CCR2+ monocytes promote white matter injury and cognitive dysfunction after myocardial infarction.

Survivors of myocardial infarction are at increased risk for vascular dementia. Neuroinflammation has been implicated in the pathogenesis of vascular dementia, yet little is known about the cellular and molecular mediators of neuroinflammation after myocardial infarction. Using a mouse model of myocardial infarction coupled with flow cytometric analyses and immunohistochemistry, we discovered increased monocyte abundance in the brain after myocardial infarction, which was associated with increases in brain-resident perivascular macrophages and microglia. Myeloid cell recruitment and activation was also observed in post-mortem brains of humans that died after myocardial infarction. Spatial and single cell transcriptomic profiling of brain-resident myeloid cells after experimental myocardial infarction revealed increased expression of monocyte chemoattractant proteins. In parallel, myocardial infarction increased crosstalk between brain-resident myeloid cells and oligodendrocytes, leading to neuroinflammation, white matter injury, and cognitive dysfunction. Inhibition of monocyte recruitment preserved white matter integrity and cognitive function, linking monocytes to neurodegeneration after myocardial infarction. Together, these preclinical and clinical results demonstrate that monocyte infiltration into the brain after myocardial infarction initiate neuropathological events that lead to vascular dementia.

Cellular mechanisms underlying carry-over effects after magnetic stimulation.

Magnetic fields are widely used for neuromodulation in clinical settings. The intended effect of magnetic stimulation is that neural activity resumes its pre-stimulation state right after stimulation. Many theoretical and experimental works have focused on the cellular and molecular basis of the acute neural response to magnetic field. However, effects of magnetic stimulation can still last after the termination of the magnetic stimulation (named "carry-over effects"), which could generate profound effects to the outcome of the stimulation. However, the cellular and molecular mechanisms of carry-over effects are largely unknown, which renders the neural modulation practice using magnetic stimulation unpredictable. Here, we investigated carry-over effects at the cellular level, using the combination of micro-magnetic stimulation (µMS), electrophysiology, and computation modeling. We found that high frequency magnetic stimulation could lead to immediate neural inhibition in ganglion neurons from Aplysia californica, as well as persistent, carry-over inhibition after withdrawing the magnetic stimulus. Carry-over effects were found in the neurons that fired action potentials under a variety of conditions. The carry-over effects were also observed in the neurons when the magnetic field was applied across the ganglion sheath. The state of the neuron, specifically synaptic input and membrane potential fluctuation, plays a significant role in generating the carry-over effects after magnetic stimulation. To elucidate the cellular mechanisms of such carry-over effects under magnetic stimulation, we simulated a single neuron under magnetic stimulation with multi-compartment modeling. The model successfully replicated the carry-over effects in the neuron, and revealed that the carry-over effect was due to the dysfunction of the ion channel dynamics that were responsible for the initiation and sustaining of membrane excitability. A virtual voltage-clamp experiment revealed a compromised Na conductance and enhanced K conductance post magnetic stimulation, rendering the neurons incapable of generating action potentials and, therefore, leading to the carry over effects. Finally, both simulation and experimental results demonstrated that the carry-over effects could be controlled by disturbing the membrane potential during the post-stimulus inhibition period. Delineating the cellular and ion channel mechanisms underlying carry-over effects could provide insights to the clinical outcomes in brain stimulation using TMS and other modalities. This research incentivizes the development of novel neural engineering or pharmacological approaches to better control the carry-over effects for optimized clinical outcomes.

Neuron matters: neuromodulation with electromagnetic stimulation must consider neurons as dynamic identities.

Neuromodulation with electromagnetic stimulation is widely used for the control of abnormal neural activity, and has been proven to be a valuable alternative to pharmacological tools for the treatment of many neurological diseases. Tremendous efforts have been focused on the design of the stimulation apparatus (i.e., electrodes and magnetic coils) that delivers the electric current to the neural tissue, and the optimization of the stimulation parameters. Less attention has been given to the complicated, dynamic properties of the neurons, and their context-dependent impact on the stimulation effects. This review focuses on the neuronal factors that influence the outcomes of electromagnetic stimulation in neuromodulation. Evidence from multiple levels (tissue, cellular, and single ion channel) are reviewed. Properties of the neural elements and their dynamic changes play a significant role in the outcome of electromagnetic stimulation. This angle of understanding yields a comprehensive perspective of neural activity during electrical neuromodulation, and provides insights in the design and development of novel stimulation technology.

Somatic amplifications and deletions in genome of papillary thyroid carcinomas.

Somatic gene copy number variation contributes to tumor progression. Using comparative genomic hybridization (CGH) array, the presence of genomic imbalances was evaluated in a series of 27 papillary thyroid carcinomas (PTCs). To detect only somatic imbalances, for each sample, the reference DNA was from normal thyroid tissue of the same patient. The presence of the BRAF V600E mutation was also evaluated. Both amplifications and deletions showed an uneven distribution along the entire PTC cohort; amplifications were more frequent than deletions (mean values of 17.5 and 7.2, respectively). Number of aberration events was not even among samples, the majority of them occurring only in a small fraction of PTCs. Most frequent amplifications were detected at regions 2q35, 4q26, and 4q34.1, containing FN1, PDE5A, and GALNTL6 genes, respectively. Most frequent deletions occurred at regions 6q25.2, containing OPMR1 and IPCEF1 genes and 7q14.2, containing AOAH and ELMO1 genes. Amplification of FN1 and PDE5A genomic regions was confirmed by quantitative PCR. Frequency of amplifications and deletions was in relationship with clinical features and BRAF mutation status of tumor. In fact, according to the American Joint Committee on Cancer stage and American Thyroid Association (ATA) risk classification, amplifications are more frequent in higher risk samples, while deletions tend to prevail in the lower risk tumors. Analysis of single aberrations according to the ATA risk grouping shows that amplifications containing PDE5A, GALNTL6, DHRS3, and DOCK9 genes are significantly more frequent in the intermediate/high risk group than in the low risk group. Thus, our data would indicate that analysis of somatic genome aberrations by CGH array can be useful to identify additional prognostic variables.