Yong Xu

Research topics

Matched from this investigator's NIH project titles and abstracts.

• Alzheimer's and Dementia
• Learning and Memory
• Developmental Cognitive Neuroscience

Active NIH awards

• 5-HT 2C Receptor and Alzheimer's Disease

  7R01AG080392-04

  NIA · FY 2025 · $547K

  PROJECT SUMMARY Owing to the aging of populations worldwide, Alzheimer’s disease (AD) is reaching epidemic proportions, with a large social and economic burden. While the most notable symptom of AD is the severe memory loss, patients with AD also suffer from neuropsychiatric symptoms, including impaired sociability and aggression, which represent significant challenges to the care for these patients. Unfortunately, the mechanisms underlying these neuropsychiatric deficits during AD pathogenesis remain to be fully understood and effective treatments are limited. The brain 5-hydroxytryptamine (5-HT, serotonin) regulates multiple physiological functions, including the control of anger, aggression, mood and cognition. Interestingly, numerous studies reported that the brains of AD patients display extensive “5-HT denervation”, as demonstrated by reduced 5-HT neuron numbers or 5-HT bioavailability. These suggest that impaired brain 5-HT signaling contributes to certain AD symptoms. We identified several loss-of-function point mutations in the human HTR2C gene, encoding 5-HT 2C receptor (5-HT2CR), from individuals with cognitive deficits and social incompetence. We generated a knock-in mouse model, Htr2cF327L, to mimic one such mutation and found that these mutant mice recapitulate human symptoms, including impaired memory, decreased sociability and increased aggression. Given the similarity between the Htr2cF327L-induced phenotypes and those seen in AD, we tested effects of lorcaserin (a selective 5-HT2CR agonist) in an amyloid precursor AppNL-G-F knock-in AD mouse model. Interestingly, lorcaserin ameliorates cognitive and neuropsychiatric deficits in AppNL-G-F mice, associated with enhanced neural plasticity in the ventral hippocampal CA1 (vCA1). These findings led to a general hypothesis that the 5-HT/5-HT2CR signaling ameliorates cognitive and social behaviors in AD. To test this hypothesis, we will first combine the retrograde chemogenetics and loss- or gain-of-function mouse models to determine the role of the 5-HT→vCA1 circuit in cognition, sociability and aggression in health and AD pathogenesis. Using site-specific gene manipulation and the humanized genetic mouse models, we will also determine the role of vCA1 5-HT2CRs in cognition, sociability and aggression in health and AD pathogenesis. Finally, we will test lorcaserin effects in two pre-clinical AD models (with distinct pathogenic mechanisms): AppNL-G-F and PS19. Importantly, we will test these mice at various ages along the disease progression to determine the crucial time window for this pharmacological strategy to be most effective. Results obtained from these studies are expected to advance our understanding about the fundamental biology of cognitive/social behaviors and the neurobiology of human AD progression. In addition, these studies carry significant translational values and will provide a framework for novel therapeutic strategies to ameliorate cognitive and neuropsychiatric symptoms in AD.

• Trpc5-activated neural circuits and maternal behavior

  7R01HD114146-03

  NICHD · FY 2025 · $524K

  PROJECT SUMMARY Parental behavior is the hallmark feature of all mammals, and is critical to the health of both parents and offspring. In the majority of mammals, since only the female can lactate, it is the mother who provides maternal care and protection of the young. Inadequate maternal care can adversely influence the development of the offspring and impair their health in adulthood. However, the neurobiological mechanisms for the regulation of maternal behavior remain to be fully understood. In women who exhibit impaired bonding with their infants, we identified several loss-of-function mutations in the TRPC5 gene, which encodes the TRPC5 ion channel, a transient receptor potential channel that conducts calcium inward currents. We used the CRISPR-Cas9 approach to generate a knock-in mouse line that mimics one such human mutation, Trpc5K34del, and found that this mutation causes severe impairments in a wide range of maternal behaviors in mouse dams, including ignoring pups, reduced nursing/crouching, inefficient retrieval, disrupting nests, and impaired prolactin release upon suckling. These findings demonstrate that intact Trpc5 function is required for normal maternal behavior, but the neurobiological mechanisms for its effect remain unclear. One objective is to test a hypothesis that Trpc5 maintains maternal behavior via activating oxytocin neurons in the paraventricular nucleus of the hypothalamus, which have been implicated in maternal behavior and mother-infant bonding. The second objective is to test whether Trpc5 acts upon dopamine neurons in the substantia nigra to provide a redundant or complementary mechanism to regulate maternal behavior. Finally, we will evaluate whether a Trpc5 activator can ameliorate impaired maternal behavior in wild-type dams induced by psychological stress. Our work, combining human genetic and mouse genetic experiments, has provided evidence to identify a novel molecular basis underlying normal maternal behavior. As a logical extension of this initial and exciting discovery, we will continue to unravel the neurobiological mechanisms by which Trpc5 maintains normal maternal behavior during the postpartum period and will provide pre-clinical evidence to identify Trpc5 as a potential target improve maternal care.