Morphological principles of neuronal mitochondria.

In the highly dynamic metabolic landscape of a neuron, mitochondrial membrane architectures can provide critical insight into the unique energy balance of the cell. Current theoretical calculations of functional outputs like adenosine triphosphate and heat often represent mitochondria as idealized geometries, and therefore, can miscalculate the metabolic fluxes. To analyze mitochondrial morphology in neurons of mouse cerebellum neuropil, 3D tracings of complete synaptic and axonal mitochondria were constructed using a database of serial transmission electron microscopy (TEM) tomography images and converted to watertight meshes with minimal distortion of the original microscopy volumes with a granularity of 1.64 nanometer isotropic voxels. The resulting in-silico representations were subsequently quantified by differential geometry methods in terms of the mean and Gaussian curvatures, surface areas, volumes, and membrane motifs, all of which can alter the metabolic output of the organelle. Finally, we identify structural motifs present across this population of mitochondria, which may contribute to future modeling studies of mitochondrial physiology and metabolism in neurons.

Supporting research, protecting data: one institution's approach to clinical data warehouse governance.

Institutions must decide how to manage the use of clinical data to support research while ensuring appropriate protections are in place. Questions about data use and sharing often go beyond what the Health Insurance Portability and Accountability Act of 1996 (HIPAA) considers. In this article, we describe our institution's governance model and approach. Common questions we consider include (1) Is a request limited to the minimum data necessary to carry the research forward? (2) What plans are there for sharing data externally?, and (3) What impact will the proposed use of data have on patients and the institution? In 2020, 302 of the 319 requests reviewed were approved. The majority of requests were approved in less than 2 weeks, with few or no stipulations. For the remaining requests, the governance committee works with researchers to find solutions to meet their needs while also addressing our collective goal of protecting patients.

Feedforward Thalamocortical Connectivity Preserves Stimulus Timing Information in Sensory Pathways.

Reliable timing of cortical spikes in response to visual events is crucial in representing visual inputs to the brain. Spikes in the primary visual cortex (V1) need to occur at the same time within a repeated visual stimulus. Two classical mechanisms are employed by the cortex to enhance reliable timing. First, cortical neurons respond reliably to a restricted set of stimuli through their preference for certain patterns of membrane potential due to their intrinsic properties. Second, intracortical networking of excitatory and inhibitory neurons induces lateral inhibition that, through the timing and strength of IPSCs and EPSCs, produces sparse and reliably timed cortical neuron spike trains to be transmitted downstream. Here, we describe a third mechanism that, through preferential thalamocortical synaptic connectivity, enhances the trial-to-trial timing precision of cortical spikes in the presence of spike train variability within each trial that is introduced between LGN neurons in the retino-thalamic pathway. Applying experimentally recorded LGN spike trains from the anesthetized cat to a detailed model of a spiny stellate V1 neuron, we found that output spike timing precision improved with increasing numbers of convergent LGN inputs. The improvement was consistent with the predicted proportionality of [Formula: see text] for n LGN source neurons. We also found connectivity configurations that maximize reliability and that generate V1 cell output spike trains quantitatively similar to the experimental recordings. Our findings suggest a general principle, namely intra-trial variability among converging inputs, that increases stimulus response precision and is widely applicable to synaptically connected spiking neurons.SIGNIFICANCE STATEMENT The early visual pathway of the cat is favorable for studying the effects of trial-to-trial variability of synaptic inputs and intra-trial variability of thalamocortical connectivity on information transmission into the visual cortex. We have used a detailed model to show that there are preferred combinations of the number of thalamic afferents and the number of synapses per afferent that maximize the output reliability and spike-timing precision of cortical neurons. This provides additional insights into how synchrony in thalamic spike trains can reduce trial-to-trial variability to produce highly reliable reporting of sensory events to the cortex. The same principles may apply to other converging pathways where temporally jittered spike trains can reliably drive the downstream neuron and improve temporal precision.

Synchrony of thalamocortical inputs maximizes cortical reliability.

Thalamic inputs strongly drive neurons in the primary visual cortex, even though these neurons constitute only approximately 5% of the synapses on layer 4 spiny stellate simple cells. We modeled the feedforward excitatory and inhibitory inputs to these cells based on in vivo recordings in cats, and we found that the reliability of spike transmission increased steeply between 20 and 40 synchronous thalamic inputs in a time window of 5 milliseconds, when the reliability per spike was most energetically efficient. The optimal range of synchronous inputs was influenced by the balance of background excitation and inhibition in the cortex, which could gate the flow of information into the cortex. Ensuring reliable transmission by spike synchrony in small populations of neurons may be a general principle of cortical function.

The STAR*D study: treating depression in the real world.

The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study evaluated feasible treatment strategies to improve clinical outcomes for real-world patients with treatment-resistant depression. Although the study found no clear-cut "winner", it does provide guidance on how to start therapy and how to proceed if initial treatment fails.

Major depression symptoms in primary care and psychiatric care settings: a cross-sectional analysis.

PURPOSE: We undertook a study to confirm and extend preliminary findings that participants with major depressive disorder (MDD) in primary care and specialty care settings have with equivalent degrees of depression severity and an indistinguishable constellation of symptoms. METHODS: Baseline data were collected for a distinct validation cohort of 2,541 participants (42% primary care) from 14 US regional centers comprised of 41 clinic sites (18 primary care, 23 specialty care). Participants met broadly inclusive eligibility criteria requiring a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of MDD and a minimum depressive symptom score on the 17-item Hamilton Rating Scale for Depression. The main outcome measures were the 30-item Inventory of Depressive Symptomatology--Clinician Rated and the Psychiatric Diagnostic Screening Questionnaire. RESULTS: Primary care and specialty care participants had identical levels of moderately severe depression and identical distributions of depressive severity scores. Both primary care and specialty care participants showed considerable suicide risk, with specialty care participants even more likely to report prior suicide attempts. Core depressive symptoms or concurrent psychiatric disorders were not substantially different between settings. One half of participants in each setting had an anxiety disorder (48.6% primary care vs 51.6% specialty care, P = .143), with social phobia being the most common (25.3% primary care vs 32.1% specialty care, P = .002). CONCLUSIONS: For outpatients with nonpsychotic MDD, depressive symptoms and severity vary little between primary care and specialty care settings. In this large, broadly inclusive US sample, the risk factors for chronic and recurrent depressive illness were frequently present, highlighting a clear risk for treatment resistance and the need for aggressive management strategies in both settings.

A direct comparison of presenting characteristics of depressed outpatients from primary vs. specialty care settings: preliminary findings from the STAR*D clinical trial.

PURPOSE: No study has directly compared the clinical features of depression for patients entering clinical trials using identical enrollment criteria at primary care (PC) and specialty care (SC) settings. The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study (http://www.star-d.org) provides a unique opportunity to provide this comparison for patients with a major depressive disorder (MDD) requiring treatment. SUBJECTS AND METHODS: We report baseline data for the first 1500 patients enrolled in this trial involving 41 clinic sites (18 PC, 23 SC). Broadly inclusive eligibility criteria required that patients have a DSM-IV diagnosis of nonpsychotic MDD, have not failed an adequate medication trial during their current episode and score>or=14 on the 17-item Hamilton Rating Scale for Depression (HAM-D17). Primary outcomes included the 30-item Inventory of Depressive Symptomatology-Clinician-Rated (IDS-C30) and the HAM-D17. RESULTS: Specialty care and PC patients had equivalent degrees of depressive severity (IDS-C30=35.8; HAM-D17=20.4). Specialty care patients were almost twice as likely to report a prior suicide attempt than PC patients (21% vs. 12%, P<.0001) and slightly less likely to endorse suicidal ideation in the past week (45.0% vs. 50.8%, P=.006). The only other distinguishing core symptoms were a slightly lower likelihood of PC patients endorsing depressed mood (95.2% vs. 97.7%, P=.032) or anhedonia (66.3% vs. 70.7%, P=.042, IDS-C30) and a lower likelihood of PC patients endorsing weight loss (IDS-C30). HAM-D17 results were identical. CONCLUSION: Depressive severity was not different, and symptomatic presentations did not differ substantially. Major depressive disorder is more similar than different among patients at SC and PC settings. Thus, similar clinical and research methods for screening, detecting and measuring treatment outcomes can be applied in both settings.

Chloroplasts in Living Cells and the String-of-Grana Concept of Chloroplast Structure Revisited.

In 1980, Wildman et al. (Bot Gaz 141: 24-36) proposed a three-dimensional model for chloroplast structure whereby the grana were arranged in non-overlapping rows, like beads on a string. This string-of-grana model was developed from phase microscope analysis of living cells and partially disrupted, isolated chloroplasts. However, models based on analyses by various electron microscope (EM) techniques (which inevitably encompass a relatively small fraction of the whole chloroplast) indicated that grana are interconnected in all directions by intergranal lamellae and not just along a single 'string.' Hence the string-of-grana model was not widely accepted. Recently, confocal laser scanning microscopy (CLSM) of both living and fixed cells, which gives views of the three-dimensional disposition of grana by imaging Photosystem II fluorescence over much larger sample volumes, that is, the entire chloroplast, has revealed that, although many grana are apparently not in any discernible arrangement, some are indeed present in strings of varying lengths in a range of taxa. The topic therefore warrants revisiting, using techniques, for example, such as EM tomography to assess the degree of variation in the geometry of intergranal connections in whole chloroplasts, and its possible functional consequences and developmental origins.

Changes in methylation during progressive transcriptional silencing in transgenic subterranean clover.

A transgenic line of subterranean clover (Trifolium subterraneum) containing a gene for a sulphur-rich sunflower seed albumin (ssa gene) and a gene conferring tolerance to the herbicide phosphinothricin (bar gene) was previously shown to stably express these genes as far as the T3 generation. In subsequent generations there was a progressive decline in the level of expression of both of these genes such that, by the T7 generation, the plants were almost completely susceptible to the herbicide and the mean level of sunflower seed albumin was reduced to 10-30% of the level in the T2 and T3 generations. The decline in SSA protein correlated closely with a decline in the level of ssa RNA. In vitro transcription experiments with nuclei isolated from plants of the early and late generations showed that the reduced mRNA level was associated with a reduced level of transcription of the ssa transgene. Transcription of the bar transgene was also reduced in the late generations. Bisulphite sequencing analysis showed that the decline in expression of the ssa gene between T3 and subsequent generations correlated closely with increased CpG methylation in the promoter, but not in the coding region. Analysis of the bar gene promoter showed that high levels of CpG methylation preceded the first detectable decline in expression of the bar gene by one generation, suggesting that methylation was not the direct cause of transgene silencing in these plants.