Increased number of excitatory synapsis and decreased number of inhibitory synapsis in the prefrontal cortex in autism.

Previous studies in autism spectrum disorder demonstrated an increased number of excitatory pyramidal cells and a decreased number of inhibitory parvalbumin+ chandelier interneurons in the prefrontal cortex of postmortem brains. How these changes in cellular composition affect the overall abundance of excitatory and inhibitory synapses in the cortex is not known. Herein, we quantified the number of excitatory and inhibitory synapses in the prefrontal cortex of 10 postmortem autism spectrum disorder brains and 10 control cases. To identify excitatory synapses, we used VGlut1 as a marker of the presynaptic component and postsynaptic density protein-95 as marker of the postsynaptic component. To identify inhibitory synapses, we used the vesicular gamma-aminobutyric acid transporter as a marker of the presynaptic component and gephyrin as a marker of the postsynaptic component. We used Puncta Analyzer to quantify the number of co-localized pre- and postsynaptic synaptic components in each area of interest. We found an increase in the number of excitatory synapses in upper cortical layers and a decrease in inhibitory synapses in all cortical layers in autism spectrum disorder brains compared with control cases. The alteration in the number of excitatory and inhibitory synapses could lead to neuronal dysfunction and disturbed network connectivity in the prefrontal cortex in autism spectrum disorder.

Two-Month Voluntary Ethanol Consumption Promotes Mild Neuroinflammation in the Cerebellum but Not in the Prefrontal Cortex, Hippocampus, or Striatum of Mice.

Chronic ethanol exposure often triggers neuroinflammation in the brain's reward system, potentially promoting the drive for ethanol consumption. A main marker of neuroinflammation is the microglia-derived monocyte chemoattractant protein 1 (MCP1) in animal models of alcohol use disorder in which ethanol is forcefully given. However, there are conflicting findings on whether MCP1 is elevated when ethanol is taken voluntarily, which challenges its key role in promoting motivation for ethanol consumption. Here, we studied MCP1 mRNA levels in areas implicated in consumption motivation-specifically, the prefrontal cortex, hippocampus, and striatum-as well as in the cerebellum, a brain area highly sensitive to ethanol, of C57BL/6 mice subjected to intermittent and voluntary ethanol consumption for two months. We found a significant increase in MCP1 mRNA levels in the cerebellum of mice that consumed ethanol compared to controls, whereas no significant changes were observed in the prefrontal cortex, hippocampus, or striatum or in microglia isolated from the hippocampus and striatum. To further characterize cerebellar neuroinflammation, we measured the expression changes in other proinflammatory markers and chemokines, revealing a significant increase in the proinflammatory microRNA miR-155. Notably, other classical proinflammatory markers, such as TNFα, IL6, and IL-1ß, remained unaltered, suggesting mild neuroinflammation. These results suggest that the onset of neuroinflammation in motivation-related areas is not required for high voluntary consumption in C57BL/6 mice. In addition, cerebellar susceptibility to neuroinflammation may be a trigger to the cerebellar degeneration that occurs after chronic ethanol consumption in humans.

Enhanced Spine Stability and Survival Lead to Increases in Dendritic Spine Density as an Early Response to Local Alpha-Synuclein Overexpression in Mouse Prefrontal Cortex.

Lewy Body Dementias (LBD), including Parkinson's disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. However, the impact of local pathology in the cortex is unknown. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used in vivo 2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of Thy1-YFP transgenic mice at 1-week intervals from 1 to 2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly-persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow-up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex.

Single-cell dissection of the human motor and prefrontal cortices in ALS and FTLD.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) share many clinical, pathological, and genetic features, but a detailed understanding of their associated transcriptional alterations across vulnerable cortical cell types is lacking. Here, we report a high-resolution, comparative single-cell molecular atlas of the human primary motor and dorsolateral prefrontal cortices and their transcriptional alterations in sporadic and familial ALS and FTLD. By integrating transcriptional and genetic information, we identify known and previously unidentified vulnerable populations in cortical layer 5 and show that ALS- and FTLD-implicated motor and spindle neurons possess a virtually indistinguishable molecular identity. We implicate potential disease mechanisms affecting these cell types as well as non-neuronal drivers of pathogenesis. Finally, we show that neuron loss in cortical layer 5 tracks more closely with transcriptional identity rather than cellular morphology and extends beyond previously reported vulnerable cell types.

Involvement of CB1 and CB2 receptors in neuroprotective effects of cannabinoids in experimental TDP-43 related frontotemporal dementia using male mice.

BACKGROUND: The elevation of endocannabinoid levels through inhibiting their degradation afforded neuroprotection in CaMKIIα-TDP-43 mice, a conditional transgenic model of frontotemporal dementia. However, which cannabinoid receptors are mediating these benefits is still pending to be elucidated. METHODS: We have investigated the involvement of the CB1 and the CB2 receptor using chronic treatments with selective ligands in CaMKIIα-TDP-43 mice, analysis of their cognitive deterioration with the Novel Object Recognition test, and immunostaining for neuronal and glial markers in two areas of interest in frontotemporal dementia. RESULTS: Our results confirmed the therapeutic value of activating either the CB1 or the CB2 receptor, with improvements in the animal performance in the Novel Object Recognition test, preservation of pyramidal neurons, in particular in the medial prefrontal cortex, and attenuation of glial reactivity, in particular in the hippocampus. In addition, the activation of both CB1 and CB2 receptors reduced the elevated levels of TDP-43 in the medial prefrontal cortex of CaMKIIα-TDP-43 mice, an effect exerted by mechanisms that are currently under investigation. CONCLUSIONS: These data reinforce the notion that the activation of CB1 and CB2 receptors may represent a promising therapy against TDP-43-induced neuropathology in frontotemporal dementia. Future studies will have to confirm these benefits, in particular with one of the selective CB2 agonists used here, which has been thoroughly characterized for clinical development.

A concerted neuron-astrocyte program declines in ageing and schizophrenia.

Human brains vary across people and over time; such variation is not yet understood in cellular terms. Here we describe a relationship between people's cortical neurons and cortical astrocytes. We used single-nucleus RNA sequencing to analyse the prefrontal cortex of 191 human donors aged 22-97 years, including healthy individuals and people with schizophrenia. Latent-factor analysis of these data revealed that, in people whose cortical neurons more strongly expressed genes encoding synaptic components, cortical astrocytes more strongly expressed distinct genes with synaptic functions and genes for synthesizing cholesterol, an astrocyte-supplied component of synaptic membranes. We call this relationship the synaptic neuron and astrocyte program (SNAP). In schizophrenia and ageing-two conditions that involve declines in cognitive flexibility and plasticity1,2-cells divested from SNAP: astrocytes, glutamatergic (excitatory) neurons and GABAergic (inhibitory) neurons all showed reduced SNAP expression to corresponding degrees. The distinct astrocytic and neuronal components of SNAP both involved genes in which genetic risk factors for schizophrenia were strongly concentrated. SNAP, which varies quantitatively even among healthy people of similar age, may underlie many aspects of normal human interindividual differences and may be an important point of convergence for multiple kinds of pathophysiology.

Correlation of GABA+ levels in the medial prefrontal cortex and circulating follicular helper T cells in neuromyelitis optica spectrum disorder patients with cognitive impairment.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) associated with cognitive impairment (CI) is acknowledged. However, the underlying pathogenesis and involvement of the immune system remain unclear. OBJECTIVES: This study aimed to investigate the alterations in immune cells, cytokines, and GABA+ levels in NMOSD patients with cognitive deficits. METHODS: Thirty-eight NMOSD patients and 38 healthy controls (HCs) were included. NMOSD patients were stratified as NMOSD-CI and NMOSD-CP groups. The difference in cognitive functions, Tfh and cytokines, and GABA+ levels were assessed, and their correlations were calculated. RESULTS: NMOSD-CI patients showed worse performance on all cognitive tests, and the percentage of circulating follicular helper T cells (cTfh) was significantly elevated. The frequency of cTfh was positively and negatively correlated with Stroop-A and AVLT long-delayed scores, respectively. IL-21 was remarkably higher in NMOSD-CI and NMOSD-CP. The level of GABA+ in medial prefrontal cortex (mPFC) was significantly decreased in NMOSD-CI and was proved positively and negatively correlated with Symbol Digit Modalities Test and the frequency of circulating Tfh cells, respectively. CONCLUSION: In NMOSD-CI patients, all cognitive domains were impacted, , while GABA+ levels in mPFC were decreased. GABA+ levels in NMOSD-CI were negatively correlated with the frequency of cTfh, suggesting the underlying coupling mechanism between immune responses and neurotransmitter metabolism in CI in NMOSD patients.

Time-sensitive changes in the maternal brain and their influence on mother-child attachment.

Pregnancy and the postpartum period are characterized by an increased neuroplasticity in the maternal brain. To explore the dynamics of postpartum changes in gray matter volume (GMV), magnetic resonance imaging was performed on 20 healthy postpartum women immediately after childbirth and at 3-week intervals for 12 postpartum weeks. The control group comprised 20 age-matched nulliparous women. The first 6 postpartum weeks (constituting the subacute postpartum period) are associated with decreasing progesterone levels and a massive restructuring in GMV, affecting the amygdala/hippocampus, the prefrontal/subgenual cortex, and the insula, which approach their sizes in nulliparous women only around weeks 3-6 postpartum. Based on the amygdala volume shortly after delivery, the maternal brain can be reliably distinguished from the nulliparous brain. Even 12 weeks after childbirth, the GMV in the dorsomedial prefrontal cortex, and the cortical thickness of the subgenual and lateral prefrontal cortices do not reach the pre-pregnancy levels. During this period, a volume decrease is seen in the cerebellum, the thalamus, and the dorsal striatum. A less hostile behavior toward the child at 6-12 weeks postpartum is predicted by the GMV change in the amygdala, the temporal pole, the olfactory gyrus, the anterior cingulate, the thalamus and the cerebellum in the same period. In summary, the restructuring of the maternal brain follows time-dependent trajectories. The fact that the volume changes persist at 12 weeks postpartum indicates that the maternal brain does not fully revert to pre-pregnancy physiology. Postpartum neuroplasticity suggests that these changes may be particularly significant in the regions important for parenting.

Continuous inhalation of essential oil increases gray matter volume.

Research into the health benefits of scents is on the rise. However, little is known about the effects of continuous inhalation, such as wearing scents on clothing, on brain structure. Therefore, in this study, an intervention study was conducted on a total of 50 healthy female people, 28 in the intervention group and 22 in the control group, asking them to wear a designated rose scent on their clothes for a month. The effect of continuous inhalation of essential oil on the gray matter of the brain was measured by calculating changes in brain images of participants taken before and after the intervention using Magnetic Resonance Imaging (MRI). The results showed that the intervention increased the gray matter volume (GMV) of the whole brain and posterior cingulate cortex (PCC) subregion. On the other hand, the GMV of the amygdala and orbitofrontal cortex (OFC) did not change. This study is the first to show that continuous scent inhalation changes brain structure.

Transdiagnostic symptom of depression and anxiety associated with reduced gray matter volume in prefrontal cortex.

Dimensional models of psychopathology may provide insight into mechanisms underlying comorbid depression and anxiety and improve specificity and sensitivity of neuroanatomical findings. The present study is the first to examine neural structure alterations using the empirically derived Tri-level Model. Depression and anxiety symptoms of 269 young adults were assessed using the Tri-level Model dimensions: General Distress (transdiagnostic depression and anxiety symptoms), Anhedonia-Apprehension (relatively specific depression symptoms), and Fears (specific anxiety symptoms). Using structural MRI, gray matter volumes were extracted for emotion generation (amygdala, nucleus accumbens) and regulation (orbitofrontal, ventrolateral, and dorsolateral prefrontal cortex) regions, often implicated in depression and anxiety. Each Tri-level symptom was regressed onto each region of interest, separately, adjusting for relevant covariates. General Distress was significantly associated with smaller gray matter volumes in bilateral orbitofrontal cortex and ventrolateral prefrontal cortex, independent of Anhedonia-Apprehension and Fears symptom dimensions. These results suggests that prefrontal alterations are associated with transdiagnostic dysphoric mood common across depression and anxiety, rather than unique symptoms of these disorders. Additionally, no regions of interest were associated with Anhedonia-Apprehension or Fears, highlighting the importance of studying transdiagnostic features of depression and anxiety. This has implications for understanding mechanisms of and interventions for depression and anxiety.

Trauma-related intrusive memories and anterior hippocampus structural covariance: an ecological momentary assessment study in posttraumatic stress disorder.

Trauma-related intrusive memories (TR-IMs) are hallmark symptoms of posttraumatic stress disorder (PTSD), but their neural correlates remain partly unknown. Given its role in autobiographical memory, the hippocampus may play a critical role in TR-IM neurophysiology. The anterior and posterior hippocampi are known to have partially distinct functions, including during retrieval of autobiographical memories. This study aimed to investigate the relationship between TR-IM frequency and the anterior and posterior hippocampi morphology in PTSD. Ninety-three trauma-exposed adults completed daily ecological momentary assessments for fourteen days to capture their TR-IM frequency. Participants then underwent anatomical magnetic resonance imaging to obtain measures of anterior and posterior hippocampal volumes. Partial least squares analysis was applied to identify a structural covariance network that differentiated the anterior and posterior hippocampi. Poisson regression models examined the relationship of TR-IM frequency with anterior and posterior hippocampal volumes and the resulting structural covariance network. Results revealed no significant relationship of TR-IM frequency with hippocampal volumes. However, TR-IM frequency was significantly negatively correlated with the expression of a structural covariance pattern specifically associated with the anterior hippocampus volume. This association remained significant after accounting for the severity of PTSD symptoms other than intrusion symptoms. The network included the bilateral inferior temporal gyri, superior frontal gyri, precuneus, and fusiform gyri. These novel findings indicate that higher TR-IM frequency in individuals with PTSD is associated with lower structural covariance between the anterior hippocampus and other brain regions involved in autobiographical memory, shedding light on the neural correlates underlying this core symptom of PTSD.

Alpha-Synuclein Pre-Formed Fibrils Injected into Prefrontal Cortex Primarily Spread to Cortical and Subcortical Structures.

BACKGROUND: Parkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are characterized by diffuse spread of alpha-synuclein (α-syn) throughout the brain. Patients with PDD and DLB have a neuropsychological pattern of deficits that include executive dysfunction, such as abnormalities in planning, timing, working memory, and behavioral flexibility. The prefrontal cortex (PFC) plays a major role in normal executive function and often develops α-syn aggregates in DLB and PDD. OBJECTIVE: To investigate the long-term behavioral and cognitive consequences of α-syn pathology in the cortex and characterize pathological spread of α-syn. METHODS: We injected human α-syn pre-formed fibrils into the PFC of wild-type male mice. We then assessed the behavioral and cognitive effects between 12- and 21-months post-injection and characterized the spread of pathological α-syn in cortical, subcortical, and brainstem regions. RESULTS: We report that PFC PFFs: 1) induced α-syn aggregation in multiple cortical and subcortical regions with sparse aggregation in midbrain and brainstem nuclei; 2) did not affect interval timing or spatial learning acquisition but did mildly alter behavioral flexibility as measured by intraday reversal learning; and 3) increased open field exploration. CONCLUSIONS: This model of cortical-dominant pathology aids in our understanding of how local α-syn aggregation might impact some symptoms in PDD and DLB.

The effect of Vortioxetine on the NLRP3 pathway and microglial activity in the prefrontal cortex in an experimental model of depression.

BACKGROUND: Increasing evidence suggests that early life stress (ELS) and neuroinflammation are associated with the pathophysiology of depression. The purpose of this study was to determine the effects of Vortioxetine (VOR), a novel antidepressant, on ELS-induced behavioral changes and neuroinflammation. METHOD: Wistar Albino 4-week-old male rats were divided into four groups: control; chronic unpredictable stress (CUMS), VOR, CUMS + VOR. Neurobehavioral assessment was performed on the first, 21st, and 42nd days. RT-PCR was used to detect the expression of P2X7, NLRP3, IL1ß, IL18 in the prefrontal cortex. To assess the microglial activities of the prefrontal cortex, immunohistochemically stained CD68, and leukocyte common antigen (LCA) preparations were scanned with Manual WSI software, Basler camera, and scored. RESULT AND DISCUSSION: Exposure to CUMS was associated with depression and anxiety-like behaviors, and administration of VOR led to improvement in these behaviors. NLRP3, IL-1ß, and IL-18 were shown to be upregulated in the prefrontal cortex of CUMS rats, while their high expression was inhibited by VOR treatment. CD68 and LCA expressions were significantly higher in the CUMS group compared to the other groups. CONCLUSION: According to these results, it may be considered that NLRP3 inflammasome-associated neuroinflammatory response and microglial activation may play a role in the etiopathogenesis of ELS.

TAF15 amyloid filaments in frontotemporal lobar degeneration.

Frontotemporal lobar degeneration (FTLD) causes frontotemporal dementia (FTD), the most common form of dementia after Alzheimer's disease, and is often also associated with motor disorders1. The pathological hallmarks of FTLD are neuronal inclusions of specific, abnormally assembled proteins2. In the majority of cases the inclusions contain amyloid filament assemblies of TAR DNA-binding protein 43 (TDP-43) or tau, with distinct filament structures characterizing different FTLD subtypes3,4. The presence of amyloid filaments and their identities and structures in the remaining approximately 10% of FTLD cases are unknown but are widely believed to be composed of the protein fused in sarcoma (FUS, also known as translocated in liposarcoma). As such, these cases are commonly referred to as FTLD-FUS. Here we used cryogenic electron microscopy (cryo-EM) to determine the structures of amyloid filaments extracted from the prefrontal and temporal cortices of four individuals with FTLD-FUS. Surprisingly, we found abundant amyloid filaments of the FUS homologue TATA-binding protein-associated factor 15 (TAF15, also known as TATA-binding protein-associated factor 2N) rather than of FUS itself. The filament fold is formed from residues 7-99 in the low-complexity domain (LCD) of TAF15 and was identical between individuals. Furthermore, we found TAF15 filaments with the same fold in the motor cortex and brainstem of two of the individuals, both showing upper and lower motor neuron pathology. The formation of TAF15 amyloid filaments with a characteristic fold in FTLD establishes TAF15 proteinopathy in neurodegenerative disease. The structure of TAF15 amyloid filaments provides a basis for the development of model systems of neurodegenerative disease, as well as for the design of diagnostic and therapeutic tools targeting TAF15 proteinopathy.

Top-down and bottom-up alterations of connectivity patterns of the suprachiasmatic nucleus in chronic insomnia disorder.

The importance of the suprachiasmatic nucleus (SCN, also called the master circadian clock) in regulating sleep and wakefulness has been confirmed by multiple animal research. However, human studies of SCN in vivo are still nascent. Recently, the development of resting-state functional magnetic resonance imaging (fMRI) has made it possible to study SCN-related connectivity changes in patients with chronic insomnia disorder (CID). Hence, this study aimed to explore whether sleep-wake circuitry (i.e., communication between the SCN and other brain regions) is disrupted in human insomnia. Forty-two patients with CID and 37 healthy controls (HCs) underwent fMRI scanning. Resting-state functional connectivity (rsFC) and Granger causality analysis (GCA) were performed to find abnormal functional and causal connectivity of the SCN in CID patients. In addition, correlation analyses were conducted to detect associations between features of disrupted connectivity and clinical symptoms. Compared to HCs, CID patients showed enhanced rsFC of the SCN-left dorsolateral prefrontal cortex (DLPFC), as well as reduced rsFC of the SCN-bilateral medial prefrontal cortex (MPFC); these altered cortical regions belong to the "top-down" circuit. Moreover, CID patients exhibited disrupted functional and causal connectivity between the SCN and the locus coeruleus (LC) and the raphe nucleus (RN); these altered subcortical regions constitute the "bottom-up" pathway. Importantly, the decreased causal connectivity from the LC-to-SCN was associated with the duration of disease in CID patients. These findings suggest that the disruption of the SCN-centered "top-down" cognitive process and "bottom-up" wake-promoting pathway may be intimately tied to the neuropathology of CID.

Network Localization of Spontaneous Confabulation.

OBJECTIVE: Spontaneous confabulation is a symptom in which false memories are conveyed by the patient as true. The purpose of the study was to identify the neuroanatomical substrate of this complex symptom and evaluate the relationship to related symptoms, such as delusions and amnesia. METHODS: Twenty-five lesion locations associated with spontaneous confabulation were identified in a systematic literature search. The network of brain regions functionally connected to each lesion location was identified with a large connectome database (N=1,000) and compared with networks derived from lesions associated with nonspecific (i.e., variable) symptoms (N=135), delusions (N=32), or amnesia (N=53). RESULTS: Lesions associated with spontaneous confabulation occurred in multiple brain locations, but they were all part of a single functionally connected brain network. Specifically, 100% of lesions were connected to the mammillary bodies (familywise error rate [FWE]-corrected p<0.05). This connectivity was specific for lesions associated with confabulation compared with lesions associated with nonspecific symptoms or delusions (FWE-corrected p<0.05). Lesions associated with confabulation were more connected to the orbitofrontal cortex than those associated with amnesia (FWE-corrected p<0.05). CONCLUSIONS: Spontaneous confabulation maps to a common functionally connected brain network that partially overlaps, but is distinct from, networks associated with delusions or amnesia. These findings lend new insight into the neuroanatomical bases of spontaneous confabulation.

A right convergence area of the prefrontal lobe is involved in the improvement of semantic fluency in patients with post-stroke aphasia.

OBJECTIVES: This study aimed to longitudinally observe the improvement mechanism of semantic fluency in subacute post-stroke aphasia (PSA) patients using resting-state functional magnetic resonance imaging (rs-fMRI). METHODS: Twelve PSA patients, about one month after onset, were enrolled in this study and received speech-language therapy (SLT) for one month. Auditory comprehension and semantic fluency were evaluated using the Western Aphasia Battery (WAB) and the Animal Fluency Test. Before and after treatment, rs-fMRI data were collected, and the dice similarity coefficient was used to measure the spatial similarity between each patient's lesion and a reference lesion. The left posterior inferior temporal gyrus (pITG) was used as a seed to calculate the normalized functional connectivity in whole-brain voxel analysis using DPABI software for statistical analysis. RESULTS: The dice similarity coefficient between each patient's lesion and the reference lesion showed moderate to high intensity (0.57 ± 0.14) in the Montreal Neurological Institute space. After treatment, we found a significant increase in functional connectivity between the left pITG and the right prefrontal lobe convergence area (peak t = 8.219, Gaussian random field multiple comparison correction, voxel p < 0.001, cluster p < 0.05). The increase in functional connectivity was negatively correlated with the improvement in auditory comprehension (r =-0.707, p = 0.033) and positively correlated with the improvement in semantic fluency (r = 0.79, p = 0.02). CONCLUSION: The improvement of semantic fluency in subacute PSA patients may require the participation of the right convergence area of the prefrontal lobe.

Higher Levels of C-reactive Protein Are Associated With Higher Cortical Surface Area and Lower Cortical Thickness in Youth With Bipolar Disorder.

BACKGROUND: Inflammation is implicated in the neuropathology of bipolar disorder (BD). The association of C-reactive protein (CRP) with brain structure has been examined in relation to BD among adults but not youth. METHODS: Participants included 101 youth (BD, n = 55; control group [CG], n = 46; aged 13-20 years). Blood samples were assayed for levels of CRP. T1-weighted brain images were acquired to obtain cortical surface area (SA), volume, and thickness for 3 regions of interest (ROI; whole-brain cortical gray matter, prefrontal cortex, orbitofrontal cortex [OFC]) and for vertex-wise analyses. Analyses included CRP main effects and interaction effects controlling for age, sex, and intracranial volume. RESULTS: In ROI analyses, higher CRP was associated with higher whole-brain SA (ß = 0.16; P = .03) and lower whole-brain (ß = -0.31; P = .03) and OFC cortical thickness (ß = -0.29; P = .04) within the BD group and was associated with higher OFC SA (ß = 0.17; P = .03) within the CG. In vertex-wise analyses, higher CRP was associated with higher SA and lower cortical thickness in frontal and parietal regions within BD. A significant CRP-by-diagnosis interaction was found in frontal and temporal regions, whereby higher CRP was associated with lower neurostructural metrics in the BD group but higher neurostructural metrics in CG. CONCLUSIONS: This study found that higher CRP among youth with BD is associated with higher SA but lower cortical thickness in ROI and vertex-wise analyses. The study identified 2 regions in which the association of CRP with brain structure differs between youth with BD and the CG. Future longitudinal, repeated-measures studies incorporating additional inflammatory markers are warranted.

Altered single-subject gray matter structural networks in first-episode drug-naïve adolescent major depressive disorder.

Although previous studies have demonstrated regional gray matter (GM) structural abnormalities in adolescents with major depressive disorder (MDD), how the topological organization of GM networks is affected in these patients is still unclear. Structural magnetic resonance imaging data were acquired from 100 first-episode drug-naïve adolescent MDD patients and 80 healthy controls (HCs). Whole-brain GM structural network was constructed for each subject, and a graph theory analysis was used to calculate the topological metrics of GM networks. Adolescent MDD patients showed significantly lower cluster coefficient and local efficiency compared to HCs. Compared to controls, adolescent MDD patients showed higher nodal centralities in the bilateral cuneus, left lingual gyrus, and right middle occipital gyrus and lower nodal centralities in the bilateral dorsolateral superior frontal gyrus, bilateral middle frontal gyrus, right anterior cingulate and paracingulate gyri, bilateral hippocampus, bilateral amygdala, bilateral caudate nucleus, and bilateral thalamus. Nodal centralities of the hippocampus were negatively associated with symptom severity and illness duration. Our findings suggest disrupted topological organization of GM structural networks in adolescent MDD patients. Impaired local segregation and abnormal nodal centralities in the prefrontal-subcortical-limbic areas and visual cortex regions may play important roles in the neurobiology of adolescent-onset MDD.

Arsenic exposure induced anxiety-like behaviors in male mice via influencing the GABAergic Signaling in the prefrontal cortex.

Arsenic contamination in drinking water causes a global public health problem. Emerging evidence suggests that arsenic may act as an environmental risk factor for anxiety disorders. However, the exact mechanism underlying the adverse effects has not been fully elucidated. This study aimed to evaluate the anxiety-like behaviors of mice exposed to arsenic trioxide (As2O3), to observe the neuropathological changes, and to explore the link between the GABAergic system and behavioral manifestations. For this purpose, male C57BL/6 mice were exposed to various doses of As2O3 (0, 0.15, 1.5, and 15 mg/L) through drinking water for 12 weeks. Anxiety-like behaviors were assessed using the open field test (OFT), light/dark choice test, and elevated zero maze (EZM). Neuronal injuries in the cerebral cortex and hippocampus were assessed by light microscopy with H&E and Nissl staining. Ultrastructural alteration in the cerebral cortex was assessed by transmission electron microscope (TEM). The expression levels of GABAergic system-related molecules (i.e., glutamate decarboxylase, GABA transporter, and GABAB receptor subunits) in the prefrontal cortex (PFC) were determined by qRT-PCR and western blotting. Arsenic exposure showed a striking anxiogenic effect on mice, especially in the group exposed to 15 mg/L As2O3. Light microscopy showed neuron necrosis and reduced cell counts. TEM revealed marked ultrastructural changes, including the vacuolated mitochondria, disrupted Nissl bodies, an indentation in the nucleus membrane, and delamination of myelin sheath in the cortex. In addition, As2O3 influenced the GABAergic system in the PFC by decreasing the expression of the glutamate decarboxylase 1 (GAD1) and the GABAB2 receptor subunit, but not the GABAB1 receptor subunit. To sum up, sub-chronic exposure to As2O3 is associated with increased anxiety-like behaviors, which may be mediated by altered GABAergic signaling in the PFC. These findings shed light on the mechanisms responsible for the neurotoxic effects of arsenic and therefore more cautions should be taken.