Liu Laboratory

The research in Liu lab is geared toward determining the mechanisms mediating functional recovery and neural plasticity following cerebral ischemia and brain trauma. Stroke remains the leading cause of long-term disability in the US. Ischemic brain injury is also a common endpoint of multiple disease states including stroke and traumatic brain injury (TBI). Although most stroke patients make some degree of recovery in weeks to months after the insult, it has become increasingly apparent that promoting recovery in the stroke patients requires appropriate rehabilitation therapy taxing available brain plasticity. The major focus of Dr. Liu's current work is to define mechanisms supporting endogenous neural regeneration following ischemic injury. Using rodent models of focal cerebral ischemia, her lab studies the functional recovery associated with the hippocampus, an area that is known to be involved in memory function but often spared in human stroke or in many rodent models of cerebral focal ischemia. The adult hippocampus is known to regenerate after cerebral ischemia by means of the neuroprogenitor cells located in the dentate gyrus. Ongoing have been carried out to investigate the role of neural regeneration in mediating functional recovery and ways to augment this regeneration by environmental enrichment and behavioral interventions. Other ongoing projects involve elucidating neurogenesis signaling events and pathways by using proteomic approaches including 2-D gel electrophoresis and tandem mass spectrometry.

Current Research Projects


Hippocampus

The resolution of hippocampal diaschisis after stroke
While motor impairment is a hallmark of ischemic stroke, the underlying mechanisms leading to cognitive dysfunction after cerebral ischemia remain unclear. The dysfunction of the hippocampus is reminiscent of the phenomenon of diaschisis, described by Von Monakow in 1914 as reduced cerebral function resulting from deafferentation or the interruption of normal input to a region not directly involved in the stroke. He speculated that recovery from a brain lesion may be caused at least partially by an attenuated depression of brain function in remote brain region suffered temporary loss of function and regained its original excitability during the course of recovery. Ongoing studies will address how focal stroke affects function in remote brain regions including the limbic structures and the beneficial effects of environmental enrichment (EE) as a rehabilitative therapy. In collaboration with Drs Philip R Weinstein (Neurosurgery, UCSF) and Gary Abrams (Neurology, UCSF), we will first map out the remote brain regions that are functionally impaired using activity-gene imaging techniques. We will then determine whether EE reduces limbic hypofunction caused by brain ischemia and whether EE enhances hippocampal synaptic transmission and excitability in processing spatial information in subjects with ischemic stroke. Lastly, we will determine whether hippocampal regeneration is involved in the resolution of hippocampal diaschisis.


Preventing neurodegeneration after TBI
TBI is a serious and disabling brain injury that frequently affects relatively young population in our society. One of the long-term neurological sequelae associated with TBI is memory dysfunction. Moreover, according to many epidemiological studies, head trauma is one of the most potent environmental risk factors for subsequent neurodegeneration including the development of Alzheimer’s disease. Interestingly, pathological features that are present also in Alzheimer’s disease, in particular the deposition of beta-amyloid protein, were observed in traumatized brains already a few hours after the initial insult. Ongoing studies will determine whether cognitive therapy reduces fibrillar aggregates or amyloid deposition, promotes cognitive function and enhances hippocampal regeneration in an experimental model of Alzheimer’s disease following TBI. This work is conducted in collaboration with Drs Linda Noble-Haeusslein (Neurosurgery, UCSF) and Holger Wille (Institute of Neurodegeneration, UCSF).


Neurogenesis signaling
The molecular pathways that govern neurogenesis are only beginning to emerge. Mammalian homeobox gene Emx family is involved in the development of the rostral brain. Although previous studies have established that the formation of the dentate gyrus (DG) requires Emx2, we found that the adult Emx1 mutants also exhibited a smaller DG, reduced number of proliferating progenitor cells and immature neurons in the DG. In an attempt to determine whether the attenuated hippocampal neurogenesis resulted from a reduced stem cell pool during development, we assayed the frequency of embryonic neural stem cells of Emx1 KO. We found that the deletion of Emx1 gene reduced the neural stem cell pool and this defect was not related to FGF signaling, since both wild type and KO neurospheres responded to FGF-2. Using a proteomic approach, we have compared the expression profile between the WT and KO neurosphere extracts by 2-D electrophoresis and tandem mass spec (MS/MS). We identified a number of proteins that were differentially expressed by the neurospheres between the two genotypes. We are conducting validating analysis to determine the role of these proteins in neurogenesis and the frequency of neurosphere formation.