Intrinsic Adrenal TWIK-Related Acid-Sensitive TASK Channel Dysfunction Produces Spontaneous Calcium Oscillations Sufficient to Drive AngII (Angiotensin II)-Unresponsive Hyperaldosteronism.

BACKGROUND: Ion channel mutations in calcium regulating genes strongly associate with AngII (angiotensin II)-independent aldosterone production. Here, we used an established mouse model of in vivo aldosterone autonomy, Cyp11b2-driven deletion of TWIK-related acid-sensitive potassium channels (TASK-1 and TASK-3, termed zona glomerulosa [zG]-TASK-loss-of-function), and selective pharmacological TASK channel inhibition to determine whether channel dysfunction in native, electrically excitable zG cell rosette-assemblies: (1) produces spontaneous calcium oscillatory activity and (2) is sufficient to drive substantial aldosterone autonomy. METHODS: We imaged calcium activity in adrenal slices expressing a zG-specific calcium reporter (GCaMP3), an in vitro experimental approach that preserves the native rosette assembly and removes potentially confounding extra-adrenal contributions. In parallel experiments, we measured acute aldosterone production from adrenal slice cultures. RESULTS: Absent from untreated WT slices, we find that either adrenal-specific genetic deletion or acute pharmacological TASK channel inhibition produces spontaneous oscillatory bursting behavior and steroidogenic activity (2.4-fold) that are robust, sustained, and equivalent to activities evoked by 3 nM AngII in WT slices. Moreover, spontaneous activity in zG-TASK-loss-of-function slices and inhibitor-evoked activity in WT slices are unresponsive to AngII regulation over a wide range of concentrations (50 pM to 3 µM). CONCLUSIONS: We provide proof of principle that spontaneous activity of zG cells within classic rosette assemblies evoked solely by a change in an intrinsic, dominant resting-state conductance can be a significant source of AngII-independent aldosterone production from native tissue.

Neuroepigenetic impact on mentalizing in childhood.

Mentalizing, or the ability to understand the mental states and intentions of others, is an essential social cognitive function that children learn and continue to cultivate into adolescence. While most typically developing children acquire sufficient mentalizing skills, individual differences in mentalizing persist throughout childhood and are likely influenced by a combination of cognitive functioning, the social environment, and biological factors. DNA methylation of the oxytocin receptor gene (OXTRm) impacts gene expression and is associated with increased brain activity in mentalizing regions during displays of animacy in healthy young adults. The establishment, fine-tuning, and implications of such associations in the context of broader social functioning remain unclear. Using a developmental neuroimaging epigenetic approach, we investigated the contributions of OXTRm to individual variability in brain function during animate motion perception in middle childhood. We find that higher levels of OXTRm are associated with increased neural responses in the left temporo-parietal junction and inferior frontal gyrus. We also find a positive association between neural activity in LTPJ and social skills. These findings provide evidence of epigenetic influence on the developing child brain and demonstrate that variability in neural social perception in childhood is multifaceted with contributions from individual social experience and the endogenous oxytocin system.

An Image Registration-Based Morphing Technique for Generating Subject-Specific Brain Finite Element Models.

Finite element (FE) models of the brain are crucial for investigating the mechanisms of traumatic brain injury (TBI). However, FE brain models are often limited to a single neuroanatomy because the manual development of subject-specific models is time consuming. The objective of this study was to develop a pipeline to automatically generate subject-specific FE brain models using previously developed nonlinear image registration techniques, preserving both external and internal neuroanatomical characteristics. To verify the morphing-induced mesh distortions did not influence the brain deformation response, strain distributions predicted using the morphed model were compared to those from manually created voxel models of the same subject. Morphed and voxel models were generated for 44 subjects ranging in age, and simulated using head kinematics from a football concussion case. For each subject, brain strain distributions predicted by each model type were consistent, and differences in strain prediction was less than 4% between model type. This automated technique, taking approximately 2 h to generate a subject-specific model, will facilitate interdisciplinary research between the biomechanics and neuroimaging fields and could enable future use of biomechanical models in the clinical setting as a tool for improving diagnosis.

Angiotensin II induces coordinated calcium bursts in aldosterone-producing adrenal rosettes.

Aldosterone-producing zona glomerulosa (zG) cells of the adrenal gland arrange in distinct multi-cellular rosettes that provide a structural framework for adrenal cortex morphogenesis and plasticity. Whether this cyto-architecture also plays functional roles in signaling remains unexplored. To determine if structure informs function, we generated mice with zG-specific expression of GCaMP3 and imaged zG cells within their native rosette structure. Here we demonstrate that within the rosette, angiotensin II evokes periodic Cav3-dependent calcium events that form bursts that are stereotypic in form. Our data reveal a critical role for angiotensin II in regulating burst occurrence, and a multifunctional role for the rosette structure in activity-prolongation and coordination. Combined our data define the calcium burst as the fundamental unit of zG layer activity evoked by angiotensin II and highlight a novel role for the rosette as a facilitator of cell communication.