrus (MFG) and superior frontal gyrus (SFG). Additionally, we evaluated the volumes of the dorsal anterior cingulate cortex (dACC), perigenual (rostral) anterior cingulate cortex (pgACC), subgenual cingulate cortex (sgACC), posterior cingulate cortex (PCC), hippocampus (HPC), and parahippocampus (paraHPC). Hamilton Depression Scale (HAM-D) scores and count of the depressive episodes of patients were also obtained. A regression analysis with sex as the confounding factor has been made. RESULTS: Analysis of covariances, controlling for sex, showed significant atrophy in the sgACC in the depression group: F(1, 63) = 4.013, p = 0.049 (left) and F(1, 63) = 8.786, p < 0.004 (right). Poisson regression, also controlling for sex, found that each additional depressive episode was associated with a significant reduction in left posterior MFG volume (0.952 times, 95 % CI, 0.906 to 1.000; p = 0.049). CONCLUSIONS: Findings in this study highlight the structural abnormalities in MDD patients in correlation to either current depression severity or chronicity of the disease.

Correlation between compulsive behaviors and plastic changes in the dendritic spines of the prefrontal cortex and dorsolateral striatum of male rats.

Obsessive-compulsive disorder (OCD) is a mental affliction characterized by compulsive behaviors often manifested in intrusive thoughts and repetitive actions. The quinpirole model has been used with rats to replicate compulsive behaviors and study the neurophysiological processes associated with this pathology. Several changes in the dendritic spines of the medial prefrontal cortex (mPFC) and dorsolateral striatum (DLS) have been related to the occurrence of compulsive behaviors. Dendritic spines regulate excitatory synaptic contacts, and their morphology is associated with various brain pathologies. The present study was designed to correlate the occurrence of compulsive behaviors (generated by administering the drug quinpirole) with the morphology of the different types of dendritic spines in the mPFC and DLS. A total of 18 male rats were used. Half were assigned to the experimental group, the other half to the control group. The former received injections of quinpirole, while the latter rats were injected with physiological saline solution, for 10 days in both cases. After the experimental treatment, the quinpirole rats exhibited all the parameters indicative of compulsive behavior and a significant correlation with the density of stubby and wide neckless spines in both the mPFC and DLS. Dendritic spines from both mPFC and DLS neurons showed plastic changes correlatively with the expression of compulsive behavior induced by quinpirole. Further studies are suggested to evaluate the involvement of glutamatergic neurotransmission in the neurobiology of OCD.

Cellular communities reveal trajectories of brain ageing and Alzheimer's disease.

Alzheimer's disease (AD) has recently been associated with diverse cell states1-11, yet when and how these states affect the onset of AD remains unclear. Here we used a data-driven approach to reconstruct the dynamics of the brain's cellular environment and identified a trajectory leading to AD that is distinct from other ageing-related effects. First, we built a comprehensive cell atlas of the aged prefrontal cortex from 1.65 million single-nucleus RNA-sequencing profiles sampled from 437 older individuals, and identified specific glial and neuronal subpopulations associated with AD-related traits. Causal modelling then prioritized two distinct lipid-associated microglial subpopulations-one drives amyloid-ß proteinopathy while the other mediates the effect of amyloid-ß on tau proteinopathy-as well as an astrocyte subpopulation that mediates the effect of tau on cognitive decline. To model the dynamics of cellular environments, we devised the BEYOND methodology, which identified two distinct trajectories of brain ageing, each defined by coordinated progressive changes in certain cellular communities that lead to (1) AD dementia or (2) alternative brain ageing. Thus, we provide a cellular foundation for a new perspective on AD pathophysiology that informs personalized therapeutic development, targeting different cellular communities for individuals on the path to AD or to alternative brain ageing.

Effects of social dominance and acute social stress on morphology of microglia and structural integrity of the medial prefrontal cortex.

Chronic stress increases activity of the brain's innate immune system and impairs function of the medial prefrontal cortex (mPFC). However, whether acute stress triggers similar neuroimmune mechanisms is poorly understood. Across four studies, we used a Syrian hamster model to investigate whether acute stress drives changes in mPFC microglia in a time-, subregion-, and social status-dependent manner. We found that acute social defeat increased expression of ionized calcium binding adapter molecule 1 (Iba1) in the infralimbic (IL) and prelimbic (PL) and altered the morphology Iba1+ cells 1, 2, and 7 days after social defeat. We also investigated whether acute defeat induced tissue degeneration and reductions of synaptic plasticity 2 days post-defeat. We found that while social defeat increased deposition of cellular debris and reduced synaptophysin immunoreactivity in the PL and IL, treatment with minocycline protected against these cellular changes. Finally, we tested whether a reduced conditioned defeat response in dominant compared to subordinate hamsters was associated with changes in microglia reactivity in the IL and PL. We found that while subordinate hamsters and those without an established dominance relationships showed defeat-induced changes in morphology of Iba1+ cells and cellular degeneration, dominant hamsters showed resistance to these effects of social defeat. Taken together, these findings indicate that acute social defeat alters microglial morphology, increases markers of tissue degradation, and impairs structural integrity in the IL and PL, and that experience winning competitive interactions can specifically protect the IL and reduce stress vulnerability.

Post-treatment alterations in white matter integrity in PTSD: Effects on symptoms and functional connectivity a secondary analysis of an RCT.

Post-traumatic stress disorder (PTSD) has been linked to altered communication within the limbic system, including reduced structural connectivity in the uncinate fasciculus (UNC; i.e., decreased fractional anisotropy; FA) and reduced resting-state functional connectivity (RSFC) between the hippocampus and ventromedial prefrontal cortex (vmPFC). Previous research has demonstrated attenuation of PTSD symptoms and alterations in RSFC following exposure-based psychotherapy. However, the relationship between changes in structural and functional connectivity patterns and PTSD symptoms following treatment remains unclear. To investigate this, we conducted a secondary analysis of data from a randomized clinical trial of intensive exposure therapy, evaluating alterations in UNC FA, hippocampus-vmPFC RSFC, and PTSD symptoms before (pre-treatment), 7 days after (post-treatment), and 30 days after (follow-up) the completion of therapy. Our results showed that post-treatment changes in RSFC were positively correlated with post-treatment and follow-up changes in UNC FA and that post-treatment changes in UNC FA were positively correlated with post-treatment and follow-up changes in PTSD symptoms. These findings suggest that early changes in functional connectivity are associated with sustained changes in anatomical connectivity, which in turn are linked to reduced PTSD symptom severity.

Astrocyte-derived dominance winning reverses chronic stress-induced depressive behaviors.

Individuals with low social status are at heightened risk of major depressive disorder (MDD), and MDD also influences social status. While the interrelationship between MDD and social status is well-defined, the behavioral causality between these two phenotypes remains unexplored. Here, we investigated the behavioral relationships between depressive and dominance behaviors in male mice exposed to chronic restraint stress and the role of medial prefrontal cortex (mPFC) astrocytes in these behaviors. Chronic restraint stress induced both depressive and submissive behaviors. Chemogenetic mPFC astrocyte activation significantly enhanced dominance in chronic stress-induced submissive mice by increasing the persistence of defensive behavior, although it did not affect depressive behaviors. Notably, repetitive winning experiences following mPFC astrocyte stimulation exerted anti-depressive effects in chronic restraint stress-induced depressive mice. These data indicate that mPFC astrocyte-derived winning experience renders anti-depressive effects, and may offer a new strategy for treating depression caused by low status in social hierarchies by targeting mPFC astrocytes.

Neurophysiological, structural, and molecular alterations in the prefrontal and auditory cortices following noise-induced hearing loss.

It is well established that hearing loss can lead to widespread plasticity within the central auditory pathway, which is thought to contribute to the pathophysiology of audiological conditions such as tinnitus and hyperacusis. Emerging evidence suggests that hearing loss can also result in plasticity within brain regions involved in higher-level cognitive functioning like the prefrontal cortex; findings which may underlie the association between hearing loss and cognitive impairment documented in epidemiological studies. Using the 40-Hz auditory steady state response to assess sound-evoked gamma oscillations, we previously showed that noise-induced hearing loss results in impaired gamma phase coherence within the prefrontal but not the auditory cortex. To determine whether region-specific structural or molecular changes accompany this differential plasticity following hearing loss, in the present study we utilized Golgi-Cox staining to assess dendritic organization and synaptic density, as well as Western blotting to measure changes in synaptic signaling proteins in these cortical regions. We show that following noise exposure, impaired gamma phase coherence within the prefrontal cortex is accompanied by alterations in pyramidal cell dendritic morphology and decreased expression of proteins involved in GABAergic (GAD65) and glutamatergic (NR2B) neurotransmission; findings that were not observed in the auditory cortex, where gamma phase coherence remained unchanged post-noise exposure. In contrast to the noise-induced effects we observed in the prefrontal cortex, plasticity in the auditory cortex was characterized by an increase in NR2B suggesting increased excitability, as well as increases in the synaptic proteins PSD95 and synaptophysin within the auditory cortex. Overall, our results highlight the disparate effect of noise-induced hearing loss on auditory and higher-level brain regions as well as potential structural and molecular mechanisms by which hearing loss may contribute to impaired cognitive and sensory functions mediated by the prefrontal and auditory cortices.

Temporal organization of narrative recall is present but attenuated in adults with hippocampal amnesia.

Studies of the impact of brain injury on memory processes often focus on the quantity and episodic richness of those recollections. Here, we argue that the organization of one's recollections offers critical insights into the impact of brain injury on functional memory. It is well-established in studies of word list memory that free recall of unrelated words exhibits a clear temporal organization. This temporal contiguity effect refers to the fact that the order in which word lists are recalled reflects the original presentation order. Little is known, however, about the organization of recall for semantically rich materials, nor how recall organization is impacted by hippocampal damage and memory impairment. The present research is the first study, to our knowledge, of temporal organization in semantically rich narratives in three groups: (1) Adults with bilateral hippocampal damage and severe declarative memory impairment, (2) adults with bilateral ventromedial prefrontal cortex (vmPFC) damage and no memory impairment, and (3) demographically matched non-brain-injured comparison participants. We find that although the narrative recall of adults with bilateral hippocampal damage reflected the temporal order in which those narratives were experienced above chance levels, their temporal contiguity effect was significantly attenuated relative to comparison groups. In contrast, individuals with vmPFC damage did not differ from non-brain-injured comparison participants in temporal contiguity. This pattern of group differences yields insights into the cognitive and neural systems that support the use of temporal organization in recall. These data provide evidence that the retrieval of temporal context in narrative recall is hippocampal-dependent, whereas damage to the vmPFC does not impair the temporal organization of narrative recall. This evidence of limited but demonstrable organization of memory in participants with hippocampal damage and amnesia speaks to the power of narrative structures in supporting meaningfully organized recall despite memory impairment.

Altered prefrontal and cerebellar parvalbumin neuron counts are associated with cognitive changes in male rats.

Exposure to valproic acid (VPA), a common anti-seizure medication, in utero is a risk factor for autism spectrum disorder (ASD). People with ASD often display changes in the cerebellum, including volume changes, altered circuitry, and changes in Purkinje cell populations. ASD is also characterized by changes in the medial prefrontal cortex (mPFC), where excitatory/inhibitory balance is often altered. This study exposed rats to a high dose of VPA during gestation and assessed cognition and anxiety-like behaviors during young adulthood using a set-shifting task and the elevated plus maze. Inhibitory parvalbumin-expressing (PV +) neuron counts were assessed in the mPFC and cerebellar lobules VI and VII (Purkinje cell layers), which are known to modulate cognition. VPA males had increased PV + counts in crus I and II of lobule VII. VPA males also had decreased parvalbumin-expressing neuron counts in the mPFC. It was also found that VPA-exposed rats, regardless of sex, had increased parvalbumin-expressing Purkinje cell counts in lobule VI. In males, this was associated with impaired intra-dimensional shifting on a set-shifting task. Purkinje cell over proliferation may be contributing to the previously observed increase in volume of Lobule VI. These findings suggest that altered inhibitory signaling in cerebellar-frontal circuits may contribute to the cognitive deficits that occur within ASD.

Increased regional activity of a pro-autophagy pathway in schizophrenia as a contributor to sex differences in the disease pathology.

Based on recent genome-wide association studies, it is theorized that altered regulation of autophagy contributes to the pathophysiology of schizophrenia and bipolar disorder. As activity of autophagy-regulatory pathways is controlled by discrete phosphorylation sites on the relevant proteins, phospho-protein profiling is one of the few approaches available for enabling a quantitative assessment of autophagic activity in the brain. Despite this, a comprehensive phospho-protein assessment in the brains of schizophrenia and bipolar disorder subjects is currently lacking. Using this direction, our broad screening identifies an increase in AMP-activated protein kinase (AMPK)-mediated phospho-activation of the pro-autophagy protein beclin-1 solely in the prefrontal cortex of female, but not male, schizophrenia subjects. Using a reverse translational approach, we surprisingly find that this increase in beclin-1 activity facilitates synapse formation and enhances cognition. These findings are interpreted in the context of human studies demonstrating that female schizophrenia subjects have a lower susceptibility to cognitive dysfunction than males.

Brain structural and functional abnormalities in affective network are associated with anxious depression.

BACKGROUND: Anxious depression (AD) is a common subtype of major depressive disorder (MDD). Neuroimaging studies of AD have revealed inconsistent and heterogeneous brain alterations with the use of single-model methods. Therefore, it is necessary to explore the pathogenesis of AD using multi-model imaging analyses to obtain more homogeneous and robust results. METHODS: One hundred and eighty-two patients with MDD and 64 matched healthy controls (HCs) were recruited. Voxel-based morphometry (VBM) was used to estimate the gray matter volume (GMV) of all subjects. The GMV differences between the AD and non-anxious depression (NAD) participants were used as regions of interest (ROIs) for subsequent resting state functional connectivity (rs-FC) analyses. Correlation analysis was used to evaluate the associations between clinical symptoms and abnormal function in specific brain areas. RESULTS: Decreased GMV in the medial frontal gyrus (MFG) and the superior frontal gyrus (SFG) was observed in the AD group compared to the NAD group. Taking the MFG and SFG as ROIs, the rs-FC analysis revealed decreased FC between the left SFG and left temporal pole and between the left SFG and right MFG in the AD group compared to the NAD group. Finally, the FC between the left SFG and left temporal pole was negatively correlated with HAMD-17 scores in the AD group. CONCLUSION: By combining the GMV and rs-FC models, this study revealed that structural and functional disruption of the affective network may be an important pathophysiology underlying AD. The structural impairment may serve as the foundation of the functional impairment.

Neuronal ferroptosis and ferroptosis-mediated endoplasmic reticulum stress: Implications in cognitive dysfunction induced by chronic intermittent hypoxia in mice.

Obstructive sleep apnea, typically characterized by chronic intermittent hypoxia (CIH), is linked to cognitive dysfunction in children. Ferroptosis, a novel form of cell death characterized by lethal iron accumulation and lipid peroxidation, is implicated in neurodegenerative diseases and ischemia-reperfusion injuries. Nevertheless, its contribution to CIH-induced cognitive dysfunction and its interaction with endoplasmic reticulum stress (ERS) remain uncertain. In this study, utilizing a CIH model in 4-week-old male mice, we investigated ferroptosis and its potential involvement in ERS regulation during cognitive dysfunction. Our findings indicate ferroptosis activation in prefrontal cortex neurons, leading to neuron loss, mitochondrial damage, decreased levels of GPX4, SLC7A11, FTL, and FTH, increased levels of reactive oxygen species (ROS), malondialdehyde (MDA), Fe2+, ACSL4, TFRC, along with the activation of ERS-related PERK-ATF4-CHOP pathway. Treatment with the ferroptosis inhibitor liproxstatin-1 (Lip-1) and the iron chelator deferoxamine (DFO) effectively mitigated the neuron injury and cognitive dysfunction induced by CIH, significantly reducing Fe2+ and partly restoring expression levels of ferroptosis-related proteins. Furhermore, the use of Lip-1 and DFO downregulated p-PERK, ATF4 and CHOP, and upregulated Nrf2 expression, suggesting that inhibiting ferroptosis reduce ERS and that the transcription factor Nrf2 is involved in the process. In summary, our findings indicate that cognitive impairment in CIH mice correlates with the induction of neuronal ferroptosis, facilitated by the System xc - GPX4 functional axis, lipid peroxidation, and the iron metabolism pathway, along with ferroptosis-mediated ERS in the prefrontal cortex. Nrf2 has been identified as a potential regulator of ferroptosis and ERS involved in the context of CIH.

Proteomic networks of gray and white matter reveal tissue-specific changes in human tauopathy.

OBJECTIVE: To define tauopathy-associated changes in the human gray and white matter proteome. METHOD: We applied tandem mass tagged labeling and mass spectrometry, consensus, and ratio weighted gene correlation network analysis (WGCNA) to gray and white matter sampled from postmortem human dorsolateral prefrontal cortex. The sampled tissues included control as well as Alzheimer's disease, corticobasal degeneration, progressive supranuclear palsy, frontotemporal degeneration with tau pathology, and chronic traumatic encephalopathy. RESULTS: Only eight proteins were unique to gray matter while six were unique to white matter. Comparison of the gray and white matter proteome revealed an enrichment of microglial proteins in the white matter. Consensus WGCNA sorted over 6700 protein isoforms into 46 consensus modules across the gray and white matter proteomic networks. Consensus network modules demonstrated unique and shared disease-associated microglial and endothelial protein changes. Ratio WGCNA sorted over 6500 protein ratios (white:gray) into 33 modules. Modules associated with mitochondrial proteins and processes demonstrated higher white:gray ratios in diseased tissues relative to control, driven by mitochondrial protein downregulation in gray and upregulation in white. INTERPRETATION: The dataset is a valuable resource for understanding proteomic changes in human tauopathy gray and white matter. The identification of unique and shared disease-associated changes across gray and white matter emphasizes the utility of examining both tissue types. Future studies of microglial, endothelial, and mitochondrial changes in white matter may provide novel insights into tauopathy-associated changes in human brain.

Executive dysfunction and cortical variations among intimate partner violence perpetrators and the association with sexism.

Malfunctioning in executive functioning has been proposed as a risk factor for intimate partner violence (IPV). This is not only due to its effects on behavioral regulation but also because of its association with other variables such as sexism. Executive dysfunctions have been associated with frontal and prefrontal cortical thickness. Therefore, our first aim was to assess differences in cortical thickness in frontal and prefrontal regions, as well as levels of sexism, between two groups of IPV perpetrators (with and without executive dysfunctions) and a control group of non-violent men. Second, we analyzed whether the cortical thickness in the frontal and prefrontal regions would explain sexism scores. Our results indicate that IPV perpetrators classified as dysexecutive exhibited a lower cortical thickness in the right rostral anterior cingulate superior frontal bilaterally, caudal middle frontal bilaterally, right medial orbitofrontal, right paracentral, and precentral bilaterally when compared with controls. Furthermore, they exhibited higher levels of sexism than the rest of the groups. Most importantly, in the brain structures that distinguished between groups, lower thickness was associated with higher sexism scores. This research emphasizes the need to incorporate neuroimaging techniques to develop accurate IPV profiles or subtypes based on neuropsychological functioning.

Dendritic spine head diameter is reduced in the prefrontal cortex of progranulin haploinsufficient mice.

Loss-of-function mutations in the progranulin (GRN) gene are an autosomal dominant cause of Frontotemporal Dementia (FTD). These mutations typically result in haploinsufficiency of the progranulin protein. Grn+/- mice provide a model for progranulin haploinsufficiency and develop FTD-like behavioral abnormalities by 9-10 months of age. In previous work, we demonstrated that Grn+/- mice develop a low dominance phenotype in the tube test that is associated with reduced dendritic arborization of layer II/III pyramidal neurons in the prelimbic region of the medial prefrontal cortex (mPFC), a region key for social dominance behavior in the tube test assay. In this study, we investigated whether progranulin haploinsufficiency induced changes in dendritic spine density and morphology. Individual layer II/III pyramidal neurons in the prelimbic mPFC of 9-10 month old wild-type or Grn+/- mice were targeted for iontophoretic microinjection of fluorescent dye, followed by high-resolution confocal microscopy and 3D reconstruction for morphometry analysis. Dendritic spine density in Grn+/- mice was comparable to wild-type littermates, but the apical dendrites in Grn+/- mice had a shift in the proportion of spine types, with fewer stubby spines and more thin spines. Additionally, apical dendrites of Grn+/- mice had longer spines and smaller thin spine head diameter in comparison to wild-type littermates. These changes in spine morphology may contribute to altered circuit-level activity and social dominance deficits in Grn+/- mice.

Lesions to the mediodorsal thalamus, but not orbitofrontal cortex, enhance volatility beliefs linked to paranoia.

Beliefs-attitudes toward some state of the environment-guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia.

Structural and functional neural patterns among sub-threshold bulimia nervosa: Abnormalities in dorsolateral prefrontal cortex and orbitofrontal cortex.

BACKGROUND: Disordered eating behaviors are prevalent among youngsters and highly associated with dysfunction in neurocognitive systems. We aimed to identify the potential changes in individuals with bulimia symptoms (sub-BN) to generate insights to understand developmental pathophysiology of bulimia nervosa. METHODS: We investigated group differences in terms of degree centrality (DC) and gray matter volume (GMV) among 145 undergraduates with bulimia symptoms and 140 matched control undergraduates, with the secondary analysis of the whole brain connectivity in these regions of interest showing differences in static functional connectivity (FC). RESULTS: The sub-BN group exhibited abnormalities of the right dorsolateral prefrontal cortex and right orbitofrontal cortex in both GMV and DC, and displayed decreased FC between these regions and the precuneus. We also observed that sub-BN presented with reduced FC between the calcarine and superior temporal gyrus, middle temporal gyrus and inferior parietal gyrus. Additionally, brain-behavioral associations suggest a distinct relationship between these FCs and psychopathological symptoms in sub-BN group. CONCLUSIONS: Our study demonstrated that individuals with bulimia symptoms present with aberrant neural patterns that mainly involved in cognitive control and reward processing, as well as attentional and self-referential processing, which could provide important insights into the pathology of BN.