Research

The focus of our lab is on GABA and glutamate ligand-gated channels at the inhibitory and excitatory synapses relevant to the understanding of mechanisms of synaptic plasticity and the plasticity of disease . Over the years we have utilized many techniques and animal models. This includes classical slice electrophysiology, calcium imaging, immunhistochemistry, and behavior. We have primarily focused on GABAergic and glutamatergic neurons in various brain area including brainstem, cortex and hippocampus. The main projects currently in the lab currently are as follows:

GABAergic connectivity within the DorsoVagal Complex

Our studies with Dr Niaz Sahibzada, focus on the major brain nuclei of this circuit that form the dorsal vagal complex (DVC) in the hindbrain, namely the medial nucleus tractus solitarius (mNTS) and dorsal motor nucleus of the vagus (DMV), indicate that GABA and glutamate signaling from specific local neurons in these nuclei is critical for modulation of vagal output to the stomach. However, the identity of the the neurons to which this inhibitory signaling can be attributed is lacking. Recent advances in transgenic mouse models, virus injection and optogenetic techniques have made it possible to isolate and selectively stimulate specific cell types. Using these technologies, we have begun to acquire nascent data on the identity and role of the neurons involved in signaling in the DVC.

Synaptic Plasticity Deficits in Alzheimer's Disease

Homeostasis of neuronal activity is an important mechanism to prevent extremes in excitation or inhibition. Such mechanisms operate by negative feedback control to adjust neuronal activity to the desired optimum level. Many neurological disorders are associated with brain deviations from normal range of activity. Our collaborator Dr Daniel Pak hypothesize that impaired homeostatic control may be the cause of various neurological disorders including epilepsy and Alzheimer's Disease. These disorders, in particular, exhibit hyperexcitation during pathogenesis- a key characteristic of impaired homeostatic regulation. Amyloid precursor protein is a critical protein in Alzheimer's Disease, but it's physiological and pathological roles on synaptic function are still poorly understood. We are investigating the effect of specific APP phosphorylation sites on synaptic plasticity in primary culture and novel knock-in mice.

Sharp wave ripples and perineuronal nets.

Synchronous neuronal events known as sharp wave ripples (SWRs) have a critical role in memory consolidation, and are critically regulated by the activity of parvalbumin-expressing (PV) inhibitory interneurons. PV interneurons are unique in that they are the major neuronal subtype ensheathed in perineuronal nets (PNNs), components of the extracellular matrix that support and regulate cellular activity. In collaboration with Dr Katherine Conant and Dr Jian young Wu we are investigating the dysregulation of SWRs, PV cells, and the PNNs that surround them via electrophysiology, immunohistochemistry, calcium imaging, and computational modeling.

Microglia morphology and motility

Microglia, the resident macrophages of the CNS, play a central role in the neuroinflammatory response that characteristic of many brain disorders. A specific pattern of changes in microglial physiology, motility and morphology have been described in the animal model of Alzheimer's Disease. In collaboration with Dr William Rebeck we aim to further characterize morphology and the microglial motility response to ATP in brain slices of d APOE knock-in mice, which express the human APOE alleles under the endogenous mouse APOE promote.

Alterations of synaptic plasticity after neonatal anticonvulsant exposure

Seizures in neonates are a common occurrence after hypoxia (or hypoxia-ischemia); these seizures are typically aggressively treated with anticonvulsant drugs. Hypoxia-induced seizures are associated with a profound increase in risk for later-in-life seizures, as well as significant developmental delays and intellectual disabilities. The major goals of this project in collaboration with Dr Patrick Forcelli are to evaluate with local field potential and patch-clamp recordings from hippocampal neurons the effect on excitatory synaptic transmission and synaptic plasticity of hypoxia-induced seizures and the effect of most common anti-seizure drugs used in infants.

Synaptic adaptations consequent to high-frequency head impacts.

Repeated head impact exposure in athletes can cause memory and behavioral impairments. In collaboration with Dr Mark Burns we are studying in hippocampal neurons brain slices synaptic adaptation after exposure to non-damaging, but high frequency, head impacts that underlie changes to cognition. Our work use combination of electrophysiology and calcium imaging and focus on neurons identified to be part of memory engrams with parallel behavioral conditioning.