Nineteen human fetal brains ranging from 9-23 weeks of gestation were examined immunocytochemically for evidence of glial and neuronal differentiation. Radial glia were positive for vimentin and glial fibrillary acidic protein (GFAP) throughout the age range. S100-positive cells which were presumed to be astrocytes were present from 9 weeks; they were always more widespread in the cerebrum and the brainstem than GFAP-positive mature astrocytes, which could be detected with certainty only at 14 weeks. Carbonic anhydrase II (CA II)-positive oligodendrocytes were present in the brainstem in small numbers from 17 weeks. Neuronal fibre tracts in the cerebrum were positive for 160 kD phosphorylated neurofilament protein (BF10) from 9 weeks, but negative for 200 kD phosphorylated neurofilament protein (RT97) and for 70 and 200 kD non-phosphorylated neurofilament protein (NFP) whereas most tracts in the brainstem were positive for BF10 from 9 weeks and positive for the other neurofilament proteins from 14 weeks. Corticospinal tracts differed in remaining negative for neurofilament proteins other than BF10, which showed positive reaction throughout. Perikarya of differentiated neurons in all areas of the brain were neurofilament-negative but neuron specific enolase (NSE)-positive. Germinal eminence cells were focally vimentin-positive from 15 weeks, focally GFAP-positive from 17 weeks, and negative for all NFP and for NSE. The value of a short fixation time and pretreatment with trypsin in the immunocytochemical demonstration of GFAP is stressed.

The thalamus plays an important role in signal relays in the brain, with thalamocortical (TC) neuronal pathways linked to various sensory/cognitive functions. In this study, we aimed to see fetal and postnatal development of the thalamus including neuronal migration to the thalamus and the emergence/maturation of the TC pathways. Pathways from/to the thalami of human postmortem fetuses and in vivo subjects ranging from newborns to adults with no neurological histories were studied using high angular resolution diffusion MR imaging (HARDI) tractography. Pathways likely linked to neuronal migration from the ventricular zone and ganglionic eminence (GE) to the thalami were both successfully detected. Between the ventricular zone and thalami, more tractography pathways were found in anterior compared with posterior regions, which was well in agreement with postnatal observations that the anterior TC segment had more tract count and volume than the posterior segment. Three different pathways likely linked to neuronal migration from the GE to the thalami were detected. No hemispheric asymmetry of the TC pathways was quantitatively observed during development. These results suggest that HARDI tractography is useful to identify multiple differential neuronal migration pathways in human brains, and regional differences in brain development in fetal ages persisted in postnatal development.

Background.-The prevalence of neurodevelopmental disorders is biased towards males with male:female ratios of 2:1 in intellectual disability (ID) and 4:1 in autism spectrum disorder (ASD). However, the molecular mechanisms of such bias remain unknown. While characterizing a mouse model for loss of the signaling scaffold coiled-coil and C2 domain containing 1A (CC2D1A), which is mutated in ID and ASD, we identified biochemical and behavioral differences between males and females, and explored whether CC2D1A controls male-specific intracellular signaling.Methods.-CC2D1A is known to regulate phosphodiesterase 4D (PDE4D) which regulates cAMP signaling. We tested for activation PDE4D and downstream signaling molecules in the hippocampus of Cc2d1a-deficient mice. We then performed behavioral studies in females to analyze learning and memory, and then targeted PDE4D activation with a PDE4D inhibitor to define how changes in cAMP levels affect behavior in males and females.Results.-We found that in Cc2d1a-deficient males PDE4D is hyperactive leading to a reduction in CREB signaling, but this molecular deficit is not present in females. Cc2d1a-deficient males show a deficit in spatial memory which is not present in Cc2d1a-deficient females. Restoring PDE4D activity using an inhibitor rescues cognitive deficits in males, but has no effect on females.Conclusions.-Our findings show that CC2D1A regulates cAMP intracellular signaling in a malespecific manner in the hippocampus leading to male-specific cognitive deficits. We propose that male-specific signaling mechanisms are involved in establishing sex bias in neurodevelopmental disorders.

Major long-range white matter pathways (cingulum, fornix, uncinate fasciculus [UF], inferior fronto-occipital fasciculus [IFOF], inferior longitudinal fasciculus [ILF], thalamocortical [TC], and corpus callosal [CC] pathways) were identified in eighty-three healthy humans ranging from newborn to adult ages. We tracked developmental changes using high-angular resolution diffusion MR tractography. Fractional anisotropy (FA), apparent diffusion coefficient, number, length, and volume were measured in pathways in each subject. Newborns had fewer, and more sparse, pathways than those of the older subjects. FA, number, length, and volume of pathways gradually increased with age and reached a plateau between 3 and 5 years of age. Data were further analyzed by normalizing with mean adult values as well as with each subject’s whole brain values. Comparing subjects of 3 years old and under to those over 3 years old, the studied pathways showed differential growth patterns. The CC, bilateral cingulum, bilateral TC, and the left IFOF pathways showed significant growth both in volume and length, while the bilateral fornix, bilateral ILF and bilateral UF showed significant growth only in volume. The TC and CC took similar growth patterns with the whole brain. FA values of the cingulum and IFOF, and the length of ILF showed leftward asymmetry. The fornix, ILF and UF occupied decreased space compared to the whole brain during development with higher FA values, likely corresponding to extensive maturation of the pathways compared to the mean whole brain maturation. We believe that the outcome of this study will provide an important database for future reference.

IntroductionThe goal of this project was to study the white and gray matter brain pathways of young children with autism spectrum disorder (ASD) and investigate how ASD brains differ from those of typically developing children of the same age.MethodsHigh angular resolution resolution diffusion imaging tractography and diffusion tensor imaging tractography were used to analyze the brains of two 3‐year‐old children with ASD and two age‐matched controls.ResultsIn the ASD brains, the callosal and corticopontine pathways were thinner overall and terminal areas in the cortical gray matter were significantly smaller. The ASD brains had more short‐range u‐fibers in the frontal lobe compared to the control brains. Gray matter pathways were found disorganized with less coherency in the ASD brain, specifically the lateral aspects of the middle part of the brain including motor areas, and both medial and lateral surfaces of the anterior frontal brain regions.ConclusionThese findings show our tractography technique is useful for identifying differences in brain pathways between the ASD and control groups. Given that scanning the brain of 3‐year‐old children with or even without ASD is challenging, postmortem scanning may offer valuable insights into the connectivity in the brain of young children with ASD.

No abstract

Digging behavior is often used to test motor function and repetitive behaviors in mice. Different digging paradigms have been developed for behaviors related to anxiety and compulsion in mouse lines generated to recapitulate genetic mutations leading to psychiatric and neurological disorders. However, the interpretation of these tests has been confounded by the difficulty of determining the motivation behind digging in mice. Digging is a naturalistic mouse behavior that can be focused toward different goals, that is foraging for food, burrowing for shelter, burying objects, or even for recreation as has been shown for dogs, ferrets, and human children. However, the interpretation of results from current testing protocols assumes the motivation behind the behavior often concluding that increased digging is a repetitive or compulsive behavior. We asked whether providing a choice between different types of digging activities would increase sensitivity to assess digging motivation. Here, we present a test to distinguish between burrowing and exploratory digging in mice. We found that mice prefer burrowing when the option is available. When food restriction was used to promote a switch from burrowing to exploration, males readily switched from burrowing to digging outside, while females did not. In addition, when we tested a model of intellectual disability and autism spectrum disorder that had shown inconsistent results in the marble burying test, the Cc2d1a conditional knockout mouse, we found greatly reduced burrowing only in males. Our findings indicate that digging is a nuanced motivated behavior and suggest that male and female rodents may perform it differently.

Fractional anisotropy (FA) threshold is commonly used to perform diffusion MRI tractography. However, FA threshold may be one aspect of tractography that needs additional scrutiny in accurately assessing pathways in immature, developing brains, as well as in adult brains. Using high-angular resolution diffusion MRI (HARDI) tractography without an FA threshold, we identified the arcuate fasciculus (AF) of 83 healthy subjects ranging in age from 40 gestational weeks (GW) (newborns) to 28-year-old adults. The AF was identified in both hemispheres in all subjects with high inter-rater reliability. The detected AF included regions with very low FA values. The entire AF was segmented into anterior, posterior, and long tracts. Growth and laterality patterns were investigated using tract count (number of detected streamlines), total volume of imaging voxels (touched by the detected streamlines), mean length, mean FA, and mean apparent diffusion coefficient (ADC). Comparison of subjects under 3 years old, to those that were older, revealed the three AF tracts that took different developmental courses. As expected, the anterior and long tracts showed lower ADC values in subjects over 3 years old, while the posterior tract showed higher ADC in that same age range. The posterior tract did not show age-related effect in terms of FA, tract count, length, and volume. These results suggest that the posterior AF tract shows a matured state, indexed by most of the used measurements in early postnatal developmental ages, and ADC is a measurement that can detect further maturation of the posterior tract. Interestingly, in all tracts, hemispheric asymmetries were found in raw (leftright) tract count, as well as in raw volume (left