Gene-Based Analysis of Regionally Enriched Cortical Genes in GWAS Data Sets of Cognitive Traits and Psychiatric Disorders

Background: Despite its estimated high heritability, the genetic architecture leading to differences in cognitive performance remains poorly understood. Different cortical regions play important roles in normal cognitive functioning and impairment. Recently, we reported on sets of regionally enriched genes in three different cortical areas (frontomedial, temporal and occipital cortices) of the adult rat brain. It has been suggested that genes preferentially, or specifically, expressed in one region or organ reflect functional specialisation. Employing a gene-based approach to the analysis, we used the regionally enriched cortical genes to mine a genome-wide association study (GWAS) of the Norwegian Cognitive NeuroGenetics (NCNG) sample of healthy adults for association to nine psychometric tests measures. In addition, we explored GWAS data sets for the serious psychiatric disorders schizophrenia (SCZ) (n = 3 samples) and bipolar affective disorder (BP) (n = 3 samples), to which cognitive impairment is linked. Principal Findings: At the single gene level, the temporal cortex enriched gene RAR-related orphan receptor B (RORB) showed the strongest overall association, namely to a test of verbal intelligence (Vocabulary, P = 7.7E-04). We also applied gene set enrichment analysis (GSEA) to test the candidate genes, as gene sets, for enrichment of association signal in the NCNG GWAS and in GWASs of BP and of SCZ. We found that genes differentially expressed in the temporal cortex showed a significant enrichment of association signal in a test measure of non-verbal intelligence (Reasoning) in the NCNG sample. Conclusion: Our gene-based approach suggests that RORB could be involved in verbal intelligence differences, while the genes enriched in the temporal cortex might be important to intellectual functions as measured by a test of reasoning in the healthy population. These findings warrant further replication in independent samples on cognitive traits

Gene expression in the rat brain: High similarity but unique differences between frontomedial-, temporal- and occipital cortex

<p>Abstract</p> <p>Background</p> <p>The six-layered neocortex of the mammalian brain may appear largely homologous, but is in reality a modular structure of anatomically and functionally distinct areas. However, global gene expression seems to be almost identical across the cerebral cortex and only a few genes have so far been reported to show regional enrichment in specific cortical areas.</p> <p>Results</p> <p>In the present study on adult rat brain, we have corroborated the strikingly similar gene expression among cortical areas. However, differential expression analysis has allowed for the identification of 30, 24 and 11 genes enriched in frontomedial -, temporal- or occipital cortex, respectively. A large proportion of these 65 genes appear to be involved in signal transduction, including the ion channel <it>Fxyd6</it>, the neuropeptide <it>Grp </it>and the nuclear receptor <it>Rorb</it>. We also find that the majority of these genes display increased expression levels around birth and show distinct preferences for certain cortical layers and cell types in rodents.</p> <p>Conclusions</p> <p>Since specific patterns of expression often are linked to equally specialised biological functions, we propose that these cortex sub-region enriched genes are important for proper functioning of the cortical regions in question.</p

Internally coupled ears in living mammals.

It is generally held that the right and left middle ears of mammals are acoustically isolated from each other, such that mammals must rely on neural computation to derive sound localisation cues. There are, however, some unusual species in which the middle ear cavities intercommunicate, in which case each ear might be able to act as a pressure-difference receiver. This could improve sound localisation at lower frequencies. The platypus Ornithorhynchus is apparently unique among mammals in that its tympanic cavities are widely open to the pharynx, a morphology resembling that of some non-mammalian tetrapods. The right and left middle ear cavities of certain talpid and golden moles are connected through air passages within the basicranium; one experimental study on Talpa has shown that the middle ears are indeed acoustically coupled by these means. Having a basisphenoid component to the middle ear cavity walls could be an important prerequisite for the development of this form of interaural communication. Little is known about the hearing abilities of platypus, talpid and golden moles, but their audition may well be limited to relatively low frequencies. If so, these mammals could, in principle, benefit from the sound localisation cues available to them through internally coupled ears. Whether or not they actually do remains to be established experimentally.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00422-015-0675-

Whole-scalp EEG mapping of somatosensory evoked potentials in macaque monkeys

High-density scalp EEG recordings are widely used to study whole-brain neuronal networks in humans non-invasively. Here, we validate EEG mapping of somatosensory evoked potentials (SSEPs) in macaque monkeys (Macaca fascicularis) for the long-term investigation of large-scale neuronal networks and their reorganisation after lesions requiring a craniotomy. SSEPs were acquired from 33 scalp electrodes in five adult anaesthetized animals after electrical median or tibial nerve stimulation. SSEP scalp potential maps were identified by cluster analysis and identified in individual recordings. A distributed, linear inverse solution was used to estimate the intracortical sources of the scalp potentials. SSEPs were characterised by a sequence of components with unique scalp topographies. Source analysis confirmed that median nerve SSEP component maps were in accordance with the somatotopic organisation of the sensorimotor cortex. Most importantly, SSEP recordings were stable both intra- and interindividually. We aim to apply this method to the study of recovery and reorganisation of large-scale neuronal networks following a focal cortical lesion requiring a craniotomy. As a prerequisite, the present study demonstrated that a 300-mm2 unilateral craniotomy over the sensorimotor cortex necessary to induce a cortical lesion, followed by bone flap repositioning, suture and gap plugging with calcium phosphate cement, did not induce major distortions of the SSEPs. In conclusion, SSEPs can be successfully and reproducibly recorded from high-density EEG caps in macaque monkeys before and after a craniotomy, opening new possibilities for the long-term follow-up of the cortical reorganisation of large-scale networks in macaque monkeys after a cortical lesion

Cortical Integration of Simple Somatosensory and Visual Input

Introduction Primates, probably more than most other mammals, have developed a host of complex behaviors that require integration across sensory systems and between sensory systems and the motor system. One such ability is goal- directed reaching. This ability requires the brain to generate body centered coordinates for conjugal eye and hand movements. Thus, there should be regions of the brain, particularly the neocortex, that have access to both visual and somatic inputs, as well as information regarding eye position. One likely site of this multimodal integration is posterior parietal cortex (areas 5 and 7a). Studies in non-human primates indicate that neurons here have somatic receptive fields, and respond to wrist and arm movements, and reaching and grasping [1-3]. Further, neurons in this region participate in integration of visual inputs regarding target location and kinesthetic information regarding the position of the limbs in space [5]; instructed movements [6]; and attenti

Neural Coding of Whisker-Mediated Touch in Primary Somatosensory Cortex Is Altered Following Early Blindness

Sensory systems do not develop and function independently of one another, yet they are typically studied in isolation. Effects of multisensory interactions on the developing neocortex can be revealed by altering the ratios of incoming sensory inputs associated with different modalities. We investigated neural responses in primary somatosensory cortex (S1) of short-tailed opossums (Monodelphis domestica; either sex) after the elimination of visual input through bilateral enucleation very early in development. To assess the influence of tactile experience after vision loss, we also examined naturally occurring patterns of exploratory behavior. In early blind (EB) animals, overall levels of tactile experience were similar to those of sighted controls (SC); locomotor activity was unimpaired and accompanied by whisking. Using extracellular single-unit recording techniques under anesthesia, we found that EB animals exhibited a reduction in the magnitude of neural responses to whisker stimuli in S1, coupled with spatial sharpening of receptive fields, in comparison to SC animals. These alterations manifested as two different effects on sensory processing in S1 of EB animals: the ability of neurons to detect single whisker stimulation was decreased, whereas their ability to discriminate between stimulation of neighboring whiskers was enhanced. The increased selectivity of S1 neurons in EB animals was reflected in improved population decoding performance for whisker stimulus position, particularly along the rostrocaudal axis of the snout, which aligns with the primary axis of natural whisker motion. These findings suggest that a functionally distinct form of somatosensory plasticity occurs when vision is lost early in development.SIGNIFICANCE STATEMENT After sensory loss, compensatory behavior mediated through the spared senses could be generated entirely through the recruitment of brain areas associated with the deprived sense. Alternatively, functional compensation in spared modalities may be achieved through a combination of plasticity in brain areas corresponding to both spared and deprived sensory modalities. Although activation of neurons in cortex associated with a deprived sense has been described frequently, it is unclear whether this is the only substrate available for compensation or if plasticity within cortical fields corresponding to spared modalities, particularly primary sensory cortices, may also contribute. Here, we demonstrate empirically that early loss of vision alters coding of sensory inputs in primary somatosensory cortex in a manner that supports enhanced tactile discrimination

Neural Coding of Whisker-Mediated Touch in Primary Somatosensory Cortex Is Altered Following Early Blindness

Sensory systems do not develop and function independently of one another, yet they are typically studied in isolation. Effects of multisensory interactions on the developing neocortex can be revealed by altering the ratios of incoming sensory inputs associated with different modalities. We investigated neural responses in primary somatosensory cortex (S1) of short-tailed opossums (Monodelphis domestica; either sex) after the elimination of visual input through bilateral enucleation very early in development. To assess the influence of tactile experience after vision loss, we also examined naturally occurring patterns of exploratory behavior. In early blind (EB) animals, overall levels of tactile experience were similar to those of sighted controls (SC); locomotor activity was unimpaired and accompanied by whisking. Using extracellular single-unit recording techniques under anesthesia, we found that EB animals exhibited a reduction in the magnitude of neural responses to whisker stimuli in S1, coupled with spatial sharpening of receptive fields, in comparison to SC animals. These alterations manifested as two different effects on sensory processing in S1 of EB animals: the ability of neurons to detect single whisker stimulation was decreased, whereas their ability to discriminate between stimulation of neighboring whiskers was enhanced. The increased selectivity of S1 neurons in EB animals was reflected in improved population decoding performance for whisker stimulus position, particularly along the rostrocaudal axis of the snout, which aligns with the primary axis of natural whisker motion. These findings suggest that a functionally distinct form of somatosensory plasticity occurs when vision is lost early in development.SIGNIFICANCE STATEMENT After sensory loss, compensatory behavior mediated through the spared senses could be generated entirely through the recruitment of brain areas associated with the deprived sense. Alternatively, functional compensation in spared modalities may be achieved through a combination of plasticity in brain areas corresponding to both spared and deprived sensory modalities. Although activation of neurons in cortex associated with a deprived sense has been described frequently, it is unclear whether this is the only substrate available for compensation or if plasticity within cortical fields corresponding to spared modalities, particularly primary sensory cortices, may also contribute. Here, we demonstrate empirically that early loss of vision alters coding of sensory inputs in primary somatosensory cortex in a manner that supports enhanced tactile discrimination