The genetic architecture of the human cerebral cortex

INTRODUCTION The cerebral cortex underlies our complex cognitive capabilities. Variations in human cortical surface area and thickness are associated with neurological, psychological, and behavioral traits and can be measured in vivo by magnetic resonance imaging (MRI). Studies in model organisms have identified genes that influence cortical structure, but little is known about common genetic variants that affect human cortical structure. RATIONALE To identify genetic variants associated with human cortical structure at both global and regional levels, we conducted a genome-wide association meta-analysis of brain MRI data from 51,665 individuals across 60 cohorts. We analyzed the surface area and average thickness of the whole cortex and 34 cortical regions with known functional specializations. RESULTS We identified 306 nominally genome-wide significant loci (P < 5 × 10−8) associated with cortical structure in a discovery sample of 33,992 participants of European ancestry. Of the 299 loci for which replication data were available, 241 loci influencing surface area and 14 influencing thickness remained significant after replication, with 199 loci passing multiple testing correction (P < 8.3 × 10−10; 187 influencing surface area and 12 influencing thickness). Common genetic variants explained 34% (SE = 3%) of the variation in total surface area and 26% (SE = 2%) in average thickness; surface area and thickness showed a negative genetic correlation (rG = −0.32, SE = 0.05, P = 6.5 × 10−12), which suggests that genetic influences have opposing effects on surface area and thickness. Bioinformatic analyses showed that total surface area is influenced by genetic variants that alter gene regulatory activity in neural progenitor cells during fetal development. By contrast, average thickness is influenced by active regulatory elements in adult brain samples, which may reflect processes that occur after mid-fetal development, such as myelination, branching, or pruning. When considered together, these results support the radial unit hypothesis that different developmental mechanisms promote surface area expansion and increases in thickness. To identify specific genetic influences on individual cortical regions, we controlled for global measures (total surface area or average thickness) in the regional analyses. After multiple testing correction, we identified 175 loci that influence regional surface area and 10 that influence regional thickness. Loci that affect regional surface area cluster near genes involved in the Wnt signaling pathway, which is known to influence areal identity. We observed significant positive genetic correlations and evidence of bidirectional causation of total surface area with both general cognitive functioning and educational attainment. We found additional positive genetic correlations between total surface area and Parkinson’s disease but did not find evidence of causation. Negative genetic correlations were evident between total surface area and insomnia, attention deficit hyperactivity disorder, depressive symptoms, major depressive disorder, and neuroticism. CONCLUSION This large-scale collaborative work enhances our understanding of the genetic architecture of the human cerebral cortex and its regional patterning. The highly polygenic architecture of the cortex suggests that distinct genes are involved in the development of specific cortical areas. Moreover, we find evidence that brain structure is a key phenotype along the causal pathway that leads from genetic variation to differences in general cognitive function

Lack of effect of bilateral locus coeruleus lesion and antidepressant treatment on gamma-aminobutyric acid(B) receptors in the rat frontal cortex

The aim of the present study was to investigate whether a disturbance of the central noradrenergic (NA) system could cause changes in gamma- aminobutyric acid(B) (GABA(B)) receptors in the rat frontal cortex. Manipulation of the NA projection to the frontal cortex was achieved by bilateral lesion of the locus coeruleus with 6-hydroxydopamine (6-OHDA) or chronic treatment with the NA reuptake blocker and antidepressant drug, desipramine. Precautions were taken to ensure that the GABA(B) receptor assay was performed optimally and was not confounded by the presence of endogenously generated GABA. The results show conclusively that manipulation of the NA projection did not result in any significant change in the number (Bmax) or affinity (Kd) of GABA(B) receptors in the frontal cortex. These results do not support the hypothesis that hypoactivity of the central NA system can lead to changes in cortical GABA(B) receptors and that antidepressant drugs act by increasing GABA(B) receptor binding in the frontal cortex.The aim of the present study was to investigate whether a disturbance of the central noradrenergic (NA) system could cause changes in gamma- aminobutyric acid(B) (GABA(B)) receptors in the rat frontal cortex. Manipulation of the NA projection to the frontal cortex was achieved by bilateral lesion of the locus coeruleus with 6-hydroxydopamine (6-OHDA) or chronic treatment with the NA reuptake blocker and antidepressant drug, desipramine. Precautions were taken to ensure that the GABA(B) receptor assay was performed optimally and was not confounded by the presence of endogenously generated GABA. The results show conclusively that manipulation of the NA projection did not result in any significant change in the number (Bmax) or affinity (Kd) of GABA(B) receptors in the frontal cortex. These results do not support the hypothesis that hypoactivity of the central NA system can lead to changes in cortical GABA(B) receptors and that antidepressant drugs act by increasing GABA(B) receptor binding in the frontal cortex.ArticleArticl

Imipramine binding sites on platelets of patients with major depressive disorder

[No abstract available]Articl

Alpha2-adrenoceptor levels on platelets of patients with major depressive disorders

[No abstract available]Articl

The effect of intrahippocampal injection of kainic acid on corticosterone release in rats

The aim of the present study was to investigate whether the hippocampus exerts a modulatory effect on the activity of the hypothalamic-pituitary-adrenal (HPA) axis. Kainic acid was stereotaxically injected into the CA1 pyramidal cell layer of the dorsal hippocampus, causing histological and behavioural changes typical of kainic acid toxicity. The CA3 pyramidal cells of the dorsal hippocampus were selectively lesioned. Rats treated with kainic acid were hyperactive, executed clockwise rotatory movements and displayed epileptic seizures. The acute excitatory effect of kainic acid on glutamatergic receptors in the hippocampus resulted in an elevation in plasma corticosterone levels, suggesting a stimulation of HPA axis activity. Direct or indirect stimulation of the CA1 pyramidal cells of the dorsal hippocampus appeared to have caused the increase in corticosterone secretion.Articl

Kindled seizures do not affect adenosinergic inhibition of DA or ACh release in rat accumbens or PFC

Epileptic seizures are thought to terminate largely as a result of the extracellular accumulation of the purinergic neuromodulator, adenosine, released by discharging neurons. However, the postictal surge in extracellular adenosine and its widespread inhibitory effects are limited in time to only a few minutes and cannot directly account for increased resistance to seizures and the complex behavioural and motivational effects that may persist for hours or days after a seizure. The present study examined whether kindled seizures might after the sensitivity or efficacy of inhibitory presynaptic adenosine receptors, and thereby induce more enduring changes in downstream transmitter systems. Rats were kindled in the amygdala of the dominant cerebral hemisphere, contralateral to the preferred direction of rotation, and their brains were removed either 2 h or 28 days after completion of kindling. Inhibition of electrically stimulated release of dopamine (DA) and acetylcholine (ACh) by the A1 adenosine-receptor agonist, R-phenylisopropyladenosine (R-PIA) was then measured in the prefrontal cortex (PFC) and nucleus accumbens. R-PIA (1.0 μM) inhibited [3H]DA release from PFC and nucleus accumbens tissue, and [14C]ACh release from nucleus accumbens tissue, but release was unaffected by prior kindling, regardless of the intervening interval. These results do not support suggestions that DA or ACh might mediate the effects of seizure-induced changes in purinergic inhibitory tone so as to cause long-term shifts in seizure threshold and postictal behavior.Revie

Evidence that noradrenergic neuronsin the A1 and A2 nuclei are lesioned by low doses of 6-OHDA injected into the locus coeruleus

In order to determine the specificity of a lesion aimed at the locus coeruleus (LC), various doses of 6-hydroxydopamine (6-OHDA), a neurotoxin which selectively lesions catecholaminergic neurons, were bilaterally infused into the LC. The noradrenaline (NA) concentration in the frontal cortex, hippocampus, hypothalamus, LC, A1 and A2 nuclei decreased with increasing doses of 6-OHDA. A 1 μg dose of 6-OHDA injected bilaterally into the LC caused maximal depletion of the NA concentration in the frontal cortex, hippocampus and A1 and A2 nuclei. A dose of 2 μg 6-OHDA caused further depletion of the NA content of the hypothalamus and LC. These findings suggest that A1 and A2 neurons which project to the hypothalamus may have been lesioned or that the noradrenergic projection from the LC to the hypothalamus may be greater than was previously suspected. Alternatively, leakage of 6-OHDA into the cerebrospinal fluid may have occurred at the higher doses, thus directly exposing the hypothalamus to the toxic effects of 6-OHDA.Articl