The strengths of the genetic approach to understanding neural systems development and function: Ray Guillery's synthesis

The organization and function of sensory systems, especially the mammalian visual system, has been the focus of philosophers and scientists for centuries—from Descartes and Newton onward. Nevertheless, the utility of understanding development and its genetic foundations for deeper insight into neural function has been debated: Do you need to know how something is assembled—a car, for example—to understand how it works or how to use it—to turn on the ignition and drive? This review addresses this issue for sensory pathways. The pioneering work of the late Rainer W. (Ray) Guillery provides an unequivocal answer to this central question: Using genetics for mechanistic exploration of sensory system development yields essential knowledge of organization and function. Ray truly built the foundation for this now accepted tenet of modern neuroscience. His work on the development and reorganization of visual pathways in albino mammals—all with primary genetic mutations in genes for pigmentation—defined the genetic approach to neural systems development, function and plasticity. The work that followed his lead in a variety of sensory systems, including my own work in the developing olfactory system, proceeds directly from Ray's fundamental contributions.     

Human paleoneurology: Shaping cortical evolution in fossil hominids

Evolutionary neuroanatomy must integrate two different sources of information, namely from fossil and from living species. Fossils supply information concerning the process of evolution, whereas living species supply information on the product of evolution. Unfortunately, the fossil record is partial and fragmented, and often cannot support validations for specific evolutionary hypotheses. Living species can provide more comprehensive indications, but they do not represent ancestral groups or primitive forms. Macaques or chimpanzees are frequently used as proxy for human ancestral conditions, despite the fact they are divergent and specialized lineages, with their own biological features. Similarly, in paleoanthropology independent lineages (such as Neanderthals) should not be confused with ancestral modern human stages. In this comparative framework, paleoneurology deals with the analysis of the endocranial cavity in extinct species, in order to make inferences on brain evolution. A main target of this field is to distinguish the endocranial variations due to brain changes, from those due to cranial constraints. Digital anatomy and computed morphometrics have provided major advances in this field. However, brains and endocasts can be hard to analyze with geometrical models, because of uncertainties due to the localization of cortical landmarks and boundaries. The study of the evolution of the parietal cortex supplies an interesting case-study in which paleontological and neontological data can integrate and test evolutionary hypotheses based on multiple sources of evidence. The relationships with visuospatial functions and brain–body–tool integration stress further that the analysis of the cognitive system should go beyond the neural boundaries of the brain.     

Chronic intraventricular administration of lysergic acid diethylamide (LSD) affects the sensitivity of cortical cells to monocular deprivation

In kittens, but not in adult cats, depriving one eye of pattern vision by suturing the lids shut (monocular deprivation or MD) for one week reduces the proportions of binocular units in the visual cortex. A sensitivity of cortical units in adult cats to MD can be produced by infusing exogenous monoamines into the visual cortex²³. Since LSD interacts with monoamines, we have examined the effects of chronic administration of LSD on the sensitivity to MD for cortical cells in adult cats. Cats were assigned randomly to one of four conditions: MD/LSD, MD/No-LSD, No-MD/No-LSD. An osmotic minipump delivered either LSD or the vehicle solution alone during a one-week period of MD. The animals showed no obvious anomalies during the administration of the drug. After one week the response properties of single units in urea 17 of the visual cortex were studied without knowledge of the contents of the individual minipumps.

With the exception of ocular dominance, the response properties of units recorded in all animals did not differ from normal. In the control animals (MD/No-LSD, No-MD/LSD, No-MD/No-LSD) the average proportion of binocular cells was 78%; similar to that observed for normal adult cats. However, in the experimental animals, which received LSD during the period of MD, only 52% of the cells were binocular. Our results suggest that chronic intraventricular administration of LSD affects either directly or indirectly the sensitivity of cortical neurons to MD.     

Regulation of cortical interneurons by neurotrophins: from development to cognitive disorders.

Parvalbumin-positive interneurons, which include basket and chandelier cells, represent a unique class of interneurons. By innervating the soma and the axonal initial segment of pyramidal cells, these interneurons can elicit powerful control on the output of pyramidal cells and consequently are important for a number of physiological processes in the mammalian brain. Recent evidence indicates that neurotrophins regulate the development and functions of parvalbumin-positive interneurons. Disruption of neurotrophin-mediated regulation of interneurons is thought to contribute to the pathological processes underlying CNS dysfunction. This review brings together recently described roles of neurotrophins in migration, differentiation, synaptogenesis during development, and acute effects of neurotrophins in transmission at inhibitory synapses, Cl(-) homeostasis, and network activity of cortical interneurons. The authors also discuss the importance of neurotrophin regulation of GABAergic neurons in schizophrenia and epilepsy.     

Age-dependent effect of apolipoprotein E4 on functional outcome after controlled cortical impact in mice

The apolipoprotein E4 (APOE4) gene leads to increased brain amyloid beta (Aβ) and poor outcome in adults with traumatic brain injury (TBI); however, its role in childhood TBI is controversial. We hypothesized that the transgenic expression of human APOE4 worsens the outcome after controlled cortical impact (CCI) in adult but not immature mice. Adult and immature APOE4 mice had worse motor outcome after CCI (P<0.001 versus wild type (WT)), but the Morris water maze performance was worse only in adult APOE4 mice (P=0.028 at 2 weeks, P=0.019 at 6 months versus WT), because immature APOE4 mice had performance similar to WT for up to 1 year after injury. Brain lesion size was similar in adult APOE4 mice but was decreased (P=0.029 versus WT) in injured immature APOE4 mice. Microgliosis was similar in all groups. Soluble brain Aβ₄₀ was increased at 48 hours after CCI in adult and immature APOE4 mice and in adult WT (P<0.05), and was dynamically regulated during the chronic period by APOE4 in adults but not immature mice. The data suggest age-dependent effects of APOE4 on cognitive outcome after TBI, and that therapies targeting APOE4 may be more effective in adults versus children with TBI.     

Towards a science of eating disorders: Replacing myths with realities: The fourth Birgit Olsson lecture

Background: For too long we have been “stuck” in old perspectives that have hampered the advance of knowledge. In part, this is related to the challenges that people have in unlearning misinformation. Aim: To address the need for an upgrade in the eating disorders field. Method: To assist with replacing outdated and inaccurate ideas with new data, this lecture reviewed novel approaches to eating disorders that engage scientists and clinicians from diverse fields to approach questions about aetiology and treatment of eating disorders through new lenses. This forward-looking lecture outlined critical questions that need to be addressed to move the field forward and strategies for engaging scientists from different fields. Results: Leading-edge findings on genetics, intestinal microbiota, and neuroscience are reviewed. Conclusions: This review encourages the integration of new evidence-based knowledge to form the backbone of our understanding of and approach to eating disorders.     

Postnatal development of aminergic projections to frontal cortex: effects of cortical lesions

The effects of lesions induced by fetal treatment with methylazoxymethanol acetate (MAM) on the developmental synaptic chemistry of the frontal cortex of rats were examined. Treatment at 14 days' gestation (DG) resulted in a 50% decrease in frontal cortical mass whereas treatment at 15 DG caused a 40% decrement. No difference in concentration between MAM and control rats was observed in the postnatal development of the GABA-ergic markers, glutamate decarboxylase, and GABA. In contrast, the concentrations of the presynaptic markers for the dopaminergic, noradrenergic, and serotonergic terminals were generally elevated in the MAM lesioned frontal cortex throughout postnatal development. The effects of MAM lesion on cholinergic markers were mixed, with minimal alterations in concentration during the first 2 postnatal weeks followed by an increasing disparity thereafter. The results of this study provide additional evidence in support of the differential impact of the cortical hypoplasia on intrinsic neurons as contrasted to aminergic afferents.     

Fetal development of the human amygdala

The intricate development of the human amygdala involves a complex interplay of diverse processes, varying in speed and duration. In humans, transient cytoarchitectural structures deliquesce, leading to the formation of functionally distinct nuclei as a result of multiple interdependent developmental events. This study compares the amygdala's cytoarchitectural development in conjunction with specific antibody reactivity for neuronal, glial, neuropil, and radial glial fibers, synaptic, extracellular matrix, and myelin components in 39 fetal human brains. We recognized that the early fetal period, as a continuation of the embryonic period, is still dominated by relatively uniform histogenetic processes. The typical appearance of ovoid cell clusters in the lateral nucleus during midfetal period is most likely associated with the cell migration and axonal growth processes in the developing human brain. Notably, synaptic markers are firstly detected in the corticomedial group of nuclei, while immunoreactivity for the panaxonal neurofilament marker SMI 312 is found dorsally. The late fetal period is characterized by a protracted migration process evidenced by the presence of doublecortin and SOX-2 immunoreactivity ventrally, in the prospective paralaminar nucleus, reinforced by vimentin immunoreactivity in the last remaining radial glial fibers. Nearing the term period, SMI 99 immunoreactivity indicates that perinatal myelination becomes prominent primarily along major axonal pathways, laying the foundation for more pronounced functional maturation. This study comprehensively elucidates the rate and sequence of maturational events in the amygdala, highlighting the key role of prenatal development in its behavioral, autonomic, and endocrine regulation, with subsequent implications for both normal functioning and psychiatric disorders.     

An fMRI-study of locally oriented perception in autism: altered early visual processing of the block design test

Autism has been associated with enhanced local processing on visual tasks. Originally, this was based on findings that individuals with autism exhibited peak performance on the block design test (BDT) from the Wechsler Intelligence Scales. In autism, the neurofunctional correlates of local bias on this test have not yet been established, although there is evidence of alterations in the early visual cortex. Functional MRI was used to analyze hemodynamic responses in the striate and extrastriate visual cortex during BDT performance and a color counting control task in subjects with autism compared to healthy controls. In autism, BDT processing was accompanied by low blood oxygenation level-dependent signal changes in the right ventral quadrant of V2. Findings indicate that, in autism, locally oriented processing of the BDT is associated with altered responses of angle and grating-selective neurons, that contribute to shape representation, figure-ground, and gestalt organization. The findings favor a low-level explanation of BDT performance in autism.     

Genetics of anxiety disorders: the complex road from DSM to DNA

Anxiety disorders are among the most common psychiatric disorders, affecting one in four individuals over a lifetime. Although our understanding of the etiology of these disorders is incomplete, familial and genetic factors are established risk factors. However, identifying the specific casual genes has been difficult. Within the past several years, advances in molecular and statistical genetic methods have made the genetic dissection of complex disorders a feasible project. Here we provide an overview of these developments, with a focus on their implications for genetic studies of anxiety disorders. Although the genetic and phenotypic complexity of the anxiety disorders present formidable challenges, advances in neuroimaging and experimental animal models of anxiety and fear offer important opportunities for discovery. Real progress in identifying the genetic basis of anxiety disorders will require integrative approaches that make use of these biologic tools as well as larger‐scale genomic studies. If successful, such efforts may yield novel and more effective approaches for the prevention and treatment of these common and costly disorders. Depression and Anxiety, 2009. © 2009 Wiley‐Liss, Inc.     

Structural development of cortical lobes during the first 6 months of life in infant macaques

This study mapped the developmental trajectories of cortical regions in comparison to overall brain growth in typically developing, socially-housed infant macaques. Volumetric changes of cortical brain regions were examined longitudinally between 2–24 weeks of age (equivalent to the first 2 years in humans) in 21 male rhesus macaques. Growth of the prefrontal, frontal, parietal, occipital, and temporal cortices (visual and auditory) was examined using MRI and age-specific infant macaque brain atlases developed by our group. Results indicate that cortical volumetric development follows a cubic growth curve, but maturational timelines and growth rates are region-specific. Total intracranial volume (ICV) increased significantly during the first 5 months of life, leveling off thereafter. Prefrontal and temporal visual cortices showed fast volume increases during the first 16 weeks, followed by a plateau, and significant growth again between 20–24 weeks. Volume of the frontal and temporal auditory cortices increased substantially between 2–24 weeks. The parietal cortex showed a significant volume increase during the first 4 months, whereas the volume of the occipital lobe increased between 2–12 weeks and plateaued thereafter. These developmental trajectories show similarities to cortical growth in human infants, providing foundational information necessary to build nonhuman primate (NHP) models of human neurodevelopmental disorders.     

Network over‐connectivity differentiates autism spectrum disorder from other developmental disorders in toddlers: A diffusion MRI study

Advanced connectivity studies in toddlers with Autism Spectrum Disorder (ASD) are increasing and consistently reporting a disruption of brain connectivity. However, most of these studies compare ASD and typically developing subjects, thus providing little information on the specificity of the abnormalities detected in comparison with other developmental disorders (other‐DD). We recruited subjects aged below 36 months who received a clinical diagnosis of Neurodevelopmental Disorder (32 ASD and 16 other‐DD including intellectual disability and language disorder) according to DSM‐IV TR. Structural and diffusion MRI were acquired to perform whole brain probabilistic and anatomically constrained tractography. Network connectivity matrices were built encoding the number of streamlines (D_NUM) and the tract‐averaged fractional anisotropy (D_FA) values connecting each pair of cortical and subcortical regions. Network Based Statistics (NBS) was finally applied on the connectivity matrices to evaluate the network differences between the ASD and other‐DD groups. The network differences resulted in an over‐connectivity pattern (i.e., higher D_NUM and D_FA values) in the ASD group with a significance of P < 0.05. No contra‐comparison results were found. The over‐connectivity pattern in ASD occurred in networks primarily involving the fronto‐temporal nodes, known to be crucial for social‐skill development and basal ganglia, related to restricted and repetitive behaviours in ASD. To our knowledge, this is the first network‐based diffusion study comparing toddlers with ASD and those with other‐DD. Results indicate the detection of different connectivity patterns in ASD and other‐DD at an age when clinical differential diagnosis is often challenging. Hum Brain Mapp 38:2333–2344, 2017. © 2017 Wiley Periodicals, Inc.     

Advances in SMA research: Review of gene deletions

The term spinal muscular atrophy (SMA) is used to encompass a group of inherited disorders in which the striking pathological feature is loss of the cell bodies of alpha motor neurons in the anterior horn cell of the spinal cord and, in some cases, of the bulbar motor nuclei. Although the pathological features of these disorders have been well characterized, the nature of the primary underlying biochemical abnormality remains to be determined. In the 1990s genetic linkage was established for the childhood onset recessive forms of SMA (types I, II and III) to markers mapping to the chromosomal region 5q11.2–13.3. Physical maps of the region were then constructed, several candidate genes isolated and in 1995 deletions in two genes, the survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene, were identified in significant numbers of patients. Already the impact of the characterization of these deletions is being seen in clinical practice in terms of aiding diagnosis in symptomatic cases and in prenatal diagnosis. As discussed in this review however, several questions remain unresolved. It is unclear whether deletions in one or both of these genes, or indeed in other, as yet unidentified, genes are important in generating the SMA phenotype. The function of the protein product of the SMN gene is unknown. The NAIP gene encodes a protein which inhibits apoptosis in a mammalian cell line: is it disruption of this function which is relevant in SMA? What underlies the variation in disease severity evident both between and within families? Resolution of such issues is of crucial importance if the identification of these deleted gene sequences is to lead to the development of rational therapies for motor neuron diseases.     

Therapeutic strategies for neurodegenerative disorders: emerging clues from Parkinson's disease.

Our knowledge of Parkinson's disease pathophysiology has greatly expanded during the last century, resulting in successful new medical and neurosurgical approaches toward this common neurodegenerative disorder. These approaches might also be useable in the treatment of psychiatric disorders, which often are linked to atrophic and degenerative processes in the brain; however, the successful application of these techniques in psychiatry requires thorough elucidation of disease pathophysiology to identify proper intervention sites. Likewise, awareness of the differences between the parkinsonian and psychiatric patient populations in terms of age, disease course, and life expectancy, as well as ethical considerations might in the end determine the appropriateness of these therapeutic strategies in psychiatry.     

MarsAtlas: A cortical parcellation atlas for functional mapping

An open question in neuroimaging is how to develop anatomical brain atlases for the analysis of functional data. Here, we present a cortical parcellation model based on macroanatomical information and test its validity on visuomotor‐related cortical functional networks. The parcellation model is based on a recently developed cortical parameterization method (Auzias et al., [2013]: IEEE Trans Med Imaging 32:873–887), called HIP‐HOP. This method exploits a set of primary and secondary sulci to create an orthogonal coordinate system on the cortical surface. A natural parcellation scheme arises from the axes of the HIP‐HOP model running along the fundus of selected sulci. The resulting parcellation scheme, called MarsAtlas, complies with dorsoventral/rostrocaudal direction fields and allows inter‐subject matching. To test it for functional mapping, we analyzed a MEG dataset collected from human participants performing an arbitrary visuomotor mapping task. Single‐trial high‐gamma activity, HGA (60–120 Hz), was estimated using spectral analysis and beamforming techniques at cortical areas arising from a Talairach atlas (i.e., Brodmann areas) and MarsAtlas. Using both atlases, we confirmed that visuomotor associations involve an increase in HGA over the sensorimotor and fronto‐parietal network, in addition to medial prefrontal areas. However, MarsAtlas provided: (1) crucial functional information along both the dorsolateral and rostrocaudal direction; (2) an increase in statistical significance. To conclude, our results suggest that the MarsAtlas is a valid anatomical atlas for functional mapping, and represents a potential anatomical framework for integration of functional data arising from multiple techniques such as MEG, intracranial EEG and fMRI. Hum Brain Mapp 37:1573‐1592, 2016. © 2016 Wiley Periodicals, Inc.     

The development of antisocial behaviour from childhood to adolescence

Abstract Recent theory proposes that aggressive and nonaggressive antisocial behaviour (ASB) represent different pathways toward delinquency. It has also been suggested that Aggressive ASB is heritable, whereas nonaggressive ASB is more influenced by shared environment.The twin study of child and adolescent development is a Swedish population-based study of 1,480 twin pairs. The present study included 1,226 twin pairs. We used the parental-reported Aggression and Delinquency scales from the CBCL measured at age 8–9. Delinquent behaviour was measured through self-report at age 16–17. We explored how genetic and environmental effects influence the relationships between aspects of ASB in childhood and adolescent delinquency using structural equations modelling.For girls we found that the relationship between Aggressive Behaviour and Self-Reported Delinquency was explained by genetic influences. The correlation between Delinquent Behaviour and Self-Reported Delinquency was due to continuity of genetic influences. For boys, there was no significant mediation between Aggressive Behaviour and Self-Reported Delinquency, but there were significant shared environmental effects on the relationship between Delinquent Behaviour and Self-Reported Delinquency.Our results suggest that there are sex differences in the development of ASB. The hypothesis that the aggressive pathway is genetically mediated was supported in girls, whereas the hypothesis that the nonaggressive pathway is environmentally dependent was supported in boys.