Biology subjects

Lerch, J. P.

Publications and source records attributed to Lerch, J. P..

At least 37 records · Page 2Linked to original sources

bioRxiv2023

Comparative neuroimaging of sex differences in human and mouse brain anatomy

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.

neuroscience↗

bioRxiv2023

Lasting dynamic effects of the psychedelic 2,5-dimethoxy-4-iodoamphetamine (+/-)-DOI) on cognitive flexibility

Psychedelic drugs can aid fast and lasting remission from various neuropsychiatric disorders, though the underlying mechanisms remain unclear. Preclinical studies suggest serotonergic psychedelics enhance neuronal plasticity, but whether neuroplastic changes can also be seen at cognitive and behavioural levels is unexplored. Here we show that a single dose of the psychedelic 2,5-dimethoxy-4-iodoamphetamine (({+/-})-DOI) affects structural brain plasticity and cognitive flexibility in young adult mice beyond the acute drug experience. Using ex vivo magnetic resonance imaging, we show increased volumes of several sensory and association areas one day after systemic administration of 2mgkg-1 ({+/-})-DOI. We then demonstrate lasting effects of ({+/-})-DOI on cognitive flexibility in a two-step probabilistic reversal learning task where 2mgkg-1 ({+/-})-DOI improved the rate of adaptation to a novel reversal in task structure occurring one-week post-treatment. Strikingly, ({+/-})-DOI-treated mice started learning from reward omissions, a unique strategy not typically seen in mice in this task, suggesting heightened sensitivity to previously overlooked cues. Crucially, further experiments revealed that ({+/-})-DOIs effects on cognitive flexibility were contingent on the timing between drug treatment and the novel reversal, as well as on the nature of the intervening experience. ({+/-})-DOIs facilitation of both cognitive adaptation and novel thinking strategies may contribute to the clinical benefits of psychedelic-assisted therapy, particularly in cases of perseverative behaviours and a resistance to change seen in depression, anxiety, or addiction. Furthermore, our findings highlight the crucial role of time-dependent neuroplasticity and the influence of experiential factors in shaping the therapeutic potential of psychedelic interventions for impaired cognitive flexibility.

animal behavior and cognition↗

bioRxiv2023

Lifespan Changes in Brain Structure and Cognitive Performance Associated with Normal Aging in Mice

IntroductionAs the population skews toward older age, elucidating mechanisms underlying human brain aging becomes imperative. Structural MRI has facilitated non-invasive investigation of lifespan brain morphology changes, yet this domain remains uncharacterized in rodents despite increasing use as models of disordered human brain aging. MethodsYoung (2m, n=10), middle-age (10m, n=10) and old (22m, n=9) mice were utilized for maturational (young vs. middle-age) and aging-related (middle-age vs. old mice) comparisons. Regional brain volume was averaged across hemispheres and reduced to 32 brain regions. Pairwise group differences in regional volume, residualized for total brain volume, and associations between volume and cognitive performance on the Y-maze task were tested. General linear models with total brain volume as a covariate, and logistic regression for sample wide associations were employed respectively, correcting for multiple comparisons. Structural covariance networks were generated using the R package igraph. Group differences in network centrality (degree), integration (mean distance), and segregation (transitivity, modularity) were tested across network densities (5-40%), using 5,000 (1,000 for degree) permutations with significance criteria of p<0.05 at [≥]5 consecutive density thresholds. ResultsWidespread significant maturational changes in volume occurred in 18 brain regions, including considerable loss in isocortex regions and increases in brainstem regions and white matter tracts. The aging-related comparison yielded 6 significant changes in brain volume, including further loss in isocortex regions and increases in white matter tracts. No significant volume changes were observed across either comparison for subcortical regions. Additionally, smaller volume of the anterior cingulate area ({chi}2=2.325, pO_SCPLOWBHC_SCPLOW=0.044) and larger volume of the hippocampal formation ({chi}2=-2.180, pO_SCPLOWBHC_SCPLOW=0.044) were associated with poorer cognitive performance. Maturational network comparisons yielded significant degree changes in 9 regions, but no aging related changes, aligning with network stabilization trends in humans. Maturational decline in modularity occurred (24-29% density), mirroring human trends of decreased segregation in young adulthood, while mean distance and transitivity remained stable. Conclusions/ImplicationsThese findings offer a foundational account of age effects on brain volume, structural brain networks, and cognition in mice, informing future work in facilitating translation between rodent models and human brain aging.

neuroscience↗

bioRxiv2022

A cross-species study of sex chromosome dosage effects on mammalian brain anatomy

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) vs. XY controls. We show that total brain size is substantially altered by SCT in humans (significantly decreased by XXY and increased by XYY), but not in mice. Controlling for global effects reveals robust and spatially convergent effects of XXY and XYY on regional brain volume in humans, but not mice. 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 (cerebellum, 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. HighlightsO_LIParallel structural neuroimaging in humans and mice with sex chromosome trisomies C_LIO_LIDivergent X- and Y-chromosome effects on human brain size, but convergent effects on regional anatomy C_LIO_LIMuted impact of additional X or Y on mouse brain, but subtle regional effects evident C_LIO_LIEvidence for conserved cross-species impact of X and Y on fronto-parietal cortices and cerebellum C_LI

neuroscience↗

bioRxiv2022

Transcriptomic similarity in the mouse and human brain

The ever-increasing use of mouse models in preclinical neuroscience research calls for an improvement in the methods used to translate findings between mouse and human brains. Using openly accessible brain-wide transcriptomic data sets, we evaluated the similarity of mouse and human brain regions on the basis of homologous gene expression. Our results suggest that mouse-human homologous genes capture broad patterns of neuroanatomical organization, but that the resolution of cross-species correspondences can be improved using a novel supervised machine learning approach. Using this method, we demonstrate that sensorimotor subdivisions of the neocortex exhibit greater similarity between species, compared with supramodal sub-divisions, and that mouse isocortical regions separate into sensorimotor and supramodal clusters based on their similarity to human cortical regions. We also find that mouse and human striatal regions are strongly conserved, with the mouse caudoputamen exhibiting an equal degree of similarity to both the human caudate and putamen.

neuroscience↗

bioRxiv2022

Organization of thalamocortical structural covariance and a corresponding 3D atlas of the mouse thalamus

For information from sensory organs to be processed by the brain, it is usually passed to appropriate areas of the cerebral cortex. Almost all of this information passes through the thalamus, a relay structure that reciprocally connects to the vast majority of the cortex. The thalamus facilitates this information transfer through a set of thalamocortical connections that vary in cellular structure, molecular profiles, innervation patterns, and firing rates. Additionally, corticothalamic connections allow for intracortical information transfer through the thalamus. These efferent and afferent connections between the thalamus and cortex have been the focus of many studies, and the importance of cortical connectivity in defining thalamus anatomy is demonstrated by multiple studies that parcellate the thalamus based on cortical connectivity profiles. Here, we examine correlated morphological variation between the thalamus and cortex, or thalamocortical structural covariance. For each voxel in the thalamus as a seed, we construct a cortical structural covariance map that represents correlated cortical volume variation, and examine whether high structural covariance is observed in cortical areas that are functionally relevant to the seed. Then, using these cortical structural covariance maps as features, we subdivide the thalamus into six non-overlapping regions (clusters of voxels), and assess whether cortical structural covariance is associated with cortical connectivity that specifically originates from these regions. We show that cortical structural covariance is high in areas of the cortex that are functionally related to the seed voxel, cortical structural covariance varies along cortical depth, and sharp transitions in cortical structural covariance profiles are observed when varying seed locations in the thalamus. Subdividing the thalamus based on structural covariance, we additionally demonstrate that the six thalamic clusters of voxels stratify cortical structural covariance along the dorsal-ventral, medial-lateral, and anterior-posterior axes. These cluster-associated structural covariance patterns are prominently detected in cortical regions innervated by fibers projecting out of their related thalamic subdivisions. Together, these results advance our understanding of how the thalamus and the cortex couple in their volumes. Our results indicate that these volume correlations reflect functional organization and structural connectivity, and further provides a novel segmentation of the mouse thalamus that can be used to examine thalamic structural variation and thalamocortical structural covariation in disease models.

neuroscience↗

bioRxiv2021

Genetic Mouse Models of Autism Spectrum Disorder Present Subtle Heterogenous Cardiac Abnormalities.

BackgroundAutism Spectrum Disorder (ASD) and Congenital Heart Disease (CHD) are strongly linked on a functional and genetic level. Most work has been focused on neurodevelopmental abnormalities in CHD. Conversely, cardiac abnormalities in ASD have been less studied. In this work we investigate the prevalence of cardiac comorbidities relative to genetic contributors of ASD. MethodsUsing high frequency ultrasound imaging, we screened 9 mouse models with ASD-related genetic alterations (Arid1b(+/-), Chd8(+/-), 16p11.2 (deletion), Sgsh(+/-), Sgsh(-/-), Shank3 {Delta}exon 4-9(+/-), Shank3 {Delta}exon 4-9(-/-), Fmr1(-/-), Vps13b(+/-)), and pooled wild-type littermates (WT). Using a standardised imaging protocol, we measured heart rate (HR), aorta diameter (AoD), thickness and thickening of the left-ventricular (LV) anterior and posterior walls, LV chamber diameter, fractional shortening, stroke volume and cardiac output, Peak E and A velocity ratio of mitral inflow, Velocity Time Integral (VTI) through the ascending aorta. ResultsMutant groups presented small-scale alterations in cardiac structure and function compared to WTs. A greater number of significant differences was observed among mutant groups than between mutant groups and WTs. Mutant groups differed primarily in measures of structure (LV chamber diameter and anterior wall thickness, HR, AoD). When compared to WTs, they differed in both structure and function (LV anterior wall thickness and thickening, chamber diameter and fractional shortening, HR). The mutant groups with most differences to WTs were 16p11.2 (deletion), Fmrl(-/-), Arid1b(+/-). Among mutant groups, the groups differing most from others were 16p11.2 (deletion), Sgsh(+/-), Fmrl(-/-). Our results broadly recapitulate the associated clinical findings. LimitationsVarious genetically driven cardiac abnormalities occur early in life, so repeating this work in non-adult mice may be valuable. To identify possible sex differences, we must extend this work to female mice. The downsampling procedure used (total correlation calculation) must be verified. Only indirect comparison between our results and clinical literature is possible due to differing study designs. ConclusionsThe characteristic heterogeneity of ASD was recapitulated in the observed cardiac phenotype. The type of measures (morphological, functional) mutant groups differ in can highlight common underlying mechanisms. Clinically, knowledge of cardiac abnormalities in ASD can be essential as even non-lethal cardiac abnormalities can impact normal development.

neuroscience↗

bioRxiv2021

Behavioral and Neurostructural changes associated with Chronic Amygdala Hyperactivation

BackgroundThe amygdala (AMY) is a key brain region of the limbic system that plays a critical role in emotion processing and stress response. Functional magnetic resonance imaging (fMRI) studies identified abnormal AMY activation in psychiatric illnesses including major depressive disorder (MDD). Stress exposure is a major precipitating factor of MDD episodes which are associated with AMY hyperactivity. Preclinical studies using of pharmacologic, opto- and chemogenetic approaches to activate AMY neurons have consistently demonstrated that acute AMY hyperactivation induces anxiety-like behaviors in mice. However, it remains unknown if chronic hyperactivation of the amygdala (cHOA) is sufficient to induce chronic stress-like deficits or is a susceptibility factor for chronic stress-induced behavioral, volumetric and synaptic deficits. MethodsUsing designer receptor exclusively activated by designer drug (DREADD) approach, basolateral amygdala (BLA) neurons of Camk2a-cre mice infected with a virus driving the expression of the Gq-coupled DREADD were activated with clozapine-N-oxide (in drink water for 5 weeks). Mice were then exposed to chronic restraint stress (CRS; 1X/day for 1hr) for 2 weeks. All mice were behaviorally assessed in the Phenotyper (PT), and sucrose consumption tests (SCT) each week and in the novelty supressed feeding (NSF, once at the end of the experiment). Animals were then perfused for ex vivo-MRI and puncta density analysis. ResultsWe found that mice with cHOA displayed a progressive increase in baseline anxiety-like deficits in the PT test and slightly more marked deficits following CRS compared to controls, but not statistically different from animals subjected to CRS alone. Also, cHOA did not exacerbate CRS effect in the NSF. No significant cAH effect was found in the SCT before or after CRS. MRI analysis revealed no statistical charges between groups, while increased synaptic puncta density was found in cHOA mice subjected to CRS compared to cHOA or CRS alone. ConclusionWe demonstrate that cAH is sufficient to induce anxiety and may exacerbate CRS effects on anxiety and synaptic measures. Results also suggest that cHOA was not sufficient to induce depressive-like behavior and was not a vulnerability factor for stress-induced depressive-like behavior in mice. Altogether, our findings imply that a strong causal link between AMY hyperactivity and elevated anxiety, but not depressive-like behaviors and provide critical information to clinical research focused on using AMY activity level as a biomarker in stress-related illnesses.

neuroscience↗

bioRxiv2021

Subtle alterations in neonatal neurodevelopment following early or late exposure to prenatal maternal immune activation

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, we first 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) 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-expsoure 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.

neuroscience↗

bioRxiv2021

Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment

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 magnetic resonance imaging (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 hippocampal neuroanatomy 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 dark neurons and glia, putative markers for 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.

neuroscience↗

bioRxiv2021

A unique cerebellar pattern of microglia activation in a mousemodel of encephalopathy of prematurity

Preterm infants often show pathologies of the cerebellum, which are associated with impaired motor performance, lower IQ and poor language skills at school ages. Because 1 in 10 babies is born preterm cerebellar injury is a significant clinical problem. The causes of cerebellar damage are yet to be fully explained. Herein, we tested the hypothesis that perinatal inflammatory stimuli may play a key role in cerebellar injury of preterm infants. We undertook our studies in an established mouse model of inflammation-induced encephalopathy of prematurity driven by systemic administration of the prototypic pro-inflammatory cytokine interleukin-1{beta} (IL-1{beta}). Inflammation is induced between postnatal day (P) 1 to day 5, timing equivalent to the last trimester for brain development in humans the period of vulnerability to preterm birth related brain injury. We investigated acute and long-term consequences for the cerebellum on brain volume expansion, oligodendroglial maturation, myelin levels and the microglial transcriptome. Perinatal inflammation induced global mouse brain volume reductions, including specific grey and white matter volume reductions in cerebellar lobules I and II (5% FDR) in IL-1{beta} versus control treated mice from P15 onwards. Oligodendroglia damage preceded the MRI-detectable volume changes, as evidenced by a reduced proliferation of OLIG2+ cells at P10 and reduced levels of the myelin proteins MOG, MBP and MAG at P10 and P15. Increased density of Iba1+ cerebellar microglia was observed at P5 and P45, with evidence for increased microglial proliferation at P5 and P10. Comparison of the transcriptome of microglia isolated from P5 cerebelli and cerebrum revealed significant enrichment of pro-inflammatory markers in microglia from both regions, but in the cerebellum microglia displayed a unique type I interferon signalling dysregulation. Collectively, these data suggest that in our model that systemic inflammation causes chronic activation of microglia and maldevelopment of cerebellum that includes myelin deficits which is driven in the cerebellum by type I interferon signalling. Future protective strategies for preterm infants should consider sustained type I interferon signalling driven cerebellar inflammation as an important target.

neuroscience↗

bioRxiv2021

Mouse models of immune dysfunction: Their neuroanatomical differences reflect their anxiety-behavioural phenotype

Extensive evidence supports the role of the immune system in modulating brain function and behaviour. However, past studies have revealed striking heterogeneity in behavioural phenotypes produced from immune system dysfunction. Using magnetic resonance imaging (MRI), we studied the neuroanatomical differences among 11 distinct genetically-modified mouse lines (n=371), each deficient in a different element of the immune system. We found a significant and heterogeneous effect of immune dysfunction on the brains of both male and female mice. However, by imaging the whole brain and using bayesian hierarchical modelling, we were able to identify patterns within the heterogeneous phenotype. Certain structures -- such as the corpus callosum, midbrain, and thalamus -- were more likely to be affected by immune dysfunction. A notable brain-behaviour relationship was identified with neuroanatomy endophenotypes across mouse models clustering according to anxiety-like behaviour phenotypes reported in literature, such as altered volume in brains regions associated with promoting fear response (e.g., the lateral septum and cerebellum). Interestingly, genes with preferential spatial expression in the most commonly affected regions are also associated with multiple sclerosis and other immune-mediated diseases. In total, our data suggest that the immune system modulates anxiety behaviour through well-established brain networks.

neuroscience↗

bioRxiv2021

Cortico-amygdalar connectivity and externalizing/internalizing behavior in children with neurodevelopmental disorders

BackgroundExternalizing and internalizing behaviors are common and contribute to impairment in children with neurodevelopmental disorders (NDDs). Associations between externalizing or internalizing behaviors and cortico-amygdalar connectivity have been found in children with and without clinically significant internalizing/externalizing behaviors. This study examined whether such associations are present across children with different NDDs. MethodsMulti-modal neuroimaging and behavioral data from the Province of Ontario Neurodevelopmental Disorders (POND) Network were used. POND participants aged 6-18 years with a primary diagnosis of autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD), as well as typically developing children (TDC) with T1-weighted, resting-state fMRI or diffusion weighted imaging and parent-report Child Behavioral Checklist (CBCL) data available, were analyzed (n range=157-346). Associations between externalizing or internalizing behavior and cortico-amygdalar structural and functional connectivity indices were examined using linear regressions, controlling for age, gender, and image-modality specific covariates. Behavior-by-diagnosis interaction effects were also examined. ResultsNo significant linear associations (or diagnosis-by-behavior interaction effects) were found between CBCL-measured externalizing or internalizing behaviors and any of the connectivity indices examined. Post-hoc bootstrapping analyses indicated stability and reliability of these null results. ConclusionsThe current study provides evidence in favour of the absence of a shared linear relationship between internalizing or externalizing behaviors and cortico-amygdalar connectivity properties across a transdiagnostic sample of children with various NDDs and TDC. Detecting shared brain-behavior relationships in children with NDDs may benefit from the use of different methodological approaches, including incorporation of multi-dimensional behavioral data (i.e. behavioral assessments, neurocognitive tasks, task-based fMRI) or clustering approaches to delineate whether subgroups of individuals with different brain-behavior profiles are present within heterogeneous cross-disorder samples.

neuroscience↗

bioRxiv2021

Developmental and behavioral phenotypes in a new mouse model of DDX3X syndrome

BackgroundMutations in the X-linked gene DDX3X account for ~2% of intellectual disability in females, often co-morbid with behavioral problems, motor deficits, and brain malformations. DDX3X encodes an RNA helicase with emerging functions in corticogenesis and synaptogenesis. MethodsWe generated a Ddx3x haploinsufficient mouse (Ddx3x+/-) with construct validity for DDX3X loss-of-function mutations. We used standardized batteries to assess developmental milestones and adult behaviors, as well as magnetic resonance imaging and immunostaining of cortical projection neurons to capture early postnatal changes in brain development. ResultsDdx3x+/- mice show physical, sensory, and motor delays that evolve into behavioral anomalies in adulthood, including hyperactivity, anxiety-like behaviors, cognitive impairments, and motor deficits. Motor function further declines with age. These behavioral changes are associated with a reduction in brain volume, with some regions (e.g., cortex and amygdala) disproportionally affected. Cortical thinning is accompanied by defective cortical lamination, indicating that Ddx3x regulates the balance of glutamatergic neurons in the developing cortex. ConclusionsThese data shed new light on the developmental mechanisms driving DDX3X syndrome and support face validity of this novel pre-clinical mouse model.

neuroscience↗

bioRxiv2021

Examining the effect of chronic intranasal oxytocin administration on the neuroanatomy and behavior of three autism-related mouse models

1Although initially showing great potential, oxytocin treatment has encountered a translational hurdle in its promise of treating the social deficits of autism. Some debate surrounds the ability of oxytocin to successfully enter the brain, and therefore modify neuroanatomy. Moreover, given the heterogeneous nature of autism, treatment will only amerliorate symptoms in a subset of patients. Therefore, to determine whether oxytocin changes brain circuitry, and whether it does so variably, depending on genotype, we implemented a large randomized, blinded, placebo-controlled, preclinical study on chronic intranasal oxytocin treatment in three different mouse models related to autism with a focus on using neuroanatomical phenotypes to assess and subset treatment response. Intranasal oxytocin (0.6IU) was administered daily, for 28 days, starting at 5 weeks of age to the 16p11.2 deletion, Shank3 (exon 4-9) knockout, and Fmr1 knockout mouse models. Given the sensitivity of structural magnetic resonance imaging (MRI) to the neurological effects of interventions like drugs, along with many other advantages, the mice underwent in vivo longitudinal and high-resolution ex vivo imaging with MRI. The scans included three in vivo T1-weighted, 90um isotropic resolution scans and a T2-weighted, 3D fast spin echo with 40um isotropic resolution ex vivo scan to assess the changes in neuroanatomy using established automated image registration and deformation based morphometry approaches in response to oxytocin treatment. The behavior of the mice was assessed in multiple domains, including social behaviours and repetitive behaviours, among others. Treatment effect on the neuroanatomy did not reach significance, although the pattern of trending effects was promising. No significant effect of treatment was found on social behavior in any of the strains, although a significant effect of treatment was found in the Fmr1 mouse, with treatment normalizing a grooming deficit. No other treatment effect on behavior was observed that survived multiple comparisons correction. Overall, chronic treatment with oxytocin had limited effects on the three mouse models related to autism, and no promising pattern of response susceptibility emerged.

developmental biology↗

bioRxiv2020

Reduced anterior cingulate cortex volume induced by chronic stress correlates with increased behavioral emotionality and decreased synaptic puncta density

Clinical and preclinical studies report that chronic stress induces behavioral deficits as well as volumetric and synaptic alterations in corticolimbic brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), nucleus accumbens (NAc) and hippocampus (HPC). Here, we aimed to investigate the volumetric changes associated with chronic restraint stress (CRS) and link these changes to the CRS-induced behavioral and synaptic deficits. We first confirmed that CRS increases behavioral emotionality, defined as collective scoring of anxiety- and anhedonia-like behaviors. We then demonstrated that CRS induced a reduction of total brain volume which negatively correlated with behavioral emotionality. Region-specific analysis identified that only the ACC showed significant decrease in volume following CRS (p<0.05). Reduced ACC correlated with increased behavioral emotionality (r=-0.56; p=0.0003). Although not significantly altered by CRS, AMY and NAc (but not the HPC) volumes were negatively correlated with behavioral emotionality. Finally, using structural covariance network analysis to assess shared volumetric variances between the corticolimbic brain regions and associated structures, we found a progressive decreased ACC degree and increased AMY degree following CRS. At the cellular level, reduced ACC volume correlated with decreased PSD95 (but not VGLUT1) puncta density (r=0.35, p<0.05), which also correlated with increased behavioral emotionality (r=-0.44, p<0.01), suggesting that altered synaptic strength is an underlying substrate of CRS volumetric and behavioral effects. Our results demonstrate that CRS effects on ACC volume and synaptic density are linked to behavioral emotionality and highlight key ACC structural and morphological alterations relevant to stress-related illnesses including mood and anxiety disorders. HighlightsO_LIChronic restraint stress (CRS) decreases anterior cingulate cortex (ACC) volume C_LIO_LIACC and amygdala (AMY) volumes negatively correlate with behavioral emotionality C_LIO_LICRS decreased the strength and degree of the ACC structural covariance network C_LIO_LICRS increased the strength and degree of the AMY structural covariance network C_LIO_LIPSD95 puncta density correlates with behavioral emotionality and ACC volume. C_LI

neuroscience↗

bioRxiv2020

Characterization of Mice Bearing Humanized Androgen Receptor Genes (h/mAr) Varying in Polymorphism Length

The androgen receptor (AR) is known for masculinization of behavior and brain. To better understand the role that AR plays, mice bearing humanized Ar genes with varying lengths of a polymorphic N-terminal glutamine (Q) tract were created (Albertelli et al 2006). The length of the Q tract is inversely proporitional to AR activity. Biological studies of the Q tract length may also provide a window into potential AR contributions to sex-biases in disease risk. Here we take a multi-pronged approach to characterizing AR signaling effects on brain and behavior in mice using the humanized Ar Q tract model. We first map effects of Q tract length on regional brain anatomy, and consider if these are modified by gonadal sex. We then test the notion that spatial patterns of anatomical variation related to Q tract length could be organized by intrinsic spatiotemporal patterning of AR gene expression in the mouse brain. Finally, we test influences of Q tract length on four behavioral tests. Altering Q tract length led to neuroanatomical differences in a non-linear dosage-dependent fashion. Gene expression analyses indicated that adult neuroanatomical changes due to Q tract length are only associated with neurodevelopment (as opposed to adulthood). No significant effect of Q tract length was found on the behavior of the three mouse models. These results indicate that AR activity differentially mediates neuroanatomy and behavior, that AR activity alone does not mediate sex differences, and that neurodevelopmental processes are associated with spatial patterns of volume changes due to Q tract length in adulthood. They also indicate that androgen sensitivity in adulthood does not directly lead to autism-related behaviors or neuroanatomy, although neurodevelopmental processes may play a role earlier. Further study into sex differences, development, other behaviors, and other sex-specific mechanisms are needed to better understand AR sensitivity, neurodevelopmental disorders, and the sex difference in their prevalence.

neuroscience↗

bioRxiv2020

Exposure to maternal high-fat diet induces extensive changes in the brain of adult offspring

Maternal environmental exposures, such as high-fat diets, diabetes and obesity, can induce long term effects in offspring. These effects include increased risk of neurodevelopmental disorders (NDDs) including autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), depression and anxiety. The mechanisms underlying these late-life neurologic effects are unknown. In this article, we measured changes in the offspring brain and determined which brain regions are sensitive to maternal metabolic milieu and therefore may mediate NDD risk. We showed that mice exposed to maternal high-fat diet display extensive brain changes in adulthood despite being switched to low-fat diet at weaning. Brain regions impacted by early-life diet include the extended amygdalar system, which plays an important role in reward-seeking behaviour. Genes preferentially expressed in these regions have functions related to feeding behavior, while also being implicated in human NDDs, such as autism. Our data demonstrated that exposure to maternal high-fat diet in early-life leads to brain alterations that persist into adulthood, even after dietary modifications.

neuroscience↗