Jordan S. Farrell received a K99/R00 Career Development Award, entitled “Dissecting hypothalamic pathways for seizure control”.
December 17, 2021
Farrell JS, Lovett-Barron M, Klein PM, Sparks FT, Gschwind T, Ortiz AL, Ahanonu B, Bradbury S, Terada S, Oijala M, Hwaun E, Dudok B, Szabo G, Schnitzer MJ, Deisseroth K, Losonczy A, Soltesz I. Science, 2021, Dec 16. Vol 374, Issue 6574, pp. 1492-1496, DOI: 10.1126/science.abh4272.
Locomotor speed is a basic input used to calculate one’s position, but where this signal comes from is unclear. We identified neurons in the supramammillary nucleus (SuM) of the rodent hypothalamus that were highly correlated with future locomotor speed and reliably drove locomotion when activated. Robust locomotion control was specifically identified in Tac1 (substance P)–expressing (SuMTac1+) neurons, the activation of which selectively controlled the activity of speed-modulated hippocampal neurons. By contrast, Tac1-deficient (SuMTac1−) cells weakly regulated locomotion but potently controlled the spike timing of hippocampal neurons and were sufficient to entrain local network oscillations. These findings emphasize that the SuM not only regulates basic locomotor activity but also selectively shapes hippocampal neural activity in a manner that may support spatial navigation.
Barna Dudok, Miklos Szoboszlay, Anirban Paul, Peter M. Klein, Zhenrui Liao, Ernie Hwaun, Gergely G. Szabo, Tristan Geiller, Bert Vancura, Bor-Shuen Wang, Sam McKenzie, Jesslyn Homidan, Lianne M.F. Klaver, Daniel F. English, Z. Josh Huang, György Buzsáki, Attila Losonczy, Ivan Soltesz. Neuron. 2021 Oct 13. doi: 10.1016/j.neuron.2021.09.033.
The axon initial segment of hippocampal pyramidal cells is a key subcellular compartment for action potential generation, under GABAergic control by the “chandelier” or axo-axonic cells (AACs). Although AACs are the only cellular source of GABA targeting the initial segment, their in vivo activity patterns and influence over pyramidal cell dynamics are not well understood. We achieved cell-type-specific genetic access to AACs in mice and show that AACs in the hippocampal area CA1 are synchronously activated by episodes of locomotion or whisking during rest. Bidirectional intervention experiments in head-restrained mice performing a random foraging task revealed that AACs inhibit CA1 pyramidal cells, indicating that the effect of GABA on the initial segments in the hippocampus is inhibitory in vivo. Finally, optogenetic inhibition of AACs at specific track locations induced remapping of pyramidal cell place fields. These results demonstrate brain-state-specific dynamics of a critical inhibitory controller of cortical circuits.
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.
We are excited to announce that our graduate student Darian Hadjiabadi was awarded by the American Epilepsy Society with the AES Early Career Fellowship. Darian will be investigating the cellular pathways underlying pathological high-frequency oscillations during his pre-doctoral research fellowship.
Quynh Anh Nguyen received a K99/R00 Career Development Award, entitled “Neural circuit mechanisms controlling seizures”. Quynh Anh will utilize recently developed molecular and optogenetic tools to identify and study neuronal circuits active during seizures in mouse models of temporal lobe epilepsy.
We are pleased to announce that Dr. Ernie Hwaun has been awarded with the 2021 Interdisciplinary Scholar Award from the Wu Tsai Neurosciences Institute. The promising young postdoctoral researchers of this Interdisciplinary Scholar Award come from the schools of Medicine, Engineering, Education and Humanities & Sciences, and stand out for their drive to challenge themselves and the traditional boundaries of their field. The postdoctoral Interdisciplinary Scholar Awards include a two-year fellowship, career development and funds for experiments or travel. The newest scholars join thirty previous fellowship recipients including alumni who have made important advances in the neurosciences and gone on to careers in academia, industry, nonprofit and government organizations.
Ernie Hwaun is currently a postdoctoral fellow in Dr. Soltesz Lab. Ernie received his Bachelor of Science in Physiology & Neuroscience and Master of Science in Biology from the University of California, San Diego. He then moved to the University of Texas at Austin to pursue PhD in Neuroscience. In his doctoral studies, Ernie investigated how rodents acquire memory of new locations during awake behaviors and subsequent sleep. As a postdoctoral researcher in the Soltesz lab at Stanford, he has been investigating the distinct roles of key inhibitory cell types in normal and abnormal circuit functions in mice. To explore whether neural mechanisms that support spatial memory in mammals also exist in invertebrates, Ernie has turned to octopuses, which possess the most advanced nervous system among invertebrates, with the ability to learn and navigate in open water. In collaboration with Prof. Zhenan Bao’s laboratory in the Department of Chemical Engineering, Ernie plans to employ new soft-material probes suitable to collect neural signals from behaving octopuses. With these new tools, he aims to gain insights into common fundamental neuronal mechanisms underlying spatial navigation in evolutionarily distant species living in markedly different natural environments.