Brain Structures Research Articles

Monorhinal and Birhinal Odor Processing in Humans: an fMRI investigation.

The olfactory nerve, also known as cranial nerve I, is known to have exclusive ipsilateral projections to primary olfactory cortical structures. However, the lateralization of olfactory processes is known to depend on the task and nature of stimuli. It still remains unclear whether olfactory system projections in humans also correspond to functional pathways during olfactory tasks without any trigeminal, perceptual or cognitive-motor components. Twenty young healthy subjects with a normal sense of smell took part in an olfactory functional magnetic resonance imaging (fMRI) study. We used two types of nostril specific stimulation, passive (no sniffing) and active (with sniffing), with phenyl ethyl alcohol, a pure olfactory stimulant, to investigate fMRI activity patterns in primary and secondary olfactory-related brain structures. Irrespective of the stimulated nostril and the type of stimulation, we detected symmetrical activity in primary and secondary olfactory-related brain structures such as the primary olfactory cortex, entorhinal cortex, and orbitofrontal cortex. In the absence of perceptual or cognitive-motor task demands, the perception of monorhinally presented pure odors is processed bilaterally in the brain.

Investigating cross-sectional and longitudinal relationships between brain structure and distinct dimensions of externalizing psychopathology in the ABCD sample.

Externalizing psychopathology in childhood is a predictor of poor outcomes across the lifespan. Children exhibiting elevated externalizing symptoms also commonly show emotion dysregulation and callous-unemotional (CU) traits. Examining cross-sectional and longitudinal neural correlates across dimensions linked to externalizing psychopathology during childhood may clarify shared or distinct neurobiological vulnerability for psychopathological impairment later in life. We used tabulated brain structure and behavioural data from baseline, year 1, and year 2 timepoints of the Adolescent Brain Cognitive Development Study (ABCD; baseline n = 10,534). We fit separate linear mixed effect models to examine whether baseline brain structures in frontolimbic and striatal regions (cortical thickness or subcortical volume) were associated with externalizing symptoms, emotion dysregulation, and/or CU traits at baseline and over a two-year period. The most robust relationships found at the cross-sectional level was between cortical thickness in the right rostral middle frontal gyrus and bilateral pars orbitalis was positively associated with CU traits (β = |0.027-0.033|, pcorrected = 0.009-0.03). Over the two-year follow-up period, higher baseline cortical thickness in the left pars triangularis and rostral middle frontal gyrus predicted greater decreases in externalizing symptoms ((F = 6.33-6.94, pcorrected = 0.014). The results of the current study suggest that unique regions within frontolimbic and striatal networks may be more strongly associated with different dimensions of externalizing psychopathology. The longitudinal findings indicate that brain structure in early childhood may provide insight into structural features that influence behaviour over time.

Structural and functional whole brain changes in autism spectrum disorder at different age stages.

Autism spectrum disorder (ASD) is a developmental disorder involving regional changes and local neural disturbances. However, few studies have investigated the dysfunctional phenomenon across different age stages. This study explores the structural and functional brain changes across different developmental stages in individuals with ASD, focusing on childhood (6-12 years), adolescence (12-18 years), and adulthood (18 + years). Using a comprehensive set of neuroimaging metrics, including modulated and non-modulated voxel-based morphometry (VBM), regional homogeneity (ReHo), amplitude of low-frequency fluctuation (ALFF), and fractional ALFF (fALFF), we identified significant stage-specific alterations in both VBM and functional measurements. Our results reveal that ASD is associated with progressive and stage-specific abnormalities in brain structure and function, with distinct patterns emerging at each developmental stage. Specifically, we observed significant modulated VBM reductions in the precuneus, lentiform nucleus, and inferior parietal lobule, accompanied by increases in the midbrain and sub-gyral regions. Moreover, we observed unmodulated VBM increment in regions including lentiform nucleus and thalamus. Functionally, ReHo analyses demonstrated disrupted local synchronization in the medial frontal gyrus, while ALFF and fALFF metrics highlighted altered spontaneous brain activity in the sub-gyral and sub-lobar. Finally, correlation analyses revealed that stage-specific findings are closely linked to clinical social- and behavior-related scores, with VBM in the inferior parietal lobule and putamen as well as ReHo in supplemental motor area being significantly associated with restrictive repetitive behaviors in childhood. These findings underscore the importance of considering age-specific brain changes when studying ASD and suggest that targeted interventions may be necessary at different developmental stages.

Abnormal changes in neuropsychological function, brain structure and cerebral perfusion in patients with unruptured intracranial aneurysms

BackgroundPatients with unruptured intracranial aneurysms (UIAs) often experience emotional changes and cognitive impairments. However, the specific mechanisms underlying these impairments are still not fully understood.MethodsIn the present study, voxel-based morphometry (VBM) and surface-based morphometry (SBM) were employed to investigate structural alterations in 49 patients diagnosed with UIAs compared with 50 healthy controls. Additionally, this study aimed to analyze the correlations among cortical morphological indices, cerebral blood perfusion values and neuropsychological test results.ResultsCompared with control group, UIA patients exhibited increased gray matter volume in the right anterior orbitofrontal cortex and decreased gray matter volume in the left thalamus pulvinar and hippocampus. Furthermore, the fractal dimension was lower in the right postcentral gyrus and entorhinal cortex. The cerebral perfusion values in the abnormal brain regions demonstrated a downward trend, which was associated with a reduction in gray matter volume in the left thalamus pulvinar and hippocampus, elevated anxiety levels and impaired executive function.ConclusionUIA patients are prone to cognitive impairment and emotional dysregulation, which are accompanied by subtle changes in local gray matter volume and decreases in fractal dimension and cerebral blood flow. These findings provide new insights into the potential mechanisms underlying the cognitive impairment observed in UIA patients.

Effects and mechanisms of supramaximal high-intensity interval training on extrapulmonary manifestations in people with and without chronic obstructive pulmonary disease (COPD-HIIT): study protocol for a multi-centre, randomized controlled trial

BackgroundBeyond being a pulmonary disease, chronic obstructive pulmonary disease (COPD) presents with extrapulmonary manifestations including reduced cognitive, cardiovascular, and muscle function. While exercise training is the cornerstone in the non-pharmacological treatment of COPD, there is a need for new exercise training methods due to suboptimal adaptations when following traditional exercise guidelines, often applying moderate-intensity continuous training (MICT). In people with COPD, short-duration high-intensity interval training (HIIT) holds the potential to induce a more optimal stimulus for training adaptations while circumventing the ventilatory burden often associated with MICT in people with COPD. We aim to determine the effects of supramaximal HIIT and MICT on extrapulmonary manifestations in people with COPD compared to matched healthy controls.MethodsCOPD-HIIT is a prospective, multi-centre, randomized, controlled trial with blinded assessors and data analysts, employing a parallel-group designed trial. In phase 1, we will investigate the effects and mechanisms of a 12-week intervention of supramaximal HIIT compared to MICT in people with COPD (n = 92) and matched healthy controls (n = 70). Participants will perform watt-based cycling two to three times weekly. In phase 2, we will determine how exercise training and inflammation impact the trajectories of neurodegeneration, in people with COPD, over 24 months. In addition to the 92 participants with COPD performing HIIT or MICT, a usual care group (n = 46) is included in phase 2. In both phases, the primary outcomes are a change from baseline in cognitive function, cardiorespiratory fitness, and muscle power. Key secondary outcomes include change from baseline exercise tolerance, brain structure, and function measured by MRI, neuroinflammation measured by PET/CT, systemic inflammation, and intramuscular adaptations. Feasibility of the interventions will be comprehensively investigated.DiscussionThe COPD-HIIT trial will determine the effects of supramaximal HIIT compared to MICT in people with COPD and healthy controls. We will provide evidence for a novel exercise modality that might overcome the barriers associated with MICT in people with COPD. We will also shed light on the impact of exercise at different intensities to reduce neurodegeneration. The goal of the COPD-HIIT trial is to improve the treatment of extrapulmonary manifestations of the disease.Trial registrationClinicaltrials.gov: NCT06068322. Prospectively registered on 2023-09-28.

Mass spectrometry imaging of two neocortical areas reveals the histological selectivity of schizophrenia-associated lipid alterations

BACKGROUND: Schizophrenia is a psychiatric disorder known to affect brain structure and functionality. Structural changes in the brain at the level of gross anatomical structures have been fairly well studied, while microstructural changes, especially those associated with changes in the molecular composition of the brain, are still being investigated. Of special interest are lipids and metabolites, for which some previous studies have shown association with schizophrenia. AIM: To utilize a spatially resolved analysis of the brain lipidome composition to investigate the degree and nature of schizophrenia-associated lipidome alterations in the gray and white matter structures of two neocortical regions — the dorsolateral prefrontal cortex (Brodmann area 9, BA9) and the posterior part of the superior temporal gyrus (Brodmann area 22, posterior part, BA22p), as well compare the distribution of the changes between the two regions and tissue types. METHODS: We employed Matrix-Assisted Laser Desorption/Ionization Mass Spectrometric Imaging (MALDI-MSI), supplemented by a statistical analysis, to examine the lipid composition of brain sections. A total of 24 neocortical sections from schizophrenia patients (n=2) and a healthy control group (n=2), representing the two aforementioned neocortical areas, were studied, yielding data for 131 lipid compounds measured across more than a million MALDI-MSI pixels. RESULTS: Our findings revealed an uneven distribution of schizophrenia-related lipid alterations across the two neocortical regions. The BA22p showed double the differences in its subcortical white matter structures compared to BA9, while less bias was detected in the gray matter layers. While the schizophrenia-associated lipid differences generally showed good agreement between brain regions at the lipid class level for both gray and white matter, there were consistently more discrepancies for white matter structures. CONCLUSION: Our study found a consistent yet differential association of schizophrenia with the brain lipidome composition of distinct neocortical areas, particularly subcortical white matter. These findings highlight the need for broader brain coverage in future schizophrenia research and underscore the potential of spatially resolved molecular analysis methods in identifying structure-specific effects.

Mechanisms and functions of the cerebral-cognitive reserve in patients with Alzheimer's disease: a narrative review

BACKGROUND: The need for scientific knowledge about aging is predicated on the demand of modern society to extend the active life of a person. To maintain intellectual longevity, it is necessary to take into account not only the pathological, but also compensatory mechanisms that arise during aging. The cerebral-cognitive reserve (CCR) influences the rate of transition from pre-phenomenological stages to the clinical stage of the disease, thereby changing the prognosis of Alzheimer’s disease (AD). AIM: The aim of this work was to review meta-analyses from studies that have examined the principles and functions of the CCR in people with AD. METHODS: The work included 83 scientific publications devoted to the issues of the CCR in neurodegenerative diseases such as AD. The Results and Discussion sections of this article provide reviews of the results of 12 meta-analyses published from 2012 to 2024 and selected from the PubMed and eLibrary databases using the following keywords in English and Russian: “cerebral reserve”, “cognitive “reserve”, and “Alzheimer’s disease”. The scope of the definition was not limited, since the goal here was to determine the terminological boundaries of the concepts of “cognitive reserve” and “single brain reserve”. RESULTS: The modern understanding of AD as a biological continuum covering the preclinical, prodromal, and clinical phases of the disease makes it possible to infer that insufficiency of protective factors underlies the progression of AD. The cognitive reserve is involved in the sanogenetic protective mechanism during neurodegeneration. The cognitive reserve is a theoretical concept that reflects modern research’s understanding of how the integrative functioning of the brain (cerebral) and cognitive reserves extend the period of active intellectual longevity through energy-saving mechanisms. It considers these mechanisms as central to healthy mental activity and in slowing the progression of neurodegenerative diseases. At some point, an increase in excess interneuronal activity that reflects the hypercompensatory function of the reserve would accelerate the depletion of brain structures and contribute to clinical and psychopathological manifestations of AD. CONCLUSION: The concept of the CCR puts the spotlight on the need to determine the compensatory indicators of cognitive deficit in AD, assess the architecture and volume of the reserve, and develop and follow protocols for its maintenance. It appears just as crucial to adopt measures to prevent the Reserve’s depletion as early as at the preclinical stages of the disease. Elaborating protective and compensatory mechanisms that help to maintain the functional activity of the brain in conditions of neurodegeneration, that is, CCR, require further research and can form a conceptual basis for the prevention of AD, starting from the preclinical stages of the disease.

Evaluation of Anterior and Middle Brain Structures With Cerebrovascular Flow in Fetuses With Fetal Growth Restriction: A Prospective Study.

To investigate the adaptation of the anterior cerebral artery (ACA) in fetuses with fetal growth restriction (FGR) and assess if forebrain and midbrain structures are affected by vascular adaptations. A prospective case-control study involving normally developed fetuses and those with late-onset FGR (estimated fetal weight < 3rd percentile and/or abdominal circumference < 3rd percentile). Doppler indices of the middle cerebral artery (MCA), ACA and umbilical artery (UA) were determined between 32 + 0 and 37 + 0 weeks. Neurosonography assessed the depth of the insula, the sylvian fissure, and the antero-posterior diameter of the frontal lobes (FAPD). The cerebral-placental ratio (CPR) and cerebro-placental-uterine ratio (CPUR) were lower in FGR cases. ACA PI percentile values were significantly lower in the FGR group (p = 0.020). Sylvian fissure depth was significantly lower in FGR fetuses. The ACA may be the first cranial vascular structure affected in fetuses with FGR. This may be related to the impact on postnatal cognitive functions in FGR patients. NCT06215690.

Hormonal status in women with respiratory viral infections during critical periods

Pregnancy and menopause are critical periods in a woman’s life. Due to physiological changes in the neuroendocrine system regulation, susceptibility to respiratory viral infections increases in these periods, while affecting all organs and systems of the human body. The aim of this review was to analyze the literature data on the effect of acute respiratory viral infections on neuroendocrine regulation in women during pregnancy and menopause. We reviewed full-text publications in the public domain from the PubMed, eLibrary.ru, and Google Scholar databases with a coverage period of more than twenty years (2000–2023). Disruptions of the progesterone and estrogen production during infection with the influenza A (H1N1) and influenza B viruses have been shown in experimental studies. Hormonal status changes in pregnant women are detected during infection with the influenza A virus (H3N2) and depend on antiviral antibody titers and the presence of fetoplacental insufficiency. Pregnant women with COVID-19 may experience changes in the brain structure activities, as indicated by a high frequency of those in olfactory sensitivity and psychoemotional disorders. During menopause, infection with the SARS-CoV-2 virus leads to changes in the production of thyroxine, prolactin, estradiol, testosterone, cortisol, 17-hydroxyprogesterone, and dehydroepiandrosterone sulfate.

Discovering prominent differences in structural and functional connectomes using a multinomial stochastic block model

ABSTRACT Understanding the differences between functional and structural human brain connectivity has been a focus of an extensive amount of neuroscience research. We employ a novel approach using the multinomial stochastic block model (MSBM) to explicitly extract components that characterize prominent differences across graphs. We analyze structural and functional connectomes derived from high-resolution diffusion-weighted MRI and fMRI scans of 250 Human Connectome Project subjects, analyzed at group connectivity level across 50 subjects. The inferred brain partitions revealed consistent, spatially homogeneous clustering patterns across inferred resolutions demonstrating the MSBM’s reliability in identifying brain areas with prominent structure-function differences. Prominent differences in low-resolution brain maps (K = {3, 4} clusters) were attributed to weak functional connectivity in the bilateral anterior temporal lobes, while higher resolution results (K ≥ 25) revealed stronger interhemispheric functional than structural connectivity. Our findings emphasize significant differences in high-resolution functional and structural connectomes, revealing challenges in extracting meaningful connectivity measurements from both modalities, including tracking fibers through the corpus callosum and attenuated functional connectivity in anterior temporal lobe fMRI data, which we attribute to increased noise levels. The MSBM emerges as a valuable tool for understanding differences across graphs, with potential future applications and avenues beyond the current focus on characterizing modality-specific distinctions in connectomics data.

Locus coeruleus co-activation patterns at rest show higher state persistence in patients with dissociative seizures: A Pilot Study.

Dissociative seizures are paroxysmal disruptions of awareness and behavioral control in the context of affective arousal. Alterations in stress-related endocrine function have been demonstrated, but the timescale of dissociation suggests that the central locus coeruleus (LC) noradrenergic system is likely pivotal. Here, we investigate whether LC activation at rest is associated with altered brain network dynamics. A preliminary co-activation pattern (CAP) analysis of resting-state functional magnetic resonance imaging (fMRI) in 14 patients with dissociative seizures and 14 healthy controls was performed by using the LC as a seeding region. The red nucleus served as a control condition. Entry rates, durations, and state transition probabilities of identified CAPs were calculated. Analyses were corrected for demographic, technical, and clinical confounders including depression and anxiety. Three LC-related CAPs were identified, with the dominant two showing inverse activations and deactivations of the default mode network and the attention networks, respectively. Analysis of transition probabilities between and within the three CAPs revealed higher state persistence in patients compared to healthy controls for both CAP2LC (Cohen's d = -0.55; p = 0.01) and CAP3LC (Cohen's d = -0.57; p = 0.01). The control analysis using the red nucleus as a seed yielded similar CAPs, but no significant between-group differences in transition probabilities. Higher state persistence of LC-CAPs in patients with dissociative seizures generates the novel hypothesis that arousal-related impairments of network switching might be a candidate neural mechanism of dissociation. Dissociative seizures often arise during high affective arousal. The locus coeruleus is a brain structure involved in managing such acute arousal states. We investigated whether the activity of the locus coeruleus correlates with activity in other regions of the brain (which we refer to as "brain states"), and whether those brain states were different between patients with dissociative seizures and healthy controls. We found that patients tended to stay in certain locus coeruleus-dependent brain states instead of switching between them. This might be related to the loss of awareness and disruptions of brain functions ("dissociation") that patients experience during seizures.

Association between the Val66Met (rs6265) polymorphism of the brain-derived neurotrophic factor (BDNF) gene, BDNF protein level in the blood and the risk of developing early‑onset Parkinson’s disease

Brain-derived neurotrophic factor (BDNF) is involved in the maintenance of dopamine level and the survival of dopaminergic neurons, which may affect the functionality of brain structures responsible for motor and cognitive function. The aim of the study was to assess the association of individual and combined single nucleotide polymorphism (SNP) in the rs6265 BDNF (Val66Met), rs397595 DAT (SLC6A3), and rs4680 COMT (Val158Met) genes with early‑onset of Parkinson’s disease (PD) patients. Moreover, we assessed the association between the BDNF Val66Met polymorphism and the level of BDNF protein in the serum of patients with PD and controls. The study involved 163 patients with idiopathic PD divided into early onset (&lt;55 years) and late‑onset (&gt;55 years) groups and 91 healthy age‑matched people (Control). The SNP were determined using the TaqMan Real‑Time PCR method. Serum BDNF levels were determined by ELISA assay. The risk of developing early PD in people with the BDNF genotype AG increases threefold in comparison with the carriers of the BDNF genotype GG. In PD patients and healthy people with the BDNF genotypes AG and AA, a lower serum BDNF level was found compared to those with the BDNF genotype GG in both groups. The results of our study indicate that the presence of the Val66Met BDNF gene polymorphism is associated with reduced blood BDNF levels and an elevated risk of developing early‑onset PD. This effect appears to be more pronounced in men.

Key neuroprotective mechanisms of the MIND diet - a review paper

Introduction and purpose: Impaired cognitive function is a growing public health problem, where dementia is affecting about 47 million people worldwide, and that number is expected to triple by 2050. The MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diet is intended to overcome this problem. This article aims to raise awareness of the MIND diet, highlighting how dietary choices can promote cognitive health and delay disease progression. Brief description of the state of knowledge: The MIND diet focuses on foods that support cognitive health and may mitigate these degenerative processes. It emphasizes green leafy vegetables, berries, nuts, olive oil, whole grains, fish, and poultry while limiting red meat, dairy, sweets, and fried foods. These products contain several components with multidirectional neuroprotective effects. Material and method: This work was based on material found on Google Scholar. Articles were selected based on citation counts, publication dates, and relevance, ensuring a comprehensive review of recent findings on the MIND diet's impact on cognitive health. Summary: The MIND diet enhances brain health by incorporating nutrient-dense foods that reduce inflammation, combat oxidative stress, and support neuronal function. Green leafy vegetables, berries, nuts, whole grains, and healthy fats work together to improve cognitive function, support synaptic plasticity, and protect brain structure, leading to slower cognitive decline and a lower risk of neurodegenerative diseases.

Structural brain correlates of creative personality: a voxel-based morphometric study

ABSTRACT The current study explored the neuroanatomical basis of creative personality using the voxel-based morphometric (VBM) approach. The sample comprised two groups – Creative (CR) group (professional creative artists) and matched controls with no demonstrated artistic creativity (NC) with 20 participants in each group, in the age range of 20–40 years, right-handed (screened using Edinburgh Handedness Inventory) and had minimum average intelligence (IQ > 90 on Raven’s Progressive Matrices). Professional creative artists were selected using the creativity achievement questionnaire, creativity was assessed using the Wallach & Kogan test of creativity, and personality was administered using NEO-FFI. The result indicates that creative individuals have significantly higher openness to new experiences and it positively correlates with the right middle frontal gyrus. VBM analysis indicates increased gray matter volume in the inferior frontal gyrus and anterior cingulate gyrus in the CR group, pointing toward the integration of cognitive and imaginative processes that might be implicated in creative personality.

Cacna1c deficiency in forebrain glutamatergic neurons alters behavior and hippocampal plasticity in female mice

CACNA1C, coding for the α1 subunit of L-type voltage-gated calcium channel (LTCC) Cav1.2, has been associated with multiple psychiatric disorders. Clinical studies have revealed alterations in behavior as well as in brain structure and function in CACNA1C risk allele carriers. These findings are supported by rodent models of Cav1.2 deficiency, which showed increased anxiety, cognitive and social impairments as well as a shift towards active stress-coping strategies. These behavioral alterations were accompanied by functional deficits, such as reduced long-term potentiation (LTP) and an excitation/inhibition (E/I) imbalance. However, these preclinical studies are largely limited to male rodents, with few studies exploring sex-specific effects. Here, we investigated the effects of Cav1.2 deficiency in forebrain glutamatergic neurons in female conditional knockout (CKO) mice. CKO mice exhibited hyperlocomotion in a novel environment, increased anxiety-related behavior, cognitive deficits, and increased active stress-coping behavior. These behavioral alterations were neither influenced by the stage of the estrous cycle nor by the Nex/Neurod6 haploinsufficiency or Cre expression, which are intrinsically tied to the utilization of the Nex-Cre driver line for conditional inactivation of Cacna1c. In the hippocampus, Cav1.2 inactivation enhanced presynaptic paired-pulse facilitation without altering postsynaptic LTP at CA3-CA1 synapses. In addition, CA1 pyramidal neurons of female CKO mice displayed a reduction in dendritic complexity and spine density. Taken together, our findings extend the existing knowledge suggesting Cav1.2-dependent structural and functional alterations as possible mechanisms for the behavioral alterations observed in female Cav1.2-Nex mice.

Shared and distinct alterations in brain morphology in children with ADHD and obesity: Reduced cortical surface area in ADHD and thickness in overweight/obesity

ObjectiveTo investigate shared versus distinct differences in brain structure among children with ADHD and obesity, we examined the morphology of regions implicated in cognitive control and reward function in a single cross-sectional cohort of children with and without ADHD and overweight/obesity (OV/OB). MethodParticipants included 471 children ages 8–12 years with ADHD (n = 244; 58 OV/OB) and neurotypical (NT) controls (n = 227; 81 OV/OB) classified as healthy-weight (HW; BMI %ile 5th to <85th) vs. having OV/OB (BMI %ile≥85th). Structural MRI was performed to obtain measures of cortical and subcortical morphology and compared across ADHD × BMI groups. ResultsSurface area was generally lower in ADHD vs. NT including in anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (dlPFC), medial (m)PFC, and primary motor (M1) cortex. In contrast, cortical thickness was generally lower in OV/OB vs. HW for ACC, dlPFC, orbitofrontal cortex (OFC), mPFC, and supplementary motor cortex (SMC). Furthermore, ADHD × OV/OB interactions were observed for the ACC and OFC, with the lowest ACC volume in the ADHD + OV/OB group and the highest OFC surface area in the NT + OV/OB group. Subcortical volumes did not differ between groups. ConclusionsOur findings reveal distinct alterations in cortical morphology in association with ADHD and overweight, with cortical surface area reduced in ADHD vs. thickness reduced in OV/OB. Additionally, the findings provide evidence of combined effects of ADHD × OV/OB in brain regions integral to cognition and motivation. Our results support further investigation of causes and correlates of shared and distinct ADHD- and OV/OB-associated differences in developing frontocingulate morphology.

12321 The Neurotransmitter Glutamate Promotes The Endocrine Functions Of Bone

Abstract Disclosure: I. Canal Delgado: None. G. Karsenty: None. The osteoblast-derived hormone osteocalcin must be decarboxylated to become active. This can be achieved by neurite-derived glutamate, which once in osteoblasts, inhibits the enzyme responsible of osteocalcin carboxylation. Glutamate enters osteoblasts through the EAAT1/Glast transporter, a gene highly expressed in glial cells but whose functions in peripheral organs has not been systematically investigated. To precisely define the functions of glutamate in osteoblasts, we generated mice lacking Glast only in osteoblasts (Glastosb-/-). We first observed that deleting Glast from osteoblasts decreased circulating levels of the uncarboxylated and active form of osteocalcin. Phenotypic analysis showed that Glastosb-/- mice experience a much weaker acute stress response following exposure to a physical stressor, are hyperglycemic and hypoinsulinemic compared to wild-type (WT) littermates. These abnormalities are the ones seen in mice lacking osteocalcin and were corrected by exogenous osteocalcin. We next used this mutant mouse strain as a tool to ask whether any of the symptoms observed in GLAST-deficient patients might be due, in part, to the absence of glutamate signaling in osteoblasts. We focused on cognition because this central function is impaired in GLAST-deficient subjects, and it is regulated by osteocalcin. We observed that Glastosb-/- mice had a severe cognitive impairment. To define more precisely the contribution of bone to the cognitive defect caused by the absence of GLAST, we relied on both pharmacological and genetic experiments. First, we treated WT mice with a Glast inhibitor that does not cross the blood-brain barrier (BBB) and therefore, does not affect any brain structure, or with another Glast inhibitor that crosses the BBB. In the conditions of this experiment, only the Glast inhibitor that does not cross the BBB impaired cognition in WT mice, further suggesting that glutamate signaling regulates behavior in part by regulating the release of active osteocalcin from bone. To strengthen these results, we are currently comparing cognition functions in mutant mice lacking Glast in glial cells or neurons. Together, our observations illustrate the important functions played by of glutamate in osteoblasts and suggest that some behavioral phenotype caused by the absence of GLAST in humans may originate, at least in part, from the disruption of glutamate signaling in the skeleton. Presentation: 6/2/2024

Physiological and behavioural implications of the portosystemic shunt in C57Bl/6J mice.

A significant fraction of the popular inbred C57Bl/6J mice show structural and biochemical features of the congenital portosystemic shunt (PSS). How this hepatic abnormality affects physiological and behavioural parameters has not been explored in detail. Here, we confirmed the frequent occurrence of the PSS in C57Bl/6J mice by three different methods. We screened a cohort of 119 C57Bl/6J mice for total bile acids (TBA) in plasma, identified 11 animals (9.2%) with high TBA (>11µm; 171.1 ± 76.8µm), and confirmed PSS presence in that subset by magnetic resonance angiography and 1H-magnetic resonance spectroscopy of brain metabolites in the hippocampal area. In addition to the high glutamine and low myo-inositol levels, we detected lower levels of several neurotransmitters and metabolites in the hippocampus, higher brain weight and volume, as well as enhanced brain glucose utilisation in the PSS mice. We also observed differences in peripheral organ weights, haematological cell counts and clinical chemistry parameters in C57Bl/6J mice with and without PSS. Animals with PSS were slightly hyperlocomotive, had better balance on the rotarod, showed altered gait properties, and displayed attenuated fear memory in the fear conditioning test. Furthermore, we revealed a significant alteration of the pharmacokinetic profile of diazepam in C57Bl/6J mice with PSS. Our data support previous reports of hepatic disturbances and demonstrate an altered neurobiological phenotype in C57Bl/6J mice with PSS. Such congenital differences between inbred C57Bl/6J littermates may significantly distort experimental outcomes of pharmacological, behavioural and genetic studies. KEY POINTS: A significant proportion of C57Bl/6J mice, an inbred strain popular in preclinical research, have congenital portosystemic shunts (PSS) that allow venous blood to enter systemic circulation bypassing the liver. In this study, we extended existing knowledge of PSS consequences, particularly with respect to the effects on brain structure and function. We demonstrated that C57Bl/6J mice with PSS differ from their normal counterparts in brain size and contents of several neuroactive substances, as well as in peripheral organ weights, rate of glucose utilisation, blood cell counts and blood clinical chemistry parameters. C57Bl/6J mice with PSS showed altered locomotor behaviour, performed worse in a memory test and had abnormal blood pharmacokinetics of a benzodiazepine drug after a single administration. PSS presence may significantly complicate the interpretation of experiments in C57Bl/6J mice; therefore, we propose that before their use in biomedical studies, these mice should be screened with a simple blood test.

Deciphering autism heterogeneity: a molecular stratification approach in four mouse models

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition characterized by impairments in social interaction and communication, as well as restrained or stereotyped behaviors. The inherent heterogeneity within the autism spectrum poses challenges for developing effective pharmacological treatments targeting core features. Successful clinical trials require the identification of robust markers to enable patient stratification. In this study, we identified molecular markers within the oxytocin and immediate early gene families across five interconnected brain structures of the social circuit. We used wild-type and four heterogeneous mouse models, each exhibiting unique autism-like behaviors modeling the autism spectrum. While dysregulations in the oxytocin family were model-specific, immediate early genes displayed widespread alterations, reflecting global changes across the four models. Through integrative analysis, we identified Egr1, Foxp1, Homer1a, Oxt, and Oxtr as five robust and discriminant molecular markers that allowed the successful stratification of the four models. Importantly, our stratification demonstrated predictive values when challenged with a fifth mouse model or identifying subgroups of mice potentially responsive to oxytocin treatment. Beyond providing insights into oxytocin and immediate early gene mRNA dynamics, this proof-of-concept study represents a significant step toward the potential stratification of individuals with ASD. This work has implications for the success of clinical trials and the development of personalized medicine in autism.

Parasagittal dural volume correlates with cerebrospinal fluid volume and developmental delay in children with autism spectrum disorder

BackgroundThe parasagittal dura, a tissue that lines the walls of the superior sagittal sinus, acts as an active site for immune-surveillance, promotes the reabsorption of cerebrospinal fluid, and facilitates the removal of metabolic waste products from the brain. Cerebrospinal fluid is important for the distribution of growth factors that signal immature neurons to proliferate and migrate. Autism spectrum disorder is characterized by altered cerebrospinal fluid dynamics.MethodsIn this retrospective study, we investigated potential correlations between parasagittal dura volume, brain structure volumes, and clinical severity scales in young children with autism spectrum disorder. We employed a semi-supervised two step pipeline to extract parasagittal dura volume from 3D-T2 Fluid Attenuated Inversion Recovery sequences, based on U-Net followed by manual refinement of the extracted parasagittal dura masks.ResultsHere we show that the parasagittal dura volume does not change with age but is significantly correlated with cerebrospinal fluid (p-value = 0.002), extra-axial cerebrospinal fluid volume (p-value = 0.0003) and severity of developmental delay (p-value = 0.024).ConclusionsThese findings suggest that autism spectrum disorder children with severe developmental delay may have a maldeveloped parasagittal dura that potentially perturbs cerebrospinal fluid dynamics.