Research

Research

Goal

Our laboratory focuses on the physiology of the thalamic circuit, more specifically the interaction among neurons and glia, in sensory perception of a normal and diseased brain, so that we may better understand the function of glia and neurons to integrate the information in the brain and expand our knowledge of how sensory perception occurs in the normal and diseased states.

Our main goal is to identify mechanisms of glial modulation of tonic GABA in the thalamus and its function involved in physiology and behaviors.

Approaches

We utilize multidisciplinary approach in genetic and pharmacological animal models with integrating the molecular/cellular approaches and systems neuroscience. The main approach tools are as follows:

  • - Animal models: Mouse genetics is being used to express or suppress particular molecules to analyze the function of the gene.
  • - Molecular biology: single cell RNA sequencing, optogenetics and chemogenetics
  • - Electrophysiology: in vitro and ex vivo patch-clamp recording, in vivo single-unit, local filed potential and EEG/EMG recordings
  • - Computational modeling
  • - Function and Anatomical imaging: in vivo calcium imaging, confocal and epifluorescence microscopy
  • - Animal Behavior: Mouse behavior tests for sensory/motor function, learning and memory, mood, and sociability, and sleep

Ongoing Projects

1. Thalamo-cortico-thalamic network connectivity

Thalamus, located in the center of the brain, is the hub for receiving and sending sensory information and the center for the brain rhythm generation. It consists of multiple subnuclei, which have divergent connection with other brain regions, and however, large part of its connectivity are still unknown.

We are currently working on tracing the connectivity of the thalamic reticular nucleus, which is mostly composed of GABAergic neurons, with other brain regions by using rabies virus injection into Cre-recombinase mouse model for retrograde tracing in order to investigate the neuronal circuitry of thalamic modulation in the brain function.

2. Glia-Neuron and Glia-Glia interaction in Thalamus

Glia cells and neurons interact to support normal communications including sensory information processing and perception in the thalamus.

We recently reported that astrocytes synthesize and release tonic GABA, whose increase enhanced the temporal fidelity of neuronal responses to distinguish inputs in the thalamus thus improving tactile discriminability in mice.

Thus, we hypothesized that the glial network consisting of multiple cell types plays a pivotal role in mediating tonic GABA and tuning thalamic sensory processing, specifically by dynamically regulating the synaptic integration and membrane properties of thalamocortical neurons.

In order to identify thalamic glial network and its role in tonic GABA, we are using glia specific Ca2+ sensors and measuring tonic GABA currents in the thalamus with patch-clamp technique.

3. Thalamic control of Sensory perception and Consciousness

Neuronal representation of sensory input in the thalamus is not well understood when compared to those in the cortex.

To elucidate how the neurons and glia represent sensory features in the thalamus, we study the thalamic representation of sensory information by measuring glia and neuronal activities in vivo with behavioral consequences, which can demonstrate the thalamic contribution to sensory perception.

4. Pathophysiology of Thalamus in Neurodegenerative Disease

Alzheimer’s disease is a progressive neurological disorder with memory loss, and its pathogenesis has been attributed to extracellular aggregates of amyloid beta, intracellular neurofibrillary tangles made of hyperphosphorylated tau protein, and inflammation in the cortex and hippocampus.

Notably, thalamus is important in memory and attention, and its pathology has been involved in the early stage of AD. However, pathophysiology of thalamus in AD remains largely unknown.

We are currently investigating amyloid beta and tau pathology, synaptic changes and neuroinflammation involved in glial function in the thalamus by using mouse models of AD.

We are also working on identifying biomarkers and finding therapeutic targets of AD.

5. Neuroinflammation

Neuroinflammation has been attributed to cognitive dysfunction including memory deficits, and thus, it is involved in potential pathogenesis of neurological disorders including dementia and delirium.

Thalamocortical circuits play a pivotal role in cognitive functions and has been implicated in pathological condition in such neurological disorder.

However, how neuroinflammation alters thalamocoritcal circuits to cause cognitive deficits is not yet clearly understood.

We are studying glial and neuronal modifications by inflammasome-dependent neuroinflammation in the thalamocortical circuits in animal models of dementia and delirium at the cellular, circuits and behavioral levels.

6. Stress and depression

Stress is generally defined as any stimulus that disrupts physiological, biological, or psychological body’s balance.

According to the type, timing, and severity of the stressors, stress could lead to an increased risk of many diseases, including cardiovascular diseases, autoimmune diseases, and psychiatric disorders.

Although major depressive disorder (MDD) is one of the most common mental diseases caused by stress, the mechanism is not clear.

Therefore, we have studied the behavioral, molecular, and electrophysiological changes in the mice models, such as acute/chronic restraint stressed model and learned helplessness model, to find out the mechanism of depression.