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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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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 (
=0.30). This cross-species congruence is greater in the cortex (
=0.33) than non-cortex (
=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.
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.
Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental disorders later in life. The impact of the gestational timing of MIA exposure on downstream development ...remains unclear.
We characterized neurodevelopmental trajectories of mice exposed to the viral mimetic poly I:C (polyinosinic:polycytidylic acid) either on gestational day 9 (early) or on day 17 (late) using longitudinal structural magnetic resonance imaging from weaning to adulthood. Using multivariate methods, we related neuroimaging and behavioral variables for the time of greatest alteration (adolescence/early adulthood) and identified regions for further investigation using RNA sequencing.
Early MIA exposure was associated with accelerated brain volume increases in adolescence/early adulthood that normalized in later adulthood in the striatum, hippocampus, and cingulate cortex. Similarly, alterations in anxiety-like, stereotypic, and sensorimotor gating behaviors observed in adolescence normalized in adulthood. MIA exposure in late gestation had less impact on anatomical and behavioral profiles. Multivariate maps associated anxiety-like, social, and sensorimotor gating deficits with volume of the dorsal and ventral hippocampus and anterior cingulate cortex, among others. The most transcriptional changes were observed in the dorsal hippocampus, with genes enriched for fibroblast growth factor regulation, autistic behaviors, inflammatory pathways, and microRNA regulation.
Leveraging an integrated hypothesis- and data-driven approach linking brain-behavior alterations to the transcriptome, we found that MIA timing differentially affects offspring development. Exposure in late gestation leads to subthreshold deficits, whereas exposure in early gestation perturbs brain development mechanisms implicated in neurodevelopmental disorders.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Starting in adolescence, a litter-effect is observed in mice brain and behaviors.•Variables patterns complexity explaining litter-effects increase within lifespan.•More litters of smaller size ...improve statistical power for litter modulated models.•The litter-effect and sex-effect are closely intertwined.•Litter modulated brain regions overlap with regions associated to social behaviors.
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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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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 GD9) 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.
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.sup.+ 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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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Clinical research has shown that chronic antipsychotic drug (APD) treatment further decreases cortical gray matter and hippocampus volume, and increases striatal and ventricular volume in patients ...with schizophrenia. D2-like receptor blockade is necessary for clinical efficacy of the drugs, and may be responsible for inducing these volume changes. However, the role of other D2-like receptors, such as D3, remains unclear. Following our previous work, we undertook a longitudinal study to examine the effects of chronic (9-week) typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs on the neuroanatomy of wild-type (WT) and dopamine D3-knockout (D3KO) mice using magnetic resonance imaging (MRI) and histological assessments in a sub-region of the anterior cingulate cortex (the prelimbic PL area) and striatum. D3KO mice had larger striatal volume prior to APD administration, coupled with increased glial and neuronal cell density. Chronic HAL administration increased striatal volume in both WT and D3KO mice, and reduced PL area volume in D3KO mice both at trend level. CLZ increased volume of the PL area of WT mice at trend level, but decreased D3KO PL area glial cell density. Both typical and atypical APD administration induced neuroanatomical remodeling of regions rich in D3 receptor expression, and typically altered in schizophrenia. Our findings provide novel insights on the role of D3 receptors in structural changes observed following APD administration in clinical populations.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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 β-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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Sex differences have been widely observed in clinical presentation, functional outcome and neuroanatomy in individuals with a first-episode of psychosis, and chronic patients suffering from ...schizophrenia. However, little is known about sex differences in the high-risk stages for psychosis. The present study investigated sex differences in cortical and subcortical neuroanatomy in individuals at clinical high risk (CHR) for psychosis and healthy controls (CTL), and the relationship between anatomy and clinical symptoms in males at CHR. Magnetic resonance images were collected in 26 individuals at CHR (13 men) and 29 CTLs (15 men) to determine total and regional brain volumes and morphology, cortical thickness, and surface area (SA). Clinical symptoms were assessed with the brief psychiatric rating scale. Significant sex-by-diagnosis interactions were observed with opposite directions of effect in male and female CHR subjects relative to their same-sex controls in multiple cortical and subcortical areas. The right postcentral, left superior parietal, inferior parietal supramarginal, and angular gyri <5% false discovery rate (FDR) were thicker in male and thinner in female CHR subjects compared with their same-sex CTLs. The same pattern was observed in the right superior parietal gyrus SA at the regional and vertex level. Using a recently developed surface-based morphology pipeline, we observed sex-specific shape differences in the left hippocampus (<5% FDR) and amygdala (<10% FDR). Negative symptom burden was significantly higher in male compared with female CHR subjects (
= 0.04) and was positively associated with areal expansion of the left amygdala in males (<5% FDR). Some limitations of the study include the sample size, and data acquisition at 1.5 T. This study demonstrates neuroanatomical sex differences in CHR subjects, which may be associated with variations in symptomatology in men and women with psychotic symptoms.
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