August 2021

Peter M. Klein, Yasaman Alaghband, Ngoc-Lien Doan, Ning Ru, Olivia G. G. Drayson, Janet E. Baulch, Enikö A. Kramár, Marcelo A. Wood, Ivan Soltesz, Charles L. Limoli. International Journal of Molecular Sciences. 2021 Aug 21. doi: 10.3390/ijms22169020

A recognized risk of long-duration space travel arises from the elevated exposure astronauts face from galactic cosmic radiation (GCR), which is composed of a diverse array of energetic particles. There is now abundant evidence that exposures to many different charged particle GCR components within acute time frames are sufficient to induce central nervous system deficits that span from the molecular to the whole animal behavioral scale. Enhanced spacecraft shielding can lessen exposures to charged particle GCR components, but may conversely elevate neutron radiation levels. We previously observed that space-relevant neutron radiation doses, chronically delivered at dose-rates expected during planned human exploratory missions, can disrupt hippocampal neuronal excitability, perturb network long-term potentiation and negatively impact cognitive behavior. We have now determined that acute exposures to similar low doses (18 cGy) of neutron radiation can also lead to suppressed hippocampal synaptic signaling, as well as decreased learning and memory performance in male mice. Our results demonstrate that similar nervous system hazards arise from neutron irradiation regardless of the exposure time course. While not always in an identical manner, neutron irradiation disrupts many of the same central nervous system elements as acute charged particle GCR exposures. The risks arising from neutron irradiation are therefore important to consider when determining the overall hazards astronauts will face from the space radiation environment.

Darian Hadjiabadi, Matthew Lovett-Barron, Ivan Georgiev Raikov, Fraser T. Sparks, Zhenrui Liao, Scott C. Baraban, Jure Leskovec, Attila Losonczy, Karl Deisseroth, Ivan Soltesz. Neuron, 2021 Jun 30. doi: 10.1016/j.neuron.2021.06.007. Online ahead of print.

Neurological and psychiatric disorders are associated with pathological neural dynamics. The fundamental connectivity patterns of cell-cell communication networks that enable pathological dynamics to emerge remain unknown. Here, we studied epileptic circuits using a newly developed computational pipeline that leveraged single-cell calcium imaging of larval zebrafish and chronically epileptic mice, biologically constrained effective connectivity modeling, and higher-order motif-focused network analysis. We uncovered a novel functional cell type that preferentially emerged in the preseizure state, the superhub, that was unusually richly connected to the rest of the network through feedforward motifs, critically enhancing downstream excitation. Perturbation simulations indicated that disconnecting superhubs was significantly more effective in stabilizing epileptic circuits than disconnecting hub cells that were defined traditionally by connection count. In the dentate gyrus of chronically epileptic mice, superhubs were predominately modeled adult-born granule cells. Collectively, these results predict a new maximally selective and minimally invasive cellular target for seizure control.

Jordan S Farrell, Roberto Colangeli, Ao Dong, Antis G George, Kwaku Addo-Osafo, Philip J Kingsley, Maria Morena, Marshal D Wolff, Barna Dudok, Kaikai He, Toni A Patrick, Keith A Sharkey, Sachin Patel, Lawrence J Marnett, Matthew N Hill, Yulong Li, G Campbell Teskey, Ivan Soltesz. Neuron. 2021 Aug 4. doi: 10.1016/j.neuron.2021.05.026.

The brain’s endocannabinoid system is a powerful controller of neurotransmitter release, shaping synaptic communication under physiological and pathological conditions. However, our understanding of endocannabinoid signaling in vivo is limited by the inability to measure their changes at timescales commensurate with the high lability of lipid signals, leaving fundamental questions of whether, how, and which endocannabinoids fluctuate with neural activity unresolved. Using novel imaging approaches in awake behaving mice, we now demonstrate that the endocannabinoid 2-arachidonoylglycerol, not anandamide, is dynamically coupled to hippocampal neural activity with high spatiotemporal specificity. Furthermore, we show that seizures amplify the physiological endocannabinoid increase by orders of magnitude and drive the downstream synthesis of vasoactive prostaglandins that culminate in a prolonged stroke-like event. These results shed new light on normal and pathological endocannabinoid signaling in vivo.