Studies of sensory and motor circuits in health and disease.

The Seal laboratory studies the neural circuitry that drives behavior in health and disease. Our work is focused on: 

1. identifying the neural circuits that mediate persistent forms of pain.  
2. plasticity mechanism that give rise to the motor symptoms of Parkinson’s disease. 

For both neurological problems, we are developing novel therapies.

Pain Circuits: Persistent pain remains a major clinical problem largely due to an incomplete understanding of the underlying neuronal circuits and mechanisms.  Our work in this area has focused on identifying the neurons required for mechanical allodynia, a condition in which touch becomes painful in the setting of injury (Peirs et al, Neuron, 2015, Seal and Peirs, Science 2016) as well as those that convey spontaneous pain using a combination of chemogenetics, viral tracing and behavior. As part of this effort, we are also working to uncover mechanisms of central sensitization that maintain persistent pain states using in vivo calcium imaging and slice electrophysiology. A second area of import is the study of cholecystokinin, the most common neuropeptide in the mammalian nervous system, which has been implicated in mechanical allodynia as well as in antagonizing the analgesic effects of morphine and in promoting morphine tolerance. We have generated mouse lines to dissect the neural circuitry underlying these therapeutically relevant signaling mechanisms. Since we are interested in using the information and tools that we have developed to intervene in the neural circuitry for therapeutic purposes, we have also embarked on a study of the cellular and molecular organization of the primate dorsal horn comparing to human and mouse using single cell transcriptome analysis, bioinformatics and in situ single cell sequencing.  Together these studies will provide important insights into how the nervous system transmits persistent pain and reveal novel treatment strategies. 

Basal Ganglia Circuits: Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which loss of dopamine leads to cognitive and motor impairments. Motor symptoms include resting tremor, rigidity, altered gait, and bradykinesia. The most effective treatment for PD is dopamine replacement therapy, which is currently the DA precursor, L-dopa. Continued use of this drug, however, results in decreased efficacy and dyskinesias. For these reasons, L-dopa is typically prescribed in the later stages of PD. Treatments that effectively mimic dopamine without causing dyskinesias would greatly improve the standard of care for PD. Studies in our laboratory take advantage our discovery that mice lacking VGLUT3 do not develop motor deficits in a model of Parkinson’s disease. The KO mice show increased synthesis, packaging and release of dopamine in the striatum during their waking cycle, but not during their sleep cycle. The density of immature spines on direct pathway MSNs is also increased only at night. Remarkably, motor function after dopamine depletion is normal not only during the waking cycle when dopamine levels are elevated but throughout the circadian cycle, pointing to a more permanent form of plasticity (Divito et al J. Neurosci, 2015, Brague et al, submitted 2020). Our work further indicates that the transient elevation of dopamine during the induction of PD, preserves the morphology and connectivity of direct pathway (go) medium spiny neurons, likely rebalancing the basal ganglia circuitry to produce normal movement. We are using chemogenetics, slice electrophysiology, 2-photon in vivo calcium imaging, single cell sequencing and functional circuit mapping to better understand the mechanisms that underlie this previously unappreciated form of plasticity and how it impacts the basal ganglia.  Ultimately, we would like to apply these findings therapeutically to stave off the debilitating motor symptoms of Parkinson’s disease and to determine if similar mechanisms apply to co-morbid non-motor symptoms, such as depression and cognitive disfunction.