Biology subjects

Kircher, T.

Publications and source records attributed to Kircher, T..

25 records · Page 2Linked to original sources

bioRxiv2021

Bipolar-associated miR-499-5p controls neuroplasticity by downregulating the Cav1.2 L-type voltage gated calcium channel subunit CACNB2

Bipolar disorder (BD) is a chronic mood disorder characterized by alternating manic and depressive episodes, often in conjunction with cognitive deficits. Dysregulation of neuroplasticity and calcium homeostasis as a result of complex genetic environment interactions are frequently observed in BD patients, but the underlying molecular mechanisms are largely unknown. Here, we show that a BD-associated microRNA, miR-499-5p, regulates neuronal dendrite development and cognitive function by downregulating the BD risk gene CACNB2. miR-499-5p expression is increased in peripheral blood of BD patients and healthy subjects at risk of developing the disorder due to a history of childhood maltreatment. This up-regulation is paralleled in the hippocampus of rats which underwent juvenile social isolation. Elevating miR-499-5p levels in rat hippocampal pyramidal neurons impairs dendritogenesis and reduces surface expression and activity of the voltage-gated L-type calcium channel Cav1.2. We further identified CACNB2, which encodes a regulatory {beta}-subunit of Cav1.2, as a direct target of miR-499-5p in neurons. CACNB2 downregulation is required for the miR-499-5p dependent impairment of dendritogenesis, suggesting that CACNB2 is an important downstream target of miR-499-5p in the regulation of neuroplasticity. Finally, elevating miR-499-5p in the hippocampus in vivo is sufficient to induce short-term memory impairments in rats haploinsufficient for the Cav1.2 pore forming subunit Cacna1c. Taken together, we propose that stress-induced upregulation of miR-499-5p contributes to dendritic impairments and deregulated calcium homeostasis in BD, with specific implications for the neurocognitive dysfunction frequently observed in BD patients.

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bioRxiv2021

Sensorimotor temporal recalibration: the contribution of motor-sensory and inter-sensory components

Adaptation to delays between actions and sensory feedback is important for efficiently interacting with our environment. Adaptation may rely on predictions of action-feedback pairing (motor-sensory component), or predictions of tactile-proprioceptive sensation from the action and sensory feedback of the action (inter-sensory component). Reliability of temporal information might differ across sensory feedback modalities (e.g. auditory or visual), influencing adaptation. Here, we investigated the role of motor-sensory and inter-sensory components on sensorimotor temporal recalibration for motor-auditory events (button press-tone) and motor-visual events (button press-Gabor patch). In the adaptation phase of the experiment, the motor action-feedback event pairs were presented with systematic temporal delays (0ms or 150ms). In the subsequent test phase, sensory feedback of the action were presented with variable delays. The participants were then asked whether this delay could be detected. To disentangle motor-sensory from inter-sensory component, we varied movements (active button press or passive depression of button) at adaptation and test. Our results suggest that motor-auditory recalibration is mainly driven by motor-sensory component, whereas motor-visual recalibration is mainly driven by inter-sensory component. Recalibration transferred from vision to audition, but not from audition to vision. These results indicate that motor-sensory and inter-sensory components of recalibration are weighted in a modality-dependent manner.

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bioRxiv2021

Action-based predictions affect visual perception, neural processing, and pupil size, regardless of temporal predictability

Sensory consequences of ones own action are often perceived as less intense, and lead to reduced neural responses, compared to externally generated stimuli. Presumably, such sensory attenuation is due to predictive mechanisms based on the motor command (efference copy). However, sensory attenuation has also been observed outside the context of voluntary action, namely when stimuli are temporally predictable. Here, we aimed at disentangling the effects of motor and temporal predictability-based mechanisms on the attenuation of sensory action consequences. During fMRI data acquisition, participants (N = 25) judged which of two visual stimuli was brighter. In predictable blocks, the stimuli appeared temporally aligned with their button press (active) or aligned with an automatically generated cue (passive). In unpredictable blocks, stimuli were presented with a variable delay after button press/cue, respectively. Eye tracking was performed to investigate pupil-size changes and to ensure proper fixation. Self-generated stimuli were perceived as darker and led to less neural activation in visual areas than their passive counterparts, indicating sensory attenuation for self-generated stimuli independent of temporal predictability. Pupil size was larger during self-generated stimuli, which correlated negatively with blood oxygenation level dependent (BOLD) response: the larger the pupil, the smaller the BOLD amplitude in visual areas. Our results suggest that sensory attenuation in visual cortex is driven by action-based predictive mechanisms rather than by temporal predictability. This effect may be related to changes in pupil diameter. Altogether, these results emphasize the role of the efference copy in the processing of sensory action consequences.

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bioRxiv2020

Modality-specific dysfunctional neural processing of social and non-social information in schizophrenia

Schizophrenia is characterized by marked communication dysfunctions encompassing potential impairments in the processing of social-abstract and non-social-concrete information, especially in everyday situations where multiple modalities are present in the form of speech and gesture. To date, the neurobiological basis of these deficits remains elusive. In a functional magnetic resonance imaging (fMRI) study, 17 patients with schizophrenia or schizoaffective disorder, and 18 matched controls watched videos of an actor speaking, gesturing (unimodal), and both speaking and gesturing (bimodal) about social or non-social events in a naturalistic way. Participants were asked to judge whether each video contains person-related (social) or object-related (non-social) information. When processing social-abstract content, patients showed reduced activation in the medial prefrontal cortex (mPFC) only in the gesture but not in the speech condition. For non-social-concrete content, remarkably, reduced neural activation for patients in the left postcentral gyrus and the right insula was observed only in the speech condition. Moreover, in the bimodal conditions, patients displayed improved task performance and comparable activation to controls in both social and non-social content. To conclude, patients with schizophrenia displayed modality-specific aberrant neural processing of social and non-social information, which is not present for the bimodal conditions. This finding provides novel insights into dysfunctional multimodal communication in schizophrenia, and may have potential therapeutic implications.

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bioRxiv2019

Brain Aging in Major Depressive Disorder: Results from the ENIGMA Major Depressive Disorder working group

BackgroundMajor depressive disorder (MDD) is associated with an increased risk of brain atrophy, aging-related diseases, and mortality. We examined potential advanced brain aging in MDD patients, and whether this process is associated with clinical characteristics in a large multi-center international dataset. MethodsWe performed a mega-analysis by pooling brain measures derived from T1-weighted MRI scans from 29 samples worldwide. Normative brain aging was estimated by predicting chronological age (10-75 years) from 7 subcortical volumes, 34 cortical thickness and 34 surface area, lateral ventricles and total intracranial volume measures separately in 1,147 male and 1,386 female controls from the ENIGMA MDD working group. The learned model parameters were applied to 1,089 male controls and 1,167 depressed males, and 1,326 female controls and 2,044 depressed females to obtain independent unbiased brain-based age predictions. The difference between predicted "brain age" and chronological age was calculated to indicate brain predicted age difference (brain-PAD). FindingsOn average, MDD patients showed a higher brain-PAD of +0.90 (SE 0.21) years (Cohens d=0.12, 95% CI 0.06-0.17) compared to controls. Relative to controls, first-episode and currently depressed patients showed higher brain-PAD (+1.2 [0.3] years), and the largest effect was observed in those with late-onset depression (+1.7 [0.7] years). In addition, higher brain-PAD was associated with higher self-reported depressive symptomatology (b=0.05, p=0.004). InterpretationThis highly powered collaborative effort showed subtle patterns of abnormal structural brain aging in MDD. Substantial within-group variance and overlap between groups were observed. Longitudinal studies of MDD and somatic health outcomes are needed to further assess the predictive value of these brain-PAD estimates. FundingThis work was supported, in part, by NIH grants U54 EB020403 and R01 MH116147.

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bioRxiv2019

Subcortical Shape Alterations in Major Depressive Disorder: Findings from the ENIGMA Major Depressive Disorder Working Group

Alterations in regional subcortical brain volumes have been widely investigated as part of the efforts of an international consortium, ENIGMA, to determine reliable structural brain signatures for Major Depressive Disorder (MDD). Given that subcortical structures are comprised of distinct subfields, we sought to build significantly from prior work to precisely map localized MDD-related differences in subcortical regions using shape analysis. In this meta-analysis of subcortical shape from the ENIGMA-MDD working group, we compared 1,781 patients with MDD and 2,953 healthy controls (CTL) on individual measures of shape metrics (thickness and surface area) on the surface of seven bilateral subcortical structures: nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen, and thalamus. Harmonized data processing and statistical analyses were conducted locally at each site, and findings were aggregated by meta-analysis. Relative to CTL, patients with MDD had lower surface area in the subiculum of the hippocampus, the basolateral amygdala, and the nucleus accumbens shell. Relative to CTL, patients with adolescent-onset MDD ([≤] 21 years) had lower thickness and surface area of the subiculum of the hippocampus and the basolateral amygdala. Relative to first-episode MDD, recurrent MDD patients had lower thickness and surface area in the CA1 of the hippocampus and the basolateral amygdala. Our results suggest that previously reported MDD-associated volumetric differences may be localized to specific subfields of these structures that have been shown to be sensitive to the effects of stress, with important implications for mapping treatments to patients based on specific neural targets and key clinical features.

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bioRxiv2019

10Kin1day: A bottom-up neuroimaging initiative

We organized 10Kin1day, a pop-up scientific event with the goal to bring together neuroimaging groups from around the world to jointly analyze 10,000+ existing MRI connectivity datasets during a 3-day workshop. In this report, we describe the motivation and principles of 10Kin1day, together with a public release of 8,000+ MRI connectome maps of the human brain.

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