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Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental and psychiatric disorders. MIA-induced deficits in adolescent and adult offspring have been well characterized; however, less is known about the effects of MIA exposure on embryo development. To address this gap, we performed high-resolution ex vivo MRI to investigate the effects of early (gestational day [GD]9) and late (GD17) MIA exposure on embryo (GD18) brain structure. We identify striking neuroanatomical changes in the embryo brain, particularly in the late-exposed offspring. We further examined the putative neuroanatomical underpinnings of MIA timing in the hippocampus using electron microscopy and identified differential effects due to MIA timing. An increase in apoptotic cell density was observed in the GD9-exposed offspring, while an increase in the density of neurons and glia with ultrastructural features reflective of increased neuroinflammation and oxidative stress was observed in GD17-exposed offspring, particularly in females. Overall, our findings integrate imaging techniques across different scales to identify differential impact of MIA timing on the earliest stages of neurodevelopment.
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Trastorno del Espectro Autista , Sistema Inmunológico , Efectos Tardíos de la Exposición Prenatal , Esquizofrenia , Adolescente , Animales , Encéfalo , Modelos Animales de Enfermedad , Femenino , Humanos , Sistema Inmunológico/fisiología , Inflamación , Imagen por Resonancia Magnética , Ratones , EmbarazoRESUMEN
All eutherian mammals show chromosomal sex determination with contrasting sex chromosome dosages (SCDs) between males (XY) and females (XX). Studies in transgenic mice and humans with sex chromosome trisomy (SCT) have revealed direct SCD effects on regional mammalian brain anatomy, but we lack a formal test for cross-species conservation of these effects. Here, we develop a harmonized framework for comparative structural neuroimaging and apply this to systematically profile SCD effects on regional brain anatomy in both humans and mice by contrasting groups with SCT (XXY and XYY) versus XY controls. Total brain size was substantially altered by SCT in humans (significantly decreased by XXY and increased by XYY), but not in mice. Robust and spatially convergent effects of XXY and XYY on regional brain volume were observed in humans, but not mice, when controlling for global volume differences. However, mice do show subtle effects of XXY and XYY on regional volume, although there is not a general spatial convergence in these effects within mice or between species. Notwithstanding this general lack of conservation in SCT effects, we detect several brain regions that show overlapping effects of XXY and XYY both within and between species (cerebellar, parietal, and orbitofrontal cortex), thereby nominating high priority targets for future translational dissection of SCD effects on the mammalian brain. Our study introduces a generalizable framework for comparative neuroimaging in humans and mice and applies this to achieve a cross-species comparison of SCD effects on the mammalian brain through the lens of SCT.SIGNIFICANCE STATEMENT Sex chromosome dosage (SCD) affects neuroanatomy and risk for psychopathology in humans. Performing mechanistic studies in the human brain is challenging but possible in mouse models. Here, we develop a framework for cross-species neuroimaging analysis and use this to show that an added X- or Y-chromosome significantly alters human brain anatomy but has muted effects in the mouse brain. However, we do find evidence for conserved cross-species impact of an added chromosome in the fronto-parietal cortices and cerebellum, which point to regions for future mechanistic dissection of sex chromosome dosage effects on brain development.
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Encéfalo , Cromosomas Sexuales , Masculino , Femenino , Humanos , Ratones , Animales , Encéfalo/anatomía & histología , Neuroimagen , Cerebelo , Ratones Transgénicos , MamíferosRESUMEN
Sex chromosome aneuploidies (SCAs) are collectively common conditions caused by carriage of a sex chromosome dosage other than XX for females and XY for males. Increases in sex chromosome dosage (SCD) have been shown to have an inverted-U association with height, but we lack combined studies of SCA effects on height and weight, and it is not known if any such effects vary with age. Here, we study norm-derived height and weight z-scores in 177 youth spanning 8 SCA karyotypes (XXX, XXY, XYY, XXXX, XXXY, XXYY, XXXXX, and XXXXY). We replicate a previously described inverted-U association between mounting SCD and height, and further show that there is also a muted version of this effect for weight: both phenotypes are elevated until SCD reaches 4 for females and 5 for males but decrease thereafter. We next use 266 longitudinal measures available from a subset of karyotypes (XXX, XXY, XYY, and XXYY) to show that mean height in these SCAs diverges further from norms with increasing age. As weight does not diverge from norms with increasing age, BMI decreases with increasing age. These findings extend our understanding of growth as an important clinical outcome in SCA, and as a key context for known effects of SCA on diverse organ systems that scale with body size.
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Aberraciones Cromosómicas Sexuales , Cromosomas Sexuales , Masculino , Femenino , Humanos , Niño , Adolescente , Índice de Masa Corporal , Cariotipo , AneuploidiaRESUMEN
Our current understanding of litter variability in neurodevelopmental studies using mice may limit translation of neuroscientific findings. Higher variance of measures across litters than within, often termed intra-litter likeness, may be attributable to both pre- and postnatal environment. This study aimed to assess the litter-effect within behavioral assessments (2 timepoints) and anatomy using T1-weighted magnetic resonance images across 72 brain region volumes (4 timepoints) (36 C57bl/6J inbred mice; 7 litters: 19F/17M). Between-litter comparisons of brain and behavioral measures and their associations were evaluated using univariate and multivariate techniques. A power analysis using simulation methods was then performed on modeled neurodevelopment and to evaluate trade-offs between number-of-litters, number-of-mice-per-litter, and sample size. Our results show litter-specific developmental effects, from the adolescent period to adulthood for brain structure volumes and behaviors, and for their associations in adulthood. Our power simulation analysis suggests increasing the number-of-litters in experimental designs to achieve the smallest total sample size necessary for detecting different rates of change in specific brain regions. Our results demonstrate how litter-specific effects may influence development and that increasing the litters to the total sample size ratio should be strongly considered when designing neurodevelopmental studies.
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Tamaño de la Camada , Embarazo , Femenino , Animales , Ratones , Simulación por Computador , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: Neuroanatomical alterations are well established in patients suffering from schizophrenia, however the extent to which these changes are attributable to illness, antipsychotic drugs (APDs), or their interaction is unclear. APDs have been extremely effective for treatment of positive symptoms in major psychotic disorders. Their therapeutic effects are mediated, in part, through blockade of D2-like dopamine (DA) receptors, i.e. the D2, D3 and D4 dopamine receptors. Furthermore, the dependency of neuroanatomical change on DA system function and D2-like receptors has yet to be explored. METHODS: We undertook a preclinical longitudinal study to examine the effects of typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs in wild type (WT) and dopamine D2 knockout (D2KO) mice over 9-weeks using structural magnetic resonance imaging (MRI). RESULTS: Chronic typical APD administration in WT mice was associated with reductions in total brain (pâ¯=â¯0.009) and prelimbic area (PL) (pâ¯=â¯0.02) volumes following 9-weeks, and an increase in striatal volume (pâ¯=â¯0.04) after six weeks. These APD-induced changes were not present in D2KOs, where, at baseline, we observed significantly smaller overall brain volume (pâ¯<â¯0.01), thinner cortices (qâ¯<â¯0.05), and enlarged striata (qâ¯<â¯0.05). Stereological assessment revealed increased glial density in PL area of HAL treated wild types. Interestingly, in WT and D2KO mice, chronic CLZ administration caused more limited changes in brain structure. CONCLUSIONS: Our results present evidence for the role of D2 DA receptors in structural alterations induced by the administration of the typical APD HAL and that chronic administration of CLZ has a limited influence on brain structure.
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Antipsicóticos/administración & dosificación , Encéfalo/anatomía & histología , Encéfalo/efectos de los fármacos , Antagonistas de los Receptores de Dopamina D2/administración & dosificación , Receptores de Dopamina D2/fisiología , Animales , Clozapina/administración & dosificación , Femenino , Haloperidol/administración & dosificación , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Dopamina D2/genéticaRESUMEN
Psychosis is associated with abnormal structural changes in the brain including decreased regional brain volumes and abnormal brain morphology. However, the underlying causes of these structural abnormalities are less understood. The immune system, including microglial activation, has been implicated in the pathophysiology of psychosis. Although previous studies have suggested a connection between peripheral proinflammatory cytokines and structural brain abnormalities in schizophrenia, no in-vivo studies have investigated whether microglial activation is also linked to brain structure alterations previously observed in schizophrenia and its putative prodrome. In this study, we investigated the link between mitochondrial 18â¯kDa translocator protein (TSPO) and structural brain characteristics (i.e. regional brain volume, cortical thickness, and hippocampal shape) in key brain regions such as dorsolateral prefrontal cortex and hippocampus of a large group of participants (Nâ¯=â¯90) including individuals at clinical high risk (CHR) for psychosis, first-episode psychosis (mostly antipsychotic-naïve) patients, and healthy volunteers. The participants underwent structural brain MRI scan and [18F]FEPPA positron emission tomography (PET) targeting TSPO. A significant [18F]FEPPA binding-by-group interaction was observed in morphological measures across the left hippocampus. In first-episode psychosis, we observed associations between [18F]FEPPA VT (total volume of distribution) and outward and inward morphological alterations, respectively, in the dorsal and ventro-medial portions of the left hippocampus. These associations were not significant in CHR or healthy volunteers. There was no association between [18F]FEPPA VT and other structural brain characteristics. Our findings suggest a link between TSPO expression and alterations in hippocampal morphology in first-episode psychosis.
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Encéfalo/metabolismo , Encéfalo/patología , Trastornos Psicóticos/metabolismo , Trastornos Psicóticos/patología , Receptores de GABA/biosíntesis , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Estudios de Casos y Controles , Femenino , Hipocampo/diagnóstico por imagen , Hipocampo/metabolismo , Hipocampo/patología , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Tomografía de Emisión de Positrones/métodos , Corteza Prefrontal/diagnóstico por imagen , Corteza Prefrontal/patología , Trastornos Psicóticos/diagnóstico por imagen , Trastornos Psicóticos/genética , Receptores de GABA/genética , Receptores de GABA/metabolismo , Transcriptoma , Adulto JovenRESUMEN
Exposure to immune dysregulation in utero or in early life has been shown to increase risk for neuropsychiatric illness. The sources of inflammation can be varied, including acute exposures due to maternal infection or acute stress, or persistent exposures due to chronic stress, obesity, malnutrition, or autoimmune diseases. These exposures may cause subtle alteration in brain development, structure, and function that can become progressively magnified across the life span, potentially increasing the likelihood of developing a neuropsychiatric conditions. There is some evidence that males are more susceptible to early-life inflammatory challenges than females. In this review, we discuss the various sources of in utero or early-life immune alteration and the known effects on fetal development with a sex-specific lens. To do so, we leveraged neuroimaging, behavioral, cellular, and neurochemical findings. Gaining clarity about how the intrauterine environment affects offspring development is critically important for informing preventive and early intervention measures that may buffer against the effects of these early-life risk factors.
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In vivo neuroimaging studies have established several reproducible volumetric sex differences in the human brain, but the causes of such differences are hard to parse. While mouse models are useful for understanding the cellular and mechanistic bases of sex-specific brain development, there have been no attempts to formally compare human and mouse neuroanatomical sex differences to ascertain how well they translate. Addressing this question would shed critical light on the use of the mouse as a translational model for sex differences in the human brain and provide insights into the degree to which sex differences in brain volume are conserved across mammals. Here, we use structural magnetic resonance imaging to conduct the first comparative neuroimaging study of sex-specific neuroanatomy of the human and mouse brain. In line with previous findings, we observe that in humans, males have significantly larger and more variable total brain volume; these sex differences are not mirrored in mice. After controlling for total brain volume, we observe modest cross-species congruence in the volumetric effect size of sex across 60 homologous regions (r=0.30). This cross-species congruence is greater in the cortex (r=0.33) than non-cortex (r=0.16). By incorporating regional measures of gene expression in both species, we reveal that cortical regions with greater cross-species congruence in volumetric sex differences also show greater cross-species congruence in the expression profile of 2835 homologous genes. This phenomenon differentiates primary sensory regions with high congruence of sex effects and gene expression from limbic cortices where congruence in both these features was weaker between species. These findings help identify aspects of sex-biased brain anatomy present in mice that are retained, lost, or inverted in humans. More broadly, our work provides an empirical basis for targeting mechanistic studies of sex-specific brain development in mice to brain regions that best echo sex-specific brain development in humans.
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Encéfalo , Caracteres Sexuales , Humanos , Masculino , Femenino , Ratones , Animales , Encéfalo/diagnóstico por imagen , Encéfalo/anatomía & histología , Neuroimagen/métodos , Imagen por Resonancia Magnética/métodos , MamíferosRESUMEN
The pre- and perinatal environment is thought to play a critical role in shaping brain development. Specifically, maternal mental health and maternal care have been shown to influence offspring brain development in regions implicated in emotional regulation such as the amygdala. In this study, we used data from a neuroimaging follow-up of a prenatal birth-cohort, the European Longitudinal Study of Pregnancy and Childhood, to investigate the impact of early postnatal maternal anxiety/co-dependence, and prenatal and early-postnatal depression and dysregulated mood on amygdala volume and morphology in young adulthood (n = 103). We observed that in typically developing young adults, greater maternal anxiety/co-dependence after birth was significantly associated with lower volume (right: t = -2.913, p = 0.0045, ß = -0.523; left: t = -1.471, p = 0.144, ß = -0.248) and non-significantly associated with surface area (right: t = -3.502, q = 0.069, <10%FDR, ß = -0.090, left: t = -3.137, q = 0.117, <10%FDR, = -0.088) of the amygdala in young adulthood. Conversely, prenatal maternal depression and mood dysregulation in the early postnatal period was not associated with any volumetric or morphological changes in the amygdala in young adulthood. Our findings provide evidence for subtle but long-lasting alterations to amygdala morphology associated with differences in maternal anxiety/co-dependence in early development.
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Depresión Posparto , Efectos Tardíos de la Exposición Prenatal , Femenino , Embarazo , Adulto Joven , Humanos , Adulto , Niño , Estudios Longitudinales , Salud Mental , Amígdala del Cerebelo/diagnóstico por imagen , Encéfalo , Depresión/diagnóstico por imagen , Efectos Tardíos de la Exposición Prenatal/diagnóstico por imagenRESUMEN
Prenatal exposure to maternal immune activation (MIA) and chronic adolescent cannabis use are both risk factors for neuropsychiatric disorders. However, exposure to a single risk factor may not result in major mental illness, indicating that multiple exposures may be required for illness onset. Here, we examine whether combined exposure to prenatal MIA and adolescent delta-9-tetrahydrocannabinol (THC), the main psychoactive component of cannabis, lead to enduring neuroanatomical and behavioural changes in adulthood. Mice were prenatally exposed to viral mimetic, poly I:C (5 mg/kg), or vehicle at gestational day (GD) 9, and postnatally exposed to chronic THC (5 mg/kg, intraperitoneal) or vehicle during adolescence (postnatal day [PND]28-45). Longitudinal magnetic resonance imaging (MRI) was performed pre-treatment, PND 25, post-treatment, PND 50, and in adulthood, PND85, followed by behavioural tests for anxiety-like, social, and sensorimotor gating. Post-mortem assessment of cannabinoid (CB)1 and 2 receptor expressing cells was performed in altered regions identified by MRI (anterior cingulate and somatosensory cortices, striatum, and hippocampus). Subtle deviations in neurodevelopmental trajectory and subthreshold anxiety-like behaviours were observed in mice exposed to both risk factors. Sex-dependent effects were observed in patterns of shared brain-behaviour covariation, indicative of potential sex differences in response to MIA and THC. Density of CB1 and CB2 receptor positive cells was significantly decreased in all mice exposed to MIA, THC, or both. These findings suggest that there may be a cumulative effect of risk factor exposure on gross neuroanatomical development, and that the endocannabinoid system may be sensitive to both prenatal MIA, adolescent THC, or the combination.
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Cannabis , Alucinógenos , Efectos Tardíos de la Exposición Prenatal , Embarazo , Animales , Ratones , Femenino , Masculino , Humanos , Cannabis/efectos adversos , Dronabinol/efectos adversos , Endocannabinoides , Receptor Cannabinoide CB2 , Agonistas de Receptores de Cannabinoides , Poli I-C/toxicidadRESUMEN
In vivo neuroimaging studies have established several reproducible volumetric sex differences in the human brain, but the causes of such differences are hard to parse. While mouse models are useful for understanding the cellular and mechanistic bases of sex-biased brain development in mammals, there have been no attempts to formally compare mouse and human sex differences across the whole brain to ascertain how well they translate. Addressing this question would shed critical light on use of the mouse as a translational model for sex differences in the human brain and provide insights into the degree to which sex differences in brain volume are conserved across mammals. Here, we use cross-species structural magnetic resonance imaging to carry out the first comparative neuroimaging study of sex-biased neuroanatomical organization of the human and mouse brain. In line with previous findings, we observe that in humans, males have significantly larger and more variable total brain volume; these sex differences are not mirrored in mice. After controlling for total brain volume, we observe modest cross-species congruence in the volumetric effect size of sex across 60 homologous brain regions (r=0.30; e.g.: M>F amygdala, hippocampus, bed nucleus of the stria terminalis, and hypothalamus and F>M anterior cingulate, somatosensory, and primary auditory cortices). This cross-species congruence is greater in the cortex (r=0.33) than non-cortex (r=0.16). By incorporating regional measures of gene expression in both species, we reveal that cortical regions with greater cross-species congruence in volumetric sex differences also show greater cross-species congruence in the expression profile of 2835 homologous genes. This phenomenon differentiates primary sensory regions with high congruence of sex effects and gene expression from limbic cortices where congruence in both these features was weaker between species. These findings help identify aspects of sex-biased brain anatomy present in mice that are retained, lost, or inverted in humans. More broadly, our work provides an empirical basis for targeting mechanistic studies of sex-biased brain development in mice to brain regions that best echo sex-biased brain development in humans.
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Evidence suggests that subcortical hyperdopaminergia alters cognitive function in schizophrenia and antipsychotic drugs (APD) fail at rescuing cognitive deficits in patients. In a previous study, we showed that blocking D2 dopamine receptors (D2R), a core action of APD, led to profound reshaping of mesohippocampal fibers, deficits in synaptic transmission and impairments in learning and memory in the mouse hippocampus (HP). However, it is currently unknown how excessive dopamine affects HP-related cognitive functions, and how APD would impact HP functions in such a state. After verifying the presence of DAT-positive neuronal projections in the ventral (temporal), but not in the dorsal (septal), part of the HP, GBR12935, a blocker of dopamine transporter (DAT), was infused in the CA1 of adult C57Bl/6 mice to produce local hyperdopaminergia. Chronic GBR12935 infusion in temporal CA1 induced a mild learning impairment in the Morris Water Maze and abolished long-term recognition memory in novel-object (NORT) and object-place recognition tasks (OPRT). Deficits were accompanied by a significant decrease in DAT+ mesohippocampal fibers. Intrahippocampal or systemic treatment with sulpiride during GBR infusions improved the NORT deficit but not that of OPRT. In vitro application of GBR on hippocampal slices abolished long-term depression (LTD) of fEPSP in temporal CA1. LTD was rescued by co-application with sulpiride. In conclusion, chronic DAT blockade in temporal CA1 profoundly altered mesohippocampal modulation of hippocampal functions. Contrary to previous observations in normodopaminergic mice, antagonising D2Rs was beneficial for cognitive functions in the context of hippocampal hyperdopaminergia.
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Antipsicóticos , Animales , Ratones , Antipsicóticos/farmacología , Antipsicóticos/uso terapéutico , Sulpirida/farmacología , Sulpirida/uso terapéutico , Hipocampo , Trastornos de la Memoria/tratamiento farmacológico , Ratones Endogámicos C57BLRESUMEN
Noradrenaline (NE) plays an integral role in shaping behavioral outcomes including anxiety/depression, fear, learning and memory, attention and shifting behavior, sleep-wake state, pain, and addiction. However, it is unclear whether dysregulation of NE release is a cause or a consequence of maladaptive orientations of these behaviors, many of which associated with psychiatric disorders. To address this question, we used a unique genetic model in which the brain-specific vesicular monoamine transporter-2 (VMAT2) gene expression was removed in NE-positive neurons disabling NE release in the entire brain. We engineered VMAT2 gene splicing and NE depletion by crossing floxed VMAT2 mice with mice expressing the Cre-recombinase under the dopamine ß-hydroxylase (DBH) gene promotor. In this study, we performed a comprehensive behavioral and transcriptomic characterization of the VMAT2DBHcre KO mice to evaluate the role of central NE in behavioral modulations. We demonstrated that NE depletion induces anxiolytic and antidepressant-like effects, improves contextual fear memory, alters shifting behavior, decreases the locomotor response to amphetamine, and induces deeper sleep during the non-rapid eye movement (NREM) phase. In contrast, NE depletion did not affect spatial learning and memory, working memory, response to cocaine, and the architecture of the sleep-wake cycle. Finally, we used this model to identify genes that could be up- or down-regulated in the absence of NE release. We found an up-regulation of the synaptic vesicle glycoprotein 2c (SV2c) gene expression in several brain regions, including the locus coeruleus (LC), and were able to validate this up-regulation as a marker of vulnerability to chronic social defeat. The NE system is a complex and challenging system involved in many behavioral orientations given it brain wide distribution. In our study, we unraveled specific role of NE neurotransmission in multiple behavior and link it to molecular underpinning, opening future direction to understand NE role in health and disease.
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Encéfalo , Transcriptoma , Ratones , Animales , Encéfalo/metabolismo , Norepinefrina/metabolismo , Depresión/metabolismo , Antidepresivos/farmacologíaRESUMEN
The presence, magnitude, and significance of sex differences in the human brain are hotly debated topics in the scientific community and popular media. This debate is largely fueled by studies containing strong, opposing conclusions: either little to no evidence exists for sex differences in human neuroanatomy, or there are small-to-moderate differences in the size of certain brain regions that are highly reproducible across cohorts (even after controlling for sex differences in average brain size). Our Commentary uses the specific comparison between two recent large-scale studies that adopt these opposing views-namely the review by Eliot and colleagues (2021) and the direct analysis of ~ 40k brains by Williams and colleagues (2021)-in an effort to clarify this controversy and provide a framework for conducting this research. First, we review observations that motivate research on sex differences in human neuroanatomy, including potential causes (evolutionary, genetic, and environmental) and effects (epidemiological and clinical evidence for sex-biased brain disorders). We also summarize methodological and empirical support for using structural MRI to investigate such patterns. Next, we outline how researchers focused on sex differences can better specify their study design (e.g., how sex was defined, if and how brain size was adjusted for) and results (by e.g., distinguishing sexual dimorphisms from sex differences). We then compare the different approaches available for studying sex differences across a large number of individuals: direct analysis, meta-analysis, and review. We stress that reviews do not account for methodological differences across studies, and that this variation explains many of the apparent inconsistencies reported throughout recent reviews (including the work by Eliot and colleagues). For instance, we show that amygdala volume is consistently reported as male-biased in studies with sufficient sample sizes and appropriate methods for brain size correction. In fact, comparing the results from multiple large direct analyses highlights small, highly reproducible sex differences in the volume of many brain regions (controlling for brain size). Finally, we describe best practices for the presentation and interpretation of these findings. Care in interpretation is important for all domains of science, but especially so for research on sex differences in the human brain, given the existence of broad societal gender-biases and a history of biological data being used justify sexist ideas. As such, we urge researchers to discuss their results from simultaneously scientific and anti-sexist viewpoints.
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Encéfalo , Caracteres Sexuales , Encéfalo/diagnóstico por imagen , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Proyectos de InvestigaciónRESUMEN
Dysregulation of hippocampus glutamatergic neurotransmission and reductions in hippocampal volume have been associated with psychiatric disorders. The endocannabinoid system modulates glutamate neurotransmission and brain development, including hippocampal remodeling. In humans, elevated levels of anandamide and lower activity of its catabolic enzyme fatty acid amide hydrolase (FAAH) are associated with schizophrenia diagnosis and psychotic symptom severity, respectively (Neuropsychopharmacol, 29(11), 2108-2114; Biol. Psychiatry 88 (9), 727-735). Although preclinical studies provide strong evidence linking anandamide and FAAH to hippocampus neurotransmission and structure, these relationships remain poorly understood in humans. We recruited young adults with and without psychotic disorders and measured FAAH activity, hippocampal glutamate and glutamine (Glx), and hippocampal volume using [11C]CURB positron emission tomography (PET), proton magnetic resonance spectroscopy (1H-MRS) and T1-weighted structural MRI, respectively. We hypothesized that higher FAAH activity would be associated with greater hippocampus Glx and lower hippocampus volume, and that these effects would differ in patients with psychotic disorders relative to healthy control participants. After attrition and quality control, a total of 37 participants (62% male) completed [11C]CURB PET and 1H-MRS of the left hippocampus, and 45 (69% male) completed [11C]CURB PET and hippocampal volumetry. Higher FAAH activity was associated with greater concentration of hippocampal Glx (F1,36.36 = 9.17, p = 0.0045; Cohen's f = 0.30, medium effect size) and smaller hippocampal volume (F1,44.70 = 5.94, p = 0.019, Cohen's f = 0.26, medium effect size). These effects did not differ between psychosis and healthy control groups (no group interaction). This multimodal imaging study provides the first in vivo evidence linking hippocampal Glx and hippocampus volume with endocannabinoid metabolism in the human brain.
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Endocannabinoides , Ácido Glutámico , Ácidos Araquidónicos , Encéfalo/metabolismo , Endocannabinoides/metabolismo , Femenino , Ácido Glutámico/metabolismo , Glutamina/metabolismo , Hipocampo/metabolismo , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Imagen Multimodal , Alcamidas Poliinsaturadas , Tomografía de Emisión de Positrones/métodos , Espectroscopía de Protones por Resonancia Magnética , Adulto JovenRESUMEN
INTRODUCTION: Recent studies have observed that patients with treatment-resistant schizophrenia as well as patients with schizophrenia who do not respond within a medication trial exhibit excess activity of the glutamate system. In this study we sought to replicate the within-trial glutamate abnormality and to investigate the potential for structural differences and treatment-induced changes to improve identification of medication responders and non-responders. METHODS: We enrolled 48 medication-naïve patients in a 4-week trial of risperidone and classified them retrospectively into responders and non-responders using clinical criteria. Proton magnetic resonance spectroscopy and T1-weighted structural MRI were acquired pre- and post-treatment to quantify striatal glutamate levels and several measures of subcortical brain structure. RESULTS: Patients were classified as 29 responders and 19 non-responders. Striatal glutamate was higher in the non-responders than responders both pre- and post-treatment (F1,39 = 7.15, p = .01). Volumetric measures showed a significant group x time interaction (t = 5.163, <1%FDR), and group x time x glutamate interaction (t = 4.23, <15%FDR) were seen in several brain regions. Striatal volumes increased at trend level with treatment in both groups, and a positive association of striatal volumes with glutamate levels was seen in the non-responders. CONCLUSIONS: Combining anatomic measures with glutamate levels offers the potential to enhance classification of responders and non-responders to antipsychotic medications as well as to provide mechanistic understanding of the interplay between neuroanatomical and neurochemical changes induced by these medications. Ethical statement The study was approved by the Ethics and Scientific committees of the Instituto Nacional de Neurología y Neurocirugía in Mexico City. All participants over 18 years fully understood and signed the informed consent; in case the patient was under 18 years, informed consent was obtained from both parents. Participants did not receive a stipend.
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Cuerpo Estriado , Ácido Glutámico/metabolismo , Trastornos Psicóticos , Risperidona/administración & dosificación , Esquizofrenia Resistente al Tratamiento , Antagonistas de la Serotonina/administración & dosificación , Adulto , Encéfalo/metabolismo , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Espectroscopía de Protones por Resonancia Magnética , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/metabolismo , Estudios Retrospectivos , Risperidona/farmacología , Esquizofrenia Resistente al Tratamiento/tratamiento farmacológico , Esquizofrenia Resistente al Tratamiento/metabolismo , Antagonistas de la Serotonina/farmacología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
Acute exposure to cannabis has been associated with an array of cognitive alterations, increased risk for neuropsychiatric illness, and other neuropsychiatric sequelae including the emergence of acute psychotic symptoms. However, the brain alterations associating cannabis use and these behavioral and clinical phenotypes remains disputed. To this end, neuroimaging can be a powerful technique to non-invasively study the impact of cannabis exposure on brain structure and function in both humans and animal models. While chronic exposure studies provide insight into how use may be related to long-term outcomes, acute exposure may reveal interesting information regarding the immediate impact of use and abuse on brain circuits. Understanding these alterations could reveal the connection with symptom dimensions in neuropsychiatric disorders and, more specifically with psychosis. The purpose of the present review is to: 1) provide an update on the findings of pharmacological neuroimaging studies examining the effects of administered cannabinoids and 2) focus the discussion on studies that examine the sensitive window for the emergence of psychosis. Current literature indicates that cannabis exposure has varied effects on the brain, with the principal compounds in cannabis (delta-9-tetrahydrocannabinol and cannabidiol) altering activity across different brain regions. Importantly, we also discovered critical gaps in the literature, particularly regarding sex-dependent responses and long-term effects of chronic exposure. Certain networks often characterized as dysregulated in psychosis, like the default mode network and limbic system, were also impacted by THC exposure, identifying areas of particular interest for future work investigating the potential relationship between the two.
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Cannabidiol , Cannabinoides , Cannabis , Trastornos Psicóticos , Animales , Cannabis/efectos adversos , Dronabinol , Humanos , Neuroimagen , Trastornos Psicóticos/diagnóstico por imagenRESUMEN
Prenatal exposure to maternal immune activation (MIA) is a risk factor for a variety of neurodevelopmental and psychiatric disorders. The timing of MIA-exposure has been shown to affect adolescent and adult offspring neurodevelopment, however, less is known about these effects in the neonatal period. To better understand the impact of MIA-exposure on neonatal brain development in a mouse model, we assess neonate communicative abilities with the ultrasonic vocalization task, followed by high-resolution ex vivo magnetic resonance imaging (MRI) on the neonatal (postnatal day 8) mouse brain. Early exposed offspring displayed decreased communicative ability, while brain anatomy appeared largely unaffected, apart from some subtle alterations. By integrating MRI and behavioural assays to investigate the effects of MIA-exposure on neonatal neurodevelopment we show that offspring neuroanatomy and behaviour are only subtly affected by both early and late exposure. This suggests that the deficits often observed in later stages of life may be dormant, not yet developed in the neonatal period, or not as easily detectable using a cross-sectional approach.
Asunto(s)
Efectos Tardíos de la Exposición Prenatal , Animales , Conducta Animal , Encéfalo/diagnóstico por imagen , Modelos Animales de Enfermedad , Femenino , Ratones , EmbarazoRESUMEN
BACKGROUND: Alterations in the immune system, particularly C4A, have been implicated in the pathophysiology of schizophrenia. C4A promotes synapse elimination by microglia in preclinical models; however, it is unknown whether this process is also present in living humans and how it affects brain morphology. METHODS: Participants (N = 111; 33 patients with psychosis, 37 individuals at clinical high risk, and 41 healthy control subjects) underwent a TSPO [18F]FEPPA positron emission tomography scan and a magnetic resonance imaging scan. Brain C4A expression was genetically predicted as a function of the dosage of each of 4 structural elements (C4AL, C4BL, C4AS, C4BS). RESULTS: Higher genetically predicted brain C4A expression was associated with higher brain microglial marker (TSPO) and altered hippocampal morphology, including reduced surface area and medial displacement in the CA1 area. This study is the first to quantify genetically predicted brain C4A expression in individuals at clinical high risk, showing significantly lower C4A in individuals at clinical high risk compared with healthy control subjects. We also showed a robust effect of sex on genetically predicted brain C4A expression and effects of both sex and cannabis use on brain TSPO. CONCLUSIONS: This study shows for the first time complement system (C4A) coupling with a microglial marker (TSPO) and hippocampal morphology in living human brain. These findings pave the way for future research on the interaction between C4A and glial cell function, which has the potential to inform the disease mechanism underlying psychosis and schizophrenia.