Browsing by Subject "Interneurons"
Now showing 1 - 2 of 2
Results Per Page
Sort Options
Item Optogenetic Investigation into the Role of Cerebellar Interneurons in Social Behavior(2021-02) Zhang, HaoAppropriate social behavior is vital for survival and developmental success of humans and animals. Impaired social behavior is a common symptom in mental illness. However, the neural basis underlying social behavior is not well understood. The cerebellum is classically recognized to be involved in motor control, but recently there has been an increasing appreciation of its role in cognitive and social functions. Human neuroimaging and postmortem studies have shown that cerebellar abnormalities, particularly in Purkinje neurons, are associated with neuropsychiatric disorders. Research using animal models suggests dysfunction of Purkinje neurons, which conduct the output from the entire cerebellar cortex, can generate abnormal social behavior. Yet, how the cerebellar dysfunction is transformed to global pathogenesis of social deficits remains unknown. In the cerebellar circuitry, the activity of Purkinje neurons is critically regulated by molecular layer interneurons (MLIs). In this study, we applied an optogenetic approach to selectively manipulate the excitability of MLIs using a mouse line with genetically encoded channelrhodopsin. By developing an optical stimulation protocol, we demonstrated that the cerebellum was critical for social recognition, which provides a mechanistic insight for the cerebellum-mediated neuropsychiatric disorders.Item The Potential to Generate Exogenic Interneurons for Alzheimer’s Disease via Blastocyst Complementation(2022-12) Johnson, SetherAlzheimer’s disease (AD) currently affects millions of patients worldwide, and to date the development of effective therapies has been slow. In AD, numerous types of neural cells become dysfunctional and are susceptible to degeneration, leading to cognitive deficits. One particular cell type affected are GABAergic inhibitory interneurons. Normally, these cells function as modulators of neural circuits, and are associated with maintenance of network synchrony and oscillatory signaling important for memory encoding. Impairments in short term memory, electrophysiological abnormalities such as neural hyperactivity and epileptiform spikes, and loss of interneurons are seen in AD patients and AD mouse models. These observations suggest that degeneration and dysfunction of interneurons contributes to cognitive deficits in AD. Thus, restoring interneuron activity is one potential approach to treat AD. The generation of exogenic interneurons via blastocyst complementation is one promising method to generate these cells. In this method, interspecies chimeras are created by genetic editing in a host blastocyst, which establishes a developmental niche to be filled during expansion of the progeny of donor pluripotent stem cells (PSCs) injected into the blastocyst. Blastocyst complementation has several advantages compared to in-vitro directed differentiation of stem cells, namely that development occurs in an in-vivo context. Thus, progenitor cells are exposed to all the inductive cues needed for differentiation to the appropriate cell phenotype of interest, and therefore may more faithfully recapitulate the intended cell-type specific gene networks and biomolecular characteristics of those cells. Studies have shown that this technique can be applied for CNS tissues including specific brain regions. Specifically, previous work from the Low Lab at the University of Minnesota has shown that targeting the homeobox gene HHEX establishes a niche for the formation of various organs from donor cells including liver, pancreas, and brain (Ruiz-Estevez et al., 2021). HHEX may be a viable target gene for the generation of exogenic interneurons as previous work has indicated that knockout of HHEX impairs development of the medial ganglionic eminence (MGE), a developmental structure enriched in GABAergic interneuron progenitors (Martinez-Barbera et al., 2000). In addition, many studies have demonstrated that engraftment of MGE cells can reduce cognitive and electrophysiological deficits in AD mouse models. This suggests that the transplant of exogenic interneurons may be a feasible strategy to restore interneuron activity and reduce cognitive deficits in AD. While the generation of human-animal brain chimeras is controversial, recent surveys indicate the public is amenable to the concept for research and therapeutic use (Crane et al., 2020). Thus, future translation of this approach using human-porcine chimeras may provide exogenic human interneurons to treat AD patients. This thesis will describe the scientific background and rationale for exogenic interneuron generation by HHEX KO/blastocyst complementation as a potential approach to treat AD. It will also show preliminary analysis of HHEX KO/complemented mice, and show testing of a primary antibody for Lhx6 in wild type mouse tissue prior to the antibody being used to search for donor-derived interneuron progenitors in chimeras.