| 2016 — 2017 |
Medina, Javier F |
R21Activity Code Description:
To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Targets of Low Dose Alcohol During Cerebellar-Driven Behavior in Mice @ Baylor College of Medicine
PROJECT SUMMARY Cerebellar neurons are among the most sensitive targets of alcohol in the nervous system. At concentrations just above the legal limit for driving in the United States (>17mM BAC), alcohol causes cerebellar dysfunction, leading to impairments in gait, balance and motor coordination that are responsible for thousands of injuries and deaths every year. There is also evidence from electrophysiology experiments in cerebellar slices that at lower concentrations (<10mM), alcohol alters the function of multiple neurons in the cerebellum. However, our understanding of the action of low doses of alcohol in the cerebellum is still in its infancy. A critical barrier to progress in the field has been to understand how the effects of low dose alcohol observed in vitro translate to the unanesthetized animal and lead to impaired function during cerebellar-driven behaviors. The goal of this proposal is to overcome this prior limitation, by being the first to measure the impact of low doses of alcohol in the cerebellum of behaving mice. Mice will be trained in cerebellum-dependent eyeblink conditioning because our preliminary data indicates that low doses of alcohol (<5mM BAC) impair performance in this task. Our general strategy is to search for cell-specific targets of low dose alcohol during eyeblink conditioning, by recording and manipulating the activity of cerebellar circuits at three different stages of processing: the output stage, processed by neurons of the interpositus nucleus (specific aim 1), the intermediate stage, processed by Purkinje cells (specific aim 2), and the input stage, processed by granule cells (specific aim 3). The proposed experiments will break new ground and advance the field substantially: By combining the simplicity of eyeblink conditioning with new technologies for optogenetics, electrophysiology, and two-photon calcium imaging, this project will provide a first look at the mechanistic links between low dose alcohol, the cerebellum, and behavior.
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| 2017 |
Medina, Javier F |
RF1Activity Code Description:
To support a discrete, specific, circumscribed project to be performed by the named investigator(s) in an area representing specific interest and competencies based on the mission of the agency, using standard peer review criteria. This is the multi-year funded equivalent of the R01 but can be used also for multi-year funding of other research project grants such as R03, R21 as appropriate. |
The Impact of Cerebellar Tdcs in Local and Downstream Brain Circuits: How Much Is Neuralactivity Modulated in the Resting State and During Sensorimotor Processing? @ Baylor College of Medicine
PROJECT SUMMARY Non-invasive stimulation of the cerebellum holds great promise for investigating brain function, and for diagnosing and treating a variety of brain disorders. Given the classical role of the cerebellum in motor control, it is not surprising that many studies have reported that cerebellar transcranial direct current stimulation (CB- tDCS) can be used to enhance motor function and mitigate the symptoms of ataxia, dystonia and essential tremor. More recent studies have shown that CB-tDCS can modulate cognitive function as well, including working memory and emotional processing. Despite the great success that CB-tDCS has enjoyed in the last 15 years, we know very little about the way it works. The goal of this proposal is to fill this gap in knowledge by measuring for the first time the impact that CB-tDCS has on the activity of neurons in different regions of the brain. Mice will be used, and the polarity (anodal or cathodal) and the intensity of the stimulation will be systematically varied to determine the dose/response relationship between CB-tDCS and neural activity. To help translate the results to the human brain, the stimulation doses will be comparable to those that have been applied in clinical studies. In addition, the responses of neurons to CB-tDCS will be examined under different physiological states, including during rest as well as during sensory processing and motor performance. The experiments will take advantage of powerful genetic strategies to target specific neural populations, and to manipulate and record their activity with an unprecedented level of spatial and temporal resolution. The general plan is to start by assessing the local effects of CB-tDCS in the cerebellar cortex, and gradually move downstream, first to neurons in the deep cerebellar nucleus, and then to other regions of the brain that are connected to the cerebellum. The results of these experiments will provide critical information to help optimize the use of CB-tDCS for neuroscience research as well as for clinical application.
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