Authors :
Presenting Author: Yang Zheng, MD, PhD – Yale
Jiayang Liu, PhD – Yale University
Jessey Li, BS – Yale University
Samiksha Chopra, BS – Yale University
Taruna Yadav, PhD – Yale School of Medicine
Stefan Sumsky, PhD – Yale University School of Medicine
Hal Blumenfeld, MD, PhD – Yale University
Rationale:
Focal limbic seizures exert widespread effects on cortical function and frequently result in loss of consciousness, a debilitating issue for epilepsy patients. The mechanisms by which focal seizures from the hippocampus lead to impaired consciousness are unresolved. Ventral tegmental area (VTA), a region rich in dopaminergic (DA) neurons, promotes arousal in normal conditions and has decreased connectivity in patients with temporal lobe epilepsy. Nevertheless, the role of dopaminergic neurons in the VTA (VTADA) in impaired consciousness during seizures remains unknown.Methods:
We recently developed a novel awake mouse model of focal limbic seizures with reduced cortical electrophysiological and behavioral arousal. Local field potentials were recorded from the hippocampus and the orbitofrontal cortex. To assess behavioral arousal during seizures, we measured licking responses to auditory stimuli and wheel-running speed. We first recorded multiunit activity in the VTA during seizures while simultaneously evaluating arousal. We then measured calcium dynamics in VTADA using fiber photometry in DAT-Cre mice experiencing focal limbic seizures with impaired arousal. Additionally, we recorded dopamine levels in the medial or orbitofrontal cortex with genetically encoded DA sensors using fiber photometry during seizures. Results:
During focal limbic seizures with impaired arousal, we observed overall decreased licking responses and running wheel speed, and increased slow wave activity in the orbitofrontal cortex. Overall neuronal firing rates were reduced in VTA (n = 6 seizures from 6 mice). However, spike sorting revealed a divergence in activity: putative DA neurons exhibited increased firing, whereas putative non-DA neurons showed decreased firing. Fiber photometry recordings demonstrated elevated calcium activity in VTADA (n = 14 seizures from 5 mice), and a selective increase in dopamine levels in the medial prefrontal cortex during seizures (n = 8 seizures from 3 mice).
Conclusions:
Our findings reveal apparently paradoxical increases in VTADA and their medial prefrontal cortical projections during focal limbic seizures. Ongoing work in the orbitofrontal cortex, where we observed slow wave activity consistent with decreased arousal, may reveal the potential role of DA modulation of arousal in this network. Overall, our results highlight the significance of VTA neuromodulation in focal limbic seizures. With further work, modulation of this pathway may represent a promising therapeutic target for restoring consciousness during seizures.Funding:
This work was supported by NIH R01 NS066974.