A Potential Role for a Genetic Variation of AKAP5 in Human Aggression and Anger Control

The A-kinase-anchoring protein 5 (AKAP5), a post-synaptic multi-adaptor molecule that binds G-protein-coupled receptors and intracellular signaling molecules has been implicated in emotional processing in rodents, but its role in human emotion and behavior is up to now still not quite clear. Here, we report an association of individual differences in aggressive behavior and anger expression with a functional genetic polymorphism (Pro100Leu) in the human AKAP5 gene. Among a cohort of 527 young, healthy individuals, carriers of the less common Leu allele (15.6% allele frequency) scored significantly lower in the physical aggression domain of the Buss and Perry Aggression Questionnaire and higher in the anger control dimension of the state-trait anger expression inventory. In a functional magnetic resonance imaging experiment we could further demonstrate that AKAP5 Pro100Leu modulates the interaction of negative emotional processing and executive functions. In order to investigate implicit processes of anger control, we used the well-known flanker task to evoke processes of action monitoring and error processing and added task-irrelevant neutral or angry faces in the background of the flanker stimuli. In line with our predictions, Leu carriers showed increased activation of the anterior cingulate cortex (ACC) during emotional interference, which in turn predicted shorter reaction times and might be related to stronger control of emotional interference. Conversely, Pro homozygotes exhibited increased orbitofrontal cortex (OFC) activation during emotional interference, with no behavioral advantage. Immunohistochemistry revealed AKAP5 expression in post mortem human ACC and OFC. Our results suggest that AKAP5 Pro100Leu contributes to individual differences in human aggression and anger control. Further research is warranted to explore the detailed role of AKAP5 and its gene product in human emotion processing

Reduced density of glutamine synthetase immunoreactive astrocytes in different cortical areas in major depression but not in bipolar I disorder

There is increasing evidence for disturbances within the glutamate system in patients with affective disorders, which involve disruptions of the glutamate-glutamine- cycle. The mainly astroglia-located enzyme glutamine synthetase catalyzes the ATP-dependent condensation of ammonia and glutamate to form glutamine, thus playing a central role in glutamate and glutamine homoeostasis. However, glutamine synthetase is also expressed in numerous oligodendrocytes, another class of glial cells implicated in mood disorder pathology. To learn more about the role of glia-associated glutamine synthetase in mental illnesses, we decided to find out if numerical densities of glial cells immunostained for the enzyme protein differ between subjects with major depressive disorder, bipolar disorder and psychically healthy control cases. Counting of glutamine synthetase expressing astrocytes and oligodendrocytes in eight cortical and two subcortical brain regions of subjects with mood disorder (N=14), bipolar disorder (N=15) and controls (N=16) revealed that in major depression the densities of astrocytes were significantly reduced in some cortical but not subcortical gray matter areas, whereas no changes were found for oligodendrocytes. In bipolar disorder no alterations of glutamine synthetase-immunoreactive glia were found. From our findings we conclude that (1) glutamine synthetase expressing astrocytes are prominently involved in glutamate-related disturbances in major depression, but not in bipolar disorder and (2) glutamine synthetase expressing oligodendrocytes, though being present in significant numbers in prefrontal cortical areas, play a minor (if any) role in mood disorder pathology. The latter assumption is supported by findings of others showing that - at least in the mouse brain cortex - glutamine synthetase immunoreactive oligodendroglial cells are unable to contribute to the glutamate-glutamine cycle due to the complete lack of amino acid transporters (Takasaki et al

Integration of ultra-high field MRI and histology for connectome based research of brain disorders

Ultra-high field magnetic resonance imaging (MRI) became increasingly relevant for in vivo neuroscientific research because of improved spatial resolutions. However, this is still the unchallenged domain of histological studies, which long played an important role in the investigation of neuropsychiatric disorders. While the field of biological psychiatry strongly advanced on macroscopic levels, current developments are rediscovering the richness of immunohistological information when attempting a multi-level systematic approach to brain function and dysfunction. For most studies, histology sections lost information on three-dimensional reconstructions. Translating histological sections to 3D-volumes would thus not only allow for multi-stain and multi-subject alignment in post mortem data, but also provide a crucial step in big data initiatives involving the network analyses currently performed with in vivo MRI. We therefore investigated potential pitfalls during integration of MR and histological information where no additional blockface information is available. We demonstrated that strengths and requirements from both methods seem to be ideally merged at a spatial resolution of 200 μm. However, the success of this approach is heavily dependent on choices of hardware, sequence and reconstruction. We provide a fully automated pipeline that optimizes histological 3D reconstructions, providing a potentially powerful solution not only for primary human post mortem research institutions in neuropsychiatric research, but also to help alleviate the massive workloads in neuroanatomical atlas initiatives. We further demonstrate (for the first time) the feasibility and quality of ultra-high spatial resolution (150 µm isotopic) imaging of the entire human brain MRI at 7T, offering new opportunities for analyses on MR-derived information

Calretinin and parvalbumin in schizophrenia and affective disorders: A mini-review, a perspective on the evolutionary role of calretinin in schizophrenia, and a preliminary post-mortem study of calretinin in the septal nuclei.

2.Objective: The septal nuclei are important limbic regions that are involved in 3.emotional behavior and connect to various brain regions such as the habenular 4.complex. Both the septal nuclei and the habenular complex are involved in the 5.pathology of schizophrenia and affective disorders.6. Methods: We characterized the number and density of calretinin-immunoreactive 7.neurons in the lateral, medial, and dorsal subregions of the septal nuclei in three 8.groups of subjects: healthy control subjects (N = 6), patients with schizophrenia (N 9.= 10), and patients with affective disorders (N = 6). 10.Results: Our mini-review of the combined role of calretinin and parvalbumin in 11.schizophrenia and affective disordres summarizes18 studies. We did not observe 12.significant differences in the numbers of calretinin-immunoreactive neurons or 13.neuronal densities in the lateral, medial, and dorsal septal nuclei of patients with 14.schizophrenia or patients with affective disorders compared to healthy control 15.subjects. 16.Conclusions: Most post-mortem investigations of patients with schizophrenia have 17.indicated significant abnormalities of parvalbumin-immunoreactive neurons in 18.various brain regions including the hippocampus, the anterior cingulate cortex, and 19.the prefrontal cortex in schizophrenia. This study also provides an explanation 20.from an evolutionary perspective for why calretinin is affected in schizophrenia