Brain Regions Research Articles

A diffusion kurtosis imaging study of the relationship between whole brain microstructure and cognitive function in older adults with mild cognitive impairment.

The association of Mini-Mental State Examination (MMSE) with microstructure of individual regions across the entire brain remains unexplored. To investigate the relationship between cognitive function and the microstructure of each brain region in the gray matter using diffusion kurtosis imaging (DKI) in older adults with mild cognitive impairment (MCI), which is the transitional stage before the onset of dementia. DKI and MMSE were obtained for 34 older adults with MCI and 16 cognitively normal (CN) individuals aged 65-85 years. The DKI parameters were measured from 31 distinct regions of interest in the gray matter. A multiple regression analysis was used to examine the association between DKI parameters and MMSE scores; subsequently, interactions between the DKI parameters and the groups (MCI and CN) were examined. The mean (±SD) MMSE score for the MCI group was 27.67 ± 1.90. Significant positive correlations were observed between MMSE score and mean kurtosis (MK) in the superior frontal, middle frontal, inferior frontal, precentral, postcentral, angular, middle temporal, and inferior occipital gyri, and superior parietal lobe for the MCI group. In addition, the interaction term of the MK in the middle frontal, precentral, postcentral, and angular gyri, and the groups was statistically significant. Older adults with MCI may exhibit histological damage in certain regions of the brain, such as the middle frontal and angular gyri, as observed in this study. The findings could provide insights into understanding the pathophysiology of cognitive decline in this population group.

Distinct expression profile reveals glia involvement in the trigeminal system attributing to post-traumatic headache

BackgroundPost-traumatic headache (PTH) is a common comorbid symptom affecting at least one-third of patients with mild traumatic brain injury (mTBI). While neuroinflammation is known to contribute to the development of PTH, the cellular mechanisms in the trigeminal system crucial for understanding the pathogenesis of PTH remain unclear.MethodsA non-invasive repetitive mTBI (4 times with a 24-h interval) was induced in male mice and effect of mTBI was tested on either bregma or pre-bregma position on the head. Periorbital allodynia and spontaneous pain behavior were assessed using von Frey test and grimace score, respectively. Quantitative PCR was used to assess extent of mTBI pathology. RNA sequencing was performed to obtain transcriptomic profile of the trigeminal ganglion (TG), trigeminal nucleus caudalis (Sp5C) and periaqueductal gray (PAG) at 7 days post-TBI. Subsequently, quantitative PCR, in situ hybridization and immunohistochemistry were used to examine mRNA and protein expression of glia specific markers and pain associated molecules.ResultsThe repetitive impacts at the bregma, but not pre-bregma site led to periorbital hypersensitivity, which was correlated with enhanced inflammatory gene expression in multiple brain regions. RNA sequencing revealed mTBI induced distinct transcriptomic profiles in the peripheral TG and central Sp5C and PAG. Using gene set enrichment analysis, positive enrichment of non-neuronal cells in the TG and neuroinflammation in the Sp5C were identified to be essential in the pathogenesis of PTH. In situ assays also revealed that gliosis of satellite glial cells in the TG and astrocytes in the Sp5C were prominent days after injury. Furthermore, immunohistochemical study revealed a close interaction between activated microglia and reactive astrocytes correlating with increased calretinin interneurons in the Sp5C.ConclusionsTranscriptomics analysis indicated that non-neuronal cells in peripheral TG and successive in situ assays revealed that glia in the central Sp5C are crucial in modulating headache-like symptoms. Thus, selective targeting of glia cells can be a therapeutic strategy for PTH attributed to repetitive mTBI.

Cafeteria Diet Abstinence Induces Depressive Behavior and Disrupts Endocannabinoid Signaling in Dopaminergic Areas: A Preclinical Study.

Alterations of dopamine (DA) transmission in the brain reward system can be associated with an addictive-like state defined as food addiction (FA), common in obese individuals. Subjects affected by FA experience negative feelings when abstinent from their preferred diet and may develop mood disorders, including depression, sustained by alterations in brain DA pathways. This study aims to investigate the impact of long-term abstinence from a palatable diet on depressive-like behavior in rats, exploring neurochemical alterations in monoamine and endocannabinoid signaling in DA-enriched brain regions, including ventral tegmental area, dorsolateral striatum, substantia nigra and medial prefrontal cortex. Rats underwent exposure and subsequent abstinence from a palatable cafeteria diet. During abstinence, animals were treated with fatty acid amide hydrolase (FAAH) inhibitor PF-3845 (10 mg/kg, intraperitoneal administration every other day). Lastly, animals were subjected to a forced swimming test, and their brains were dissected and processed for high-performance liquid chromatography measurement of monoamines and western blot analyses of markers of the endocannabinoid machinery. After the withdrawal from the palatable diet, animals showed depressive-like behavior, coupled with significant variations in the concentration of brain monoamines and in the expression of endocannabinoid signalling machinery proteins in cited brain areas. Treatment with PF-3845 exerted an antidepressant- like effect and restored part of the alterations in monoaminergic and endocannabinoid systems. Overall, our results suggest that abstinence from a cafeteria diet provokes emotional disturbances linked to neuroadaptive changes in monoamines and endocannabinoid signalling in brain areas partaking to DA transmission that could partially be restored by the enhancement of endocannabinoid signalling through FAAH inhibition.

Sex and estradiol effects in the rodent dorsal striatum.

17β-Estradiol (E2) is a sex hormone that acts on many brain regions to produce changes in neuronal activity and learning. A key brain region sensitive to E2 is the dorsal striatum (also called caudate-putamen), which controls motor behaviour, goal-directed learning and habit learning. In adult rodents, oestrogen receptors (ERs) in the dorsal striatum are localized to the plasma membrane and include ERα, ERβ and G protein-coupled ER (GPER). E2, either naturally produced or exogenously applied, may influence neuronal excitability, basal synaptic transmission and long-term synaptic potentiation. These effects may be due to direct action on signalling pathways or may be due to changes in dopamine availability. In particular, estradiol influences dopamine release, dopamine receptor expression and dopamine transporter expression. We review the cellular effects that E2 has in the dorsal striatum, distinguishing between exogenously applied E2 and the oestrous cycle, as well as its influence on dorsal striatal-dependent motor and learning behaviour.

O FENÓTIPO ESTENDIDO: A FACE E A MAQUIAGEM, A VANTAGEM FEMININA

O FENÓTIPO ESTENDIDO: A FACE E A MAQUIAGEM, A VANTAGEM FEMININA

Age-dependent effects of vaping on the prefrontal cortex, ventral tegmental area, and nucleus accumbens

Electronic nicotine delivery systems (ENDS) are unique from combustible cigarettes due to the availability of flavor options which make these devices popular among adolescents. However, there are no preclinical investigations into the impact of vaporized nicotine on late-developing brain regions such as the prefrontal cortex. Here, we investigated how neuronal function and drug self-administration differed between adult-exposed and adolescent-exposed mice. Male and female adolescent and adult C57BL/6J mice were used in a 20-session e-Vape® self-administration (EVSA) assay. Brains were then extracted and acute slices were used for either patch-clamp electrophysiology or fast-scan cyclic voltammetry. Adolescent-exposed males exhibited greater reinforcement-related behavior compared to their adult-exposed counterparts. However, adolescent-exposed and adult-exposed females exhibited similar levels of reinforcement-related behavior. Adolescent-exposed mice exhibited significant increases in intrinsic excitability of medial prefrontal cortex (mPFC) pyramidal neurons. Additionally, reinforcement-related behavior observed during EVSA assays correlated with adolescent-exposed mPFC neuronal excitability. This did not occur in adult-exposed mice. In the ventral tegmental area (VTA), we observed that upregulation of nicotinic acetylcholine receptors (nAChRs) only correlated with nicotine self-administration in adult and not adolescent-exposed mice. The relationship between self-administration and changes in neuronal excitability in adolescent mice indicates that the mPFC may be important for adolescent nicotine dependence.

Sequential replacement of PSD95 subunits in postsynaptic supercomplexes is slowest in the cortex.

The concept that dimeric protein complexes in synapses can sequentially replace their subunits has been a cornerstone of Francis Crick's 1984 hypothesis, explaining how long-term memories could be maintained in the face of short protein lifetimes. However, it is unknown whether the subunits of protein complexes that mediate memory are sequentially replaced in the brain and if this process is linked to protein lifetime. We address these issues by focusing on supercomplexes assembled by the abundant postsynaptic scaffolding protein PSD95, which plays a crucial role in memory. We used single-molecule detection, super-resolution microscopy and MINFLUX to probe the molecular composition of PSD95 supercomplexes in mice carrying genetically encoded HaloTags, eGFP, and mEoS2. We found a population of PSD95-containing supercomplexes comprised of two copies of PSD95, with a dominant 12.7 nm separation. Time-stamping of PSD95 subunits in vivo revealed that each PSD95 subunit was sequentially replaced over days and weeks. Comparison of brain regions showed subunit replacement was slowest in the cortex, where PSD95 protein lifetime is longest. Our findings reveal that protein supercomplexes within the postsynaptic density can be maintained by gradual replacement of individual subunits providing a mechanism for stable maintenance of their organization. Moreover, we extend Crick's model by suggesting that synapses with slow subunit replacement of protein supercomplexes and long-protein lifetimes are specialized for long-term memory storage and that these synapses are highly enriched in superficial layers of the cortex where long-term memories are stored.

Spectral graph model for fMRI: a biophysical, connectivity-based generative model for the analysis of frequency-resolved resting state fMRI

Abstract Resting state functional MRI (rs-fMRI) is a popular and widely used technique to explore the brain’s functional organization and to examine if it is altered in neurological or mental disorders. The most common approach for its analysis targets the measurement of the synchronized fluctuations between brain regions, characterized as functional connectivity (FC), typically relying on pairwise correlations in activity across different brain regions. While hugely successful in exploring state- and disease-dependent network alterations, these statistical graph theory tools suffer from two key limitations. First, they discard useful information about the rich frequency content of the fMRI signal. The rich spectral information now achievable from advances in fast multiband acquisitions is consequently being under-utilized. Second, the analyzed FCs are phenomenological without a direct neurobiological underpinning in the underlying structures and processes in the brain. There does not currently exist a complete generative model framework for whole brain resting fMRI that is informed by its underlying biological basis in the structural connectome. Here we propose that a different approach can solve both challenges at once: the use of an appropriately realistic yet parsimonious biophysics-informed signal generation model followed by graph spectral (i.e. eigen) decomposition. We call this model a Spectral Graph Model (SGM) for fMRI, using which we can not only quantify the structure-function relationship in individual subjects, but also condense the variable and individual-specific repertoire of fMRI signal’s spectral and spatial features into a small number of biophysically-interpretable parameters. We expect this model-based analysis of rs-fMRI that seamlessly integrates with structure can be used to examine state and trait characteristics of structure-function relations in a variety of brain disorders.

Charting brain GABA and glutamate levels across psychiatric disorders by quantitative analysis of 121 1H-MRS studies.

Psychiatric diagnosis is based on categorical diagnostic classification, yet similarities in genetics and clinical features across disorders suggest that these classifications share commonalities in neurobiology, particularly regarding neurotransmitters. Glutamate (Glu) and gamma-aminobutyric acid (GABA), the brain's primary excitatory and inhibitory neurotransmitters, play critical roles in brain function and physiological processes. We examined the levels of Glu, combined glutamate and glutamine (Glx), and GABA across psychiatric disorders by pooling data from 121 1H-MRS studies and further divided the sample based on Axis I disorders. Statistically significant differences in GABA levels were found in the combined psychiatric group compared with healthy controls (Hedge's g = -0.112, p = 0.008). Further analyses based on brain regions showed that brain GABA levels significantly differed across Axis I disorders and controls in the parieto-occipital cortex (Hedge's g = 0.277, p = 0.019). Furthermore, GABA levels were reduced in affective disorders in the occipital cortex (Hedge's g = -0.468, p = 0.043). Reductions in Glx levels were found in neurodevelopmental disorders (Hedge's g = -0.287, p = 0.022). Analysis focusing on brain regions suggested that Glx levels decreased in the frontal cortex (Hedge's g = -0.226, p = 0.025), and the reduction of Glu levels in patients with affective disorders in the frontal cortex is marginally significant (Hedge's g = -0.172, p = 0.052). When analyzing the anterior cingulate cortex and prefrontal cortex separately, reductions were only found in GABA levels in the former (Hedge's g = - 0.191, p = 0.009) across all disorders. Altered glutamatergic and GABAergic metabolites were found across psychiatric disorders, indicating shared dysfunction. We found reduced GABA levels across psychiatric disorders and lower Glu levels in affective disorders. These results highlight the significance of GABA and Glu in psychiatric etiology and partially support rethinking current diagnostic categories.

Water-Soluble Lynx1 Upregulates Dendritic Spine Density and Stimulates Astrocytic Network and Signaling.

Secreted and membrane-tethered mammalian neuromodulators from the Ly6/uPAR family are involved in regulation of many physiological processes. Some of them are expressed in the CNS in the neurons of different brain regions and target neuronal membrane receptors. Thus, Lynx1 potentiates nicotinic acetylcholine receptors (nAChRs) in the brain, while others like Lypd6 and Lypd6b suppress it. However, the mechanisms underlying the regulation of cognitive processes by these neuromodulators remain unclear. Here, we showed that water-soluble analogue of Lynx1 (ws-Lynx-1) targets α7-nAChRs both in the hippocampal neurons and astrocytes. Incubation of astrocytes with ws-Lynx1 increased expression of connexins 30 and 43; α4, α5, and β4 integrins; and E- and P-cadherins. Ws-Lynx1 reduced secretion of pro-inflammatory adhesion factors ICAM-1, PSGL-1, and VCAM-1 and downregulated secretion of CD44 and NCAM, which inhibit synaptic plasticity. Moreover, increased astrocytic secretion of the dendritic growth activator ALCAM and neurogenesis regulator E-selectin was observed. Incubation of neurons with ws-Lynx1 potentiated α7-nAChRs and upregulated dendritic spine density. Thus, the pro-cognitive activity of ws-Lynx1 observed previously can be explained by stimulation of astrocytic network and signaling together with up-regulation of spinogenesis, potentiation of the α7-nAChRs, and neuronal and synaptic plasticity. For comparison, influence of water-soluble analogues of a set of Ly6/uPAR proteins (SLURP-1, SLURP-2, Lypd6, Lypd6b, and PSCA) on dendritic spine density and diameter was studied. Data obtained give new insights on the role of Ly6/uPAR proteins in the brain and open new prospects for the development of drugs to improve cognitive function.

BMAL1-Potential Player of Aberrant Stress Response in Q31L Mice Model of Affective Disorders: Pilot Results.

Dysregulation in the stress-response system as a result of genetical mutation can provoke the manifestation of affective disorders under stress conditions. Mutations in the human DISC1 gene is one of the main risk factors of affective disorders. It was known that DISC1 regulates a large number of proteins including BMAL1, which is involved in the regulation of glucocorticoid synthesis in the adrenal glands and the sensitivity of glucocorticoid receptor target genes. Male mice with a point mutation Q31L in the Disc1 gene were exposed to chronic unpredictable stress (CUS), after which the behavioral and physiological stress response assessed. To assess whether there were any changes in BMAL1 in key brain regions involved in the stress response, immunohistochemistry was applied. It was shown that the Q31L mice had an aberrant behavioral response, especially to the 2 weeks of CUS, which was expressed in unchanged motor activity, increased time of social interaction, and alterations in anxiety and fear-related behavior. Q31L males did not show an increase in blood corticosterone levels after CUS and a decrease in body weight. Immunohistochemical analysis in intact Q31L mice revealed a decrease in BMAL1 immunofluorescence in the CA1 hippocampal area and lateral habenula. Thus, the Q31L mutation of the Disc1 gene disrupts behavioral and physiological stress response and the BMAL1 dysregulation may underlie it, so this protein can act as a molecular target for the treatment of affective disorders.

Brain multi-omic Mendelian randomisation to identify novel drug targets for gliomagenesis.

Genetic variants associated with molecular traits that are also associated with liability to glioma can provide causal evidence for the identification and prioritisation of drug targets. We performed comprehensive two-sample Mendelian randomisation (Wald ratio and/or IVW) and colocalisation analyses of molecular traits on glioma. Instrumentable traits (QTLs P < 5×10-8) were identified amongst 11 985 gene expression measures, 13 285 splicing isoforms and 10 198 protein abundance measures, derived from 15 brain regions. Glioma summary-level data was extracted from a genome-wide association meta-analysis of 12 496 cases and 18 190 controls. We found evidence for causal effect of 22 molecular traits (across 18 genes/proteins) on glioma risk. Thirteen molecular traits have been previously linked with glioma risk and five were novel; HBEGF (5q31.3) expression and all glioma [OR 1.36 (95%CI 1.19-1.55); P = 4.41×10-6]; a CEP192 (18p11.21) splice isoform and glioblastoma [OR 4.40 (95%CI 2.28-8.48); P = 9.78×10-4]; a FAIM (3q22.3) splice isoform and all glioma [OR 2.72-3.43; P = 1.03×10-5 to 1.09×10-5]; a SLC8A1 (2p22.1) splice isoform and all glioma [OR 0.37 (95%CI 0.24-0.56; P = 5.72×10-6]; D2HGDH (2q37.3) protein and all glioma [OR 0.86 (95%CI 0.80-0.92); P = 5.94×10-6)]. We provide robust causal evidence for prioritising genes and their protein products in glioma research. Our results highlight the importance of alternative splicing as a mechanism in gliomagenesis and as an avenue for exploration of drug targets.

Integrated Transcriptome Analysis Reveals Novel Molecular Signatures for Schizophrenia Characterization.

Schizophrenia (SCZ) is a complex psychiatric disorder presenting challenges for characterization. The current study aimed to identify and evaluate disease-responsive essential genes (DREGs) to enhance the molecular characterization of SCZ. RNA-sequencing data from PsychENCODE (536 SCZ patients, 832 controls) and peripheral blood transcriptome data from 144 recruited subjects (59 SCZ patients, 6 non-SCZ psychiatric patients, 79 controls) are analyzed. Shared differential expression genes are obtained using three algorithms. Support vector machine (SVM)-based recursive feature elimination is employed to identify DREGs. The biological relevance of these DREGs is examined through protein-protein interaction network, pathway enrichment, polygenic scoring, and brain tissue expression. Key DREGs are validated in SCZ animal models. A DREGs-based machine-learning model for SCZ characterization is developed and its performance is assessed using multiple datasets. The analysis identified 184 DREGs forming an interconnected network involved in synaptic plasticity, inflammation, neuronal development, and neurotransmission. DREGs exhibited distinct expression in SCZ-related brain regions and animal models. Their genetic contributions are comparable to genome-wide polygenic risk scores. The DREG-based SVM model demonstrated high performance (AUC 85% for SCZ characterization, 79% for specificity). These findings provide new insights into the molecular mechanisms underlying SCZ and emphasize the potential of DREGs in improving SCZ characterization.

Quantitative susceptibility mapping reveals brain iron accumulation in minimal hepatic encephalopathy: associations with neurocognitive changes.

Brain iron deposition is correlated with minimal hepatic encephalopathy (MHE). This study aimed to investigate the pattern of altered iron distribution, using quantitative susceptibility mapping (QSM), and to clarify the relationship between iron deposition and neurocognitive changes in MHE.We enrolled 32 cirrhotic patients without MHE (NHE), 21 cirrhotic patients with MHE, and 24 healthy controls, and used the Psychometric Hepatic Encephalopathy Score (PHES) to assess neurocognitive function. All participants underwent magnetic resonance scans with a gradient-echo sequence reconstructing for QSM. We performed voxel-wise and region-of-interest (ROI)-wise analyses to investigate the QSM difference across three groups and to examine the relationship between susceptibility value and PHES.MHE patients exhibited increased susceptibility value in widespread brain areas (family-wise error (FWE)-corrected P < 0.05), which was located mainly in cognition-related regions (such as the prefrontal lobe, precuneus, inferior parietal lobule, insula, thalamus, and superior longitudinal fasciculus), sensorimotor regions (such as the precentral/postcentral gyrus, superior parietal lobule, and posterior corona radiata), visual regions (such as the occipital cortex and posterior thalamic radiation), and auditory regions (such as the temporal lobe). NHE patients also followed a trend of increasing susceptibility in the scattered brain regions, but which did not reach statistical significance (FWE-corrected P > 0.05). We observed negative correlations between cirrhotic patients' PHES and regional susceptibility values (FWE-corrected P < 0.05).Brain iron accumulation (measured using QSM) contributes to cognitive impairments in MHE patients. QSM could provide new insights into the pathogenesis of MHE and facilitate monitoring disease development.

Resting-state functional magnetic resonance imaging and support vector machines for the diagnosis of major depressive disorder in adolescents

BACKGROUND Research has found that the amygdala plays a significant role in underlying pathology of major depressive disorder (MDD). However, few studies have explored machine learning-assisted diagnostic biomarkers based on amygdala functional connectivity (FC). AIM To investigate the analysis of neuroimaging biomarkers as a streamlined approach for the diagnosis of MDD in adolescents. METHODS Forty-four adolescents diagnosed with MDD and 43 healthy controls were enrolled in the study. Using resting-state functional magnetic resonance imaging, the FC was compared between the adolescents with MDD and the healthy controls, with the bilateral amygdala serving as the seed point, followed by statistical analysis of the results. The support vector machine (SVM) method was then applied to classify functional connections in various brain regions and to evaluate the neurophysiological characteristics associated with MDD. RESULTS Compared to the controls and using the bilateral amygdala as the region of interest, patients with MDD showed significantly lower FC values in the left inferior temporal gyrus, bilateral calcarine, right lingual gyrus, and left superior occipital gyrus. However, there was an increase in the FC value in Vermis-10. The SVM analysis revealed that the reduction in the FC value in the right lingual gyrus could effectively differentiate patients with MDD from healthy controls, achieving a diagnostic accuracy of 83.91%, sensitivity of 79.55%, specificity of 88.37%, and an area under the curve of 67.65%. CONCLUSION The results showed that an abnormal FC value in the right lingual gyrus was effective as a neuroimaging biomarker to distinguish patients with MDD from healthy controls.

Association between intercellular adhesion molecule-1 to depression and blood-brain barrier penetration in cerebellar vascular disease

BACKGROUND Cerebral small vessel disease (CSVD) is a prevalent cerebrovascular disease in clinical practice that is often associated with macrovascular disease. A clear understanding of the underlying causes of CSVD remains elusive. AIM To explore the association between intercellular adhesion molecule-1 (ICAM-1) and blood-brain barrier (BBB) penetration in CSVD. METHODS This study included patients admitted to Fuyang People’s Hospital and Fuyang Community (Anhui, China) between December 2021 and March 2022. The study population comprised 142 patients, including 80 in the CSVD group and 62 in the control group. Depression was present in 53 out of 80 patients with CSVD. Multisequence magnetic resonance imaging (MRI) and dynamic contrast-enhanced MRI were applied in patients to determine the brain volume, cortical thickness, and cortical area of each brain region. Moreover, neuropsychological tests including the Hamilton depression scale, mini-mental state examination, and Montreal cognitive assessment basic scores were performed. RESULTS The multivariable analysis showed that age [P = 0.011; odds ratio (OR) = 0.930, 95% confidence interval (CI): 0.880-0.983] and ICAM-1 levels (P = 0.023; OR = 1.007, 95%CI: 1.001-1.013) were associated with CSVD. Two regions of interest (ROIs; ROI3 and ROI4) in the white matter showed significant (both P &lt; 0.001; 95%CI: 0.419-0.837 and 0.366-0.878) differences between the two groups, whereas only ROI1 in the gray matter showed significant difference (P = 0.046; 95%CI: 0.007-0.680) between the two groups. ICAM-1 was significantly correlated (all P &lt; 0.05) with cortical thickness in multiple brain regions in the CSVD group. CONCLUSION This study revealed that ICAM-1 levels were independently associated with CSVD. ICAM-1 may be associated with cortical thickness in the brain, predominantly in the white matter, and a significant increase in BBB permeability, proposing the involvement of ICAM-1 in BBB destruction.

Formoterol dynamically alters endocannabinoid tone in the periaqueductal gray inducing headache

BackgroundHeadache is a pain disorder present in populations world-wide with a higher incidence in females. Specifically, the incidences of medication overuse headache (MOH) have increased worldwide. Comorbidities of MOH include photosensitivity, anxiety, “brain fog”, and decreased physical activity. The FDA-approved long-lasting selective β2-adrenergic receptor agonist, formoterol, is currently approved for use in severe asthma and chronic obstructive pulmonary disease. Recently, interest in repurposing formoterol for use in other disorders including Alzheimer’s disease, and neuropathic pain after spinal cord injury and traumatic brain injury has gained traction. Thus, revisiting known side-effects of formoterol, like headache and anxiety, could inform treatment paradigms. The endocannabinoid (eCB) system is implicated in the etiology of preclinical headache, with observed decreases in the circulating levels of endogenous cannabinoids, referred to as Clinical Endocannabinoid Deficiency. As cross-talk between the eCB system and adrenergic receptors has been reported, this study investigated the role of the eCB system and ability of formoterol to induce headache-like periorbital allodynic behavior.MethodsFemale 8-week-old C57Bl/6J mice were treated daily with formoterol (0.3 mg/kg, i.p.) for up to 42-days, during which they were assessed for periorbital allodynia, open field/novel object recognition, and photosensitivity. At the end of the study, the periaqueductal grey (PAG), a brain region known to contribute to both headache induction and maintenance, was collected and subjected to LC-MS to quantify endocannabinoid levels.ResultsMice exhibited periorbital allodynia at nearly all time points tested and photosensitivity from 28-days onward. Levels of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with cannabinoid receptor 1 (CB1R) expression were altered by both age and upon treatment with formoterol. Administration of FAAH/MAGL inhibitors, to target the eCB system, and a non-selective cannabinoid receptor agonist, WIN 55,212 reversed the formoterol-induced periorbital allodynia.ConclusionsThese results suggest that formoterol is dysregulates eCB tone to drive headache-like periorbital allodynic behaviors. These results could help inform preventative treatment options for individuals receiving formoterol, as well as provide information on the interaction between the eCB and adrenergic system.Graphical

Optogenetic control of dopamine receptor 2 reveals a novel aspect of dopaminergic neurotransmission in motor function.

Dopaminergic neurotransmission plays a crucial role in motor function through the coordination of dopamine receptor (DRD) subtypes, such as DRD1 and DRD2, thus the functional imbalance of these receptors can lead to Parkinson's disease. However, due to the complexity of dopaminergic circuits in the brain, it is limited to investigating the individual functions of each DRD subtype in specific brain regions. Here, we developed a light-responsive chimeric DRD2, OptoDRD2, which can selectively activate DRD2-like signaling pathways with spatiotemporal resolution. OptoDRD2 was designed to include the light-sensitive component of rhodopsin and the intracellular signaling domain of DRD2. Upon illumination with blue light, OptoDRD2 triggered DRD2-like signaling pathways, such as Gαi/o subtype recruitment, a decrease in cAMP levels, and ERK phosphorylation. To explore unknown roles of DRD2 in glutamatergic cell populations of basal ganglia circuitry, OptoDRD2 was genetically expressed in excitatory neurons in lateral globus pallidus (LGP) of the male mouse brain. The optogenetic stimulation of OptoDRD2 in the LGP region affected a wide range of locomotion-related parameters, such as increased frequency of movement and decreased immobility time, resulting in the facilitation of motor function of living male mice. Therefore, our findings indicate a potential novel role for DRD2 in the excitatory neurons of the LGP region, suggesting that OptoDRD2 can be a valuable tool enabling the investigation of unknown roles of DRD2 at specific cell types or brain regions.Significance Statement We developed a light-responsive chimeric dopamine receptor type 2, OptoDRD2, by combining the blue-light sensing part of rhodopsin and intracellular functional regions of DRD2. OptoDRD2 can selectively trigger DRD2-like downstream signaling pathways upon illumination of blue light. To explore unknown roles of DRD2 in glutamatergic cell populations of basal ganglia circuitry, OptoDRD2 was genetically expressed in excitatory neurons at lateral globus pallidus (LGP) in the mouse brain. Optogenetic stimulation of OptoDRD2 in living mice suggested a potential novel function of DRD2 in the LGP that enhances motor outputs. Therefore, OptoDRD2 enabled the precise control of DRD2-like signaling in specific cell types and brain regions, allowing the exploration of potential novel DRD2 functions in living mice.

Brain morphometry in hepatic Wilson disease patients.

Wilson disease (WD) primarily presents with hepatic and neurological symptoms. While hepatic symptoms typically precede the neurological manifestations, copper accumulates in the brain already in this patient group and leads to subclinical brain MRI abnormalities including T2 hyperintensities and atrophy. This study aimed to assess brain morphological changes in mild hepatic WD. WD patients without a history of neurologic symptoms and decompensated cirrhosis and control participants underwent brain MRI at 3T scanner including high-resolution T1-weighted images. A volumetric evaluation was conducted on the following brain regions: nucleus accumbens, caudate, pallidum, putamen, thalamus, amygdala, hippocampus, midbrain, pons, cerebellar gray matter, white matter (WM), and superior peduncle, using Freesurfer v7 software. Whole-brain analyses using voxel- and surface-based morphometry were performed using SPM12. Statistical comparisons utilized a general linear model adjusted for total intracranial volume, age, and sex. Twenty-six WD patients with mild hepatic form (30 ± 9 years [mean age ± SD]); 11 women; mean treatment duration 13 ± 12 (range 0-42) years and 28 healthy controls (33 ± 9 years; 15 women) were evaluated. Volumetric analysis revealed a significantly smaller pons volume and a trend for smaller midbrain and cerebellar WM in WD patients compared to controls. Whole-brain analysis revealed regions of reduced volume in the pons, cerebellar, and lobar WM in the WD group. No significant differences in gray matter density or cortical thickness were found. Myelin or WM in general seems vulnerable to low-level copper toxicity, with WM volume loss showing promise as a marker for assessing brain involvement in early WD stages.

Prediction of Post Traumatic Epilepsy Using MR-Based Imaging Markers.

Post-traumatic epilepsy (PTE) is a debilitating neurological disorder that develops after traumatic brain injury (TBI). Despite the high prevalence of PTE, current methods for predicting its occurrence remain limited. In this study, we aimed to identify imaging-based markers for the prediction of PTE using machine learning. Specifically, we examined three imaging features: Lesion volumes, resting-state fMRI-based measures of functional connectivity, and amplitude of low-frequency fluctuation (ALFF). We employed three machine-learning methods, namely, kernel support vector machine (KSVM), random forest, and an artificial neural network (NN), to develop predictive models. Our results showed that the KSVM classifier, with all three feature types as input, achieved the best prediction accuracy of 0.78 AUC (area under the receiver operating characteristic (ROC) curve) using nested cross-validation. Furthermore, we performed voxel-wise and lobe-wise group difference analyses to investigate the specific brain regions and features that the model found to be most helpful in distinguishing PTE from non-PTE populations. Our statistical analysis uncovered significant differences in bilateral temporal lobes and cerebellum between PTE and non-PTE groups. Overall, our findings demonstrate the complementary prognostic value of MR-based markers in PTE prediction and provide new insights into the underlying structural and functional alterations associated with PTE.