Qiaojie Xiong, Ph.D. - US grants

Every day we make behavioral decisions based on our environment, in which the transformation of sensory information to motor command through learning and experience is essential. The behavior and neuronal mechanisms underlying the establishment of association between single sensory modality and motor decision are widely studied. However, many of decisions are made based on combined information from multiple sensory modalities. A few cross-modality studies showed that multiple sensory information significantly influenced the behavioral decisions that differs from single modality both in human and animals. Therefore, examining the behavior and neuronal mechanisms underlying how we learn to associate multiple sensory information to one motor decision will substantially advance our knowledge in sensory-cued decision making. Recent works including our own study have demonstrated that corticostriatal activity drives animal?s decision in an auditory frequency-discrimination task, and the plasticity pattern of these corticostriatal synapses encodes the learned associated between auditory cue and rewarded action. In the task, the animals learned to go to corresponding ports for reward based on different frequencies of the tones in the auditory cues. Interestingly, in these studies the navigation process between the end of auditory cues and the time that animals reached reward ports is largely ignored. In addition to the learning of auditory discrimination, the proper navigation to the ports is obviously an important learning part in this task. Therefore, we modified the task with a prolonged path between initiation port and reward port for better navigation analysis, and propose to examine how processes of spatial information and auditory information are coordinated during task learning. Hippocampus serves as an essential circuit unit to process spatial information. Our preliminary results indicated that the intact activity of hippocampal tri-synaptic circuit is required for learning this auditory task. To understand the functional role of hippocampal spatial coding for animal learning the auditory task, in aim I we will examine the role of spatial encoding in the learning of an auditory discrimination task. To understand how spatial information and auditory information processes are combined and coordinated during the task learning, in aim II we will dissect the circuit mechanism underlying the spatial coding in the learning of the auditory task.

Animals facing a decision routinely use sensory including auditory information from the outside world to guide optimal behavior. For example, we listen for instructions from the GPS when trying to take the best route to a destination. The dorsal striatum is a critical brain region in this sensory-guided decision-making process. The long-term goal of my laboratory is to understand the circuitry and mechanisms through which the dorsal striatum transforms auditory stimuli into appropriate actions. Anatomical studies have shown that individual neurons in the dorsal striatum receive convergent inputs from both the thalamus and the cortex. Previous studies in associative striatum (rostral dorsal striatum) suggest that these two input pathways play distinct roles in behaviors. Our studies in sensory striatum (caudal dorsal striatum) indicate that projections from both the auditory thalamus and the auditory cortex are required for decision-making in rodents performing an auditory frequency-discrimination task. The primary objective of this proposal is to determine how the auditory striatum integrates these thalamic and cortical inputs, and how this integration contributes to auditory frequency-discrimination decision-making and learning. The studies proposed address the fundamental hypothesis that both thalamic and cortical inputs contribute to auditory decision- making by differentially modulating striatal sound representations, and by shaping striatal synaptic plasticity during task learning. In Aim 1, we will determine how striatal sound representation is regulated by the thalamic and cortical inputs. We will use in vivo tetrode recording on awake mice to examine the responses of striatal neurons to pure tones while thalamic or cortical inputs are selectively silenced during stimulus presentation. In Aim 2, we will examine how striatal neurons integrate the thalamic and cortical inputs using whole-cell patch recording in brain slice combined with opto-genetic and pharmacological applications. In Aim 3, we will examine the development of thalamostriatal plasticity during task learning and test how thalamic input influences the learning-induced corticostriatal plasticity, using in vivo tetrode recording on behaving mice. The proposed experiments will determine how thalamostriatal and corticostriatal pathways regulate auditory striatal activity and plasticity, the physiological mechanisms underlying their functions in auditory decision-making. We focus on the auditory striatum in this study, but the findings may be generalized to the whole sensory striatum. These results will also contribute to the understanding of brain disorders like Parkinson?s and Huntington?s disease that involve differential changes of activity and plasticity at thalamostriatal and corticostriatal synapses.

With an ever-aging population and an estimated prevalence of Alzheimer disease of 5.7 million people in the United States alone, the impetus for more targeted treatments for age-related cognitive disorders is greater now than ever. Neuroplasticity, the ability of neural networks to adapt and remodel given experience, dwindles with age, providing possible mechanistic insights into this decline. An important layer of neuroplasticity, unique to a couple of discrete areas of the adult mammalian brain, is the addition of newly-generated neurons into existing circuits, a process known as neurogenesis. While the existence and importance of adult hippocampal neurogenesis in young adults has been well-established, we know very little about hippocampal neurogenesis in aging brains. Importantly, hippocampal neurogenesis continues into old age although there is a substantial decline in the number of newborn neurons. For example, in 26-month-old rodents, ~1000 proliferating cells could be detected per day, although only half that detected in 5-month-old adult rats. A recent study demonstrated that thousands of new neurons could be detected in the aged adult human dentate gyrus, and further, that in patients with Alzheimer disease, newborn neurons were fewer in number and exhibited delayed maturation. As a starting point, we ask why neurogenesis declines in the aging brain. Based on our preliminary studies, we found that biased circuit activity may regulate hippocampal neurogenesis in the aging brain. During screening of potential molecules biasing circuit activity, we found that one sphingolipid signaling is active in interneurons and becomes less active in the aging brain. We propose to genetically intervene this signaling to study its role in regulating neurogenesis in the aging brain. Lastly, we determine how biased circuit activity regulates hippocampal neurogenesis. Our results will not only provide mechanistic insights into the understanding of neurogenesis in the aging brain it also provides a possible strategy to intervene aging circuit activity to regulate neurogenesis.

Goal of Proposed Research Alzheimer?s disease (AD) is the most common neurodegenerative disease, presenting with progressive and irreversible memory loss and dementia. Although medications and management strategies can temporarily improve symptoms, no cure so far exists. Therefore, there is a high demand for underlying the cause, pathological conditions and behavioral symptoms of AD for advancing possible preventions and treatments. The central goal of the proposed research is to determine functional neurovascular coupling of the dentate gyrus and its underlying neural circuit mechanism in a mouse model of AD.