Our laboratory is interested in elucidating the circuitry that drives behavior normally and in disease. We are currently focused on the somatosensory system, which detects touch, temperature and pain, basal ganglia circuits that shape motor output in Parkinson’s disease.
Somatosensory System: Understanding the neural basis of touch and pain.
One major effort of our laboratory is to study neural circuits underlying touch and pain. Our work in this area began with the observation that the vesicular glutamate transporter (VGLUT) 3 is required for mechanical allodynia (touch or movement becomes painful) as a result of nerve injury or inflammation (Seal et al, Nature, 2009). Although tactile allodynia is one of the most clinically relevant forms of pain, the mechanisms that generate and maintain it are still not well-understood nor are there efficacious, non-addictive treatment options. We recently reported that a population of neurons in the spinal cord dorsal horn are responsible for the defect in persistent pain in the VGLUT3 KO mice. (Peirs et al, Neuron, 2015). Our current interests are centered around the concept that while mechanical allodynia manifests as one main symptom (i.e. light touch/movement feels painful) the neural circuits that encode the pain differ depending on if the pain is evoked by indentation of the skin (static allodynia) or light brushing across the skin (dynamic allodynia) as well as by the type of injury (e.g. inflammatory or neuropathic insult). The laboratory has expertise in the creation of genetically modified mice and viruses, as well as in combining chemogenetics to activate or silence neuronal populations with behavior or with in vitro electrophysiology. We also use viral and functional circuit tracing strategies to map circuits within the dorsal horn, with primary sensory neurons and neurons in the brain.
Basal Ganglia Circuits: Mechanisms that shape motor output in Parkinson’s disease.
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 outlined here 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 the dopamine levels are abnormally elevated but throughout the circadian cycle, pointing to a more permanent form of plasticity. We are currently testing whether the preservation of motor function is due to the repeated, transient increase in striatal dopamine release and subsequent increase in immature spines on that occurs during the waking cycle. We hypothesize that during the depletion, these immature spines mature and that the increase in mature spines balances direct and indirect pathway output and normalizes motor function. Elevated dopamine signaling in the KO mice suggests a circuit that modulates dopamine neuron output. Our goals are to identify this circuit as well as the mechanisms that underlie normal motor function in the knockout mice after depletion. Both areas of investigation will provide important insights into basal ganglia circuits as well as open new avenues for therapeutic intervention into basal ganglia related disorders.
Auditory Circuits: Cochlear outer hair cell glutamate release.
Cochlear outer hair cells are important for normal hearing as they amplify sound transmitted through inner hair cells as well as sharpen the frequency-tuning curve. The electro-motility or movement of the hair cell in response to sound underlies these outer hair cell functions. Interestingly, like inner hair cells, outer hair cells also release vesicular glutamate. but the role of the glutamate signaling is not known. We are using genetic mouse models to study the role of glutamate signaling by these cells in hearing. We are also interested in the functional connectivity of outer hair cells to cochlear nucleus neurons. Mapping the connectivity will provide additional insight into function.